Deprecated: The each() function is deprecated. This message will be suppressed on further calls in /home/zhenxiangba/zhenxiangba.com/public_html/phproxy-improved-master/index.php on line 456
AU779730B2 - Compounds for the modulation of PPARgamma activity - Google Patents
[go: Go Back, main page]

AU779730B2 - Compounds for the modulation of PPARgamma activity - Google Patents

Compounds for the modulation of PPARgamma activity Download PDF

Info

Publication number
AU779730B2
AU779730B2 AU60643/00A AU6064300A AU779730B2 AU 779730 B2 AU779730 B2 AU 779730B2 AU 60643/00 A AU60643/00 A AU 60643/00A AU 6064300 A AU6064300 A AU 6064300A AU 779730 B2 AU779730 B2 AU 779730B2
Authority
AU
Australia
Prior art keywords
alkyl
group
compound
halogen
condition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
AU60643/00A
Other versions
AU6064300A (en
Inventor
Noboru Furukawa
Atsushi Hagiwara
Jonathan B. Houze
Lawrence R. Mcgee
Steven M. Rubenstein
Hisashi Shinkai
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Japan Tobacco Inc
Amgen Inc
Original Assignee
Japan Tobacco Inc
Tularik Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Japan Tobacco Inc, Tularik Inc filed Critical Japan Tobacco Inc
Priority claimed from PCT/US2000/018178 external-priority patent/WO2001000579A1/en
Publication of AU6064300A publication Critical patent/AU6064300A/en
Application granted granted Critical
Publication of AU779730B2 publication Critical patent/AU779730B2/en
Assigned to JAPAN TOBACCO INC., AMGEN, INC. reassignment JAPAN TOBACCO INC. Alteration of Name(s) in Register under S187 Assignors: JAPAN TOBACCO INC., TULARIK INC.
Anticipated expiration legal-status Critical
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/09—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton the carbon skeleton being further substituted by at least two halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/46—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms
    • C07C323/49—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms to sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/28—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/70—Sulfur atoms
    • C07D277/74—Sulfur atoms substituted by carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

1 COMPOUNDS FOR THE MODULATION OF PPARy ACTIVITY Field of the Invention The present invention relates to compounds that modulate the PPARy receptor and are useful in the diagnosis and treatment of type II diabetes (and complications thereof), hypercholesterolemia (and related disorders associated with abnormally high or low plasma lipoprotein or triglyceride levels) and inflammatory disorders.
Background of the Invention The peroxisome proliferator-activated receptors (PPARs) are transducer proteins belonging to the steroid/thyroid/retinoid receptor superfamily. The PPARs were originally o1 identified as orphan receptors, without known ligands, but were named for their ability to mediate the plelotropic effects of fatty acid peroxisome proliferators. These receptors function as ligand-regulated transcription factors that control the expression of target genes by binding to their responsive DNA sequence as heterodimers with RXR. The target genes encode enzymes involved in lipid metabolism and differentiation of adipocytes. Accordingly, the discovery of transcription factors involved in controlling lipid metabolism has provided insight into regulation of energy homeostasis in vertebrates, and further provided targets for the development of therapeutic agents for disorders such as obesity, diabetes and dyslipidemia.
PPARy is one member of the nuclear receptor superfamily of ligand-activated 20 transcription factors and has been shown to be expressed in an adipose tissue-specific manner. Its expression is induced early during the course of differentiation of several preadipocyte cell lines. Additional research has now demonstrated that PPARy plays a pivotal role in the adipogenic signalling cascade. PPARy also regulates the ob/leptin gene which is involved in regulating energy homeostasis, and adipocyte differentiation which 25 has been shown to be a critical step to be targeted for anti-obesity and diabetic conditions.
In an effort to understand the role of PPARy in adipocyte differentiation, several investigators have focused on the identification of PPARy activators. One class of compounds, the thiazolidinediones, which were known to have adipogenic effects on preadipocyte and mesenchymal stem cells in vitro, and antidiabetic effects in animal models of non-insulin-dependent diabetes mellitus (NIDDM) were also demonstrated to be PPARy-selective ligands. More recently, compounds that selectively activate murine PPARy were shown to possess in vivo antidiabetic activity in mice.
[R:\LIBH]03959.doc:aak 2 Despite the advances made with the thiazolidinedione class of antidiabetes agents, unacceptable side effects have limited their clinical use. Accordingly, there remains a need for potent, selective activators of PPARy which will be useful for the treatment of NIDDM and other disorders related to lipid metabolism and energy homeostasis. Still further, compounds that block PPARy activity would be useful for interfering with the maturation of preadipocytes into adipocytes and thus would be useful for the treatment of obesity and related disorders associated with undesirable adipocyte maturation.
Surprisingly, the present invention provides compounds that are useful as activators as well as antagonists of PPARy activity and compositions containing them, along with methods for their use.
Summary of the Invention The present invention relates to methods of modulating conditions which are mediated by PPARy.
According to a first aspect of the invention there is provided a compound having the formula: Ar 1
X
R'
wherein Ar' is an unsubstituted or substituted 3-quinolinyl; X is selected from the group consisting of-CH 2
-CH(CH
3
-CH(CH
2
CH
3 20 -CH(isopropyl)-, wherein R" is a member selected from the group consisting of hydrogen and (Ci-Cs)alkyl; and the subscript k is an integer of from 0 to 2; Y is -N(R' 2 wherein R 12 is hydrogen or (Ci-Cs)alkyl, and the subscript m is an integer from 0 to 2; 25 R' is a member selected from the group consisting of halogen, cyano, nitro, (Ci-Cs)alkyl, (Ci-Cs)alkoxy, -C(0)R 14
-CO
2 R14, and -C(O)NR R I6 wherein
R'
4 is a member selected from the group consisting of hydrogen, (Ci-C 8 )alkyl, (Ci-Cs)heteroalkyl, aryl and aryl(Ci-C 4 )alkyl;
R
1 5 and R 1 6 are members independently selected from the group consisting of hydrogen, (Ci-Cs)alkyl, (Ci-C 8 )heteroalkyl, aryl, and aryl(CI-C 4 )alkyl, or taken together with the nitrogen to which each is attached form a 6- or 7-membered ring; [R:\L13-H]04573.doc:aak 2a
R
2 is a member selected from the group consisting of aryl and aryl(Ci- C4)alkyl; and
R
3 is a member selected from the group consisting of halogen, cyano, nitro, and (Ci-Cs)alkoxy; and the pharmaceutically acceptable salts and solvates of the compound.
According to a second aspect of the invention there is provided a composition comprising a pharmaceutically acceptable excipient and a compound according to the first aspect of the invention.
According to a third aspect of the invention there is provided the use of an o0 efficacious amount of a compound according to the first aspect of the invention for the manufacture of a medicament for preventing or modulating a condition mediated by PPAR in a host.
According to a fourth aspect of the invention there is provided a method of preventing or modulating a condition mediated by PPARy in a host, comprising administering to said host an efficacious amount of a compound according to the first aspect of the invention or a composition according to the second aspect of the invention.
According to a fifth aspect of the invention there is provided the use of an efficacious amount of a compound according to the first aspect of the invention for the manufacture of a medicament for treating a condition selected from the group consisting 20 of rheumatoid arthritis and atherosclerosis in a host.
According to a sixth aspect of the invention there is provided a method for treating a condition selected from the group consisting of rheumatoid arthritis and atherosclerosis in a host, comprising administering to said host an efficacious amount of a compound according to the first aspect of the invention or a composition according to the second 25 aspect of the invention.
According to a seventh aspect of the invention there is provided a compound having the formula:
R
3 Ar
R
wherein Ar' is 2-benzothiazolyl; X is Y is -N(R' 2 wherein R 12 is hydrogen or (Ci-Cs)alkyl, and the subscript m is an integer from 0 to 2; [R:\L1 1H04573doc:aak 2b R' is a member selected from the group consisting of hydrogen, halogen, cyano, nitro, (Ci-Cs)alkyl, (CI-C8)alkoxy, -CO 2
R
14 and -C(O)NR'R 1 6 wherein R 1 4 is a member selected from the group consisting of hydrogen,
(C
1
-C
8 )alkyl, (Ci-Cs)heteroalkyl, aryl and aryl(Ci-C 4 )alkyl; and R 15 and R 6 are members independently selected from the group consisting of hydrogen, (Ci-Cs)alkyl, (Ci-Cs)heteroalkyl, aryl, and aryl(Ci-C 4 )alkyl, or taken together with the nitrogen to which each is attached form a 6- or 7-membered ring;
R
2 is aryl;
R
3 is a member selected from the group consisting of halogen, cyano, nitro, and (C 1 -Cs)alkoxy; and the pharmaceutically acceptable salts and solvates of the compound.
According to an eighth aspect of the invention there is provided a composition comprising a pharmaceutically acceptable excipient and a compound according to the seventh aspect of the invention.
According to a ninth aspect of the invention there is provided the use of an efficacious amount of a compound according to the seventh aspect of the invention for the manufacture of a medicament for preventing or modulating a condition mediated by PPARy in a host.
According to a tenth aspect of the invention there is provided a method of 20 preventing or modulating a condition mediated by PPARy in a host, comprising administering to said host an efficacious amount of a compound according to the seventh aspect of the invention or a composition according to the eighth aspect of the invention.
According to an eleventh aspect of the invention there is provided the use of an efficacious amount of a compound according to the seventh aspect of the invention for the 25 manufacture of a medicament for treating a condition selected from the group consisting Sof rheumatoid arthritis and atherosclerosis in a host.
According to a twelfth aspect of the invention there is provided a method of treating a condition selected from the group consisting of rheumatoid arthritis and atherosclerosis in a host, comprising administering to said host an efficacious amount of a compound according to the seventh aspect of the invention or a composition according to the eighth aspect of the invention.
[R:\LIB H 04573.doc:aak 2c According to a thirteenth aspect of the invention there is provided a compound having the formula: R 3 2 Ar 1
X
R
wherein Ar' is a 3-quinolinyl group having from 0 to 3 substituents selected from the group consisting of halogen, -OCF 3 -OH, -O(Ci-C 6 )alkyl, -CF 3 (Ci-Cs)alkyl, -CO 2
H,
-CO
2
CH
3 and -NO 2 X is or Y is -NH-SO 2 R' is a member selected from the group consisting of halogen, (Ci-Cs)alkyl, (C1-Cs)heteroalkyl and (Ci-Cs)alkoxy;
R
2 is a phenyl group having from 0 to 3 substituents selected from the group consisting of halogen, -OCF 3 -OH, -O(Ci-Cs)alkyl, -C(O)-(Ci-Cs)alkyl, -CN, -CF 3 (Ci-C 8 )alkyl and -NH 2 and
R
3 is selected from the group consisting of halogen, methoxy and trifluoromethoxy and the pharmaceutically acceptable salts and solvates of the compound.
:*According to a fourteenth aspect of the invention there is provided a compound •having the formula l l l .:...irteenth aspect of the invention.
St HN CI CI and the pharmaceutically acceptable salts and solvates thereof.
20 According to a fifteenth aspect of the invention there is provided a composition .comprising a pharmaceutically acceptable excipient and a compound according to the thirteenth aspect of the invention.
According to a sixteenth aspect of the invention there is provided a composition comprising a compound of the fourteenth aspect of the invention and a pharmaceutically acceptable excipient.
R:\L I B H]04 5 73.doc:aak 2d According to a seventeenth aspect of the invention there is provided the use of an efficacious amount of a compound according to the thirteenth or fourteenth aspect of the invention for the manufacture of a medicament for preventing or treating a condition mediated by PPARy in a host.
According to an eighteenth aspect of the invention there is provided a method of preventing or treating a condition mediated by PPARy in a host comprising administering to said host an efficacious amount of a compound according to the thirteenth or fourteenth aspect of the invention or a composition according to the fifteenth or sixteenth aspect of the invention.
According to a nineteenth aspect of the invention there is provided the use of an efficacious amount of a compound in accordance with the thirteenth or fourteenth aspect of the invention for the manufacture of a medicament for treating a condition selected from the group consisting of rheumatoid arthritis and atherosclerosis in a host.
According to a twentieth aspect of the invention there is provided a method of treating a condition selected from the group consisting of rheumatoid arthritis and atherosclerosis in a host comprising administering to said host an efficacious amount of a compound according to the thirteenth or fourteenth aspect of the invention or a composition according to the fifteenth or sixteenth aspect of the invention.
According to a twenty-first aspect of the invention there is provided a compound S: 20 having the formula:
R
1 wherein Ar' is substituted or unsubstituted 2-benzothiazolyl; X is Y is -NH-SO 2 25 R' is a member selected from the group consisting of hydrogen, halogen, (CI-Cs)alkyl, (Ci-Cs)heteroalkyl, (Ci-Cs)alkoxy, -C(O)R 14
-CO
2
R
4 -C(O)NRR16 S(O)p-R' 4 and -S(O)q-NR' 5
R
16 wherein
R
14 is a member selected from the group consisting of hydrogen, (Ci-C 8 )alkyl, (Ci-Cs)heteroalkyl, aryl and aryl(Ci-C 4 )alkyl;
R
15 and R 6 are members independently selected from the group consisting of hydrogen, (Ci-C 8 )alkyl, (Ci-Cs)heteroalkyl, aryl, and aryl(Ci-C 4 )alkyl, or taken together with the nitrogen to which each is attached form a 6- or 7-membered ring; [R:\LIBH]04573.doc:aak 2e
R
2 is a phenyl group having from 0 to 3 substituents selected from the group consisting of halogen, -OCF 3 -OH, -O(Ci-C8)alkyl, -C(O)-(Ci-Cs)alkyl, -CN, -CF 3 (Ci-Cs)alkyl and -NH 2
R
3 is selected from the group consisting of halogen, methoxy and trifluoromethoxy; and the pharmaceutically acceptable salts and solvates thereof.
According to a twenty-second aspect of the invention there is provided a composition comprising a pharmaceutically acceptable excipient and a compound according to the twenty-first aspect of the invention.
According to a twenty-third aspect of the invention there is provided the use of an efficacious amount of a compound according to the twenty-first aspect of the invention for the manufacture of a medicament for preventing or treating a condition mediated by PPARy in a mammal.
According to a twenty-fourth aspect of the invention there is provided a method of preventing or treating a condition mediated by PPARy in a mammal comprising administering to said mammal an efficacious amount of a compound of the twenty-first aspect of the invention or a composition according to the twenty-second aspect of the invention.
According to a twenty-fifth aspect of the invention there is provided the use of an S: 20 efficacious amount of a compound according to the twenty-first aspect of the invention for the manufacture of a medicament for treating a condition selected from the group consisting of rheumatoid arthritis and atherosclerosis in a human.
According to a twenty-sixth aspect of the invention there is provided a method of treating a condition selected from the group consisting of rheumatoid arthritis and atherosclerosis in a human comprising administering to said human an efficacious amount of a compound according to the twenty-first aspect of the invention or a composition according to the twenty-second aspect of the invention.
SDisclosed herein are methods which comprise contacting a host with a PPARymodulating amount of a compound having the formula: [R:\LIBH104573.doc:aak WO 01/00579 WO 0100579PCT[USOO/18178 Ar'" Y-R 2 in which the symbol Ar' represents a substituted or unsubstituted aryl group; the letter X represents a divalent linkage selected from the group consisting of substituted or unsubstituted 6 )alkylene, substituted or unsubstituted 6 alkylenoxy, substituted or unsubstituted 1
-C
6 )alkylenamino, substituted or unsubstituted
C
6 )alkylene-S(O)k-, and a single bond, in which R" is a member selected from the group consisting of hydrogen, (C,-C8)alkyl, (02- Cg)heteroalkyl and aryl(C,-C4)alkyl and the subscript k is an integer of from 0 to 2. The letter Y, in the above formula represents a divalent linkage, in either orientation, selected from thc group consisting of substituted or unsubstituted (C,-C 6 )alkylene, _N(R1 2 -N(R1 2 a single bond, and combinations thereof in which R 1 2 and R 1 3 are members independently selected from the group consisting of hydrogen, substituted or unsubstituted (C I-C 8 )alkyl, substituted or unsubstituted (C 2 -Cg)heteroalkyl and aryl(C,-C 4 )alkyl; and the subscripts m and n are independently integers of from 0 to 2.
The symbol R' represents a member selected from hydrogen, halogen, cyano, nitro, (C i-C8)alkyl, (C I-C8)alkox y, -C0 2 R 4 -C(O)NR1 5 R 1 6
-C(O)R'
4 -S(O)p-R 1 4 -S(O)q-NR R 6, -0-C(O)-OR1 7 -0C(O)-R 7, -O-C(O)-NR' 5 R 1 6 -N(R1 4 )-C(O)-NRS R6 -N(R 4 and -NR 4
-C(O)-OR'
7 in which R' is a member selected from hydrogen, (C,-Cg)alkyl, (C 2 -C8)heteroalkyl, aryl and aryl(C,-C 4 )alkyl; R" and R 16are members independently selected from hydrogen, (C,-C8)alkyl, (C 2
-C
8 )heteroalkcyl, aryl, and aryi(C,-C 4 )alkyl, or taken together with the nitrogen to which each is attached formi a 6- or 7-membered ring; and R 1 7 is a member selected from hydrogen, (C 1-Cs)alkyl,
(C
2
-C
8 )heteroalkyl, aryl and aryl(C,-C 4 )alkyl. In each of the descriptions of, for example, alkyl, alkoxy and heteroalkyl, the groups can be substituted or uinsubstituted.
The symbol R 2 represents a substituted or unsubstituted aryl group.
Preferably, R 2 represents a phenyl, naphthyl, pyridazinyl or pyridyl group. More preferably, R 2 Is a phenyl, naphthyl, pyridazinyl or pyridyl group substituted with from 0- 3 substituents selected from halogen, -OCF 3 -OH, -O(C,-C8)alkyl, -CN, -CF 3 C8)alkyl, ,-C8)alkyl and -NH 2 While certain preferred substituents have been provided -OCF 3 and -CFA) the terms alkyl and alkoxy are also meant to include 4 substituted versions thereof, preferably halosubstituted versions including those specifically noted.
The symbol R 3 represents a halogen, cyano, nitro or a substituted or unsubstituted (Ci-Cs)alkoxy, preferably a halogen, cyano, or (Ci-C 4 )alkoxy group. Most preferably, halogen, methoxy, or trifluoromethoxy.
Also disclosed herein are compounds of the formula above, as well as pharmaceutical compositions containing the compounds described above.
Detailed Description of Embodiments of the Invention Abbreviations and Definitions: The following abbreviations are used herein: PPARy: peroxisome proliferatoractivated receptor y; NIDDM: non-insulin-dependent diabetes mellitus; Et 3
N:
triethylamine; MeOH: methanol; and DMSO: dimethylsulfoxide.
The term "alkyl", by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated Ci-Clo means one to ten carbon atoms). Examples of saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)ethyl, cyclopropylmethyl, homologs and isomers of, for example, 20 n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having on or more double or triple bonds. Examples of unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-dipentadienyl, 3-(1,4pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The term "alkyl", unless otherwise noted, is also meant to include those 25 derivatives of alkyl defined in more detail below as "heteroalkyl", "cycloalkyl", and "alkylene". The term "alkylene" by itself or as part of another substituent means a i" divalent radical derived from an alkane, as exemplified by -CH 2
CH
2
CH
2
CH
2 Typically, an alkyl group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A "lower alkyl" or "lower [R:\]IRH]03959.doc:aak WO 01/00579 PCT/US00/18178 alkylene" is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom may optionally be quatemized. The heteroatom(s) 0, N and S may be placed at any interior position of the heteroalkyl group. The heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. Examples include -CH 2
-CH
2
-O-CH
3
-CH
2
CH
2
-NH-CH
3
-CH
2
-CH
2
-N(CH
3
)-CH
3
-CH
2
-S-CH
2
-CH
3
-CH
2
-CH
2 -S(0)-CH 3
-CH
2
CH
2 -S(0) 2
-CH
3
-CH-CH-O-CH
3 -Si(CH 3 3
-CH
2
-CH=N-OCH
3 and -CH=CH-N(CH 3
CH
3 Up to two heteroatoms may be consecutive, such as, for example, -CH 2
-NH-OCH
3 and -CH2-O-Si(CH 3 3 Also included in the term "heteroalkyl" are those radicals described in more detail below as "heteroalkylene" and "heterocycloalkyl." The term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH 2
-CH
2
-S-CH
2
CH
2 and -CH 2
-S-CH
2
CH
2 -NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini. Still further, for alkylene and heteroalkylene linking groups, as well as all other linking group provided in the present invention, no orientation of the linking group is implied.
The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include 1 (1,2,5,6-tetrahydropyridyl), I -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
WO 01/00579 WO 0100579PCT/USOO/18 178 Additionally, terms such as "fluoroalkyl," are meant to include monofluoroalkyl and polyfluoroalkyl.
The term "aryl," employed alone or in combination with other terms aryloxy, arylthioxy, arylalkyl) means, unless otherwise stated, an aromatic substituent which can be a single ring or multiple rings (up to three rings) which are fuised together or linked covalently. The rings may each contain from zero to four heteroatoms selected from N, 0, and 5, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemnized. The aryl groups that contain heteroatoms may be referred to as "heteroaryl" and can be attached to the remainder of the molecule through a heteroatomn Non-limiting examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, I1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3fury], 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2benzothiazolyl, 5-benzothiazolyl, 2-benzoxazolyl, 5-benzoxazolyl, purinyl, 2benzimidazolyl, 5-indolyl, I -isoquinolinyl, 5-isoquinolinyl, 2-quinoxalinyl, quinoxalinyl, 3-quinolinyl, and 6-quinolinyl. Substituents for each of the above noted aryl ring systems are selected from the group of acceptable substituents described below.
T'he term "arylalkyl" is meant to include those radicals in which an aryl group is attachcd to an alkyl group benzyl, phenethyl, pyridylmethyl and the like) or a heteroalkyl group phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).
Each of the above termns "alkyl," "heteroalkyl" and "aryl") are meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be a variety of groups selected from: -halogen, OC(O)R', -CO 2 CONR'R", -OC(O)NR'R", -NRW-
-NR"C(O)
2
-NH-C(NH
2 )=NII, -NR'C(N- 2
-NH-C(NI{
2
-S(O)
2
-S(O)
2 NR'R", -CN and -NO 2 in a number ranging from zero to (2N+ where N is the total number of carbon atoms in such radical. R" and each independently refer to hydrogen, unsubstituted(C 1-CB)alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, WO 01/00579 WO 0100579PCTIUSOOII8I 78 or aryl-(C 1
-C
4 )alkyl groups. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a or 7-membered ring. For example, -NR'R" is meant to include 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups such as haloalkyl -CF 3 and -CH 2
CF
3 and acyl
C(O)CH
3
-C(O)CF
3
-C(O)CH
2
OCH
3 and the like). Preferably, the alkyl groups (and related alkoxy, heteroalkyl, etc.) are unsubstituted or have 1 to 3 substituents selected from halogen, -CO 2 -CONqR'R",
-S(O)
2
-S(O)
2 NR'R", -CN and -NO 2 More preferably, the alkyl and 0 related groups have 0, 1 or 2 substituents selected from halogen, -SR',
-CO
2 -CONR'R", -CN and -NO 2 Similarly, substituents for the aryl groups are varied and are selected from halogen, -CN, -NO 2
-CO
2 -CONR'R", -OC(O)NR -NR"C(O) 2 -NR' -NII-C(NH 2
)=NH,
-NR'C(NH
2
-NH--C(NH
2
-S(O)
2
-S(O)
2 NR'R", -N 3 -GH(Ph) 2 perfluoro(Cj-C 4 )alkoxy, and perfluoro(CI-C 4 )alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R" and are independently selected from hydrogen, (C 1 -CS)alkyl and heteroalkyl, unsubstituted aryl, (unsubstituted arl)(CI -C 4 )alkyl, and (unsubsti tuted aryl)oxy-(CI -C 4 )alkyl. Preferably, the aryl groups are unsubstituted or have from I to 3 substituents selected from halogen, OR', -CN, -NO 2
-CO
2 -CONR'R", NR"C(O)R', -S(O) 2
-S(O)
2 NR perfluoro(Cj -C 4 )alkoxy, and perfluoro(CI -C 4 )alkyl.
Still more prefcrably, the aryl groups have 0, 1 or 2 substituents selected from halogen, -CN, -NO 2
-CO
2 -CONR'R", -S(O) 2
R',
-S(O)
2 NR'R", perfluoro(C, -C4)alkoxy, and perfluoro(CI -C 4 )alkyl.
Two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula wherein T and U are independently
-CH
2 or a single bond, and q is an integer of from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formnula wherein A and B are independently -CH 2 NH-, -S(0) 2
-S(O)
2 NR'- or a single bond, and r is an integer of from 1 to 3.
One of the single bonds of the new ring so fonned may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substitueht of the formula -(CH 2 2 where s WO 01/00579 PCT/US00/18178 and t are independently integers of from 0 to 3, and X is -S(O) 2 or -S(0) 2 The substituent R' in and -S(0) 2 NR'- is selected from hydrogen or unsubstituted (Ci-C 6 )alkyl.
As used herein, the term "heteroatom" is meant to include oxygen nitrogen sulfur and silicon (Si).
The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzeriesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
WO 01/00579 PCT/US0O/18178 In addition to salt forms, the present invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present invention.
The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium 3 iodine-125 (125j) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
General: A new class of compounds that interact with PPARy has now been discovered. Depending on the biological environment cell type, pathological condition of the host, etc.), these compounds can activate or block the actions of PPARy.
By activating the PPARy receptor, the compounds will find use as therapeutic agents capable of modulating conditions mediated by the PPARy receptor. As noted above, example of such conditions is NIDDM. Additionally, the compounds are useful for the prevention and treatment of complications of diabetes neuropathy, retinopathy, glomerulosclerosis, and cardiovascular disorders), and treating hyperlipidemia. Still further, the compounds are useful for the modulation of inflammatory conditions which most recently have been found to be controlled by PPARy (see, Ricote, et Nature, 391:79-82 (1998) and Jiang, et al., Nature, 391:82-86 (1998). Examples of inflammatory conditions include rheumatoid arthritis and atherosclerosis.
Compounds that act via antagonism of PPARy are useful for treating obesity, hypertension, hyperlipidemia, hypercholesterolemia, hyperlipoproteinemia, and metabolic disorders.
Embodiments of the Invention: Disclosed herein are compounds which are represented by the formula:
R
3
R'
Ar-.X
Y-R
2
(I)
In formula the symbol Ar' represents a substituted or unsubstituted aryl group. Preferably, Ar t is a monocyclic or fused bicyclic aryl group having from zero to four heteroatoms as ring members. More preferably, Ar' is a monocyclic or fused bicyclic aryl group comprising two fused six-membered rings, two fused five-membered S rings, or a six-member ring having a fused five-membered ring. heteroaryl group :20 containing from 1 to 3 nitrogen atoms in the ring or rings. Particularly preferred embodiments are those in which Ar' is phenyl, naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-quinolinyl, 3-quinolinyl, 4-isoquinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, 3-pyrazolyl, 2-phenyl-4-isoxazolyl and the like. Ar' can be both unsubstituted and substituted. In preferred embodiments, Ar' is :25 substituted with from 0 to 3 substituents selected from halogen, -OCF 3 -OH, -O-(CI-
C
6 )alkyl, -CF 3 (Ci-C 6 )alkyl, or -NO 2 In one group of preferred embodiments, Ar' is a Smonocyclic heteroaryl group containing 1 to 2 nitrogen atoms in the ring and being monosubstituted by halogen, -OCF 3 or -CF 3 In another group of preferred embodiments, Ar' is'a phenyl or naphthyl group having from 1 to 3 substituents selected from halogen, cyano, nitro, (Ci-Cs)alkyl or (Ci-Cs)alkoxy.
WO 01/00579 WOOI/0579PCT/USOO/18178 The letter X represents a divalent linkage selected from substituted or unsubstituted (C 1
-C
6 )alkylcne, substituted or unsubstituted (C 1
-C
6 )alkylenoxy, substituted or unsubstituted (C,-C 6 )alkylenamino, substituted or unsubstituted (CI-C6)alkylene-S(O)k, and a single bond, in which R' is a member selected from hydrogen, (C,-Cs)alkyl, (C 2 -CS)heteroalkyl and aryl(C 1
-C
4 )alkyl and the subscript k is an integer of from 0 to 2. In preferred embodiments, X represents substituted or unsubstituted (C,-C 6 )lkylene, or Most preferably, X represents -CH 2
-CH(CH
3
-CH(CH
2
CH
3 -CH(isopropyl)-, CH(CN)-, or Still further preferred are those embodiments in which X represents -CR 2
-CH(CH
3 -N(R1 or wherein R" is hydrogen, methyl, ethyl, propyl and isopropyl.
The letter Y, in the above formula represents a divalent linkage selected from substituted or unsubstituted (C 1
-C
6 )alkylene, -N(R1 2
-N(R'
2 S(0)m,-N(R -N(R 1 2 a single bond, and combinations thereof, in which R 12and R 1 3 are members independently selected from hydrogen, substituted or unsubstituted (C 2 -CS)alkyl, substituted or unsubstituted (C 2 -Cg)heteroalkyl and substituted or unsubstituted aryl(CI-C 4 )alkyl; and the subscripts m and n are independently integers of from 0 to 2. In preferred embodiments, Y represents -N(R' 2 2 or -N(R' 2 More preferably, Y represents -N(R 1)_S (0) 2 in1 which R'1 2 is hydrogen or substituted or unsubstituted (CI-Cg)alkyl. Most preferably, Y represents -NI{-S(O) 2 Additionally, the linkages provided herein (represented by X and Y) can be in either orientation. More particularly, for example, the nitrogen atom of -N(R 1 2 2 can be attached to either the central benzene ring or to the R 2 group.
The symbol R' represents a member selected from hydrogen, halogen, cyano, nitro, (Ca-C 8 )alkyl, (CI-Cg)alkoxy, -CO 2
R'
4 -C(0)NR' 5
-C(Q)R'
4 -S(0)p-R' 4 -N(R 1 4 7 and -N(R' 4 1 7 in which R 1 4 Is a member selected from hydrogen, (CI-C 8 )alkyl, (C 2 -Cg)heteroalkyl, aryl and aryl(C 1
-C
4 )alkyl; R1 and R, are members independently selected from hydrogen, (C 1 -C8)alkyl, (C 2 -Cs)heteroalkyl, aryl, and aryl(C 1
-C
4 )alkyl, or taken together with the nitrogen to which each is attached form a 6- or 7-membered ring; and R 1 7 is a member selected from hydrogen, (C,-C8)alkyl,
(C
2 -C8)heteroalkyl, aryl and aryl(C,-C 4 )alkyl. In each of the descriptions of, for example, alkyl, alkoxy and heteroalkyl, the groups can be substituted or unsubstituted. Preferably, when substituted the substituents are halogen -CF 3
-OCF
3 In preferred WO 01/00579 PCT/USOO/18178 embodiments, R' represents hydrogen, halogen, cyano, (Ci-Cs)alkyl, (CI-Cs)alkoxy,
CO
2
R
4 and -C(O)NR'SR'. More preferably, R' represents hydrogen, halogen, cyano, (Ci-Cs)alkyl, (Ci-Cs)alkoxy, -CO 2
R
1 4 and -C(O)NRSR 16 in which R' 4 is (Ci-Cs)alkyl, and R' 5 and R' 6 are independently hydrogen or (Ci-Cs)alkyl, or taken together with the nitrogen to which each is attached form a 5- or 6-membered ring. Other preferred R' groups are discussed below with reference to groupings of compounds wherein Ar is phenyl, pyridyl, naphthyl, quinolinyl, isoquinolinyl, benzoxazolyl, bcnzothiazolyl and benzimidazolyl.
The symbol R 2 represents a substituted or unsubstituted aryl group.
Preferably, R 2 represents a phenyl, naphthyl, pyridazinyl or pyridyl group. More preferably, R 2 is a phenyl, naphthyl, pyridazinyl or pyridyl group substituted with from 0- 3 substituents selected from halogen, -OCF 3 -OH, -O(Ci-Cs)alkyl, -CN, -CF3, Cs)alkyl, -(Ci-Cg)alkyl and -NH 2 While certain preferred substituents have been provided -OCF 3 and -CF 3 the terms alkyl and alkoxy are also meant to include substituted versions thereof, preferably halosubstituted versions including those specifically noted.
The symbol R 3 represents a halogen, cyano, nitro or a substituted or unsubstituted (Ci-Cs)alkoxy group, preferably a halogen, cyano or (Ci-C 4 )alkoxy group.
Most preferably, halogen, methoxy or trifluoromethoxy.
A number of preferred embodiments are provided herein. For example, in one preferred embodiment, X is a divalent linkage selected from -CH 2
-CH(CH
3 and and Y is -N(R' 2 2 wherein R 1 2 is a member selected from hydrogen and (Ci-C8)alkyl. In another preferred embodiment, X is a divalent linkage selected from -CH 2 -CH(CH3)-, and Y is -N(R 2 2 wherein R 1 2 is a member selected from hydrogen and (Ci-Cs)alkyl; and R 2 is a substituted or unsubstituted aryl selected from phenyl, pyridyl, naphthyl and pyridazinyl. In yet another preferred embodiment, X is a divalent linkage selected from -CH 2
-CH(CH
3 and Y is -N(Ri 2 2 wherein R' 2 is a member selected from hydrogen and (Ci-Cs)alkyl; R 2 is a substituted or unsubstituted aryl selected from phenyl, pyridyl, naphthyl and pyridazinyl; and Ar' is a substituted or unsubstituted aryl selected from pyridyl, phenyl, naphthyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzothiazolyl, and benzimidazolyl.
One of skill in the art will understand that a number of structural isomers are represented by formula I. In one group of embodiments, the isomers are those in WO 01/00579 PCT/US00/18178 which the groups on the phenyl ring occupy positions that are not contiguous. In other embodiments, the compounds are those having the structural orientations represented by the formulae: rX
Y-R
2 Arl 3 x' (Ic) (Id) (If) (Ig)
AR''
R~x
~R
2 und X-Ar' (0J) Still further preferred are those compounds having the structural orientation represented by formula Ia or Ib. Still other preferred compounds, are those of formula Ia or Ib in which the positions of R' and R 3 are switched (or reversed).
Yet other preferred compounds are those in which Ar'-X- and -Y-R occupy positions ortho to one another (exemplified by Ij).
(Ij) Still another group of preferred compounds are represented by the formula:
R
3
Y-
A-X
WO 01/00579 WO 0100579PCTUSOO/181 78 Ar' is substituted or unsubstituted phenvi In one group of particularly preferred embodiments, Arlis a substituted or unsubstituted phenyl group. Further preferred are those embodiments in which the compound is represented by any of formulae la through Ij. Still further preferred are those embodiments in which X is -NH- or Y is -NH-SO 2 R1 is a member selected from hydrogen, halogen, (C,-C8)alkyl, (C 2 -C8)heteroalkyl, (C,-C8)alkoxy, C(O)R 14
-CO
2 R1 4
-C(O)NR
5
R
1 -S(O)p-R 1 4 and -S(O)q-NR"'R' 6 R 2 is aphenyl group having from 0 to 3 substitutents selected from halogen, -OCF 3 -OH, -0(C,-Cg)alkyl, C(O)-(CI-C8)alkyi, -CN, -CF 3
(C
1 -C8)alkyl and -Ni- 2 and R 3 is selected from halogen, methoxy and trifluoromethoxy.
Other particularly preferred embodiments wherein Arl is substituted or unsubstituted phenyl, are those that are represented by either of formulae Ii or Ij. In this group of embodiments, X is a divalent linkage selected from -CH 2
-CH(CH
3 and wherein R' is a member selected firomn hydrogen and (Ci- Cg)alkyl; Y is a divalent linkage selected from -N(R 1 2 2 wherein R 12is a member selected from hydrogen and (C,-Cg)alkyl; R' is a member selected from hydrogen, halogen, (C,-C8)alkyl, (C 2
-C
8 )heteroalkyl, (C,-Cg)alkoxy, -C(O)R' 4
-CO
2
R'
4 -C(O)NRR 5
R
6 -S(O)q-NR 15
R'
6 1 7 and -N(R'1 4 )-C(O)-R1 7 wherein R 1 4 is a member selected from hydrogen, (C,-C8)alkyl, (C 2
-C
8 )heteroalkyl, aryl and aryl(C, -C 4 )alkyl; R1 5 and R 1 6 aemembers independently selected from hydrogen,
(C,-C
8 )alkyl and (C 2 -C8)heteroalkyl, or taken together with the nitrogen to which each is attached form a 6- or 7-inembered ring; R 1 7 is a member selected from hydrogen, (Cj- CB)alkyl and (C 2 -Cg)heteroalkyl; the subscript p is an integer of from 0 to 2; the subscript q is 2; R 2 is a substituted or unsubstituted phenyl; and R 3 is a halogen or (C,-Cg)alkoxy.
In further preferred embodiments, X is -NH- or Y is -NH-SO?-; R' is a member selected from hydrogen, halogen, (C,-C8)alkyl, (C 2 -C8)heteroalkyl, Co)alkoxy, -C(O)R 1 4
-CO
2 R 1 4
-C(O)NR'
5 1 4 and -S(O)q-NR' 5 R 6 R 2 is a phenyl group having from 0 to 3 substitutents selected from halogen, -OCF 3 -OH, -O(C I- Cg)alkyl, -C(O)-(C,-C8)alkyl, -CN, -CF 3 (C,-Cg)alkyl and -NH 2 and R 3 is selected from halogen, methoxy and trifluoromethoxy.
In still further preferred embodiments, Ar' is a phenyl group having from I to 3 substituents selected from halogen, -OCF 3 -OH, -0(C,-C 6 )alkyl, -CF 3 (C,-Cs)alkyl and -NO 2 R' is a member selected from halogen, (C,-C8)alkyl, (C 2 -Cg)heteroalkyl and WO 01/00579 PCT/US00/18178 (C-Cs)alkoxy; R 2 is a phenyl group having from 0 to 3 substitutents selected from halogen, -OCF 3 -OH, -O(C,-Cs)alkyl, 1 -Cg)alkyl, -CN, -CF3, (C 1 -Cs)alkyl and
NH
2 more preferably 1 to 3 substituents selected from halogen, -OCF 3 and -CF 3 and R' is selected from halogen, methoxy and trifluoromethoxy. Yet further preferred embodiments are those in which R' and R 3 are each independently a halogen, and R 2 is a phenyl group having from I to 3 substitutents selected from halogen, -OCF 3 and -CF 3 Ar' is substituted or unsubstituted pyridl In one group of particularly preferred embodiments, Ar' is a substituted or unsubstituted pyridyl group. Further preferred are those embodiments in which the compound is represented by any of formulae Ia through Ij. Still further preferred are those embodiments in which X is -NH- or Y is -NH-SO 2 R' is a member selected from hydrogen, halogen, (C 1 -Cs)alkyl, (C 2 -Cs)heteroalkyl, (CI-Cs)alkoxy,
C(O)R
4 -C0 2
R"
4
-C(O)NRISR'
6 -S(O)p-R' 4 and -S(O)q-NR sR R2 Is a phenyl group having from 0 to 3 substitutents selected from halogen, -OCF 3 -OH, -O(C 1 -Cs)alkyl, C(O)-(C,-Cs)alkyl, -CN, -CF 3 (C,-Cs)alkyl and -NH 2 and R' is selected from halogen, methoxy and trifluoromethoxy.
Other particularly preferred embodiments wherein Ar' is substituted or unsubstituted pyridyl, are those that are represented by either of formulae Ii or Ij. In this group of embodiments, X is a divalent linkage selected from -CH 2
-CH(CH
3 and wherein R" is a member selected from hydrogen and (Ci- C&)alkyl; Y is a divalent linkage selected from -N(R12)-S(0) 2 wherein R' 2 is a member selected from hydrogen and (C 1 I-C)alkyl; R' is a member selected from hydrogen, halogen, (C 1 -Cs)alkyl, (C 2 -C)heteroalkyl, (C,-Cs)alkoxy, -C(O)R' 4
-CO
2
R'
4 -C(O)NR'sR 6 4 -S(O)q-NR 5
R'
6 and -N(R' 4 wherein R' 4 is a member selected from hydrogen, (C,-Cs)alkyl, (C 2
-C
8 )heteroalkyl, aryl and aryl(C 1
-C
4 )alkyl; R1 5 and R16 are members independently selected from hydrogen, (C,-Cs)alkyl and (C 2 -Cs)heteroalkyl, or taken together with the nitrogen to which each is attached form a 6- or 7-membered ring; R' 7 is a member selected from hydrogen, Cs)alkyl and (C 2 -Cs)heteroalkyl; the subscript p is an integer of from 0 to 2; the subscript q is 2; R 2 is a substituted or unsubstituted phenyl; and R 3 is a halogen or (C,-Cs)alkoxy.
In further preferred embodiments, X is -NH- or Y is -NH-SO 2 R' is a member selected from hydrogen, halogen, (CI-Cs)alkyl, (C 2
-C
8 )heteroalkyl, Cs)alkoxy, -C(O)R' 4
-CO
2 R -C(O)NRISR 16 -S(O)-R14 and R is a phenyl group having from 0 to 3 substitutents selected from halogen, -OCF 3 -OH, WO 01/00579 PCT/US00/18178 Cs)alkyl, -C(O)-(Ci-Cg)alkyl, -CN, -CF3, (Ci-Cs)alkyl and -NH 2 and R 3 is selected from halogen, methoxy and trifluoromethoxy.
In still further preferred embodiments, Ar' is a pyridyl group having from 0 to 3 substituents selected from halogen, -OCF 3 -OH, -O(Ci-C 6 )alkyl, -CF3, (Ci- Cs)alkyl and -NOz; R' is a member selected from halogen, (Ci-Cs)alkyl, (C 2 Cs)heteroalkyl and (Ci-Cs)alkoxy; R 2 is a phenyl group having from 0 to 3 substitutents selected from halogen, -OCF 3 -OH, -O(Ci-Cs)alkyl, -C(O)-(Ci-Cs)alkyl, -CN, -CF3, Cg)alkyl and -NH2, more preferably 1 to 3 substituents selected from halogen, -OCF 3 and
-CF
3 and R 3 is selected from halogen, methoxy and trifluoromethoxy. Yet further preferred embodiments are those in which R' and R 3 are each independently a halogen, and R 2 is a phenyl group having from 1 to 3 substitutents selected from halogen, -OCF 3 and -CF 3 Most preferably, Ar' is a 3-pyridyl group having preferred substituents as indicated above.
In still other particularly preferred embodiments, the compounds are represented by formula I, in which Ar' is a pyridyl ring having a single substituent selected from halogen, -OCF 3 and -CF 3 X is a divalent linkage selected from the group of
-CH
2 and combinations thereof; Y is a divalent linkage selected from the group of-NH-S(0) 2 and R' is selected from hydrogen, halogen, cyano, (Ci- Cg)alkyl, (Ci-C 8 )alkoxy and -C(O)NRiSR' 6 in which R' 5 and are selected from hydrogen, (Ci-Cs)alkyl, aryl and aryl(CI-C 4 )alkyl; R 2 is a phenyl or pyridyl ring, optionally substituted by 0-3 groups selected from halogen, (Ci-Cs)alkyl, -O-(Ci-Cs)alkyl and -CN; and R 3 is halogen, cyano or (Ci-C4)alkoxy.
Ar' is substituted or unsubstituted naphthyl In one group of particularly preferred embodiments, Ar' is a substituted or unsubstituted naphthyl group. Further preferred are those embodiments in which the compound is represented by any of formulae Ia through Ij. Still further preferred are those embodiments in which X is -NH- or Y is -NH-SO 2 R' is a member selected from hydrogen, halogen, (Ci-Cs)alkyl, (C 2
-C
8 )heteroalkyl, (Ci-Cs)alkoxy,
C(O)R'
4
-CO
2
R
14 -C(O)NRIR6, -S(O)p-R 1 4 and 6; R 2 is a phenyl group having from 0 to 3 substitutents selected from halogen, -OCF 3 -OH, -O(Ci-Cs)alkyl, C(O)-(Ci-Cs)alkyl, -CN, -CF 3 (CI-Cs)alkyl and -NH 2 and R 3 is selected from halogen, methoxy and trifluoromethoxy.
Other particularly preferred embodiments wherein Ar' is substituted or unsubstituted naphthyl, are those that are represented by either of formulae Ii or Ij. In this WO 01/00579 WO 0100579PCTIUS00118178 group of embodiments, X is a divalent linkage selected from -CH 2
-CH(CH
3 and wherein R" is a member selected from hydrogen and (C 1 CS)alkyl; Y is a divalent linkage selected from -N(R 1 2 2 wherein R' 2 isa member selected from hydrogen and (C I-Cg)alkyl; R' is a member selected from hydrogen, halogen, (C 1 -Cs)alkyl, (C 2 -Cg)heteroalkyl, (C 1 -CB)alkoxy, -C(O)R' 4 -C0 2
R
1 4
-C(O)NR'
5
R'
6 -S(O)p-R' 4 S(O)q-NRR 5 7 afld -N(R' 4 wherein R 1 4 is a member selected from hydrogen, -C8)alkyl, (C 2 -C8)heteroalkyl, aryl and aryl(C 1
-C
4 )alkyl; R 1 5 and R 1 6 are members independently selected from hydrogen,
(C
1 -C8)alkyl and (C 2 -C8)heteroalkyl, or taken together with the nitrogen to which each is attached form a 6- or 7-membered ring; R1 7 is a member selected from hydrogen, (C I- Cg)alkyl and (C 2 -C8)heteroalkyl; the subscript p is an integer of from 0 to 2; the subscript q is 2; R 2 is a substituted or unsubstituted phenyl; and R 3 isa halogen or (C 1 -Cg)alkoxy.
In further preferred embodiments, X is -NI-I- or Y is -NHI-SO 2 R' is a member selected from hydrogen, halogen, (C 1 -Cg)alkyl, (C 2 -Cg)heteroalkyl, (C 1
C
8 )alkoxy, -C(O)R 1 4
-CO
2 R 1 4
-C(O)NR'
5 R 6 P-R 1 4 and -S(O)q-NR 5
R'
6 k1 is a phenyl group having from 0 to 3 substitutents selected from halogen, -OCF 3 -OH, -O(C 1 Cg)alkyl, 1 -Cg)alkyl, -CN, -CF 3
(C
1
-C
8 )alkyI and -NH 2 and R 3 is selected from halogen, methoxy and trifluoromethoxy.
In still further preferred embodiments, Ar 1 is a iiaphithyl group having from 0 to 3 substituents selected from halogen, -OCF 3 -OH, -O(C 1
-C
6 )alkyl, -CF 3 (Cl- Cg)alkyl and -NO 2 R' is a member selected from halogen, (C 1 -C8)alkyl, (C 2 C8)heteroalkyl and (C 1 -Cg)allcoxy; R 2 is a phenyl group having from 0 to 3 substitutents selected from halogcn, -OCF 3 -OH, -O(CI-Cg)alkyl, 1 -Cg)atkyl, -CN, -CF 3
(C
1 Cs)alkyl and -NH 2 more preferably I to 3 substituents selected from halogen, -OCF 3 and
-CF
3 and R 3 is selected from halogen, methoxy and tifluoromethoxy. Yet further preferred embodiments are those in which R' and R 3 are each independently a halogen, and R 2 is a phenyl group having from I to 3 substitutents selected from halogen, -OCF 3 and -CF 3 Ar 1 is substituted or unsubstituted benzothiazolvl In another group of particularly preferred embodiments, Arl is a substituted or unsubstituted benzothiazolyl group. Further preferred are those embodiments in which the compound is represented by any of formulae la through Ij.
Still further preferred are those embodiments in which X is -NH- or Y is -NiH-SO 2 R' is a member selected from hydrogen, halogen, (CI-CS)alkyl, (C 2 WO 01/00579 WO 0100579PCTUSOO/181 78 Cg)heteroalkyl, (C,-Cg)alkoxy, -C(O)R 1 4 -COR 1 4
-C(O)NR'
5
R
1 -S(O)p-R' 4 and -S(O)q-NR1 5 R 16 R' is a phenyl group having from 0 to 3 substitutents selected from halogen, -OCF 3 -OH, -O(C,-Cg)alkyl, -C(O)-(C,-Ca)alkyl, -CN, -CF 3 (C,-Cs)alkyl and
NH
2 and R 3 is selected from halogen, methoxy and trifluoromethoxy.
Other particularly preferred embodiments wherein Ar' is substituted or unsubstituted benzothiazolyl, are those that are represented by either of formulae li or Ij.
In this group of embodiments, X is a divalent linkage selected from -CH 2
-CH(CH
3 and wherein R' 1is a member selected from hydrogen and (Cj- CB)alkyl; Y is a divalent linkage selected from -N(R1 2 2 wherein R 1 2 is a member selected from hydrogen and (C,-C8)alkyl; R' is a member selected from hydrogen, halogen, (C,-C 8 )alkyl, (C 2 -C8)heteroalkyl, (C,-Cg)alkoxy, -C(O)R' 4
-CO
2
R'
4
-C(O)NR'
5 -S(O)p-R 1 4 5
R
6 -O-C(O)-R1 7 and -N(R 1 4 7 wherein R 1 is a member selected from hydrogen, (C,-Cs)alkyl, (C 2 -C8)heteroalkyl, aryl and aryl(C,-C 4 )alkyl; R1 5 and R 16 are members independently selected from hydrogen, (CI-C8)alkyl and (C 2 -Cs)heteroalkyl, or taken together with the nitrogen to which each is attached form a 6- or 7-membered ring; R 1 7 is a member selected from hydrogen, Cg)alkyl and (C 2 -C8)heteroalkyl; the subscript p is an integer of from 0 to 2; the subscript q is 2; R2 is a substituted or unsubstituted phenyl; and R3 is a halogen or (C,-C8)alkoxy.
In further preferred embodiments, X is or Y is -NH-SO 2 R' is a member selected from hydrogen, halogen, (C,-CB)alkyl, (C 2 -Cg)heteroalkyl,
C
8 )alkoxy, -C(O)R 1 4
-CO
2 R 1 4
-C(O)NR'
5 R 6 -S(O)p-R 1 and -S(O)q-NR 5 R 16 P2 is a phenyl group having from 0 to 3 substitutents selected from halogen, -OCF 3 -OH, C8)alkyl, 8 )alkyl, -CN, -CF 3 (C,-Cg)alkyl and -NH 2 and R3 is selected from halogen, methoxy and trifluoromethoxy.
In still further preferred embodiments, Arl is a benzothiazolyl group having from I to 3 substituents selected from halogen, -OCF 3 -OH, -O(C,-C 6 )alkyl, -CF 3 (C,-Cg)alkyl and -NO 2 R' is selected from halogen, (C,-Ca)alkyl, (C 2 -Cg)heteroalkyl and
(C
1 -Cg)alkoxy; R 2 is a phenyl group having from 0 to 3 substitutents selected from halogen, -OCF 3 -OH, -O(C,-C8)alkyl, -C(0)-(C,-C8)alkyl, -CN, -CF 3 (C,-C8)alkyl and
NH-
2 more preferably I to 3 substituents selected from halogen, -OCF 3 and -CF 3 and R 3 is selected from halogen, methoxy and trifluoromethoxy. Yet further preferred embodiments are those in which R' and R 3 are each independently a halogen, and R 2 is a phenyl group having from 1 to 3 substitutents selected from halogen, -OCF 3 and -CF 3 In particularly preferred embodiments, the benzothiazolyl group is a 2-benzothiazolyl group.
WO 01/00579 WO 0100579PCTIUSOO/18 178 Arl is substituted or unsubstituted benzoxazolyl In another group of particularly preferred embodiments, Ar' is a substituted or unsubstituted benzoxazolyl group. Further preferred are those embodiments in which the compound is represented by any of formulae la through Ij.
Still fuirther preferred are those embodiments in which X is or Y is
-NH-SO
2 R1 is a member selected from hydrogen, halogen, (C,-C8)alkyl, (C 2 C8)heteroalkyl, (C,-Cg)alkoxy, -C(O)R 1 4
-CO
2 R 1 4
-C(O)NR'
5 4 and -S(0)q-NR R R' is a phenyl group having from 0 to 3 substitutents sele cted from halogen, -OCF 3 -OH, -O(C,-C 8 )alkyl, -C(O)-(G,-Cg)alkyl, -CN, -CF 3 (C,-Cg)alkyl and
NH
2 and R 3 is selected from halogen, metboxy and trifluoromethoxy.
Other particularly preferred embodiments wherein Ar' is substituted or unsubstituted benzoxazolyl, are those that are represented by either of formulae Ii or Ij.
In this group of embodiments, X is a divalent linkage selected from -CH 2
-CI-(CH
3 and wherein R' is a member selected from hydrogen and C8)alkyl; Y is a divalent linkage selected from -N(R 1 2 2 wherein R 1 2 is a member selected from hydrogen and -Cg)alkyl; R1 is a member selected from hydrogen, halogen, (C,-Cg)alkyl, (C 2 -CS)heteroalkyl, (C,-CS)alkoxy, -C(O)R' 4
-GO
2
R'
4
-C(O)NR'
5 R 1 6 -S(O)q-NRR 5
R
6 -0-C(O)-R1 7 and _N(R1 4 1 wherein R 1 4 is a member selected from hydrogen, (C,-C8)alkyl, (C 2 -Cg)heteroalkyl, aryl and aryl(C,-C 4 )alkyl; R'1 5 and R 1 6 aemembers independently selected from hydrogen, (C,-CB)alkyl and (C 2 -C8)heteroalkyl, or taken together with the nitrogen to which each is attached form a 6- or 7-membered ring; R 1 7 is a member selected from hydrogen, Cg)alkyl and (C 2 -CS)heteroalkyl; the subscript p is an integer of from 0 to 2; the subscript q is 2; R 2 is a substituted or unsubstituted phenyl; and R 3 is a halogen or (CI-C 8 )alkoxy.
In further preferred embodiments, X Is -NH- or Y is -NI-I-SO 2 R' is a member selected from hydrogen, halogen, (C,-C 8 )alkyl, (C 2 -CS)heteroalkyl, (Cl- Cg)alkoxy, -C(O)R' 4
-CO
2 R 1 4
-C(O)NR'
5 R 6 1 4 and -S(O)q-NR 5 R' 6
R
2 is a phenyl group having from 0 to 3 substitutents selected from halogen, -OCF 3 -OH, -O(CI- Cg)alkyl, (C,-C 8 )alkyl, -CF 3 (Ci-Cs)alkyl and -NH 2 and R 3 is selected from halogen, methoxy and trifluoromethoxy.
In still1 further preferred embodiments, Ar' is a benzoxazolyl group having from 0 to 3 substituents selected from halogen, -OCF 3 -OH, -O(C I-C 6 )alkyl, -CF 3 (C I- C&)alkyl and -NO 2 R1 is selected from halogen, (C,-C8)alkyl, (C 2 -Cg)heteroalkyl and CS)alkoxy; R2 is a phenyl group haying from 0 to 3 substitutents selected from halogen, WO 01/00579 WO 0100579PCTUSOO/18178 OCF3, -OH, -O(Ct-Csalkyl, 1 -CB)alkyl, -CN, -CF 3
(C
1 -C8)alkyl and -NH 2 more preferably I to 3 substituents selected from halogen, -OCF 3 and CF 3 and R 3 is selected from halogen, methoxy and trifluoromethoxy. Yet further preferred embodiments are those in which R I and R 3 are each independently a halogen, and R 2 is a phenyl group having from I to 3 substitutents selected from halogen, -OCF 3 and -CF 3 In particularly preferred embodiments, the benzoxazolyl group is a 2-benzoxazolyl group.
Ar'is substituted or unsubstituted benzimidazolyl In another group of particularly preferred embodiments, Ar 1 is a substituted or unsubstituted benzimidazolyl group. Further preferred are those embodiments in which the compound is represented by any of formulae Ta through Ij.
Still further preferred are those embodiments in which X is -NH- or Y is
-NH-SO
2 R' is a member selected from hydrogen, halogen, (C 1 -Cg)alkyl, (C 2 C8)heteroalkyl, (C 1 -C8)alkoxy, 14, -CO 2 R 1 4
-C(O)NR'
5 -S(O)p-R 1 4 and -S(O)q-NR' 5 R 1 6
R
2 is a phenyl group having from 0 to 3 substitutents selected fromn halogen, -OCF 3 -OH, -O(C 1 -C8)alkyl, 1 -C8)alkyl, -CN, -CF 3 (CI-Cg)alkyl and N11 2 and R 3 is selected from halogen, methoxy and trifluoromethoxy.
Other particularly preferred embodiments wherein Arl is substituted or unsubstituted benzimidazolyl, are those that are represented by either of formulae 11 or Tj.
In this group of embodiments, X is a divalent linkage selected from -CR 2
-CH(CH
3 and wherein R' is a member selected from hydrogen and (C 1 Ca)alkyl; Y is a divalent linkage selected from -N(R 1 2 2 wherein R, 2 is a member selected from hydrogen and (C 1 -C8)alkyl; R1 is a member selected from hydrogen, halogen, (C 1 -C&)alkyl, (C 2 -Cg)heteroalkyl, (C 1 -Cg)alkoxy, -C(O)R' 4 -CO2R' 4
-C(O)NR
1 5 R 1 6 -S(O)p-R 4 -S(O)q-NR' 5 R 6 -O-C(O)-R1 7 and -N(R 1 4 1 wherein R 1 4 is amember selected from hydrogen, (C 1 -Cg)alkyl, (C 2
-C
8 )heteroalkyl aryl and aryl(Ci -C 4 )alkyl; R1 5 and R1 6 aemembers independently selected from hydrogen, (C 1-C 8 )alkyl and (C 2 -C8)heteroalkyl, or taken together with the nitrogen to which each is attached form a 6- or 7-membered ring; R 1 7 is a member selected from hydrogen, (C I- Cg)alkyl and (C 2 -Cg)heteroalkyl; the subscript p is an integer of from 0 to 2; the subscript q is 2; R 2 is a substituted or unsubstituted phenyl; and R 3 isa halogen or (C 1
-C
8 )alkoxy.
In further preferred embodiments, X is -NI-I- or Y is -NH-SO 2 R' is a member selected from hydrogen, halogen, (C I-C8)alkyl, (C 2 -CS)beteroatkyl, (C 1 C8)alkoxy, -C(O)R 1 4
-CO
2 R 1 4
_C(O)NR
15 R 1 6 -S(O)p-R 1 4 and -S(O)q-NR' 5 R1 6 R 2 is a phenyl group having from 0 to 3 substitutents selected from halogen, -OCF 3 -OH, -O(C 1 WO 01/00579 WO 0100579PCTUSOO/181 78 CB)allcyl, (C,-Ca)alkyl, -CN, -CF 3 (C,-Cg)alkyl and -Ni- 2 and R 3 is selected from halogen, methoxy and trifluoromethoxy.
In still further preferred embodiments, Ar' is a benzimidazolyl group having from 0 to 3 substituents selected from halogen, -OCF 3 -OH, -O(C,-C 6 )alkyl, -CF 3
(C,-C
8 )alkyl and -NO 2 R1 is selected from halogen, (C,-Cg)alkyl, (C 2 -C8)heteroalkyl and (C I- C 8 )alkoxy; R 2 is a phenyl group having from 0 to 3 substitutents selected from halogen, -OCF 3 -OH, -O(C,-Cg)alkyl, -C(Q)-(C,-C8)alkyl, -CN, -CF 3 (CI-Cg)alkyl and
NH
2 more preferably I to 3 substituents; selected from halogen, -OCF 3 and CF3; and R 3 is selected from halogen, methoxy and trifluoromethoxy. Yet further preferred embodiments are those in which R' and R 3 are each independently a halogen, and R 2 is a phenyl group having from 1 to 3 substitutents selected from halogen, -OCF 3 and -CF 3 In particularly preferred embodiments, the benzimidazolyl group is a 2-benzimidazolyl group.
Ar' is substituted or unsubstituted quinolinyl or isoquinolinyl In another group of particularly preferred embodiments, Ar' is a substituted or unsubstituted quinolinyl or isoquinolinyl group. Further preferred are those embodiments in which the compound is represented by any of formulae Ia through Ij.
Still further preferred are those embodiments in which X is -NH- or Y Is -Nil-SO 2 R1 is a member selected from hydrogen, halogen, (C,-C8)alkYl, (C 2 C8)heteroalkyl, (C,-C8)alkoxy, -COR', -C(O)NR' 5 R 6 4 and -S(O)q-NR 5R"; R 2 is a phenyl group having from 0 to 3 substitutents selected from halogen, -OCF 3 -OH, -O(C,-C8)alkyl, -C(O)-(C,-C8)alkyl, -CN, -CF 3 (C,-Cg)alcyl and NH2; and R 3 is selected from halogen, methoxy and trifluoromethoxy.
Other particularly preferred embodiments wherein Ar' is substituted or unsubstituted quinolinyl or isoquinolinyl, are those that are represented by either of formulae Ii or Ij. In this group of embodiments, X is a divalent linkage selected from
CH
2
-CH(CH
3 and wherein R' is a member selected from hydrogen and (C,-Cg)alkyl; Y is a divalent linkage selected from -N(R 1 2 2 wherein R 1 2 isa member selected from hydrogen and (CI-Cg)alkyl; R1 is a member selected from hydrogen, halogen, (C,-Cg)alkyl, (C 2 -Cg)heteroalkyl, (C,-C 8 )alkoxy, C(O)R 1 4
-CO
2 R 1 4
-C(O)NRI
5 -S(O)p-R 4 -S(O)q-NRR 5
R
6 1 7 and N(R1 4 1 7 wherein R 1 4 is a member selected from hydrogen, (C,-C 8 )alkyl, (C 2 Cg)heteroalkyl, aryl and aryl(C,-C 4 )alkyl; R 1 5 and R 1 6 aemembers independently selected from hydrogen, (C,-C8)alkyl and (C 2
-C
8 )heteroalkyl, or taken together with the nitrogen to which each is attached form a 6- or 7-membered ring; R 17 is a member selected from hydrogen, (Ci-Cs)alkyl and (C 2 -Cs)heteroalkyl; the subscript p is an integer of from 0 to 2; the subscript q is 2; R 2 is a substituted or unsubstituted phenyl; and R 3 is a halogen or (Ci-Cs)alkoxy.
In further preferred embodiments, X is -NH- or Y is -NH-SO 2 R' is a member selected from hydrogen, halogen, (Ci-Cs)alkyl, (C 2 -Cs)heteroalkyl, (Cl- Cs)alkoxy, -C(O)R 14
-CO
2
R
14 -C(O)NRi 5
R
6 -S(O)p-R 14 and -S(O)q-NR"R' 6
R
2 is a phenyl group having from 0 to 3 substitutents selected from halogen, -OCF 3 -OH, -O(Ci- Cs)alkyl, (Ci-Cs)alkyl, -CN, -CF 3 (Ci-Cg)alkyl and -NH 2 and R 3 is selected from halogen, methoxy and trifluoromethoxy.
In still further preferred embodiments, -Ar' is a quinolinyl or isoquinolinyl group having from 0 to 3 substituents selected from halogen, -OCF 3 -OH, -O(CI-
C
6 )alkyl, -CF 3 (Ci-Cs)alkyl and -NO 2 R' is selected from halogen, (Ci-Cs)alkyl, (C 2 Cs)heteroalkyl and (Ci- Cs)alkoxy; R 2 is a phenyl group having from 0 to 3 substitutents selected from halogen, -OCF 3 -OH, -O(Ci-Cs)alkyl, -C(O)-(C,-Cs)alkyl, -CN, -CF3, (Cl- Cs)alkyl and -NH 2 more preferably 1 to 3 substituents selected from halogen, -OCF 3 and -CF3; and R 3 is selected from halogen, methoxy and trifluoromethoxy. Yet further preferred embodiments are those in which R' and R 3 are each independently a halogen, and R 2 is a phenyl group having from 1 to 3 substitutents selected from halogen, -OCF 3 20 and -CF 3 In particularly preferred embodiments, the quinolinyl or isoquinolinyl group is :selected from 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 3-isoquinolinyl and 4isoquinolinyl groups.
In another aspect, the present invention provides pharmaceutical compositions comprising at least one of the above compounds in admixture with a pharmaceutically acceptable excipient.
i: In yet another aspect, the present invention provides methods for modulating conditions mediated by PPARy in a host. More particularly, the conditions are selected from non-insulin-dependent diabetes mellitus, obesity, conditions associated with abnormal plasma levels of lipoproteins or triglycerides, and inflammatory cbnditions such as, for example, rheumatoid arthritis and atherosclerosis.
Preparation of the Compounds The compounds disclosed herein can be prepared using standard synthetic methods.
For exemplary purposes, Scheme I illustrates methods for the preparation of compounds of structural formula One of skill in the art will understand that similar methods can be used for the synthesis of compounds in the other structural classes.
As shown in Scheme I, compounds disclosed herein can be prepared beginning with commercially available 2-chloro-5-nitrobenzonitrile Treatment of J with a phenol, thiophenol, or optionally protected aniline in the presence of base and heat provides the adduct Reduction of the nitro group in ii with, for example, H 2 in the presence of o0 Raney nickel catalyst provides an aniline derivative (iii). Sulfonylation of iii with an appropriate arylsulfonyl halide (Ar'SO 2 Cl) in the presence of base (typically a tertiary amine) provides a target compound Compound iii can also be converted to a related compound of formula (vi) in which the orientation of the sulphonamide linkage is reversed. Thus, conversion of the aniline iii to the benzenesulfonyl chloride v can be accomplished using methods described in Hoffman, Organic Syntheses Collective Volume VII, p. 508-511. Subsequent treatment of v with an appropriate aniline provides the target compound vi.
S *5* [R:\LIBH]03959.doc:aak WO 01/00579 WO 0100579PCTIUSOO/18178 Scheme 1 Arz-
N
L2F ArOH or ArSH C or Ar-NIH-SO 2
CF
3 base beat r- \H 2 and Raney Ni MN- X'Y 0 0 x base
CN
iv 0 0 MN N" Ae A.,x Ar'NH 2 CN base 'S0 2
C'
Other compounds of the present invention can be prepared beginning with, for example, 3 ,4-di fluoroni trobenzene, 3-chiloro-4-fluoronitrobenzene, nitroanisole, 3 -bromo-4-fluoronitrobenzene and the like.
Analysis of the Compounds The compounds of the present invention can be evaluated for modulation of the PPARy receptor using assays such as those described in Jiang, et al., Nature 391:82-86 (1998), Ricote, et al., Nature 391:79-82 (1998) and Lehmann, et al., J Biol.
Chema. 270(12): 12953-12956 (1995). Alternatively, the compounds can be evaluated for their ability to displace radiolabeled BRIL 49653 from a PPARy-GST fuision protein as follows: WO 01/00579 PCT/US00/18178 Materials: PPARy-GST fusion protein (prepared according to standard procedures), 3 H]-BRL 49653 having 50 Ci/mmol specific activity, Polyfiltronics Unifilter 350 filtration plate and glutathione-Sepharose® beads (from Pharmacia: washed twice with 10x binding buffer in which BSA and DTI can be left out).
Method: Binding buffer (10 mM Tris-HCl, pH 8.0, 50 mM KCI, 10 mM DTT, 0.02% BSA and 0.0 1% NP-40) is added in 80 microliter amounts to the wells of the filtration plate. The test compound is then added in 10 microliters ofDMSO. The PPARy-GST fusion protein and radiolabeled BRL compound are premixed in binding buffer containing 10 mM DTT and added in 10 microliter amounts to the wells of the plate to provide final concentrations of 1 pg/well of PPARy-GST fusion protein and nM 3 H]-BRL 49653 compound. The plate is incubated for 15 minutes. Glutathioneagarose bead is added in 50 lL of binding buffer, and the plate is vigorously shaken for one hour. The plate is washed four times with 200 PL/well of binding buffer (without BSA and DTT). The bottom of the plate is sealed and 200 iL/well of scintillation cocktail is added. The top of the plate is then sealed and the radioactivity is determined.
Formulation and Administration of the Compounds (Compositions) The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds described herein can be administered by inhalation, for example, intranasally.
Additionally, the compounds of the present invention can be administered transderinally.
Accordingly, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and either a compound of formula or a pharmaceutically acceptable salt of a compound of formula For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as WO 01/00579 PCT/US00/18178 diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from 5% or 10% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
WO 01/00579 PCT/USOO/18178 The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 1000 mg, preferably 1.0 mg to 100 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
In therapeutic use for the treatment of obesity, NIDDM, or inflammatory conditions, the compounds utilized in the pharmaceutical method of the invention are administered at the initial dosage of about 0.001 mg/kg to about 100 mg/kg daily. A daily dose range of about 0.1 mg/kg to about 10 mg/kg is preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
The following examples are offered by way of illustration and are not intended to limit the scope of the invention.
EXAMPLES
Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). 'H-NMR spectra were recorded on a Varian Gemini 400 MHz NMR spectrometer. Significant peaks are tabulated in the order: number of protons, multiplicity singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet) and coupling constant(s) in Hertz. Electron Ionization (El) mass spectra were recorded on a Hewlett Packard 5989A mass spectrometer.* Mass spectrometry results are reported as the ratio of mass over charge, followed by the relative abundance of each ion (in parentheses). In tables, a single m/e value is reported for the M+H (or as noted M-H) ion containing the most common atomic WO 01/00579 WO 0100579PCTLJSOO/18178 isotopes. Isotope patterns correspond to the expected formula in all cases. Electrospray ionization (ESI) mass spectrometry analysis was conducted on a Hewlett-Packard 1 100 MSD electrospray mass spectrometer using the HP I 100 HPLC for sample delivery.
Normally the analyte was dissolved in methanol at 0.lmg/mL and I microliter was infused with the delivery solvent into the mass spectrometer which scanned from 100 to 1500 daltons. All compounds could be analyzed in the positive ESI mode, using 1: 1 acetonitrile/water with 1% acetic acid as the delivery solvent. The comnpounds provided below could also be analyzed in the negative ESI mode, using 2mnM NH 4 OAc in acetonitrile/water as delivery solvent.
Abbreviations: N-hydroxybenzotriazole (HQBT), 1 H-benzotriazole- I yI)- 1,1 ,3,3-tetrainethyluronium hexafluorophosphate (HBTU), N-methylmorpholine 1 -hydroxy-7-azabenzotriazole (HOAT), O-(7-azabenzotriazole- I -yl)-N,N,N' ,N'--tetramethyluroniurn hexafluorophosphate (HATU), 1 -diznethylamninopropyl)-3ethylcarbodiimide hydrochloride (EDCD).
EXAMPLE 1 This example illustrates the preparation of 5-nitro-2-(3-chloro-5pyridyloxy)benzonitrile C1 N0 2 N
CN
To a solution of 2-chloro-5-nitrobenzonitnle (10. g, 100 rnmiol) and chloro 3-pyridinol (13 g, 100 mmol) in DMIF (100 mL) was added powdered K2C03 (13.9 g, 100 mmol). After heating at 60'C for 12 hours, the suspension was poured into water (1 The resulting solid was collected by filtration, rinsed with water and dried under vacuum to afford 27.6 g (100%) of the title compound, rnp 104-107 'C.
'H NMR (400 MHz) (DMSO-d 6 8 8.755 J=2.8 Hz, I 8.734 (br s, I 8.576 (br s, I 8.542 (dd, J=9.2, 2.7 Hz, I 7.689 J2.2 Hz, 1H); 7.122 (d, J= 9.2 Hz, I H).
WO 01/00579 PCT/USOO/18178 EXAMPLE 2 This example illustrates the preparation of 5-amino-2-(3-chloro-5pyridyloxy)benzonitrile NH2
CN
2.1 To a vigorously stirred solution of the intermediate from Example 1 (6.23 g) in ethanol and THF was added a slurry ofRaney Nickel (-300 mg, Aldrich). The flask was filled with H 2 at atmospheric pressure and the reduction was monitored by TLC.
Starting material disappeared rapidly, to form a nitroso intermediate which gradually was converted to the desired aniline over about 5 hours. Stirring was stopped and Raney Nickel was attracted to the magnetic stirbar. The remaining solution was filtered through Celite® which was then rinsed with ethanol and methylene chloride. The combined organic portions were concentrated to provide 5.75 g of the product aniline as an oil which was used without further purification.
'H NMR (400 MHz) (CDC13) 8 8.456 J=1.9 Hz, 1H); 8.3 89 J=2.6 Hz, 1H); 7.38 IH); 7.03 3H); 4.06 (m 2H).
EXAMPLE 3 This example illustrates the synthesis of 3.1.
O C 1 Cl CN OO Cl 2.1 3.1 To a mixture of 5-amino-2-(3-chloro-5-pyridyloxy)benzonitrile from Example 2 (0.457 g) in methylene chloride was added 2,4-dichlorobenzenesulfonyl chloride (0.456 g, from Maybridge), followed by pyridine (150 tL). The reaction progress was monitored by TLC, and upon completion the solvent was removed under vacuum. The resulting residue was partitioned between methylene chloride and water.
The organic layer was drawn off and concentrated. The residue was triturated with ether to provide 0.447 g of the title compound as a white solid, mp 154-156 °C.
WO 01/00579 WO 0100579PCT/USOO/18178 'H NMR (400 MHz) (CDCI 3 8 8.59 1H); 8.42 1H) 8.08 Hz, III); 7.72(t, 1=1.8, IH); 7.605 J=2.7 Hz, 1H) 7.53 (dd, J=8.5, 2 Hz, 1H); 7.48 (dd,.P1=9.4 Hz, LH); 7.22 I 7.0 J=9.0 Hz, I1H). rive 456.
The title compound was oxidized to the corresponding pyridine N-oxide using 3-chloroperoxybenzoic acid in methylene chloride to provide 3.2 as a white solid.
m/e 470 Cl
CI
CN
3.2 EXAMPLE 4 This example illustrates the synthesis of 4.1.
I r~YCF3 3-N 2 s CN doCN 2.1 .4.1 The title compound was prepared in a manner similar to Example 3, beginning with 1.6 g of the aniline of Example 2 and 1.6 g of 4- (trifluoromcthyl)benzenesulfonyl chloride (from Maybridge). The crude product remaining after workup was purified by flash chromatography on silica eluting with ethyl acetate dichloromethane and then triturated in diethyl ether and collected as a white powder (1 .04 g, 35% yield), nip 143-144 'C.
EXAMPLE This example illustrates the synthesis of 5.1.
Cl I
CCI
NH
2
CNH,~
lipIAJ ol 01S 0 CN 0 0 CN 2.1 5.1 WO 01/00579 PCT/US00/18178 The title compound was prepared in a manner similar to Example 3, beginning with 397 mg of the aniline prepared as described in Example 2 and 345 mg of chloride (prepared according to Hoffman, Org. Syn.
Coll. Vol. VII., p. 508-511). The crude product remaining after workup was purified by flash chromatography on silica eluting with 15% ethyl acetate dichloromethane. The resulting solid was recrystalized from dichloromethane to provide the title compound (270 mg, 40%) as a white solid, m/e 419 EXAMPLE 6 This example illustrates the synthesis of 6.1.
CN dO
CN
2.1 6.1 The title compound was prepared in a manner similar to Example 3, beginning with 400 mg of the aniline prepared as described in Example 2 and 349 mg of 3-pyridylsulfonyl chloride (prepared using methods similar to those described in J. Med.
Chem. 40:1149 (1997)). The crude product remaining after workup was purified by flash chromatography on silica eluting with 1% ethanol dichloromethane. The resulting solid was recrystalized from dichloromethane diethyl ether and collected as a white solid (121 mg, mp 161-2 OC.
In a similar manner, 6.2 was prepared from aniline 2.1 and trifluoromethyl-2-pyridinesulfonyl chloride, mp 174-176 °C.
O' CF 3
CN
6.2 WO 01/00579 PCT/US00/18178 EXAMPLE 7 This example illustrates the preparation of 7.1.
1 1 a COC-I 3 Y NH 2
COCH
3 O OCH-N I" c CN 0j CN 2.1 7.1 A round-bottomed flask was charged with the aniline prepared according to Example 2 (229 mg, 0.94 minol), 4-acetylbenzenesulfonyl chloride (205 mg, 0.94 mmol, prepared according to Hoffman, Org. Syn. Coll. Vol. VII, p. 508-511), pyridine (75 mg, 0.94 mmol, Aldrich Chemical and a catalytic amount of DMAP (Aldrich Chemical Five mL of dichloromethane were added and the reaction was stirred at room temperature for eight hours. The reaction was then diluted with 25 mL of dichloromethane and washed successively with 10 mL of IN HCI and brine. The organic portion was dried over MgSO 4 and passed through a plug of silica gel to remove baseline impurities. The resulting solid was triturated in hexanes to provide 362 mg of the title compound as a white solid.
'HNMR (400MHz) (d 6 -DMSO) 8 10.81 (1H, 8.52 (1H, d, J=1.8 Hz); 8.43 (1H, d, J=2.3 Hz); 8.11 (2H, dd, J=6.8 Hz, 2.0 Hz); 7.90 (2H, dd, J=6.8 Hz, 2.0 Hz); 7.85 (1H, dd, J=4 .4 Hz, 2.2 Hz); 7.53 (1H, d, J=2.7 Hz); 7.35 (IH, dd, J-9.1 Hz, 2.8 Hz); 7.35 (1H, d, J=9.1 Hz); 2.61 (3H, s).
MS ESI m/e: 425.8 (M H).
The compounds provided in Table 1 were prepared using the methods described in Examples 1-7.
Table 1 Rd Rc Cl SRb N0 0 Ra
CN
Ra Rb Rc Rd mp 0
C)
7.2 Cl H Cl CH3 181-182 WO 01/00579 WO 0100579PCT/USOO/181 78 7.3 H H OCF 3 H 118-120 7.4 H H CN H 160-163 H H SQ 2
CH
3 H 174-175 EXAMPLE 8 This example illustrates the preparation of 3-fluoro-4-(3-chloro-5pyridyloxy)nitrobenzene 0q0
F
8.1 3,4-Difluoronitrobenzene (5.0 g, 32 mmol) and 5-chloro-3-pyridinol were combined using the procedure described in Example 1, to produce 8.2 g of the title compound.
'H NMR (400 MHz) (DMSO-d 6 8 8.562 J=1.9 Hz, I 8.537 (d, J=2.5 Hz, 1H); 8.384 (dd, J=10.8, 2.8 Hz, lH); 8.117 (ddd, 1=9.1, 2.7, 1.5 Hz, IH); 7.967 J=2.2 Hz, I 7.418 (dd, J= 9.2, 8.4 Hz, I H).
EXAMPLE_9 This example illustrates the preparation of 3-fluoro-4-(3-chloro-5pyridyloxy)ani line Cl 0 -2
F
9.1 Using the method of Example 2, 3-fluoro-4-(3-chloro-5pyridyloxy)nitrobenzene 8.0 g) was converted to the-title compound which was used directly in subsequent reactions.
MS (M +H)239. 1.
'H NMR (400 MHz) (CDC1 3 8 8.242 (br s, 2H); 7.142 J=2.2 Hz, IH); 6.9 37 J=8.7 Hz, I 6.5 12 (dd, J= 12, 2.6 Hz, I 6.444 (ddd, J=8.4, 2.7, 1.4 H z, I 3.62 (br s, 2 H).
WO 01/00579 PCT/US00/18178 EXAMPLE This example illustrates the preparation of 10.1.
SO Cl
I
2 f l r r H^ S X Io d'b F 1Th 9.1 10.1 3-Fluoro-4-(3-chloro-5-pyridyloxy)aniline (239 mg, see Example 9) and 2,4-dichlorobenzenesulfonyl chloride (416 mg, Maybridge), were combined in a similar manner to that described in Example 3. The crude product was purified by flash chromatography on silica, eluting with 5% ethyl acetate dichloromethane. The product fractions were concentrated and the solid was recrystallized from diethyl ether hexanes to provide the title compound as a white solid (350 mg, mp 149-151 OC.
EXAMPLE 11 This example illustrates the preparation of 11.1.
0 S H
SCH
3 O NH 2 SCH 3 O O S o Cl-s o b F db F 9.1 11.1 3-Fluoro-4-(3-chloro-5-pyridyloxy)aniline (310 mg, see Example 9) and 4methylthiobenzenesulfonyl chloride (298 mg, prepared as described in Burton, et al., J.
Chem. Soc., 604-5 (1948)), were combined in a manner similar to that described in Example 3. The crude product was purified by flash chromatography on silica, eluting with ethyl acetate hexanes dichloromethane The product fractions were concentrated and the solid was recrystallized from hexanes diethyl ether to provide the title compound as a white solid (315 mg, mp 130-131 OC.
The title compound was oxidized with mCPBA to the corresponding sulfoxide (11.2, mp 140-144 The corresponding sulfone (11.3) was prepared using 4-(methylsulfonyl)benzenesulfonyl chloride (mp 165-168 EXAMPLE 12 This example illustrates the preparation of 12.1.
WO 01/00579 WO 0100579PCTIUSOO/18178 Cl Cl
N
2 )AN IF 00 F 9.1 12.1 The title compound was prepared in a manner similar to Example 3, beginning with 3-pyridylsulfonyl chloride (335 mg, see Example 6) and 3-fluoro-4-(3line (310 mg, see Example 9) with the addition of a catalytic amount of 4-dimethylaminopyridine. When reaction was complete by TLC, the mixture was filtered to remove amine salts. The filtrate was concentrated and the residue was purified by flash chromatography on silica, eluting with 5% methanol dichioromethane.
The product fractions were combined, concentrated, and the residue was triturated with diethyl ether to provide the title compound as a white solid (221 mg, mp 129 'C.
EXAMPLE 13 This illustrates the synthesis of 5-(4-acetylbenzenesulfonamido-2fluorophenoxy)-3-chloropyridine (13.1).
01,11 N11 2
SN
F
F
Cl "'IcCl N- N 9.1 13.1 This was prepared using methods outlined in Examples 10- 12, starting with 238 mg (1.0 mmnol) of aniline 9.1, 218 mg (1.0 mmol) of 4-acetylbenzenesulfonyl chloride, 79 mg (1.0 mmol) of pyridine, catalytic DMAP, and S ml, of methylene chloride. The title compound was obtained as a white solid (269 mg, 64%).
'H NMR (400MHz) (d 6 -DMSO) 8 10.75 (1IH, d, J4.7 Hz); 8.38 (11-H, dd,
J
1 =4.8 Hz J 2 =2.1 Hz); 8.26 (1IH, dd, J 1 =5.0 Hz J.=2.4 Hz) 8.09 (2H, in); 7.91 (2H, in); 7.52 (111, dd, .I=4.7 Hz J 2 =2.6 Hz); 7.21 (1 H, dt, J 1 =5 Hz J 2 =1 .0 Hz); 7.12 dd, WO 01/00579 WO 0100579PCTIUSOO/18178
J
1 =12.2 Hz J2=1 .0 Hz); 6.92 (111, d, J=8.8 Hz); 2.59 (3H, t, J=2.1 Hz). MIS ESI ml/e: 418.7 (M H).
EXAMPLE 14 This example illustrates the synthesis of 3-chloro-4-(3-chloro-5pyridyloxy)nitrobenzene (14.1).
00 Cl 14.1 3-Chloro-4-fluoronitrobenzene (5.0 g, 28 mmol) and 5-chloro-3-pyridinol were combined using the procedure described in Example 1, to produce 7.9 g of the title compound.
'H NMR (400 MHz) (DMSO-d 6 8 8.571 J=2.0 Hz, I1H); 8.509 (d, J=2.4 Hz, I1H); 8.499 J=2.7 Hz, I 8.208 (dd, J=9.0, 2.7 Hz, I1H); 7.949 (tJ=2.3 Hz, I1H); 7.3 35 J= 9.1 Hz, IlH).
EXAMPLE This example illustrates the preparation of 3-chloro-4-(3-chloro-5pyridyloxy)ani line (15.1).
Cl S NH2 Using the method of Example 2, 3-chloro-4-(3-chloro-5pyridyloxy)nitrobenzene (7.6 g) was converted to the title compound (7.2 g) and which was used directly in subsequent reactions.
'11NMR (400 MHz) (CDCI 3 8 8.244 (br s, I 8.211 (br s, 7.096 (br 5, IH); 6.929 1=8.6 Hz, 1H); 6.785 J=2.6 Hz, 1H); 6.592 (dd, J=8.6, 2.6 Hz, 1H); 3.577 (br s, 2H). MS (M 255.1.
EXAMPLE 16 This example illustrates the preparation of 16.1.
N
2
SCH
3 -I I- IN 0Cl.- 0 F 00 Cl 9.1 16.1 3-Chloro-4-(3-chloro-5-pyridyloxy)aniline (410 mg, 15.1) and 2,4dichlorobenzenesulfonyl chloride (390 mg, Maybridge), were combined in a similar manner to that described in Example 3. The crude product was purified by flash chromatography on silica, eluting with 5% ethyl acetate dichioromethane. The product fractions were concentrated and the residue was triturated in hexanes to provide the title compound as a white solid (538 mg, mp 128-130 *C.
'H NMR (400 MHz) (DMSO) 8 8.40 1= 1.8 Hz., IHM; 8.24 J=2.4 Hz, 111); 8.06 J=8.5 Hz, 1H); 7.90 .1=2.0 Hz, IH); 7.65 (dd, 8.5 Hz, 111); 7.48 (t, IH); 7.28 J=2.5 Hz, 111); 7.21 J=8.84 Hz, 1H); 7.10 (dd, J=2.5, 7.1, IH).
MS m/e 465 Compound 16.1 was oxidized with 3-chloroperoxybenizoic acid to produce the corresponding pyridine N-oxide, 16.2, as a white solid after trituration in diethyl ether, mp 205-207 'C.
CI
CI
16.2 EXAMPLE 17 This example illustrates the preparation of 17.1.
0 Cl- (j SCH3
S
N\ 000 15.1 1.
17.1 WO 01/00579 PCT/US00/18178 3-Chloro-4-(3-chloro-5-pyridyloxy)aniline (309 mg, 15.1) and 4methylthiobenzenesulfonyl chloride (223 mg, prepared as described in Burton, et al. .J Chem. Soc., 604-5 (1948)), were combined in a manner similar to that described in Example 3. The crude product was purified by flash chroinatography on silica, eluting with ethyl acetate hexanes dichloromethane The product fractions were concentrated and the residue obtained was triturated in hex.nes to provide the title compound as a white solid (200 mg, mp 96-98 OC.
Oxidation of 17.1 to sulfoxide 17.2 Cl H /S(O)CH 3 o 00 Cl 17.2 Compound 17.1 was oxidized to the corresponding sulfoxide using Oxidation to sulfoxide potassium peroxymonosulfate in methanol and acetone. The reaction was monitored by TLC. After the reaction was complete, the mixture was filtered and the filtrate was washed with water, dried over MgSO 4 filtered and concentrated. The residue was purified by chromatography on silica, eluting with 50% to 100% ethyl acetate dichloromethane. Solvent was removed from the product fractions, and the residue was triturated in hexanes. The white solid product was collected by filtration to provide 121 mg of 17.2 mp 127-128 °C.
EXAMPLE 18 This example illustrates the preparation of 18.1.
CI Cl N -CN 0 6' 0 1 Cl d Cl 15.1 18.1 The title compound was prepared in a manner similar to Example 3, beginning with 3-pyridylsulfonyl chloride (335 mg, see Example 6) and 3-chloro-4-(3- WO 01/00579 PCT/US00/18178 (411 mg, 15.1) with the addition of a catalytic amount of 4dimethylaminopyridine. When the reaction was completed by TLC, the mixture was filtered to remove amine salts. The filtrate was concentrated and the residue was purified by flash chromatography on silica, eluting with 5% methanol dichloromethane. The product fractions were combined, concentrated, and the residue was triturated dichloromethane to provide the title compound as a white solid (149 mg, mp 164- 165 oC.
In a similar manner, 18.2 (mp 174- 175 was prepared from aniline 15.1 and 5-trifluoromethyl-2-pyridinesulfonyl chloride.
C I CF 3 N- N-S N Cl 18.2 The compounds provided in Table 2 were prepared using commercially available intermediates and/or using the intermediates and methods described in the examples above.
Table 2 Rd Rc NS Rb I c?
I
Cl Ra Rb Rc Rd mp (OC) or m/e 18.3 H H CF 3 H 172-174 0
C
18.4 Cl H CF 3 H 111-113 0
C
18.5 H H COCH 3 H 434.7 18.6 H Cl Cl H 460.9 WO 01/00579 WO 0100579PCTIUSOO/18178 EXAMPLE 19 This example illustrates the preparation of 3-bromo-4--(3-chloro-5pyridyloxy)nitrobenzene (19.1).
Br 19.1 3-Bromo-4-fluoronitrobeinzene (available from Reidel) and 5-chloro-3pyridinol were combined using the procedure described in Example 1, to produce the title compound.
'H NMR (400MHz, DMSO-d 6 8 8.61 J 2.6 Hz, IlH), 8.57 J 2.2 Hz, 11H), 8.49 IJ 2.5 Hz, 1H), 8.24 (dd, J 9.3, 2.6 Hz, lH), 7.94 (dd, J 2.4, 2.2 Hz, IH), 7.3 J 9.0 Hz, 21-1). MS m/z 333 (25, 332 (15, 331 (100, 330 (10, 329 (76, M+H).
EXAMPLE This example illustrates the preparation of 3-bromo-4-(3-chloro-5pyrtidyloxy)ani line (20.1).
C1 Br 20.1 Using the method of Example 2, 3-bromo-4-(3-chloro-5pyridyloxy)nitrobenzene (19.1) was converted to the title compound which was used directly in subsequent reactions.
'H NMR (400M-Hz, DMSO-d 6 8 8.32 J 2.1 Hz, I 8.19 J Hz, I 7.28 (dd, J 2.4, 2 Hz, I 7.2 J 8.7 Hz, I 6.9 J 2.6 Hz, I1H), 6.62 (dd, J 8.7, 2.6 Hz, I MS ?nz/e 304 303 (35, 302 (20, M+H), 3 01 (100, 3 00 (15, 2 99 (90, M+H).
WO 01/00579 WO 0100579PCTIUSOO/18178 The compounds provided in Table 3 were prepared using 20.1 and commercially available intermediates and/or using the intermediates and methods described in the examples above.
Table 3 Rd Re Cl NH S Rb r 20.2 20.3 20.4 Rc Cl.
SCH
3
S(O)CH
3 lup (C) 114-115 160- 162 169-171 Similarly, 20.5 was prepared from aniline 20.1 and 5-trifluoromethyl-2pyridinesulfonyl chloride, mp 202-204 *C.
EXAMPLE 21 This example illustrates the preparation of 5-(4-nitro-2-methoxyphenoxy)- 3-chloropyridine (21.1).
WO 01/00579 PCT/US00/18178 21.1 A round-bottomed flask was charged with 2-chloro-5-nitroanisole (1.03 g, 5.49 mmol, Avocado Chemical 5-chloro-3-pyridinol (750 mg, 5.76 mmol, Aldrich Chemical cesium carbonate (1.97 g, 6.04 mmol, Aldrich Chemical and anhydrous DMF (16 mL). The mixture was heated at 100 °C for 18 hours. The temperature was then increased to 130 0 C for an additional two hours, after which the reaction was allowed to cool to room temperature. The reaction mixture was poured into 800 mL of distilled water, and extracted three times with 300 mL ethyl acetate. The combined extracts were dried over MgSO 4 and filtered. Solvent was removed from the filtrate under vacuum and the crude product was purified by flash chromatography on silica gel hexanes in CH 2
CI
2 as eluant) to provide the title compound (1.42 g, 93%) as a yellow solid. MS ESI m/e: 281.1 (M HI).
EXAMPLE 22 This example illustrates the synthesis of 5-(4-arnino-2-methoxyphenoxy)- 3-chloropyridine (22.1).
NO
2
NH
2 OMe OMe Cl Cli O N N 21.1 22.1 Using the method of Example 2, the nitro compound prepared in Example 21 (1.54 g, 6.56 mmol) was converted to 1.38 g of the title compound as an offwhite solid. The product was used without further purification (upon standing several WO 01/00579 WO 0100579PCTUSOO/18 178 days in air the compound developed a very dark brown color). MIS ESI m/e: 25 1.1 (M
H).
EXAMPLE 23 This example illustrates the synthesis of dichlorobenzenesul fonamnido)-2-methoxyphenoxy)-3-chloropyridifle (23.1).
NH
2
SNH
CCl N N 22.1 23.1 A round-bottomed flask was charged with aniline 22.1 (96 mg, 0.39 mmol), 2,4-dichlorobenzenesulfonyl chloride (104 mg, 0.42 mmol, Maybridge Chemical pyridine (28 mg, 0.39 mmol, Aldrich Chemical and a catalytic amount of DMAP (Aldrich Chemical Three m.L of dichioromethane was added and the reaction mixture was stirred at room temperature for eight hours. The resulting mixture was then diluted with 15 mL of dichloromethane and washed successively with 10 mL of 1N HCI and brine. The combined organic portions were dried over MgSO 4 then passed through a plug of silica gel to remove baseline impurities. Solvent was removed from the filtrate and the resulting solid was triturated in hexanes to provide the title compound (69 mg, 40%) as a white powder.
'H NMR (400M1-z) (d 6 -DMSO) 8 10.81 (1 H, 8.29 (1IH, d,J=2.1 Hz); 8.11 (1 H, d, J=2.4 Hz); 8.07 (1 H, d, J=8.5 Hz); 7.88 (1IH, d, J=2.0 Hz); 7.63 (1 H, dd, J=-8.7 Hz, 2.1 Hz); 7.20 (1 H, dd, .1=4 .4 Hz, 2.1 Hz); 7.07 (1 H, d, .1=8.7 Hz); 6.91 (1 H, d, J= 2.4 Hz); 6.68 (III, dd, J8.7 Hz, 2.5 Hz); 3.65 (3H, MS ESI mle: 459.0 (M H).
EXAMPLE 24 This examnple illustrates the synthesis of 5-(4methylsul fonylbenzenesulfonamido-2-methoxyphenoxy)-3-chloropyridine (24.1).
WO 01/00579 WO 0100579PCT/USOO/18178 O~e MeO 2 9 O~e OMe
N'NT
22.1 24.1 The title compound was prepared using the general procedure described in Example 22, starting with 150 mg (0.61 mmol) of the aniline, 155 mg (0.61 mmol, Aldrich Chemi'cal Co.) of 4-methylsulfonebenzenesulfonyl chloride, 48 mg (0.61 mnxol) of pyridine, catalytic DMAP, and 5 mL of methylene chloride. Following workup, the title compound was obtained (67 mg, 24%) as a white solid.
'H NMR (400MHz) (d 6 -DMSO) 8 10.63 (11H, 8.30 (1IH, d, j=2.0 Hz); 8.14 (2H, in); 8.04 (1IH, dd, .1=8.6 Hz, 1.9 Hz); 7.27 (1IH, dd, Hz, 2.2 Hz); 7.08 (1 H, d, J1=8.6 Hz); 6.93 (1IH, d, J=2.4 Hz); 6.70 (1 H, dd, J=8.6 Hz, 2.4 Hz); 3.67 (3H 3.28 (3H, MS ESI rn/c: 467.0 (M H).
EXAMPLE This example illustrates the synthesis of 5 -(4-acetylbenzenesulfonamido-2methoxyphenoxy)-3-chloropyridine (25.1).
~S OMe OMe CI N.CI' NT.
22.1 25.1 The title compound was prepared using the procedure described in Example 7, starting with 82 mg (0.33 mmol) of aniline 22.1, 72 mng (0.33 mmol) of 4acetylbenzenesulfonyl chloride, 26 mg (0.33 mmol) of pyridine, catalytic DMAP, and 2 WO 01/00579 WO 0100579PCT/USOO/18178 mL of methylene chloride. The title compound was produced (92 mg, 65%) as a white solid.
'H NMR (400MHz) (d 6 -DMSO) 8 10.52 (1H, 8.29 (1 H, d, J=1.9 Hz); 8.10 (3H, in); 7.92 (2H, dd, J=8.0 Hz, 2.3 Hz); 7.23 (11-H, dd, Hz, 2.4 Hz); 7.06 (1IH, d, J=8.6 Hz); 6.93 (1lH, dd, J=8.6 Hz, 2.4 Hz); 6.70 (1 H, dd, J =8.6 Hz, 2.4 Hz); 3.65 (3H, 2.60 (3H, MS ESI mle: 43 1.1 (M H).
In a similar manner, 25.2 and 25.3 were prepared from aniline 22.1 and the appropriate sulfonyl chloride.
&0)CH 3 25.2 Z= N 25.3 Z =CH EXAMPLE 26 This example illustrates the preparation of 5-nitro-2-(3,5difluarophenoxy)-benzonitrile (26.1).
F
NO
2 F 0
CN
26.1 (4.6 g, 25 mmol) and 3,5-difluorophenol were combined using the procedure described in Example 1, to produce 6.6 g of the title compound.
'H NMR (400 MHz) (CDCI 3 8 8.598 J=2.8 Hz, IlH); 8.396 (ddd, J=9.3, 2.8, 1.2 Hz, I 7.259 J=0.8 Hz, I1H); 7.044 J=9.6 Hz, I 6.821 (in, I H; 6.722 (mn, 2H).
WO 01/00579 WO 0100579PCTIUSOO/18178 In a similar manner, 4-chloro-3-nitrobenzonitrile (4.6 g, 25 mmol) and difluorophenol were combined to produce 6.9 g of 3-nitro-4-(3,5-difluorophenoxy)benzonitrile mp 132-136 'C.
'H NMR (400 MHz) (DMSO-d 6 5 8.72 J2.0 Hz, I 8.165 (dd, J=8.8, 1.9 Hz, IH); 7.422 J=8.8 Hz, IH); 7.227 (in, 1H); 7.103 (in, 2H).
EXAMPLE 27 This example illustrates the preparation of 5-amino-2-(3,5difluorophenoxy)benzonitri le (27.1).
Using the method of Example 2, 5-nitro-2-(3,5-difluorophenoxy)benzonitrile (26.1, 6.6 g) was converted to the title compound (5.47 g, mp 80-84*C) which was used directly in subsequent reactions.
'H NMR (400 MHz) (TFADMSO-d 6 6 11.2 (br s, 2H); 7.083 (d,J=9.2 Hz, I1H); 7.077 J=2.8 Hz, I1H); 7.033 (dd, 2.4 Hz, 1I-H); 6.998 (tt, J=r9.2, 2.4 Hz, I 6.727 (dd, J=8.4, 2.0 Hz, 2H).
Similarly, 3-amino-4-(3 ,5-difluorophenoxy)benzonitrile (27.2) was prepared from 26.2.
WO 01/00579 WO 0100579PCTIUSOO/181 78 27.2 'H NUR (400 MHz) (DMSO-d 6 8 7.14 J=2.0 Hz, I 7.03-6.96 (n 3H); 6.70 (dd, J=8.6, 2.3 Hz, 2H); 5.60 2H).
The compounds provided in Table 4 were prepared using 27.1 and commercially available substituted benzenesulfonyl chlorides and/or using the intermediates and methods described in the examples above.
Table 4 Rd Re NH I' R K #SR 0 Ra F' 0
N
Ra Rb Rc Rd mp(*C)or ni/e 27.3 CI H Cl H 452.7 27.4 H H OCH 3 H 414.8 27.5 H H I H 510.6 27.6 H H C(O)CH 3 H 482.7 27.7 H H CF 3 H 141-144 OC WO 01/00579 WO 0100579PCTIUSOO/18178 EXAMPLE 28 This example illustrates the preparation of 28.1.
0 F 0 Cl +ci NHF CN S'
H_-
FI
CN
28.1 3-Amino-4-(3,5-difluoropheloxy)belzofitrile (201 mg, 27.2) and 2,4dichlorobenzenesulfonyl chloride (302 mg, Maybridge), were combined in a similar manner to that described in Example 3, then heated to 40 The crude product obtained after workup was purified by flash chromatography on silica, eluting with dichioromethane. The product fractions were concentrated and the residue was triturated with diethyl. ether to provide the title compound as a white solid (150 mg, mp 197- 200 0
C.
EXAMPLE 29 This example illustrates the preparation of 5-nitro-2-(3 dichlorophenoxy)-benzonitrile (29.1).
Cl
CN
29.1 2-Chloro-S-nitrobenzonitrile (0.9 g, 5 mmol) and 3,5-dichiorophenol were combined using the procedure described in Example 1, to produce 1.5 g of the title compound, mp 188-190 'C.
'H NMR (400 MHz) (CDC1 3 8 8.597 J=2.4 Hz, 1H); 8.397 (ddd, J=9.2, 2.8, 0.8 Hz, 111); 7.360 (dd, J=3.2, 2.0 Hz, IH); 7.089 (dd, J=1.6, 0.8 Hz, 211) 7.008 J=9.6 Hz, I1H).
WO 01/00579 PCT/US00/18178 EXAMPLE This example illustrates the preparation of 5-amino-2-(3,5dichlorophenoxy)benzonitrile (30.1).
Cl
NH
2 Clf O
CN
30.1 To a solution of 5-nitro-2-(3,5-dichlorophenoxy)benzonitrile (29.1, 1.5 g) in ethyl acetate (45 mL) was added stannous chloride dihydrate (5.47 The mixture was heated to 85 0 C for 30 minutes during which time a thick white precipitate formed.
The reaction vessel was cooled and the mixture was treated with 100 mL of 0.5 N NaOH.
The resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were dried over MgSO4 and concentrated under vacuum to afford the title compound which was used without further purification. MS m/e 279 The compounds provided in Table 5 were prepared using 30.1 and commercially available substituted benzenesulfonyl chlorides and/or using the intermediates and methods described in the examples above.
Table Rd Cl NIRc NH X Rb C I 0 -OO -R a
CN
Ra Rb Re Rd mp 30.2 Cl H CI H 143-144 30.3 H H CF 3 H 148-149 EXAMPLE 31 This example illustrates the preparation of 5-nitro-2-(3,5dimethoxyphenoxy)benzonitrile (31.1).
WO 01/00579 PCT/US00/18178 31.1 (5.3 g) and 3,5-dimethoxyphenol (4.5 g, Aldrich) were combined using the procedure described in Example 1, to produce the title compound as a brown solid.
'HNMR (400 MHz) (DMSO) 8 8.84 J=2.8, 1H); 8.44 (dd, J=9.3, 2.8 Hz, 1H); 7.07 J=9.3 Hz, IH); 6.51 3H); 3.76 6H).
EXAMPLE 32 This example illustrates the preparation of 5-amino-2-(3,5dimethoxyphenoxy)benzonitrile (32.1).
OCH3
NH
H
3 CO O
CN
32.1 To a solution of 5-nitro-2-(3,5-dichlorophenoxy)benzonitrile (31.1, 8.76 g) in ethyl acetate was added tin chloride (33 The mixture was heated to reflux for one hour. The resulting mixture was cooled and 0.5 N sodium hydroxide solution was added to induce the precipitation of tin salts which were removed by filtration. The filtrate was concentrated to provide 7.5 g of the title compound as an orange solid which was used in subsequent reactions without purification.
'H NMR (400 MHz) (DMSO-d 6 8 6.95-6.87 3H); 6.25 J=2.2 Hz, 1H); 6.04 J=2.2 Hz, 2H); 5.49 2H); 3.70 6H).
The compounds provided in Table 6 were prepared using 32.1 and commercially available substituted benzenesulfonyl chlorides and/or using the intermediates and methods described in the examples above.
WO 01/00579 WO 0100579PCT/USOO/181 78 Table 6 Rd
CH
3 Rc N H
I~
I~ 0OA Ra R
H
3 COr 0? Ra Rb Rc Rd mp (*C)or rn/c 32.2 Cl H Cl H 477 32.3 Cl H CF 3 H 101-105 0
C
32.4 H H I H 439 32.5 H H OCH 3 H 162-164 0
C
EXAMPLE 33 This example illustrates the preparation of 3-rnethoxy-4-(3,5difluorophenoxy)-nitrobenzene (33.1).
F
N 2
OCH
3 33.1 4-Chloro-3 -methoxynitrobenzcne (2.64 g) and 3 (Aldrich) were combined using the procedure described in Example I and heated to 125'C, to produce the title compound as a thick brown oil which solidified on trituration with hexane/methanol to yield 1.33 g of 33.1 as a red solid.
H NMR (400 MHz) (DMSO-d 6 5 7.963 J=2.6 Hz, 1I-H); 7.903 (dd, J=8.8, 2.7 Hz, I1H); 7.3 16 J=8.8 Hz, I 7.035 (in, I 6.796 (rn, 3.909 (s, 3H).
In a similar manner, 3-methoxy-4-(3,5-dichlorophenoxy)niitrobenzene (33.2) and 3-methoxy-4-(3,5-dimethoxyphenoxy)nitrobelzene (33.3) were prepared beginning with 3,5 -dichlorophenol and 3,5-dimethoxyphenol, respectively.
WO 01/00579 WO 0100579PCTIUSOO/18178 33.2 33.3 33.2 3-methoxy-4-(3,S-dichlorophenoxy)nitrobelzefle 'HNMR (400 MHz) (DMSO-d 6 8 7.960 J=2.6 Hz, I 7.900 (dd, 1=8.9,2.7Hz, 1H); 7.394(t,J=1.7 Hz, IH); 7.3 l0(d,J=8.8 Hz, 1H); 7.107(t,J=1.4 Hz, 2HM; 3.907 31H).
33.3 3-methoxy-4-(3,5-dimethoxyphenoxy)iitrobenzefle 'H NMR (400 MHz) (DMSO-d 6 8 7.9 10 J=2.6 Hz, 1H); 7.862 (dd, J=8.8, 2.6 Hz, 1H); 7.064 J=8.8 Hz, 11H); 6.353 J=2.2 Hz, I 6.207 J=2.2 Hz, 2H); 3.927(s, 3H); 3.716 6H).
Each of the nitrobenzene derivatives (33.1, 33.2 and 33.3) were reduced to the corresponding aniline derivative using the Raney nickel procedure of Example 2. The aniline derivatives were then converted to the compounds shown in Table 7 using commercially available substituted benzenesulfonyl chlorides and/or using the intermediates and methods described in the examples above.
Table 7 Rd
NI-IC
1 Rc Ra Rb 0 0 R OCH3 Ar Ra Rb Rc I 3,5-dichiorophenyl CI H CI 3,5-difluorophenyl H H CF 3 3,5-dichiorophenyl H- H CF 3 3,5-difluorophenyl Cl H Cl 3,5-difluorophenyl H H OCH 3 33.4 33.5 33.6 33.7 33.8
MP(
0
C)
128-131 141-143 165-166 120- 124 129- 133 WO 01/00579 WO 0100579PCTUSOO/18 178 Ar. Ra Rb Re Rd mp(*C) 33.9 3,5-dimethoxyphenyl Cl H CI H 100-103 33.10 3,5-dimethoxyphenyl Cl H CF 3 H 72-79 33.11 3,5-dimethoxyphenyl H H OCH 3 H 92-95 EXAMPLE 34 This example illustrates the synthesis of 5-(4-cblorosulfonyl-2cyanophenoxy)-3-chloropyridine (34.1).
NH
2
SOPC
CN CN 0 0 52.1 34.1 Aniline 2.1 (3.11 g, 12.69 mmol) was converted to the corresponding sulfonyl chloride according to the procedure of R. V. Hoffman (Org. Syn. Coll. VUl, VII, 508-51 yielding 770 mg of 34.1 as a white solid. MS ESI m/e: 33 1.0 (M H) EXAMPLE This example illustrates the synthesis of compound 35.1.
H
~CN CN Cl 0 CI N N 34.1 35.1 The title compound was prepared using the method described in Example 3, starting with 4-iodoaniline (136 mg, 0.6 197 mmol, Aldrich Chemical 5-(4chlorosulfonyl-2-cyanophenoxy)-3-chloropyridine (136 mg, 0.4131 mmol, 34. pyridine (49 mg, 0.6 197 mmol), catalytic DMAP, and 3 mL of methylene chloride. The product was obtained as a white solid (187 mg, 89%).
WO 01/00579 WO 0100579PCT/USOO/18178 'H NMR (400MHz) (d 6 -DMSO) 8 10.57 (1 H, 8.62 (1 H, d, J=1.8 Hz); 8.60 (IHd, J=2.2 Hz); 8.28 (1IH, d, J=2.4 8.12 (1IH, d, J2.2 Hz); 7.93 (1IH, dd, J,=8.9 Hz J 2 =2.3 Hz); 7.61 (2H, dd, J 1 =8 .8 Hz J 2 =2.0 Hz); 7.17 (1IH, d, 6.93 (2H, dd, J, 8.8 Hz J12=2.0 Hz). \MS ESI m/e: 509.9 (M H).
EXAMPLE 36 This example illustrates the synthesis of compound 36.1.
H
0 2 C' 02 1-00 ~CN CN Cl N0 l 0K- N N 34.1 36.1 The title compound was prepared using the method described in Example 35, starting with 4-acetylaniline (100 mg, 0.31 mmol, Aldrich Chemical 5-(4chlorosulfonyl-2-cyanophenoxy)-3-chloropyridine (62 mg, 0.46 mmol), pyridine (36 mg, 0.46 mmol), catalytic DMAP, and 3 mL of methylene chloride. The title compound 36.1 was obtained as a white solid (120 mg, 92%).
'H NMR (400MHz) (d 6 -DMSO) 8 10.53 (1 H, 8.58 (1IH, d, J=1 .9 Hz); 8.53 (IH, d, J=2.4 Hz); 8.15 (1H, d, J=2.5 Hz); 7.99 (IH, dd, .11=4.4 Hz J 2 =2.2 Hz); 7.86 (I1H, dd, J,=8.8 Hz J 2 =2.5 Hz); 7.59 (2H, dd, JI=8.8 Hz J12=2.0 Hz); 7.13 (lH, d, J=8.7 Hz); 6.93 (2H, dd, =8.8 Hz J 2 =2.0 Hz); 2.61 (1iH, MIS ESI mn/e: 425.9 (M H).
EXAMPLE 37 This example illustrates the synthesis of 5-(4-chlorostilfonyl-2chlorophenoxy)-3-chloropyridine (37.1).
WO 01/00579 WO 0100579PCT/USOO/18 178 15.1 37.1 Aniline 15.1 10 g, 8.24 mmol) was converted to the corresponding sulfonyl chloride 37.1, according to the procedure of R. V. Hoffmnan (Org. Syn. Coil.
Vol., VII, 508-5 11). The title compound was obtained as a slightly yellow solid (1.65 g 59%) MS ESI mle: 338.0 (M H).
EXAMPLE 38 This example illustrates the synthesis of compound 38.1.
CI CI CI0 ci0 37.1 38.1 The title compound was prepared usidg the method described in Example 3 5, starting with 4-iodoaniline (10 1 mg, 0.46 mmol), S-(4-chlorosulfonyl-2chlorophenoxyy3 chloropyridine (104 mg, 0.31 minol), pyridine (35 mg, 0.46 mmol), catalytic DMAP, and 3 mL of methylene chloride. Compound 38.1 was obtained as a white solid (150 mg, 94%).
1 HNMR (400MHz) (d 6 -DMSQ) 8 10.50 (1 H, 8.55 (1 H, d, J=2.1 Hz); 8.45 (1H, d, J=2.5 Hz); 7.93 (lH, d, J=2.2 Hz); 7.89(1H, dd, JI=4.4 Hz J 2 =2.2 Hz); 7.67 (lH, dd, JI=8.7 Hz .12=2.2 Hz); 7.61 (2H, dd, J=8 .8 Hz J2="2.0 Hz); 7.22 (lH, d, J1=8.7 Hz); 6.94 dd, J,=8.8 Hz.J 2 =2.0 Hz). MS ESI m/e: 518.9 (M H).
WO 01/00579 WO 0100579PCTIUSOO/18178 EXAMPLE 39 This example illustrates the synthesis of compound 39.1.
C1 0 N C 37.1 39.1 The title compound was prepared using the method of Example 38, starting with 4-acetylaniline (55 mg, 0.41 mniol), 5-(4-chlorosulfonyl-2-chlorophenoxy)- 3-chloropyridine (92 mg, 0.27 mmnol), pyridine (33 mg, 0.41 mniol), catalytic DMAP, and 3 mL of inethylene chloride. After workup, 39.1 was obtained as a white solid (130 mg, 93%).
'H NMR (400MHz) (d 6 -DMSO) 6 10.94 (IH, 8.54 (1IH, d, J=2.0 Hz); 8.44 (1lH, d, J=2.2 Hz); 8. 01 (1IH, d, J=2.1 Hz); 7.90 (11H, dd, J, =4.4 Hz J2=2.2 Hz); 7.86 (2H, dd,J 1 =8 .8 HzJ2=1.6 Hz); 7.75 (IH,dd,J=8 .7 1-zJ 2 =2.2 Hz); 7.23 (3H,mi). MS ESI in.e: 435.0 (M H).
EXAMPLE 1 5 This example illustrates the preparation of 5-(4-amino-2,5dibromophenoxy)3-chloropyridine 5-(4-amino-2,3 -dibromophenoxy)-3chioropyridine and 5-(4-amino-2,3 ,5-tribromophenoxy)-3-chloropyridine (40.3).
NH
2
NH
2
NH
2 IBr Br Br- Br BrBr Br C 0 CI C 0 40.1 40.2 40.3 WO 01/00579 WO 0100579PCTIUSOO/18178 To a 0.1 M solution of 3-bromo-4-(3-chloro-5-pyridyloxy)aniline (20.1) in acetic acid was added bromine (Aldrich). The resulting solution was stirred for two days.
Most of the acetic acid was removed azeotropically using hexanes and the residue was adjusted to pH 6 using 4 M aqueous NaGH. The aqueous layer was extracted with ethyl acetate and the combined organic portions were washed with brine dried over sodium sulfate, filtered and concentrated under reduced pressure. The products were separated by chromatography to provide 5-(4-arnino-2,5 -dibromophenoxy)-3chloropyridine (40.1, 5-(4-amino-2,3-dibromophenoxy)-3 -chloropyridline (40.2, and 5-(4-amino-2,3 ,5-tribromophenoxy)-3 -chioropyridine (40.3, 13%).
40. 1: 'H NMR (400M~z, DMSO04 6 8 8.3 5 (d,J 1. 5 Hz, I1H), 8.22 J Hz, ILH), 7.46 J 1.0 Hz, I1H), 7.39 (dd, J 2.8, 2.6 Hz, IRH), 7.14 I1H), 5.6 (s, 2H). MS m/z 383 (18, 382 (10, 381 (75, 380 (15, 379 (100, 378 377 (50, M+H).
40.2: 'H NMR (400M~z, DMSO-d 6 8 8.34 J 2 Hz, I1H), 8.21 J= 2.6 Hz, I 7.36 (dd, J 2.4, 2.2 Hz, I 7.32 (dd, J =8.8 Hz, I 6.49 J 8.8 Hz, lH), 5.7 2H). MS m/lz 383 (18, 382 (10, 381 (75, 380 379 (100, 378 377 (50, M+H).
40.3: 'H1 NMIR (400MHz, DMSO-d 6 8 8.36 J 2.2 Hz, I 8.26 J =2.4 Hz, IHf), 7.63 I 7.48 (dd, J 2.4, 1.9 Hz, IlH), 5.65 2H). MIS ni/z 463 (10, 462 461 (50, 460 (12, 459 (100, 458 (12, 457 (85, 456 455 (25, M+H).
EXAMPLE 41 This example illustrates the preparation of 5-(4-(2,4-dicblorobenzenesulfonamido)-2,5-dibromophenoxy)-3-chloropyridine (41.1).
WO 01/00579 WO 0100579PCT/USOO/181 78 41.1 5-(4-(2,4-dichlorobenzenesul fonamido)-2,5-dibrOin~phenOxy)-3chioropyridine was prepared in 39% yield from 40.1 and 2,4-dichlorobenzenesulfonyl chloride using the method of Example 3.
'H NMR (400MHz, DMSO-d 6 8 10.6 IlH), 8.47 (bs, I 8.33 (bs, I1H), 7.9 I 7.8 8 J 8.8 Hz, ILH), 7.68 (bs, IlH), 7.61 J 8.8 Hz, I 7.5 7 I H 7.52 1H). MIS m/z 593 592 591 (27, 90 (10, M+H) 589 (50, 588 (10, MI-H), 587 (45, 586 585 (17, M+H).
EXAMPLE 42 This example illustrates the preparation of 5-(4-amino-2-cyano-3bromophenoxy))-3-chloropyridine (42.1).
NH
2 Br
CN
C'I -0 42.1 3 -Cyano-4-(3-chloro-5 -pyridyloxy)ani line (see Example 2) was combined with bromine in acetic acid in a manner similar to that described in Example 40 to produce 5 .(4..amino-2..cyano-3-bromophenoxy)-3-chloropyridine after chromatography.
WO 01/00579 WO 0100579PCT/USOO/18178 'H NMR (400Mh4z, DMSO-d 6 8 8.44 J 1.8 Hz, I 8.37 J 2.2 Hz, I1H), 7.7 (dd, J 1.8 Hz, I 7.13 (1/2ABq, J 9.1 Hz, I1H), 7.11 (1/2A-Bq, J 9.1 Hz, IH), 5.83 2H). MS m/z 328 (30, 327 (13, 326 (100, M+H),325 (10, 324 (75, M+H).
EXAMPLE 43 This example illustrates the synthesis of 5-(4-(2,4-dichlorobenzenesulfonamido)-2-cyano-3-bromophenoxy)-3-chloropyridine (43.1).
CI.
N ~NH Rr
CN
0 43.1 5-(4-(2,4-dichlorobenzenesul fonamido)-2-cyano-3 -bromophenoxy)-3chioropyridine was prepared in 28% yield from 42.1 and 2,4-dichlorobenzenesulfonyl chloride using the method of Example 3.
'H NMvR (400 MHz, DMS0-! 6 8 10.7 11-1), 8.59 J 1.6 Hz, I1H), 8.53 J 2 Hz, IJH), 8.05 (bs, I 7.9 I 7.84 J 8.4 Hz, 1H), 7.6 (dd, J 8.4, 1.6 Hz, IH), 7.41 J =8.8 Hz, I1H), 7.01 J =9.2 Hz, 1H). MS m/z537 535 (73, 533 (100, 53 1(52, M+H).
EXAMPLE 44 This example illustrates the preparation of 5-(4-amino-5-bromo-2methoxyphenoxy))-3-chloropyridine (44.1).
WO 01/00579 WO 0100579PCT/USOO/18178 To a 0.2M solution of 5-(4-amino-2-methoxyphenoxy)-3-chloropyrdifle (200 mg, 0.8 mmol, 22.1) in CH 2
CI
2 at 0 'C was added 2,4,4,6-tetrabromo-2,5cyclohexadieneone (334 mg, 0.82 mmol, Lancaster). The resulting solution was stirred for 21 hours at ambient temperature. The reaction mixture was diluted with CH1 2
CI
2 mL), washed twice with a 2M solution of aqueous sodium hydroxide (50 TIL), once with brine (50 mL), dried over Na 2
SO
4 and concentrated under vacuum. The crude solid was purified by column chromatography MeOH in CH 2 C 12) to furnish 133 mg of the title compound as a brown solid.
'H NMR (400M-lz, DMSO-d 6 8 8.27 J =2.2 Hz, I1H), 8.17 J 2.6 Hz, I 7.26 (dd, J 2.3, 1.9 Hz, I 7.24 IRH), 6.64 I 5.38 2H1), 3.65 (s, 3H). MS in/z 329 (80, 330 (12, 331 (100, 332 (16, M+H), 333 (28, 334 M+H).
EXAMPLE This example illustrates thie preparation of 5 -(4-(2,4-dichlorobenzenesulfonainido)-5-bromo-2-methoxyphenoxy)-3-chloropyrndine (45.1).
WO 01/00579 WO 0100579PCTUSOO/181 78 5-(4-(2,4-dichlorobenzenessulfonamido)-5-bromo-2-methoxypheloxy)- 3 chioropyridine was prepared in 25% yield from 44.1 and 2,4-dichlorobenzenesulfonyl chloride using the method of Example 3.
'H NMR (400M~z, DMSO-d 6 8 10.4 IlH), 8.36 J 1.8 Hz, I 8.2 J 2.5 Hz, I 7.9 J 8.6 Hz, 11H), 7.9-7.65 (in, 111), 7.68 (bs, IlH), 7.59 (dd, J= 8.6, 2.2 Hz, I 7.45 I 7.42 (dd, J 2.4, 1.9 Hz, I 6.99 IlH), 3.65 3H).
MS m/z 537 (58, 538 (10, 539 (100, 540 (20, 541 542 (15, 543 (25, M+H).
EXAMPLE46 This example. illustrates the preparation of 5-(4-amino-5-bromo-2chlorophenoxy))-3-chloropyfidine (46.1).
NH
2 Br C1 46.1 5-(4-Aniino-5-bromo-2-chlorophenoxy)-3-chloropyfidifle was synthesized in a similar manner as described by Example 44 using 3-chloro-4-(3-chloro-5pyfidyloxy)ani line (15.1).
'H NMR (400MHz, DMSO-d 6 6 8.35 J 1.9 Hz, I 8.23 J Hz, I 7.48 I 7.41 (dd, J 2.4, 2.2 Hz, I 6.98 I1H), 5.62 2H). MS (El): m/z 333 (55, 334 (12, MI-H), 335 (90, 336 (12, 337 (40, 338
M+H).
EXAMPLE 147 This example illustrates the preparation of 5-(4-(2,4-dichlorobenzenesulfonamnido)-5-bromo-2-chlorophenoxy)-3-chloropyridine (47.1).
WO 01/00579 WO 0100579PCTUSOO/181 78 47.1 5-(4-(2,4-dichlorobenzenesulfonamido)-5-bromo-2-chloropheloxy)-3chloropyridine was prepared in 17% yield from 46.1 and 2,4-dichlorobenzenesulfonyl chloride using the method of Example 3.
'H NMR (400 MHz, DMSO-d 6 8 10.6 1H), 8.47 J 2.2 Hz, I H), 8.34 J 2.6 Hz, I 7.89 J 2.1 Hz, I 7.88 J 8.6 Hz, I 7.7 (dd, J 2.3, 2.2 Hz, I 7.6 (dd, J 8.5, 2.0 Hz, I1H), 7.5 5 I 7.47 I MS m/z 539 (40, 540 (10, 541 (100, 542 (20, 543 (80, 544 545 (35, 546 M-H).
EXAMPLE 48 This example i llustrates the preparation of 5 -(3-chloro-4-amnino-2-(Nethylcarboxamidophenoxy))-3 -chloropyridine (48.1) and 5-(5-chloro-4-amino-2-(Nethylcarboxamnidophenoxy))-3-chloropyfldifle (48.2).
NH2
NH
2 Br N t Br N t N 0 C
N'
48.1 48.2 To a 0. 1 M solution of 5-(4-amino- -(N-ethylcarboxamidopheloxy))-3chloropyridine, (1 g, 3.6 mmol, prepared as described in U.S.S. N. 09/234,327) in AcOH was added bromine (194 .iL, 3.8 mmol) and the risulting solution was stirred for 2 days.
Most of the AcOH was azeotropically removed using hexanes and the resulting solution WO 01/00579 WO 0100579PCT/USOO/18178 was adjusted to ph 6 using a 4M aqueous solution of NaOH. The aqueous layer was extracted three times with EtOAc (50 mL) and the combined organic layers were washed twice with an aqueous brine solution (100 mL), dried over Na 2
SO
4 and concentrated under vacuum. The crude solid was purified by chromatography (50-100% EtOAc in hexanes) to separate the products 48.1 and 48.2 from the starting materials and dibrominated materials. The desired products were then rechroinatographed (1-3% MeOH in CH 2
CI
2 to furnish 478 mg of 48.1 and 198 mg of 48.2 as white solids.
48.1: 1 H NMR (400M1-Iz, DM5O-d 6 8 8.37 J =5.2 Hz, I 8.3 (bs, 1 8.24 J =2.2 Hz, 1KH), 7.3 8 (in, I1H), 6.94 J 8.8 Hz, IlH), 6.84 J 8.8 Hz, 111), 3.1 (pentet, J 7.0 Hz, 2H), 0.91 J 7.1 Hz, 3H). MIS m/z 370 (80, M H), 371 (15, Mi-H), 372 (100, 373 (18, 374 (25, M+H).
48.2: 1H NMR (400MHz, DMSO-d 6 8 8.3 J 1.75 Hz, I1H), 8.23 J =5.4 Hz, 1KH), 8.2 J 2.0 Hz, IlH), 7.34-7.28 (in, 2H), 6.99 J 1.6 Hz, I1H), 3.08 (pentet, J 7.2 Hz, 2H), 0.88 J 7.3 Hz, 3H). MS rn/z 370 (80, 371 372 (100, 373 (18, 374 (25, M+H).
EXAMPLE 49 This example illustrates the preparation of 5-(5-bromo-4-(2,4-dichloro-5methylbenzenesulfonamido)-2-(N-ethylcarboxamido)phenoxy)-3-chloropyridine (49.1).
Cl
CH
3 CONHEt Cl
N
49.1 The title compound was prepared in 67% yield from 48.1 and 2,4chloride using the method of Example 3.
'HNMR (400MHz, DMSO-d 6 8 10.41 i1-1), 8.4 8 J =2.1 Hz, I M, 8.35 J 5.4 Hz, 1H), 8.31 J1 2.5 Hz, lH), 7.85 (bs, 2H), 7.6 (dd, J 2.3, 2.2 Hz, 1H), 7.41 1K), 7.39 1H), 3.14 (pentet, J 7.2 Hz, 2H), 2.34 3H), 0.94 J 7.2 WO 01/00579 WO 0100579PCTIUSOO/181 78 Hz, 3M. MS m/z 597 596 (25, 595 (20, 594 (70, 593 592 (100, 591 (12, 590 (50, M-H).
EXAMPLE This example illustrates the preparation of 5-(5-bromo-4-(2.4dichlorobenzenesulfonamido)-2-(N-ethylcarboxamido)phenoxy)-3 -chloropyridine (50.1).
C1
HN
Br CONHEt
C
C' N' 50.1 The title compound was prepared in 28% yield from 48..1 and 2,4dichloro-benzenesulfonyl chloride using the method of Example 3.
'H NMR (400MIHz, DMSO04 6 8 10.5 IlH), 8.44 J 2.1 Hz, I1H), 8.34 J =5.6 Hz, 1H), 8.31 J 2.3 Hz, 1H), 7.9 J 2.0 Hz, IH), 7.85 J 8.6 Hz, I1H), 7.62 (dd, J 2.4, 2.1 Hz, IlH), 7.59 (dd, J 8.6, 2.2 Hz, I 7.41 IlH), 7.3 8 (s,1 3.14 (pentet, J 7.0 Hz, 2H), 0.94 J 7.3 Hz, 3H). MS m/z 585 (8, 584 (25, 583 (18, 5 82 (70, 581 (25, 580 (100, M-Hf), 579 (12, 578 (50, M+H).
EXAMPLE 51 This example illustrates the preparation of 5-(3-bromo-4-(2,4-dichloro-5methylbenzenesul fonamido)-2-(N-ethylcarboxamido)phenoxy)-3-chloropyridifle (51.1).
WO 01100579 WO 0100579PCTIUSOOII8178 The title compound was prepared in 37% yield from 48.2 and 2,4chloride using the method of Example 3.
'H NMvR (400MHz, DMSO-d 6 8 10.39 IlH), 8.5 5 I 8.42 I H), 8.31 I 7.89 I 7.88 IlH), 7.6 (dd, IlH), 7.12 I 7.02 I 3.14 (pentet, 2H), 2.35 3H), 0.94 MS m/z 599 598 (25, 597 (18, 596 (70, 595 (25, 594 (100, 593 (12, 592 EXAMPLE 52 This example illustrates the synthesis of 5-(5-bromo-4-chlorosulfonyl-2methoxyphenoxy)-3-chloropyridine (52.1).
Nil 2 SOPC Br Br OMe OMe 44.1 Compound 44.1 (1.20 g, 3.66 mmol) was converted to the title compound using the general procedure of R. V. Hoffmnan (Org. Syn. Coil. Vol., VII, 508-51 to provide 1.26 g of 52.1 as a clear oil which was carried on without purification. MS ESI in/c: 412.0(M+H).
WO 01/00579 WO 0100579PCT[USOO/18178 EXAMPLE 53 This example illustrates the preparation of 53.1.
53.1 4-Chloroaniline (73 mg, 0.57 mmol, Aldrich Chemical 4-chlorosulfonyl-2-methoxyphenoxy)-3-chloropyridine (236 mg, 0.57 mmol), pyridine mg, 0.57 mmnol), catalytic DMAP, and 2 mL of methylene chloride were combined using the general method of Example 35. The title compound was obtained (245 mg, as a white solid.
'H NMR (400MHz) (d 6 -DMSO) 8 10.80 (1 H, 8.43 (1 H, d, J=2.0 Hz); 8.30 (1 H, d, J=2.4 Hz); 7.74 (1 H, 7.64 (IH, dd, J=4.4 Hz, 2.2 Hz); 7.52 (1 H, 7.31 (2H, dd, J=8.8 Hz, 2.1 Hz); 7.14 (1IH, dd, J=8.8 Hz, 2.1 Hz); 3.83 (3H, MS ESI mile.
435.0 (M H).
WO 01/00579 WO 0100579PCTUSOO/18178 EXAMPLE 54 This example illustrates the preparation of 54.1.
1 S0 2 C1 Br. 'S Br CI O~e N CI 0 52.1 54.1 In a manner similar to that described in Example 53, 4-iodoaniline (83 rng, 0.38 mniol), 5-(5-bromo-4-chlorosulfonyl-2-methoxyphenoxy)-3-chloropyridine (155 mg, 0.38 mmol), pyridine (30 mg, 0.38 mniol), catalytic DMAP, and 2 mL of methylene chloride were combined and stirred. After workup, the title compound was obtained (162 mg, 73%) as a white solid.
I'H NMR (400MHz) (d 6 -DMSO) 8 10.80 (1IH, 8.43 (lH, d, J=2.0 Hz); 8.31 (1 H, d, J=2.4 Hz); 7.75 (1 H, 7.64 (1 H, dd, J=4.4 Hz, 2.2 Hz); 7.58 (2H, 7.51 (IH, s) 6.95 (1IH, dd, J=8.6 Hz, 2.2 Hz); 3.84 (3H, MIS ESI mle: 592.8 (M H).
EXAMPLE This example illustrates the preparation of 55.1.
WO 01/00579 PCT/US00/18178 In a manner similar to that described in Example 53, 4-acetylaniline (69 mg, 0.51 mmol), 5-(5-bromo-4-chlorosulfonyl-2-methoxyphenoxy)-3-chloropyridine (210 mg, 0.51 mmol), pyridine (40 mg, 0.51 mmol), catalytic DMAP, and 2 mL of methylene chloride were combined and stirred. After workup, the title compound was obtained (192 mg, 74%) as a white solid.
'H NMR (400MHz) (d-DMSO) 8 10.80 (1H, 8.43 (1H, d, J=2.0 Hz); 8.31 (1H, d, J=2.4 Hz); 7.75 (1H, 7.64 (1H, dd, J=4.4 Hz, 2.2 Hz); 7.58 7.51 (1H, s) 6.95 (1H, dd, J=8.6 Hz, 2.2 Hz); 3.84 (3H, MS ESI in/e: 509.0 (M H).
EXAMPLE 56 This example illustrates the preparation of 3-chloro-4-(2naphthylxoy)nitrobenzene (56.1).
Cl 56.1 To a 250 mL flask, were added 3-chloro-4-fluoro-nitrobenzene g, 28 mmol), 2-naphtol (Aldrich)(4.Sg, 31 mmol), Cs 2
CO
3 (Aldrich)(9.7g, 30 mmol) and DME (80 mL). The mixture was heated at 100 OC overnight. After removal of DMF under vacuum, the mixture was poured into water and extracted with dichloromethane. The organic solution was then washed with brine, dried over magnesium sulfate. After filtration, the filtrate was concentrated under vacuum to give a crude product, which was then chromatographed with eluent (30% dichloromethane hexanes) to give the title compound (6.8 g, 24 mmol, 86%).
EXAMPLE 57 This example illustrates the preparation of compounds 57.1, 57.2, 57.3 and 57.4.
Compound 56.1 was reduced to the corresponding aniline derivative (57.1) using the procedure of Example 2, and converted to the compounds in Table 8 using commercially available substituted benzenesulfonyl chlorides and/or using the intermediates and methods described in the examples above.
WO 01/00579 WO 0100579PCTUSOO/181 78 Table 8 Rd Rc N Rb 0 0
R
Ra Rb Rc Rd m/e 57.2 Cl H Cl H 476 57.3 Cl H I H 534 57.4 H H OCH 3 H 438 EXAMPLE 58 This illustrates the synthesis of 3-chloro-(2,4-dichlorobenzenesulfonainido)benzene (58.1).
1 Cl
NH
2
NH
58.1 The title compound was prepared using the method described in Example 3, starting with 800 mg (6.29 mmol) of 3-chloroani line, 1.53 g (6.29 mmol) of 2,4dichiorosulfonyichloride, 497 mg (6.29 mmol) of pyridine, catalytic DMAP, and 10 mL of methylene chloride. The title compound was obtained as a white foam (928 mg, 44%).
MS ESI mle: 334.0 (M ED.
EXAMPLE 59 This example illustrates the synthesis of compound 59.1.
WO 01/00579 PCT/US00/18178 58.1 59.1 A round-bottomed flask was charged with 330 mg (0.99 mmol) of 3chloro-(2,4-dichlorobenzenesulfonamido)benzene 397 mg (2.97 mmol, Aldrich Chemical Co.) of anhydrous aluminum trichloride, and 2 mL of dry dichloroethane. Then 210 mg (1.19 mmol, Aldrich Chemical Co.) of 3,5-difluorobenzoyl chloride was added dropwise and the deep red solution was allowed to stir at room temperature overnight.
The reaction was then diluted with 30 mL of methylene chloride, washed consecutively with 2N HCI and brine, dried over MgSO 4 and concentrated to a dark oil. This was further purified by silica gel flash chromatography (eluting with 1:24 ethyl acetate:methylene chloride). The resulting clear glaze was recrystallized from ether/hexanes to yield 273 mg of a white solid.
'H NMR (400MHz) (d 6 -DMSO) 8 8.15 (1H, d, J=8.5 Hz); 7.91 (1H, d, J=2.1 Hz); 7.68 (1H, dd, J=8.6 Hz, 2.1 Hz); 7.63 (1H, t, J=8.6 Hz); 7.46 (1H, d, J=8.4 Hz); 7.31 (2H, dd, J=7.8 Hz, 2.1 Hz); 7.23 (1H, d, J=1.9 Hz); 7.17 (1H, dd, J=8.4 Hz, 2.2 Hz). MS ESI m/e: 473.9 (M H).
WO 01/00579 WO 0100579PCTUSOO/181 78 EXAMPLE This illustrates the synthesis of compound 60.1.
CI
CI
CI
o s CI
NH
CII
CI
58.1 60.1 The title compound was prepared using the method of Example 59, starting with 286 mg (0.85 mmol) of 3-chloro-(2,4-dichlorobenzenesulfonamnido)benzene 341 mg (1.02 mniol) of anhydrous aluminum trichloride, 214 mg (1.02 mmol, Aldrich Chemical Co.) of 3,5-dichlorobenzoyl chloride, and 2 mL of dry dichioroethane.
The title compound was obtained as a white solid (139 mg, 3 'H NMR (400MHz) (d 6 -DMSO) 8 11.49 (1H, s) 8.15 (11-H, d, 1=8.6 Hz); 7.97 (1lH, d, J=3.8 Hz); 7.91 (1 H, d, J=2.1 Hz 7.69 dd, J=8.5 Hz, 2.0 Hz); 7.58 (2H, d, J=1.9 7.47 (1IH, d, 1 =8.4 Hz); 7.24 (1H, d,J=2.0 Hz); 7.17 (1IH, dd, J=8.4 Hz, 2.1 Hz). NIS EST mle: 505.9 (M H).
I EXAMPLE 61 This illustrates the synthesis of compound 61.1.
WO 01/00579 WOOI/0579PCTIUSOO/18178 59.1 61.1 Biaryl ketone 59.1 (103 mg, 0.22 mimol) was reduced to the methylene compound 61.1 according to the procedure of West, et. al., Org. Chem., 38(15):2675-2681 (1973).
The title compound was obtained as a white solid (86 mg, 86%).
'H NMR (400MHz) (d 6 -DMSO) 8 10.96 (IH, s) 8.05 (IH, d, J=8.6 Hz); 7.87 (IH, d, J=2.0 Hz); 7.63 (1H, dd, J=8.5 Hz, 2.1 Hz); 7.23 (1H, d, J=8.5 Hz); 7.14 (IH, d, J=2.2 Hz); 7.02 (2H, in); 7.17 (2H, in). MIS ESI mle: 460.0 (M H).
EXAMPLE 62 This example illustrates the preparation of 2-chloro-4-(3-chloro-5pyridyloxy)-nitrobenzene 62.1.
WO 01/00579 WO 0100579PCT/USOO/18 178 5-Chloro-3-pyridinol (5 g, Aldrich) and 2,4-dichloronitrobenzene (7.4 g, Aldrich) were combined as described in Example 1. The title compound was isolated as the minor product using gravity chromatography on silica elutinig with 10% ethyl acetate/ hexanes.
'H NMR (400 MHz) (DMSO-d 6 5 8.53 I 8.4 I 8.0 .1=8.9 Hz, 1IH); 7.44 J=1.9 Hz, 11H); 7.26 1=1.5 Hz, 1IH); 7.14 1 =2.7 Hz, 111); 6.99 (dd, 1 2.6 Hz, IlH) 1. 6 (impurity).
EXAMPLE 63 This example illustrates the preparation of 2-chloro-4-(3-chloro-5pyridyloxy)-aniline 63.1.
NH
2 CI 0 1:N 63.1 Compound 62.1 was reduced using the method of Example 2 to provide the title compound as a yellow solid.
NMR (400 MHz) (DMSO) 8 8.33 J-2.1 Hz, 111); 8.25 (d,J=2.4 Hz, 1IH); 7.41 J=2.2 Hz, 1IH); 7.12 J=2.6 Hz, I 6.91 (dd, J=2.6, 8.8 Hz, IH); 6.84 J=8.8 Hz, 111); 5.35 2H).
WO 01/00579 PCT/US00/18178 EXAMPLE 64 This example illustrates the preparation of 64.1.
CI CI 0 NH Clio CI 0
N
64.1 Compound 63.1 and 2,4-dichlorobenzenesulfonyl chloride were combined with pyridine and DMAP using the method described in Example 3. The crude product was purified by flash chromatography on silica eluting with dichloromethane. The resulting product was then triturated in diethyl ether/hexanes to furnish the title compound as a white solid. MS ESI m/e: 461 EXAMPLE This example illustrates the preparation of 65.1.
Cl 0 NH
K-
CCll
N
65.1 Compound 63.1 and 3,4-dichlorobenzenesulfonyl chloride were combined with pyridine and DMAP using the method described in Example 3. The crude product was purified by flash chromatography on silica eluting with 5% ethyl acetate/ WO 01/00579 PCT/US00/18178 dichloromethane. The resulting product was then triturated in hexanes to furnish the title compound as a white solid. MS ESI m/e: 461 EXAMPLE 66 This example illustrates the preparation of 66.1.
66.1 Compound 63.1 and 4-iodobenzenesulfonyl chloride were combined with pyridine and DMAP using the method described in Example 3. The crude product was purified by flash chromatography on silica eluting with dichloroinethane. The resulting product was then triturated in hexanes to furnish the title compound as a white solid. MS ESI m/e: 519 EXAMPLE 67 This example illustrates the preparation of 67.1.
67.1 Compound 63.1 and 2-chloro-4-trifluoroinethylbenzenesulfonyl chloride were combined with pyridine and DMAP using the method described in Example 3. The WO 01/00579 PCT/US00/18178 crude product was purified by flash chromatography on silica eluting with 5% ethyl acetate dichloroinethane. The resulting product was then triturated in hexanes to furnish the title compound as a white solid. MS ESI m/e: 495 EXAMPLE 68 This example illustrates the preparation of 2-chloro-4-(3pyridyloxy)nitrobenzene (68.1).
NO
2
CI
0 68.1 2,4-Dichloronitrobenzene (10.2 g, Aldrich) and 3-hydroxypyridine (5 g, Aldrich) were combined using the method of Example 1, to provide the 0.82 g of the title compound as a yellow solid.
'H NMR (400 MHz) (CDCI 3 5 8.58 1H); 8.52 1H); 8.0 Hz, 1H); 7.44 2H); 7.10 J=2.6 Hz, 1 H) 6.96 (dd, J=9.0, 6.65 Hz).
EXAMPLE 69 This example illustrates the preparation of 2-chloro-4-(3pyridyloxy)aniline.
NH
2
CI
Compound 68.1 was reduced using the method of Example 2 to provide the title compound as a brown oil, which was used without further purification.
'H NMR (400 MHz) (DMSO) 8 8.29-8.26 2H); 7.35 (dd, J=4.6, 8.4 Hz, 1H); 7.29-7.26 1H); 7.04 J=2.0 Hz, IH); 6.85-6.84 2H); 5.29 2H).
WO 01/00579 PCT/US00/18178 EXAMPLE This example illustrates the preparation of 70.1.
s o o 'NH 70.1 Compound 69.1 and 2,4-dichlorobenzenesulfonyl chloride were combined with pyridine and DMAP using the method described in Example 3. The crude product was purified by flash chromatography on silica cluting with 5% ethyl acetate/ dichloromethane. The resulting product was then triturated in diethyl ether to furnish the title compound as a white solid. MS ESI m/e: 429 EXAMPLE 71 This example illustrates the preparation of 71.1.
O NH
CI
K"-
N
71.1 Compound 69.1 and 4-iodobenzenesulfonyl chloride were combined with pyridine and DMAP using the method described in Example 3. The crude product was purified using flash chromatography on silica eluting with 5-20% ethyl acetate/ WO 01/00579 PCT/US00/18178 dichloromethane. The resulting product was then triturated in diethyl ether to furnish the title compound as a white solid. MS ESI m/e: 485 EXAMPLE 72 This example illustrates the preparation of 72.1.
NH
2 Cl'C Cl 72.1 To a solution of3,4-dichlorothiophenol (0.87 mL) and 4-fluoro-3chloronitrobenzene (1.2 g) in THF (12 mL) was added a solution of potassium t-butoxide in THF (1 M, 3.7 mL). Ethanol was added to form a precipitate and the mixture was heated to dissolve the solid. The mixture was then cooled to ambient temperature and water was added. The resulting solids were colledted by filtration and washed with water.
The product was dissolved in methylene chloride, dried over magnesium sulfate, filtered and concentrated to provide a yellow nitro intermediate (2.08 g).
SnCl2 hexahydrate (7 g) was added to a solution of the intermediate nitro compound in ethyl acetate (40 mL) at 85 0 C. After 12 hr, the reaction was treated with 420 mL of 0.5 N NaOH solution and diluted with EtOAc (100 mL). The milky suspension was filtered through Celite and rinsed with additional EtOAc. The layers were separated and the water layer was extracted with additional EtOAc. The combined organic portions were dried over MgSO 4 filtered and concentrated under vacuum to provide the aniline derivative 72.1, which was used without purification.
The compounds provided in Table 9 were prepared using 72.1 and commercially available substituted benzenesulfonyl chlorides and/or using the intermediates and methods described in the examples above.
WO 01/00579 WO 0100579PCTIUSOO/18178 Table 9 Rd CI CIRc 4 Rb 0 Ra
CI
Ra Rb Rc Rd mn/e (M-H) 72.2 H Cl CI H 510 72.3 Cl H Cl H 510 72.4 H H I H 568 Compound 72.3 was converted to the corresponding biaryl sulfoxide (72.5, nile 526) and biaryl sulfone (72.6, ni/e 542) using an oxone procedure (see, for example, Trost, et al., Tetrahedron Lett., 22:1287 (1981) and Webb, Tetrahedron Lelt., 35:3457- 3460 (1994)). Similarly, compound 72.2 was converted to the biaryl sulfoxide (72.7, nil/e 526) using a routine oxidation with mCPBA.
EXAMPLE 73 This example illustrates the preparation of 73.4 through 73.9.
ci N N >c 73.1 73.2 s l_ _N S C l 73.4 73.3 2,3 dichloronitrobenzcne (19.04g) was suspended in 40% Na 2
CS
3 Solution in water (66 ml) with 5 nil of ethanol and heated at 130*C bath temperature for 3 days.
After cooling, the residue was diluted in water and acidified with 5N HCI (caution: WO 01/00579 PCT/US00/18178 foaming gas evolution). The tan solids were collected by filtration, rinsed with water and dried under vacuum to give 19.9g of an intermediate complex The crude 73.1 (6.03 g) was added to neat sulfuryl chloride (20 ml) cautiously over about 5 minutes. The mixture was then heated at 500 C. The character of the solid changed but did not dissolve. The reaction was quenched by pouring onto ice. The ice mixture was stirred until the initial heavy dark oil solidified. The solids were collected by filtration, dissolved in ethyl ether and washed with water. The product was purified by flash chromatography using hexane, then 20% methylene chloride/hexane to afford 3.2 g of a 2,7dichlorobenzothiazole (73.2) as a low melting solid.
'H NMR (CDCI 3 8 7.823 J=8.4 Hz), 7.417 J=8.4 Hz), 7.371 (d, J=8.4 Hz). Anal. calc: 41.20% C, 1.48% H, 6.86 N; found: 41.06 1.46% H, 6.75% N 3-Chloro-4-mercapto nitrobenzene (prepared by the method of Price and Stacy Amer. Chem. Soc. 68, 498-500 (1946)) (1.33 g) and 2,7dichlorobenzothiazole (73.2) (1.43g) were dissolved in ethanol (20 ml) with heating.
Pyridine (1.1g, 2 eq) was added. After a solid formed, additional ethanol (20 ml) was added and the mixture maintained at 500 C overnight. The solid was collected by filtration and rinsed with water. The solids were dried as a solution in methylene chloride and concentrated to afford the nitro compound 73.3 (2.22g) as an off-white solid. (mp 210-212 0
C)
'H NMR (DMSO) 8 8.544 J=2.4 Hz, 1H), 8.273 (dd, J=8.8, 2.5 Hz, 1 H) 8.081 J=8.6 Hz, 1H) 7.961 (dd, J=6.3, 2.4 Hz, 1H), 7.60 m, 2H).
Using the method of example 32, the nitro derivative 73.3 was converted to the corresponding aniline Flash chromatography gave a white solid. (mp 165- 167 0
C).
'H NMR (DMSO) 6 7.775 J=8.4 Hz, IH), 7.606 J=8.0 Hz, 1H), 7.367 J=8.0 Hz, 1H), 7.265 J=8.0 Hz, 1H), 6.931 J=2.0 Hz, 1H), 6.672 (dd, J=8.4, 2.4 Hz, 1H), 4.15 (br s, 2H). ESI MS 327 Anal. calcd. 47.71% C, 2.46% H, 8.56 N; found: 47.93 2.48 H, 8.47% N Reaction of 2-chloro-4-trifluoromethylbenzene sulfonyl chloride with aniline 73.4 according to the method of Example 3 gave sulfonamide 73.5 (see Table H NMR (DMSO) 8 11.712 (br s, 1H) 8.377 J=8.4 Hz, 1H), 8.187 (d, J=2 Hz, 1H), 7.995 (dd, J=8.4, 1.2 Hz, 1H), 7.880 J=8.4 Hz, 1H), 7.822 (dd, 7.2, Hz, 1H), 7.509 J=8.0 Hz, 1H), 7.474 (dd, J=7.6, 2.0 Hz, 1H), 7.443 J=2.4 Hz, 1H), WO 01/00579 WO 0100579PCT/USOO/18178 7.256 (dd, J=8.8, 2.4 Hz, I MIS 569; MS 567. Anal. calcd. 42.15% C, 1.77% H, 4.92 N; found: 42.30 1.76 H, 4.94% N.
The additional compounds provide in Table 10 were prepared similarly using aniline 73.4 and the corresponding sulfonyl chlorides using the method of Example 3.
Table ,p Ra
HN
5 ~Rb Rd Cl.
Ra Rb Rc Rd nile (M-H) 73.5 Cl H CF 3 H 567 73.6 H Cl Cl H 533 73.7 Cl H Cl H 533 73.8 H H I H 591 73.9 Cl H Cl Me 547 EXAMPLE 74 The following benzenesul fonyl chlorides were prepared by the procedure of R. V. Hoff-man (Org. Syn. Coll. Vol. VII, 508-511) from the corresponding commercially available anilines and used to make the indicated examples.
74a 2-chloro-4-t-butylbenzenesulfonyl chloride, yield 34% for examples 76.8 and 79.9 'H NMR (CDC1 3 8 8.06 (1 H, d, J =8.4 Hz), 7.62 (1IH, 7.48 (1IH, d, J 8.4 Hz), 1.3 7 (9H, m.p. 68.8 'C.
74b 2-trifluoromethyl-4-chlorobenzenesulfonyI chloride, yield 76% as a solid.
for examples 176 and 347 'HNMR (CDC1 3 8 8.325 J=8.4 Hz, IlH), 7.966 (br s, I 7.829 (br d, J=8.4 Hz, I1H). m.p. 37.0 0
C.
74c 2-chloro-4-methylbenzenesulfonyl chloride, yield 47% as an olI.
WO 01/00579 WO 0100579PCT/USOO/18 178 for examples 76.9, 79.8 and 3 51.
'11NMR (CDCI,) 8 8.02 (1lH, d, 1= 8.8 Hz), 7.46 (1 H, 7.28 (1LH, d, J 8.8 Hz), 2.47 (3H, s) EXAMPLE This illustrates the synthesis of compound 75.1 R=N02
O>N-H
By the method of example 201, 2-chlorobenzoxazole (5 g) and 2-chloro-4nitroaniline (6.1 g) were coupled to provide nitro compound 75.1 (2.6g) as a yellow solid.
1 H NMR (d6-acetone) 8 9.514 I 9.01 J=9 Hiz, I 8.4 I H), 8.37 (cid, J=8.4, 2 Hz, 1H), 7.58 (ci, J=8.4 Hz, 1H), 7.52 J=8 Hz, 1H), 7.34 J=7.6 Hz, I 7.28 1= 7.6 Hz, I MS 288; (2M-2H+Na) 599.
Reduction by the method of example 32 gave the aniline 75 as a grey solid.
'H NMR (d6-acetone) 8 8.45 (hr s, 1H), 7.796 J=8.4 Hz, Ili), 7.353 (d, J=7.6 Hz, I1H), 7.3 35 J=7.6 Hz, I 7.191 J=7.6 Hz, I 7.088 J=8 Hz, I H), 6.846 J=2.4 Hz, I1H), 6.673 (dd, J=8.8, 2.4 Hz, I 4.9 12 (br s. 2H). MS (M+H) 260.1 EXAMPLE 76 This example illustrates the preparation of 76.2 and sulfonamides derived ftrm it.
I C
I
'N -S Cl
N
76.1 76.2 WO 01/00579 WO 0100579PCT/USOO/18 178 3,5-dichloro-4-mercapto nitrobenzene (prepared by the method of Price and Stacy, J Amer. Chem. Soc. 68, 498-500 (1946)) (0.65g) and 2,7dichlorobenzothiazole (73.2) were combined by the method of Example 73, to afford the nitro derivative (76.1) as a yellow solid (0.95g).
'H NMR (DMSO) 6 8.587 2H), 7.852 (in, IH), 7.54 (m 2H). Anal.
calcd: 39.87 C, 1.29 H, 7.15 N; found 39.62 1.21 H, 7.00 N.
Reduction of the nitro derivative (76.1) (0.92 g) by the method of example 32 gave the aniline (76.2) (0.76g) after flash chromatography.
'H NMR (DMSO) 5 7.822 J=8 Hz, IH) 7.509 J=8Hz, IH), 7.465 (d, J=6.8 Hz, IH) 6.882 2H), 6.529 (br s, 2H). MS 361. Anal. calcd: 43.177 C, 1.95 H, 7.74 N; found: 43. 10 2.05 H, 7.65 N.
Reaction of the aniline 76.2 according to the method of example 3 with various sulfonyl chlorides gave the sulfonamides of Table 11.
Table 11 0 ,Ra HN S ~Rb C" ~Rc I >S Cl Ra Rb Rc Rd Wie (M-H) 76.3 Cl H CF 3 H 601 76.4 H H t-Bu H 76.5 Cl H Cl H 567 76.6 Cl H H H 535 (M+H) 76.7 H H H H 76.8 CI H t-Bu H 589 76.9 C1 H Me H 547 Example 76.3 'H NMR (DMSO) 8 11.96 (br s, IlH) 8.417 J=8.4 Hz, I 8.209 (s, 2H), 8.013 J=8 Hz, 1H), 7.819 J=6.8 Hz, IH), 7.5 14 (in, 2 7.411 2H). Anal.
WO 01/00579 WO 0100579PCT/USOO/18178 calcd: 39.75 C, 1.50 H, 4.64 N; found: 39.48 1.73 H, 4.37 N. MS (M- H) 601.
Example 76.4 Anal. calcd. for M+0.5 H 2 0: 48.72 C, 3.56 H, 4.94 N; found: 48.80 3.68 H, 4.78 N.
Example 76.5 'H NMR (DMSO) 8 11.83 (br s, 1H) 8.212 J=8.4 Hz, 11H), 7.962 (d, J=2H, 1 7.827 (dd, J=6.8, 2 Hz, I 7.723 (dd, J=8.5, 2.1 Hz, I 7.518 J=7.9 Hz, I 7.492 (dd, J=7.8, 2.0 Hz, I 7.3 85 2H). MS 5 67. nip 216 0 C. Anal.
calcd: 39.98% C, 1.59 H, 4.91 N; found: 39.81 1.59 H, 4.85 N.
Example 76.6 'H NMR (DMSO) 8 11.72 (br s, I1H), 8.222 J=8 Hz, I 7.822 (dd, J=7.2, 2.0 Hz, I1H), 7.730 J=4 Hz, 2H), 7.636 (in, I 7.5 16 J=8 Hz, I 7.490 J=8 Hz, I 7.379 2H1). MS 535.
Example 76.7 'H NMR (DMSO) 8 11.38 (br s, 111), 8.906 J=8 Hz, 2H), 7.827 (dd, J=7.2, 2.0 Hz, I 7.721 J1=6.8 Hz, 1 7.655 J=8 Hz, 2H), 7.5 19 J=8 Hz, IlH), 7.493 J=6.8 Hz, I1H), 7.4 12 2H).
Example 76.8 'H NMR (DMSO) 8 11.70 (1 H, 8.13 (1IH, d, 7.80-7.87 (11-1,i) 7.63-7.71 (2H, in), 7.48-7.55 (2H, in), 7.39 (2H1, MIS 589. mp 131.3 0 C. Anal.
caled: C 46.63, H 3.06, N 4.73; found C 48.09, H 3.65, N 4.35 Example 76.9 'H NMIR (DMSO) 6 11.70 (1IH, 8.07-8.20 (1IH, in), 7.80-7.93 (1IH, in), 7.35-7.65 (6H4, in). MS 546.8. mip 220.9 DC.
EXAMPLE 77 This example illustrates the preparation of anilines 77.7, 77.8 and 77.9 WO 01/00579
H
3 1NH 2
I
PCT/US00/18178
H
3
H
3 -N 2YNH 2 -X Cl Cl 77.1' 77.2 X NH 2 77.3 X C1
NH
2
H
3 Y- I S x
S
77.7 X Y C 77.8 X CI, Y H 77.9 X=F,Y=H
NO
2
H
3 NY-/ I s X Cl 77.4 =Y=Cl 77.5 X=C, Y=H 77.6 X F, Y H In analogy to the procedures of Weinstock et. al Med. Chem. 30:1166- 1176 (1987), cone. sulfuric acid (8.74 g) was added slowly to a solution of 5-chloro-2methylaniline (25g) in chlorobenzene (120 mL) to form a thick slurry. Powdered NaSCN (18.6g) was added. The mixture was heated at 110 0 C for one hour then maintained at overnight. After dilution with hexane (300 mL), the solid was collected by filtration, washed with hot water and rinsed with ethyl ether to afford 15.65g of intermediate thiourea 77.1 which was used directly in the next step.
Preparation of2-amino-4-methyl- 7-chlorobenzothiazole (77.2).
Bromine (25.44g) was added to a suspension of 77.1 (15g) in chloroform (110 mL) maintained below +10°C. After the addition was complete, the reaction was allowed to warm to RT then heated at reflux for 30 minutes. After cooling, the orange solid was collected by filtration and suspended in acetone (100mL) which discharges the remaining color. Solids were collected by filtration and rinsed with ethyl ether to afford the HBr salt.
'H NMR (DMSO) 5 7.182 J=8 Hz, 1H), 7.137 J=8 Hz, 1H), 2.40 (s, 3H).
The salt was suspended in water at 95 0 C. The pH of the suspension was adjusted to pH 9 with 0.5 N NaOH. After cooling, the solids were collected by filtration, WO 01/00579 PCT/US00/18178 rinsed with water and dissolved in ethylether/methylene chloride. The organic layer was dried over magnesium sulfate. After concentration, 2-amino-4-methyl-7chlorobenzothiazole (77.2) (7.47g) was obtained as a white solid.
MS 199. Anal. calcd.: 48.36 C, 3.55 H, 14.10 N; found: 48.29 3.55 H, 14.01 N.
Preparation of 2-7-dichloro-4-methyl-benzothiazole (77.3) To a slurry of 2-amino-4-methyl-7-chlorobenzothiazole(77.2) (6.37g) in
H
3
PO
4 213 ml) in a 500 ml 3-necked flask with mechanical stirring and an internal temperature of< -10 0 C, was added dropwise a solution of NaNO 2 (6.87g) in water (11 ml). The mixture was warmed to 0° for 30 minutes and then recooled. The slurry was then slowly added to a cold 0 C) solution of CuSO4*5 H 2 0 (32 g) and NaCI (40g) in water (128 ml) with vigorous mechanical stirring. After the foaming subsides and warming to RT, the solids were collected by filtration and rinsed with water. The solids were dissolved in ether leaving some insoluble residue. The ether solution was washed with water, and sodium bicarbonate solution. After the organic layer was concentrated, the residue was purified by flash chromatography with 10% methylene chloride in hexane to afford 2-chloro-4-methyl-7-chlorobenzothiazole (77.3) (4.48g).
'H NMR (CDCI 3 6 7.288 J=8 Hz, 7.231 (dq, J=8. 0.8 Hz, IH), 2.651 J=0.8Hz, 3H). Anal. calcd.: 44.06 C, 2.31 H, 6.42% N; found: 44.16 %C, 2.34 H, 6.32 N.
Coupling of 77.3 (0.65 g) with 3,5-dichloro-4-mercapto nitrobenzene by the method of example 73 gave after flash chromatography the nitro derivative 77.4 (0.97g) as a yellow solid.
'H NMR (DMSO) 6 8.394 2H), 7.237 J=8 Hz, 1H), 7.209 J=8 Hz, 1H), 2.621 3H). MS 405 Coupling of 77.3 (0.7 g) with 3-chloro-4-mercapto nitrobenzene by the method of example 73 gave the nitro derivative 77.5 (1.02 g) as a yellow solid.
'H NMR (DMSO) 6 8.535 (br s, 1H), 8.261 (dd, J= 8.4, 2 Hz, 1H), 8.040 J=8.4 Hz, 1H), 7.496 J=8.4 Hz, IH), 7.419 J=8.4 Hz, 1H), 2.601 3H). MS M+H) 371. Anal. calcd.: 45.40 C, 2.18 H, 7.57 N; found: 45.25 2.23 H, 7.49 N.
WO 01/00579 PCT/US00/18178 Coupling of 77.3 (1.12 g) with 3-fluoro-4-mercapto nitrobenzene by the method of example 73 gave after flash chromatography the nitro derivative 77.6 (SY1904-2) (1.8 g) 'H NMR Reduction of 77.4 (0.96g) with tin dichloride by the method of example 32 gave the aniline (77.7) (0.84g) used directly in later reactions: 'H NMR (DMSO) 8 7.352 J=8 Hz, 1H), 7.322 J=8 Hz, 1H), 6.884 2H), 6.533 (br s, 2H), 2.565 3H).
Reduction of 77.5 (1.13 g) with tin dichloride by the method of example 32 gave the aniline (77.8) (1.04 g) used directly in later reactions: 'H NMR (DMSO) 5 7.543 J=8.4 Hz, 1H), 7.329 J=8 Hz, 1H), 7.301 J=8 Hz, 1H), 6.889 J=2 Hz, 1H), 6.663 (dd, J= 8.4, 2.4Hz, 1H), 6.231 (br s, 2H), 2.557 3H). MS 341. Anal. calcd. for M+0.25 H 2 0: 48.63 C, 3.06 H, 8.10 N; found: 48.67 3.06 H, 7.96 N.
Reduction of 77.6 (1.75 g) with tin dichloride by the method of example 32 gave after chromatography the aniline (77.9) (1.2 g) 'H NMR: 6 7.43 (lH, t, 7.30-7.37 (2H, 6.53-6.58 (2H, 6.28 (2H, s).
EXAMPLE 78 Treatment of the anilines 77.7, 77.8 or 77.9 by the method of example 3 with various sulfonyl chlorides gave the sulfonamides of Table 12.
Table 12 OO Ra HS X Rb H3 Y- "Rc S N Rd
S
X Y Ra Rb Re Rd m/e (M-H) 78.1 Cl Cl Cl H Cl H 581 78.2 Cl Cl Cl H CF3 H 615 78.3 Cl Cl Cl H Cl Me 595 78.4 Cl H Cl H CF 3 H 581 WO 01/00579 WO 0100579PCT/USOO/181 78 78.5 CI H CI H CI H 565 78.6 F H Cl H CF 3 H 565 78.7 F H Cl H Cl H 531 Example 78.1 'H NMR (DMS0) 8 11.813 (br s, 111), 8.208 J=8.8 Hz, 1H), 7.951 (d, J=2 Hz, 11H), 7.716 (dd, J=8.4, 2 Hz, 1H), 7.396 2H), 7.377 J=8.4 Hz, IH), 7.334 J=8 Hz, 1H), 2.5 16 3H). MIS 581. Anal. calcd.: for M+ H 2 0: 39.85 C, 2.17 H, 4.65 N; found: 40. 10 1.89 H, 4.57 N.
Example 78.2 'H NMR (DMSO) 8 11.975 (br s, I1H), 8.416 J=8.4 Hz, I1-1), 8.205 (br s, I 8.012 J=8 Hz, I1H), 7.423 2H), 7.376 J=8 Hz, Il-H), 7.3 32 J=8 Hz, 1H), 2.5 12 3H). MS 615. Anal. caled.: 40.79 C, 1.79 H, 4.53 N; found: 41.05 1.86 4.57 %N.
Example 78.3 'H NMR (DMS0) S 11.748 8.233 1H), 7.880 111I), 7.407 (s, 211), 7.370 J=8 HZ, 1H), 7.330 J=8 Hz, IH), 2.408 3H). MIS 595. Anal.
calcd.: 42.12 C, 2.19 H, 4.68 N; found: 41.84 2.23 H, 4.51 N.
Example 78.4 'H NMR (DMSO) 6 11.73 (IH, 8.38 (1 H, d, J= 8.3 Hz), 8.19 (1IH, s), 7.99 (1IH, d, J 8.3 Hz), 7.88 (IH, d, J 8.6 Hz), 7.45 (1 H, d, J= 2.3 Hz), 7.23-7.40 (3H, in). MIS 580.8 mp 189.0 0
C.
Example 78.5 'H NMR (DMSO) 6 11.57 (111, 8.17 (IH, d,J= 8.6 Hz), 7.92 (1H, d, J =2.1 Hz), 7.78 (1IH, d, J= 8.5 Hz), 7.69 (1IH, dd, J 2.1 Hz), 7.43 (1IH, d, J =2.3 Hz), 7.30-7.38 (2H, in), 7.25 (1H, dd,J= 8.6, 2.4 Hz). MS 546.9. mp 218.1 0
C.
WO 01/00579 PCT/US00/18178 Example 78.6 'H NMR: 8 8.04 (IH, d, 8.18 (LH, 7.99 (1H, d, 7.80 (1H, t, 7.30-7.40 (2H, 7.10-7.22 (2H, MS 565.0. mp 221.2 C. Anal.
calcd.: C 44.45, H 2.13, N 4.94; found C 44.01, H 2.18, N 4.67.
Example 78.7 'H NMR (DMSO) 8 11.60 (1H, 8.18 (1H, d, 7.91 (1H, d, 7.79 (1H, t, 7.69 (1H, dd, 8.6, 7.30-7.40 (2H, 7.10-7.20 (2H, MS (M- H) 530.9. mp 230.4 Anal. calcd.: C 44.99, H 2.27, N 5.25; found C 44.49, H 2.26, N 5.08.
EXAMPLk 79 This example illustrates the preparation of compounds 79.1 to 79.7.
To a solution of 5-chloro-2-mercaptobenzothiazole (Acros) KOH (630 mg) in water (8 mL) at 1000 C was added a solution of 3,4-dichloronitrobenzene (1.88g) in n-propanol (24 mL). The mixture was heated at reflux for 72 hrs. After cooling, the solids were collected by filtration and rinsed with water. The solids were dried under vacuum to afford the nitro derivative 79.1 (2.25 g) as a yellow solid used directly in the next step.
'H NMR (DMSO) 8 8.54 J=2.4 Hz, 1H), 8.26 (dd, J=8.6, 2.4 Hz, 1H), 8.123 J=8.6 Hzl, 1H), 8.08 J=1.9 Hz, 1H), 8.03 J=8.7 Hz, 1H), 7.533 (dd, J=8.6, 2.1).
Reduction of 79.1 (2.2 g) with tin dichloride by the method of example 32 gave after work-up the aniline (79.2) (1.2 g) which was used directly in later reactions.
'H NMR (DMSO) 6 7.94 J=8.4 Hz, 1H), 7.891 J=1.6 Hz, 1H), 7.537 J=8.4 Hz, 1H), 7.371 (dd, J=8.4, 2.1 Hz, 1H), 6.877 J=2.4 Hz, 1H), 6.651 (dd, J=8.4, 2.4 Hz, 1H), 6.203 2H). MS 327 Treatment of the aniline 79.2 by the method of example 3 with various sulfonyl chlorides gave the sulfonamides of Table 13.
WO 01/00579 WO 0100579PCTIUSOO/181 78 Table 13 q 0Ra
HN
5 X Rb Rc Cl P~ Rd CI Cl,
-S
Ra Rb Rc Rd rn/c (NI-H) 79.3 Cl H Cl Me 547 79.4 Cl H Cl H 533 (M+H) 79.5 CI H CF 3 H 567 79.6 H CI Cl H 533 79.7 Me H Cl Me 527 Example 79.3 'H NMR(DMSO) S 11.52 (1H, 8.20 (IH, 7.84-8.00 (4H, mn), 7.35- 7.43 in), 7.22 (1H, d, J= 8.5 Hz), 2.41 (3H, MS 546.8. mp 203.7 0
C.
Example 79.4 'H NMR(DMSO) 8 11.57 (IH, 8.18 (1 H, d, J= 8.5 Hz), 7.90-7.98 (2H, mn), 7.86 (IH, d, J= 8.5 Hz), 7.72 (lH, d, J= 8.7 Hz), 7.37-7.43 (2H, mn), 7.22(IH, d, J= 8.8 Hz). MS 532.8. mp 174.7 0
C.
Example 79.5 'H NMR(DMSO) 8 8.3 8 (1 H, d, 8.4 Hz), 8.21 (1IH, 8. 01 (1IH, d, J =8.2 Hz), 7.90-7.96 (2H, in), 7.86 (IH, d, J= 7.7 Hz), 7.42 (2H, 7.23 (11H, d, J= 8.6 Hz).
MS 566.9. mp 158.8 0
C.
Example 79.6 'H NMIR(DMSO) 8 11.25 (1lH, 8.06 (1IH, d, J= 1.5 Hz), 7.80-7.96 mn), 7.40-7.46 (2H, mn), 7.27-7.32 in). MS 532.8. mp 201.2 0
C.
WO 01/00579 WO 0100579PCT/USOO/18 178 Example 79.7 'H NMR(DMSQ) 8 11.30 (1IH, 8.00 (1IH, 7.90-7.98 (2H, in), 7.84 (IH, d,J= 8.6 Hz), 7.57 (i14, 7.35-7.44 (2H4, in), 7.18-7.23 (11-1, in,2.57 2.37 (3H1, mp 205.1 TC.
Table 14 H a Rb Rc CI Rd Cj
-S
Ra Rb Rc Rd inle (M-H) 79.3 CI H CI Me 547 79.4 Cl H CI H 533 (M+H) 79.5 Cl H CF 3 H 567 79.6 H Cl CI H 533 79.7 Me H Cl Me 527 79.8 Cl H Me 1-1 513 79.9 Cl H t-Bu H 555 Example 79.8 'H NMR (d 6 -DMSO) 8 11.43 (1IH, 8.08 (1 H, d, J 8.0 Hz), 7.90-8.00 (2H, mn), 7.85 (1IH, d, J= 8.5 Hz), 7.57 (1IH, 7.37-7.47 (3H, mn), 7.21 d,J= 8.4 Hz), 2.38 (3H, MS 512.9. mp 201.0 0 C. Anal. calcd.: C46.56, H 2.54, N 5.43; found C 46.93,1H 2.58, N 5.40.
Example 79.9 'H NMR (d 6 -DMSO) 8 11.44 (1IH, 8. 10 (INH, d, J =8.3 Hz), 7.90-7.97 (2H, in), 7.86 (1lH, d, J 8.6 Hz), 7.60-7.68 (214, in), 7.37-7.43 in), 7.23 (iNH, dd, J 2.4 Hz), 1.29 (9H4, MIS 554.9. nip 177.8 0 C. Anal. calcd.: C 49.5 1, H 3.43, N 5.02; found C 49.67, H 3.44, N 4.97.
WO 01/00579 PCT/US00/18178 EXAMPLE This illustrates the synthesis of compound 80.4.
NO
2
NO
2
H
3 C CH 3
H
3 C) CH 3 H Tf 80.1 2,6-dimethyl-4-nitro-phenol (4.93 g, 29.5 mmol) was suspended in anhydrous CH 2
CI
2 (30 mL). Hiinig's base (12.4 mL, 70 mmol) was added to give a homogeneous, dark red solution. The reaction mixture was cooled to -15 °C and triflic anhydride (10 g, 35 mmol) was slowly added. The very dark reaction mixture was stirred at -15 OC for 15 minutes, then poured into 3N HCI (100 mL). The layers were separated and the aqueous layer was extracted 1 x 150 mL CH 2 C1 2 The combined organic layers were washed 1 x 50 mL sat. brine, dried over MgSO 4 and concentrated to a dark red oil.
This oil was filtered through a 2 cm plug of silica gel (eluting with 3:1 hexanes:ethyl acetate) and concentrated to an orange oil which was diluted with 10 mL of hexanes and allowed to stand at room temperature until crystallization of the product took place. The crystals were collected and dried under vacuum. The mother liquor was concentrated, then diluted with 5 mL of CH 2
CI
2 and 25 mL of hexanes and again allowed to stand until crystallization was complete. The second crop was collected by filtration and dried under vacuum. Combined yield of the two crops was 7.87 g of triflate 80.1.
'H NMR (CDCI 3 8 8.03 2H); 2.50 6H).
NO
2
NHI
2
NO
2 I
I
H
3 CH
CH
3 H3C CH3
HSCH
3 C H3 OTf 245
CH
3
CH
3 80.1 80.2 80.3 5-methyl-2-mercaptobenzothiazole (1.45 g, 8 mmol) was suspended in anhydrous THF (3.5 mL). A solution of potassium tert-butoxide (7.35 mL, 1.0 N in THF) was added in one portion. The very thick precipitate of the mercaptobenzothiazole potassium salt was dissolved by addition ofDMF (1 mL). Triflate 80.1 (2 g, 6.7 mmol) WO 01/00579 PCT/US00/18178 was dissolved in DMF (1 mL) and added to the reaction mixture which was then heated to °C for 16 h. The reaction mixture was pouted into 100 mL DI water and extracted 2 x mL of ethyl acetate. The combined organic layers were washed with sat. brine, dried over MgSO 4 filtered, concentrated, and the residue purified by flash chromatography (silica gel, 19:1 to 4:1 hexanes:ethyl acetate). Fractions containing the desired product were concentrated and the residue recrystallized from hot hexanes:ethyl acetetate.
Filtration and drying provided the S-arylated compound 80.2 as bright yellow crystals (0.90 g).
'H NMR (CD 3 CN) 5 8.12 2H); 7.68 IH); 7.61 1H); 7.17 IH); 2.60 6H); 2.42 3H). MS 331.1 Reduction of 80.2 (0.88 g) by the method of Example 32 gave aniline 80.3 (0.4 g) as a solid.
'H NMR (CDC 3 8 7.723 1H), 7.598 1H), 7.122 J=8.4Hz, 1H), 6.706 2H), 5.304 (br, 2H), 2.399 3H), 2.338 6H) Sulfonylation of 80.3 (400 mg) by the method of example 3 gave 80.4 (Table 15)(0.36 g).
'H NMR (DMSO) 5 11.284 1H), 8.369 J=8.2Hz, 1H), 8.170 1H), 7.969 J=8.2 Hz, 1H), 7.676 J=8.2 Hz, 1H), 7.591 1H), 7.126 J=8.2Hz, 1H), 7.056 2H), 2.372 3H), 2.326 6H). MS 543 EXAMPLE 81 This illustrates the synthesis of compound 81.4.
NO
2
NO
2
H
3 C Cl H 3 C Cl H Tf 81.1 2-chloro-6-methyl-4-nitro-phenol (2.5 g, 13.3 mmol) was converted to triflate 81.1 according to the method given in Example 80. Triflate 81.1 was an oil and could not be recrystallized. 4.0 g oftriflate 81.1 was obtained.
'H NMR (CD 3 CN) 8 8.24 1H); 8.77 1H); 2.56 3H).
WO 01/00579 WO 0100579PCTIUSOO/18178 N0 2
NH
2 S
H
3 C C1 H 3 C1 T f 245' CHHC3I 81.1 81.2 81.3 5-methyl-2-mercaptobenzothiazole (1.36 g, 7.5 mmol) and tinflate 81.1 (2 g, 6.26 mmol) were reacted according to the procedure given in Example 80. S-arylated compound 81.2 was obtained as bright yellow crystals (1.2 This product contained a minor amount of a contaminant of unknown structure. This contaminant had no effect on subsequent reactions, nor was it found in subsequent products.
'H NMR (CDCN) 8 8.2 8 I 8.14 I1H); 7.67 I 7.5 6 1 H); 7.14 I 2.68 3H); 2.45 3H). MIS 35 1.
Reduction of 81.2 (0.88 g) by the method of Example 32 gave aniline 81.3 (0.4 g) as asolid.
'H NMR (DMS0) 8 7.740 J=8 Hz, 7.608 1H), 7.131 J=8 Hz, I 6.732 J=2.6 Hz, I 6.588 J=2.6 Hiz, I 6.048 2.403 3H), 2.334 3H); Sulfonylation of 81.3 by the method of example 3 gave 81.4 (see Table 'H1 NMR (DMSO) 8 11.610 I1-i), 8.398 J=8.4 Hz, ImH, 8.2 10 (s, 111), 8.005 J=8.4Hz, I1H), 7.730 J=8Hz I 7.621 IRH), 7.7.276 J=2.8Hz, 1 7.167 (in, 2H), 2.409 3H), 2.397 3H).
EXAMPLE 82 This illustrates the synthesis of compound 82.3.
WO 01/00579 WO 0100579PCTIUSOO/18178 Hs-<\IS 1 13 aC
NH
2
H
3 e CH 3 SyS
C'
82.2 80.1 82.1 5-chloro-2-mercaptabenzothiazole (202 mg, I mniol) and triflate 80.1 (270 mg, 0.9 mmol) were reacted according to the procedure given in Example 80. S-arylated compound 82.1 was obtained as a light yellow solid (203 mg).
'H NMR (ODC1 3 8 8.09 2H); 7.83 11H); 7.56 11H); 7.26 (dd, III); 2.63 3H1). MS (M+Hf) 35 Reduction of 82.1 (0.7 g) by the method of example 32 gave aniline 82.2 (0.62 g).
'H NMR (DMS0) 8 7.884 J=8.4 Hz, 1H), 7.846 J=2 Hz, 1H), 7.329 (dd, J=8.4, 2 Hz, IH), 6.495 2H), 5.669 2H), 2.283 3H). MS 321 Sulfonylation of 82.2 by the method of example 3 gave 82.3 (see Table 'H NMR (DMS0) 8 11.304 111), 8.377 J=8 Hz, IlH), 8.180 J=1.2 Hz, I1-1), 7.980 (br d, J=8.4, I1H), 7.874 J=2.4 Hz, I 7.866 J=8 Hz, IH), 7.365 (dd, J=8.4, 2 Hz, 1H), 7.068 (br s, 2H), 2.341 3H). MS 561 EXAMPLE 83 This illusttates the synthesis of compound 83.3.
NO
2 1' 3 C CI Tf +HS--\~Ir 81.1 8.183.1 83.2 WO 01/00579 WO 0106579PCT/USOO/18178 5-chloro-2-mercaptobenzothiazole (0.76 g, 3.75 mmnol) and triflate 81.1 g, 3.44 mimol) were reacted according to the procedure given in Example 80. Sarylated compound 83.1 was obtained as a light yellow solid (0.83 g).
'H NMR (CDCI 3 8 8.30 IHl); 8.17 1H); 7.85 IH); 7.61 I11); 7.30 1H); 2.71 3H). MS 371 Reduction of 83.1 (0.8 g) by the method of Example 32 gave aniline 83.2 (0.47 g).
'H NMR (DMS0) S 7.918 J=8.8 Hz, 1H), 7.874 J=2 Hz, 1H), 7.356 (dd, J=8.4, 2 Hz, 1H), 6.745 J=2.4 Hz, 6.600 J=2 Hz, 1H), 6.089 (br s, 2H), 2.336 3H). MS 341.
Sulfonylation of 83.2 by the method of example 3 gave 83.3 (see Table 'H NMR (DM50) 5 11.647 1H), 8.407 J=8.4 Hz, 1H), 8.2 13 (br s, I1H), 8.008 (br d, J=8.4, I1H), 7.910 J=8 Hz, I 7.90 IlH), 7.396 J=8.8 H, I H), 7.290 (br s, 1H), 7.188 (br s, 1H), 2.416 3H). MS 581.
Table 80.4 81.4 82.3 83.3 84.3 W/e (M-H) 543 (M+H) 561 581 547 EXAMPLE 84 This illustrates the synthesis of compound 84.3 WO 01/00579 WO 0100579PCTIUSOO/181 78
NO
2
NH
2 3 S~a H 3
H
3
C
C1 84.1 84.2 Sodium hydride (1g, 60% in oil) was added to a solution of 5-chloro-2mercaptobenzothiazole (5.4 g) in DMF (50 mL). After gas evolution had subsided a solution of 2-chloro-5 -nitro toluene in DMF was added and the mixture heated at for 2 days. After coaling, the solution was filtered. The filtrate was diluted with water and extracted into ethyl ether. The organic layer was concentrated to a brown oil which was treated with hexane to form a solid precipitate which was collected by filtration as 84.1 (0.624 g).
'H NMR (DMSO) 8 8.372 J=2.4 Hz, I 8.17 1 (dd, J=8.8, 2.4 Hz, 111), 8.027 J=8.8 Hz, 8.003 J=8 Hz, 11-1), 7.988 J=2 Hx, 1H), 7.454 (dd, J=8.4, 1.6 Hz, I1H), 2.553 3H).
Reduction of 84.1 (0.6 g) with SnCl2 by the method of example 32 gave after chromatography 84.2 (0.48 g) as a solid.
'H NMR (DMSO) 8 7.899 J=8.8 Hz, 1H), 7.853 J=2 Hz, 1H), 7.345 J=8.4 Hz, 1H), 7.336 (dd, J=8.4, 2 Hz, 1H), 6.63 1 1=2 Hz) 111), 6.531 (dd, J=8.4, 2 Hz, 111), 5.766 (br s, 2H1). MS (M+Na) 329 Sulfonylation of 84.2 (0.4 g) by the method of example 3 gave 84.3 (Table 15) (0.66 g) as a foam.
'H NMR (DMSO) 8 11.376 IH), 8.355 (d,J=8 Hz, LH), 8.180 (d,1J1.2 Hz, I1H), 7.983 (dd, J=8.4, 2 Hz, I 7.893 J--9.2 Hz, I1H), 7.88 I 7.656 (d, J=8.4 H, I 7.377 (dd, J=8.8, 1.6 Hz, I 7.211 J=2.8 Hz, I 7.108 (dd, J=8.4, 2 Hz, I 2.334 3H). MIS 547 EXAMPLE This illustrates the synthesis of compound 85.3 WO 01/00579 PCT/US00/18178 SH Cr Ci Li 85.1 85.2 85.3 Compound 85.1 was prepared by a modification of the published procedure of Albert and Barlin Chem. Soc. 2384-2396 (1959). 3-Aminoquinoline (15.0 g, 105 mmol) was suspended in a mixture of O1N HCI (40 mL), ice (21g) and water (100 mL) at 0-5 OC, before sodium nitrite (7.6 g, 110 mmol) was added slowly. The mixture was then added portionwise to another solution of potassium ethyl xanthate.(20.8 g, 125 mmol) in water (60 mL) at 45 The mixture was heated for 1 hr before cooling off. The mixture was then extracted with ether. The ethereal solution was washed with 2N NaOH solution, water, and brine before drying over magnesium sulfate. After filtration, the removal of the solvent gave a brown oil (15g), which was then dissolved in ethanol (150 mL) and refluxed with KOH (25g) under nitrogen overnight. The ethanol solvent was then removed under vacuum, and the residue was separated between water and ether. The ethereal solution was discarded. The aqueous solution was acidified to pH before it was extracted with ether. Then ethereal solution was washed with brine, dried over magnesium sulfate, filtered and concentrated under vacuum to give crude product (7.5g) as a brown oil. Subsequent flash chromatography with eluent 5%-10% ethyl acetate dichloromethane) produced 3-mercaptoquinoline (85.1) (5.35g, 32% yield) as a solid.
'H NMR (DMSO) 8 9.02 (IH, d, J= 2.3 Hz), 8.63 (1H, d, J= 2.2 Hz), 7.95-8.05 (2H, 7.75-8.02 (1H, 7.60-7.67 (1H, m).
To a mixture of 3-mercaptoquinoline (85.1)(1.18 g, 7.33 mmol) and 1,2,3- (1.66 g, 7.33 mmol) dissolved in ethanol (100 mL), was added a THF solution of t-BuOK (7.5 mL, 1M). The mixture was then heated at 80 OC overnight before cooling off. After the removal of ethanol solvent, the mixture was separated between ethyl acetate and water. The organic solution was washed with brine, dried over magnesium sulfate and filtered. The filtrate was then concentrated to give a crude WO 01/00579 PCT/US00/18178 product, which was then flash chromatographed with eluent (10% hexanes dichloromethane) to afford 85.2 (1.80 g, 70% yield) as a yellow oil.
'H NMR (DMSO) 8 8.75 (1H, d, J= 8.51 (1H, 8.22 (IH, 8.01 (1H, d, J= 8.4 Hz), 7.92 (1H, d, J= 7.6 Hz), 7.74-7.80 (1H, 7.60-7.66 (1H, m).
An ethyl acetate solution (100 mL) of 85.2 (1.80 g, 5.1 mmol) and tin chloride dihydrate (6.88 g, 30 mmol) was heated at reflux overnight before cooling off. The solution was then poured into IN NaOH solution (400 mL). After stirring for min, the mixture was separated, and the organic solution was washed with water, saturated sodium bicarbonate and brine. After drying over magnesium sulfate, the solution was filtered and concentrated under vacuum. The residue was mixed with dichloromethane (10 mL) and sonicated. Subsequent vacuum filtration provided the aniline 85.3 (1.35g, 82% yield) as an off-white solid.
'H NMR (DMSO) 8 8.61 (IH, d, J= 7.96 (11, d, J= 8.4 Hz), 7.88 (1H, d,J= 8.2 Hz), 7.83 (1H, d,J= 2.2 Hz), 7.67-7.72 (1H, 7.54-7.60 (1H, mp 213.2 OC.
EXAMPLE 86 This illustrates the synthesis of compound 86 (see Table 16).
The aniline 85.3 (250 mg, 0.78 mmol) and 2-chlorobenzenesufonyl chloride (339 mg, 1.60 mmol) were dissolved in a mixed solvent of THF (5 mL) and dichloromethane (5 mL). To the solution was added pyridine (0.185 mL, 2.34 mmol) and catalytic amount of DMAP. The solution was heated at 50 OC to distill off dichloromethane, and then THF with assistance of vacuum. The residue was flash chromatographed with eluent ethyl acetate dichloromethane) to give sulfonamide 86 (302 mg, 78%) as an off-white solid.
'H NMR(DMSO) 8 11.58 (1H, 8.61 (1H, d, J= 2.4 Hz), 8.19 (IH, d, J 7.6 Hz), 7.83-8.00 (3H, 7.67-7.75 (3H, 7.56-7.65 (2H, 7.31 (2H, MS 494.9. mp: 219.6 Anal. calcd: C 50.87, H 2.64, N 5.65; found C 50.86, H 2.62, N 5.52.
The compounds of Table 16 were prepared by the method of example 86 from compound 84.3 and the corresponding arylsulfonyl chloride.
WO 01/00579 WO 0100579PCT/USOO/18178 Table 16 Sp Ra ff S Is Rb Rd ci (O)k
N
k R. We R~R~ l(M+H) 86 0 Cl H H H 495 87.1 0 CI H Cl H 529 87.2 0 H H H H 461 87.3 0 Cl H CF 3 H 561 (M-H) 88.1 1 Cl H H H 511 88.2 1 CI H Cl H 543 (M-H) 88.3 1 H H H H 477 EXAMPLE 87 Example 87.1 'H NMR(DMSO) 8 11.66 (IH, broad), 8.63 (IH, d, J= 2.3 Hz), 8.18 (11-1 d, J= 8.6 Hz), 7.85-8.00 (4H, in), 7.70-7.75 (2H, in), 7.57-7.62 (1 H, in), 7.32 (2H, s).
MIS 529.0. mp 214.0 0 C. Elemental Analysis: theory C 47.56, H 2.28, N 5.28; found C47.30, H 2.36, N 5.37.
Example 87.2 'H NMR(DMSO): 8 11.22 (IH, 8.61 (1H, d, J= 2.3 Hz), 7.82-7.98 in), 7.57-7.75 (5H, mn), 7.34 (211, MS 461.0. mp 246.8 TC. Elemental Analysis theory C 54.67, H 3.06, N 6.07; found C 54.71, H 3.05, N 5.94.
Example 87.3 'H NMR (DMSO) 8 11.70-12.00 (1H, broad), 8.60-8.67 (IH, in), 8.35- 8.43 (IH, nm), 8.20-8.25 (1 H, in), 7.56-8.06 (6H, in), 7.32-7.38 (2H, in). MS (M-H) 560.9. mp: 225.1 TC. Elemental Analysis: theory C 46.86, H 2.15, N 4.97; found C.
47.0 1, H 2.26, N 4.98.
WO 01/00579 PCT/US00/18178 EXAMPLE 88 General procedure for sulfur oxidation to the sulfoxide: A naphthylthioether of examples 86 or 87 (0.2 mmol) was dissolved in a mixed solvent ofdichloromethane (10 mL) and methanol (5 mL). To the solution was added mCPBA (120 mg, 0.7 mmol, 77% pure) in six batches over 20 minute intervals.
Then the solution was washed with 5% sodium thiosulfate solution, 1% sodium bicarbonate solution and brine and then dried over magnesium sulfate. After filtering, the filtrate was concentrated to give a crude product, which was then flash chromatographed with eluent ethyl acetate dichloromethane) to afford the corresponding sulfoxide.
Example 88.1 'H NMR (DMSO): 5 11.75 (1H, 8.82 (1H, 8.68 (1H, 8.15-8.20 (2H, 8.09 (1H, d, J= 8.5 Hz), 7.85-7.91 (1H, 7.67-7.75 (3H, 7.57-7.64 (1H, 7.17 (2H, MS 511. mp 239.5 °C with decomposition. Elemental Analysis: theory C 49.28, H 2.56, N 5.47; found C 49.30, H 2.63, N 5.37.
Example 88.2 'H NMR(DMSO): 8 11.5-12.0 (broad), 8.83 (1H, 8.68 (1H, 8.15- 8.20 (2H, 8.09 (1H, d, J= 8.5 Hz), 7.85-7.92 (2H, 7.55-7.75 (2H, 7.17 (2H, MS 542.9. mp: 234.4. Elemental Analysis: theory C 46.17, H 2.21, N 5.13; found C 45.97, H 2.26, N 4.92.
Example 88.3 'H NMR(DMSO) 8 11.43 (1H, 8.81 (1H, 8.68 (1H, 8.18 (1H, d, J 8.2 Hz), 8.09 (1H, d, J= 8.5 Hz), 7.82-7.90 (3H, 7.58-7.74 (4H, 7.21 (2H, s).
MS 476.9. mp 261.8 OC with decomposition. Elemental Analysis: theory C 52.83, H 2.96, N 5.87; found C 52.71, H 3.05, N 5.71.
WO 01/00579 WOOI/0579PCTIUSOO/18178 EXAMPLE 89
NO
2 C"'4 2-(2,6-Dichloro-4-n itro-phenylsulfanyl)-napth alene (89) 2-(2,6-Dichloro-4-nitro-phenylsul fanyl)-napthalene was synthesized (100%) from 3,4,5-trichloronitrobenzene (Acros) and napthalene-2-thiol (Avocado) in a similar manner as described in example I using DMSO as solvent instead of DMF.
'H NMR (DMSO-d 6 8 8.48 2H), 7.95-7.85 (in, 1H), 7.88 J 8.6 Hz, I 7.85-7.8 (in, I 7.75 J 1.8 Hz, I 7.55-7.45 (in, 2H), 7.25 (dd, J =8.7, Hz, I1H).
EXAMPLE CI Cl 3,5-dichloro4-(napthalen-2-yISulfal)-phelylaminC To a 0. 1iM solution 2-26Dclr4ntopeyslay)nphln (89) (774 mng, 2.2 inmol), in EtOAc was added tin(II)chiloride dihydrate, obtained from Aldrich, (2.49 g, 11 .05 inmol). The resulting mixture was refluxed for 2 hour. The crude reaction mixture was cooled to ambient temperature and excess 2M aqueous NaOH was added and allowed to stir for 15 minutes. Solid tin salts precipitated from the solution, were filtered off through a pad of celite and washed with EtOAc; (200 mL). The organic layer was washed twice with brine (200 mL), dried over Na 2
SO
4 and concentrated under vacuum to yield 592 mg of (90) which was used without further purification.
'H NMR (DMSO-d 6 8 7.88-7.82 (in, IH), 7.83 J 8.7 Hz, 111), 7.75 J 7.7 Hz, 111), 7.5-7.4 (in, 311), 7.13 (dd, J 8.7, 1.9 Hz, I1H), 6.83 2H), 6.21 (s, 2H1). NIS(M-H) 318.
WO 01/00579 WO 0100579PCTJUSOO/18178 EXAMPLE 91 N0 2 2-(2-Chloro-4-nitro-phenylsulfanyl)-naptbalefle (91) 2-(2-Chloro-4-nitro-phenylsulfanyl)-napthalene was synthesized (100%) from 3-chloro-4-fluoro-nitrobenzene (Aldrich) and napthalene-2-thiol (Avocado) in a similar manner as described in example 89.
'H NMR (DMS0-cl 6 8 8.4-8.34 (in, 2HM, 8.14 J =8.6 Hz, 1H), 8.09- (in, 3H), 7.72-7.6 (mn, 3H), 6.88 J =8.9 Hz, 1H).
EXAMPLE 92 cry2 3-chloro-4-(napthalen-2-ylsulfanyl)-phenylamine 3 .chloro-4-(naptlialen-2-ylsul fanyl)-plhenylarnine (92) was synthesized from 2-(2-Chloro-4-nitro-phenylsulfanyl)-napthalene (91) in a similar manner as described in example 'H NMR (DMSO-cl6) 5 7.88-7.8 (in, 7.75 J 7.5 Hz, IH), 7.42 (in, 3H), 7.35 J 8.4 Hz, IH), 7.18 (dcl, J 8.6, 1.8 Hz, IH), 6.82 J 2.4 Hz, 1H), 6.6 (dd, J 8.4, 2.4 Hz, I1H). MS 286 WO 01/00579 WO 0100579PCT/USOO/181 78 EXAMPLE 93 100 Y NH
WN.I
2,4-Dichloro-N-j3,5-dichloro-4-(napthaen-2-ylsulfalyl)-phellbeuzenesulfonamide (93) To a 0.4M solution of 3,5-dichloro-4-(napthalen-2-ylsulfanyl)phenylamine (90)(153 mg, 0.48 mmol in THIF was added pyridine, obtained from aldrich, 19 mL, 2.4 mmol) followed by 2,4-dichlorobenzenesulfonyl chloride, obtained from Maybridge, (129 mg, 0.53 mmol). The resulting mixture was stirred for 6 days. A I M aqueous solution of HCI (20 mL) was added and the crude reaction mixture was extracted 3x with EtOAc (20 mnL). The organic layers were combined and washed once with a brine solution (20 mL), dried over Na 2
SO
4 and concentrated under vacuum.
The crude solid was chromatographed (5-15% EtOAc in hexane) to yield 125 mg (49%) of 93 as an off white solid.
'H NMR (DMSO0-d 6 8 11.6 I 8.17 J 8.6 Hz, I 7.96 J 2.1 Hz, I 7.88-7.83 (in, I 7.83 J 8.7 Hz, I 7.76-7.73 (in, I1H), 7.1 (dd, J 8.6, 2.1 Hz, I 7.5 2-7.44 (in, 3 7.32 2H), 7.21 2 7.1 (dd, J 2. 0 Hz, 1H). MS 526 EXAMPLE 94
C
~i~ WO 01/00579 WO 0100579PCTfUSOO/18178 6-Chloro-pyridine-3-sulfonic acid I3-cloro-4-(naphthalen-2ylsulfanyl)-phenyll-amide (94).
To a 0.35M solution of 3-chloro-4-(naphthalen-2-ylsul fanyl)-phenylamine (90)(150 mg, 0.53 mmol) in TI-F was added pyridine (Aldrich, 0.21 mL, 2.63 mmol) followed by 6-chloro-pyridine-3-sulfonyl chloride (Qorpark, 122 mg, 0.58 mm-ol). The resulting mixture was stirred for 15 hours. A IM aqueous solution of HCI (20 mL) was added and the crude reaction mixture was extracted 3x with EtOAc (50 mL). The organic layers were combined and washed twice with a brine solution (100 mL), dried over Na 2
SO
4 and concentrated under vacuum. The crude solid was chromatographed (5-15% EtOAc in hexane) to yield 140 mg of 94 as a pale yellow solid.
1H NMR (DMSO-d 6 8 10.93 IH), 8.77 J 2.0 Hz, IH), 8.19 (dd, J 2.6 Hz, I 7.97-7.90 (in, 2H), 7.90-7.84 (in, 211), 7.78 J 8.4 Hz, IH), 7.59- 7.52 (in, 2H), 7.36 (dd, J 8.6, 1.9 Hz, IH), 7.29 J 2.1 Hz, 1H), 7.12-7.04 (in, 2H).
MS (M-H) EXAMPLE lqp
F
3 C f
XCI
2-Chloro-N-13-chloro-4-(naphthalen-2-yIsulfanyl)-phenyI-4trifluoromethyl-benzenesulfonamide The title compound was prepared using the method of example 94, starting with 3-chloro-4-(naphthalen-2-ylsulfanyl)-phenylaine (150 mg, 0.53 inmol), pyridine (Aldrich, 0.21 inL, 2.63 ininol) and 2-chloro-4-trifluoromethylbenzenesul fonyl chloride (Maybridge, 162 mng, 0.58 minol) in THF. 250 mg of title compound (95) was obtained as a pale yellow solid.
'H NMR (DMSO-d 6 8 11.30 I 8.23 J 8.3 Hz, I 8.18 J= 1.6 Hz, 11H), 7.97-7.84 (mn, 3H), 7.84-7.80 (mn, 2H), 7.58-7.50 (in, 2H), 7.32 (dd, J 8.6, 1.9 Hz, 111), 7.28 J 2.3 Hz, 111), 7.11 J 8.6 Hz, IH), 7.04 (dd, J 8.6, 2.3 Hz, IJH). MIS 526 WO 01/00579 WO 0100579PCTIUSOO/18178 *EXAMPLE 96 0 Cl CI 6-Chloro-pyridine-3-sulfon ic acid 13,5-dichloro-4-(n aphtbalen-2ylsulfanyl)-phenyll-amide (96) The title compound was prepared using the method of example 94, starting with 3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (90) (150 mg, 0.47 mrnol), pyridine (Aldrich, 0. 19 mL, 2.34 mmol) and 6-chloro-pyridine-3-sulfonyl chloride (Qorpark, 109 mg, 0.52 minol) in TI-F. 130 mg of 96 was obtained as a pale yellow solid.
'H NMR DMSO-d 6 8 11.40 (br s, I 8.88 J 1.9 Hz, 1H), 8.28 (dd, J 8.4,1.6 H-z, IH), 7.88-7.80 (in, 3H), 7.76 J 9.1, 1.8 Hz, 1H), 7.52-7.42 (in, 3H), 7.38 214), 7.14 (dd, J 2.0 Hz, 1IH). MS 493 EXAMPLE 97
F
3 C -1 Cl~ C, 2-Chloro-N-[3,5-dichloro-4-(naphthalen-2-ylsulfany)-phenlI-4trifluoromethyl-benzenesulfonamide (97) The title compound was prepared using the method of example 94, starting with 3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (90)(1 50 mg, 0.47 mmo!), pyridine (Aldrich, 0.19 mL, 2.34 mniol) and 2-chloro-4-trifluoromethylbenzenesulfoflyI chloride (Maybridge, 144 mg, 0.52 inmol) in THE. 137 mg of 97 was obtained as a pale yellow solid.
WO 01/00579 WO 0100579PCT[USOO/18 178 'H NMR (DMSQ-d 6 8 8.38 J 8.0 Hz, 1H), 8.21 J 1.4 Hz, 11H), 8.01 (dd, J 8.4, 1.1 Hz, 1H4), 7.88-7.80 2H4), 7.76-7.71 (in, lE), 7.5 1-7.42 (in, 2H), 7.34 2H), 7.12 (dd, J 2.0 Hz, 11H). MS 560 EXAMPLE 98 C 00 N S.-.NH
-CI
6-Chioro-imidazo [2,1-bi thiazole-5-sulfonic acid 13-chloro-4- (napbthalen-2-ylsulfanyl)-phenyll-amide (98) The title compound was prepared using the method of example 94, starting with 3-chloro-4-(naphthaten-2-ylsulfanyl)-phenylamine (92) (150 mng, 0.53 inmol), pyridine (Aldrich, 0.21 mL, 2.63 mnmol) and 6-chloro-imidazo[2,1-b]tliazole-5-sulfonyI chloride (Maybridge, 149 mng, 0.58 inmol) in THF. 172 mg of 98 was obtained as a pale yellow solid.
'H NMR (DMSO-d 6 8 11.26 I 7.9 8 J 4.4 Hz, I 7.96 -7.8 8 (in, 214), 7.88-7.84 (in, 214), 7.68 J 2.4 Hz, I 7.58-7.52 (in, 2H), 7.33-7.28 (mn, 2H), 7.14 J 8.5 Hz, I 7.01 (dd,]J 8.5, 2.4 Hz, I 7.04 (dd, J 8.6, 2.3 Hiz, 114). MS 504 EXAMPLE 99 lcp
S'NH
CI)
-CI
I~ I~~ WO 01/00579 WO 0100579PCTUSOO/18178 sulfonamide(99) sulfoniamide was synthesized from 3-chloro-4-(napthalen-2-ysulfanyl)phenylaniine (92) and 2,4-dichlorobenzenesulfonyl chloride, obtained from Maybridge, in a similar manner as described in example 93.
'H NMR (DMSO-d 6 8 11.1 114), 8.06 J =8.6 Hz, 111), 7.95- 7.88(m, 3H), 7.86-7.81 (in, 211), 7.65 (dd, J =8.4 Hz, 11H), 7.57-7.51 (in, 2H), 7.31 (dd, J 8.6, 1.9 Hz, I 7.26 J =2.2 Hz, I1H), 7.12 J =8.7 Hz, 11) 7.03 (dd, J 2.3 Hz, MS 492 EXAMPLE 100 0 0
CI
N-13-Chlo ro-4-(naphthalen-2-ylsulfanyl)-phelyl-4-iodobenzenesulfonamide (100) The title compound was prepared using the method of example 94, starting with 3 -chloro-4-(naphthalen-2-ylsulfanyl)-phelylamifle 150 mng, 0.53 minol), pyridine (Aldrich, 0.21 mL, 2.63 minol) and 4-iodobenzenesulfonyl chloride (Acros, 175 ing, 0.58mimol) in THF. 153 mng of 100 was obtained as a pale yellow solid.
'H NMR (DMSO-d 6 8 10.75 111), 8.0 1-7.95 (mn, 2H), 7.95-7.89 (in, 2H), 7.87-7.82 (mn, 2H), 7.59-7.50 (mi, 4H), 7.32 (dd, J 8.6, 1.9 Hz, I 7.26 J 2.3 Hz, IlH), 7.13 J 8.6 Hz, IlH), 7.04 (dd, J 2.2 Hz, IlH). MS 5 WO 01/00579 WO 0100579PCTIUSOO/18178 EXAMPLE 101 0/0 Cl C loro-4-(n aphthalen-2-ylsulfanyl)-ph enyl]-4-iodo- The title compound was prepared using the method of example 94, starting with 3,5-dichlOrO-4-(naphthalen-2-ylsulfanyl)-phelylanfifle (90) (150 mg, 0.47 mmol), pyridine (Aldrich, 0.19 mL, 2.34 mmol) and 4-iodobenzenesulfonyl chloride (Acros, 155 mg, 0.52 mmol) in THE. 254 mg of 101 was obtained as a pale yellow solid.
'H NMR (DMSO-d, 6 5 11.22 I 8.08-8.02 (in, 2H), 7.88-7.82 (in, 2H), 7.74 J 7.7 Hz, IH), 7.65-7.58 (in, 7.52-7.40 (in, 3H), 7.35 2H), 7.12 (dd, J 1.9 Hz, I-IH). MS 584 EXAMPLE 102 N qo Cl Cl 0 6-Chloro-imidazo[2,1 -bJ thiazole-5-su Ifonic acid 13,5-dicbloro-4- (naphthalen-2-ylsulfaoyl)-phenyll-amide (102) The title compound was prepared using the method of example 94, starting with 3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phelylalifle 150 mg, 0.47 mmol), pyridine (Aldrich, 0. 19 mL, 2.34 inmol) and 6-chloro-imidazo[2,1 chloride (Maybridge, 132 mg, 0.52 inmol) in TI-f. 172 mng of 102 was obtained as a pale yellow solid.
WO 01/00579 WO 0100579PCTUSOO/181 78 'H NMR (DMSO-d 6 5 11.71 (hr s, 11H), 8.02 I 4.4 Hz, IH), 7.89- 7.82 (mn, 7.77 (in, IH), 7.72 J 4.4 Hz, IHM, 7.52-7.432 (mn, 3H), 7.35 2H), 7.11 (dd, 1 8.7, 2.0 Hz, 1H). MS 504 EXAMPLE 103 00 N S-NH C1 cm 0 6-Chloro-pyridioe-3-sulironic acid 13-cb Ioro-4-(napli thalene-2sulfinyl)-pheoyll-amide (103) To a solution of 6-Chloro-pyridine-3-sulfonic acid [3-chloro-4- (naphthalen-2-ylsulfanyl)-phenyl]-amide (94, 55 ing, 0. 12 mmnol) in CH 2 Cl 2 (2 inL), was added dropwise a solution of m-chloroperoxybenzoic acid (mCPBA, Aldrich, 36mg, 0. 12 mmol) in CH 2
CI
2 (I mL). The resulting mixture was stirred at ambient temperature for I hour and diluted with EtOAc (60 inL). The organic layer was washed with saturated aqueous NaHCO 3 solution (50 inL), twice with brine solution (50 mL), dried over Na 2 S 04, and concentrated under vacuum. The crude solid was chroniatographed EtOAc in hexane) to yield 17 mg of 103 as an off white solid.
'H NMR (DMSO-d 6 8 11.25 I 8.82 J 2.6 Hz, I 8.43 J Hz, 1H), 8.19 (dd, J 8.4, 2.6 Hz, I1H), 8.10 (mn, 8.04 J 8.5 Hz, I 7.98 (in, I1-H), 7.88 J 8.7 Hz, I 7.74 J 8.5 Hz, 1 7.70-7.60 2H), 7.53 (dd, J 8.7, 1.8 Hz, I 7.40 (dd, J 8.5, 2.2 Hz, I 7.19 J 2.1 Hz, I MS (M-H) 475 WO 01/00579 WO 0100579PCTIUSOO/18178 EXAMPLE 104 00 N S- I C Cl 6-Chloro-pyridine-3-sulfonic acid [3,5-dichloro-4-(naphthalene-2sulronyl)-phenyll-amide (104) To a solution of 6-Chloro-pyridirie-3-sulfonic acid [3 ,5-dichloro-4- (naphthalen-2-ylsulfanyl)-phenyl]-amfide (96, 20 mg, 0.04 mmol) in CH 2 Cl 2 (1 mL), Was added dropwise a solution of mCPBA (Aldrich, 36 mg, 0. 12 mmol) in CH 2
CI
2 (1 mL).
The resulting mixture was stirred at ambient temperature overnight and diluted with EtOAc (60 mL). The organic layer was washed twice with 5% aqueous Na2S2O3 solution (20 mL), twice with 1% aqueous NaHCO 3 solution (20 niL), and brine solution mL), dried over Na 2
SO
4 Removal of the solvent under vacuum gave 21 mig of 104 as an off white solid.
'H NMR (DMSO-d 6 5 8.68 J 2.5 Hz, I1H), 8.58 J 1. 8 Hz, I H), 8.22 J 8.1 Hz, IlH), 8.12-8.05 (mn, 8.02 J 8.0 Hz, I 7.79 (dd, J Hz, IH), 7.76-7.64 (in, 2H), 7.58 IJ 8.4 Hz, 1H), 6.93 2H). MS 525 EXAMPLE 105
F
3
C
Cl 2-Chloro-N-13-chloro-4-(n aphtbalene-2-sulfonyl)-phenyll-4trifluoromethyl-benzenesulfonamide(105) The title compound was prepared using the method of example 104, starting with 2-hooN[-hoo4(ahhln2iufnl-hnl4 WO 01/00579 WOOI/0579PCTIUSOO/18 178 trifluoromethylbenzene-sulfonamnide (95, 35 mg, 0.066 mmol), mCPBA (Aldrich, 100 mg, 0.33 mnmol) in CH 2
CI
2 38 mg (100%) of 105 was obtained as an off white solid.
'H NMR (DMSO-d6) 8 11.90 (br s, 1K), 8.62 J 1.8 Hz, IH), 8.28 (d, J 8.1 Hz, I1K), 8.20 J 8.1 Hz ILH), 8.16-8.00 (in, 4H), 7.90 J 8.5 Hz, I1H), 7.77-7.64 (in, 3H), 7.20 J =9.0 Hz, 1H), 7.09 1KI). MS 558 EXAMPLE 106 N: I,
S---NH
Cl
CI
6-Chloro-pyridine-3-sulfonic acid 13-chloro-4-(napbtbalene-2sulfonyl)-phenyll-amide (106) The title compound was prepared using the method of example 104, starting with 6-Chloro-pyridine-3-sulfonic acid [3-chloro-4-(naphthalen-2-ylsulfanyi)phenyl]-amide (94, 15 mg, 0.03 mmol), mCPBA (Aldrich, 50 mg, 0. 15 mmol) in CK 2
CI
2 16 mg (100%) of 106 was obtained as an off white solid.
'H NMvR (DMSO-d 6 8 11.60 br s, I1H), 8.82 J 2.5 Hz, I1H), 8.62 (d, J =1.8 Hz, 1K), 8.24-8.16 (in, 2H), 8.14 J 8.8 Hz, 1K), 8.08 J 8.8 Hz, 1K), 8.03 J 8.4 Hz, I 7.76-7.64 (in, 4H), 7.27 (dd, J3 8.8, 2.0 Hz, 1KH), 7. 10 J= 2.1 Hz, 1K). MIS 491 EXAMPLE 107 1 FCJ rr-NB1 WO 01/00579 WO 0100579PCTIUSOO/18178 trifluoromethy-benzenesulfoflamide (107) The title compound was prepared using the method of example 104, starting with 2-hooN[,-ihoo4(ahhln2yslay)pey]4 trifluoromethylbenzene-sulfoflamide (97, 30 mg, 0.05 mmol), rnCPBA (Aldrich, 80 mg, 0.26 mmol) in CH 2 C1 2 32 mg (100%) of 107 was obtained as an off white solid.
'H NMR (DMSO-d 6 5 8.59 J 1. 1 Hz, I 8.22 J =8.1 Hz, I H), 8.15 .J 8.1 Hz, I1H), 8. 10 J 8.6 Hz, 1 8.03 J 8.1 Hz, I 7.90 I H), 7.84-7.77 (in, 2H), 7.75-7.64 (in, 2H), 6.92 2H). MS 592 EXAMP~LE 108 This example illustrates the preparation of 108.1 through 108.6.
NO
2
NHM
2 CI Cl Cl-' CI CI Cl N N 108.1 108.2 A solution of potassium I-butoxide (1 M in THF; 26.5 mL) was added to a solution of 3,4,5-trichloronitrobenzene (3 g) and 5-chloro-3-hydroxypyridine (1.7 g) in THF (15 inL). The deep red solution was heated at 50'C overnight, then poured into water. The precipitate was collected by filtration and purified by chromatography on silica (10% ethyl acetate/hexanes; as eluant) to provide 108.1.
'H NMR (400 MHz) (DMSO-d 6 8 8.5 8 2H); 8.47 J=2 Hz, I H); 8.41 J"'2.6 Hz, I1H); 7.72 (dd, J=2.6, 2 Hz, I1H).
Using the method of Example 2, 108.1 (2.2 g) was converted to the aniline 108.2.
'H NMvR (400 MHz) (DMSO-d 6 8 8.3 5 J=2 Hz, IlH); 8.21 Hz, IH); 7.37 (dd, J=2.5, 2 Hz, IH); 6.73 2H); 5.78 (br s, 2H).
WO 01/00579 PCT/US00/18178 The compounds provided in Table 17 were prepared using 108.2 and commercially available substituted benzenesulfonyl chlorides and/or using the intermediates and methods described in the examples above.
Table 17 108.3 108.4 108.5 108.6 Ra Rb Re Rd H Cl Cl H Cl H Cl H H H I H Cl H CF 3
H
mp (OC) 199-200 166-169 211-214 185-189 EXAMPLE 109 This example illustrates the synthesis of 109.1.
0, 109.1 A round-bottomed flask was charged with 2-chloro-4-nitrobenzoyl chloride (3.50 g, 15.9 mmol), 2-ethylbenzofuran (2.11 g, 14.4 mmol), and anhydrous methylene chloride (20 mL). This was cooled in an ice/water bath and titanium tetrachloride (5.49 g, 28.9 mmol) was added in a dropwise fashion with vigorous stirring.
After addition was complete, the reaction was stirred at O'C for 20 minutes and then was warmed to room temperature for an additional four hours. The reaction was then diluted with 80 mL of methylene chloride and washed twice with 50 mL volumes of 2N HCI and then once with 50 mL of brine. The organics were dried over Na 2
SO
4 and concentrated to WO 01/00579 PCT/US00/18178 a yellow oil. This oil was further purified using silica gel flash chromatography (eluting with 20% hexanes in methylene chloride). The desired fractions were concentrated to give 2.9 g of ketone 109.1 as an off-white solid. MS ESI m/e: 330.0 (M H).
EXAMPLE 110 (2,6-Dichloro-4-nitro-phenyl)-acetic acid (110) To a solution ofdiethyl malonate (Aldrich, 13.8 mL, 90 mmol) in DMF mL) was added cesium carbonate (Aldrich, 48.9 g, 150 mmol). The mixture was heated to 70 °C and then was added 1,2,3-trichloro-5-nitrobenzene (Aldrich, 13.56 g, mmol). The mixture was stirred at 70 0 C for 3 hours and cooled to room temperature. A 2M aqueous solution of HCI (50 mL) was added and the crude reaction mixture was extracted 3x with EtOAc (150 mL). The organic layers were combined and washed twice with a brine solution (150 mL), dried over Na 2
SO
4 and concentrated under vacuum. The light yellow oil was used for the next reaction without further purification.
The light yellow oil was suspended in 90 mL of 6 N aqueous HC1. The mixture was refluxed overnight (15 hours). The mixture was cooled in the ice bath for 2 hours and filtered. The crude solid product was triturated with CHzCl2/Hexanes to give compound 110 (11.5 g 77%) as pale brown solid.
'H NMR (DMSO-d) 8 13.00 (br s, 1H), 8.23 2H), 4.16 2H).
EXAMPLE 111 (2-Chloro-4-nitro-phenyl)-acetic acid (111) The title compound was prepared using the method of example 110, starting with diethyl malonate (Aldrich, 30.5 mL, 200 mmol), 3,4-dichloronitrobenzene (Aldrich, 19.2 g, 100 mmol), cesium carbonate (Aldrich, 81.5 g, 250 mmol) and 150 mL of aqueous 6N HCI solution. 18.8 g of compound Ill was obtained as pale yellow solid.
'H NMR (DMSO-d6) 5 12.80 (br s, 1H), 8.29 J 2.4 Hz, 1H), 8.18 (dd, J 8.4, 2.4 Hz, IH), 7.73 J 8.4 Hz, 1H), 3.90 2H).
EXAMPLE 112 2-Amino-4-chloro-benzenethiol hydrochloride (112) By the procedure of R.L.Danley and D. A. Zazaris (Can. J. Chem. 43, 2610-2612 (1965) sodium tetrasulfide was obtained by dissolving sulfur (Aldrich, 9.6 g, WO 01/00579 PCT/US00/18178 300 mmol) in molten sodium sulfide nonahydrate (Aldrich, 24.0 g, 100 mmol). This hot liquid was added to a solution of 2,5-dichloronitrobenzene (Aldrich, 38.4 g, 200 mmol) in ethanol (140 mL). After the exothermic reaction had ceased, the mixture was refluxed for 2 hours and filtered while hot. The precipitate was washed with water mL) and ethanol (50 mL) to give 37.7 g of intermediate trisulfide as a yellow solid.
'H NMR (CDC1 3 5 8.83 J 2.3 Hz, 1H), 7.76 J 8.6 Hz, 1H), 7.55 (dd, J 8.6, 2.3 Hz, IH).
Concentrated hydrochloric acid (125 mL) was slowly (overnight, hours) added to a well-stirred suspension of the trisulfide (37.7 g) described above and tin (Aldrich, 88 g, 737 mmol) in 95% ethanol (200 mL). After filtration of the hot solution, the filtrate was allowed to stand at room temperature overnight to precipitate the crude product. The precipitate was collected by filtration, washed withl:1 ethanol/concentrated HC1. Recrystalization from 1:1 MeOH/concentrated HCI gave compound 112 (13.8 g) as white needles.
'H NMR DMSO-d 6 8 6.96 J 8.3 Hz, 1H), 6.86 J 2.3 Hz, IH), 6.50 (dd, J 8.3, 2.3 Hz, 1H).
EXAMPLE 113 2-Amino-4-methyl-benzenethiol hydrochloride (113) bis-(4-Methyl-2-nitrophenyl)-trisulfide was prepared using the method in example 112, starting from 4-chloro-3-nitro-toluene (Aldrich, 34.3 g, 200 mmol), sulfur (Aldrich, 9.6 g, 300 mmol) and sodium sulfide nonahydrate (Aldrich, 24.0 g, 100 mmol) in 95% EtOH (150 mL). 27.7 g of the trisulfide was obtained as a yellow solid.
'H NMR (400MHz, CDCI 3 8 8.21 J 8.3 Hz, 1H), 8.07 (br s, IH), 7.58 (dd, J 8.3, 1.3 Hz, IH), 2.48 3H).
Reduction of the bis-(4-Methyl-2-nitrophenyl)trisulfide as in example 112 gave compound 113 (11.3 g) as a mixture after recrystalization, but which was used directly in subsequent reactions.
EXAMPLE 114 5-Chloro-2-(2,6-dichloro-4-nitro-benzyl)-benzothiazole (114) By a modification of the procedure of D.L. Boger Org. Chem. 43, 2296-2297 (1978) a solution of P 2 0s/MeSO 3 H (Aldrich, 7.5 g, 1:10, w:w) was treated with 2-amino-4-chloro-benzenethiol hydrochloride (example 112, 1.96 g, 10.0 mmol) and WO 01/00579 WO 0100579PCTUSOO/181 78 (2,6-dichloro-4-nitro-pheny)-acetic acid (example 110, 2.50 g, 10.0 mimol). The resulting mixture was stirred at room temperature for 1 hour, then heated at overnight (15 hours). After cooled to room temperature, the reaction mixture was poured to ice and the resulting mixture was extracted 3x with EtOAc (50 mL). The organic layers were combined and washed twice with a brine solution (100 mL), dried over Na 2
SO
4 and concentrated under vacuum. The crude solid was chromatographed
(CH
2
CI
2 to yield 3.7 g of compound 114 as a pale yellow solid.
'H NMR (CDCI 3 8 8.2 8 2H), 7.98 J 1. 9 Hz, I 7.76 J Hz, IH), 7.38 (dd, J 8.5, 1.9 Hz, IH), 4.87 2H). MIS 373 The compounds of Table 18 were prepared using the method of example 114.
Table 18 Example 114 115 116 117 118 119 120 121
A
Cl Cl
CF
3
CF
3
H
H
Me Me yield 99% 98% 96% 89% 92% 77% 28% EXAMPLE 115 5-Cbloro-2-(2-chloro-4-nitro-belzyl)-belzotiazoIC 'H NMR (400MHz, DMSQ-d 6 858.3 5 J 2.3 Hz, I 8.25 (dd, J 2.4 Hz, I 8. 10 J 8.6 Hz, I 8.02 J 2.0 Hz, I1H), 7.8 9 J 8.5 Hz, IH), 7.48 (dd, J 8.6, 2.0 Hz, 11H), 4.77 2H). MS 339 WO 01/00579 WO 0100579PCTIUSOO/181 78 EXAMPLE 116 2-26Dclr--ir-ezl--rfurmty-eztizl 'H NMR (DMSO-d 6 5 8.42 2H1), 8.34 J 8.4 Hz, I1H), 8.28 (br s, I 7.76 J 8.4 Hz, 111), 4.94 2H). MS 407 EXAMPLE 117 2-2Clr--ir-ezl--rfurmty-eztizl 'H NlvfR (CDCI 3 8.33 J 2.3 Hz, I1H), 8.27 br s, 11H), 8.14 (dd, J= 8.5, 2.3 Hz, I 7.96 br d, J 8.3 Hz, IlH), 7.63 J 8.5 Hz, 2H) 4.70 211). MS 371 EXAMPLE 118 2-(2,6-Dichloro-4-nitro-benzy)-bezothiazoIC is 'H NMR DMSO-d 6 6 8.41 2H), 8.06 J 8.0 Hz, I1H), 7.90 J 7.9 Hz, 1H), 7.50-7.38 (in, 2H), 4.94 2H). MS 337 EXAMPLE 119 2-(2-Cbloro-4-nitro-benzyl)-benzothiazole 'H NMR (CDC1 3 8 8.35 J 2.2 Hz, 11H), 8.25 (dd, J 8.4, 2.2 Hz, I H), 8.05 J 7.9 Hz, I1H), 7.93 J 8.1 Hz, I 7.86 J 8.5 Hz, I 7.49 J 7.9 Hz, 7.42 J 7.6 Hz, 11H), 4.76 211). MS 305 EXAMPLE 120 2-26Dclr4ntobny)5mty-eztizl 'H NMR (DMSO-d 6 8 8.41 2H), 7.91 J 8.2 Hz, 1H1), 7.71 (br s, I 7.25 J 8.2 Hz, I1H), 4.85 2H), 2.41 3H). MS 353.
EXAMPLE 121 2-(2-Chloro-4-nitro-benzy)--mty-beflzothiazole 'H NMR (DMSQ-d 6 8 8.35 (d,JI= 2.3 Hz, IH), 8.24 (dd, 1 8.5, 2.3 Hz, 111), 7.91 J 8.2 Hz, IM1, 7.85 J 8.5 Hz, 111), 7.74 (br S, IH), 7.25 (dd, J 8.2, Hz, I 4.73 211), 2.42 3H). MS 317 Reduction of the compounds of Table 18 gave the anilines of Table 19.
WO 01/00579 WO 0100579PCTIUSOO/18178 Table 19 Example
A
122 cl 123 Cl 124 CF 3 125 CF7 3 126 H 127
H
128 Me 129 Me Method A: see example 90 Method yield A 100% B 88% A B 89% B 97% B B 97% B 97% Method B: see example 181 EXAMPLE 122 3,-ihoo4(-hoobnohao--lehl-hnlmn 'H NMR DMSO-d 6 8 8.03 J 8.4 Hz, IH), 8.01 J 2.1 Hz, 1H), 7.45 (dd, J 8.5, 2.2 Hz, 1H), 6.70 2H), 5.79 2H), 4.52 2H). MS 343 EXAMPLE 123 3-Chloro-4-(5-ch loro-benzothiazol-2-ylmethyl)-pheflylamiie 1 H NMR (DMSO-d 6 8 8.05-7.95 (in, 2H), 7.43 (dd, J 2.1 Hz, 1H), 7.17 J 8.2 Hz, I 6.66 J 2.2 Hz, I 6.5 3 (dd, I 8.2, 2.2 Hz, I 5.44 (s, 2ff), 4.36 2H). MS 309.
EXAMPLE 124 WO 01/00579 PCT/USOO/18178 3,5-Dichloro-4-(5-triluoromethyl-benzothiazol-2-ylmethyl)phenylamine 'H NMR (DMSO-d 6 8 8.29 (br s, IH), 8.26 J 8.4 Hz, 1H), 7.72 J 8.4Hz, IH), 6.70 2H), 5.81(s, 2H), 4.56 2H). MS 377 EXAMPLE 125 3-Ch loro-4-(5-trifluo romethyl-benzothiazol-2-ylmethyl)-phenylamine 'H NMR (DMSO-d 6 8 8.25 (br s, 1H), 8.26 J 8.4 Hz, 1H), 7.72 (dd, J 8.4, 1.3 Hz, 1H), 7.19 J 8.2 Hz, 1H), 6.67 J 2.2 Hz, 1H), 6.54 dd, J 8.2, 2.2 Hz, 1H), 5.46 2H), 4.40 2H). MS 343 EXAMPLE 126 4-Benzothiazol-2-ylmethyl-3,5-dichloro-phenylamine 'H NMR (DMSO-d 6 8 7.99 (dd, J 8.0, 0.6 Hz,, IH), 7.92 J 8.1 Hz, 1ff), 7.45 (td, J 8.2, 1.2 Hz, 1H), 7.38 (td, J 8.0, 1.0 Hz, 1H), 6.70 2H), 5.78(s, 2H), 4.51 2H). MS 309.
EXAMPLE 127 4-Benzothiazol-2-ylmethyl-3-chloro-phenyl mine 'H NMR (DMSO-d 6 8 7.98 J 8.0 Hz, 1H), 7.92 J 8.0 Hz, 1H), 7.47 (td, J 7.9, 1.2 Hz, 1H), 7.38 (td, J 7.9, 1.0 Hz, 1H), 7.17 J 8.3 HIz, 1H), 6.66 J 2.2 Hz, 1H), 6.54 (dd, J 8.2, 2.2 Hz, 1H), 5.44 2H), 4.35 2H). MS (M+H) 275 EXAMPLE 128 3,5-Dichloro-4-(5-methyl-benzothiazol-2-ylmethyl)-phenylamine 'H NMR (DMSO-d 6 8 7.84 I 8.2 Hz, 1H), 7.73 (br s, 1H), 7.21 (dd, J 8.2, 1.0 Hz, 1H), 6.69 2H), 5.77 2H), 4.48 21H), 2.43 3H). MS 323.
EXAMPLE 129 3-Chloro-4-(5-methyl-benzothiazol-2-ylmethyl)-phenylamine 'H NMR (DMSO-d 6 8 7.84 J 8.2 Hz, 1H), 7.73 IH), 7.21 J 8.2 Hz, 1H), 7.15 J 8.2 Hz, 1H), 6.65 J 2.1 Hz, IH), 6.52 (dd,,J 8.2, 2.1 Hz, 1H), 5.41 2H), 4.32 2H), 2.43 3H). MS 289.
WO 01/00579 WO 0100579PCT/USOO/18 178 The compounds of Table 20 were prepared using the method of example 94 from compounds in Table 19 and corresponding aryisulfonyl chloride.
Table CIO 0 B I Example A B D E yield 130 Cl CI CF 3 H 83% 131 C1 C1 C1 H 63% 132 C1 Cl Cl Me 73% 133 Cl H CF 3 H 78% 134 CF 3 CI CF 3 H 74% 135 CF 3 Cl Cl H 82% 136 CF 3 H CF 3 H 137 CF 3 H C1 H 26% 138 H C1 CF 3 H 67% 139 H C1 C1 H 140 H Cl Cl. Me 141 1- H CF 3 H 64% 142 Me Cl CF 3 H 84% 143 Me H CF 3 H 88% EXAMPLE 130 2-Chloro-N-13,5-dichloro4(5-chloro-bezothi2zol2-ylmethyI)phenyl]4-trifluoromethyl-belzeesulfoliamide 'H NMR (DMSO-d 6 8 11. 56 (br s, I1-H), 8.3 5 J 8.2 Hz, I 8.20 J 1 Hz, I 8.03 J =8.6 Hz, I 8.00-7.95 (in, 214), 7.45 (dd, J 8.6, 2.1 Hz, I H), 7.23 211), 4.62 2H). MS 583 WO 01/00579 PCT/USOO/18178 EXAMPLE 131 2,4-Dichlor-N3,5-dichloro-4-(5-chloro phenyll-benzenesulfonamide 'H NMR (DMSO-d,) 5 11.40 (br s, I 8.14 J 8.6 Hz, 1H), 8.05 J 8.6 Hz, 1H), 8.02 J 2.0 Hz, 1H), 7.94 J 2.1 Hz, 1H), 7.70 (dd, J 8.6, 2.1 Hz, 1H), 7.46 (dd, J 8.6, 2.0 Hz, 1H), 7.20 2H), 4.62 2H). MS 549 EXAMPLE 132 2,4-Dicbloro-N-13,5-dich Ioro-4-(5-chloro-benzothiazol-2-ylmethyl)- 'H NvR (DvSO-d 6 11.33 (br s, IH), 8.28 1H), 8.17 1H), 8.04 (d, J 8.6 Hz, IH), 8.01 J 1.9 Hz, IH), 7.87 IH), 7.45 (dd, J 8.6, 1.9 Hz, 1I), 7.22 2H), 4.61 2H), 2.40 3H). MS 563 EXAMPLE 133 2-Chloro-N-13-ch Ioro-4-(5-ch Ioro-benzothiazol-2-ylmethyl)-phenyl-4 trifluoromethyl-benzenesulfonamide 'H NMR (DMSO-d 6 S 11.24 (br s, IH), 8.29 J 8.3 Hz, 1H), 8.16 (br s, 1H), 8.02 J 8.6 Hz, IH), 8.00 J 1.8 Hz, Il), 7.96 J 8.3 Hz, 11), 7.45 (d, J 8.3 Hz, 2H), 7.20 J 2.0 Hz, IH), 7.10 (dd, J 8.4, 2.0 Hz, IH), 4.47 2H). MS (M-H)z 549 EXAMPLE 134 2-Chloro-N- [3-dichloro445-trinuoromet iazol-2ylmethyl)-phenyll-4-trifluoromethy-benzenlfonamide 'H NNR (DMSO-d 6 8 11.56 1H), 8.35 J 8.2 Hz, IH), 8.27 J 8.3 Hz, 1H), 8.26 (br s, Ii), 8.20 (br s, 1H), 7.99 (dd, J 8.3, 1.0 Hz, 1H), 7.73 (dd, J 8.2, 1.2 Hz, 11), 7.24 2H), 4.67 2H). MS 617 EXAMPLE 135 2,4-Dichloro-N- [3,5-dicloro-4-(5-trifluo rometyl-benzothiazo-2ylmethyl)-phenyll-bezenesulifonamide WO 01/00579 PCTIUSOO/18178 'H NMR (DMSO-d 6 )8 11.41 1H), 8.29 (br s, IH), 8.27 3 8.6 Hz, I 8.15 J 8.6 Hz, 1H), 7.94 J 2.0 Hz, 1H), 7.73 (dd, J 8.4, 1.4 Hz, 1H), 7.70 (dd, J 8.6, 2.0 Hz, IH), 7.21 2H), 4.67 2H). MS (M-H) EXAMPLE 136 2-Chloro-N-[3-chloro-4-(5-trifluromethy phenyl]-4-trifluoromethyl-benzenesulfonamide 'H NMR (DMSO-d 6 )8 11.25 (br s, 1H), 8.32-8.22 3H), 8.16 (br s, 1H), 7.96 J 8.4 Hz, 1H), 7.72 J 8.4 Hz, 1H), 7.46 J 8.3 Hz, IH), 7.21 (s, 1H), 7.11 J 8.4 Hz, lH), 4.52 2H). MS 583 EXAMPLE 137 2,4-Dichloro-N-13-cI Ioro-4-(5-trifluoromethyl-benzthiazol- 2 ylmethyl)-phenylj-benzenesulronamide 'H NMR (DMSO-d 6 8 11.10 (br s, 1H), 8.28 (hr s, 1H)j 8.26 J Hz, 1H), 8.08 J 8.5 Hz, I 7.89 J 2.0 Hz, 1H), 7.72 (dd, J 8.4, 1.4 Hz, 1H), 7.65 (dd, J 8.6, 2.1 Hz, IH), 7.46 J 8.4 Hz, IH), 7.18 J 2.1 Hz, IH), 7.10 (dd, J 8.3, 2.2 Hz, 1H), 4.52 2H). MS 549 EXAMPLE 138 N-(4-Benzothiazol-2-ylmethyl-3,5-dichloro-phenyl)-2trifluoromethyl-benzenesulfonamide 'H NMR (DMSO-d 6 8 11.54 1H), 8.35 J 8.3 Hz, 1H), 8.20 (br s, LH), 7.99 J 8.3 Hz, 2H), 7.88 J 7.8 Hz, IH), 7.46 (td, J 8.0, 1.0 Hz, 1H), 7.40 (td, J 7.8, 0.9 Hz, IH), 7.23 2H), 4.61 2H). MS 549 EXAMPLE 139 N-(4-Benzothiazol-2-ylmethyl-3,5-dichloro-phenyl)-2,4-dichlorobenzenesulfonamide 'H NMR (DMSO-d 6 8 11.38 1H), 8.14 J 8.6 Hz, IH), 8.00 J 7.9 Hz, IH), 7.94 J 2.0 Hz, 1H), 7.90 J 8.0 Hz, 1H), 7.70 (dd, J 8.6, 2.0 Hz, 1H), 7.46 1H), 7.40 1H), 7.20 2H), 4.60 2H). MS 515 WO 01/00579 PCTIUSOO/18178 EXAMPLE 14) N-(4-Benzothiazol-2-ylmethyl-3, ich methyl-benzenesuIfonamide 'H NMR (DMSO-d6) 6 11.32 IH), 8.17 1H), 8.00 J 7.9 Hz, IH), 7.90 J 8.1 Hz, IH), 7.88 IH), 7.46 J 7.3 Hz, IH), 7.39 J 7.4 Hz, IH), 7.16 2H), 4.60 2H), 2.40 3H). MS 531 EXAMPLE 141 N-(4-Benzothizol-2-ylmethyl-3-chloro-ph trifluoromethyl-benzenesulfonamide 'H NMR (DMSO-d6) 11.23 (br s, IH), 8.29 J 8.3 Hz, IH), 8.15 (br s, IH), 7.98 J 7.9 Hz, 1H), 7.96 J 8.4 Hz, 1H), 7.90 J 8.1 Hz, IH), 7.46 (td, J 7.9, 1.0 Hz, IH), 7.44 J 7.8 Hz, 111), 7.38 J 7.7 Hz, 1H), 7.20 J 2.1 Hz, IH), 7.11 (dd, J 8.3, 2.1 Hz, IH), 4.46 2H). MS(M-H)517 is EXAMPLE 142 2-Chloro-N- 3,5-dichloro-4-(5-methyl-benzothi azol-2-yl methyl)phenylj-4-trifluorometyl-benzenesulfonamide 'H NvR (DMSO-d 6 6 11.54 IH), 8.36 J 8.2 Hz, 1H), 8.19 (br s, IH), 8.00 (dd, J 8.2, 1.0 Hz, IH), 7.84 J 8.2 Hz, iH), 7.70 (br s, 1H), 7.26-7.18 3H), 4.58 2H), 2.40 3H). MS 563 EXAMPLE 143 2-Cloro--coro trifluoromethyl-benzenesulfonamide 'H NMR (DMSO-d 6 )6 11.22 (br s, 1H), 8.19(d, J 8.2 Hz, IH), 8.15 (br s, IH), 7.45 (dd, J 8.3, 1.1 Hz, IH), 7.83 J 8.2 Hz, IH), 7.71 (br s, IH), 7.43 J 8.4 Hz, lH), 7.24-7.19 2H), 7.05 (dd, J 8.5, 2.2 Hz, I 4.43 2H), 2.41 3H).
MS 529 EXAMPLE 144 This example illustrates the synthesis of 144.1.
WO 01/00579 PCT/US00/18178 109.1 144.1 Nitro compound 109.1 (1.91 g, 5.8 mmol) was reduced to the corresponding aniline using SnC1 2 *2H 2 O (6.54 g, 29.0 mmol) in EtOAc (40 mL) according to the procedure previously described in Example 30. This yielded 692 mg of compound 144.1 as a white powder.
MS EST m/e: 300.0 (M H).
EXAMPLE 145 This example illustrates the synthesis of 145.1.
H
2 02S'NH I
I
144.1 145.1 A round-bottomed flask was charged with aniline 144.1 (110 mg, 0.37 mmol), 2,4-dichlorobenzenesulfonyl chloride (108 mg, 0.44 mmol), 2,6-lutidine (47 mg, 0.44 mmol), catalytic DMAP, and methylene chloride (2.0 mL). The reaction was allowed to stir overnight. The reaction was then diluted with 20 mL of methylene chloride and washed with 10 mL of 1N HC1 and 10 mL of brine. The organics were dried over Na 2
SO
4 and concentrated to a yellow oil. This oil was further purified using silica gel flash chromatography. The desired fractions were combined and concentrated to yield 60 mg of compound 145.1 as a white foam.
WO 01/00579 WO 0100579PCTIUSOO/18178 'H NMR (400MIz) (d 6 -DMSO) 8 11.36 (lH, 8.12 (IH, d, J=f8.6 Hz); 7.94 (lH, J=2.1 Hz); 7.68 (IH, dd, J=8.6, 2.1 Hz); 8.63 (111, d, J=8.4 Hz); 7.47 (1 H, d, J=8.4 Hz); 7.36-7.32 (1 H, in); 7.27-7.19 (4H, in); 2.54 (2H, q, J= 7.6 Hz); 1.08 (3H, t, J=7.6 Hz). MS ESI m/e: 506.0 (M H).
EXAMPLE 146 This example illustrates the synthesis of 146.1.
NH
2 0 2S, NH 0 144.1 146.1 Aniline 144.1 (111 mg, 0.37 mmol), pipsyl chloride (135 mg, 0.45 inniol), 2,6-lutidine (48 mg, 0.45 minol), and catalytic DMAP were combined in methylene chloride (2.0 mL) according to the procedure described in Example 77. This yielded 140 mg of compound 146.1 as a white foam.
1 H NMR (400MHz) (d 6 -DMSO) 8 10.97 (1IH, 8.01 (2H, d, 1=8.4 Hz); 7.63 (1 H, d, 1=8.4 Hz); 7.58 (2H, d, J=8.4 Hz); 7.46 (1 H, d, J=8.4 Hz); 7.34 (1 H, in); 7.46-7.20 (4H, nm); 2.54 (2H, q, J=7.5 Hz); 1.09 (3H, t, J=7.5 Hz). MS ESI mle: 563.9 (M EXAMPLE 147 This example illustrates the synthesis of 147.1.
WO 01/00579 PCT/US00/18178 144.1 147.1 Aniline 144.1 (108 mg, 0.36 mmol), 3,4-dichlorobenzenesulfonyl chloride (106 mg, 0.43 mmol), 2,6-lutidine (46 mg, 0.43 mmol), and catalytic DMAP were combined in methylene chloride (2.0 mL) according to the procedure described in Example 77. This yielded 113 mg of compound 147.1 as a white foam.
'H NMR (400MHz) (CDCI 3 5 7.96 (1H, d, J=2.2 Hz); 7.66 (1H, dd, J=8.4, 2.2 Hz); 7.57 (1H, d, J=8.4 Hz); 7.46 (1H, d, J=8.3 Hz); 7.34 (1H, d, J=8.3 Hz); 7.31-7.26 (3H, 7.20-7.15 (2H, 2.79 (2H, q, J=7.6 Hz); 1.27 (3H, t, J=7.6 Hz).
MS ESI m/e: 506.0 (M H).
EXAMPLE 148 This illustrates the synthesis of(2-fluoro-4-nitro-phenyl)acetic acid 148.
A round-bottomed flask was charged with diethyl malonate (8.6 g, 54 mmol), cesium carbonate (29.3 g, 90 mmol), and anhydrous DMF (36 mL). The mixture was warmed to 70 °C and 2,4-difluoronitrobenzene (5.75 g, 36 mmol) was added in a dropwise fashion with vigorous stirring. The reaction medium immediately turned dark purple. After the addition was complete, the reaction was stirred at 70C for 30 minutes.
After cooling to room temperature, the reaction was quenched with 4 mL of acetic acid and then poured into 300 mL of 0.3 N HCl(a). The purple color discharged completely upon addition to the acid. The mixture was then neutralized by adding solid NaHCO 3 until no gas evolution took place. The mixture was extracted 2 x 150 mL 1:1 diethyl ether:hexanes. The combined organic layers were washed 2 x 100 mL DI water and 1 x 50 mL sat. brine. The organic layer was dried over MgSO4 and concentrated to a yellow oil. This oil was suspended in 40 mL of6N HCI(aq and the mixture heated to reflux for WO 01/00579 PCT/US00/18178 16 h. Upon cooling, crystals separated and were collected by filtration. The crystals were dried under vacuum to yield 2-fluoro-4-nitro-phenylacetic acid (148) as off-white crystals (5.42 g).
'H NMR (400MHz) (d 4 -MeOH) 8 8.06 (1H, 8.04 (1H, 7.60 (1H, t); 3.81 (2H, s).
EXAMPLE 149 This illustrates the synthesis of 7-chloro-2-(2-fluoro-4-nitro-benzyl)benzoxazole 149.
The benzoxazole 149 was formed according to the method of Terashima and Ishi (Synthesis 1982, 484-85.). Phenylacetic acid 148 (387 mg, 1.95 mmol), 2amino-6-chloro-phenol (233 mg, 1.67 mmol, described in J Med. Chem. 1996, 39, 3435- 3450), and boric acid (120 mg, 1.95 mmol) were combined in xylenes (24 mL) and the mixture heated to reflux in a flask equipped with a Dean-Stark trap. After 8 h, the reaction mixture was filtered, concentrated, and the residue purified by flash chromatography (silica gel, 3:1 hexanes:ethyl acetate). Fractions containing benzoxazole 149 were concentrated to a yellow solid (419 mg).
'H NMR (CDCI 3 5 8.05 1H); 8.00 (dd, 1H); 7.61 1H); 7.57 (d, 1 7.33 IH); 7.27 IH) 4.38 2H). MS 307.0 EXAMPLE 150 This illustrates the synthesis of compound 150.
NO
2 ^e N ,.S H C C CI 150 A round-bottomed flask was charged with methylbenzimidazole (4.84 g, 29.5 mmol), potassium hydroxide (1.66 g, 29.5 mmol), and water (18 mL). This suspension was heated to 120 0 C for 3.0 hours. Then 3,4,5trichloronitrobenzene (6.68 g, 29.5 mmol) dissolved in 53 mL of n-butanol was added WO 01/00579 PCT/US00/18178 dropwise while the reaction stirred at 120 0 C. All the white solids went into solution and the solution proceeded to turn a deep red color. The reaction was left stirring for five days, at which point a yellow precipitate was seen. The reaction was then cooled to room temperature and the precipitate was filtered and washed with distilled water to yield 8.10 g of compound 150 as canary yellow crystals which were a 50/50 mixture of both' possible tautomers.
'H NMR (400MHz) (d 6 -DMSO) 8 12.64 (1H, 8.48 (2H, d, J=2.2 Hz); 7.34 and 7.27 (1H, 2 tautomeric doublets, J=8.3 Hz); 7.26 and 7.19 (1H, 2 tautomeric singlets); 6.99 and 6.95 (IH, 2 tautomeric doublets, J-8.1 Hz); 2.38 and 2.35 (3H, 2 tautomeric singlets).
EXAMPLE 151 This illustrates the synthesis of compound 151.
02
NH,
C C CI e 150 151 A round-bottomed flask was charged with 8.1 g (22.8 mmol) of compound 150, 20.6 g (91.4 mmol) of tin dichloride dihydrate, and 150 mL of EtOAc. This was heated to 75°C for 3.0 hours. The reaction was cooled to room temperature, diluted with 300 mL of EtOAc and washed with 250 mL of 2N aqueous KOH solution followed by 200 mL of brine. The organics were dried over sodium sulfate and concentrated to 7.4 g of 151 as a pale yellow solid that was used without further purification. MS 324 EXAMPLE 152 This illustrates the synthesis of compound 152.
A round-bottomed flask was charged with compound 151 (749 mg, 2.31 mmol), 4-acetylbenzenesulfonyl chloride (1.01 g, 4.62 mmol), 2,6-lutidine (496 rng, 4.62 mmol), acetone (4.0 mL), and a catalytic amount of DMAP. This was stirred at room temperature for 12 hours, after which 2,6-lutidine hydrochloride was seen as a white WO 01/00579 PCT/US00/18178 precipitate. The reaction was diluted with 40 mL of EtOAc and washed with 30 mL of IN aqueous HCI followed by 30 mL of brine. The organics were dried over magnesium sulfate and concentrated to a clear oil that was dissolved in 30 mL of THF. To this was added 30 mL of 0.5N aqueous KOH. This was stirred at room temperature for 12 hours, and the reaction color progressed from a light yellow to a deep orange. Next, the pH was brought to 7.0 with 1.ON HCI and the THF was removed in vacuo. The remaining aqueous phase was extracted with 100 mL of Et 2 O. The organic layer was dried over sodium sulfate and concentrated to a yellow oil that was further purified with silica gel flash chromatography (3:2 hexanes:EtOAc). The desired fractions were combined and concentrated to an oil which was recrystallized from hot EtOAc/hexanes to yield 312 mg of 152 as an off-white solid. MS 504.
'H NMR (d 6 -DMSO) 8 12.36 (1H, broad 11.39 (1H, broad 8.18 (2H, 8.03 (2H, 7.32 (2H, 7.32-7.04 (2H, 6.96 (1H, 2.62 (3H, 2.35 (3H, s).
EXAMPLE 153 This illustrates the synthesis of compound 153.
,,0 C I
S
Compound 153 was prepared according to Example 152. In this case, 353 mg (1.1 mmol) of compound 151 was used to give 76 mg of 153 as white crystals.
'H NMR (d 6 -DMSO) 8 12.31 (IH, broad 11.42 (1H, broad 8.90 (1H, 8.29 (1H, dd); 7.81 (1H, 7.34 (2H, 7.26 (1H, broad 7.17 (1H, broad 6.92 (1H, 2.35 (3H, MS 497.0.
The additional examples of Table 21 were prepared according to the method of Example 152.
WO 01/00579 WO 0100579PCTUSOO/181 78 Table 21 152 153 154 155 156 157 158 159 160 161 162 163 164 A B C H H -C(=O)Me H [2-chlorQ-5-pyridyl] Me H Cl Cl H Cl CI H CF 3 CI H' Cl CI H Cl H CI Cl CI H CF 3 CI H CI H H I [2-chloro-5-pyridyl] Me H Cl D m/e (NI-H) 504 497 Me 524 H 530 H 564 Me 544 H 496 H 496 H 530 Me 510 H 554 463 Me 490 EXAMPLE 154 'H NMR (d 6 -DMSO) 8 12.29 (1 H, broad 11.37 (1 H, broad 8.01 (1 H, 7.57 (IH, 7.19-7.33 (4H, in); 6.91 (1H, 2.57 (3H, 2.38 (3H, 1.24 (3H, s).
MS 524.
EXAMPLE MS 529.8. 'H NMR (d 6 -DMSQ) 8 12.31 (1 H, broad 11.64 (1 H, broad 8.18 (1 H, 7.94 (1IH, 7.71 (1 H, dd); 7.34-7.09 in); 6.93 (1 H, 2.3 3 (3H, s).
WO 01/00579 WO 0100579PCTJIJSOO/18178 EXAMPLE 156 MIS 564. 'H NMR (d 6 -DMSQ) 8 12.28 (1 H, broad 11.80 (IH, broad 8.38 (1H, 8.19 (1H, 8.00 (1H, 7.29 (211, 7.24 (IH, broad 7.15 (IH, broad 6.91 (1H, 2.34 s).
EXAMPLE 157 MS 544. 'H NMIR (d 6 -DMSO) 5 12.29 (1 H, broad 11.58 (111, 8.22 (IH, 7.89 (1H, 7.29 (2H, 7.24 (1H, broad 7.16 (11H, broad 6.91 (IH, 2.41 (3H, 2.34 (3H, s).
The examples of Table 22 were prepared by analogy to the methods of Examples 150-152.
Table 22
A
NH
c
D
H
S
A B C D mle(M-H) 165 CI H Cl Me 496 166 Cl H Cl H 482 167 H H I H 540 168 H Cl Cl H 482 169 Cl H CF 3 H 516 170 Me H Cl Me 476 The examples of Table 23 were prepared by analogy to the methods of Examples 150-152.
WO 01/00579 WO 0100579PCTUSOO/18 178 Table 23 B- S 'NH C
II
C S
F
3 A B C D Wle (M-H) 171 C1 H Cl H 584 172 Cl H CF 3 H 618 173 Me H Cl Me 578 EXAMPLE 174 N0 2
NH,
C 1C C1 174 175 3-Hydroxyquinoline (prepared according to the procedure of Naumann, el.
al., Synthesis, 1990, 4, 279-28 (3 g) and 1,2,3- trichloro-5-nitrobenzene (4.7 g) were dissolved in DMI (80 mL) and heated with cesium carbonate (7.4g) for 2 hr at 60'C. The reaction was poured into ice/water (500 ml). The resulting off-white precipitate was collected by filtration and rinsed with hexane to afford compound 174 as a solid (6.9g) suitable for use in the next reaction.
'H NMR in CDC1 3 8.863 J=2.2Hz, IH), 8.360 2H), 8.106 (d, J=8.6Hz, IH), 7.646 (in, 2H), 7.529 J=8.6Hz, IH), 7.160 J=2.2Hz, 1H) EXAMPLE 175 To a solution of compound 174 (6.9 g) in ethanol/THF/water (ratio 40:20:10) was added ammonium chloride (3.3 g) and powdered iron This mixture was heated to reflux for 5 hr. The hot mixture was then filtered through Celite and concentrated. The residue was dissolved in ethyl acetate and washed with saturated NaHCO 3 solution followed by water and then brine. The solution was dried over magnesium sulfate and concentrated to afford compound 175 as an off-white solid (5.6 g).
'H NMR in (DMSO) S 8.846 J=2.9Hz, 1H), 8.010 1H), 7.915 (m, 1H), 7.645 1H), 7.560 1H), 7.401 J=2.9Hz, 1H), 6.778 2H), 5.762 2H).
Treatment of the aniline 175 with various sulfonyl chlorides according to conventional methods gave the sulfonamides of Table 24.
Table 24 9 9 9 9 9 9 9 15 Example 176 177 178 180 181 182 183 184 185 186 X Y H H H H H H H H
-CO
2 Me H H -CO 2 Me
-CO
2 H H H -CO 2
H
Me H H H
A
CF
3 Cl Cl Cl Cl Cl Cl Cl Cl Cl
C
Cl
CF
3 Cl Cl Cl Cl Cl Cl Cl Cl WO 01/00579 WO 0100579PCT/USOO/18178 EXAMPLE 176 'H NMR (DMSO) 8 11.4-11.6 (1IH, broad), 8.87 (11-H, d, J 2.9 Hz), 8.15- 8.22 (2H, in), 8.00-8.08 (2H, in), 7.87 (IH, d, J= 8.0 Hz), 7.55-7.68 (2H, in), 7.47 (1IH, d, J 2.9 Hz), 7.35 (2H, MS 545. mp 98.8 TC.
EXAMPLE 177 'H NMvR(DMSO) 8 11.58 (IH, 8.86 (11H, d, J= 2.9 Hz), 8.38 (1 H, d, J -8.4 Hz), 8.23 (IH, 8.01 (LH, d, J= 8.4 Hz), 7.86 d, J= 8.1 Hz), 7.53-7.68 (2H, in), 7.46 (IH, d,J= 2.9 Hz), 7.34 (2H, MS 545.0 EXAMPLE 178 1H NMR(d 6 -acetone) 9.9 (1lH, br 8.794 (1IH, d, J= 2.9 Hz), 8.23 (1IH, d, J 8.4H1-z), 8.035 (1IH, brd, J8.4 Hz), 7.793 (1 H,d, J= 1.5 Hz), 7.7 8 (1IH, 7.62- 7.70 (2H, 7.57 (1H, td, J =6.8,1.2 Hz), 7.476 (2H, 7.364 (1 H,d, J2.6 Hz). MIS 511. 0.
EXAMPLE 179 'H NMR(300M-HzICDC1 3 B 2.43(3H, '7.10(IH, d, J=3Hz), 7.26(2H, s )7.48-7.64(4H, in), 7.96(l H, s 8.09(I H, d, J= 8MHz), 8.78(l H, d, J=3H1z).
MS(M+H) 527. mp 233-2350 EXAMPLE 180 'H NM7R(300MHz/CDC] 3 8 7.14(IH, dd, J=2.6Hz,J=8.9Hz), 7.26(1H, d, 3=8.9Hz), 7.33(1H, d, J=2.6Hz), 7.56-7.58(2H, in), 7.66-7.69(2H,m), 7.87(IH, mn), 7.93(IH, d, J=2.OHz), 8.00(l1H, in 8.09(l H, d, J=8.5Hz), 8.80(lIH, d, J=2.9Hz), 1 1.06(1 H, brs), MS(M+H)) 479. nip 12: 0C EXAMPLE 181 3-[2,6-Dichloro-4- (2,4-dichloro-benzenesulfonyamio)-phe1oxyiquinoline-6-carboxylic acid methyl ester (181) A solution of 3 -(4-Amino-2, 6-dichloro-phenoxy)-quinoline-6-carboxylic acid methyl ester (312) (0.93rninol) and 2,4-dichlorobenzenesulfonyl chloride (250mg, I .O2imol) in Pyridine 13m1, I .53imol)-CH 2
C
2 (3.7in1) was stirred at room WO 01/00579 WO 0100579PCTIUSOO/18178 temperature for 12 hr. Sat NaHCO 3 was added to the reaction mixture, which was then extracted twice with AcOEt. Organic layer was washed by brine, dried over anhydrous MgSO 4 and concentrated. Crude residue was purified by colum chromatography (Hexane/AcOEt=2/1, 80g of silica gel) to afford compound 181 (237mg, 41%, in 3 steps).
'H NMR (300MHz,DMSO-d 6 8 3.90 (3H, 7.3 1(2H, 7.72 (1lH, dd, J=1.8, 7.8Hz), 7.79 (1H, d, 1=3.0Hz), 7.96 (1H, d, J=1.8Hz), 8.11 (2H, 8.18 (lH, d, J=7.8Hz), 8.64 (1H, 8.99 (lH, d,J=3.0Hz), 11.42 (1H,br MS 571 EXAMPLE 182 3-[2,6-Dichloro-4- (2,4-dichloro-benzenesulfonylamif)-pheIoxyIquinoline-8-carboxylic acid methyl ester (182) To a solution of 3-(4-Aniino-2, 6-dichloro-phenoxy)-quinoline-8carboxylic acid methyl ester (315) (1.26mmol) in Pyridine 15m1, l.8Ommol) and
CH
2
CI
2 (5mi), was added 2,4-Dichlorolbenzenesulfonyl chloride (381 mg, 1 The mixture was stirred at room temperature for l2hr. Sat NaHCO 3 was added to the reaction mixture, which was then extracted twice with AcOEt. Organic layer was washed by Brine, dried over MgSO4, and concentrated. The crude residue was purified by column chromatography (Hexane/AcOEt-2/1, 80g of silica gel) to afford compound 182 (506mg, 70%) as a white solid.
'H NMR (300MHz,DMSO-d 6 8 3.91 (3H, 7.3 1(2H, 7.57-7.65 (2H, in), 7.72 (1IH, dd, J=2.1, 8.6Hz), 7.83(lIH, d, J=8.6Hz), 7.96 (2H, d, J=2.lIHz), 8.03 (1 H, d, 1=8.6Hz), 8.18 (1IH, d, J=8.6Hz), 8.94 (1IH, d, J=2.lIHz), 11.4 (1LH, br MS(M+H) 5 71 EXAMPLE 183 3-12,6-Dichloro-4- (2,4-dichloro-benzenesuffonylamino)-peloxyIquinoline-6-carboxylic acid (183) To a solution of 3-[2,6-Dichloro-4- (2,4-dichloro-benzenesul fonyl amino)phenoxy]-quinoline-6-carboxyllc acid methyl ester (181) (200mg, 0.3 Smmol) in THFIMeOH(2m12m1) was added 4N NaOH 1 ml, .4mmol). This mixture was refluxed for 2.5 hr. The reaction mixture was cooled to room temperature and was neutralized with 2N HCI, and then concentrated. The residue was extracted twice with AcOEt. Organic layer was washed by Brine, dried over anhydrous MgSO 4 and WO 01/00579 WO 0100579PCT[USOO/18178 concentrated to give a solid. Crude product was recrystallized by Hexane/AcOEt to afford compound 183(153mg, 78%).
'H NMR (300MHzDMSO-d 6 8 7.16 (2H, 7.62(l1H, dd, J=2.0, 8.5 Hz), 7.73 (1 H, d, J=2.9Hz), 7.82 (1IH, 8.08-8.11 (3H, in), 8.60 (1 H, 8.95 (1IH, d, J=2.9Hz), 13.2 (LH, br MIS 557. mp 228-2 EXAMPLE 184 3-12,6-Dichloro-4- (2,4-dichloro-benzenesulfonylamilo)-pheloIYIquinoline-8-carboxylic acid (184) To a solution of 3-[2,6-Dichloro-4- (2-chloro-4-trifluoromethylbenzenesulfonylamino)-phenoxy]-quilie-8-carboxylic acid methyl ester (183) (402mg, 0.7mmol) in THFIMeOH=0.lmlO.3m1 was added 4N NaOH (0.2m1, 0.77innol). The mixture was refluxed for l2hr. After cooling to room temp. the reaction mixture was filtered to remove insoluble materials. The filtrate was concentrated and the residAe was dissolved in aq NI{ 4 C1 and extracted twice with AcOEt. Organic layer was washed by Brine, and dried over anhydrous MgSO 4 and concentrated to afford compound 184 (197mg, 50%) as a white solid.
'H NMR (300MHz,DMSO-d 6 8 7.32 (2H, 7.70-7.81(2H, in), 7.90 (1IH, d, 1=2.2Hz), 7.96 (IH, d, 1=2.2Hz), 8.17-8.19 (111, 8.22-8.24 (I11, in), 8.38-8.39 (11-, in), 9.11 (111, d, J=2.2Hz), 11.4 (IH, br 15.4 (IH, br MIS 557. mp 263-266 0C.
EXAMPLE 185 2,4-Dichloro-N- 13,5-dich Ioro-4- (6-metbyl-quinoln-3-yloxy)-phellI-5methyl-benzenesulfonamide(1 To a solution of 3,5-Dichloro-4- (6-methyl-quinlin-3-yloxy)-phenylaine (339) (400mg, 1 .25minol) in Pyridine 1 2m1, 1 .48iniol)- CH 2
CI
2 (4ml) was added 2,4chloride (325mg, 1 .25mmol). The mixture was stirred at room temperature for 1 2hr. The reaction mixture was concentrated and the residue was purified by column chromatography (Hexane/AcOEt2/l, 80g of silica gel) to provide compound (185) (453mg, 66%) as a white solid.
WO 01/00579 PCT/US00/18178 'H NMR (300MHz,DMSO-d6) 8 2.41 (3H, 2.44(3H, 7.31 (3H, s), 7.49 (1H, d, J=8.7Hz), 7.61 (lH, 7.88-7.91 (2H, 8.19 (1H, 8.74 (1H, d, 11.3 (1H, br MS 541 mp 228-230°C.
EXAMPLE 186 PART 1 Preparation of 3-chloro-5-fluoro-4-(quinolin-3-yloxy)nitrobenzene (186.1) To a solution of 3,4-Difluoronitrobenzene 1.OOg in conc.H 2
SO
4 (20ml), was added portionwise C1 2 0 in CC14(25ml, prepared as described by Cady G. H. et. al in Inorg.
Synth. Vol 5, p 1 56(1957)). The mixture was stirred at room temperature overnight. The mixture was poured into crashed ice and extracted with Et0O (30mlx3). Combined ether layers were washed with 10%Na 2
SO
3 and brine, and dried over Na 2
SO
4 The solvent was concentrated to Ca. 10ml(This solution contains 3-Chloro-4,5-difluoronitrobenzene).
This solution was diluted with acetone (60ml), and then 3-hydroxyquinoline 0.75g and
K
2
CO
3 2.2g were added to this solution. The mixture was heated to reflux for 1.5 hr.
After cooling the reaction mixture was filtered through a short celite pad. The filtrate was concentrated to give an oil, which was then purified by column chromatography (silica gel, AcOEt:Hexane=1:5) to provide the intermediate compound 186.1 (0.980g) as a yellow oil.
PART 2 Preparation of 3-Chloro-5-fluoro-4-(quinolin-3-yloxy)phenylamine (186.2) To a solution of 3-Chloro-5-fluoro-4-(quinolin-3-yloxy)nitrobenzene (186.1) (0.980g) and NH 4 C1 (1.64g) in EtOH(50ml) H 2 0 (5ml), was added iron powder (1.92g). The mixture was heated to reflux for Ihr. After cooling the reaction mixture was filtered through short celite pad. The filtrate was concentrated, diluted with sat.
NaHCO 3 and extacted with AcOEt(30mlx3). The combined organic layeres were washed with brine and dried over Na 2 S04. Concentration of solvent afford crude product, which was purified by column chromatography (silicagel, AcOEt:Hexane=1:3) to provide aniline 186.2 (0.420g) as a colorless solid.
WO 01/00579 WO 0100579PCT/USOO/18178 PART 3 Preparation of N-[3-chloro-5-fluoro-4-(quiflolil- 3 -yloxy)phenyl]-2,4- 186 To a sol ution of 3-hoo5fur--qioln3yoypeyain (186.2) 0.420g) in pyridine(2.2mi), was added 2,4-dichloro-5methylbenzenesulfonylchloride 0.360g. The mixture was stirred at room for Ilhr. The reaction mixture was purified directly by column chromatography (silicagel, AcOEt:Hexane-l The product was triturated by hexane to give title compound (0.522g). as a solid.
NMR(300M1-zICDCl 3 8 2.43(3H, s 7.05(l1H, d, J=2.6Hz), 7.09- 7.1 l(lH, in), 7.21I(IH, d, J=2.6H1z), 7.36(IH, brs 7.49-7.66(4H, in), 7.96(lIH, s) 8. 10(1IH, d, J=8.2H1z), 8.80(I H, brs). MS 511. mp 187 *C.
EXAMPLE 187 This illustrates the synthesis of 7-chloro-2-(2-fluoro-4-aiflifo-benzyl)benzoxazole 187.
To the nitro compound 149 (419 mg, 1.4 mmol) in ethyl acetate (10 mL) was added SnCI 2 -2H 2 0 (1.2 g, 5.5 mmol). The reaction mixture was heated to reflux for minutes. After allowing to cool to room temperature, the reaction mixture was poured into 13 mL of saturated 2N KO~laq). The layers were separated, and the aqueous layer extracted 1 x 30 mL ethyl acetate. The combined organic layers were washed with saturated bine and dried over Na 2
SO
4 After concentration, the yellow oil was purified by radial chromatography (2 mm silica gel layer Chromatatron plate, 3:2 hexanes:ethyl acetate). Eluant containing the desired product was concentrated to 194 mg of aniline 187.
1H NMR (d 6 -acetone) 8 7.58 (dd, 1H); 7.39-7.3 1 (in, 2H); 7.11 1H); 6.50-6.43 (mn, 211); 4.94 (bs, 2H); 4.21 2H). MS 277. 1.
EXAMPLE 188 This illustrates the synthesis of sulfonamide 188.
WO 01/00579 PCT/US00/18178 Example 188 A C=C Example 189 A=H; C=COMe To aniline 187 (95 mg, 0.34 mmol) in acetone (1 mL) was added 2,6lutidine (60 piL, 0.51 mmol) and 2,4-dichloro-benzenesulfonyl chloride (93 mg, 0.38 mmol, Maybridge Chemical After 16 hours, the reaction mixture was filtered through a 1 cm plug of silica gel. After concentration, the yellow oil was purified by radial chromatography (1 mm silica gel layer Chromatatron plate, 3:1 hexanes:ethyl acetate). Eluant containing the product was concentrated and the residue recrystallized from hot hexanes/ethyl acetate. Filtration and drying under vacuum yielded the sulphonamide 188 as light yellow crystals (65 mg).
'H NMR (d 6 -acetone) 8 9.70 (bs, 1H); 8.16 1H); 7.71 1H); 7.60- 7.56 2H); 7.42-7.32 3H); 7.11-7.09 2H); 4.32 2H). MS 482.9.
.EXAMPLE 189 This illustrates the synthesis ofsulfonamide 189.
By the method of example 188, using the aniline 187 and 4-acetylbenzenesulfonyl chloride compound 189 was obtained as light yellow crystals.
'H NMR (d6-acetone) 8 9.50 (bs, 1H); 8.11 2H); 8.11 2H); 7.98 (d, 2H); 7.57 1H); 7.42-7.32 3H); 7.12-7.06 2H); 4.33 2H); 2.61 3H). MS 482.9.
EXAMPLE 190 This illustrates the synthesis of compound 190.
WO 01/00579 PCT/US00/18178 NO
NH
2 N C
IN
U-
190 191 2-chloro-4-nitro-phenol (2 g, 11.5 mmol) was dissolved in DMF (5 mL) and treated with Cs 2
CO
3 (3.7 g, 11.5 mmol). The reaction mixture was heated to 50 °C until gas evolution stopped. 2-chlorobenzoxazole (2.65 g, 17.3 mmol) was added, and then the reaction mixture was warmed to 75 OC. After 5 hours, the heat was removed and the reaction mixture was poured into 150 mL ofdeionized water with vigorous stirring.
The precipitate was collected by filtration and rinsed several times with distilled water.
The product was dried under a stream of air for 15 minutes, then under vacuum overnight to afford compound 190 as an off-white solid (3.4 homogeneous by TLC (Rf=0.55, 3:1 hexanes:ethyl acetate). MS 291.0 EXAMPLE 191 This illustrates the synthesis of compound 191. See above.
A round-bottomed flask was charged with 2.01 g (6.93 nunol) of compound 190, 50 mL of isopropyl alcohol, and 20 mL of THF. Then 0.5 mL of a 50/50 suspension ofRaney Nickel in water was added. The reaction was then stirred under a hydrogen balloon at room temperature for 24 hours. Raney Nickel was removed by filtration through celite, and the solution was concentrated in vacuo. Recrystallization from ethanol and hexanes gave 1.01 g of aniline 191 as off-white needles. MS 261.0.
EXAMPLE 192 This illustrates the synthesis of compound 192. (See Table below) A round-bottomed flask was charged with aniline 191 (144 mg, 0.55 mmol), 2,4-dichlorobenzenesulfonyl chloride (221 mg, 0.55 mmol), 2,6-lutidine (97 mg, 0.55 mmol), catalytic DMAP, and acetone (3.0 mL). The reaction was allowed to stir overnight. The reaction was then diluted with 20 mL ofmethylene chloride and washed WO 01/00579 WO 0100579PCTJUSOO/18178 with 10 mL of IN HCI and 10 mL of brine. The organics were dried over Na 2
SO
4 and concentrated to a clear oil. This oil was further purified using silica gel flash chromatography. The desired fractions were combined and concentrated to a stiff foam.
The product was recrystallized from methylene chloride and hexanes to yield 165 mg of compound 192 as white crystals.
'H NMR (d 6 -DMSO) 5 11.21 (LR, 8.12 (1H, d, J=8.6 Hz); 7.92 (IH, d, J=2.1 Hz); 7.69-7.63 in); 7.48 (1IH, dd, J=7.3, 4.3 Hz); 7.31-7.29 (311, mn); 7.18 (1IH, dd, J=9.0, 2.6 Hz). MS 467.0 The additional examples of Tab le 25 were prepared from aniline 191 and the corresponding sulfonyl chloride by the method of example 192.
Tahle
A
02
SNH
D
Example A B C D (M-H) 192 Cl H Cl H 467 193 Cl H CI Me 481 194 Me H Cl Me 195 Cl H CF 3 H 501 196 H H -COMe H 441 197 [2-chloro-5-pyridyl] 434 EXAMPLE 193 'H NMR (d 6 -DMSO) 8 11.14 (IH, 8.14 (11H, 7.87 (IH, 7.65-7.61 in); 7.50-7.48 (1H1, in); 7.32-7.28 (3H, in); 7.19 (1IH, dd, J8.9, 2.7 Hz); 2.40 (3H1, s).
MS 481 WO 01/00579 WO 0100579PCTIUSOO/18 178 EXAMPLE 194 'H NMR (d 6 -DMSO) 8 10.92 (1 H, 7.94 (1 H, 7.65 -7.60 (2H, in); 7.54 (1lH, 7.49 (1 H, dd, J=4.8,1 .6 Hz); 7.31-7.27 (3H, in); 7.16 (11H, dd, J=8.9, 2.6 Hz); 2.56 (3H1, 2.36 (3H, s).
EXAMPLE 195 'H NMR (d 6 -DMSO) 8 11.36 (1 H, 8.32 (1 H, 8.18 (11H, 7.97 (1IH, dd); 7.64 (2H, dd); 7.47 (1 H, 7.31 (3H, in); 7.20 (11, dd). MS 501.
EXAMPLE 196 'H NMR (400MHz) (d 6 -DMSO) S 10.96 (1H, 8.15 (2H, dd); 7.97 (2H, 7.62 (2H1, 7.49 (11, 7.31 (3H, mn); 7.22 (111, 2.62 (3H, MS 441.0 EXAMPLE 197 'H NMR (d 6 -DMSO) 8 11.04 (IH, 8.89 (lH, 8.34 (1H, dd); 8.05 (1H, 7.87 (1H, 7.67 (lH, dd); 7.52 (11, 7.38 (111, 7.25 (111, 7.19 (11, t); 2.62 (311, MS 434.0 EXAMPLE 198 Preparation of 3-Chloro-4-(quinolin-3-yloxy)nitrobenzefle(1 9 8 To a solution of 3-hydroxyquinoline (1.00g) and 3-chloro-4fluoronitrobenzene (1.21g) in Acetone(20m1), was added K 2 C0 3 (2.86g). The mixture was refluxed for lhr. After cooling the reaction mixture was filtered through a short celite pad. The filtrate was concentrated to provide compound 198 2.07g, quant.) as a brown oil.
'H NMR(300MHz/CDC 3 8 7.02(l1H, d, J=9.1IHz), 7.61 (11H, in), 7.72- 7.80(3H1, in), 8.10-8.18(211, in), 8.45(111, d, J=2.7Hz), 8.82(111, d, J=2.8Hz).
EXAMPLE 199 Preparation of 3-Cbloro-4-(quinolin-3-yloxy)phenylamnine (199) To a solution of nitrobenzene 198 (2.07g) and NH 4 Cl (1 .84g) in EtOR -1120 (10 ml), was added iron powder (1.92g). The mixture was heated to WO 01100579 WOOI/0579PCT[USOO/18178 reflux for lhr. After cooling the reaction mixture was filtered through short celite pad. The filtrate was concentrated, diluted with sat. NaHCO 3 (30m1) and extacted with AcOEt(30ml). The combined organic layers were washed with brine (30m1) and dried over Na 2
SO
4 Concentration of the solvent afforded the aniline 199 (1.77g, 95%)as a yellow solid.
'H NMR(300MHZ/CDCI 3 8 3.77(2H-, brs), 6.63(IH, dd, J=2.7Hz, J=8.6Hz), 6.83(IH, d, J=2.7Hz), 6.99(1H, d, J=8.6Hz),7.24(lH, d, J=2.8Hz), 7.49(IH, in), 7.56-7.64(2H, mn), 8.08(1H, in), 8.86( lH, J=2.8Hz) The structures for examples 200-208 are illustrated in Table 26.
Table 26
EXAMPLE
200 201 203 204 205 206- 207 208 w x H Cl H H Cl H Cl H H H H Me Cl H H SO 2 Me
MS(M-H)
372 304 352 406 354 (M+H) 354 (MI-H) 372 416 EXAMPLE 200 This illustrates the synthesis of compound 200.
2-amnino-6-chlorobenzothiazole (3.68 g, 20 mmnol) and 1 ,2,3-trichloro-5nitrobenzene (4.53 g, 20 minol) were dissolved in anhydrous DMSO (10 mL). Solid
K
2 C0 3 (3.04 g, 22 mmol) was added and the reaction mixture heated to 150 'C for 4 WO 01/00579 PCT/US00/18178 hours. Let cool, then poured into 200 mL deionized water. A fine yellow solid precipitated which was collected by filtration after attempts to dissolve the product in ethyl acetate failed. The yellow solid was suspended in 100 mL of ethyl acetate and heated to reflux. After cooling to room temperature, filtration, rinsing with ethyl acetate followed by hexanes, and drying under vacuum provided the nitro compound 200 as a yellow powder. (1.06 g) 'H NMR (d 6 -DMSO) 8 8.37 2H); 7.76 (bs, 1H); 7.30 (dd, 1H); 7.23 (bs, 1H). MS 372 EXAMPLE 201 This illustrates the synthesis of compound 201.
To a solution of 2-chloro-4-nitro aniline (2 g) and potassium t-butoxide (12 mmol) in THF (18 mL) was added a solution of 2-chlorobenzothiazole (2.75 g) in THF (6 mL). The mixture was heated at reflux overnight then quenched into water (100 mL). The product is extracted with methylene chloride and purified by flash chromatography to afford compound 201 (300 mg) as a yellow solid.
'H NMR (d6-acetone) 8 9.74 (br s, 1H), 9.214 (br d, 1H), 8.346 2H), 7.891 J=8 Hz, 1H), 7.794 J=8 Hz, 1H), 7.466 J=7.2 Hz, 1H), 7.321 J=7.2 Hz, 1H). MS 304.
EXAMPLE 202 This illustrates the synthesis of compound 202.
NO
2
NO
2 Cl Ci H I H S I- Me Me 202 203 By the method of Abuzar et al, (Ind. J. Chem 20B, 230-233 (1981)) 2chloro-4-nitro phenylisothiocyanate (Lancaster) (0.95g) was coupled with 2-amino-4chlorotoluene (0.69g) in reluxing acetone to form the mixed thiourea 202 WO 01/00579 PCT/US00/18178 'H NMR (DMSO) 5 10.021 1H), 9.789 1H), 8.373 1H), 8.197 2H), 7.441 J=1.6Hz, 1H), 7.315 J=8.4 Hz, 1H), 7.268 (dd, J= 8.4, 2. Hz, 1H), 2.237 3H). MS 356. Anal. calcd.: 47.20 3.11 11.80 found: 47.24 3.15 11.69%N.
EXAMPLE 203 This illustrates the synthesis of compound 203.
To a cool solution of thiourea 202 (0.63 g) in chloroform (6 mL) was added bromine (0.6 g) slowly. The mixture was then heated to reflux for 2 hours. On cooling, the solids were collected by filtration and then triturated with acetone to afford benzothiazole 203 as its HBR salt (0.5 g).
'H NMR (DMSO) 5 8.989 (br d, J=8.4 Hz, 1H), 8.365 J=2.4 Hz, 1H), 8.291 (dd, J=9.2, 2.8 Hz, 1H), 7.259 2H), 5.4 (br 2.557 3H). MS 352.
Anal.: calc for M+0.9HBr: 39.38 2.34 9.84 found: 39.44 2.35 %H, 9.66 %N.
EXAMPLE 204 This illustrates the synthesis of compound 204.
By the method of examples 202 and 203, 2,6-dichloro-4nitrophenylisothiocyanate (GB 1131780 (1966)) was coupled with 3,5-dichloroaniline to form the corresponding mixed thiourea which was cyclized with bromine to afford benzothiazole 204 suitable for use in the next reaction. MS 406 EXAMPLE 205 By the method of example 200, benzothiazole 205 was prepared in 78% yield as a yellow solid. MS 354.
EXAMPLE 206 By the method of example 200, benzothiazole 206 was prepared in yield as a yellow solid. MS 354 EXAMPLE 207 This illustrates the synthesis of compound 207.
WO 01/00579 PCT/US00/18178 2,7-dichlorobenzothiazole (Example 73.2) (0.85 g, 4.2 mmol) and 2,6dichloro-4-nitroaniline (2.1 g, 10.4 mmol) were dissolved in anhydrous DMSO (10 mL).
Solid Cs 2
CO
3 (4.1 g, 12.5 mmol) was added and the reaction mixture heated to 80 °C for 16 hours. Let cool, then poured into 200 mL DI water. Excess cesium carbonate was neutralized with acetic acid. The aqueous layer was extracted 2 x 100 mL of ethyl acetate. The combined organic layers were washed with saturated brine, dried over MgSO 4 filtered, and concentrated to a yellow-brown solid. The insolubility of this compound prevented purification, so the crude material was used directly in the next reaction.
'H NMR (400MHz) (d 6 -acetone) 8 10.35 (bs, 1H); 8.36 2H); 7.37 (t, 1H); 7.30 (dd, 1H); 7.21 (dd, 1H). MS 371.9.
EXAMPLE 208 By the method of examples 202 and 203, 2,6-dichloro-4nitrophenylisothiocyanate (GB1131780 (1966)) was coupled with methyl-(4aminophenyl)-sulfone to form the corresponding mixed thiourea which was cyclized with bromine to afford benzothiazole 208 suitable for use in the next reaction.
'H NMR (DMSO) 6 8.44 2H), 8.28 (br s, 2H), 7.82 (br d, 1H), 7.41 (br d, 1H), 3.19 3H). MS 416.
EXAMPLES 209-216 Reduction of the nitro derivatives of Table 26 by the methods of example 32 or example 175 gave the corresponding anilines illustrated in Table 27.
The structures for examples 209-216 are illustrated in Table 27.
Table 27 WO 01/00579 EXAMPLE V 209 Cl 210 H 211 H 212 Cl 213 Cl 214 CI 215 Cl 216 Cl w x Y Z H Cl H H H H H H C1 H H Me CI H Cl H H H H Me H Me H H CI H H H H SO 2 Me H H PCT/USOO/18 178
MS(M+H)
344 276 324 378 324 324 344 388 EXAMPLE 209 'H NlvlR (d 6 -acetone) 5 8.78 ILH); 7.29 I 7.41 I 7.27 (d, IlH); 6.86 2H1); 5.42 I1H). MS 344 EXAMPLE 212 'H NMR (DMSO) 8 10.09 I 7.48 (br s, 1 7.31 J=1.8 Hz, IH), 6.72 2H), 5.91 (br s, 2H). MS 378 EXAMPLE 215 Crude 207 was reduced with SnCl 2 *2H 2 0 according to the procedure of Example 32 to afford compound 215 as a greenish/gray solid after recrystallization from hot ethyl acetate/hex anes 14 g).
'H1 NMR (d 6 -acetone) 8.87 (bs, I1H); 7.40 (dd, 111); 7.30 11H); 7.11 (d, 114); 6.87 214); 5.44 (bs, 2H4). MIS 344.0 EXAMPLE 216 'H NMR (DMS0) 8 10.08 114), 8.31 114), 7.76 J=8.4 Hz, 1H4), 7.57 J=8.4 Hiz, 11H), 6.73 2H), 5.90 214), 3.17 314). MS 388 EXAMPLES 217-238 Sulfonation of the anilines of Table 27 by the methods of example 3 or 192 provides the compounds illustrated in Table 28.
WO 01/00579 WO 0100579PCTIUSOO/18178 Example A B C D V W X Y Z MS(M-H) 217 CI 218 CI 219 Cl 220 Cl 221 Cl 222 CI 223 Cl 224 CI 225 CI 226 CI 227 CI 228 CI 229 Cl 230 CI 231 H 232 Ci 233 Cl 234 Cl 235 CI 236 Cl 237 Cl Cl Me CI H
CF
3
H
Cl H
CF
3
H
CI Me CI H
CF
3
H
Cl H
CF
3
H
CI Me Cl H
CF
3
H
Cl Me -COMe H CI H
CF
3
H
CI Me
CI
Cl
C'
H
H
H
Cl Cl
CI
CI
Cl
CI
CI
CI
CI
CI
CI
Cl CI H CI
CF
3 H CI CI H CI H S 2 Me. H H 594 WO 01/00579 WO 0100579PCT/USOO/18 178 238 CI H CF 3 H Cl H S 2 Me H H 628 EXAMPLE 217 'H NMR (d 6 -acetone) 8 9.19 (bs, IH); 8.51 1H); 7.74 1H); 7.72 (s, 1H); 7.43 2H); 7.37 IH); 7.28 (dd, IH); 2.46 3H). MS (NI-H) 563.9 EXAMPLE 218 'H NNM (d, 6 -acetone) 8 9.19 (bs, 1H); 8.22 IH); 7.78 lIH); 7.74 (d, 1H); 7.67 (dd, 1H); 7.43 2H); 7.37 IH); 7.28 (dd, 1H). MS 549.8 EXAMPLE 219 1H NMR (d 6 -acetone) 8 10.05 (bs, 1H); 9.22 (bs, lH); 8.45 IH); 8.06 I 7.98 I 7.73 (in, I 7.45 2H); 7.36 I1H); 7.28 (dt, I1H). MS (NI-H) 583.8.
EXAMPLE 223 'H NMR (DMS0) 8 10.96 (1 H, 10. 11 (1 H, 8.12-8.22 (1IH, broad), 8.06 (1IH, d, 7.90 (1IH, d, J 2.1 H 7.65 (1 H, dd, J 2.1 Hz), 7.23 (1 H, d, J Hz), 7.10-7.20 (3H, mn), 2.44 (3H, MS (NI-H) 529,8 EXAMPLE 224 'H NMIR (DMSO) 8 11.11 (1H, 10.11 (IH, 8.27 (1IH, d, J= 8.0 Hz), 8.16 (2H, 7.94 (IH, d, J= 8.6 Hz), 7.10-7.26 (4H, in), 2.43 (3H, MS 563.9.
mp 192.6' 0
C
EXAMPLE 225 'H NMR (DMSO) 8 11.49 1H), 10.44 1H), 8.164 J=8.4 Hz, 1H) 7.95 J=2 Hz, 1H), 7.71 (dd, J=8.4, 2Hz, IH), 7.50 (br s, IH), 7.35 J=1.6 Hz, 1H), 7.25 2H). MS (NI-H) 584 WO 01/00579 WO 0100579PCTUSOO/18 178 EXAMPLE 226 'H NMR(DMSO) 8 11.59 111), 10.40 1H), 8.368 (d,J=8.4 Hz, IH), 8.20 (br s, IHf), 8.00 (br d, J=8.4 Hz, 7.48 (br s, IH), 7.344 J1.6 HzIH), 7.274 J=1.6 Hz, 2 MS 618.
EXAMPLE 227 'H NMR (DMSO) 8 11.37 lH), 10.40 IH), 8.19 (br s, IH), 7.90 (mn, I M, 7.53 (br s, IN), 7.35 (br s, 1H), 7.25 (br s, 2 2.415 3H). MS 598.
EXAMPLE 228 'H NMR (d 6 -DMSO) 8 11.44 (1H, broad 9.96 (IH, broad 8.33 (IH, 8.19 (1IN, 7.99 (1 H, dd); 7.43 (1IH, broad 7.26 (2H, 7.07 (1iH, 6.97 (1iH, t); 2.35 (3H, MS (M H) 529.9.
EXAMPLE 229 'H NMR(d 6 -DMSO) 8 11.26 (1IH, broad 9.96 (1 H, broad 8.12 (1 H, 7.93 (1 H, 7.69 (1 H, dd); 7.43 (INH, broad 7.23 (2H, 7.08 (1 H, 6.97 (1 H, t);l 2.36 (3H, MS 564.
EXAMPLE 230 'H NMR (d 6 -DMSO) 8 11.23 (lH, broad 9.96 (iN, broad 8.14 (IH, 7.88 (iH, 7.43 (1H, broad 7.24 (2H, 7.08 (IH, 6.97 (iN, 2.40 (3H, s); 2.36 (3H, MS 543.9.
EXAMPLE 231 'H NMR (d 6 -DMSO) 8 1 1.02 (1 H, broad 9.96 (1 H, broad 8.16 (2H, 7.97 (2H, 7.43 (iN, broad 7.26 (1H, 7.07 (1H, 6.97 (iH, 2.62 (3H, s); 2.36 (3H, s).
EXAMPLE 232 'H NMR (d 6 -DMSO) 6 11.28 (IN, broad 9.79 (1H, broad 8.13 (1H, 7.93 (2H, 7.70 (INH, dd); 7.44 (1iN, broad 7.21 (3H, 7.05 (1 H, 2.30 (3H, MS 529.9.
WO 01/00579 WO 0100579PCT/USOO/18178 EXAMPLE 233 'H NMR (d 6 ,-DMSO) 8 11.43 (1IH, broad 9.79 (1 H, broad 8.34 (1IH, 8.19 (1H, 7.99 (1H, 7.44 broad 7.24 (3H, 7.04 (lH, 2.30 (3H, s).
MS (M 564.
EXAMPLE 234 'H NMR (d 6 -DMSQ) 8 11.22 (iH, broad 9.79 (LH, broad 8.15 (1H, 7.89 (1IH, 7.44 (1 H, broad 7.23 (3H, 7.04 (1IH, 2.41 (3H, 2.31 (3H, s).
MS (M 543.9.
EXAMPLE 235 'H NMR (d 6 -acetone) 8 9.92'(bs, I 9.35 (bs, I 8.23 I 7.78 (d, lIM'; 7.67 (dd, 1H); 7.45 2H); 7.36-7.29 (in, 2H); 7.16 (dd, IH). MS 549.8.
EXAMPLE 236 'H NMR (d 6 -acetone) 8 8.45 I11); 8.06 I11); 7.97 I 7.46 (s, 2H); 7.33-7.29 (in, 2H); 7.16 (dd, I MS 583.8.
EXAMPLE 237 'H NMR (DMSO) 8 11.43 (hr s, 1H), 10.40 (br s, 1H), 8.33 (hr s, IH), 8.16 J= 8 Hz, I1-H); 7.94 J=2 Hz, 1I1), 7.75 3 (dd, J=8.2, 2 H-z, I 7.71 (dd, J=8.4, 2 Hz, I H),7.55 (hr s, I 7.265 2H), 3.22 3H). MS 594.
EXAMPLE 238 'H NMR (DMS0) 8 11.55 (br s, 1H), 10.40 (hr s, 1H), 8.38 (in, 2H), 8.22 (hr s, 1ff), 8.02 (br d, IH), 7.77 (dd, J= 8.4, 2 Hz, 1H), 7.55 (hr s, IH), 7.295 2H), 3.1t9 MS 628.
WO 01/00579 WO 0100579PCT/USOO/18178 Table 29
XUOI
Example A X Y yield 239 SH H CF 3 92% 240 SH H C0 2 H 66% 241 SH CN H 97% 243 SH H CN 49% 245 SH H Me 53% 250 Cl H Cl 96% EXAMPLE 239 2-Mercapto-S-trifluoromethyl-benzoth jazole (239) In analogy to the procedure of Chaudhuri, N. Synth. Co,'rnun. 1996, 26, 20, 3 783, O-ethylxanthic acid, potassium salt (Lancaster, 7.5 g, 46.9 mmnol) was added to a solution of 2-bromo-5-trifluoromethylphenylamine (Aldrich, 5.0 g, 20.8 mmol) in A'Ndimethylformamide (DMF, 30 mL). The mixture was heated to reflux for 4 hours. After cooling to room temperature, the mixture was poured into ice water and acidified with 214 HCl. The solid product was collected by filtration. Recrystalization from CHClfiiexanes gave 239 (4.5 g 92%) as a white solid.
'H NMR (400MHz, DMSO-d 6 8 14.00 I 7.94 J 8.1 Hz, I H), 7.62 (dd, J 1.0 H4z, I 7.48 J 1.0 Hz, I11). MS 234.
EXAMPLE 240 2-Mercapto-bcnzothiazol-5-carboxylic acid (240) acid (240) (3.5 g, 66%) was synthesized from 4-chloro-3-nitro-benzoic acid, obtained from Fluka, and potassium dithiocarbonate 0-ethyl ester, obtained from Lancaster, according to the procedure of Chaudhuri, N. Synth. Cornmun. 1996, 26, 20, 3783.
'H NMR (400MHz, DMSO-d 6 6 14.0 1H), 13.3 (bs, I 7.85-7.79 3 H).
WO 01/00579 WO 0100579PCTUSOO/18178 EXAMPLE 241 2-Mercapto-benzothiazole-6-carbonitrile (241) The title compound was prepared using the method of example 239, starting with 4-amino-3-chloro-benzonitrile (Lancaster, 5.0 g, 32.7 nol), O-ethylxanthic acid, potassium salt (Lancaster, 11.8 g, 73.7 mmol) in DMF (40 mL). The mercaptobenzothiazole (241) (6.1 g, 97%) was obtained as a pale brown solid.
'H NMR (DMSO-d 6 8 14. 10 I 8.22 J= 1. 3 Hz, IlH), 7.82 (dd, J 8.4, 1.5 Hz, 1H), 7.40 (di, J 8.5 Hz, 1H). MS 191.
EXAMPLE 242 3-A min o-4-chloro-b enzon itrile (242) The title compound was prepared using the method of example 32, starting with 4-chloro-3-nitro-benzonitrile (Fluka, 11.0 g, 60 mmol), tin chloride dihydrate (Aldrich, 67.8 g, 300 nimol). 9.0 g of crude compound 242 was obtained as a yellowish solid.
'H NMR (DMSO-d 6 8 7.39 J 8.1 Hz, IlH), 7. 10 (di, J 2.0 Hz, 11-H), 6.93 (dci, J 8.2, 2.0 Hz, I 5.88 2H). MS (M-11) 15 1.
EXAMPLE 243 2-Mercapto-benzotbiazole-5-carbonitrile (243) The title compound was prepared using the method of example 239, starting with 3-amino-4-chloro-benzonitrile (242) (9.0 g, 59.0 rumol), O-ethylxanthic acid, potassium salt (Lancaster, 21.23 g, 132.7 mmol) in DMF (90 mL). 5.6 g of compound. 243 was obtained as a pale brown solid.
'H1 NMR (DMSO-d 6 8 14. 10 (br s, I 7.90 (ci, J 8.3 Hz, I 7.70 (dci, J 1.1 Hz, I 7.60 (br s, I MS 19 1.
EXAMPLE 244 enyla mine (244) The title compound was prepared using the method of example 32, starting with 1-bromo-4-methyl-2-nitro-benzene (Lancaster, 10.1 g, 46.7 rumol), tin chloride dihydrate (Aldrich, 52.8 g, 233 mmnol). 8.2 g of crude compound 244 was obtained as a pale brown oil.
WO 01/00579 PCT/USOO/18178 'H NMR (DMSO-d 6 8 7.18 J 8.1 Hz, 1H), 6.60 J 2.1 Hz, 1H), 6.93 (dd, J 8.1, 1.8 Hz, 1H), 5.34 2H), 2.26 3H). MS (M+H)186.
EXAMPLE 245 2-Mercapto -5-Methyl-benzothiazole (245) The title compound was prepared using the method of example 239, starting with 2-bromo-5-methyl-phenylamine (244) (4.48 g, 24.0 mmol), O-ethylxanthic acid, potassium salt (Lancaster, 8.70 g, 54 mmol) in DMF (35 mL). The mercaptobenzothiazole 245 was obtained as an pale brown solid (2.31 g, 53%).
'H NMR (DMSO-d) 8 13.70 (br s, 1H), 7.56 J 8.6 Hz, 1H), 7.15- 7.10 2H), 2.38 3H). MS 180.
EXAMPLE 246 247 2,3-Dichloro-5-nitrobenzoic acid (246) 2,3-Dichlorobenzoic acid, obtained from Aldrich, (40 g, 0.2 lmole) was added portion wise to a -20 OC concentrated H 2
SO
4 obtained from Acros, (233 mL) solution which was fitted with a mechanical overhead stirrer. During the addition process, a separate flask containing concentrated H 2
SO
4 (50 mL) was cooled to 0 °C and fuming HNO3, obtained from Acros, (16.6 mL) was slowly added. This solution was then added dropwise to the 2,3-Dichlorobenzoic acid solution at a rate which kept the reaction mixture at or slightly below -15 OC. After the addition was complete the resulting solution was allowed to warm to 10 oC over 3 hours. The crude solid material was filtered through a fritted filter funnel, washed with cold HzO (200 mL), and dried under a stream of air followed by high vacuum to yield 21.7 g of product (246) which contained 4% of the undesired regioisomer (2,3-Dichloro-6-nitrobenzoic. acid 247) based on 'H NMR analysis. The filtrate was slowly poured over ice and additional solid precipitated. This solid was observed to be a 3:1 mixture of 2,3-dichloro-6-nitrobenzoic acid (247) to 2,3-dichloro-5-nitrobenzoic acid (246) based on 'H NMR analysis.
2,3-Dichloro-5-nitrobenzoic acid (246): 'H NMR (DMSO-d 6 5 8.63 J 2.7 Hz, 1H), 8.47 J 2.7 Hz, 1H). 2,3-Dichloro-6-nitrobenzoic acid: (247). 'H NMR (DMSO-d 6 8 8.22 J 9.0 Hz, 1H), 8.02 J 9.0 Hz, 1H).
WO 01/00579 PCT/US00/18178 EXAMPLE 248 1-(2,3-Dichloro-5-nitro-phenyl)-ethanone (248) To thionyl chloride, obtained from Aldrich, (125 mL) at 0 OC was slowly added 2,3-Dichloro-5-nitrobenzoic acid (246) (21.7 g, 91.9 mmol). The ice bath was taken away and the resulting solution was heated to reflux for 17 hours (note: acid completely dissolves upon heating). After cooling to ambient temperature, the excess thionyl chloride was removed under vacuum and the resulting acid chloride was allowed to stand under high vacuum for 15 h and used in the next step without further purification.
To a 1M solution of NaH, 60% oil dispersion obtained from Aldrich, (11.39 g, 285 mmol) in DMF at 0 °C was slowly added diethylmalonate, obtained form Aldrich, (14.65 mL, 96.5 mmol) dropwise and the resulting solution was allowed to stir for 30 minutes. The acid chloride was dissolved in DMF (184 mL) and slowly added via cannula to the reaction mixture. The resulting solution was then allowed to stir for 16 h as ambient temperature was reached followed by recooling to 0 and slowly quenching with excess 2M aqueous HCI (200 mL). To the crude reaction was added HzO (500 mL) and EtOAc (500 mL). The aqueous layer was extracted three times with EtOAc (500 mL), the organic layers were combined, washed four times with saturated aqueous brine (500 mL), dried over Na 2
SO
4 and concentrated under vacuum to yield an oil which was used in the next step without further purification. The resulting product was dissolved in 111 mL of a 7.7/5/1 AcOH/H 2 0/conc. H 2
SO
4 solution and heated to reflux for 22 hours. The AcOH was removed under vacuum followed by EtOAc addition (200 mL). The solution was neutralized using 2M aqueous NaOH, extracted 3 times with EtOAc (200 mL). The combined organic layers were washed twice with saturated aqueous brine (200 mL), dried over Na 2
SO
4 and concentrated under reduced pressure. The crude material was purified by column chromatography (30% CH 2
C
2 in hexane) to yield 17.6 g of ketone 248 as a light brown solid.
'H NMR (DMSO-d 6 5 8.61 J 2.6 Hz, IH), 8.48 J 2.6 Hz, 1H), 2.65 3H).
WO 01/00579 WO 0100579PCT/USOO/18178 EXAMPLE 249 2.Methoxy-4-nitrobenzenethlol (249) 2-Methoxy-4-nitrobenzenethiol (249) was prepared according to the method of Price and Stacy J. Amer. Chem. Soc. 68, 498-500 (1946)) in 67% yield from I1-chloro-2-metboxy-4-nitro-benzene, obtained from Aldrich._ 'H NN{R (DMSO-d 6 6 7.8 (bd, J 8.4 Hz, INH), 7.73 (bs, IlH), 7.62 (bd, J -8.4 Hz, 1H), 5.8 (bs, IN), 3.95 3H). MIS 184.
EXAMPLE 250 2,5-Dichloro-beuzeneth iazole(250) 5-Chloro-benzenethiazole-2-thiol, obtained from Aldrich, (2 g, 9.9 mmol) was added slowly to sulfuryl chloride, obtained from Aldrich, (20 mL) and stirred for 1 hi followed by heating to 50 *C for 15 minutes. The mixture was cooled, poured slowly over ice water and stirred for 30 minutes. The product precipitated out of solution as a yellow solid and was collected by vacuum filtration and dried under a stream of air followed by high vacuum to give 1.92 g of compound 250..
'H NMR (400MHz, DMSO-d 6 8 8.18 J 8.7 Hz, I J 1 7.5 9 (dd, J 2.1 Hz, I H).
Table Table 30 illustrates the structures of examples 251-264.
NO
2 N Ii X V W Yield 251 5-Cl Cl -COMe 52% 252 5-CF 3 CI H 92% 253 5-CO 2 H Cl H 66% 254 5-CO 2 Me Cl H 100% 255 5-CO 2 H Cl Cl 100% 256 5-CO 2 Me Cl Cl 100% WO 01/00579 WO 0100579PCT[USOO/18178 .257 5-Cl H -OMe 258 5-CF 3 C1 Cl 99% 259 5-CF 3 Cl -come 260 6-CN Cl Cl 99% 261 6-CN CI H 93% 262 5-CN Cl Cl 99% 263 5-CN Cl H 92% 264 5-Me CI -Come 98% EXAMPLE 251 1-[3-Chloro-2-(5-chloro-benzothiazol-2-ylsulfany)-5-lltro-phenylIethanone (251) To a 0.55M solution of 5-chloro-2-mercaptobenzothiazole, obtained from Aldrich, (5.55 g, 27.5 mmol) in DMF at ambient temperature was added NaH, 60% oil dispersion obtained from Aldrich, (1.2 g, 30.0 mmnol) portionwise followed by l-(2,3- (248) (5.83 g, 25 mmol). The reaction solution turned from bright orange to deep red upon acetophenone addition and was heated to 60 *C for 1 hour. The mixture was allowed to cool for a couple of minutes and the product was precipitated out of solution by the slow addition of H-20 (250 mL). After Ih of stirring the product was collect by vacuum filtration using a buAnal. calcd.: er funnel, dried under a stream of air for 3h, and triterated with a 1:1 MeOHICH 2
CI
2 solutiodi (200 mL) to yield 5.2 g of 251 as an orange solid. An additonal 3.77 g cotlld be isolated by puri fying the mother liquor using column chromatography (dry load,l100% CH 2
CI
2 'H NMR (DMSO-d 6 8 8.68 J 2.5 Hz, I 8.6 J 2.4 Hz, Il-H), 8.05 8.6 Hz, lH), 7.95 J 2.0 Hz, 1H), 7.56 (dd, J 2.0 Hz, lH), 2.65 (s, 3H).
EXAMPLE 252 2-2Clr--ir-hnlufnl--rfurmty-eztizl (252) 2-2Clr4ntopeyslay)--rfurmty-eztizl (252) was prepared from 2-chloro-1-fluoro-4-nitrobenzene, obtained from Aldrich, and WO 01/00579 WO 0100579PCT[USOO/18178 5-trifluoromethyl-benzothiazol-2-tbiol (239) in a similar manner as described in example 251.
'H NMR (DMSO-d 6 8 8.58 J 2.4 Hz, I 8.38-8.32 (in, 2 8.05 8.6 H z, I 8.28 (dd, J 8.7, 2.5 Hz, I1H), 8.09 J 8.7 1-z, I 7.8 (bd, J 9.9 Hz, ILH).
EXAMPLE 253 2-(2-chloro--nitro-phenylsulfany)-benzothiazoI-5-carboxyic acid (253) 2-(2-chloro-4-nitro-phenysulfanyl)-bnzothiazo1-5-carboxyic acid was prepared from 2-mercapto-benzothiazol-5-carboxylic acid (240) and 2-chloro- Ifluoro-4-nitrobenzene, obtained from Aldrich, in a similar maniner as described in example 25 1.
'H NMR (DMSO-d,) 8 8.56 J 2.4 Hz, I 8.42 (bs, I 8.27 (dd, 2.4 Hz, 111), 8.28 J 8.4 Hz, I1H), 8.17 J 8.7 Hz, 1H), 8.0 (dd, J 1.4 Hz, IH). MS 365.
EXAMPLE 254 2-2Clr4ntopeyslay)bnohaoe5croyi acid methyl ester (254) To a 0.25M solution of 2-(2-chloro-4-nitro-phenylsulfanyl)-benzothiaZOlacid (253), (1.38 g, 3.8 mniol) in 10% McOH in THE was added a 2M solution of (trimethylsilyl)diazomethane in hexane, obtained from Aldrich, (2.1 mL, 4.18 minol) and the resulting solution was allowed to stir for 18 hours. 'the crud e reaction mixture was concentrated under vacuum to yield 1.4 g (100%) of ester 254 Which was taken on without further purification.
'H NMR (DMSQ-d 6 8 8.6 J 2.5 Hz, I 8.45 J i4 Hz, 1 H), 8.28 (dd, 8.7, 2.5 Hz, I 8.24 J 8.5 Hz, I1H), 8.1 J 8.7 Hz, I1-H), 8.0 (dd, J 8.4, 1.4 Hz, I 3.9 3H).
EXAMPLE 255 2-(2,6-Dichloro-4-nitro-phenylsulfanyl)-belzoth acid (255) WO 01/00579 WO 0100579PCT/USOO/18178 2-(2,6-Dichloro-4-nitro-phenylsulfany1)-benzoth azole-5-carboxylic acid (255) was prepared (100%) from 2-mercapto-benzothiazol-5-carboxylic acid (240) and 1,2,3-trichloro-5-nitrobenzene, obtained from Aldrich, in a similar manner as described iri example 251.
'H NMR (DMSO-d,),B 11.2 (bs, 111), 8.6 2H), 8.31 J =1.4.Hz, IH), 8.13 J 8.4 Hz, I 7.94 (dd, J 8.5, 1.4 Hz, I1H). MS 3 99.
EXAMPLE 256 2-(2,6-Dichloro-4-nitro-phenysufanyl)-benzothiazol-5-carboxylic acid methyl ester (256) 2-(2,6-Dichloro-4-nitro-phenylsulfany)-benzothiazole-5-carboxylic acid methyl ester (256) was prepared (100%) from 2-(2,6-dichloro-4-nitro-phenylsulfanyl)acid 255 in a similar manner as described in example 254.
'H NMVR (400MHz, DMSO-d 6 8 8.6 2H0,'8.3 3 J 1.6 Hz, I1H), 8.16 J 8.5 Hz, IH), 7.95 (dd, J 8.4, 1.6 Hz, 1H), 3.9 3H).
EXAMPLE 257 loro-2-(2-methoxy-4-n itro-phenylsulfanyl)-benzothiazole (257) 5-Chloro-2-(2-methoxy-4-nitro-phenylsulfanyl)-belzothiazole (257) was prepared from 2-niethoxy-4-nitrobenzenethiol (249) and (250), in a similar manner as described in example 25 1.
'H NMR (DMSO-d 6 8 8.05 (bd, J 8.6 Hz, 1 8.03 J 2. 0, 1 H), 7.99-7.94 (in, 3H), 7.48 (dd, J 8.6, 2.1 Hz, 111), 3.95 3H).
EXAMPLE 258 2-(2,6-Dich beozothiazole (258) To a solution of 2-mercapto-5-trifluoromethyl-benzothiazole (239) (470 mg, 2.0 mniol) in DMF (20 mL) was added NaH (Aldrich, 60% suspension in hexanes, 80 mg, 2.0 minol). After the resulting mixture was stirred at ambient temperature for minutes, was added I ,2,3-trichloro-5-nitrobenzene (Acros, 452 mng, 2.0 mmol). The mixture was then heated at 60 TC for 4 hours. After cooled to room temperature, the mixture was poured to water and stirred for 1 hour. The solid product was collected by WO 01/00579 WO 0100579PCT/USOO/18178 vacuum filtration to give 258 as a pale yellow solid (840 mg, 99%) which was used in the next reaction without further purification.
'H NMR (DMS0-l 6 8 8.61 2H), 8.27 J 8.4 Hz, 1H), 7.21 (br s, I 7.74 (dd, J 8.4,1.5 Hz, I MS 425.
EXAMPLE 259 1-[3-Chloro-5-nitro-2-(5-trifluorometni-beozothiazol-2-ylsulfalyl)phenyll-ethanone (259) The title compound was prepared using the method of example 258, starting with 5-trifluoromethyl-benzothiazole-2-thiol (239) 470 mg, 2.0 mmol), 1 (248) (466 mg, 2.0 mmol) and NaH (Aldrich, suspension, 80 mg, 2.0 mmol) in DMF (20 mL). Compound 259 (750 mg, 87%) was obtained as a yellow solid.
'H NMR (DMSO-d 6 8 8.6 8 J 2.6 Hz, I1H), 8.62 J3 2.5 Hz, I H), 8.27 J 8.4 Hz, 1 8.20 (br s, IlH), 7.74 (dcl, J 8.5, 1.7 Hz, I 2.65 3H). MIS (M-fH) 433.
EXAMPLE 260 2-(2,6-Dichloro-4-nitro-phenyIsulfany)-benzothiazole-6-carboflitrile (260) The title compound was prepared using the method of example 258, starting with 2-mercapto-benzothiazole-6-carbonitrile (241) (960 mg, 5.0 mmol), 1,2,3- (Acros, 1.13 g, 5.0 mmol) and Nal- (Aldrich, 60% suspension, 200 mg, 5.0 mmol) in DMF (25 mL). Compound 260 (1.9 g, 99%) was obtained as a yellow solid.
'H NMR (DMSO-d 6 8 8.61 2H), 8.58 J 1. 8 Hz, I 7.99 J Hz, IlH), 7.88 (dd, J 1.8 Hz, I1-H).
EXAMPLE 261 2-(2-Chloro4-nitro-phenylsulfanyl)-benzothiazole-6-carboflitrile (261) The title compound was prepared using the method of example 258, starting with 2-mercapto-benzothiazole-6-carbonitrile (241) (960 mg, 5.0 mmol), 2chloro-1-fluoro-4-nitrobenzene (Aldrich, 878 mg, 5.0 mmol) and NaH (Aldrich, WO 01/00579 WO 0100579PCTIUSOO/181 78 suspension, 200 mg, 5.0 mmol) in DMff (25 mnL). Compound 261 (1.62 g, 93%) was obtained as a yellow solid.
'H NMR (DMSO-d6) 8 8.62 J 1.5 Hz, I 8.56 J 2.4 Hz, I H), 8.29 (dd, J 2.4 Hz, I1H), 8.16 J 8.6 Hz, I1H), 8.06 J 8.6 Hz, I 7.91 (dd, J 1.6 Hz, I1H). NIS 348.
EXAMPLE 262 2-(2,6-Dichloro-4-nltro-phenylsulfa (262) The title compound was prepared using the method of example 258, starting with 2-mercapto-beftzothiazole-5-carbonitnile (243) (960 mg, 5.0 mmol), 1,2,3- (Acros, 1. 13 g, 5.0 mmol) and NaH (Aldrich, 60% suspension, 200 mg, 5.0 numol) in DMF (25 mL). Compound 262 (1.9 g, 99%) was obtained as a yellow solid.
'H NMR (DMSO-d 6 8 8.62 2H), 8.38 J 1.2 Hz, 1H), 8.24 J 8.4 Hz, I1H), 7.8 8 (dd, J 8.4, 1.5 Hz, 1 H).
EXAMPLE 263 2-(2-Chloro-4-niitro-phenysulfay)-belzothiazole-S-Carboflitrile (263) The title compound was prepared using the method of example 258, starting with 2-mercapto-benzothiazole-5-carbonitrile (243) (960 mg, 5.0 mmol), 2chloro-1-fluoro-4-nitrobenzene (Aldrich, 878 mg, 5.0 mmol) and NaR (Aldrich, suspension, 200 mg, 5.0 mmol) in DMF (25 mL). Compound 26.3 (1.60 g, 92%) was obtained as a yellow solid.
'H NMR (400MHz, DMSO-d 6 8 8.56 J1 2.4 Hz, 1H), 8.49 J =1.2 HZI, I1H), 8.29 J 8.4 Hz, IlH), 8.29 (dd, J 2.5 Hz, I 8.12 J 8.7 Hz, I H), 7.85 (dd, J 8.5, 1.5 Hz, I MS 348.
EXAMPLE 264 1-1- oo2(-ehlbnohaol2yslay)5ntopeyl ethanone (264) The title compound was prepared using the method of example 258, starting with 5-methyl-benzothiazole-2-thiol (245) (1.90 g, 10.5 mmnol), 1-(2,3-dichloro- WO 01/00579 WO 0100579PCT/USOO/18178 (248) (2.45 g, 10.5 mmol) and NaH (Aldrich, 60% suspension, 420 mug, 10.5 numol) in DMF (20 mL). Compound 264 (3.87 g 98%) was obtained as a yellow solid.
'H NMR (400MHz, DMSO-d 6 8 8.65 J 2.3 Hz, I1H), 8.5 8 J Hz, I1H), 7.87 J 8.3 Hz, I 7.67 (hr s, 1IH), 7.24 (dd, J 8.2, 1.5 Hz, I 2.65 (s, 3H), 2.41 3H1). MS 379.
Examples 265-276: Reduction of the compounds of Table 30 provides thc compounds illustrated in Table 31 Table 31 Table 31 illustrates the structures of examples 265-276
Y
Cl
CF
3
CQ
2 Me
CO
2 Me Cl
CF
3
CF
3
H
H
CN
CN
Me w come
H
H
Cl OMe Cl COMe Cl
H
Cl
H
come Yield 83% 97% 96% 93% 100% 96% 100% 98% 93% 93% 68% EXAMPLE 265 I -I5-Amino-3-chloro-2-(5-chloro-benzoth iazol-2-ylsulfanyl)-plhenylJethanione (265) WO 01/00579 WO 0100579PCTUSOO/18178 To a 0. 14M solution of I -[3-Chloro-2-(5-chloro-benzothiazol-2ylsulfanyl)-S-nitro-phenyl]-ethanone (251)(4.08 g, 10.26 mmol) in a 2:2:1 solution of EtOH, obtained from gold sbield,:THF, obtained from Aldrich,:H 2 0 was added N{ 4 +Cl-, obtained from Aldrich, (2.74 g, 51.29 mmol) followed by iron(0) powder, obtained from Aldrich, (2.86 g, 51.29 mnmol). The resulting solution was heated to reflux for 2.5 h with vigorous stirring. TLC and mass spectral analysis showed starting material and hydroxyl amnine intermediate so an additional 5 Eq. of both NH.
4 +CG and iron powder were subsequently added and the reaction mixture was allowed to continue to reflux for an additional 1.75 hours. The hot solution was immediately filtered through a plug of celite and the celite was washed with copious amounts of EtOAc. The organic layer was concentrated under vaccum, resuspended in EtOAc (100 mL) and NaH-C0 3 (IlOOmL), and extracted 3 times with EtOAc (100 mL). The organic layer was washed twice with saturated aqueous brine (100 mL), dried over Na 2
SO
4 concentrated under vacuum, and purified by column chromatography (10-50% EtOAc in hexane) to yield compound 265 (3.14 g, 83%) as a yellow solid.
'H NMR (DMSO-d 6 8 7.95 J 8.6 Hz, I 7.89 J 2.0 Hz, I H), 7.39 (dd, J= 8.6, 2.1 Hz, I 6.95 J =2.4 Hz, I 6.72 J =2.4 Hz, IlH), 6.41 (s, 214), 2.45 3H). MIS 369.
EXAMPLE 266 3-Ch loro-4-(5-trifluoromethyl-beozothiazol-2-ylsu lfanyl)-phenyl amine (266) 3-Chloro-4-(5-tifluorometliyl-benzothiazol-2-ylsulfanyl)-phenylamihne (266) was prepared from 2-(2-Chloro-4-nitro-phenylsul fanyl)-5-i 'fluoromethylbenzothiazole (252), in a similar manner as described in example 'H NMR (DMSO-d 6 8 8.2-8.12.(in, 2 7.65 (dd, J 8.5, 1.7 Hz, 1 H), 7.52 J 8.5 Hz, 1H1), 6.9 J 2.4 Hz, 1H), 6.7 (dd, J 8.5, 2.4 Hz, 111), 6.25 (bs, 2 MIS 359.
EXAMPLE 267 2-4Aio2clr-hniufny)hnohaoe5croyi acid methyl ester (267) WO 01/00579 WO 0100579PCT[USOO/181 78 2-(4-Amino-2-chloro-phenylsulfanyl)-benzothiazoC-5-carboxylic acid methyl ester (267) was prepared from 2-(2-Chloro-4-nitro-phenylsulfaflyl)acid methyl ester (254) by the method of example 'H NMR (DMSO-d 6 8 8.3 J 1.6 Hz, I 8.05 J 8.4 Hz, 1 H), 7.88 (dd, 8.4, 1.6 Hz, 1H), 7.55 J 8.5 Hz, I1H), 6.89 J 2.4 Hz, 1H), 6.65 (dd, J 2.4 Hz, I 3.9 3H). MS 349.
EXAMPLE 268 2-(4-Amino-2,6-dichloro-pbenylsulfany)-benzothiazoe-5-carboxylic acid methyl ester(268) 2-(4-Amino-2,6-dichloro-phenysulfaiyl)-benzothiazole-5-carboxyl ic acid methyl ester (268) was prepared from 2-(2,6-Dichloro-4-nitro-phenylsulfanyl)acid methyl ester (256) in a similar manner as described in example 'H NMR (DMSO-d 6 8 8.34 J 1.2 Hz, 1H), 8.09 J 8.4 Hz, III), 7.93 (dd, J 8.4, 1.6 Hz, I 6.9 2H), 6.5 2H), 3.9 3 MS 3 83.
EXAMPLE 269 4-5Clr-eztizl2ys lay)3mtoypeyamn (269) 4-(5-Chloro-benzothiazol-2-ylsulfanyl)-3-methoxy-phenylamine (269) was prepared (100%) from 5-chloro-2-(2-methoxy-4-nitro-phenylsulfanyl)-benzothiazole (257), by the method of example 265.
'H NMR (400MHz, DMSO-d 6 5 7.9 J 8.5 Hz, I 7.85 J 1 7.34 (dd, J 8.5, 2.0 Hz, 11-1), 7.3 J 8.3 Hz, IHI), 6.39 J 2.0 Hz, I 6.29 (dd, J 8.3, 2.1 Hz, I 5.93 2H1), 3.7 3H). MS 323.
EXAMPLE 270 Ioro-4-(5-tri flu oromethyl-benzo th iazol-2-yis ulIfa nyl)phenylamine (270) To a solution of 2-(2,6-dichloro-4-nitro-phenylsulfanyl)-5-trifluoromethylbenzothiazole (258) (840 mg, 1.98 mm-ol) in EtOAc (20 mL) was added tin chloride dihydrate (Aldrich, 2.15 g, 9.52 mmol) and the resulting mixture was heated to reflux for 3 hours. After cooled to room temperature, to the mixture was added excess of 4N aqueous NaOH solution and the resulting mixture was stirred for 20 minutes. The WO 01/00579 WO 0100579PCTIUSOO/181 78 mixture was filtered through Celite pad and washed with EtOAc. The organic layer was separated washed twice with a brine solution, dried over Na 2 SO4, and concentrated under vacuum. to give compound 270 (755 mg 96%) product as a pale yellow solid, which was used in the next reaction without further purification.
'H NMR (DMSO-d 6 858.20-8.15 (in, 2H), 7.66 (dd, J 8.4,1.7 Hz, I H), 6.88 2H1), 6.50 2H1). MS 395.
EXAMPLE 271 1- [5-Amino-3-chloro-2-(5-trifluoromethyl-benzothiazol-2-ylsulfalyl)phenyll-ethanone (271) The title compound was prepared using the method of example 270, starting with 1 -[3-chloro-5 -nitro-2-(5-trifluoromethyl-benzothiazol-2-ysulfanyl)-phelyl]lethanone (259) (750 mg, 1,67 mmol), tin chloride dihydrate (Aldrich, 1.89 g, 8.37 inmol).
Compound 271 (755 mg, 100%) was obtained as a yellowish solid.
'H NMR (DMS0-l 6 8 8.20-8.13 (in, 7.66 (dcl, J 1.0 Hz, I H), 6.96 J 2.4 Hz, I1H), 6.75 J 2.4 Hz, I 6.43 2H), 2.48 3H). MIS (M+H) 403.
EXAMPLE 272 2-(4-Amino-2,6-dichloro.-phenylsulfanyI)-benzothiazole-6-carbouitrile (272) The title compound was prepared using the method of example 270, starting with 2-(2,6-dichloro-4-nitro-phenylsulfanyl)-benzothiazole-6-carbonitrilc (260) (1.9 g, 4.97 minol), tin chloride dihydrate (Aldrich, 5.62 g, 24.9 inmol). Compound 272 (1.72 g, 98%) was obtained as a yellowish solid.
'H NMR (400MHz, DMSQ-d 6 8 8.48 J 1.5 Hz, IH), 7.97 J 8.7 Hz, IlH), 7.86 (dd, J 8.5, 1.7 Hz, I 6.88 2H), 6.53 MIS 352.
EXAMPLE 273 2-(4-Amino-2-chloro-phenylsulfanyl)-benzothiazole-6-carboflitrile (273) The title compound was prepared using the method of example 270, starting with 2-(2-chloro-4-nitro-phenylsulfanyl)-benzothiazole-6-carboflitrile (261) (1.6 WO 01/00579 WO 0100579PCT/USOO/18178 g, 4.6 nunol), tin chloride dihydrate (Aldrich, 5.21 g, 23.1 mmnol). Compound 273 (1.36 g, 93%) was obtained as a yellowish solid.
MS 318 EXAMPLE 274 2-(4-Aminoo2,6-dichloro-pbenylsulfanyl)-benzothiazole-5-carboflitrile (274) The title compound was prepared using the method of example 270, starting with 2-(2,6-dichloro-4-nitro-phenylsulfanyl)-benzothiazole-5-carbonitrile (262) (1.9 g, 4.97 mmol), tin chloride dihydrate (Aldrich, 5.62 g, 24.9 mmol). Compound 274 (1.40 g, 80%) was obtained as a yellowish solid.
'H NMR (DMSO-d4) 8 8.35 J 1.4 Hz,1H), 8.16 J 8.5 Hz, 1H), 7.73 (dd, J 8.4, 1.5 Hz, 1H), 6.88 2H), 6.50 MIS 352.
EXAMPLE 275 2-(4-Amino-2-chloro-phenylsulfanyl)-benzoth (275) The title compound was prepared using the method of example 270, starting with 2 -(2-ch loro-4-ni tro-phenylsu lfanyl)-benzothiazole- 5-carbon]itfl le (263) (1.59 g, 4.58 mmol), tin chloride dihydrate (Aldrich, 5.18 g, 22.9 mniol). Compound 275 (1.35 g, 93%) was obtained as a yellowish solid.
'H4 NMR (DMSO-d 6 6 8.32 J 1.4 Hz, I 8.13 J 8.1 Hz, I H), 7.71 (dd, J 8.3, 1.5 Hz, 111), 7.54 J 8.5 Hz, 1H), 6.88 J 2.4 Hz, 1lH), 6.65 (dd, J 2.4 Hz, I NIS(M+H) 318.
EXAMPLE 276 1-.j5-Amino-3-choro-2-(5-methyl-benzothiazol-2-ysulfany)-pheflylIethanone (276) To a solution of I -[3-chloro-5-nitro-2-(5-methyl-benzothiazol-2ylsulfanyl)-phenyl]-ethanone (264) (3.87 g, 10.2 mmol) in 2:2:1 of EtQH/THF/H 2 0, was added ammonium chloride (Aldrich 2.74 g, 51.2 mniol) and iron powder (Aldrich, 2.87 g, 1.2 mmol). The mixture was refluxed for 3 hours. The mixture was filtered through Celite pad while it was hot, washed the Celite pad with EtOAc. The filtrate was diluted with saturated aqueous NaHCO 3 solution and was extracted 3x with EtOAc (150 rnL).
WO 01/00579 WOOI/0579PCT/US00118178 The organic layers were combined and washed twice with a brine solution (100 mL), dried over Na 2
SO
4 and concentrated under vacuum. The crude solid was chromatographed 15% EtOAc in CH 2
CI
2 to yield 2.42 g of compound 276 as a pale yellow solid.
'H NMR (DMSO-d 6 58. 10(d, J =8.1 Hz, I 7.62 J 1 Hz, 1H), 7.16 (dd, J 8.1, 1.2 Hz, I 6.94 J 2.4 Hz, I 6.69 J 2.5 Hz, I 6.3 8 (s, 2H), 2.46 3H1), 2.40 3H). MIS 349.
Examples 277-307: The compounds illustrated in Table 32 were prepared by sulfonylation of the anilines of Table 31 by the method of Example 277 unless otherwise specified.
Table 32 Example C D V W X Y MS(M-H) Yield 277 278 279 280 281 282 283 284 285 COMe COMe COMe
H
H
H
Cl
H
CI
Cl H Cl Cl H Cl Cl H Cl Cl H CF 3 Cl H CF 3 Cl H CO 2 Me Cl H CO 2 Me CI CONH 2
H
CI CONH 2
H
72% 39% 73% 68% 68% 68% 14% WO 01/00579 WO 0100579PCTIUSOO/18178
CF
3
H
CF
3
H
CF
3
H
H C1 CN 4
H
C1 CI CN 4
H
H OMe H 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 C1 H Cl CI
CF
3 H CI CI CI H COMe CI
CF
3 H COMe Cl Cl H C1 Cl
CF
3 H CI Cl Cl H H CI
CF
3 H .H Cl CI H Cl Cl
CF
3 H Cl Cl Cl H H Cl
CF
3 H H Cl Ci H Cl Cl
CF
3 H Cl Cl Cl H CI Cl Cl H H Cl
CF
3 H H CI
CF
3 H COMe CI Cl Me COMe Cl H CF 3 H CF 3
CF
3 H CF 3 ON H ON H ON H ON H H ON
ON
H ON H ON
CN
4
H
H ON 4
H
CONII
2
CN
4 H ON 4
H
Me H Me 67% 72% 61% 76% 32% 29% 71% 83% 88% 64% 66% 72% 58% 58% 77% 82% 77% 78% 83% 73% 74% EXAMPLE 277 N-f 3-Acetyl-S-chloro-4-(5-chloro-benzothiazol-2-ylsulfanyl)-phenylI-2chloro-4-trifluoromethyl-benzenesulion amide (277) To a I M solution of 1 .[S-Amino-3-chloro-2-(5-chloro-benzothiazol-2ylsul fanyl)-phenyll-ethanone, (265) (4.12 g, 11. 19 mmol) in pyridine, obtained from Aldrich, was added 2-chloro-4-trifluoromethyl-benzenesulfonyl chloride (3.75 g, 13.43 mmol)* and heated to 90 00 for 1.5 hours. The crude reaction mixtur e was concentrated under vacuum, partitioned between 2M aqueous HOI (100 mL) and EtOAc (100 mL), and extracted 3 times with EtOAc (100 mL). The combined organic layers were washed twice with saturated aqueous brine (100 mL), dried over Na 2
SO
4 concentrated under vacuum, purified by column chromatography Et 2 O in CH 2
CI
2 and triturated with WO 01/00579 WO 0100579PCTUSOO/18178
CH
2
CI
2 /hexane mixture with 0.5 mL of MeOH added to yield compound 277 (4.9 g, 72%) as an off white solid.
'H NMIR (400MHz, DMSO-d 6 8 11.9 11H), 8.43 J =8.2 Hz, IIH), 8.23 1H), 8.01 (bd, J 7.2 Hz, IH), 7.95 J 8.6 Hz, 1H), 7.9 J =2.1 Hz, IIH), 7.48 J 2.4 Hz, I 7.42 (dd, J 8.6, 2.1 Hz, 1H1), 7.31 J 2.4 Hz, I 2.45 (s, 31-1). MS m/z 609 (38, 610 (10, 611 (50, 612 (12, 613 614 615 M-H).
EXAMPLE 278 N-3Aey5clr--5clr-bnohao- lufnl-h iyl- 2,4-dichloro-benzenesd1ifonamide (278) By the method of example 93.
'H NMR (DMS0-l 6 8 11.8 IB), 8.24 J 8.6 Hz, 1H1), 8.1-7.95 (in, 2 7.91 J 2.0 Hz, I 7.71 (dd, J 8.6, 2.1 Hz, I 7.45 J 2.4 Hz, I1-H), 7.42 (dcl, J 2.1 Hz, I 7.29 J 2.4 Hz, I 2.45 3H). MIS 575.
EXAMPLE 279 N-[3-AcetyI-5-chloro-4-(5-chlorobenzothiazol-2-ylsulfanfly)-phelI 2,4-dich Ioro-5-methyl-benzenesu rfon amide(279) 'H NMR (DMSO-d 6 8 11.8 1Hi), 8.3 1H), 7.98 J 8.6 Hz, 11H), 7.93 -7.9 (in, 211), 7.46 J 2.4 Hz, I1H), 7.42 (dd, J 8.6, 2.1 Hz, I 7.3 J 2.4 Hz, 11H), 2.45 3H), 2.4 3H). MS 589.
EXAMPLE 280 2,4-Dichloro-N-I3-chloro-4-(5trifluorometl-bnzothizoI- 2 ylsulfanyl)-phenyll-beuzenesulfoilamide (280) 'H NMR (400MHz, DMSO-d 6 8 11.6 I 8.23-8.16 (in, 3 7.96 (bs, 1 7.88 (bd, J 8.6 Hz, I1H), 7.75-7.67 (in, 2 7.4 (bs, I 7.23 (bd, J 10.7 Hz, I MIS M-H) 567.
EXAMPLE 281 .2-Chloro-N-[3-chloro-4-(5-trifluoromethy-benzothiazoI-2-ylsulfalyl)phenylj-4-trifluoromethyl-benzelesulfofamide (281) WO 01/00579 WO 0100579PCT[USOO/18178 'H NMR (400MHz, DMSO-d 6 8 11.8 I 8.4 J 8.3 Hz, 1 H), 8.23 (bs, I 7.98-7.94 (in, 2 8.03 (bd, J 8.4 Hz, I 7.9 J 8.6 Hz, 1H1), 7.69 (bd, J= 10. 1 Hz, I 7.44 J =2.4 Hz, I 7.25 (dd,J 2.4 Hz, 1 HM. MS (M- H) 601.
EXAMPLE 282 2-2Clr4(,-ihooboeeufnlmn)peyslayl acid methyl estcr(282) 'H NMR (DMSO-d 6 8 11.5 11-1), 8.32 J =1.5 Hz, 8.19 J 8.6 Hz, I 8.08 8.4 Hz, I1H), 7.96 J1 2.0 Hz, I1H), 7.92 (dd, J 9.1, 1.6 Hz, I 7.88 J 8.6 Hz, I 7.73 (dd, J 8.6, 2.1 Hz, I 7.4 J 2.2 Hz, IlH), 7.22 (dd, J 8.2, 2.0 Hz, I 3.9 3H). MS 557.
EXAMPLE 283 2-I2,6-Dichloro-4-(2,4-dichloro-benzenesulfonylamilo)acid methyl ester(283) By the method of example 93.
'H NMR (DMSO-d 6 8 11.9 I 8.32 J 0.9 Hz, 1H), &.22 J= 8.6 Hz, 1 8.09 8.4 Hz, I 8.0 J 1.9 Hz, I1H), 7.92 (dd, J 8.4, 1.6 Hz, 1 7.75 (dd, J 8.6, 2.1 Hz, IH), 7.4 2H), 3.9 3H). MS 591.
EXAMPLE 284 2-2Clr--2clr4tiuroehlbneeufnlmn) phbenylsuIfsanyll-benzot h iazole-6-ca rboxy lie acid amide (284) 2-[2-Chloro-4-(2-chloro-4-trifluoromethyl-benzenesulfonylamino)phenylsulfanyl]-benzothiazole-6-carboxylic acid amide (284) was prepared from 2-hooN[-hoo4(-yn-eztiaol2yslay)pey14tilooehl benzenesulfonamide (296) by the method of example 303.
'H NMIR (DMSO-d 6 8 11.8 8.42 J 1.3 Hz, 8.38 J =8.5 Hz, I 8.21 (bs, 1H), 8.05-7.99 (in, 211), 7.94 (dd, J 8.6, 1.5 Hz, I 7.89-7.83 (in, 2H), 7.45 I 7.42 J 1.9 Hz, 7.24 (dd, J 8.5, 2.1 Hz, I1H). MS 576.
WO 01/00579 WO 0100579PCTIUSOO/18178 EXAMPLE 285 2-12,6-Dichloro-4-(2-chlor-4-trifluromethy-benzenflUfoflylamilo)phenylsulfanyll-benzothiazole-6-carboxylic acid amide (285) 2-[2,6-Dichloro-4-(2-chloro-4-tri fluoromethyl-benzensulfonylamnfo)phenylsulfanyl]-benzothiazole-6-carboxylic acid amide (285) was prepared from 2-chloro-N-[3,5-dichloro-4-(6-cyano-benzothiazol-2-ylsulfanyl)-pheflli 4 trifluoromethyl-benzenesulfonamide (294), by the method of example 303.
'H NMR (DMSO-d 6 8 12.0 (bs, IH), 8.48-8.4 (in, 2H), 8.23 (bs, 1H-), 8.05-8.0 (in, 2H), 7.9S (dd, J 8.5, 1.7 Hz, I 7.85 J 8.5 Hz, I 7.48 114), 7.4 2H). MIS 610.
EXAMPLE 286 2-Ch Ioro-N- {3-ch loro-4-16-(I H-tetrazol-5-yI)-benzoth iazol-2ylsulfanylj-phenyl}-4-trifluoromethyl-benzenesulfon amide 2-Chloro-N- {3-chloro-4-[6-( 1H-tetrazol-5-yl)-benzothiazol-2-ylsulfanyl]phenyl) -4-trifluoromethyl-beiizenesul fonamide (286) was prepared from 2-chioro- N-3clr--6caobnohao--yslay)pey]4tilooehl benzenesulfonamide (296) by the method of example 301.
'H NMR (DMSO-d 6 8 8.62 (bs, IH), 8.36 J 8.5 Hz, 1H), 8.19 (bs, 1 8.08 J 8.1 Hz, I1H), 8.04-7.95 (in, 2H), 7.84 J 8.6 Hz, I1H), 7.3 8 J Hz, IlH), 7.2 (dd, J 7.9, 1.8 Hz, 1IH). MIS 60 1.
EXAMPLE 287 2-Chloro-N- {3,5-dicb loro-4-[6-(1 H-tetrazol-5-yl)-benzothiazot-2yisulfanyij-phenyl)-4-trifluoromethyl-benzeiesulfoflamide (287) 2-Chloro-N- {3.5-dichloro-4-[6-( 1H-tetrazol-5-yl)-benzothiazol-2ylsulfanyl]-phenyl} -4-trifluoromethyl-benzenesulfonainide (287) was prepared from 2-chloro-N-[3,5-dichloro-4-(6-cyano-bextothiazo-2-ylsuLfalyl)-pheli]- 4 trifluoromethyl-benzenesulfonamide (294) by the method of example 301.
'H NMR (DMSQ-d 6 6 8.65 (bs, IH), 8.44 IJ 8.4 Hz, 11-1), 8.24 (bs, IH), 8.09 J 8.6 Hz, I 8.06-7.98 (in, 211), 7.4 (bs, 211). MS 635.
WO 01/00579 PCT/USOO/18178 EXAMPLE 288 2-Chloro-N-14-(5-chloro-benzotb iazol-2-ylsulfanyl)-3-methoxyphenyl] -4-trifluoromethyl-benzencsulfonamide (288) By the method of example 93.
'H NMR(DMSQ-d 6 8 11.5 IH), 8.4 J 8.3 Hz, IH), 8.2 (bs, I H), 8.01 J 8.3, 1H), 7.89 J 8.5 Hz, 1H), 7.87 J 2.1 Hz, 7.63 J 8.4 Hz, IH), 7.38 (dd, J 8.6, 2.0 Hz, 1H), 6.96 J 2.0 Hz, 1H), 6.83 (dd, J 8.4, 2.1 Hz, 1H), 3.8 3H). MS 563.
EXAMPLE 289 2,4-DichIoro-N-13,5-dichloro4-(5-trifluorometiyl-benzothiazoI-2ylsulfanyl)-pbenylj-benzenesulfonamide (289) 'H NMR (DMSO-cl 6 8 11.90 1H), 8.25-8.15 3H), 7.98 J Hz, IH), 7.76-7.67 2H), 7.38 2H1). MS 601 EXAMPLE 290 2-Chloro-N-f3,5-dichloro-4-(5-trifluoromethyl-benzothiazol-2ylsulfanyl)-phenylj-4-trifluoromethyl-benzen esulfonamlde (290) 'H NMR (DMSO-d 6 5 11.90 (br s, I 8.43 J 8.4 Hz, I 8.26- 8.15 311), 8.03 (dd, J 8.4, 1.7 Hz, 1 7.68 (dd, J 8.6, 1.6 Hz, 1H), 7.40 2H).
MS 635.
EXAMPLE 291 N-[3-Acetyl-5-chloro-4-(5-trifluoromethyl-benzotbiazol-2-yIsu fanyl)phenyl]-2,4-dichloro-benzenesufonamide (291) 'H NMR (DMSO-d6) 8 11.80 (br s, 111), 8.25 J 8.6 Hz, IH), 8.22- 8.15 2H), 7.97 J 2. 1 Hz, IH), 7.72 (dd, J 8.6, 2.1 Hz, 1 7.69 (dd, I 8.6, 1.6 Hz, 1H), 7.46 1 2.4 Hz, 1H), 7.31 J 2.4 Hz, 1H), 2.47 3H). MS (M-H) 609.
EXAMPLE 292 N-[3-Acetyl-5-chloro-4-(5-trifluoromethyl-benzothiazol-2-ylsufanyl)pheoylj-2-cbloro4-trifluoromethyl-benzenesulfonamide (292) WO 01/00579 PCTIUSOO/18178 'H NMR (DMSO-d6)5 11.90 (br s, IH), 8.42 J 8.1 Hz, 1H), 8.23- 8.17 3H), 8.01 (dd, J 8.5, 1.4 Hz, IH), 7.65 (dd, J 8.5, 1. 5 Hz, IH), 7.44 J 2.4 Hz, 1H), 7.36 J 2.4 Hz, 1H), 2.48 3H). MS 643.
EXAMPLE 293 2,4-Dichloro-N-3,5-dichloro--(6-cyanophenylj-benzenesulfonamide (293) 'H NMR (DMSO-d6) 11.90 (br s, 1H), 8.49 J 1.1 Hz, IH), 8.23 (d, J 8.6 Hz, IH), 7.97 J 2.0 Hz, IH), 7.96 J 8.5 Hz, 1H), 7.86 (dd, J 8.5, 1.6 Hz, 1H), 7.74 (dd, J 8.6, 2.0 Hz, 1H), 7.38 2H). MS 558.
EXAMPLE 294 2-Chloro-N-13,5-dich loro-4-(6-cyano-benzoth iazol-2-ylsufanyl)phenyI.4-trifluoromethy-benzenesulfonamide (294) 'H NMR (DMSO-d 6 8 11.90 (br s, 1H), 8.49 J 1.5 Hz, IH), 8.43 (d, J 8.1 Hz, 1H), 8.24 (br s, IH), 8.03 (dd, J 8.2, 1.0 Hz, 1H), 7.97 J 8.5 Hz, 1H), 7.87 (dd, J 8.5, 1.7 Hz, I 7.40 2H). MS 592.
EXAMPLE 295 2,4-Dichloro-N- [3-chloro-4-(6-cyano-benzothiazo-2-ys ulfanyl)phenyll-benzenesulfonamide (295) 'HNMR (DMSO-d 6 8 11.60(br s, IH), 8.49 J 1.8 Hz, 1 8.18 (d, J 8.6 Hz, IH), 8.00-7.94 2H), 7.90-7.84 2H), 7.72 (dd, 1 8.6, 2.0 Hz, IH), 7.41 J 2.3 Hz, IH), 7.23 (dd, J 8.5, 2.4 Hz, 1H). MS 524.
EXAMPLE 296 2-Ch loro-N-I-chloro-4-(6-cyIno-benzothiazo -2-ylsulfanyI)-pheuyll-4trifluoromethyl-benzenesulfonamide (296) 'H NMR (DMSO-d6) 5 11.78 (br s, IH), 8.48 (br s, 11), 8.39 I Hz, IH), 8.22 (br s, IH), 8.02 (br d, J 8.4 Hz, IH), 7.97 J 8.6 Hz, IH), 7.90 J 8.6 Hz, Il), 7.86 (dd, J 8.5, 1.5 Hz, 1H), 7.43 J 2.3 Hz, IH), 7.25 (dd, J 8.5, 2.4 Hz, IH). MS 558.
WO 01/00579 PCT[USOO/18178 EXAMPLE 297 2,4-Dichloro-N-[3,S-dichloro-4-(5-cyano-benzothiazol-2-ytsulfanyl)phenyll-benzenesulfonamide (297) 'H NMR (DMSO-d 6 8 11.90 (br s, LH), 8.36 J 1.1 Hz, I 8.23 (d, J 8.5 Hz, iH), 8.16 J 8.2 Hz, 1f), 7.98 J 2.0 Hz, 1H), 7.77 (dd, J 8.5, Hz, 1H), 7.73 (dd, J 8.4, 2.0 Hz, I1H), 7.38 214). MS 558.
EXAMPLE 298 2-Chloro-N-13,5-dichloro-4-(5-yano-benzoth iazol-2-ylsulfanyl)phenyll-4-trifluoromethyl-benzenesulfonamide (298) 'H NMR (DMSQ-d) 8 11.98 (br s, I1H), 8.43 J 8.3 Hz, 1H), 8.35 (d, J 1.5 Hz, IH), 8.23 (br s, I 8.15 J 8.2 Hz, 1 8.03 (dd, J 8.4, 1.0 Hz, IlH), 7.76 (dd, J 8.4, 1.4 Hz, I 7.40 2H). MS 592.
EXAMPLE 299 2,4-Dichloro-N-[3-chl oro-4.(5-cyano-benzothiazol-2-yIsulfanyl)phenylj-benzenesulfonamide 'H NMR (DMSO-d 6 8 11.60 (hr s, I 8.36 J 1.5 Hz, I 8.18 (d, J 8.6 Hz, I1H), 8.15 J 8.3 Hz, I1H), 7.96 J 2.0 Hz, I1H), 7.88 J 8.6 Hz, IH), 7.75 (dd, J 8.4, 1.5 Hz, 1H), 7.72 (dd, J 8.5, 2.0 Hz, lH), 7.40 J 2.4 Hz, 1 7.23 (dd, J 8.5, 2.4 Hz, 1 MS 524.
EXAMPLE 300 2-Chloro-N-I3-chloro-4-(5-cyano-benzotiazo-2-ysufal)-phuyI-4trifluoromethyl-beuzenesulfon amide (300) 'H NMR (DMSO-d 6 8 11.70 (br s, I 8.39 J 8.4 Hz, I 8.35 (d, J 1.4 Hz, IH), 8.21 (br s, I1H), 8.13 J 8.4 Hz, I 8.03 (dd, J 8.5, 1.5 Hz, I1H), 7.88 J 8.6 Hz, 1H), 7.75 (dd, J 8.4, 1.6 Hz, IH), 7.43 J 2.4 Hz, I 7.24 (dd, J 8.5, 2.4 Hz, IH). MS 558.
EXAMPLE 301 2,4-Dichloro-N-(3,S-dich Ioro-4-[5-(1 H-tetrazol-5-yI)-benzothiazol-2ylsulfanyll-phenyl}-benzenesulfonamide (301) WO 01/00579 WO 0100579PCTIUSOO/18178 To a solution of 2,4-dichloro-N-[3 ,5-dichloro-4-(5-cyano-benzothiazol-2ylsulfanyl)-phenyl]-benzenesulfonamide (297) (250 mg, 0.45 mmol) in toluene (5 mL), was added azidotrimethylsi lane (Aldrich, 0. 12 mL, 0.90 mmol) and dibutyltin oxide (Aldrich, 11I mg, 0.045 mmol). The resulting mixture was heated at 90 *C overnight hours). A I M aqueous solution of HCl (50 mnL) and ice was added and the crude reaction mixture was extracted 3x with EtOAc (50 The organic layers were combined and washed twice with a brine solution (100 mL), dried over Na 2
SO
4 and concentrated under vacuum. The crude solid was chromatographed (20% EtOAc in CH 2
CI
2 then MeOH in CH 2
CI
2 to yield 209 mg of product as a white solid.
'H NMR (DMS O-d 6 8 8.44 J 1.7 Hz, I1H), 8.21 J 8.6 Hz, I H), 8.16 J 8.4 Hz, IlH), 8.01 (dd, J 8.4, 1.7 Hz, I1H), 7.96 J =2.0 Hz, I1H), 7.72 (dd, J 8.6, 2.0 Hz, 1H1), 7.38 2H). MS 601.
EXAMPLE 302 2-hooN(,-ihoo-5(Httao--i-eztizl2 ylsulfanylJ-phenyl}-4-trifluoromethyl-benzenesulfonamide (302) The title compound was prepared by the method of example 301.
'H NMR (DMSO-d 6 8 8.44 J 1.5 Hz, IHM, 8.42 J 8.4 Hz, 111), 8.23 J1 1.3 Hz, I 8.15 J 8.4 Hz, I1-H), 8.02 (dd, J 8.4, 1.4 Hz, I 7.40 (s, 211). MS 63 EXAMPLE 303 2-12,6-Dichloro4-(2,4-dichloro-benzenesulfony1aMilo)acid amide (303) To a solution of 2,4-dichiloro-N-[3 ,5-dichloro-4-(5-cyano-benzothiazol-2ylsulfanyl)-phenyl]-benzenesulfonamide (297) (250 mg, 0.45 mmol) in tert-butanol mL), was added KOH (EM Science Product, 126 mng, 2.25 mmol). The resulting mixture was refluxed for 1 hour. After cooling to room temperature, a I M aqueous solution of HCI (50 mL) was added and the crude reaction mixture was extracted 3x with EtOAc niL). The organic layers were combined and washed twice with a brine solution (100 mL), dried over Na 2
SO
4 and concentrated under vacuum. The crude solid was chromatographed (20% EtOAc in CH 2 Cl 2 then 10% MeOH in CH 2
CI
2 to yield 207 mig of compound 303 as a white solid.
WO 01/00579 PCT[USOO/18178 'H NMR (DMSO-d6) 5 11.80 IH), 8.33 (br s, 1H), 8.22 (dd, J 8.5, 1.9 Hz, 1H), 8.08 (brs, 1H), 8.03-7.96 2H), 7.85 7.74 1H), 7.47 (brs, 1H), 7.38 2H). MS 578.
EXAMPLE 304 2,4-Dichloro-N-{3-chloro4-15-(H-tetrazol-5-y)-bezothiazoI-2ylsulfanylj-phenyl}-benzenesulfonamide (304) The title compound was prepared by the method of example 301.
'HNMR (DMSO-d 6 )8 8.44 J 1.5 Hz, IH), 8.17 J 8.6 Hz, IH), 8.14 8.4 Hz, IH), 8.01 (dd, J 8.4, 1.6 Hz, IH), 7.95 J 2.1 Hz, 1H), 7.87 J 8.6 Hz, IH), 7.71 (dd, J 8.6, 2.1 Hz, I 7.39 J 2.4 Hz, 1H), 7.21 (dd, 8.6, 2.4 Hz, 1H). MS 567.
EXAMPLE 305 2-Chloro-N-3-chloro-4-15-(1 H-tetrazol-5-yI)-benzoth iazol-2ylsulfanylj-phenyl}-4-trifluoromethyl-benzenesulfonamide (305).
The title compound was prepared by the method of example 301.
'H NMR (DMSO-d 6 8 8.43 J 1.5 Hz, IH), 8.36 J 8.4 Hz, IH), 8.17 J 1.4 Hz, IH), 8.12 J 8.4 Hz, IH), 8.03-7.96 2H), 7.85 J 8.6 Hz, 1H), 7.40 J 2.4 Hz, 1H), 7.20 (dd, J 8.6, 2.4 Hz, IH). MS 601.
EXAMPLE 306 N-13-AcetyI-5-c1Ioro4-(5-methyl-benzzothiazo-2-yisu Ifanyl)-phenylj- 2-chloro-4-trifluoromcthyl-benzenesulfonamide (306).
'H NMR (DMSO-d 6 8 11.90 (br s, 1H), 8.43 J 8.1 Hz, 1H), 8.23 (d, J 1.2 Hz, IH), 8.01 (dd, J 8.4, 1.1 Hz, IH), 7.78 J 8.2 Hz, 1H), 7.62 IH), 7.46 J 2.4 Hz, 1H), 7.29 J 2.4 Hz, IH), 7.19 (dd, J 8.5, 1.2 Hz, 11), 2.47 3H), 2.40 3H). MS 589.
EXAMPLE 307 N-[3-Acetyl-5-chloroI4-(5-methyl-benzoth y fanyl)-phenyll- 2,4-dichloro-5-methyl-benzenesulfonamide (307) WO 01/00579 WO 0100579PCT/USOO/18178 'H NMvR (DMSO-d 6 8 11.70 (br s, 8.28 7.92 7.80 (d, I 8.1 Hz, 1H), 7.64 1H), 7.45 J 2.3 Hz, 1H1), 7.29 J =2.3 Hz, 1H), 7.19 (dd, J 8.2, 1.5 Hz, I Hf), 2.48-2.38 (in, 9H). MS 569.
EXAMPLE 308 3-Hydroxy-6-methylquinoline (308) A solution of 3-Aniino-6-methylquinoline [(1.21 g, 7.65mmol), prepared according to J.Chem.Soc.2024-2027(1948) Morley, J. Simpson, J. C. in 6N H1 2 S0 4 (25m1) was cooled in an ice bath. To the solution NaNO 2 (560mg, 8.l0mmol) in water (2m1) was added and stirred for 30min at 0 degrees. Separately 5% H 2 S0 4 Was refluxed and above Diazo reaction mixture was added to this refluxing solution. After the reaction mixture was cooled to room temperature, and was neutralized by 6N NaOH. The resulting insoluble material was collected by filtration. This solid was recrystallized by CHC1 3 /AcOEt to afford compound (308) (348mg, 29%).
'H NMR (300M~z,DMSQ-d 6 8 7.34 (1IH, dd, J=1.9, 8.6Hz), 7.42(1H, d, J=2.8Hz), 7.55 (1 H, 7.79 (1IH, d, 1=8.6Hz), 8.50 (IH, d, J=2.8Hz).
EXAMPLE 309 3-(2,6-Dichloro-4-nitro-phenoxy)-6-methyl-quinoline (309) To a solution of 3-Hydroxy-6-methylquinoline (308) (348mg, 2.l9mmol) in DMIF (3.5ml), was added NaH (60% oil suspension, 90mg, 2.2Smmol) in one portion at room temperature. After 5mmn 3,4,5-Trichloronitorobenzene (509mg, 2.25mmol) in DMF (2m1) was added and the reaction mixture was heated at 50 degrees with stirring for 2hr. After cooling to room temperature. Ice/water was added to the reaction mixture, which was then acidified with 2N HCI and extracted twice with AdOEt. Organic layer was washed with Brine, dried over anhydrous MgSO 4 and concentrated. Crude residue was purified by column chromatography (Hexane/AcOEt=4/1, 80g of silica gel) to afford compound 309 (510mg, 'H NMR (300MHz,DMSO-d6) 5 7.52-7.57(2H,m), 7.61 (lEH, 7.94(lH, d, J=8.6Hz), 8.63 (2H, 8.86 (111, d, J=2.9Hz).
EXAMPLE 310 3-(2,6-Dichloro-4-nitro-phenoxy)-quinoline-6-carboxylic Acid (310).
WO 01/00579 WO 0100579PCTIUSOO/18178 A solution of 3-26Dclr4ntopnxy--ehlqioie39 10Omg, 1.46mmol) and chromium (VI) oxide (292mg, 2.92mmol) in c H 2 SOS/ H 2 0 =2.4mLi4.7m1 was heated at 100 degrees while three 292mg portions of chromic anhydride were added eight hour intervals. After 32hr heating was stopped and allowed to stand for over night. Insoluble material was collected by filtration, and this solid was washed with water twice to afford compound (310)(443mg, 'H NMR (300M~fz,DMSO-d 6 8 7.94 (IH1, d, J=3.OHz), 8.14(2H, 8.56 (1 H, 8.65 (2H4, 9.09 (1 H, d, J=3.OHz).
EXAMPLE 311 3-(2,6-Dichloro-4-nitro-pbenoxy)-quinoline-6-carboxylic acid methyl ester (311) To a solution of 3 .{2,6-Dichloro-4-nitro-phenoxy)-quinoline-6-carboxylic acid (310) (443mg, 0.93mmol) in dry THF (20m1) was added CH 2
N
2 in Et 2 O solution [Prepared firom Nitrosomethylurea (1.65g) and 50%KOH This mixture was stirred at room temperature for thr. AcOH (Il) was added to the reaction mixture, which was then concentrated. Sat NaHCO 3 was added to the residue, which was extracted twice with AcOEt. Organic layer was washed by Brine, dried over anhydrous MgSO 4 and concentrated to afford compound 311 (4 'H NMR (300MHz,DMSO-d 6 8 3.89 (3H, 5.75(2H, br 6.76 (2H, s), 7.73 (1H, d, J=2.9Hz), 8.09 (2H, 8.67 8.94 (IH, d, J=2.9Hz).
EXAMPLE 312 3-(4-Amino-2, 6-dichloro-phcooxy)-quinoline-6-carboxyliC acid methyl ester (312) To a solution of 3-(2,6-Dichloro-4-nitro-phenoxy)-quinoline-6-carboxylic acid methyl ester (311) (0.93mmol) and NH 4 C1 (283mg, 5.3mmol) in EtOH/TH F/waler (8m/l6ml/Iml )was added Iron powder (296mg, 5.3mmol). The reaction mixture was refluxed for 4hr. Insoluble materials were removed by Celite pad, which was washed by THF, acetone and then EtOH. The filtrate was concentrated, and sat NaHCQ 3 was added and extracted twice with AeOEt. Organic layer was washed by brine, dried ove~r anhydrous MgSO4, and concentrated to afford compound 312 (372mg, over weight).
WO 01/00579 WO 0100579PCT/USOO/18178 'H NlvlR (300MHz,DMSO-d6) 6 3.89 (3H, 5.75(2H-,s), 6.76 (211, s), 7.73 (1 H, d, J='2.9Hz), 8.09 8.67 (1IH, 8.94 (1 H, d, J=2.9Hz).
EXAMPLE 313 3-Hydroxy-8-quinolinecarboxylic acid methyl ester (313) To the mixture of 8-Quinoline carboxylic acid (500mg, 2.89mmol) in TifF (80m1) was added CH 2
N
2 in Et 2 O sol. [Prepared from Nitrosomethylurea (1 .65g) and (5m1)) at room temperature. The reaction mixture was stirred for 12 hr and then concentrated to give the intermediate ester.
'H NM'R (300MHz,DMSO-d 6 3.92 7.60-7.70 (2H, in), 7.93- 7.96(lH, in), 8.14-8.17 (IH, in), 8.44-8.48(lIH, mn), 8.97-8.99(lIH, m) To a solution of the intermediate 8-Quinolinecarboxylic acid methyl ester (2.89mimol) in AcOH (4m1) was added 30% H 2 0 2 (0.6in1). The reaction mixture was heated at 85 degrees for 7.5hr. The reaction mixture was treated with sat NaHCO3, and extracted six times with CHC1 3 Organic layer was dried over anhydrous MgSO 4 and concentrated. Crude residue was triturated with CHC13'Toluene to provide compound 313 (256mg, 44%, in 2 steps).
'H NMIR (300MHz,DMSO-d 6 8 3.89 (3H, 7.52(IH, d, J=6.9Hz), 7.57 (IH, d, 1=1.5Hz), 7.66 (lH, dd, J=1.5, 6.9H-z), 7.95 (IH, dd, J=1.5, 8.1Hz), 8.63 (IH, d, 1=2.7Hz), 10.5 (IH, br s).
EXAMPLE 314 3-(2,6-Dicbloro-4-nitro-penoxy)-quiolie-8-Carboxylic acid methyl ester (314) To a solution of 3-Hydroxy-8-quinolinecarboxylic acid methyl ester (313) (256mg, 1 .26mmol) and 3,4,5-Trichloronitrobenzene (294mg, 1 .3Omniol) in Acetone (40m1) was added K 2 C0 3 (870mg, 6.3Oinmol). This mixture was refluxed for 3.51ir. The reaction mixture was cooled to room temperature and insoluble materials were removed by Celite filtration. The filtrate was concentrated and the residue was purified by column chromatography. (Hexane/AcOEt='4/1, 80g of silica gel) to afford compound 314.
'H NMR (300MIlz,DMSO-d 6 8 3.92 7.67(1H, dd, J=7.3Hz), 7.79 (111, d, J=2.9Hz), 7.88 (1W, dd, J=1.5, 7.314z), 9.05 (11H, d, J=2.9Hz):- WO 01/00579 WOOI/0579PCT/USOO/18178 EXAMPLE 315 3-(4-Amino-2, 6-dichloro-phenoxy)-quinoline-8-carboxylic acid methyl ester(315).
To a solution of 3-(2,6-Dichloro-4-nitro-phenoxy)-quinoline-8-carboxylic acid methyl ester (314) (l.26mniol) and NH 4 CI (370mg, 6.91lmmol) in EtOHJTHF/ H 2 0 =8mL/4mL/2m1 was added Iron powder (386mg, 6.9 immol). The reaction mixture wasrefluxed for 3.5hr. After cooling to room temperature and insoluble materials were filtered by Celite filtration. The filtrate was concentrated and sat NaHCO 3 was added to the residue, which was extracted twice with AcOEt. Organic layer was washed by Brine, dried over MgSO 4 and concentrated. Crude residue was purified by column chromatography (Hexane/AcOEt=2/1, 80g of silica gel) to afford compound 315 (543mg).
'H NMvR (300M1-z,DMSO-d 6 8 3.9 1(3H, 5.77(2H, br 6.78 (2H, s), 7.50 (1lH, d, 1=3.0Hz), 7.61 (1IH, dd, J=8.lIHz), 7.81 (1IH, dd, J=1.4, 6.4H4z), 8.08 (1IH, dd, J=1.4Hz, 6.4H-z), 8.93 (IH, d, J=3.OHz).
Table 33
NH
2 V4 z S Example V X Y Z 316 H Cl H Cl 317 H F F H 318 H F H F 319 Cl Me Me H EXAMPLE 316 3-cb loro-4- (3,5-dichloro-phenylsulfanyl)-phenyla mine (316).
WO 01/00579 WO 0100579PCT/USOO/18 178 A solution of potassium t-butoxide (I M in THF) (13 ml) was added via syringe to a solution of 3,5 dichlorothiophenol (2.37 g) and 3-chloro-4-fluoronitrobenzene (2.3 g) in THF (20 mL). The exothermic reaction was allowed to stir until it cooled to room temperature. It was poured into water. The resulting solid was collected by filtration and rinsed quickly with ether to leave the intermediate nitro compound. This was dissolved in ethyl acetate at reflux. Tin (II) chloride dihydrate (2.3g) was added in portions as a solid and the reflux continued for 2 hr. After cooling, the mixture was diluted in ethyl acetate, quenched with KOH (0.5 N, 500 mL) and extracted with ethyl acetate 3 X. The organic layer was washed with water, dried over magnesium sulfate and concentrated to afford the aniline (316) (2.9 g) as a light tan solid useable in subsequent reactions. Mp 157-160'.
'H NMR (DMSO) 8 7.36 J=8.4 Hz, I1H), 7.34 1 J=2 Hz, I 6.91 (in, 2H), 6.831 J=2.4 Hz, I 6.602 (dd, J=8.4, 2.8 Hz, I 6.01 (hr s, 2H).
EXAMPLES 317AND 318 3,4 difluorothiophenol and 3,5-difluorothiophenol were prepared by the method of D.K. Kim et al Med. Chem. 40, 2363-2373 (1997) and converted by the method of example 316 to the corresponding anilines.
EXAMPLE 317 3-chloro-4- (3,5-difluoro-phenylsulfanyl)-phcnylamine (317) 'H NMR (DMSO) 8 7.361 J=8.4 Hz, 1H), 6.983 (in, IH), 6.84 J=2.4 Hz, I H) 6.61 (mn, 3H), 6.02 21-).
EXAMPLE 318 3-chloro-4- (3,4-difluoro-phenylsulfanyl)-phenylamine (318) 'H1 NTMR (acetone) 8 7.377 J=8.4 Hz, 1H), 7.258 (dt J=10.4, 8.4 Hz, 111), 6.97 (in, 1H) 6.94 (in, 2H), 6.714 (dd, 8.4, 2.5 Hz, 1H), 5.42 2H).
EXAMPLE 319 3,5-Dichloro-4- (3,4-di methyl-ph enyls u Ifa nyl)-phe nyla minle (319).
A mixture of 3 ,4-dimethylthiophenol (1.38g, 10Oimol), 3,4,5tichoronitrobenzene 2.4§g, 1 Immol) and K 2 C0 3 (4.15g, 3Ommol) in acetone (15m1) was WO 01/00579 WO 0100579PCT/USOO/18178 refluxed for 2 hr. After reaction mixture was concentrated, crude product was puiified by column chromatography 180g of silica gel) to afford a yellow oil. Unpurified crude 3,5-Dichloro-4- (3 ,4-dimethyl-phenysulfanyl)-nitrobenzefle was dissolved in
CH
2 C1 2 /AcOEt (5m1120m1). To the solution was added SnC1 2 /2H 2 0(9.03g, 4Omniol) and the reaction mixture was stirred at room temperature for 12 hr. 30% NaOH was added to the reaction mixture, which was extracted twice with AcOEt. Organic layer was washed by water, dried over MgSO 4 and concentrated to give 2.86g (96% 2 steps) of compound 319 as a white solid.
'H NMR (300MI~z,DMSO-d 6 8 2.14(6H, 6.1 1(2H, br 6.66(111, dd, J=1.8, 8.1IHz), 6.77(2H, 6.82(IH, d, i=1.8Hz), 7.02(11-, d, J=8.lHz).
EXAMPLES 320-337 The anilines of Table 33 were sulfonylated by the method of example 3 and then oxidized to the corresponding sulfoxide by the method of example 103 or sulfone by the method of example 104 to provide the examples 320-337 illustrated in Table 34.
Table 34 N SB
C
D
EXAMPLE
MS
k A B C D V X Y Z (M-H) 320 0 CI H Cl H H CI H Cl 509.9 321 1 CI H Cl H H CI H C1 525.8 322 2 C1 H Cl H H Cl H Cl 541.8 323 0 CI H CI H H F H F 478 324 1 CI H CI H H F H F 325 2 Cl H Cl H H F H F 509.9 WO 01/00579 WOOI/0579PCT/USOO/181 78 326 0 CI H CF 3 H H F H F 512 327 1 CI H CF 3 H H F H F 461 328 2 CI H CF 3 H H F H F 544 329 0 CI H CI Me H F H F 491.9 330 1 CI H Cl Me H F H F 331 2 CI H Cl Me H F H F 523.8 332 0 CI H CI H H F F H 333 1 CI H CI H H F F H 493.9 334 2 Cl H CI H H F F H 509.9 335 0 CI H CF 3 H H F F H 512 336 1 Cl H CF 3 H H F F H 493.9 337 2 Cl H CF 3 H H F F H 544 338 0 Cl H CF 3 H Cl Me Me H 540 EXAMPLE 324 'H NMR (DMSO) 8 11. 5 (br s, I 8.12 J=8.8 Hz, I1H), 7.8 8 J=2 Hz, I 7.748 1= 8 Hz, I 7.661 (dd, J=8.8, 2 Hz, I 7.476 (in, IlH), 7.42 (n 2H), 7.28 (dd, J=8.4, 2 Hz, I H) 7.17 (br s, I1H).
EXAMPLE 330 'H NIM(acetone) 6 10. 1 (br s, I 8.147 I 7.80 I 7.648 (s, 1lH), 7.49 (in, I 7.40 (in, 2H), 7. 15 I 2.433 3H).
EXAMPLE 332 H NMR (acetone) 8 9.80 (br s, I 8.162 J=8.4 Hz, I1H), 7. 73 5 (d, J=2 Hiz, I1H), 7.615 (dd, J=8.4, 2.1 Hz, I1H), 7.43 6 J= 2.2 Hz, I 7.3 58 (dt, J=10. 8.4 Hz, 1IH), 7.292 (ddd, 1ff), 7.224 (dd, J=8.4, 2.3 Hz, I1H), 7.176 J=8.4 Hz, I H), 7.16 I1H).
EXAMPLE 338 2-Chloro-N-13,5-dichloro-4-(3,4-d imethyl-phenylsulfanyl)-phenyli-4trifluoromethyl-benzenesulfonamide (338) WO 01/00579 WO 0100579PCTIUSOO/18178 A solution of aniline 319 (860mg, 2.68mmol) and 3-chloro-4trifluoromethylbenzene-sulfonylchloride (658mg, 2 .68mniol) in pyridine (1 OmI) was stirred at room temperature for 2-hr. Water was added to the reaction mixture, which was then acidified by 2N HCI. Reaction mixture was extracted twice with AcOEt. Organic layer was washed by Brine, dried over MgSOj 4 and concentrated. Crude residue was purified by column chromatography (HIA=4/l, 80g of silica gel) to afford compound 317 (591 mg, 41 as a white solid.
'H NMR (400MIHz,DMSO-d 6 8 2.1 1(3H,s), 2.13(3H,s), 6.78(lH,dd, 1=2.1,8.3Hz), 6.8 1(1 7.01(1H,d, J=8.3H-z), 7.30(2H, 7.98(2H,dd, J=2.l,8.3Hz), 8.18(IH,s), 8.35(IH, d, J=8.3Hz), i .6(IH, br s).
mp 156-158 MIS 540.
EXAMPLE 339 3,5-Dichloro-4- (6-methyl-quinolin-3-yloxy)-pheflylamifle (339) To a solution of 3-26Dclr--ir-hnx)6mty-unln (309) (1 .30g, 3.71 mmol) and NII 4 CI (992mg, 18.5rnmol) in EtOH/THF/ H 2 0 =12m1112m113m1, was added Iron Powder (1.04g, 18.55nmmol). The mixture was refluxed for 4 hr. Insoluble materials were removed by Celite filtration. The filtrate was concentrated and sat NaHCO 3 was added to the residue, which was then extracted twice with AcOEt. Organic layer was washed with Brine, dried over anhydrous MgSO 4 and concentrated to afford compound 339 (1.18g, 98%).
'H NMR (300MHz,DMSO-d 6 8 2.44 5.75 br 6.77 s), 7.27 (1 H, d, J=2.8Hz), 7.48 (1 H, d, J=8.6Hz), 7.67 (11-H, 7.89 (1lH, d, J=8.6Hz), 8.74 (1H, d, 1=2.8Hz).
EXAMPLE 340 2-Mercapto -4-methyl-benzothiazole (340) The title compound was prepared using the method of example 239, starting with 2-bromo-4-methyl-phenylamifle (Acros) (27.9g), O-ethylxanthic acid, potassium salt (Lancaster, 54g) in DMF (250 mL). The mercaptobenzothiazole 340 was obtained as an pale brown solid (27 Recrystalizatibn from CHC1 3 gave pinkish white crystals WO 01/00579 WO 0100579PCTIUSOO/18178 'H NMR (DMSO0-d,) 8 7.499 (hr s, IRH), 7.223 J =8 Hz, I 7.198(d, J=8 Hz, IlH), 2.342 3H).
EXAMPLE 341 Compound 341 was prepared by the method of example 84.1 by coupling thiol 340 (9.3g) with 1,2,3,-trichloro-5-nitrobenzene (I1.3g) in DMF using NaR as base.
Trituration with ether gave 341 (12.4 g) as a yellow solid.
'H NMR (DMSO-d 6 6 8.577 2H), 7.795 (br s, 1H), 7.736 J 8.4 Hz, 1H), 7.303 J=8.4 Hz, 1H), 2.405 3H).
EXAMPLE 342 Reduction of compound 341 (12.4 g) with SnCl2 by the method of example 32 gave after trituration with methylene chloride, aniline 342 (9 g) as a solid.
'Hi NMR (DMSO-d 6 8 7.709 (hr s, 1H), 7.699 J 8 Hz, IH), 7.262 (d, J=8 Hz, 1H), 6.859 2H), 6.45 2H), 2.384 3H).
EXAMPLE 344 Compound 344 was prepared by the method of example 84.1 by coupling thiol 245 (2.01 g) with 1,2,3,-trichloro-5-nitrobenzene (2.51 g) in DMF using NaH as base. Recrystalization with ether/hexane gave compound 344 (3.2 g) as a yellow solid.
Mp 116-118*C.
EXAMPLE 345 Reduction of compound 344 (3.01. g) with SnC12 by the method of example 32 gave aniline 345 (2.8 g) as a solid.
'H NMR (DMSO-d 6 8 7.772 J 8.0 Hz, IlH), 7.630 (br s, I 7.155 (br d, J=8 Hz, I 6.85 5 2H), 6.442 2H), 2.409 3H). MIS 34 1. Anal.
Calcd.::cale. 49.27% C, 2.95% H, 8.21% N. Found. 49.39% C, 3.16 7.98 %N WO 01/00579 WOOI/0579PCTIUSOO/18178 Example 342: X=Me, Y=H Example 345: X=H, Y=Me EXAMPLES 346-351 Sulfonylation of ani lines 342 or 345 by the method of example 3 gave the sulfonamides of Table Table Example 346 347 348 349 350 351
MIS
A B C D X Y (M-H) Cl H CF 3 H Me H 581
CF
3 H- Cl H Me H 581 Cl H Cl Me Me H 561 Cl H CF 3 H H Me 581 Cl H Cl Me H Me 561 Cl H Me H H Me 527 WO 01/00579 WO 0100579PCTIUSOO/18178 EXAMPLE 346 'H NMR (DMSO-d4) 8 11.90 111), 8.416 J 8.0 Hz, 1H), 8.228 (br s, I1H), 8.024 (br d, J=8 Hz, I 7.690 (mn, 2H), 7.383 2H), 7.265 (br d, J=8 Hz, I H), 2.379 3H). MS 580.8.
EXAMPLE 347 1H NMR(d 6 -DMSO) 8 11.70-12.00 (I14, broad), 8.22 (1H, d,J= 8.6 Hz), 8.17 (IH, 8.08 (IH, d, J= 8.5 Hz), 7.68-7.75 (2H, in), 7.39 (2H, 7.28 (IH, d, J= 8.2 Hz), 2.39 (3H, MS 580.8. mp 227.0'C. Anal. Calcd.: C 43.20, H 2.07, N 4.80; found C 43.23, H 1.97, N 4.91.
EXAMPLE 348 'H NMR (DMSO-d 6 5 11.71 (br s, IHf), 8.237 (br s, Ili), 7.915 IH), 7.708 I 7.698 1=8 Hz, I 7.365 2H), 7.266 (dd, J=8, 1.6 Hz, I 2.414 (s, 3H), 2.380 3H). MS 560.8.
EXAMPLE 349 'H NMIR (DMSO-d 6 5 11.94 (br s, I 8.416 J =8.4 Hz, I1H), 8.231 J=1.6 Hz, I1H), 8.024 (dd, J=8.4. 1.6 Hz, I 7.767 J=8 Hz, I 7.628 I1H), 7.382 2H), 7.185 (dd, J=8.4, 1.6 Hz, 1K), 2.398 3H). MS 580.8.
EXAMPLE 350 'H NMR (DMSO-d 6 8 11.725 (br s, I 8.236 (br s, I1H), 7.918 IT-H), 7.785 J=8 Hz, I1-H), 7.637 1KH), 7.363 2H), 7.183 J=8 Hz, I 2.408 6H).
MS 560.9.
EXAMPLE 351 'H NMR (d 6 -DMSO) 8 11.67 (1IH, 8.12 (1 H, d, J 8.1 Hz), 7.80 (1 H, d, J 8.2 Hz), 7.5 8-7.68 (2 H, 7.46 (1 H, d, J= 8.1 Hz), 7.3 5 7.20 (1 H,d, J= 8.2 Hz), 2.40 (6H, MS: 526.8. mp 112.8 0 C. Anal. Calcd.: 47.60%C, 2.85% H, 5.29% N; found 47.28%C, 2.98%H, 5.28%/N.
WO 01/00579 WO 0100579PCT[USOO/18 178 EXAMPLE Aniline 342 was converted according to the method of example 34 to afford the corresponding sulfonyl chloride 352 as a white solid.
'H NMR (CDCI 3 8 8.131 2H), 7.786 J Hz, 1H1), 7.567 (br s, 1 7.28 (hr d, J=8 Hz, I 2.482 3H).
I Example 353 X=
S
SExample 354 X= Me Example 352 X=CI EXAMPLE 353 Coupling of compound 352 (85 mg) with 3,4-dichloroani line (42 mg) by the method of example 3 gave the sulfonamide 353 (76 mg) as a white solid.
'H NMR (d 6 -DMSO) 5 11.01 (1IH, 8.04 (1H, 7.76 (11, 7.72 (IH, d, J= 8.5 Hz), 7.62 (114, d, J= 8.7 Hz), 7.34 (LH, 7.29 (11H, d, J 7.6 Hz), 7.13-7.23 (I H, in), 2.40 MS 546.8. mp 18 1.0 0 C. Anal. Calcd.: caic. 43.65% C, 2.20% H, 5.09% N. found 43. 10% C, 2.21 4.81 %N.
EXAMPLE 354 Coupling of compound 352 (85 mg) with 2,4-dichloroaniline (42 mng) by the method of example 3 gave after recrystalization from methanol water, the sulfonamide 354 (38 mng) as a white solid.
'H NMR (d 6 -DMSO) 8 10.72 (IH, 7.96 (2H, 7.79 (111, 7.72-7.77 (2H, in), 7.47 (IH, dd, J= 8.7, 2.4 Hz), 7.33 (111, d, J= 8.6 Hz), 7.31 (IH4, d, J= 8.6 Hz), 2.41 (311, MS 548.9. mp 160.7 0 C. Anal. Calcd.: calc. 43.65% C 2.20% H, 5.09% N. found 43.83% C, 2.19% H, 5.10% N The following examples illustrate the synthesis of compounds 355-358.
WO 01/00579 PCT/US00/18178 Cl H M
F
6 x
IN
355 X=N02 357 X=N02 356 X=NH2 358 X=NH2 EXAMPLE 355 2,3-dichloronitrobenzene (6.15 g, 32 mmol), methylamine hydrochloride (2.38 g, 35 mmol), triethylamine (9.8 mL, 71 mmol), and DMF (16 mL) were combined in a 100 mL round-bottomed flask and heated to 90'C overnight. The reaction was then cooled to room temperature and dumped over 600 mL of ice-water. The resulting orange solid was collected by filtration and dried at the pump. Recrystallization from hot hexanes yielded 3.2 g of compound 355 as bright orange crystals.
1 H NMR (d 6 -DMSO) 6 7.75 (1H, dd); 7.62 (1H, dd); 6.76 (1H, 6.63 (1H, broad 2.75 (3H, t).
EXAMPLE 356 A round-bottomed flask was charged with 3.8 g (20 mmol) of compound 355, 22.9 g (102 mmol) of tin dichloride dihydrate, and 125 mL of EtOAc. This was heated to 75'C for 3.0 hours. The reaction was cooled to room temperature, diluted with 300 mL of EtOAc and washed with 250 mL of 2N aqueous KOH solution followed by 200 mL of brine. The organics were dried over sodium sulfate and concentrated to a white amorphous solid 355 (2.9 g, 90%) that was used without further purification (turned brown upon standing in air).
'H NMR (d 6 -DMSO) 8 6.68 (1H, 6.56 (2H, 4.98 (2H, broad 3.76 (1H, broad 2.59 (3H, t).
WO 01/00579 PCT/US00/18178 EXAMPLE 357 A round-bottomed flask was charged with 356 (1.0 g, 6.4 mmol), 4-nitro- 2-flourophenyl acetic acid (148) (1.4 g, 7.0 mmol), and 4N aqueous HCI (13 mL). This was refluxed overnight. The reaction was then cooled and basified with saturated aqueous sodium bicarbonate. The organics were extracted with methylene chloride, dried over Na 2
SO
4 and concentrated to a pink solid. This was recrystallized from methylene chloride and hexanes to yield compound 357 (1.4 g, 75%) as fluffy crystals.
'H NMR (400MHz) (d 6 -DMSO) 5 8.16 (1H, dd); 8.08 (1H, dd); 7.62 (1H, 7.49 (1H, dd); 7.23 (1H, dd); 7.13 (1H, 4.48 (2H, 4.08 (3H, s).
EXAMPLE 358 Nitro compound 357 (1.3 g, 4.0 mmol) was reduced by the method of example 356 to give the aniline 358 (1.0 g, 86%) as off-white crystals.
MS 290.1 EXAMPLE 359-361 Aniline 358 was coupled with various sulfonyl chlorides by the method of example 192 to give the sulfonamides illustrated in Table 36 Table 36
B
H
I D
C
N
EXAMPLE
MS
A B C D yield (M-H) 359 Cl H Cl H 36% 496 360 H H -COMe H 50% 470 361 Me H Cl Me WO 01/00579 WO 0100579PCT/USOO/181 78 362 Cl H Cl Me 496% EXAMPLE 359 'H NMR (d 6 -DMSO) 8 11 .01 (IH, 8.07 (IR, 7.87 (111, 7.63 (1H, dd); 7.49 (11H, 7.22 (1IH, 7.15 (2H, in); 6.89 (2H1, nm); 4.21 3.99 (3H, s).
MS 496.0.
EXAML 6 'H NMiR (d 6 -DMSO) 8 10.78 (1IH, 8.12 (2H1, 7.94 (2H1, 7.51 (11H, 7.26 (IH, 7.17 (2H, 6.97 (2H, in); 4.24 (2H, 4.01 (311, MS 470.1.
EXAMPLE 361 'H NMR (d 6 -DMSO) 8 10.75 (1IH, 7.91 (1IH, 7.51 (2H, in); 7.26 (I1H, 7.16 (2H1, dd); 6.88 (2H, 4.24 (2H, 4.01 (3H, 2.54 (3H, 2.34 (3H, s).
EXAMPLE 362 'H NMR (d 6 -DMSO) 8 10.97 (1 H, 8. 10 (11H, 7.83 (1 H, 7.52 (1 H, 7.27 (1IH, 7.17 (2H, 6.94 (211, in); 4.24 (211, 4.01 (3H, 2.38 (3H, s).
EXAMPLE 363 This illustrates the preparation of 2,6-dichloro-benzothiazole (363).
2-Amino-6-chlorobenzothiazole (I15.7g, 85mmol) in H 3 P0 4 (85%)(470ml) was heated to 100 degrees and dissolved. Then clear solution was cooled and vigorously stirred by mechanical stirrer. NaNO 2 (17.6g, 255mmol) in water (30ml) was added slowly keeps the temperature below 0 degrees. Separately a solution of CuSO4/5H2O(85g), NaCI (107g) in water (350m]) was cooled to -5 degrees and stirred by mechanical stirrer. Aftef Potassium Iodide Starch paper's color was disappeared Diazonium solution was keeping cold and added slowly to the copper chloride solution with vigorous stirring. The reaction Mixture was allowed to warm to room temperature. After 1 -hour water (I L) and ether (I L) were added to the reaction mixture and extracted twice. Organic layer was washed by water and dried over anhydrous MgSO 4 and concentrated.Crude residue was purified by silica gel chromatography 180g of silica gel) to provide title compound 363 (7.46g, 48%).
WO 01/00579 WO 0100579PCTIUSOO/18 178 EXAMPLE 364 This illustrates the preparation of 3,5-dichloro-4- (6-chloro-benzothiazal- 2-yloxy)-phenylamine.
To the solution of 4-amino-2, 6-dichioro phenol (6g, 26.5 turol) and 2,6dichlorobenzothiazole (363) (6g, 29.4nimol, 1.l1eq) in DMSO (25m1), was added K 2 C0 3 (I1Ig, 8Ommol, 3.Oeq). The mixture was stirred and heated to 160 degree. After water (20m1) was added to the reaction mixture, which was neutralized with 2N HCI., and was extracted with AcOEt three times. And the organic layer was washed with Brine and was dried over anhydrous MgSO 4 and then concentrated. Crude residue was purified by column chromatography (CHCl 3 /Acetone=9/1, 180g of silica gel) to afford 4- (6-chloro-benzothiazol-2-yloxy)-phenylamifle (364) as a black solid (4.52g, 49%).
'H NMNR (300M1-zDMSO-d 6 8 5.86(2H,br 6.74(2H,s), 7.48(l H,dd, 1=2.1,5.7Hz), 7.70(1 H,d, 8.Hz), 8. 10(1 H,d, 2. 1Hz).
EXAMPLE 365 This illustrates the preparation of 2-Chloro-N- [3,5-dichiloro-4- (6-chlorobeztizl2yoy-hnl--rilooehlbneeufnmd (365).
A solution of 3,5 -dichloro-4- (6-chloro-benzothiazol -2-yloxy)phenylamine (364) (2.0g, 5.79mniol) and 3-chloro-4tnfluoromethylbenzenesulfonylchloride (1.7g, 6.O8nmmol) in pyridine (l0mi) was stirred at room temperature. After 3-hr water was added to the reaction mixture, which was then acidify by 2N HCL. Reaction mixture was extracted twice with AcOEt. Organic layer was washed by brine, dried over MgSQ 4 and concentrated. Crude residue was purified by column chromatography 80g of silica gel) to afford title compound 365 (2.11 g, as a white solid. mp 82-84* 'H NMR (400MHz,DMSO-46) 8 7.32(2H,s), 7.46(l1H,dd, J=2.2,8.7Hz), 7.67(lH,d, J=8.7Hz), 8.00(lH,d, 8.0Hz), 8.14(IH,d, J=2.2Hz), 8.20(IH,s), 8.38(1H,d, J=8.3Hz), 1 1.6(l H,br MS 586.
EXAMPLE 366 This illustrates the preparation of 2,4-Dichloro-N-[3,5-dichloro-4-(6chloro-benzothiazol-2-yloxy)-pheny1]benzencsulfonamide (366).
WO 01/00579 WO 01/(1579PCT/USOO/18 178 A solution of 3,5-dichloro-4-(6-chloro-benzothiazol-2-ylo~xy)-phelylamfifle (364) (2.0g, 5.79mmol) and 2,4-dichioro benzenesulfonylchloride (1 .5g, 6.O8mmol) in pyridine (l0mi) was stirred at room temperature for 12-hr. Water was added to the reaction mixture, which was then acidified by 2N HCI. Reaction mixture was extracted twice with AcOEt. Organic layer was washed by Brine, dried over MgSO 4 and concentrated. Crude residue was purified by column chrdmatography (HIA=4/1, 80g of silica gel) to afford title compound (366) (1.49g, 46%) as a white solid. mp73-75 O 'H NMvIR (300M1{z,DMSO-d 6 8 7.29 7.46 (1 H, dd, J=2.2, 8.8Hz), 7.69 (1lH, d, J=8.8Hz), 7.71 (1 H, dd, J=2.2, 8.4Hz), 7.95 (1IH, d, J=2.2Hz), 8.14 (1 H, d, J=2.2H-z), 8.18 (1H, d, 1=8.4Hz), 11.5 (lH, br MIS 553.
EXAMPLE 367 This illustrates the preparation of 3,5-Dichloro-4-(6-meflioxybenzotbiazol- 2-yloxy)phenylanine (367).
To a solution of 2-chloro-6-methoxybenzothiazole (prepared as described by Weinstock et.al., J.Med.Chem.30: p 1166 (1987)) and 4-Amino-2:,6-dichlorophenol 1.3g(available from Tokyo Chemical Industry Co., Ltd.) in DMSO(9m1), was added
K
2 C0 3 3.12g. The mixture was heated at 150 degree for 3hr. The reaction mixture was purified by columin chrornatography(silica get, AcOEt:Hexanel to provide the aniline 367 (1.43g,56%). mp 158-160' NMR(300MHZ/CDCI 3 5 3.84(3H, 3.85(2H, brs), 6.69(2H, s) 6.97(11-, dd, J=2.6Hz, 1=8.9H-z), 7.18(IH, d, J=2.6Hz),7.61 (I H, d, J=8.9Hz).
0- N 0 C1 0 C1 EXAMPLE 368 This illustrates the preparation of 2-Chloro-N-[3,5-dichloro-4-(6methioxybenzothol-2yloxy)-pheny]4trifluoromethylbelzenesulfoflamide (368).
To a solution of 3,-ihoo4(-ehxbnohao--lx~hnlmn (367) (1.40g) in pyridine (5ml), was added 2-Chloro-4-trifluorohenzenesulfonaiflide 1. 15g. The WO 01/00579 WO 0100579PCTfUSOO/18178 mixture was stirred at room temperature for 2hr. The reaction mixture was purified directly by column chromatography (silica gel, AcOEt:Hexane=l The product was triturated by hexane to give the title compound 368 (1 .97g, 82%) as a colorless powder.
mp 164-165 NMiR (300MHz/DMSO-d6) 8 3.79(3H-, 7.O0(IH, dd, J=2.9Hz, J=8.8Hz), 7.3 1(2H, 7.55(IH, d, J=8.8Hz), 7.58(lH, d, J=2.9Hz), 8.O0(IH, dd, J=1.5Hz, J=8.lHz), 8.20 (IH1, d, J=1.5Hz), 8.37(IH, d, J=8.lHz), I 1.59(IH, brs). MIS 583.
EXAMPLES 369-370 the examples illustrated in Table 37, were prepared from aniline 75 and the corresponding sulfonyl chlorides by the method of procedure 3. The compounds were purified by chromatography on silica gel.
Table 37
HN*
I D C1
NH
Example
MS
N A B C D (M-I1) 369 Cl H Cl H 466 370 H CI Cl H 466 371 Me H C1 Me 460 372 Cl. H Cl Me 480 EXAMPLE 369 1H NMR (d6-acetone) 8 9.54 (br s, IH), 8.82 (br s, 111), 8.446 J=8.8 Hz, I 8.129 J=8.4 Hz, IlH), 7.763 J=2 Hz, I 7.602 (dd, J=8.4, 2 Hz, I H), 7.428 (in, 2H), 7.327 (dd, J=9.2, 2.4 Hz, I1H), 7.252 (td, J=7.6, 1.2 Hz, 11H), 7.17 (td, J=8, 1.2 Hz, I MS 466.0.
WO 01/00579 WO 0100579PCTIUSOO/18178 EXAMPLE 370 'H NMR (d6-DMSO) 8 10.643 (br s, 1W), 9.954 (br s, 11H), 7.983 J=2 Hz, 1H), 7.934 (br d, J=8 Hz, IH), 7.885 J=8.4 Hz, LH), 7.717 (dd, J=8.4, 2.4 Hz, 1H), 7.454 J=8 Hz, I1H), 7.360 (br d, J=7.6 Hz, I 7.226 1=2 Hz, I1H), 7.194 J=8 Hz, I1H), 7.142 (dd, J=8.8, 2 Hz, I 7.106 J=8 Hz, I MS 466.0.
EXAMPLE 371 'H4 NMR (d6-acetone) 8 9.31 (br s, 1H), 8.80 (br s, 1W), 8.403 J=8 Hz, 1H), 7.928 IH), 7.45-7.35 (in, 4H), 7.3-7.2 (in, 2H), 7.164 (br t, J=8 Hz, 1H). 2.64 (s, 3H), 2.387 MS 460.0.
EXAMPLE 372 'H NMR (d6-acetone) 8 9.48 (br s, 1H), 8.82 (br s, 1H), 8.064 IHTJ, 7.707 IH), 7.45-7.40 (in, 4H), 7.335 (dd, 1=8.8, 2HZ, 1H), 7.252 (td, J=7.6, 1.2 Hz, 1H), 7.19 (td, J=8, 1.2 Hz, 1Hf) 2.425 3H). MIS 479.9.
EXAMPLE 373 Using methods similar to Lehmann, el kW., ibid., selected compounds exhibited the following IC 5 o values in a PPARy ligand binding assay utilizing 3
H-BRL
*49653 as the radioligand. 1C 5 o values are defined as the concentration of test compounds required to reduce by 50% the specific binding of 3 H]-BRL 49653 and are represented by riM; 10 jiM; I 1 iM.
TABLE 38 C6ompound ICso(jiM) 4.1 16.1
H
27.3 27.5 49.1 50.1 72.2 WO 01/00579 PCT/US00/18178 72.3 72.4 73.4 73.5 73.6 73.7 73.8 73.9 79.5 86 87.3 97 108.4 158 160 178 179 219
H+
233 290 292 349 364 365 368 EXAMPLE 374 Selected compounds were administered to KK-Ay mice as a 0.018% mg/kg) dietary admixture in powdered diet and evaluated for anti-diabetic efficacy as described Shibata, K. Matsui, K. Nagao, H. Shinkai, F. Yonemori and K. Wakitani 1999; European Journal of Pharmacology 364:211-219). The change in serum glucose levels compared to untreated control animals is exemplified in Table 39.
WO 01/00579 PCTIUSOO/18178 TABLE 39 Example 87.3 178 179 219 233 KKAy Glucose -1* -1* 364 365 10% to 20%; glucose lowering WO 01/00579 PCT/USOO/18178 All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims (74)

1. A compound having the formula: Ar X R I wherein Ar' is an unsubstituted or substituted 3-quinolinyl; X is selected from the group consisting of -CH 2 -CH(CH 3 -CH(CH 2 CH 3 -CH(isopropyl)-, wherein R" is a member selected from the group consisting of hydrogen and (Ci-C 8 )alkyl; and the subscript k is an integer of from 0 to 2; Y is -N(R' 2 wherein R 12 is hydrogen or (Ci-Cs)alkyl, and the subscript m is an integer from 0 to 2; R' is a member selected from the group consisting of halogen, cyano, nitro, (CI-Cs)alkyl, (Ci-C 8 )alkoxy, -C(0)R 1 4 -CO 2 R 4 and -C(O)NRIR6, wherein 15 R 14 is a member selected from the group consisting of hydrogen, (Ci-C 8 )alkyl, (Ci-Cs)heteroalkyl, aryl and aryl(Ci-C 4 )alkyl; R 1 5 and R 16 are members independently selected from the group consisting of hydrogen, (Ci-Cs)alkyl, (Ci-Cs)heteroalkyl, aryl, and aryl(Ci-C 4 )alkyl, or taken together with the nitrogen to which each is attached form a 6- or 7-membered ring; S. 20 R 2 is a member selected from the group consisting of aryl and aryl(Ci- C 4 )alkyl; and R 3 is a member selected from the group consisting of halogen, cyano, nitro, and (Ci-C 8 )alkoxy; and the pharmaceutically acceptable salts and solvates of the compound. 25 2. A compound of claim 1, wherein SX is selected from the group consisting of-CH 2 -CH(CH 3 -CH(CH 2 CH 3 -CH(isopropyl)-, and-C(O)-; and the subscript k is an integer from 0 to 2; Y is -N(R' 2 wherein R' 2 is hydrogen or (Ci-C 8 )alkyl, and the subscript m is an integer from 0 to 2; R' is a member selected from the group consisting of halogen, cyano, nitro, (Ci-C 8 )alkyl, (Ci-C 8 )alkoxy, -CO 2 R' 4 and -C(O)NR' 5 R' 6 wherein [R:\LIBH04573.doc:aak 201 R 1 4 is a member selected from the group consisting of hydrogen, (Ci-Cs)alkyl, (Ci-Cs)heteroalkyl, aryl and aryl(Ci-C 4 )alkyl; R' 5 and R 1 6 are members independently selected from the group consisting of hydrogen, (Ci-Cs)alkyl, (Ci-Cs)heteroalkyl, aryl, and aryl(Ci-C 4 )alkyl, or taken together with the nitrogen to which each is attached form a 6- or 7-membered ring; R 2 is a member selected from the group consisting of aryl and aryl(Ci-C 4 )alkyl; and R 3 is a member selected from the group consisting of halogen, cyano, and (Ci-Cs)alkoxy.
3. A compound of claim 1, wherein X is selected from the group consisting of -CH 2 -CH(CH 3 -CH(CH 2 CH 3 -CH(isopropyl)-, and
4. A compound of claim 1, wherein Y is -N(RI2)-S(0) 2 R' 2 is hydrogen or (Ci-C8)alkyl; and R 2 is aryl. A compound of claim 1, wherein R' is a member selected from the group consisting of halogen, cyano, (Ci-Cs)alkyl, (Ci-Cs)alkoxy, -CO 2 R 14 -C(O)NRI 5 R 1 6 wherein R 14 is (Ci-Cs)alkyl and R 1 5 and R' 6 are members independently selected from the group consisting of hydrogen and (Ci-C8)alkyl or taken together with the nitrogen to which each is attached form a 5- or 6-membered ring. 20 6. A compound of claim 1, wherein Ar' is substituted with from one to two substituents selected from the group consisting of halogen, -OCF 3 -OH, -O(Ci-C 6 )alkyl, -CF 3 (Ci-Cs)alkyl, and -NO 2
7. A compound of claim 1, wherein X is selected from the group consisting of -CH 2 and 25 8. A compound of claim 4, wherein Y is 2 and R 2 is aryl.
9. A compound of claim 1, wherein R 2 is selected from the group consisting of substituted phenyl, substituted pyridyl, and substituted naphthyl, wherein the substituents 0 number from one to three and are independently selected from the group consisting of halogen, -OCF 3 -OH, -O(Ci-Cs)alkyl, -C(O)-(Ci-Cs)alkyl, -CN, -(Ci-Cs)alkyl, -CF 3 and -NH 2 A compound of claim 8, wherein R 2 is phenyl.
11. A compound of claim 7, wherein X is
12. A compound of claim 1, wherein X is -CH 2 or Y is -N(RI 2 2 wherein R 1 2 is hydrogen or (Ci-Cs)alkyl; [R:\LII3H]04573.doc:aak 202 R' is a member selected from the group consisting of halogen, cyano, (C 1 Cs)alkyl, (CI-C 8 )alkoxy, -CO 2 R 1 4 -C(O)NR' R 1 6 wherein R 1 4 is (C 1 -C 8 )alkyl and R 1 5 and R 16 are members independently selected from the group consisting of hydrogen and (Ci-C 8 )alkyl or taken together with the nitrogen to which each is attached form a 5- or 6-membered ring; R 2 is selected from the group consisting of substituted phenyl, substituted pyridyl, and substituted naphthyl, wherein the substituents number from one to three and are independently selected from the group consisting of halogen, -OCF 3 -OH, -O(Ci-C8)alkyl, -C(O)-(CI-Cs)alkyl, -CN, -(Ci-Cs)alkyl, -CF 3 and -NH 2 and R 3 is selected from the group consisting halogen, cyano, and (Ci-Cs)alkoxy.
13. A compound having the formula defined in claim 1, substantially as hereinbefore described with reference to any one of the examples.
14. A composition comprising a pharmaceutically acceptable excipient and a is compound according to any one of claims 1 to 13. A composition of claim 14, wherein the composition is in unit dose format.
16. A composition of claim 14, wherein the composition is in an oral S" administration format. .1 17. Use of an efficacious amount of a compound according to any one of claims 1 20 to 13 for the manufacture of a medicament for preventing or modulating a condition mediated by PPARy in a host.
18. A use in accordance with claim 17, wherein said condition is a metabolic or inflammatory disorder and said host is a mammal selected from the group consisting of humans, dogs, monkeys, mice, rats, horses and cats. *o *S 25 19. A use in accordance with claim 17, wherein said medicament is for preventing the onset of a PPARy-mediated condition.
20. A use in accordance with claim 17, wherein said condition is selected from the group consisting of NIDDM, obesity, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, and inflammatory conditions.
21. A method of preventing or modulating a condition mediated by PPARy in a host, comprising administering to said host an efficacious amount of a compound according to any one of claims 1 to 13 or a composition according to any one of claims 14 to 16. [R:\LIB14]0457 3.doc:aak 203
22. A method in accordance with claim 21, wherein said condition is a metabolic or inflammatory disorder and said host is a mammal selected from the group consisting of humans, dogs, monkeys, mice, rats, horses and cats.
23. A method in accordance with claim 21, wherein said medicament is for preventing the onset of a PPAR'y-mediated condition.
24. A method in accordance with claim 21, wherein said condition is selected from the group consisting of NIDDM, obesity, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, and inflammatory conditions. Use of an efficacious amount of a compound according to any one of claims 1 to 13 for the manufacture of a medicament for treating a condition selected from the group consisting of rheumatoid arthritis and atherosclerosis in a host.
26. A method for treating a condition selected from the group consisting of rheumatoid arthritis and atherosclerosis in a host, comprising administering to said host an efficacious amount of a compound according to any one of claims 1 to 13 or a composition according to any one of claims 14 to 16.
27. A compound having the formula: R R Aril, R oIl wherein Ar' is 2-benzothiazolyl; .X is-S(O)k-; Y is -N(R' 2 wherein R 1 2 is hydrogen or (Ci-Cs)alkyl, and the .:00 subscript m is an integer from 0 to 2; R is a member selected from the group consisting of hydrogen, halogen, cyano, nitro, (Ci-C8)alkyl, (Ci-Cs)alkoxy, -CO 2 R' 4 and -C(O)NR 5 R 1 6 wherein R 14 is a member selected from the group consisting of hydrogen, 0 25 (Ci-C8)alkyl, (Ci-Cs)heteroalkyl, aryl and aryl(Ci-C 4 )alkyl; and R 1 5 and R 16 are members independently selected from the group consisting of hydrogen, (Ci-Cs)alkyl, (Ci-Cs)heteroalkyl, aryl, and aryl(Ci-C 4 )alkyl, or taken together with the nitrogen to which each is attached form a 6- or 7-membered ring; R 2 is aryl; R 3 is a member selected from the group consisting of halogen, cyano, nitro, and (Ci-C 8 )alkoxy; and the pharmaceutically acceptable salts and solvates of the compound.
28. A compound of claim 27, wherein X is [R:\LIBH]04573.doc:aak 204
29. A compound of claim 27, wherein R' is halogen. A compound of claim 27, wherein Ar' is substituted with from one to two substituents selected from the group consisting of halogen, -OCF 3 -OH, -O(Ci-C 6 )alkyl. -CF 3 (CI-C 8 )alkyl, and -NO 2
31. A compound of claim 27, wherein X is and Y is -NHSO 2 and R 2 is phenyl.
32. A compound of claim 31, wherein R 2 is substituted phenyl and wherein the substituents number from one to three and are independently selected from the group consisting of halogen, -OCF 3 -OH, -O(Ci-Cs)alkyl, -C(O)-(Ci-C 8 )alkyl, -CN, 8 )alkyl, -CF 3 and -NH2.
33. A compound of claim 27, wherein Y is -NH-SO 2
34. A compound of claim 27, wherein R' is hydrogen; R 2 is substituted phenyl wherein the phenyl is substituted with halogen, (Ci-Cs)alkyl, or -CF 3 and R 3 is halogen.
35. A compound of claim 34, wherein Ar' is substituted 2-benzothiazolyl.
36. A compound having the formula defined in claim 27, substantially as hereinbefore described with reference to any one of the examples. 20 37. A composition comprising a pharmaceutically acceptable excipient and a compound according to any one of claims 27 to 36.
38. A composition of claim 37, wherein the composition is in an oral administration format. *39. Use of an efficacious amount of a compound according to any one of claims 25 27 to 36 for the manufacture of a medicament for preventing or modulating a condition mediated by PPARy in a host.
40. A use in accordance with claim 39, wherein said condition is a metabolic or inflammatory disorder and said host is a mammal selected from the group consisting of humans, dogs, monkeys, mice, rats, horses and cats.
41. A use in accordance with claim 39, wherein said medicament is for preventing the onset of a PPARy-mediated condition.
42. A use in accordance with claim 39, wherein said condition is selected from the group consisting of NIDDM, obesity, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, and inflammatory conditions. [R:\LIL3H]04573.doc:aak 205
43. A method of preventing or modulating a condition mediated by PPAR7 in a host, comprising administering to said host an efficacious amount of a compound according to any one of claims 27 to 36 or a composition according to claim 37 or 38.
44. A method in accordance with claim 43, wherein said condition is a metabolic or inflammatory disorder and said host is a mammal selected from the group consisting of humans, dogs, monkeys, mice, rats, horses and cats. A method in accordance with claim 43, wherein said medicament is for preventing the onset of a PPARy-mediated condition.
46. A method in accordance with claim 43, wherein said condition is selected from the group consisting of NIDDM, obesity, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, and inflammatory conditions.
47. Use of an efficacious amount of a compound in accordance with any one of claims 27 to 36 for the manufacture of a medicament for treating a condition selected from the group consisting of rheumatoid arthritis and atherosclerosis in a host.
48. A method of treating a condition selected from the group consisting of rheumatoid arthritis and atherosclerosis in a host, comprising administering to said host an efficacious amount of a compound in accordance with any one of claims 27 to 36 or a composition according to claim 37 or 38.
49. A compound having the formula: R3 'R2 2 Ar l\X x I R" wherein Ar' is a 3-quinolinyl group having from 0 to 3 substituents selected from the group consisting of halogen, -OCF 3 -OH, -O(Ci-C 6 )alkyl, -CF 3 (Ci-Cs)alkyl, CO 2 H, -CO 2 CH 3 and -NO 2 X is or i: 25 Y is-NH-S0 2 R' is a member selected from the group consisting of halogen, (Ci-Cs)alkyl, (Ci-Cs)heteroalkyl and (Ci-Cs)alkoxy; R 2 is a phenyl group having from 0 to 3 substituents selected from the group consisting of halogen, -OCF 3 -OH, -O(Ci-Cs)alkyl, -C(O)-(Ci-C8)alkyl, -CN, -CF 3 (Ci-Cs)alkyl and -NH 2 and R is selected from the group consisting of halogen, methoxy and trifluoromethoxy and the pharmaceutically acceptable salts and solvates of the compound. R:\LIBH]04573.doc:aak 206 A compound of claim 49, wherein the formula is and wherein A is CI or C173; B is H; E is a CI or CF3; is H or CH3; is F or CI; is a member selected from the group consisting of H, CH3, C02H and CO2CH13; and W is a member selected from the group consisting of H, C02H and CO2CH3.
51. A compound of claim 50, wherein Dis H; Vis Cl;and Uand Ware each H.
52. A compound of claim 50, wherein A is CI; E is CI; D is H; V is F; and U and W are each H.
53. A compound of claim 50, wherein A is CI; E is CI; V is CI; and U and W are each H.
54. A compound of claim 50, wherein V is CI. A compound having the formula 0o 0, C 2oan te hamaeuialy ccptbl slt ndsovaesthref
57. an copsiincopisne pharmaceutically acceptable saltsen and sovtsahro compound according to any one of claims 49 to 54 or 56. [R:\LIBH11}04573.doc:aak 21. DEC. 2004 14:48 SPRUSON FERGUSON NO. 0712 P. 207
58. A composition of claim 57, wherein the composition is in unit dose format.
59. A composition comprising a compound according to claim 55 and a pharmaceutically acceptable excipient. A composition of claim 59, wherein the composition is in unit dose format.
61. Use of an efficacious amount of a compound of any one of claims 49 to 54 for the manufacture of a medicament for preventing or treating a condition mediated by PPARy in a host.
62. A use in accordance with claim 61, wherein said host is a mammal selected from the group consisting of humans, dogs, monkeys, mice, rats, horses and cats. to 63. A use in accordance with claim 61, wherein said medicament is formulated for oral administration.
64. A use in accordance with claim 61, wherein said medicament is in unit dosage format. A use in accordance with claim 61, wherein said medicament is for preventing 1i the onset of a PPAR'pmediated condition.
66. A use in accordance with claim 61, wherein said condition is selected from the group consisting of NIDDM, obesity, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, and inflammatory conditions.
67. A use in accordance with claim 61, wherein said condition is a metabolic 20 disorder or an inflammatory condition.
68. A method of preventing or treating a condition mediated by PPARy in a host :comprising administering to said host an efficacious amount of a compound according to any one of claims 49 to 56 or a composition according to any one of claims 57 to
69. A method in accordance with claim 68, wherein said host is a mammal selected from the group consisting of humans, dogs, monkeys, mice, rats, horses and cats. A method in accordance with claim 68, wherein said composition is formulated for oral administration.
71. A method in accordance with claim 68, wherein said composition is in unit dosage format.
72. A method in accordance with claim 68, wherein said compound or composition is for preventing the onset of a PPAR-,-mediated condition.
73. A method in accordance with claim 68, wherein said condition is selected from the group consisting of NIDDM, obesity, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, and inflammatory conditions. [R\LIB 14 104573.doc:nk COMS ID No: SBMI-01048976 Received by IP Australia: Time 14:53 Date 2004-12-21 208
74. A method in accordance with claim 68, wherein said condition is a metabolic disorder or an inflammatory condition. Use of an efficacious amount of a compound in accordance with any one of claims 49 to 56 for the manufacture of a medicament for treating a condition selected from the group consisting of rheumatoid arthritis and atherosclerosis in a host.
76. A use in accordance with claim 75, wherein said host is a mammal selected from the group consisting of humans, dogs, monkeys, mice, rats, horses and cats.
77. A method of treating a condition selected from the group consisting of rheumatoid arthritis and atherosclerosis in a host comprising administering to said host an efficacious amount of a compound according to any one of claims 49 to 56 or a composition according to any one of claims 57 to
78. A method in accordance with claim 77, wherein said host is a mammal selected from the group consisting of humans, dogs, monkeys, mice, rats, horses and cats.
79. A compound of any one of claims 49 to 56, wherein said compound is a modulator of PPARy. A compound of claim 79, wherein said modulator has an IC 50 less than 1 pM.
81. A compound having the formula: \XV R Y2 R 1 Ar 1 R wherein Ar' is substituted or unsubstituted 2-benzothiazolyl; X is Y is -NH-S02-; R is a member selected from the group consisting of hydrogen, halogen, (Ci-Cs)alkyl, (CI-C8)heteroalkyl, (CI-Cs)alkoxy, -C(O)R 4 -C02R 4 -C(O)NRRI6 so S(O)p-R 14 and -S(O)q-NR' RI6; 25 wherein R 14 is a member selected from the group consisting of hydrogen, (Ci-Cs)alkyl, (Ci-C8)heteroalkyl, aryl and aryl(Ci-C4)alkyl; R 1 5 and R 1 6 are members independently selected from the group consisting of hydrogen, (Ci-Cs)alkyl, (Ci-Cs)heteroalkyl, aryl, and aryl(Ci-C 4 )alkyl, or taken together with the nitrogen to which each is attached form a 6- or 7-membered ring; R 2 is a phenyl group having from 0 to 3 substituents selected from the group consisting of halogen, -OCF 3 -OH, -O(C 1 -Cs)alkyl, -C(O)-(Ci-Cs)alkyl, -CN, -CF 3 (Ci-C 8 )alkyl and -NH 2 [R:\LIB 14]04573.doc:aak 209 R 3 is selected from the group consisting of halogen, methoxy and trifluoromethoxy; and the pharmaceutically acceptable salts and solvates thereof.
82. A compound of claim 81, wherein Ar' is a 2-benzothiazolyl group having from 1 to 3 substituents selected from the group consisting of halogen, -OCF 3 -OH, -O(Ci-C 6 )alkyl, -CF 3 (Ci-C 8 )alkyl and -NO 2 R' is a member selected from the group consisting of halogen, (Ci-Cs)alkyl, (Ci-Cs)heteroalkyl and (Ci-C8)alkoxy; R 2 is a phenyl group having from 0 to 3 substituents selected from the group consisting of halogen, -OCF 3 -OH, -O(Ci-Cs)alkyl, -C(O)-(Ci-Cs)alkyl, -CN, -CF 3 (Ci-Cs)alkyl and -NH 2 and R 3 is selected from the group consisting of halogen, methoxy and trifluoromethoxy.
83. A compound of claim 82, wherein the formula is 0 0 CI HN S CF 3 C N S C S Cl S: 84. A compound as defined in any one of claims 81 to 83, substantially as hereinbefore described with reference to any one of the examples. A composition comprising a pharmaceutically acceptable excipient and a compound according to any one of claims 81 to 84. S86. Use of an efficacious amount of a compound of any one of claims 81 to 84 for the manufacture of a medicament for preventing or treating a condition mediated by 20 PPARy in a mammal.
87. A use in accordance with claim 86, wherein said medicament is formulated for oral administration.
88. A use in accordance with claim 86, wherein said medicament is in unit dosage format.
89. A use in accordance with claim 86, wherein said medicament is for preventing the onset of a PPARy-mediated condition. A use in accordance with claim 86, wherein said condition is selected from the group consisting of NIDDM, obesity, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, and inflammatory conditions. [R:\LIB14]04573.doc:aak 210
91. A use in accordance with claim 86, wherein said condition is a metabolic disorder or an inflammatory condition.
92. A use in accordance with claim 86, wherein said mammal is a human.
93. A method of preventing or treating a condition mediated by PPARy in a mammal comprising administering to said mammal an efficacious amount of a compound of any one of claims 81 to 84 or a composition according to claim
94. A method according to claim 93, wherein said composition is formulated for oral administration. A method according to claim 93, wherein said composition is in unit dosage format.
96. A method according to claim 93, wherein said compound or composition is for preventing the onset of a PPARy-mediated condition.
97. A method according to claim 93, wherein said condition is selected from the group consisting of NIDDM, obesity, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, and inflammatory conditions.
98. A method according to claim 93, wherein said condition is a metabolic disorder or an inflammatory condition.
99. A method according to claim 93, wherein said mammal is a human.
100. Use of an efficacious amount of a compound according to any one of claims 81 to 84 for the manufacture of a medicament for treating a condition selected from the group consisting of rheumatoid arthritis and atherosclerosis in a human.
101. A method of treating a condition selected from the group consisting of o*so rheumatoid arthritis and atherosclerosis in a human comprising administering to said human an efficacious amount of a compound according to any one of claims 81 to 84 or a 25 composition according to claim 0f Dated 13 December, 2004 Tularik Inc. Japan Tobacco Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [R:\LIB H ]04573.doc:aak
AU60643/00A 1999-06-30 2000-06-28 Compounds for the modulation of PPARgamma activity Expired AU779730B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US14167299P 1999-06-30 1999-06-30
US60/141672 1999-06-30
US20161300P 2000-05-03 2000-05-03
US60/201613 2000-05-03
PCT/US2000/018178 WO2001000579A1 (en) 1999-06-30 2000-06-28 COMPOUNDS FOR THE MODULATION OF PPARη ACTIVITY

Publications (2)

Publication Number Publication Date
AU6064300A AU6064300A (en) 2001-01-31
AU779730B2 true AU779730B2 (en) 2005-02-10

Family

ID=34277977

Family Applications (1)

Application Number Title Priority Date Filing Date
AU60643/00A Expired AU779730B2 (en) 1999-06-30 2000-06-28 Compounds for the modulation of PPARgamma activity

Country Status (1)

Country Link
AU (1) AU779730B2 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0069585A1 (en) * 1981-07-06 1983-01-12 EASTMAN KODAK COMPANY (a New Jersey corporation) Color-forming sulfonamidodiphenylamines, photographic elements containing them and corresponding sulfonimide dyes
EP0749751A2 (en) * 1995-06-20 1996-12-27 Takeda Chemical Industries, Ltd. Pharmaceutical composition for use in tteatment of diabetes
EP0855391A1 (en) * 1996-08-07 1998-07-29 Snow Brand Milk Products Co., Ltd. Novel isoquinoline derivatives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0069585A1 (en) * 1981-07-06 1983-01-12 EASTMAN KODAK COMPANY (a New Jersey corporation) Color-forming sulfonamidodiphenylamines, photographic elements containing them and corresponding sulfonimide dyes
EP0749751A2 (en) * 1995-06-20 1996-12-27 Takeda Chemical Industries, Ltd. Pharmaceutical composition for use in tteatment of diabetes
EP0855391A1 (en) * 1996-08-07 1998-07-29 Snow Brand Milk Products Co., Ltd. Novel isoquinoline derivatives

Also Published As

Publication number Publication date
AU6064300A (en) 2001-01-31

Similar Documents

Publication Publication Date Title
US6770648B2 (en) Compounds for the modulation of PPARγ activity
CA2377309C (en) Compounds for the modulation of ppar.gamma. activity
AU2001271637B2 (en) Quinolinyl and benzothiazolyl ppar-gamma modulators
AU2005221140A1 (en) Therapeutic modulation of PPAR (gamma) activity
US6583157B2 (en) Quinolinyl and benzothiazolyl modulators
AU759255B2 (en) PPAR-gamma modulators
US7960408B2 (en) Quinolinyl and benzothiazolyl modulators
AU2001271637A1 (en) Quinolinyl and benzothiazolyl ppar-gamma modulators
AU779730B2 (en) Compounds for the modulation of PPARgamma activity
MXPA06010180A (en) Therapeutic modulation of ppar (gamma) activity

Legal Events

Date Code Title Description
MK14 Patent ceased section 143(a) (annual fees not paid) or expired