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AU756333B2 - Carboxylic acids and acylsulfonamides, compositions containing such compounds and methods of treatment - Google Patents
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AU756333B2 - Carboxylic acids and acylsulfonamides, compositions containing such compounds and methods of treatment - Google Patents

Carboxylic acids and acylsulfonamides, compositions containing such compounds and methods of treatment

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Publication number
AU756333B2
AU756333B2 AU27086/99A AU2708699A AU756333B2 AU 756333 B2 AU756333 B2 AU 756333B2 AU 27086/99 A AU27086/99 A AU 27086/99A AU 2708699 A AU2708699 A AU 2708699A AU 756333 B2 AU756333 B2 AU 756333B2
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AU
Australia
Prior art keywords
naphthyl
phenyl
thienyl
propyl
methoxy
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.)
Ceased
Application number
AU27086/99A
Other versions
AU2708699A (en
Inventor
Michel Belley
Michel Gallant
Yves Gareau
Helene Juteau
Marc Labelle
Nicolas Lachance
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.)
Merck Frosst Canada and Co
Original Assignee
Merck Frosst Canada and Co
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Filing date
Publication date
Application filed by Merck Frosst Canada and Co filed Critical Merck Frosst Canada and Co
Priority claimed from PCT/CA1999/000212 external-priority patent/WO1999047497A2/en
Publication of AU2708699A publication Critical patent/AU2708699A/en
Application granted granted Critical
Publication of AU756333B2 publication Critical patent/AU756333B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • C07C311/22—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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • 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
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D307/64—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Indole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Quinoline Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Description

WO 99/47497 PCT/CA99/00212 CARBOXYLIC ACIDS AND ACYLSULFONAMIDES, COMPOSITIONS CONTAINING SUCH COMPOUNDS AND METHODS OF TREATMENT BACKGROUND OF THE INVENTION The present invention relates to compounds which are useful for treating or preventing prostaglandin mediated diseases, methods of treatment and pharmaceutical compositions containing such compounds. The compounds are structurally different from conventional NSAIDs and opiates, and are antagonists of the pain and inflammatory effects of E-type prostaglandins.
Two review articles describe the characterization and therapeutic relevance of the prostanoid receptors as well as the most commonly used selective agonists and antagonists: Eicosanoids: From Biotechnology to Therapeutic Applications, Folco, Samuelsson, Maclouf, and Velo eds, Plenum Press, New York, 1996, chap. 14, 137-154 and Journal of Lipid Mediators and Cell Signalling, 1996, 14, 83-87. An article from The British Journal of Pharmacology (1994, 112, 735-740) suggests that Prostaglandin E 2
(PGE
2 exerts allodynia through the EP 1 receptor subtype and hyperalgesia through EP 2 and EP 3 receptors in the mouse spinal cord.
Thus, selective prostaglandin ligands, agonists or antagonists, depending on which prostaglandin E receptor subtype is being considered, have anti-inflammatory, antipyretic and analgesic properties, and in addition inhibit hormone-induced uterine contractions. Moreover, the compounds have anti-cancer effects.
The compounds have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
WO 99/47497 PCT/CA99/00212 SUMMARY OF THE INVENTION The present invention relates to compounds represented by formula I:
R'R
2
R
3 -HET O I A X-B Z
I
as well as pharmaceutically acceptable salts, hydrates and esters thereof, wherein: HET represents a 5-12 membered monocyclic or bicyclic aromatic ring system containing 0-3 heteroatoms selected from O, S(O)n and N(O)m wherein m is 0 or 1 and n is 0, 1 or 2; A is a one or two atom moiety and is selected from the group consisting of: -C(R) 2
-W-C(R
7 2 -CR7(OR 2 0 -C(R -C(R 7 2
-C(OR
20
)R
7
-C(R
7 2 or -CR 7
=CR
7 wherein W represents O, S(O)n or NR17, with n as previously defined and R17 as defined below; X represents a 5-10 membered monocyclic or bicyclic aryl or heteroaryl group having 1-3 heteroatoms selected from 0, S(O)n and N(O)m and optionally substituted with R14 and R15, and A and B are attached to the aryl or heteroaryl group ortho relative to each other; Y represents O, S(O)n NR17, a bond or -CR18 CR18-; B represents (C(R18)2)p-Y- (C(R 1 8 )2)q wherein p and q are independently 0-3, such that when Y represents O, S(O)n NR17 or -CR18 CR18-, p q 0-6, and when Y represents a bond, p q is 1-6; Z is OH or NHSO 2
R
19
R
1
R
2 and R3 independently represent H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkenyl-HET(Ra)4 9
(C(R
4 )2)pSR 5
-(C(R
4 2 )pOR, -(C(R 4 2 )pN(R 6 2 CN, NO 2
-(C(R
4 2 )pC(R) 3
CO
2
R
9
-CON(R
6 2 or -(C(R 4 2 )pS(O),R 1 wherein n and p are as previously defined; each R 4 is independently H, F, CF 3 or lower alkyl, -2- WO 99/47497 PCT/CA99/00212 or two R 4 groups are taken in conjunction and represent a ring of up to six atoms, optionally containing one heteroatom selected from O, S(O)n or N(O)m; each R 5 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 lower alkyl-HET, lower alkenyl-HET or -(C(R 8 2 )pPh(R")0- 2; each R 6 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF3, Ph, Bn and when two R 6 groups are attached to N they may be taken in conjunction and represents a ring of up to 6 atoms, optionally containing an additional heteroatom selected from O, S(O)n or N(O)m; each R 7 is independently H, F, CF 3 or lower alkyl, and when two R 7 groups are presents, they may be taken in conjunction and represent an aromatic or aliphatic ring of 3 to 6 members containing from 0-2 heteroatoms selected from O, S(O)n and N(O)m; each R 8 represents H or R 5 each R 9 is independently H, lower alkyl, lower alkenyl, lower alkynyl, Ph or Bn; each R' 1 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 Ph(R)0-3, CH 2 Ph(R 1 )0-3 or N(R6) each R" is independently lower alkyl, SR 2 0
OR
2 0
N(R
6 2
-CO
2
R
12
-CON(R
6 2
-C(O)R
12 CN, CF3, NO 2 or halogen; each R 12 is independently H, lower alkyl or benzyl; each R 1 is independently H, halo, lower alkyl, O-lower alkenyl, S-lower alkyl, N(R 6 2
CO
2
R
1 2 CN, CF 3 or NO 2
R'
4 and R15 are independently lower alkyl, halogen, CF3,
OR
1 6
S(O).R
6 or C(R16) 2 0R 17 each R 16 is independently H, lower alkyl, lower alkenyl, Ph, Bn or CF 3 each R' 7 is independently H, lower alkyl or Bn; each R 18 is independently H, F or lower alkyl, and when two
R
s groups are present, they may be taken in conjunction and represent a ring of 3 to 6 members comprising carbon atoms and optionally one heteroatom chosen from O, S(O)n or N; WO 99/47497 PCT/CA99/00212 each R 1 9 is lower alkyl, lower alkenyl, lower alkynyl, CF3, HET(Ra) 4 9 lower alkyl-HET(Ra)4.9 or lower alkenyl-HET(Ra) 4 9 each R 20 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF 3 or Ph(R 13 2 and each Ra is independently selected from the group consisting of: H, OH, halo, CN, N02, amino, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6 alkoxy, C2-6alkenyloxy, C2-6alkynyloxy, C1-6alkylamino, di-C1-6alkylamino, CF3, C(O)C1-6alkyl, C(O)C2-6alkenyl, C(O) C2- 6alkynyl, CO2H, CO2C1-6alkyl, CO2C2-6alkenyl, and CO2C2-6alkynyl, said alkyl, alkenyl, alkynyl and the alkyl portions of alkylamino and dialkylamino being optionally substituted with 1-3 of: hydroxy, halo, aryl, C1-6 alkoxy, C2-6alkenyloxy, C2-6alkynyloxy, CF3, C(O)C1-6alkyl, C(O)C2-6alkenyl, C(O)C2-6alkynyl, CO2H, CO2C1-6alkyl, CO2C2-6alkenyl, CO2C2-6alkynyl, NH2, NHC1-6alkyl and N(Cl-6alkyl)2.
Pharmaceutical compositions are also included which are comprised of a compound of formula I in combination with a pharmaceutically acceptable carrier.
A method of treating or preventing a prostaglandin mediated disease is also included which is comprised of administering to a mammalian patient in need thereof, a compound of formula I in an amount which is effective for treating or preventing a prostaglandin mediated disease.
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to carboxylic acids and acylsulfonamides, which are ligands at prostaglandin receptors, as well as a method for treating or preventing a prostaglandin mediated disease comprising administering to a patient in need of such a treatment of an amount of compound of Formula I which is effective for treating or preventing a prostaglandin mediated disease.
The invention described in this patent application is described using the following definitions unless otherwise indicated.
-4- WO 99/47497 PCT/CA99/00212 HET represents a 5-12 membered aromatic ring system containing 0-3 heteroatoms selected from O, S(O)n and N wherein n is 0, 1 or 2. HET may be substituted with up to three substituents on the aromatic ring system, R1, R2 and R 3 "Aromatic ring systems" as used herein includes aryl and heteroaryl groups such as benzene, naphthalene, biphenyl, pyridine, quinoline, isoquinoline, furan, benzofuran, thiophene, benzothiophene, oxazole, thiazole, imidazole, benzothiazole, triazole, 1,2,5-thiadiazole, thienopyridine, indole, tetrazole, imidazole, benzoxazole, 1,2-methylenedioxybenzene and pyrrole.
HET
2 is a subset of HET and represents a member selected from the group consisting of: phenyl, thienyl, naphthyl, furanyl, thiazolyl, imidazolyl and indolyl.
Aryl refers to aromatic 6-10 membered groups having 1-2 rings and alternating (resonating) double bonds. Examples include phenyl, biphenyl and naphthyl.
Heteroaryl refers to aromatic 5-12 membered groups having alternating (resonating) double bonds and containing from 1-4 heteroatoms selected from O, S(O)n and N. Examples include the following: quinoline, furan, benzofuran, thiophene, benzothiophene, thiazole, benzothiazole, 1,2,5-thiadiazole, thienopyridine, oxazole, indole, isoindole, pyridine, isoquinoline, imidazole, thiazole, triazole, 1,3methylene dioxobenzene, pyrrole and naphthyridine, Heterocyclyl refers to non-aromatic 5-12 membered cyclic groups having 1-4 heteroatoms selected from O, S(O)n and N. Examples of heterocyclic groups are piperidine, piperazine, pyrrolidine, tetrahydrofuran, tetrahydropyran and morpholine.
X represents a 5-10 membered monocyclic or bicyclic aryl or heteroaryl group having 1-3 heteroatoms selected from O, S(0)n and N(0)m, and optionally substituted with R14 and R15, and A and B are attached to the aryl or heteroaryl group X in positions which are ortho relative to each other. Examples are selected from the group consisting of: phenyl, naphthyl, biphenyl, quinoline, furan, benzofuran, pyridyl, pyrrole, thiophene, benzothiophene, thiazole, benzothiazole, 1,2,5- WO 99/47497 PCT/CA99/00212 thiadiazole, triazole, 1,2-methylenedioxybenzene, thienopyridine, oxazole and indole.
The terms alkyl, alkenyl, and alkynyl mean linear, branched, and cyclic structures and combinations thereof.
"Lower alkyl" means alkyl groups of from 1 to 7 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, s- and t-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, and the like. When propyl and butyl are recited without the isomeric form being specified, these include all isomers thereof.
"Lower alkenyl" means alkenyl groups of 2 to 7 carbon atoms. Examples of lower alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2methyl-2-butenyl, cyclopropen-1-yl, cyclohexen-3-yl and the like. When cis or trans is not specified, both are intended in pure form as well as in the form of a mixture of isomers.
"Lower alkynyl" means alkynyl groups of 2 to 7 carbon atoms. Examples of lower alkynyl groups include ethynyl, propargyl, 3methyl-1-pentynyl, 2-heptynyl, 2-(cyclopropyl)ethenyl, 3-(cyclobutyl)-1propynyl and the like.
Halogen (halo) includes F, Cl, Br and I.
The following abbreviations have the.indicated meanings: AIBN 2.2'-azobisisobutyronitrile B.P. benzoyl peroxide Bn benzyl CC14 carbon tetrachloride D -O(CH2)30- DAST diethylamine sulfur trifluoride DCC dicyclohexyl carbodiimide DCI 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide DEAD diethyl azodicarboxylate DIBAL diisobutyl aluminum hydride DME ethylene glycol dimethylether DMAP 4-(dimethylamino)pyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide Et3N triethylamine LDA lithium diisopropylamide WO 99/47497 PCT/CA99/00212 m-CPBA
NBS
NSAID
PCC
PDC
Ph 1,2-Ph Pyr Qn Rs r.t.
rac.
THF
THP
metachloroperbenzoic acid N-bromosuccinimide non-steroidal anti-inflammatory drug pyridinium chlorochromate pyridinium dichromate phenyl 1,2-benzenediyl pyridinediyl 7-chloroquinolin-2-yl -CH2SCH2CH2Ph room temperature racemic tetrahydrofuran tetrahydropyran-2-yl Alkyl group abbreviations Me Et n-Pr i-Pr n-Bu i-Bu s-Bu t-Bu c-Pr c-Bu c-Pen c-Hex methyl ethyl normal propyl isopropyl normal butyl isobutyl secondary butyl tertiary butyl cyclopropyl cyclobutyl cyclopentyl cyclohexyl It is intended that the definition of any substituent R 5
R
6 etc.) in a particular molecule be independent of its definition elsewhere in the molecule. Thus, -N(R 6 2 represents -NHH, -NHCH, NHC H and the like.
6 5' In one aspect of the invention, the invention relates to a compound represented by formula I:
R'R
2
R
3 -HET O 9 A
X-B
as well as pharmaceutically acceptable salts, hydrates and esters thereof, wherein: -7- WO 99/47497 PCT/CA99/00212 HET represents a 5-12 membered monocyclic or bicyclic aromatic ring system containing 0-3 heteroatoms selected from O, S(O)n and N(O)m wherein m is 0 or 1 and n is 0, 1 or 2; A is a one or two atom moiety and is selected from the group consisting of: -C(R) 2 -W-C(R7) 2 ,CR7(OR 20
-C(R)
2
-C(OR
2 0 7
-C(R)
2
C(R)
2 or CR 7
=CR
7 wherein W represents O, S(O)n or NR17, with n as previously defined and R1 7 as defined below; X represents a 5-10 membered monocyclic or bicyclic aryl or heteroaryl group having 1-3 heteroatoms selected from O, S(O)n and N(O)m and optionally substituted with R14 and R15, and A and B are attached to the aryl or heteroaryl group ortho relative to each other; Y represents O, S(O)n NR17, a bond or -CR18 CR1 8 B represents (C(R1 8
(C(R
1 8 )2)q wherein p and q are independently 0-3, such that when Y represents O, S(O)n, NR17 or -CR18 CR1 8 p q 0-6, and when Y represents a bond, p q is 1-6; Z is OH or NHSOR 1 9
R
1
R
2 and R3 independently represent H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkenyl-HET(Ra)49,
(C(R
4 )2)pSR 5
-(C(R
4 2 )pOR 8
-(C(R
4 2 )pN(R 6 2 CN, NO -(C(R 4 2 )pC(R7) 3
COR
9
-CON(R
6 2 or
-(C(R
4 2 )pS(O)nR 1 wherein n and p are as previously defined; each R 4 is independently H, F, CF 3 or lower alkyl, or two R 4 groups are taken in conjunction and represent a ring of up to six atoms, optionally containing one heteroatom selected from O, S(O)n or N(O)m; each R 5 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 lower alkyl-HET, lower alkenyl-HET or 8 2 )pPh(Ru)o- 2; each R 6 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF3, Ph, Bn and when two R 6 groups are attached to N they may be taken in conjunction and represents a ring of up to 6 atoms, -8- WO 99/47497 PCT/CA99/00212 optionally containing an additional heteroatom selected from O, S(O)n or N(O)m; each R 7 is independently H, F, CF 3 or lower alkyl, and when two R 7 groups are presents, they may be taken in conjunction and represent an aromatic or aliphatic ring of 3 to 6 members containing from 0-2 heteroatoms selected from O, S(O)n and N(O)m; each R8 represents H or each R 9 is independently H, lower alkyl, lower alkenyl, lower alkynyl, Ph or Bn; each R' 1 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 Ph(R")0-3, CH 2 Ph(R")0-3 or N(R6) each R 1 is independently lower alkyl, SR 2 0
OR
2 0
N(R
6 2 -CO2R 1 2
-CON(R
6 2
-C(O)R
1 2 CN, CF3, NO or halogen; each R 12 is independently H, lower alkyl or benzyl; each is independently H, halo, lower alkyl, O-lower alkenyl, S-lower alkyl, N(R 6 2
CO
2
R
1 2 CN, CF3 or NO 2
R
1 4 and R15 are independently lower alkyl, halogen, CF3,
OR
1 6
S(O),R
16 or C(R 2 0OR 17 each R 16 is independently H, lower alkyl, lower alkenyl, Ph, Bn or CF 3 each R 17 is independently H, lower alkyl or Bn; each R' s is independently H, F or lower alkyl, and when two
R
1 8 groups are present, they may be taken in conjunction and represent a ring of 3 to 6 members comprising carbon atoms and optionally one heteroatom chosen from O, S(O)n or N; each R 19 is lower alkyl, lower alkenyl, lower alkynyl, CF3, HET(Ra) 4 lower alkyl-HET(Ra)4.9 or lower alkenyl-HET(Ra)4-9; each R 2 0 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF 3 or Ph(R13) 2 and each Ra is independently selected from the group consisting of: H, OH, halo, CN, N02, amino, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -9- WO 99/47497PC/A9022 PCT/CA99/00212 C1~-6 alkoxy, C2-6alkenyloxy, C2-6alkynyloxy, C1.6alkylamino, di-Ci..
6alkylamino, CF3, C(O)Cl1.6alkyl, C(O)C2..6alkenyl, C(O) C2-.6alkynyl, CO2H, CO2C1-6alkyl, C02C2-6alkenyl, and C02C2-6alkynyl, said alkyl, alkenyl, alkynyl and the alkyl portions of alkylamino and dialkylamino being optionally substituted with 1-3 of: hydroxy, halo, aryl, C1..6 alkoxy, C2..6alkenyloxy, C2..6alkynyloxy, CF3, C(O)C1..6alkyl, C(O)C2-.6alkenyl, C(O)C2..6alkynyl, CO2H, C02C1..6alkyl, C02C2..6alkenyl, C02C2..6alkynyl, N112, NHC 1.6alkyl and N(Cl1.6alkyl)2.
In another embodiment of the invention, the invention relates to compounds represented by formula I:
R
1 R 2
R
3 HET 0
A
X-B Z as well as pharmaceutically acceptable salts, hydrates and esters thereof, wherein: HET represents a 5-12 membered monocyclic or bicyclic aromatic ring system containing 0-3 heteroatoms selected from 0, S(O)n and N(0)m wherein m is 0 or 1 and n is 0, 1 or 2; A is a one or two atom moiety and is selected from the group consisting of: -C(R 7 2 -W-C(R 7 2 (R (R 7 2
-C(R
7 2 -C(0R 20 )R 7 -C(R 7 2 C(R 7 2 or CR 7 wherein W represents 0, S(O)n or NR17,, with n as previously defined and R17 as defined below; X represents a 5-10 membered monocyclic or bicyclic aryl or heteroaryl group having 1-3 heteroatoms selected from 0, S(0)n and N(0)m and optionally substituted with R14 and R 15 and A and B are attached to the aryl or heteroaryl group ortho relative to each other; Y represents 0, S(O)n NR17, a bond or -CR18 CRl8-; B represents (C(R18)2)p.y. (C(Rl 8 )2)q WO 99/47497 PCT/CA99/00212 wherein p and q are independently 0-3, such that when Y represents O, S(O)n, NR1 7 or -CR18 CR18-, p q 0-6, and when Y represents a bond, p q is 1-6; Z is OH or NHS0 2
R
1 9 R' R 2 and R 3 independently represent H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkenyl-HET(Ra)4 9
-(C(R
4 )2)pSR5, -(C(R 4 2 )pOR 8
-(C(R
4 2 )pN(R 6 2 CN, NO 2
-(C(R
4 2 )pC(R 7 3
-CO
2
R
9
-CON(R
6 2 or -(C(R 4 2 )pS(O),Ro 1 wherein n and p are as previously defined; each R 4 is independently H, F, CF 3 or lower alkyl, or two R 4 groups are taken in conjunction and represent a ring of up to six atoms, optionally containing one heteroatom selected from O, S(O)n or N(O)m; each R 5 is independently lower alkyl, lower alkenyl, lower alkynyl, CF3, lower alkyl-HET, lower alkenyl-HET or -(C(R18) 2 )pPh(R") 0 2; each R 6 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF3, Ph, Bn and when two R 6 groups are attached to N they may be taken in conjunction and represents a ring of up to 6 atoms, optionally containing an additional heteroatom selected from O, S(O)n or N(O)m; each R 7 is independently H, F, CF 3 or lower alkyl, and when two R 7 groups are presents, they may be taken in conjunction and represent an aromatic or aliphatic ring of 3 to 6 members containing from 0-2 heteroatoms selected from O, S(O)n and N(O)m; each R8 represents H or each R 9 is independently H, lower alkyl, lower alkenyl, lower alkynyl, Ph or Bn; each R' 1 is independently lower alkyl, lower alkenyl, lower alkynyl, CF3, Ph(R")0-3, CH 2 Ph(R")0-3 or N(R) 2 each R 1 is independently lower alkyl, SR 2 0
OR
20
N(R
6 2
-CO
2
R
1 2
-CON(R
6 2 -C(0)R 1 2 CN, CF, NO 2 or halogen; each R 12 is independently H, lower alkyl or benzyl; -11- WO 99/47497 WO 9947497PCT/CA99/002 12 each R" 3 is independently H, halo, lower alkyl, O-lower alkenyl, S-lower alkyl, N(R 6 2
CO
2
R'
2 CN, CF. or NO 2
R"
4 and R 1 5 are independently lower alkyl, halogen, C7, or C(R1 6 2 0R1 7 each R' 6 is independently H, lower alkyl, lower alkenyl, Ph, Bn, CHF2 or CF 3 each R'1 7 is independently H, lower alkyl or Bn; each R' 8 is independently H, F or lower alkyl, and when two R 8groups are present, they may be taken in conjunction and represent.
a ring of 3 to 6 members comprising carbon atoms and optionally one heteroatom chosen from 0, S(O)n or N; each R' 9 is lower alkyl, lower alkenyl, lower alkynyl, CF, HET2(Ra) 4 9 lower alkyl-HET 2 (Ra)4-.9 or lower alkenyl-HET2(Ra) 4 9, wherein HET2 represents a member selected from the group consisting of: phenyl, thienyl, naphthyl, furanyl, thiazolyl, imidazolyl and indolyl; each R 20 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CHF 2
CF
3 or Ph(R 3 2 and each Ra is independently selected from the group consisting of: H, OH, halo, CN, N02, amino, C1..6alkyl, C2-.6alkenyl, C2-6alkynyl, C1-6 alkoxy, C2-6alkenyloxy, C2-6alkynyloxy, C1..6alkylamino, di-Ci.
6alkylamino, CF3, C(O)C 1-6alkyl, C(O)C2..6alkenyl, C(O) C2-6alkynyl, CO2H, CO2C 1-6alkyl, CO2C2..6alkenyl, and CO2C2..6alkynyl, said alkyl, alkenyl, alkynyl and the alkyl portions of alkylamino and dialkylamino being optionally substituted with 1-3 of: hydroxy, halo, aryl, C1-6 alkoxy, C2-6alkenyloxy, C2..6alkynyloxy, CF3, C(O)C 1-6alkyl, C(O)C2-6alkenyl, C(O)C2.-6alkynyl, CO2H, CO2C 1-6alkyl, CO2C2-6alkenyl, C02C2-6alkynyl, NH2, NHC1..alkyl and N(Cl-6alkyl)2.
An embodiment of the present invention which is of particular interest is represented by formula I wherein HET represents a member selected from the group consisting of: benzene, naphthalene, biphenyl, pyridine, quinoline, isoquinoline, furan, benzofuran, 12- WO 99/47497 PCT/CA99/00212 thiophene, benzothiophene, oxazole, thiazole, imidazole, benzothiazole, triazole, 1,2,5-thiadiazole, thienopyridine, indole, tetrazole, imidazole, benzoxazole, 1,2-methylenedioxybenzene and pyrrole.
More particularly, an embodiment of the present invention is represented by formula I wherein HET is selected from the group consisting of: benzene, biphenyl, naphthylene, indole, thiophene, benzofuran and quinoline. Within this subset of compounds of the invention, all other variables are as originally described with respect to formula I.
Another embodiment of the present invention that is of particular interest is represented by formula I wherein A represents a one or two atom moiety and is selected from the group consisting of: S, S02, CH2, -OCH2-, -CHOH-, -C(OH)(CH3)- and -CH2-O-.
More particularly, A is selected from the group consisting of: S, S(O), S02, CH2, Within this subset of compounds of the invention, all other variables are as originally described with respect to formula I.
Another embodiment of the present invention that is of particular interest is represented by formula I wherein X represents phenyl optionally substituted with R 1 4 and R 1 5 Within this subset of compounds of the invention, all other variables are as originally described with respect to formula I. More particularly, X represents phenyl and R 14 and R 15 are absent or represent halo. Within this subset of compounds of the invention, all other variables are as originally described with respect to formula I.
Another embodiment of the present invention that is of particular interest is represented by formula I wherein B is CH=CH or 1,2-cyclopropyl, and in particular, where B is CH=CH in the E-isomeric form. Within this subset of compounds of the invention, all other variables are as originally described with respect to formula I.
Another embodiment of the present invention that is of particular interest is represented by formula I wherein Z is NHSO 2
R'
9 Within this subset of compounds of the invention, all other variables are as originally described with respect to formula I.
-13- WO 99/47497 PCT/CA99/00212 Another embodiment of the present invention that is of particular interest is represented by formula I wherein Z is NHSO 2
R
19 and R 19 represents a member selected from the group consisting of: lower alkyl and HET(Ra)3. Within this aspect of the invention, HET is selected from the group consisting of: phenyl, thienyl, naphthyl, furanyl, thiazolyl, imidazolyl and indolyl.
Another embodiment of the present invention that is of particular interest is represented by formula I wherein Z is NHSO 2
R
1 9 and R 19 represents benzene or thiophene, substituted with R'R 2
R
3 Another embodiment of the present invention that is of particular interest is represented by formula I wherein Z represents OH.
Within this subset, all other variables are as originally defined.
A subset of compounds that is of particular interest is defined with respect to formula I wherein: HET represents a member selected from the group consisting of: phenyl, naphthalene, biphenyl, pyridine, quinoline, isoquinoline, furan, benzofuran, thiophene, benzothiophene, oxazole, thiazole, imidazole, benzothiazole, 1,2,5-thiadiazole, thienopyridine, indole, tetrazole, imidazole, benzoxazole and pyrrole; A represents a one or two atom moiety and is selected from the group consisting of: S, S02, CH2, -OCH2- -CHOH-, C(OH)(CH3 and -CH2-O-; X represents phenyl optionally substituted with R 1 4 and R 5 B is CH=CH; Z is NHSO 2
R
1 9 and
R
9 represents a member selected from the group consisting of: lower alkyl and HET(Ra)3.
Examples of compounds of the present invention are shown in Tables I and II below.
-14- WO 99/47497 WO 9947497PCT/CA99/002 12
R
1 R 2 R 3 HET 0
A
X-B NHSO 2
R
19 la (Compounds 1-323 and 347-454) RlR;2R 3 -Het A X B Wpd 1-naphthyl CH 1,2-Ph OH=OH- Ph(F),~ 2-naphthyl S()9 1,2-Ph OH=OH- Ph(F), 2 3-methylindol OH 2 1,2-Ph CH=CH 2-thienyl 3 2-naphthyl CH.L 1,2-Ph CH=OH 2-thienyl 4 2-naphthyl S(O) 1,2-Ph CH=CH_ phenyl 3-methylindol S(0) 2 1,2-Ph OH=CH 2-thienyl 6 -1-y 1 2-naphthyl S(0) 2 1,2-Ph OH=OH 3,5-di-(CF 3 7 phenyl 3,4-dichloro CH 2 1,2-Ph CH=CH 2-thienyl 8 phenyl__ 2-naphthyl 1,2-Ph OH=CH 2-thienyl 9 2,4-dichloro OH 2 1,2-Ph CH=CH 2-thienyl phenyl__ 1-naphthyl 1,2-Ph OH=CH Ph(F)5 11 1-naphthyl S(0) 2 1,2-Ph OH=CH 3,5-di-(CF 3 12 phenyl 2-naphthyl 1,2-Ph 1,2-c-propyl 2-thienyl 13 3,4-chioro OH 2 1,2-Ph CH=OH 2-thienyl 14 fluoro phenyl 1-naphthyl OH2 1,2-Ph OH=OH 2-thienyl 3,4-dichloro S(0) 2 1,2-Ph OH=OH 2-thienyl 16 phenyl_____ 4-methylthio OH 2 1,2-Ph OH=OH 2-thienyl 17 phenyl 4-chiorophenyl OH2 1,2-Ph OH=OH 2-thienyl 18 2-naphthyl S 1,2-Ph CH=OH. 2-thienyl 19 2-naphthyl 0-OH, 1,2-Ph OH=OH 2-thienyl 2 2-na-phthyl SO0 1,2-Ph OH-=CH 2-thienyl 21 1-naphthyl 1,2-Ph OH=OH phenyl 2 2-benzofuranyl CH 1,2-Ph OH;=OH 2-thienyl 23 WO 99/47497 PTC9/01 PCT/CA99/00212 RlR.2R 3 -Het A X B R' 9 Cpd CH2 1,2-Ph CH=CH 2-thienyl 24 phenyl 1-naphthyl S(0) 2 1,2-Ph CH=CH 3,5-di-(CF 3 1-naphthyl 1,2-Ph CH=CH 2-thienyl 2 3-(1,2-(methylene CH 2 1,2-Ph CH=CH 2-thienyl 27 dioxy)benzene)______ 2-naphthy1 0 1,2-Ph OH=CH 2-thienyl 28 Rs-2-phenyl CH 2 1,2-Ph CH 2 -0 2-thienyl 29 RS-2-phenyl CH2 1,2-Ph 0H 2
-CH
2 2-thienyl 2-naphthy 1 1,2-Ph CH 9 -0 2-thienyl 31 3-((2-(Qn)vinyl)) CH 2 1,2-Ph CH 2 -0 2-thienyl 32 phenyl__ 2-(6-benzyloxy) OH2 1,2-Ph OH=OH 2-thienyl 33 naphthyl_______ 3-((2-(Qn)vinyl)) SO 1,2-Ph CH 2 -O 2-thienyl 34 phenyl__ 3-((2-(Qn)vinyl)) -CHOH. 1,2-Ph CH 2 -O 2-thienyl phenyl__ 3-((2-(Qn)vinyl)) S(0)2 1,2-Ph CH 2 -0 phenyl 36 phenyl 3-((2-(Qn)vinyl)) 0-OH 2 1,2-Ph CH 2 -0 2-thienyl 37 3-tolyl-D-3-phenyl 0-OH2 1,2-Ph CH 9 -0 2-thienyl 3 3-((2-(Qn)vinyl)) OH(OH'-1,2-Ph CH -0 phenyl 39 phenyl 2_ 3-((2-(Qn)vinyl)) S 1,2-Ph CH 2 -O 2-thienyl phenyl 3-((2-(Qn)vinyl)) 0 1,2-Ph CH 2 -0 phenyl 41 phenyl__ 3-((2-(Qn)vinyl)) C=0 1,2-Ph CH 2 -O 2-thienyl 42 phenyl 3-((2-(Qn)vinyl)) 0 1,2-Ph C(CH 3 2 -O 2-thienyl 43 phenyl_____ 3-((2-(Qn)vinyl)) 0 1,2-Ph 0H 2 -0 2-thienyl 44 phenyl 2-naphthyl CH, 1,2-Ph 1,2-c-propyl 2-thienyl 2-(6-benzyloxy) OH 2 1,2-Ph OH=OH 2-methoxy-5- 46 naphthyl _________bromophenyl 2-naphthyl OH 2 1,2-Ph 1,2-c-propyl 3,4-dichioro 47 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl .4-fluoro 48 ____IIIlphenyl I 16- WO 99/47497 WO 9947497PCT/CA99/0021 2 RlR2R 3 -Het A X B R1 9 Cpd 2-naphthyl C2 1,2-Ph 1,2-c-propyl 4-chioro 4 phenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 4-propyl phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 2,5-dichioro 51 thienyl 2-naphthyl LH 1,2-Ph 1,2-c-propyl styryl 52 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 3-chloro-4- 53 ______fluorophenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 4-methoxy 54 ______phenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 3-bromo phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 2,5-dimethyl 56 phenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 2-nitro-4-chloro 57 ____phenyl 2-naphthyi CH 2 1,2-Ph 1,2-c-propyl 2-carbomethoxy 58 ___phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 2,4-difluoro 59 ____phenyl 2-naphthyl CH 1,2-Ph 1,2-c-propyl 4-butyl-phenyl 2-naphthyl CH 1,2-Ph 1,2-c-propyl butyl 61 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 2,5-dimethoxy 62 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 3-trifluoro 63 ________methylphenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 3,5-difluoro 64 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 3,5-dichioro 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 4-((1-hydroxy-1- 66 methyl)ethyl) phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 4-(hydroxy 67 methylphenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 3-(hydroxy 68 methyl)phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 4-(methyl 6 sulfonyl)phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 3-(methyl sulfonyl)pheny 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 4-(propyl I I_ 1 sulfonyl)pheny 17 WO 99/47497 WO 9947497PCT/CA99/002 12 RlR2W 3 -Het A X B w 9 Cpd 2-naphthyl OH 2 1,2-Ph 1,2-c-propyl 4-((bis-trifluoro- 72 methyl)-hydroxy methyl)phenyl 2-naphthyl OH 2 1,2-Ph 1,2-c-propyl 4-(benzyloxy) 73 phenyl 2-naphthyl OH 2 1,2-Ph 1,2-c-propyl 4-((1-methoxy-1- 74 methyl) ehyl)phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 4-dimethyl ________aminophenyl 2-naphthyl CH2, 1,2-Ph l,2-c-propyl cyclohexyl 76 2-naphthyl CH 1,2-Ph 1,2-c-propyl CyClopentyl 77 2-apthl H 1,2-Ph l,2-c-propyl 4-morpholinyl 78 2-naphthyl kH 1,2-Ph 1,2-c-propyl 2-naphthyl 79 2-naphthyl CH9 1,2-Ph 1,2-c-propyl 2-thiazolyl 2-naphthyl CH, 1,2-Ph 1,2-c-propyl 1-imidazolyl 81 2-naphthyl LH 1,2-Ph 1,2-c-propyl 2-furanyl 82 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 3-(2-chloro)- 83 furanyl 2-naphthyl CH 1,2-Ph 1,2-c-propyl 2-pyridinyl 84 2-naphthyl OH 2 1,2-Ph 1,2-c-propyl 2-(4-chloro) pRyridinyl 2-naphthyl OH, 1,2-Ph 1,2-c-propyl 3-indolyl 86 2-naphthyl OH2 1,2-Ph 1,2-c-propyl 4-nitrophenyl 87 2-naphthyl O H 1,2-Ph 1,2-c-propyl 4-cyanophenyl 88 2-naphthyl S(O) 2 1,2-Ph l,2-c-propyl 4-((1-hydroxy-1- 89 methyl)ethyl) 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-(hydroxy .methyl)phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3-(hydroxy 91 methyl )phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2,5-dimethyl 92 phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2-carbomethoxy 93 phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2,4-difluoro 94 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-(methyl sulfonyl)phenyl 2-naphthyl
S(O)
2 1,2-Ph 1,2-c-propyl 3-(methyl 96 sulfonyl)phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-(propyl 97 sulfonyl)phenyl 1 18- WO 99/47497PC/A9021 PCT/CA99/00212 RlR,2R 3 -Het A X B CpdE 2-nahSh()2 1,2-Ph 1,2--roy 4-butyl-phenyl 98 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3,5-di-(CF 3 99 henyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-((bis-trifluoro 100 methyl)-hydroxy ________methyl~phenyl 2-naphthyl 1,2-Ph 1,2-c-propy1 3-bromophenyl 101 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-(benzyloxy) 102 phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2-nitro-4-chloro 103 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-isopropyl 104 phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-((1-methoxy-1- 105 methyl) _________ethylphenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-methoxy 106 phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-dimethyl 107 ________aminophenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3,4-dichioro 108 phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3,4-difluoro 109 ____phenyl 2-np0tyl2 1,2-Ph 1,2-c-propyl 4-fluorophenyl 110 2-naphthyl 1,2-Ph 1,2-c-propyl cyclohexyl ill 2-naphthyl 1,2-Ph 1,2-c-propyl cyclopentyl 112 2-naphthyl S(O) 1,2-Ph 1,2-c-propyl 4-morpholinyl 113 2-nphtyl 1,2-Ph 1,2-c-propyl buty 114_ 2-naphthyl 1,2-Ph 1,2-c-propyl 4-chiorophenyl 115 S(0phtyl2 1,2-Ph 1,2-c-propyl 4-propylphenyl 116 2-naphthyl 1,2-Ph 1,2-c-propyl 2-naphthyl 117 2-naphthyl 1,2-Ph 1,2-c-propyl 2-thiazolyl 118 2-naphthyl S(9~ 1,2-Ph 1,2-c-propyl 1-imidazolyl 119 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2,5-dimethoxy 120 __phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3-trifluoro 121 ____________methylphenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2,5-dichloro-3- 12 ____thienyl 2-naphthyl 1,2-Ph 1,2-c-propyl 2-furanyl 123 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3-(2-chloro)- 124 ________furanyl 2-naphthyl jS(O)2 I 1,2-Ph I1,2-c-propyli 2-pyridinyl 1125 19- WO 99/47497 WO 9947497PCT/CA99/O 0212
R
1 R2R 3 -Het A X B Cpd 2-naphthyl 1,2-Ph 1,2-c-propyl. 2-styryl 126 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3,5-difluoro- 127 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3 ,5-dichloro- 128 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2-(4-chloro) 129 ___pyridinyl 2-naphthyl S(02 1,2-Ph 1,2-c-propyl 3-indolyl 130 2-naphthyl 1,2-Ph 1,2-c-propyl 4-nitrophenyl 131 2-naphthyl 1,2-Ph 1,2-c-propyl 4-cyanophenyl 132 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3-chloro-4- 133 _________fluorophenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 3,5-di-(CF 3 134 -l-yl phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-isopropyl 135 -1-yl phenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 3,4-dichioro 136 -1-Yl phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 3,4-difluoro 137 -1-yl phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-fluorophenyl 138 -1-Y2 3-methylindol CH2 112-Ph 1,2-c-propyl 4-cifiorophenyl 139 1 -y 1 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-propylphenyl 140 -1-Y2 3-methylindol CH2 1,2-Ph 1,2-c-propyl 2,5-dichloro-3- 141 -1-yl thienyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 2-styryl 142- 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 3-chloro-4-fluorc 143 -l-yl phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-methoxy 144- -l-yl phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 3-bromophenyl 145 -1-y2 3-methylindol CH2 1,2-Ph 1,2-c-propyl 2,5-dimethyl 146 -l-yl phenyl 3-methylindol CH2 112-Ph 1,2-c-propyl 2-nitro-4-chloro 147 -1-yl phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 2-carboinethoxy 148 1 -yl phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 2,4-difluoro 149 -1-yl I_ I_ phenyl WO 99/47497 WO 9947497PCT/CA99/002 12 Rlp.2R 3 -Het A X B W 19 Cpd 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-butylphenyl 150 1 -yl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 1 -yl 3-methylindol OH2 1 -Ph 1,2-c-propyl 2,5-dimethoxy 152- -l-yl phenyl 3-methylindol OH2 1)2-Ph 1,2-c-propyl 3-trifluoro 153 -l-yl methylphenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 3,5-difluoro 154 -l-yl phenyl 3-methylindol OH2 1,2-Ph 1,2-c-propyl 3,5-dichioro 155- -1-yl phenyl 3-methylindol CH2 1 -Ph 1,2-c-propyl 4-((1-hydroxy-1- 156 -l-yl methyl)ethyl) 3-methylindol OH2 1,2-Ph 1,2-c-propyl 4-(hydroxy 157 -1-yl methyl)phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 3-(hydroxy 158 -l-yl methyl)phenyl 3-methylindol OH2 1,2-Ph 1,2-c-propyl 4-(methyl 159 -1-yl sulfonyl)phenyl 3-methylindol OH 2 1,2-Ph 1,2-c-propyl 3-(methyl 160 -l-yl sulfonyl)phenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 4-(propyl 161 -l-yl sulfonyl)phenyl 3-methylindol OH2 12-Ph 1,2-c-propyl 4-((bis-trifluoro 162 -1-yl methyl)hydroxy methyl)phenyl 3-methylindol CH2 172-Ph 1,2-c-propyl 4-(benzyloxy) 163 -l-yl phenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 4-((1-methoxy-1- 164 -l-yl methyl) ________ethylphenyl 3-methylindol OH 2 1,2-Ph 1,2-c-propyl 4-dimethyl 165 -l-yl aminophenyl 3-methylindol OH 2 1,2-Ph 1,2-c-propyl cyclohexyl 166 1 -yl 3-methylindol OH 2 1,2-Ph l,2-c-propyl cyclopentyl 167 1 -yl 3-methylindol OH2 1,2-Ph l,2-c-propyl 4-morpholinyl 168 1 eyl in o CH 3-metylinol O 112-Ph l,--propyl 2-naphthyl 16 YI T ,22 -21- WO 99/47497 WO 9947497PCT/CA99/00212
R
1 H2R 3 -Het A X B R 19 Cpd 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 2-thiazolylI 1701 1 -yl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 1-imidazolyl 171 -1-Y2 3-methylindol CR2 1,2-Ph 1,2-c-propyl 2-furanyl 1 1 -yl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 3-(2-chloro)- 173 -l-yl furanyl 3-methylindol CR 2 1,2-Ph 1,2-c-propyl 2-pyridinyl 174 1 -y 1 3-methylindol CR 2 1,2-Ph 1,2-c-propyl 2-(4-chloro) 175 -l-yl ______pyridinyl 3-methylindol CR2 1,2-Ph 1,2-c-propyl 3-indolyl 176 1 -yl 3-methylindol CR2 1,2-Ph 1,2-c-propyl 4-nitrophenyl 177 1 -yl 3-methylindol CR2 1,2-Ph 1,2-c-propyl 4-cyanophenyl 178 1 -yl phenyl_ 3-methylindol S0 2 1,2-Ph 1,2-c-propyl 3,-i-(CF 3 )y 179 -l-yl phenyl 3-methylindol S0 2 1,2-Ph 1,2-c-propyl 34-ipro 180 phenyl 3-methylindol S02 1,2-Ph 1,2-c-propyl 3,4-diloro 181 -1-yl phenyl 3-methylindol S02 1,2-Ph 1,2-c-propyl 34-fluoroey 182 -1-A p e y 3-methylindol 502 1,2-Ph 1,2-c-propyl 4-lorophenyl 183 1 -y 1 3-methylindol 502 1,2-Ph 1,2-c-propyl 4-chiorophenyl 184 1 -yl 3-methylindol 502 1,2-Ph 1,2-c-propyl 2,5-dichloro-3- 186 thienyl 3-methylindol 502 1,2-Ph 1,2-c-propyl 2-styryl 187 1 -yl 3-methylindol 502 1,-Ph l,2-c-propyl 3-chloro-4- 188 -l-yl fluorophenyl 3-methylindol 502 1,2-Ph l,2-c-propyl 4-methoxy 189 -l-yl phenyl 3-methylindol 502 1,2-Ph 1,2-c-propyl 3-bromo 190 -l-yl phenyl 3-methylindol 502 1,2-Ph 1,2-c-propyl 2,5-dimethyl 191 -l-yl I I_ phenyl- -22- WO 99147497 WO 9947497PCT/CA99/0021 2 R1R,2R 3 -Het A X B R1 9 Cp 3-methylindol S0 2 1,2-Ph 1,2-c-propyl 2-nitro-4-chloro 192 -l-yl phenyl 3-methylindol S02 1,2-Ph 1,2-c-propyl 2-carbomethoxy 193 -l-yl phenyl 3-methylindol S02 1,2-Ph 1,2-c-propyl 2,4-difluoro 194 -l-yl ______phenyl 3-methylindol 502 1,2-Ph 1,2-c-propyl 4-butyiphenyl 195 -l-y 1 3-methylindol 502 1,2-Ph 1,2-c-propyl n-butyl 196 1 -y 1 3-methylindol 502 1,2-Ph 1,2-c-propyl 2,5-dimethoxy 197 -l-yl phenyl 3-methylindol S0 2 1,2-Ph 1,2-c-propyl 3-trifluorometh 1-198 -1-yl phenyl 3-methylindol 502 1,2-Ph 1,2-c-propyl 3 ,5-difluoro 199 -l-yl phenyl 1-(3-methyl) 502 1,2-Ph 1,2-c-propyl 3,5-dichioro 200 indolyl _____phenyl 3-methylindol S0 2 1,2-Ph 1,2-c-propyl 4-((1-hydroxy-1- 201 -l-yl methyl)ethyl) 3-methylindol S0 2 1,2-Ph 1,2-c-propyl 4-(hydroxy 202 -l-yl m ethyl)phenyl 3-methylindol 502 1,2-Ph 1,2-c-propyl 3-(hydroxy 203 -1-YI methyl)phenyl 3-methylindol 502 1,2-Ph 1,2-c-propyl 4-(methyl 204 -l-yl sulfonyl)phenyl 3-methylindol 502 1,2-Ph 1,2-c-propyl 3-(methyl 205 sulfonyl)phenyl 3-methylindol S0 2 1,2-Ph 1,2-c-propyl 4-(propyl 206 -l-yl sulfonyl)phenyl 3-methylindol S0 2 1,2-Ph 1,2-c-propyl 4-((bis-trifluoro 207 -l-yl methyl)hydroxy ________methyl)phenyl 3-methylindol S0 2 1,2-Ph 1,2-c-propyl 4-(benzyloxy) 208 -l-yl phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-((1-methoxy-1- 209 -l-yl methyl)ethyl)- ___phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-dimethyl 210 aminophenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl cyclohexyl 211 1 -yl -I
I
-23- WO 99/47497 WO 9947497PCT/CA99/002 12 RlR 2
R
3 -Het A X B Cpd 3-methylindol S0 2 1,2-Ph 1,2-c-propy cyclopent-yl 212 1 -y 1 3-methylindol S02 1,2-Ph 1,2-c-propyl 4-morpholinyl 213 1 -y 1 3-methylindol 502 1,2-Ph 1,2-c-propyl 2-naphthyl 214 -metyino SO 1,Ph 1--poy2-haoy25 3-methylindol S02 1,2-Ph 1,2-c-propyl 1-tiiazolyl 216 -i-Y 1
I
3-methylindol S0 2 1,2-Ph 1,2-c-propyl 2-furayl 217 1 -y 1 3-methylindol
SO
2 1,2-Ph 1,2-c-propyl 32-chlor)- 217 -l-yl uay 3-methylindo1 S0 2 1,2-Ph 1,2-c-propyl 2-(4-chloro)- 220 -l-yl pyridnyl 3-methylindol S0 2 1,2-Ph 1,2-c-propyl 3-idyl 2219 -meyino 50 1,-h 12cpoy4-trpey 22 3-methylindol S02 1,2-Ph 1,2-c-propyl 2-4-canopheny 223 1 -y 1 2-napthylno
SH
2 1,2-Ph 12c=CHpy 3-di-(CF 3 224 2-napthylno C0 2 1,2-Ph 12CH=CHpy 4-ioropheyl 225 3-methylindol_______ S0 12cpoy -nphenyl 23 2-naphthyl
CH
2 1,2-Ph CH=CH 2,3-di-Cior 226 phenyl 2-naphthyl
CH
2 1,2-Ph CH=CH 34-iforoy 227 phenyl 2-naphthyl
CH
2 1,2-Ph CH=CH 2,5-dichloro-3 230thenyl 2-naphthyl
CR
2 1,2-Ph CH=CH 3,-hor4fluor 231 phenyl 2-naphthyl CHI? 1,2-Ph CH=CH 4-mhooxyl 22 2-naphthyl C H phelrpey 29 2-naphthyl
OH
2 1,2-Ph CH=CH butyilo-3 233 2-naphthyl
CR
2 1,2-Ph CH=CH 3-triloro4fur 234 ________methylphenyl
I__
-24- WO 99/47497PC/A/021 PCT/CA99/00212 RlpR2R 3 -Het A X B R 9 Cpd 2-naphthyl OH 2 1,2-Ph CH=CH 4-((1-hydroxy-1- 235 methyl)ethyl) ____phenyl 2-naphthyl OH 2 1,2-Ph CH=CH 4-(methyl 236 sufonyl)phenyl 2-naphthyl OH 2 1,2-Ph CH=CH 4-(benzyloxy) 237 phenyl 2-naphthyl CH, 1,2-Ph CH=CH cyclohexyl 238 2-naphthyl CHL 1,2-Ph CH=CH 4-morpholinyl 239 2-na ht. H 9 12P CH=CH 2-thiazolyl 240 2-naphthyl CH 2 1,2-Ph CH=CH 2-furanyl 241 2-naphthyl CHL 1,2-Ph CH=CH _2-pyridinyl 242 2-naphthyl CH, 1,2-Ph CH=CH 4-cyanophenyl 243 2-naphthyl S02 1,2-Ph CH=CH 3,5-di-(CF 3 244 ______phenyl 2-naphthyl S02 1,2-Ph CH=CH 4-isopropyl 245 phenyl 2-naphthyl SO 2 1,2-Ph CH=CH 2,3-dichioro 246 ______phenyl 2-naphthyl SO 2 1,2-Ph CH=CH 3,4-difluoro 247 ___phenyl 2-naphthyl S0 -1,2-Ph OH=OH 4-chlorophenyl 248 2-naphthyl SO0 2 -1,2-Ph OH=OH 4-fluorophenyl 249 2-naphthyl 502 1,2-Ph OH=CH 2,5-dichloro-3- 250 ___thienyl 2-naphthyl 502 1,2-Ph OH=OH 3-chloro-4- 251 2-naphthyl SO 2 1,2-Ph OH=CH 4-methoxy 252 phenyl 2-naphthyl S-O? -1,2-Ph OH=OH buy 2-naphthyl 502 1,2-Ph OH=OH 3-trifluoro 254 _____methylphenyl 2-naphthyl SO 2 1,2-Ph OH=OH 4-((1-hydroxy-1-25 methyl)ethyl) penl 2-naphthyl 502 1,2-Ph OH=OH 4-(methyl 256 sufonyl)phenyl 2-naphthyl S0 2 1,2-Ph OH=CH 4-(benzyloxy) 257 2-naphthyl S-0-9 1,2-Ph OH=OH _cyclohexyl 258 2-naphthyl S02 1,2-Ph OH=OH 4-morpholinyl 259 2-naphthyl 9~ -1,2-Ph OH=OH 2-thiazolyl 260 2-naphthyl IS, 1,2-Ph IOH=OH 2-furanyl 1261 2-naphthyl ISO, 1,2-Ph IOH=OH 2-pyridinyl 12621 WO 99/47497 WO 9947497PCT/CA99/0021 2 Rlp,2R 3 -Het A X B RL 9 Cpd 2-naphthyl S0 1,2-Ph CH=CH _4-cyanophenyl 263 2-naphthyl CH 2 -O 1,2-Ph CH=CH 3,5-di-(CF 3 264 ____phenyl 2-naphthyl CH 2 -0 1,2-Ph CH=CH 4-isopropyl 265 ___phenyl 2-naphthyl CH 2 -O 1,2-Ph CH=CH 2,3-dichloro 266 phenyl 2-naphthyl CH 2 -0 1,2-Ph CH=CH 3,4-difluoro 267 phenyl 2-naphthyl O-CH 2 1,2-Ph CH=CH 3,5-di-(CF 3 268 phenyl 2-naphthyl O-CH 2 1,2-Ph CH=CH 4-isopropyl 269 2-naphthyl O-CH 2 1,2-Ph CH=CH 2,3-dichloro 270 phenyl 2-naphthyl O-CH 2 1,2-Ph CH=CH 3,4-difluoro 271 phenyl 2-naphthyl S 1,2-Ph CH=CH 3,5-di-(CF 3 272 2-naphthyl S 1,2-Ph CH=CH 4-isopropyl 273 phenyl 2-naphthyl S 1,2-Ph CH=CH 2,3-dichloro 274 ______phenyl 2-naphthyl S 1,2-Ph CH=CH 3,4-difluoro 275 ______phenyl 2-(6-benzyloxy) 02 1,2-Ph CH=CH 2-thienyl 276 2-(6-benzyloxy) S 1,2-Ph CH=CH 2-thienyl 277 naphthyl__ 2(6-benzyloxy) 502 1,2-Ph 1,2-c-propyl 2-thienyl 278 naphthyl____ 2-(6-benzyloxy) S 1,2-Ph 1,2-c-propyl 2-thienyl 279 naphthyl S0 1,2-Ph CH=CH 2-thienyl 280 naphthyl S 1,2-Ph CH=CH 2-thienyl 281 naphthyl S02 1,-Ph 1,2-c-propyl 2-thienyl 282 naphthyl S 1,2-Ph 1,2-c-propyl 2-thienyl 283 naphthyl 2(6-(4-trifluoro SO 2 1,2-Ph CH=CH 2-thienyl 284 methyl)benzyloxy) naphthyl I_ I_
I
-26- WO 99/47497PC/A9012 PCT/CA99/00212 RlR.2R 3 -Het A X B R 19 2-(6-(4-trifluoro CH2 1,2-Ph CH=CH 2-thienyl 285 methyl)benzyloxy)) naphthyl 2-(6-4-trifluoro OH2 1,2-Ph 1,2-c-propyl 2-thienyl 286 methyl~benzyl oxy))naphthyl 2(6-(4-trifluoro CH2 1,2-Ph 1,2-c-propyl 2-thienyl 287 methyl~benzyl oxy))naphthyl 1-(6-benzyloxy) SO 2 1,2-Ph CH=CH 2-thienyl 288 naphthyl 1-(6-benzyloxy) OH 2 1,2-Ph CH=CH 2-thienyl 289 naphthyl 2-(6-(3,4-difluoro S02 1,2-Ph CH=CH 2-thienyl 290 benzyloxy)) naphthyl_________ 2-(6-(3,4-difluoro CH2 1,2-Ph CH=CH 2-thienyl 291 benzyloxy)) naphthyl_________ 2-(6-4-fluoro CH2 1,2-Ph 1,2-c-propyl 2-thienyl 292 benzyloxy)) naphthyl 2-(7-benzyloxy) S02 1,2-Ph CH=CH 2-thienyl 293 2-(6-(3,4-difluoro SO 2 1,2-Ph CH=CH 3,4-difluoro 29 benzyloxy)) phenyl naphthyl__ 2-(6-(3,4-difluoro OH 2 1,-Ph CH=CH 3,4-difluoro 295 benzyloxy)) phenyl naphthyl__ 2-(6-4-fluoro CH2 1,2-Ph 1,2-c-propyl 3,4-difluoro 296 benzyloxy)) phenyl 2-(7-benzyloxy) S02 1,2-Ph CH=CH 3,5-di-(CF 3 297 naphthyl ____phenyl 2-(6-3,4-difluoro SO2 1,2-Ph CH=CH 3,5-di-(CF 3 298 benzyloxy)) phenyl naphthyl 2-(6-(3,4-difluoro CH2 1,2-Ph CH=CH 3,5-di-(CF 3 299 benzyloxy)) phenyl naphthyl 2-(7-benzyloxy) SO 2 1,2-Ph l,2-c-propyl 3,4-difluoro 300 naphthyl phenylI 2-naphthyl OH 2 1,2-Ph CH=CH 2-methoxy-5- 301 bromophenylI I -27 WO 99/47497PC/A/021 PCT/CA99/00212
R
1
R
2
R
3 -Het A X B R' 9 Cpd 2-naphthyl CH 2 4-Cl- 1,2-Ph CH=CH 2-methoxy-5- 302 ____________bromophenyl 2-naphthyl C, 4-Cl-1,2-Ph CH=CH 2-thienyl 303 2-naphthyl so 1,2-Ph GH=CH 2-methoxy-5- 304 ________bromophenyl 2-naphthyl S02 1,2-Ph CH=CH 2-methoxy-5- 305 _________bromophenyl 2-naphthyl 0 1,2-Ph CH=CH 2-methoxy-5- 306 ________bromophenyl
CH
2 1,2-Ph CH=CH 2-methoxy-5- 307 naphthyl
SO
2 1,2-Ph CH=CH 2-methoxy-5- 308 naphthyl S 1,2-Ph CH=CH 2-methoxy-5- 309 naphthyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 2-methoxy-5- 310 ________bromophenyl 1,2-Ph SO 2 1,2-Ph 1,2-c-propyl 2-methoxy-5- 311 2-naphthyl S 1,2-Ph 1,2-c-propyl 2-methoxy-5- 312 ________bromophenyl 2-naphthyl CH 2 -O 1,2-Ph CH=CH 2-methoxy-5- 313 ________bromophenyl 2-naphthyl S 1,2-Ph CH=CH 2-methoxy-5- 314 3-methyl SO 2 1,2-Ph 1,2-c-propyl 2-methoxy-5- 315 indol- l-yl bromophenyl 3-methyl S 1,2-Ph 1,2-c-propyl 2-methoxy-5- 316 indol- l-yl bromophenyl 3-methyl CH 2 -O 1,2-Ph CH=CH 2-methoxy-5- 317 indol- l-yl ___________bromophenyl 3-methyl S 1,2-Ph CH=CH 2-methoxy-5- 318 indol- 1-yl ______bromophenyl 3-methyl O-CH 2 1,2-Ph 1,2-c-propyl 2-methoxy-5- 319 indol- l-yl ___________bromophenyl 3-methyl so 1,2-Ph 1,2-c-propyl 2-methoxy-5- 320 indol- 1-yl _____bromophenyl 3-methyl CH 2 -O 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 321 indol- 1-yl 3-methyl S 4-Cl-1,2-Ph CII=CH 2-methoxy-5- 32 indol- l-yl 3-methyl S0 2 4-Cl-1,2-Ph 1,2-c-propyl 2-methoxy-5- 323 indol- 1-yl bromophenyl Ij -28- WO 99/47497PC/A/021 PCT/CA99/00212 R1R2ZR3-Het A X B R' 9 Cpd 2-(7-fluoro) S0 2 4- 01-1,2-Ph CH=CH 2-thienyl 347 naphthyl 2-(7-fluoro) 0 4-01-1,2-Ph CH=CH 2-thienyl 348 naphthyl 2-(7-fluoro) S 4-01-1,2-Ph CH=CH 2tienyl 349 .naphthyl 2-(7-fluoro) CH 2 4-01-1,2-Ph CH=CH 2-thienyl 350 naphthyl 2-(7-fluoro) OH 2 6-01-1,2-Ph CH=CH 2-thienyl 351 naphthyl____ 2-(7-fluoro) OH 2 4-01-1,2-Ph 1,2-c-Pr 2-thienyl 352 naphthyl 2-(7-fluoro) CH 2 3-C1-1,2-Ph CH=CH 2-thienyl 353 2-(7-fluoro) S0 2 4-01-1,2-Ph CH=CH 2-methoxy-5- 354 naphthyl ______bromophenyl 2-(7-fluoro) 0 4-01-1,2-Ph CH=CH 2-methoxy-5- 355 naphthyl _____bromophenyl 2-(7-fluoro) S 4-01-1,2-Ph CH=CH 2-methoxy-5- 356 naphthyl _____bromophenyl 2-naphthyl CR 2 4,5-C12- CH=CH 2-methoxy-5- 357 ______bromophenyl 2-(7-fluoro) CR 2 6-01-1,2-Ph CH=CH 2-methoxy-5- 358 naphthyl 2-(7-fluoro) OH 2 4-CI-1,2-Ph 1,2-c-Pr 2-methoxy-5- 359 naphthyl 2-(7-fluoro) CR 2 3-01-1,2-Ph CH=CH 2-methoxy-5- 360 naphthyl 2-(7-fluoro) SO 2 4-0-1,2-Ph CH=CH 2-trifluoro 361 naphthyl chlorophenyl 2-(7-fluoro) 0 4-01-1,2-Ph CH=CH 2-trifluoro 362naphthyl chlorophenyl 2-(7-fluoro) S 4-01-1,2-Ph CH=CH 2-trifluoro 363 naphthyl 2-(7-fluoro) OH 2 4-01-1,2-Ph CH=CH 2-trifluoro 364 naphthyl chiorophenyl 2-(7-fluoro) CH 2 6-01-1,2-Ph CH=CH 2-trifluoro 365 naphthyl chlorophenyl -29- WO 9/47497PC/A/021 PCT/CA99/00212 R1R 2
R
3 -Het A X B R1 9 Cpd 2-(7-fluoro) CH 2 4-01-1,2-Ph 1,2-c-Pr 2-trifluoro 366 naphthyl chiorophenyl 2-(7-fluoro) CH 2 3-01-1,2-Ph CH=OH 2-trifluoro36 naphthyl __________chlorophenyl 2-(7-fluoro) S0 2 4-01-1,2-Ph CH=CH 2-thienyl 368 naphthyl 2-(7-fluoro) 0 4-01-1,2-Ph CH=CH 2-thienyl 369 naphthyl 2-(7-fluoro) S 4-01-1,2-Ph CH=CH 2-thienyl 370 naphthyl____ 2-(7-fluoro) OH 2 4-01-1,2-Ph OH=OH 2-thienyl 371 naphthyl 2-(7-fluoro) OH 2 6-01-1,2-Ph OH=CH 2-thienyl 372 naphthyl____ 2-(7-fluoro) OH 2 4-01-1,2-Ph 1,2-c-Pr 2-thienyl 373 naphthyl____ 2-(7-fluoro) OH 2 3-01-1,2-Ph CH=CH 2-thienyl 374 2-(7-fluoro) SO 2 4-C1-1,2-Ph OH=OH 2-methoxy-5- 375 naphthyl 2-(6-fluoro) 0 4-01-1,2-Ph CH=OH 2-methoxy-5- 376 naphthyl 2-(6-fluoro) S 4-01-1,2-Ph OH=OH 2-methoxy-5- 377 naphthyl _____Jromohenyl 2-(6-fluoro) OH 2 4-01-1,2-Pb CH=OH 2-methoxy-5- 378 naphhyl ________bromophenyl 2-(6-fluoro) OH 2 6-01-1,2-Ph CH=CH 2-methoxy-5- 379 naphthyl bromophenyl 2-(6-fluoro) OH 2 4-01-1,2-Ph 1,2-c-Pr 2-methoxy-5- 380 naphhyl_____ _______bromophenyl 2-(6-fluoro) OH 2 3-01-1,2-Ph CH=OH 2-methoxy-5- 381 naphthyl 2-(7-chloro) 502 4-01-1,2-Ph OH=OH 2-thienyl 382 naphthyl 2-(7-chloro) 0 4-01-1,2-Ph CH=CH 2-thienyl 383 2-(7-chloro) S 4-01-1,2-Ph OH=CH 2-thienyl 384 naphthyl 2-(7-chloro) OH 2 4-01-1,2-Ph OH=CH 2-thienyl 385 naphthyl 2-(7-chloro) OH 2 6-01-1,2-PI CH=OH 2-thienyl 386 naphthyl WO 99/47497PC/A9022 PCT/CA99/00212 Rl,2R 3 -Het A X B WCpd 2-(7-chloro) CH 2 4-C 1-1,2-Ph 1,2-c-Pr 2-thienyl 387 naphthyl 2-(7-chloro) CH 2 3-C1-1,2-Ph CH=CH 2-thienyl 388 naphthyl 2-(6,7-difluoro) SO 2 4-C1-1,2-Pb CH=CH 2-thienyl 389 naphthyl 2-(6,7-difluoro) 0 4-C1-1,2-Ph CH=CH 2-thienyl 390 naphthyl_____ 2-(6,7-difluoro) S 4-C1-1,2-Ph CH=CH 2-thienyl 391 naphthyl 2-(6,7-difluoro) CR 2 4-C1-1,2-Ph CH=CR 2-thienyl 392 naphthyl 2T-(6,7-difluoro) CR 2 6-C1-1,2-Ph CH=CH 2-thienyl 393 naphthyl 2-(6,7-difluoro) CH 2 4-C1-1,2-Ph 1,2-c-Pr 2-thienyl 394 2-(6,7-difluoro) CH 2 3-C1-1,2-Ph CH=CH 2-thienyl 395 naphthyl 2-(6,7-difluoro) S0 2 4-C1-1,2-Ph CH=CH 2-methoxy-5- 396 naphthyl _____bromophenyl 2-(6,7-difluoro) 0 4-C1-1,2-Ph CH=CH 2-methoxy-5- 397 naphthyl 2-(6,7-difluoro) S 4-C1-1,2-Ph CH=CH 2-methoxy-5- 398 naphthyl _____bromophenyl 2-(6,7-difluoro) CR 2 4-CI-1,2-Ph CH=CR 2-methoxy-5- 399 naphthyl _____bromophenyl 2-(6,7-difluoro) CR 2 6-C1-1,2-Ph CH=CH 2-methoxy-5- 400 naphthyl _____bromophenyl 2-(6,7-difluoro) CR 2 4-C1-1,2-Ph 1,2-c-Pr 2-methoxy-5- 401 naphthyl 2-(6,7-difluoro) CR 2 3-C1-1,2-Ph CR=CH 2-methoxy-5- 402 naphthyl _________bromophenyl 2-(5,7-difluoro) CR 2 4-Cl-1,2-Ph CH=CR 2-methoxy-5- 4031 naphthyl _________bromophenyl 2-(5,7-difluoro) S 4-C1-1,2-Ph CR=CH 2-methoxy-5- 404 naphthyl _________bromophenyl 2-(5,7-clifluoro) 0 4-C1-1,2-Ph CR=CH 2-methoxy-5- 4051 naphthyl ______bromophenyl 2-(5,7-difluoro) S0 2 4-C1-1,2-Ph CR=CR 2-methoxy-5- 406 naphthyl 2(6-fluoro) SO 2 4-C1-1,2-Ph CR=CH 2-methoxy-5- 407 r gu in o lin y l b rom o p h en y l 2-(6-fluoro) S 4-C1-1,2-Pl CR=CR 2-methoxy-5- 408 quinolinyl -1 bromophenyl -31- WO 9-9/47497 WO 9947497PCT/CA99/0021 2
RI
1 RMR-Het A X B W' 9 Cpd 2-(6-fluoro) OH 2 4-01-1,2-Ph CH=CH 2-methoxy-5- 409 quinolinyl _____bromophenyl 2-(6-fluoro) OH 2 1,2-Ph CH=CH 2-methoxy-5- 410 quinolinyl _____bromophenyl 2-(6-fluoro) 0 4-C1-1,2-Ph CH=CH 2-methoxy-5- 411 guinolinyl__________ bromophenyl 2-(6-fluoro) OH 2 4-01-1,2-Ph 1,2-c-Pr 2-methoxy-5- 412 quinolinyl _____bromophenyl 2-(5,7-difluoro)- S02 4-01-1,2-Ph CH=CH 2-methoxy-5- 413 guinolinyl _________bromophenyl 2-(5,7-difluoro)- S 4-01-1,2-Ph CH=CH 2-methoxy-5- 414 quinolinyl _________bromophenyl 2-(5,7-difluoro)- CR 2 4-01-1,2-Ph CH=CH 2-methoxy-5- 415 quinolinyl _________bromophenyl 2-(5,7-difluoro)- OH 2 1,2-Ph CH=CH 2-methoxy-5- 416 quinolinyl ______bromophenyl 2-(5,7-difluoro)- 0 4-0-1,2-Ph OH=CH 2-inethoxy-5- 417 quinolinyl ______bromophenyl 2-(5,7-difluoro)- OH 2 4-01-1,2-Ph 1,2-c-Pr 2-methoxy-5- 418 quinolinyl ______bromophenyl 3,4-dichioro S02 4-01-1,2-Ph CH=CH 2-methoxy-5- 419 phenyl ______bromophenyl 3,4-dichloro S 4-01-1,2-Ph CH=CH 2-methoxy-5- 420 phenyl _____bromophenyl 3,4-dichloro OH 2 4-01-1,2-Ph CH=CH 2-methoxy-5- 421 phenyl _____bromophenyl 3,4-dichioro OH 2 1,2-Ph OH=OH 2-methoxy-5- 42 phenyl _____bromophenyl 3,4-dichioro 0 4-01-1,2-Ph CH=CH 2-methoxy-5- 423 phenyl ___bromophenyl 3,4-dichioro OH 2 4-01-1,2-Ph 1,2-c-Pr 2-methoxy-5- 424 phenyl _____bromophenyl 3,4-dichioro OH 2 5-01-1,2-Ph CH=OH 2-methoxy-5- 425 phenyl ______bromophenyl 4-chioro S0 2 4-01-1,2-Ph CH=CH 2-methoxy-5- 426 phenyl _________bromophenyl 4-chioro S 4-01-1,2-Ph CH=CH 2-methoxy-5- 427 phenyl _________bromophenyl 4-chioro OH 2 4-01-1,2-Pb OH=CH 2-methoxy-5- 428 phenyl ___________bromophenyl 4-chioro OH 2 1,2-Ph CH=CH 2-methoxy-5- 429 phenyl ___________bromophenyl 4-chioro 0 4-01-1,2-Pb OH=OH 2-methoxy-5- 430 phenyl bromophenyl I -32- WO 99/47497 WO 9947497PCT/CA99/0021 2
R
1 RWR-Het A X B R 19 Cpd 4-chioro OH 2 4-01-1,2-Ph 1,2-c-Pr 2-methoxy-5- 431 phenyl _________bromophenyl 4-chioro CR 2 4-01-1,2-Ph CH=CH 2-methoxy-5- 432phenyl _____bromophenyl 3,4-dichloro SO 2 4-01-1,2-Ph CH=CH 2-thienyl 433 phenyl 3,4-dichloro S 4-01-1,2-Ph CH=CH 2-thienyl 434 phenyl__ 3,4-dichloro CR 2 4-01-1,2-Ph CH=CH 2-thienyl 435phenyl__ 3,4-dichioro CH 2 1,2-Ph CH=CH 2-thienyl 436phenyl__ 3,4-dichioro 0 4-01-1,2-Ph CH=CH 2-thienyl 437 phenyl 3,4-dichioro CR 2 4-01-1,2-Ph CH=CH 2-thienyl 438 3,4-dichloro CR 2 5-01-1,2-Ph CH=CH 2-thienyl 439 4-chioro 502 4-C1-1,2-Ph CH=CH 2-thienyl 440 phenyl 4-chioro S 4-01-1,2-Ph CH=CH 2-thienyl 441 phenyl 4-chioro CR 2 4-01-1,2-Ph CR=OR 2-thienyl 442 phenyl__ 4-chloro CR2 1,2-Ph CH=CR 2-thienyl 443 phenyl
CR
2 3,2-Pyr CH=CH 2,4-(Me)2-44 indolyl
CR
2 3,2-Pyr CR=CR 2-thienyl 445 indolyl 1-(6-4-chloro) CH 2 4-F-1,2-Ph CH=CH 3-chloro-4- 446 phenyl)indolyl ____fluorophenyl 2-(6-difluoro OR 2 4-C1-1,2-Ph CH=CR 2-methoxy-5- 447 methoxy) bromophenyl naphthyl 2-naphthyl CR 2 4-MeO- CH=CH 2-methoxy-5- 448 ______bromophenyl 2-naphthyl CR 2 5-01-1,2-Ph CH=CR 2-methoxy-5- 449- ________bromophenyl 2-(6-chloro CR 2 4-01-1,2-Ph CR=CR 2-methoxy-5- 4i505 naphthyl)
CR
2 4-F-1,2-Ph CR=OR 2-methoxy-5- 451 methoxy) bromophenyl indolyl__ -33- WO 99/47497 WO 9947497PCT/CA99/0021 2
R
1 R,2R 3 -Het A X B W 19 Cpd 2-(benzolb] CH 2 4-F-1,2-Ph CH=CH 2-methoxy-5- 452 thiophenyl _________bromophenyl 5-(1-benzyl) CH 2 4-F -1,2-Ph CH=CH 2-methoxy-5- 453 indolyl bromophenyl 1-(6-4-chloro) OH 2 4-F-1,2-Ph CH=CH 2-methoxy-5- 454 phenyl)indolyl _____bromophenyl Table II R'R R -HET 0
A
X-B OH 1-b (Compounds 324-346 and 455-542) RlR 2 PR-Het A X B Cpd 2-naphthyl S(O)12 1,2-phenyl CH=CH 324 2-naphthyl S _1,2-phenyl CH=CH 325 4-methylthiophenyl CH, 1,2-phenyl CH=CH 326 3-methylindol-1-yl CH2 1,2-phenyl CH=CH 327 3-chloro-4-fluorophenyl _CH 2 1,2-phenyl CH=CH 328 4-chlorophenyl CH2 1,2-phenyl CH=CH 329 2-naphthyl CH, 1,2-phenyl CH=CH 330 2-naphthyl -S(0)9 1,2-phenyl 1,2-c-propyl 331 2-naphthyl S(0) 9 1,2-phenyl CH.-CH., 332 2-naphthyl S 1,2-phenyl CH=CH 333 3,4-dichiorophenyl 1,2-phenyl CH 9 -CH, 334 3,4-dichlorophenyl CH2 1,2-phenyl CH=CH 335 2-(6-benzyloxy)naphthyl CH, 1,2-phenyl CH=CH 336 2-(6-benzyloxy)naphthyl CH9 1,2-phenyl 1,2-c-propyl 337 2-(6-benzyloxy)naphthyl SO,2 1,2-phenyl 1 ,2-c-p opyl 338 2-(6-benzyloxy)naphthyl CH2-0 1,2-phenyl 1,2-c-propyl 339 2-(6-benzyloxy)naphthyl 0-CH2 1,2-phenyl 1,2-c-propyl 340 2-(6-benzyloxy)naphthyl IS02 1,2-phenyl CH=CH 341 2-(6-benzyloxy)nap thyl ICH,-0 1,2-phenyl ICH=CH 342 -34 WO 99/47497 WO 9947497PCT/CA99/00212 RIRO-Het A X B Cpd 2-(6-benzyloxy)naphthyl O-CH, 1,2-phenyl CH=CH 343 2-(6-benzyloxy)naphthyl S 1,2-phenyl CH=CI- 344 2-(7-benzyloxy)naphthyl so, 1,2-phenyl CH=OH 345 2-(6-(4-trifluoromethyl) OH 2 1,2-phenyl CH=CJI 346 2-(6-fluoro)naphthyl SO,- 4-01-1,2-Ph CH=CH 455 2-(6-fluoro)naphthyl S 4-01-1,2-Ph CH=CH 456 2-(6-fluoro)naphthyl CH2 4-01-1,2-Ph CH=CH 457 2-(6-fluoro)naphthyl OH, 1,2-Ph CH=CH 458 2-(6-fluoro)naphthyl 0 4-01-1,2-Ph OH=CH 459 2-(6-fluoro)naphthyl C H 2 4-Cl- 1,2-Ph 1,2-c-Pr 460 2-(7-fluoro)naphthyl SO2 4-01-1,2-Ph CH=CH 461 2-(7-fluoro)naphthyl S 4-01-1,2-Ph CH=CH 462 2-(7-fluoro)naphthyl
CH
2 4-01-1,2-Ph CH=OH 463 2-(7-fluoro)naphthyl CH, 1,2--Ph CH=CH 464 2-(7-fluoro)naphthyl 0 4-01-1,2-Ph CH=CH 465 7-fluoro)naphthyl C H2 4-Cl- 1,2-Ph 1,2-c-Pr 466 2-(6-chloro)naphthyl SOg 4-01-1,2-Ph CH=CH 467 2-(6-chloro)naphthyl S 4-01-1,2-Ph OH=CH 468 2-(6-chloro)naphthyl CH2 4-01-1,2-Ph OH=CH 469 2-(6-chloro)naphthyl CH, 1,2-Ph CH=CH 470 2-6-hlronahtyl0 4-01-1,2-Ph OH=OH 471 2-(6-chloro)naphthyl COH2 4-Cl- 1,2-Ph 1,2-c-Pr 472 2-(7-chloro)naphthyl S02 4-01-1,2-Ph CH=CH 473 7-chloro)naphthyl S 4-01-1,2-Ph CH=CH 474 7-chloro)naphthyl OH 2 4-Cl- 1,2-Ph OH=CH 475 2-(7-chloro)naphthyl OH 2 4-01-1,2-Ph OH=CH 476 2-(7-chloro)naphthyl OH2 4-01-1,2-Ph CH=CH 477 2-(7-chloro)naphthyl CH 2 4-01-1,2-Ph OH=OH1 478 2-(6,7-difluoro)naphthyl SO, 4-01-1,2-Ph CH=CH 479 2-(6,7-difluoro)naphthyl S 4-01-1,2-Ph OH=CH 480 2-(,7diluro~apthl H 2 4-01-1,2-Ph CH=CH 481 2-(6,7-difluoro)naphthyl
OH
2 4-01-1,2-Ph CH=%OH, 482 2-(6,7-difluoro)naphthyl OH9 4-01-1,2-Ph OH=OH 483 6,7-difluoro)naphthyl OH,- 4-01-1,2-Ph 1,2-c-Pr 484 2-6,-dflor~nphhy H9 4-01-1,2-Ph OH=OH 485- 2-(6,7-difluoro)naphthyl CH, 4-01-1,2-Ph OH=OH 486 2-(6,7-difluoro)naphthyl
OH
2 4-01-1,2-Ph CH=OH 487 2-(6,7-difluoro)naphthyl OH2 1,2-Ph OH=OH 488 6,7-difluoro)naphtyl OH2 4-01-1,2-Ph OH=OH 489 2-(6,7 -difluoro)naphthyl OH 2 4-01-1,2-Ph 1,2-c-Pr 490
SO
2 4-01-1,2-Ph OH=OH 491 indol- l-yl WO 9-9/47497 WO 9947497PCT/CA99/002 12 RlR 2
R
3 -Het A X B Cpd S 4-Cl-1,2-Ph CH=CH 492 indol- l-yl
CH
2 4-Cl-1,2-Ph CH=CH 493 indol- l-yl
CH
2 1,2-Ph CH=CH 494 indol- l-yl
CH
2 4-Cl-1,2-Ph CH=CH 495 indol- l-yl
CH
2 4-Cl-1,2-Ph CH=CH 496 indol- l-yl 2-6-lurogunoinl S02 4-Cl- 1,2-Ph CH=CH 497 2-(6-fluoro)guinolinyl S 4-Cl- 1,2-Ph CH=CH 498 2-(6-fluoro)guinolinyl CH2 4-Cl-1,2-Ph CH=CH 499 2-(6-fluoro)guinolinyl CH2 4-Cl- 1,2-Ph CH=CH 500 2-(6-fluoro)guinolinyl 0 4-Cl-1,2-Ph CH=CH 501 2-(6-fluoro)guinolinyl CH, 4-Cl- 1,2-Ph CH=CH 502 2-(6-difluoromethoxy)- S52 4-Cl-1,2-Ph CH=CH 503 naphthyl__ 2-(6-difluoromethoxy)- S0 2 4-Cl-1,2-Ph CH=CH 504 naphthyl 2-(6-difluoromethoxy)- S0 2 4-Cl- 1,2-Ph CH=CH 505 naphthyl 2-(6-difluoromethoxy)- S0 2 4-CI-112-Ph CH=CH 506 2-(6-difluoromethoxy)- S0 2 4-CI-1,2-Ph CH=CH 507 naphthyl_____ 2-(6-difluoromethoxy)- SO 2 4-Cl-i ,2-Ph CH=CH 508 naphthyl_____ 2-(7-difluoromethoxy)- S02 4-Cl-1,2-Ph CH=CH 509 naphthyl 2-(7-difluoromethoxy)- S 4-01-1,2-Ph CH=CH 510 naphthyl 2-(7-difluoromethoxy)- CH 2 4-Cl-1,2-Ph CH=CH 511 naphthyl 2-(7-difluoromethoxy)- CH 2 4-CI-1,2-Ph CH=CH 512 naphthyl 2-(7-difliuoromethoxy)- 0 4-CI-1,2-Ph CH=CH 513 aphthyl 2-(7-difluoromethoxy)- OH 2 4-01-1,2-Ph CH=CH 514' 2-6moynaphthyl 515 2-(6-methoxy)naphthyl SO 4-Cl-1,2-Ph CH=CH 515 2-(6-methoxy)naphthyl CH 4-Cl-1,2-Ph CH=CH 516 2-(6-methoxy)naphthyl IOH, 14-Cl-1,2-Ph ICH=CH 1517 -36- 0.
0 000.
:1.
0 0 R'RR-Het A X B Cpd 2-(6-methoxy)naphthyl 0 4-Cl-1,2-Ph CH=CH 519 2-(6-methoxy)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 520 2-(6-fluoro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 521 2-(6-fluoro)naphthyl CH 2 4-Cl-i ,2-Ph CH=CH 522 2-(6-fluoro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 523 2-(6-fluoro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 524 2-(6-fluoro)naphthyl CH 2 4-Cl- 1,2-Ph CH=CH 525 2-(6-fluoro)naphthyl CH 2 4-Cl- 1,2-Ph CH=CH 526 2-(7-fluoro)naphthyl CH 2 4-Cl- 1,2-Ph CH=CH 527 2-(7-fluoro)naphthyl CH 2 4-Cl- 1,2-Ph CH=CH 528 2-(7-fluoro)naphthyl CH 2 4-Cl- 1,2-Ph CH=CH 529 2-(7-fluoro)naphthyl CH 2 4-Cl- 1,2-Ph CH=CH 530 2-(7-fluoro)naphthyl CH 2 4-Cl- 1,2-Ph CH=CH 531 2-(7-fluoro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 532 2-naphthyl CH 2 4,5-C1 2 -1,2-Ph CH=CH 533 2-naphthyl CH 2 4-Cl-1,2-Ph CH=CH 534 3 ,4-dichlorophenyl CH 2 4-Cl-1,2-Ph CH=CH 535 2-naphthyl CH 2 4-Cl-1,2-Ph CH=CH 536 4-chlorophenyl CH 2 4-Cl-1,2-Ph CH=CH 537 1-(5-phenylmethoxy)indolyl CH 2 4-F-1,2-Ph CH=CH 538 2-(benzo[b]thiophenyl) CH 2 4-F-1,2-Ph CH=CH 539 5-(1-benzyl)indolyl CH 2 4-F-1,2-Ph CH=CH 540 1-(6-(4-chloro)phenyl)indolyl CH 2 4-F-1,2-Ph CH=CH 541
CH
2 3,2-Py CH=CH 54 According to another embodiment of this invention there is provided represented by formula 1: RR R R -HET 0
A
a compound or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein: HET represents a 5-12 membered monocyclic or bicyclic aromatic ring system containing 0-3 heteroatoms selected from 0, and N(O),m wherein m is 0 or 1 and n j, is 0, 1 or 2; HET can also represent tetrazole.
[I:\DayLib\L[BXX]03235.doc:aak 37a A is a one or two atom moiety and is selected from the group consisting of:
-C(R
7 2 -W-C(R 2
-CR
7
(OR
20
-C(R
7 2
-C(R)
2
-C(OR
20
)R
7
-C(R
7 2 or
-CR
7
=CR
7 wherein W represents 0, or NR 1 with n as previously defined and R as defined below; X represents a 5-10 membered monocyclic or bicyclic aryl or heteroaryl group having 1-3 heteroatoms selected from O, S(O)n and N(O)m, and optionally substituted with R' 4 and R' 5 and A and B are attached to the aryl or heteroaryl group ortho relative to each other; B represents -CH=CH- or 1,2-cyclopropyl; Z is NHSO 2
RI";
R2 and R 3 independently represent H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkenyl-HET(Ra) 4 9
-(C(R
4 2 )pSR 5
-(C(R
4 2 )pOR 8
-(C(R
4 2 )pN(R') 2 CN, NO 2
-(C(R
4 2
),C(R
7 3
-CO
2
R
9 CON(R 2 or
-(C(R
4 2 )pS(O)n)R' 0 wherein p is 0-3 and n is as previously defined; Each R 4 is independently H, F, CF 3 or lower alkyl, or two R 4 groups are taken in conjunction and represent a ring of up to six atoms, optionally containing one heteroatom selected from O, S(O)n or N(O)m; each R 5 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 lower alkyl-HET, lower alkenyl-HET or 2 )pPh(R' )0-2; each R 6 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF 3 Ph, Bn and when two R 6 groups are attached to N they may be taken in conjunction and represent a ring of up to 6 atoms, optionally containing an additional hetetoatom selected from O, S(O)n or N(O)m; each R 7 is independently H, F, CF 3 or lower alkyl, and when two R 7 groups are 25 present, they may be taken in conjunction and represent an aromatic or aliphatic ring of 3 to 6 members containing from 0-2 heteroatoms selected from O, S(0)n and N(O)m; each R 8 represents H or R 5 each R 9 is independently H, lower alkyl, lower alkenyl, lower alkynyl, Ph or Bn; each R 1 0 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 Ph(R'")o-3, 30 CH 2 Ph(R )o3 or N(R6)2; each R" is independently lower alkyl, SR 20
OR
20
N(R')
2
-CO
2
R
I2
-CON(R
6 2
C(O)R
1 2 CN, CF 3
NO
2 or halogen; each R 2 is independently H, lower alkyl or benzyl; each R 13 is independently H, halo, lower alkyl, O-lower alkenyl, S-lower alkyl 3 N(R 6 2
CO
2
R
i2 CN, CF 3 or NO 2 and R' 4 and R' 5 are independently lower alkyl, halogen, CF 3 OR' S(O)nR' 6 or 2 0R" each is independently H, lower alkyl, lower alkenyl, Ph, Bn or CF 3 each R17 is independently H, lower alkyl or Bn; each R' 8 is independently H, F or lower alkyl, and when two R8 groups are present, they may be taken in conjunction and represent a ring of 3 to 6 members comprising car-hon atoms and optionally one heteroatom chosen from 0, or N; each R' 9 is lower alkyl, lower alkenyl, lower alkynyl, CF 3
HET(R
2 4 9 lower alkyl- HlET(R') 4 or lower alkenyl-HET(Ra) 4 9 each R 20 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF 3 or Ph(R' 3 2 and each R' is independently selected from the group consisting of: H, OH, halo, CN,
NO
2 amino, Cl- 6 alkyl, C2-6alkenyl, C2- 6 a I kynyl, C,.
6 alkoxy, C 26 .alkenyloxy,
C
2 -6alkynyloxy, Cs 6 alkylamino, di-Ci- 6 alkylamino, CF 3 C(O)C I- 6 alkyl,
C(O)C
2 6 alkenyl, C(O)C2-6alkynyl, CO 2 H, CO 2 CI-6alkyl, CO 2 C2-6alkenyl, and
CO
2
C
2 6 alkynyl, said alkyl, alkenyl, alkynyl and the alkyl portions of alkylamino and dialkylamino being optionally substituted with 1-3 of: hydroxy, halo, aryl, CI, 6 alkoxy,
C
2 -6alkenyloxy, C2-6alkynyloxy, CF 3
C(O)CI-
6 alkyl, C(O)C2-6alkenyl, C(O)C2-6alkynyl,
CO
2 H, CO 2 C -6alkyl, C0 2
C
2 6 alkenyl, CO 2 C2-6alkynyl, NH 2 NHC 6 salkyl and N(Cl-6alkyl) 2 Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is *meant to comprehend such possible diastereomers as well as their racemic and resolved, enantiomrnerically pure forms and pharmaceutically acceptable salts thereof.
25 Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
*The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt, thereof, and may 0 also contain a
S
WO 99/47497 PCT/CA99/00212 pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, ptoluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
It will be understood that in the discussion of methods of treatment which follows, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
The magnitude of prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature and the -38- WO 99/47497 PCT/CA99/00212 severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to a variety of factors including the age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination and response of the individual patient. In general, the daily dose from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 10 mg per kg. On the other hand, it may be necessary to use dosages outside these limits in some cases.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain from about 0.5 mg to about 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain from about 1 mg to about 2 g of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
For the treatment of any of the prostanoid mediated diseases compound I may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the compound of the invention is effective in the treatment of humans.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, solutions, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents -39- WO 99/47497 PCT/CA99/00212 selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Patent 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water-miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturallyoccurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or WO 99/47497 PCT/CA99/00212 condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
-41- WO 99/47497 PCT/CA99/00212 Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic monoor diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Compound I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound of Formula I are employed.
(For purposes of this application, topical application shall include mouth washes and gargles.) Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.
The ability of the compounds of Formula I to interact with prostaglandin receptors makes them useful for treating, preventing or reversing undesirable symptoms caused by prostaglandins in a mammalian, especially human subject. This mimicking or antagonism -42- WO 99/47497 PCT/CA99/00212 of the actions of prostaglandins indicates that the compounds and pharmaceutical compositions thereof are useful to treat, prevent or ameliorate prostaglandin mediated diseases and conditions in mammals and especially in humans: Pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, skeletal pain, post-partum pain, dysmenorrhea, headache, migraine, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns including radiation and corrosive chemical injuries, sunburns, pain following surgical and dental procedures as well as immune and autoimmune diseases. In addition, such a compound may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer. Compound I may also be of use in the treatment and/or prevention prostaglandin-mediated proliferation disorders such as may occur in diabetic retinopathy and tumor angiogenesis. Compound I will also inhibit prostanoid-induced smooth muscle contraction by antagonizing contractile prostanoids or mimicking relaxing prostanoids and hence may be use in the treatment of dysmenorrhea, premature labor, asthma and eosinophil related disorders. It will also be of use in the treatment of Alzheimer's disease, the treatment of glaucoma, for the prevention of bone loss (treatment of osteoporosis) and for the promotion of bone formation (treatment of fractures) and other bone diseases such as Paget's disease.
By virtue of its prostanoid or prostanoid antagonist activity, compound I will prove useful as an alternative to NSAID'S particularly where such non-steroidal anti-inflammatory drugs may be contraindicated such as in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal lesions; GI bleeding, coagulation disorders including anemia such as hypoprothrombinemia, haemophilia or other bleeding problems; kidney disease; thrombosis, occlusive vascular diseases; those prior to surgery or taking anti-coagulants. Compound I -43- WO 99/47497 PCT/CA99/00212 will also be useful as a cytoprotective agent for patients under chemotherapy.
Compound of Formula I, will be useful as a partial or complete substitute for conventional antiinflammatory or analgesic compounds in preparations wherein they are presently co-administered with other agents or ingredients. Thus in further aspects, the invention encompasses pharmaceutical compositions for treating prostaglandin
E
2 mediated diseases as defined above comprising a non-toxic therapeutically effective amount of the compound of Formula I as defined above and one or more ingredients such as another pain reliever including acetaminophen or phenacetin; a COX-2 selective NSAID; a conventional NSAID; a potentiator including caffeine; an H2-antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant including phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an antiitussive including codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; another prostaglandin ligand including misoprostol, enprostil, rioprostil, ornoprostol or rosaprostol; a diuretic; a sedating or non-sedating antihistamine. In addition, the invention encompasses a method of treating prostaglandin E 2 mediated diseases comprising: administration to a patient in need of such treatment a non-toxic therapeutically effective amount of the compound of Formula I, optionally co-administered with one or more of such ingredients as listed immediately above.
Compounds of the present invention can be prepared according to the following methods. Temperatures are in degrees Celsius.
Boronic acids and esters can be prepared from the corresponding halide according to literature procedure and reference cited therein (Charette, Giroux, A. J. Org. Chem. 1996, 61, 8718; Ishiyama, Murata, Miyaura, N. J. Org. Chem. 1995, 60, 7508; Miyaura, Suzuki, A. Chem. Rev, 1995, 95, 2457; Murata, M.; Watanabe, Masuda, Y. J. Org. Chem. 1997, 62, 6458; Watanabe, T.
-44- WO 99/47497 PCT/CA99/00212 Miyaura, Suzuki, A. Synlett, 1992, 207; Maddaford, Keay, B.A. J.
Org. Chem. 1994, 59, 6501; Cristofoli, Keay, B.A. Tetrahedron Lett.
1991, 32, 5881; Passafaro, Keay, Tetrahedron Lett. 1996, 37, 429; Serafin, Makosza, M. Tetrahedron, 1963, 19, 821). In some cases, the triflate, the tin or the zinc derivatives may be used instead of the boronic acid.
Method A Cinnamic ester 1 is treated with a brominating agent such as NBS in a refluxing inert solvent such as CC1 4 with the use of an initiator like benzoyl peroxide or light. The resulting benzylic bromide is reacted in a Suzuki coupling reaction with the appropriate boronic acid or ester, a catalyst such as tetrakis(triphenylphosphine) palladium and cesium fluoride or Na2CO3 or a base in an inert refluxing solvent such as DME at 80-900 C. The new cinnamic ester 3 is hydrolyzed with aqueous sodium hydroxide to afford the acid 4 that is converted to the cinnamic sulfonamide 5 with a coupling reagent such as DCC or DCI in CH 2 C1 2 at r.t.
WO 99/47497 PCT/CA99/00212 Method B Cinnamic ester 2 is treated with an aryl or heteroaryl mercaptan, alcohol or amine, and with a base such as a hydride or an amine in benzene or THF at 0-23o C. The resulting cinnamic ester 6 is converted to 7 according to Method A.
If W= sulfur, it is oxidized to the sulfoxide or sulfone 8 with hydrogen peroxide, m-CPBA or other peracetic acid. The cinnamic ester 8 is converted to 9 according to Method A.
Method C The aldehyde 11 is prepared by an addition-elimination of a mercapto, hydroxy or amino aryl or heteroaryl with a base such as K2CO, in refluxing CHC1 3 If needed a higher boiling point solvent can be used. This type of rection can also be performed with CuO in DMF.
An Emmons-Horner type reaction (or Wittig) in toluene at r.t. followed by Method A (or oxidation as described in Method B) results in the cinnamic sulfonamide 13.
Method D Acetal 14 that came from an acetalization from a suitably substituted bromo benzaldehyde is converted to the Grignard reagent with magnesium in an etheral solvent at reflux and quenched with an aryl or heteroaryl ketone. The alcohol 16 is reacted with an halide and a base (or protected as the o-nitrobenzyl, and removed at the end of the sequence) to furnish the compound 17. Deprotection of the acetal under standard conditions followed by Method C gives 18.
Method E Alcohol 16 is converted to an acetate with acetyl chloride (or acetic anhydride and an amine base) and coupled with a Grignard reagent and a copper salt at low temperature. The alcohol 16 could also be converted to the bromide and treated in a similar way to yield Alternatively the tetrametyl acetal methyl) version of alcohol 16 can be treated with TiCl,/Me 2 Zn (or R 7 2 Zn) at -30 Compound 20 is then -46- WO 99/47497 PCT/CA99/00212 converted to the cinnamic sulfonamide 21 according to Method D. Also, 22 can be treated with A(R 7 in toluene at 80 °C for 24h and 23 converted to the aldehyde with n-BuLi/DMF followed by an Emmons-Horner reaction and Method A to yield compound 21.
Method F A suitably substituted bromo toluene 24 is treated with n- Buli at low temperature and quenched with an aryl or heteroaryl aldehyde. The resulting alcohol is oxidized to the ketone with PDC, PCC, MnO 2 or other typical oxidizing agent. The carbonyl is treated with SF 4 MoF,-BF 3 (or converted to a thioacetal and treated with nitrosonium BF 4 pyridinium*HF) to yield the difluoride. Benzylic bromination with NBS followed by oxidation with N-methylmorpholine N-oxide at 100 "C in dioxane for 4 h, yielded compound 25 that is converted to cinnamic sulfonamide 26 with Method C.
Method G The appropriately substituted methyl bromo(or triflate) benzoate 27 is converted to compound 28 by a Suzuki coupling reaction followed by hydrogenation. A Stille coupling reaction could also be used.
Benzylic bromination or benzylic oxidation followed by treatment with a brominating agent such as CBr 4 /triphenylphosphine gives compound 29 which can be treated with a boronic acid, or a tin compound (Stille) to furnish compound 30. Reduction of the ester with DIBAL, oxidation with MnO 2 and Method C gives compound 31.
Method H Compound 29 (one R 7 H) is treated with triphenyl phosphine to give the salt and, with a base such as LDA, is converted to compound 32 with the aryl or heteroaryl ketone. The halide 29 can also be converted the Grignard reagent and added to the ketone. Dehydration under acidic conditions results in compound 32. Reduction of the double bond under standard conditions, followed by Methods G and C gives compound 33. From compound 32, cyclopropanation with -47- WO 99/47497 PCT/CA99/00212 diazomethane and palladium followed by Methods G, C and A gives compound 34.
-48 WO 99/47497 PCT/CA99/00212 Method I The (heterocyclic) vinylic bromide 35 is reacted in a Suzuki coupling reaction with an aryl or hetero aryl boronic acid and converted to a new borane by 9-BBN addition followed by a second Suzuki reaction with compound 14. Compound 37 thus formed is reduced by hydrogenolysis H/metal or diimide) and deprotection followed by Method C gives cinnamic sulfonamide 39.
Method J Ketone 40 which comes from oxidation of the corresponding alcohol is reacted with a phosphonium salt or phosphono ester with a base such as LDA to give the cinnamic ester 41. Method A yields 42 and reduction of the double bond by the previously mentioned method gives the acyl sulfonamide 43.
Method K Cinnamic ester 3 is reduced to 44 by the previously mentioned method, a Alkylation with a base such as LDA followed by an alkylating agent results in 45 after conversion to the acyl sulfonamide.
Method L Cinnamic ester 3 is reduced to 46 with DIBAL and the double bond converted to a cyclopropane by a Simmons-Smith reaction, or similar reactions recently described in the literature. Compound 47 is then oxidized and the cinnamic sulfonamide 48 is prepared according to Method A.
Method M Ester 49 which can come from the homologation of the appropriately substituted methyl ortho-toluate, is treated with a base and with an alkylating agent to furnish compound 50. Benzylic bromination and Suzuki coupling gives an intermediate ester. Homologation according to J. Amer. Chem. Soc.; 1985, 1429; J. Org. Chem. 1992, 7194, -49- WO 99/47497 PCT/CA99/00212 followed by alkylation with a base such as LDA and an alkylating agent furnishes acylsulfonamide 51 by Method A.
Compound 50 can also be converted to the benzylic bromide and to compound 52 by Method A.
Method N Suitably substituted compound 53 is treated with a boronic acid to give compound 54 which is reduced with LDA to the alcohol Treatment with phosgene followed with the appropriate sulfonamide gives compound 56. This can also be prepared by mixing phosgene and the sulfonamide at 1400C to generate the isocyanate.
Compound 54 is treated with a Grignard reagent to give the corresponding alcohol and as previously described, converted to compound 57.
Method O Ester 58 is treated with Lawesson's reagent, DAST and light to give the benzylic alcohol 59. The procedure according to Method N yields compound Method P Compound 59 is brominated as described earlier (or iodinated) and reacted in a SN 2 type reaction with an ester and a base such as LDA to furnish ester 61. Method A gives the acylsulfonamide 62.
Method Q Compound 55 is treated with NH3/Ph 3 P/DEAD (or treated with CBr4/Ph 3 P and the bromide converted to the amine 63 with ammonia). Treatment with phosgene followed by sulfonamide yields 64, treatment of which with a base and an alkyl or benzylic halide gives compounds Method R WO 99/47497 PCT/CA99/00212 Aldehyde 10 is treated with a silylated source of hydroxyl or thiol at 80-130 and the silyl group removed by fluoride treatment.
Compound 66 is then treated with an aryl or heteroaryl methylene bromide with a base such as a tertiary amine in CHC13 or benzene to yield aldehyde 67. Emmons-Horner (or Wittig reaction) with LDA results in compound 68 via Method A.
Method S In the case of an amine an alternative to method R can be used. A suitably substituted nitro aldehyde 69 is converted to compound 70 as described earlier and the nitro group reduced with standard methods. Mono-alkylation followed by displacement with an aryl or heteroaryl methylene bromide and processing by Method A yields cinnamic sulfonamide 71.
Method T A suitably substituted bromo toluene 24 is converted to the anion in an etheral solvent at low temperature and trapped with an aldehyde of an aryl or heteroaryl. The resulting alcohol is oxidized with MnO 2 Jones' reagent, PDC, PCC or any other oxidant. Benzylic bromination followed by oxidation with N-methyl morpholine N-oxide, yields a ketoaldehyde. Emmons-Horner and Method A gives the cinnamic sulfonamides 72.
Generic structures 4, 5, 7, 9, 13, 18, 21, 26, 31, 33, 34, 39, 42, 43, 45, 48, 51, 52, 56, 57, 60, 62, 64, 65, 68, 71 and 72 are representative of the compounds of the present invention. It is also noted that where the chemistry allows in the generic schemes, alternate embodiments of such as heteroaryl groups, can be substituted for phenyl in the schemes.
-51- WO 99/47497PCCA/021 PCT/CA99/00212 Method A
NBS
HET-B(OH)
2 Pd(O) Hydrolysis OMe 3
HET
HET
H
2
NSO
2
R'
9
DCI
-52- WO 99/47497 WO 9947497PCT/CA99/002 12 Method B 2 HW-HET -B a s e l Method A 6[Ox] when W =sulfur S(O)n-HET 0 R 4 OMe R81 Method A Method C
HW-HET
K
2 C0 3
W-HET
CHO
R 1 Emmons-Horner R 15 Method B -53- WO 99/47497 WO 9947497PCT/CA99/002 12 Method D R7 HET
R
HOR
1- Mg 0 15 2-HET ),R 7
R
20 -Br Base R= H, Methyl R7 HET RR R 20 0 R R14
§RR
,HET
NHS0 2
R
19 Deprotection Method C. A -54- WO 99/47497 WO 9947497PCT/CA99/002 12 Method E Protection 16 Li 2
CUCI
4
R
7 -MgX
OR
AI(R
7 3 101/80 0 CI24h Method D
R
R
7
HET
Br R523
R
7
HET
N N NHSO 2
R
1 9 14..L R 15 21 Method A rne, 1- n-Buli 2- DMF 3- Emmons-Ho WO 99/47497PC/A/022 PCT/CA99/00212 Method F Br 24 F HET
F
R 1 1-Buli/-78 0
C
2-H ET-CHO 3-[Ox] 1-NBS 2- or DMSO 0 o HET
R
1
SF
4 or DAST F HET
F
R14
CHO
R
15 Method C, A F
HET
F~ 0 R 14 NHS0 2
R'
9 26
R
15 -56- WO 9-9/47497PC/A9022 PCT/CA99/00212 Method G Br
SCO
2 Me R14 1 -y
B(OH)
2 2- Hydrogenation 1 [Ox] 2- CBr 4 /Ph 3
P
HET-B(OH)
2 Pd(O)
HET
Rk 7I L 1- Reduction 2-MnO 2 Method C, A
NHSO
2
R
1 9 57 WO 99/47497 WO 9947497PCT/CA99/002 12 Method H
HET
1 Ph 3
P
29 2- Base
R
7 Het Hydrogenation 1 CH 2
N
2 /Pd 2- Method G, C, A Method G, C, Aj
HET
R 0 R~ 14NS21
HET
0 R14L~"
NHSO
2
R
19 34 Method I R 7 Br Rr
HET-B(OH)
2 R 7
HET
36 1- q-BBN 2-14/ Pd(O)
HET
R
7 R 14 37 R 1 1- [Red] R 14- NHS 2
R
19 R/ 39 dMethod
CA
-58- WO 99/47497 WO 9947497PCTICA99/0021 2 Method J
RI
8 Ph 3 P >'CO 2 Me or Base o RIB (EtO) 2 P ~C0 2 Me R 14 C 2 Me 41
R
15 4 HET R 18 0 14 NHSO 2
R
19 R
W~
Method A [Red] HET R 18 0 14
NHSO
2
R
1 9 R1 43 Method K [Red] 1 -Base RlB-Br 2- Method A NHS0 2
R
19
RIB
59- WO 99/47497 PCTICA99/002 12 Method L
HET
'OMe Reduction R 5 3
CH
2 1 2 /Zn 1 -[OX] 2- Method A
NHSO
2
R'
9 WO 99/47497 PTC9/01 PCT/CA99/00212 Method M
CO
2 Me 1- Base 2- R' 8
-X
F'I
1 -NBS 2 -Method A
-CO
2 Me 1- NBS 2- Het-B(OH) 2
R
18
R
1 8 'N CO 2 Me ,18
.NHSO
2
R
1 9 Homologation
HET,
NHS0 2
R'
9 -61 WO 99/47497 WO 9947497PCT/CA99/002 12 Method N BrHT HT
CO
2 Me HE CO 2 Me HEO 53 54
R
18 Mg-X 1- Phosgene I 2-NH 2 S0 2
R
1 9 HET or
R
18
R
18 O=C=NS0 2
R'
9 R14
OH
Q, HET
RR
1 9 1- PhosgeneR1 2-NH 2
SO
2
R
1 9
R
5 6 or
O=C-NSO
2
R'
9
HET
R'F
8
R
1 8 0 o NHS 2 R19 57 -62- WO 99/47497 PTC9/01 PCT/CA99/00212 Method 0 N0 2 1 Lawesson 2- DAST 3- Light
HET
F F 14
OH
59
HET,
1- Phosgene 2-NH 2
SO
2 Rl 9 or O=C=NS0 2
R'
9 -63 WO 9-9/47497 WO 9947497PCT/CA99/002 12 Method P
HET
F, F R14-1
OH
R
15 59 Bromination
HET
R4 Fr
R
1 0
HET
F 1 OR
FF
Base
R'
61
HET
F F 0 F F NHS0 2
R'
9
R
1 62 Method A -64- WO 99/47497 WO 9947497PCT/CA49/00212 Method Q
HET
R 14
OH
1 CBr 4 /Ph 3
P
HET
R14
NH
2 63 1- Phosgene 2-NH 2
SO
2 Rl 9 or O=C=NS0 2 Rl 9 NHS0 2
R
1 9
HET
0 Base/ R 17 _X N H02.
R1 4 L R1N7HO 2 1 WO 9-9/47497 PCT/CA99/002 12 Method R 1-Ph 3 SiSH or Ph 3 SiOH 2- Deprotection
HET
R
7
I
R 7
RA
7 HetXH
NBS
R 7 R 7 Het >1,Br
HET
R
7 F7 R 4NHS0 2
R'
9 .Method A R R 1 -66- WO 99/47497 PCT/CA99/00212 Method S Emmons-Horner
LDA
NO
2 0 R1OR
NH
2 0 [Red] O
R
7
-X
Base
NHR
7 0 R 1
OR
R
7 Het NR 7
R
7
R
7 Het IBr NHS0 2
R'
9 Method A Base -67 WO 99/47497 PCT/CA99/00212 i.
Method T Br R145 1- Mg or n-Buli 2- O H' KHET Buli/-78 0
C
SDMSO
NaHCO 3 Br HET 1- Emmons- Horner 2- Method A O HET R14j
NHSO
2
R
19
R
15 72 ASSAYS FOR DETERMINING BIOLOGICAL ACTIVITY Biological activity and thus utility for the compounds of formula I as modulators of prostaglandin mediated diseases can be demonstrated in accordance with the following assayswhich demonstrate prostanoid antagonist or agonist activity in vitro and in vivo and their selectivity. The prostaglandin receptors investigated were DP,
EP
1
EP
2
EP
3
EP
4 FP, IP and TP.
Stable expression of prostanoid receptors in the human embryonic kidney (HEK) 293(ebna) cell line -68- WO 99/47497 PCT/CA99/00212 Prostanoid receptor cDNAs corresponding to full length coding sequences were subcloned into the appropriate sites of mammalian expression vectors and transfected into HEK 293(ebna) cells. HEK 293(ebna) cells expressing the individual cDNAs were grown under selection and individual colonies were isolated after 2-3 weeks of growth using the cloning ring method and subsequently expanded into clonal cell lines.
Prostanoid receptor binding assays HEK 293(ebna) cells are maintained in culture, harvested and membranes are prepared by differential centrifugation, following lysis of the cells in the presence of protease inhibitors, for use in receptor binding assays. Prostanoid receptor binding assays are performed in mM MES/KOH (pH 6.0) (EPs, FP and TP) or 10 mM HEPES/KOH (pH 7.4) (DP and IP), containing 1 mM EDTA, 10 mM divalent cation and the appropriate radioligand. The reaction is initiated by addition of membrane protein. Ligands are added in dimethylsulfoxide which is kept constant at 1 in all incubations. Non-specific binding is determined in the presence of 1 iM of the corresponding non-radioactive prostanoid. Incubations are conducted for 60 min at room temperature or 30 °C and terminated by rapid filtration. Specific binding is calculated by subtracting non specific binding from total binding. The residual specific binding at each ligand concentration is calculated and expressed as a function of ligand concentration in order to construct sigmoidal concentration-response curves for determination of ligand affinity.
Prostanoid receptor agonist and antagonist assays Whole cell second messenger assays measuring stimulation (EP 2
EP
4 DP and IP in HEK 293(ebna) cells) or inhibition
(EP
3 in human erythroleukemia (HEL) cells) of intracellular cAMP accumulation or mobilization of intracellular calcium (EP 1 FP and TP in HEK 293(ebna) cells stably transfected with apo-aequorin) are performed to determine whether receptor ligands are agonists or -69- WO 9-9/47497 PCT/CA99/00212 antagonists. For cAMP assays, cells are harvested and resuspended in HBSS containing 25 mM HEPES, pH 7.4. Incubations contain 100 gM RO-20174 (phosphodiesterase type IV inhibitor, available from Biomol) and, in the case of the EP 3 inhibition assay only, 15 piM forskolin to stimulate cAMP production. Samples are incubated at 37 0 C for 10 min, the reaction is terminated and cAMP levels are then measured. For calcium mobilization assays, cells are charged with the co-factors reduced glutathione and coelenterazine, harvested and resuspended in Ham's F12 medium. Calcium mobilization is measured by monitoring luminescence provoked by calcium binding to the intracellular photoprotein aequorin. Ligands are added in dimethylsulfoxide which is kept constant at 1 in all incubations. For agonists, second messenger responses are expressed as a function of ligand concentration and both EC 50 values and the maximum response as compared to a prostanoid standard are calculated. For antagonists, the ability of a ligand to inhibit an agonist response is determined by Schild analysis and both KB and slope values are calculated.
Rat Paw Edema Assay The method is the same as described in Chan et al (J.
Pharmacol. Exp. Ther. 274: 1531-1537, 1995).
LPS-Induced Pyrexia in Conscious Rats The method is the same as described in Chan et al (J.
Pharmacol. Exp. Ther. 274: 1531-1537, 1995).
LPS-Induced Pvrexia in Conscious Squirrel Monkeys The method is the same as described in Chan et al (Eur. J.
Pharmacol. 327: 221- 225, 1997).
Acute Inflammatory Hyperalgesia Induced by Carrageenan in Rats The method is the same as described in Boyce et al (Neuropharmacology 33: 1609-1611, 1994).
WO 99/47497 PCT/CA99/00212 Adjuvant-Induced Arthritis in Rats Female Lewis rats (body weight -146-170 g) were weighed, ear marked, and assigned to groups (a negative control group in which arthritis was not induced, a vehicle control group, a positive control group administered indomethacin at a total daily dose of 1 mg/kg and four groups administered with a test compound at total daily doses of 0.10-3.0 mg/kg) such that the body weights were equivalent within each group. Six groups of 10 rats each were injected into a hind paw with mg of Mycobacterium butyricum in 0.1 mL of light mineral oil (adjuvant), and a negative control group of 10 rats was not injected with adjuvant. Body weights, contralateral paw volumes (determined by mercury displacement plethysmography) and lateral radiographs (obtained under Ketamine and Xylazine anesthesia) were determined before (day and 21 days following adjuvant injection, and primary paw volumes were determined before (day and on days 4 and 21 following adjuvant injection. The rats were anesthetized with an intramuscular injection of 0.03 0.1 mL of a combination of Ketamine (87 mg/kg) and Xylazine (13 mg/kg) for radiographs and injection of adjuvant. The radiographs were made of both hind paws on day 0 and day 21 using the Faxitron (45 kVp, 30 seconds) and Kodak X-OMAT TL film, and were developed in an automatic processor. Radiographs were evaluated for changes in the soft and hard tissues by an investigator who was blinded to experimental treatment. The following radiographic changes were graded numerically according to severity: increased soft issue volume narrowing or widening of joint spaces subchondral erosion periosteal reaction osteolysis (0-4) subluxation and degenerative joint changes Specific criteria were used to establish the numerical grade of severity for each radiographic change. The maximum possible score per foot was 26. A test compound at total daily doses of 0.1, 0.3, 1, and 3 mg/kg/day, indomethacin at a total daily dose of 1 mg/kg/day, or vehicle methocel in sterile water) were administered per os b.i.d. beginning post injection of adjuvant and continuing for 21 days. The compounds were -71- WO 99/47497 PCT/CA99/00212 prepared weekly, refrigerated in the dark until used, and vortex mixed immediately prior to administration.
The invention is illustrated in connection with the following non-limiting Examples. All the end products of the formula I were analyzed by NMR, TLC and mass spectrometry.
Intermediates were analyzed by NMR and TLC.
Most compounds were purified by flash chromatography on silica gel. Recrystallization and/or swish (suspension in a solvent followed by filtration of the solid) with a solvent such as ether:hexane 1:1.
The course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only.
Temperatures are in degrees Celsius.
The compounds of the examples are numbered in accordance with the compounds that appear in Tables I and II.
EXAMPLE 1 N-((E)-3-{2-[4-(METHYLTHIO)BENZYL]PHENYL)-2-PROPENOYL)-2- THIOPHENESULFONAMIDE (17) Step 1: Methyl (E)-3-(2-methvlphenvl)-2-propenoate To 2-methylcinnamic acid (100g; 617 mmol) in 1.2 L of DMF was added DBU (112.6 g; 740 mmol) and 15 min later methyl iodide (131.3 g; 925 mmol) and left overnight. The solution was diluted in ether and washed with HC1 H 2 0 and brine. The solvent was removed to give 106.8 g of the title compound.
'H NMR (CDC1,) 5 2.4 (3H, 3.8 (3H, 6.35 (1H, 7.15 (1H, 7.22 (1H, 7.5 (1H, d) and 7.95 (1H, d).
The ethyl ester can be prepared as well in the same way or from the 2-methyl benzaldehyde 5.00 g; 41.6 mmol) and triethyl phosphonoacetate (9.9 mL; 50.0 mmol) in 150 mL ot toluene at 0 cC, to which was added portionwise NaH (63.0 mmol). After 2 h of stirring the mixture was quenched with NH40Ac and extracted with EtOAc.
The solvent was removed to give 7.1 g of the ethyl cinnamate.
-72- WO 99/47497 PCT/CA99/00212 Step 2: Ethyl (E)-3-[2-(bromomethvl)phenyll-2-propenoate To the previous ethyl cinnamate (20.0 g; 105 mmol) and NBS (19.64 g; 110.3 mmol) in refluxing CC1 4 was added benzoyl peroxide (1.27 g) and the mixture was stirred for 12 h. The solution was cooled to r.t.
and filtered. The solvent was removed and the crude oil purified by silica gel chromatography EtOAc in hexane) to yield 14.18 g of the title compound.
'H NMR (CDC13) 8 1.30 (3H, 4.25 (2H, 4.60 (2H, 6.45 (1H, 7.30 (3H, 7.57 (1H, m) and 8.05 (1H, d).
-73- WO 99/47497 PCT/CA99/00212 Step 3: Ethyl (E)-3-12-14-(methvlthio)benzvl phenvll-2-propenoate A mixture of the previous benzyl bromide (0.50 g; 1.86 mmol), 4-(methylthio)benzeneboronic acid (0.63 g; 3.7 mmol) CsF (1.13 g) and Ph 3 P),Pd (0.11 g) in 10 mL of DME was heated to reflux for 10 h.
The mixture was cooled to r.t. and quenched with NH 4 OAc and extracted with EtOAc. The organic phases were combined, dried and the solvent removed. Purification by silica gel chromatography EtOAc in hexane) yielded 0.35 g of the title compound.
'H NMR (CDC1,) 8 1.27 (3H, 2.41 (3H, 4.08 (2H, 4.21 (2H, 6.30 (1H, 7.00 (1H, 7.1-7.4 (6H, 7.55 (1H, d) and 7.97 (1H, d).
Step 4: (E)-3-{2-[4-Methvlthio)benzyllphenvl}-2-propenoic acid Hydrolysis of the previous ester (0.34 g; 1.1 mmol) was run in THF/MeOH (6 mL/3 mL) with 2 equivalent of a 2N NaOH solution for 4 h. The solution was diluted with EtOAc and quenched with HC1 The organic phase was dried over Na 2
SO
4 and the solvent removed.
Purification was done by a swish in hexane to yield 0.21 g of the title compound.
'H NMR (CDC13) 8 2.42 (3H, 4.09 (2H, 6.31 (1H, 7.00- 7.35 (7H, 7.50 (1H, d) and 8.07 (1H, d).
Step 5: N-((E)-3-f2-[4-(methvlthio)benzvllphenvll-2-propenovl)-2thiophenesulfonamide (17) 2-Thiophenesulfonamide was prepared from the corresponding sulfonyl chloride with 2.2 equivalent of NH 4 OH in THF at 0 C. The solution was brought to r.t. and left 2 h. It was then quenched with NaHCO 3 and extracted with EtOAc. The organic phase was dried over Na 2
SO
4 and the solvent removed. The crude product was crystallized in toluene/EtOAc.
To the previous acid (100 mg; 0.35 mmol), 2thiophenesulfonamide (60 mg; 0.37 mmol), DMAP (86 mg; 0.7 mmol) in 2 mL of CH 2 C1 2 was added DCI (134 mg; 0.7 mmol) and the mixture was stirred overnight. The solution was diluted with EtOAc and quenched -74- WO 99/47497 PCT/CA99/00212 with HCI The organic phase was dried over Na 2
SO
4 and the solvent removed. Purification by silica gel chromatography MeOH in
CH
2 C1 2 yielded 87 mg of the title compound.
1H NMR (CDC13) 8 2.40 (3H, 4.01 (2H, 6.33 (1H, 6.9- 7.3 (8H, 7.49 (1H, 7.61 (1H, 7.89 (1H, s) and 8.03 (1H, The product was converted to the sodium salt with 1 equivalent of NaOH and freeze dried.
Elemental analysis calcd. for C 21
H,
1 NNaO 3
S
3 .1/2H 2 0: C, 54.77; H, 4.13; N, 3.04; S, 20.88; Found: C, 54.55; H, 4.01; N, 3.06; S, 20.58.
EXAMPLE 2 N-((E)-3-{2-[(3-METHYL-1H-1-INDOLYL)METHYL]PHENYL)-2- PROPENOYL)-2-THIOPHENESULFONAMIDE (3) Step 1: Ethyl (E)-3-{2-[(3-methvl-1H-l-indolvl)methvlp henyll-2propenoate To benzylic bromide (400 mg, 1.49 mmol) of step 2 in example 1 and skatole (200mg, 1.51 mmol) in 6 mL of DMF was added portionwise 1.6 equivalent of NaH. The reaction mixture was left for 6 h and quenched with NH 4 OAc and diluted with EtOAc. The organic phase was dried over Na2SO4, filtered and the solvent removed.
Purification by silica gel chromatography (10% EtOAc inhexane) yielded 260mg of the title compound.
1 H NMR (CDC13) 5 1.2 (3H, 2.3 (3H, 4.25 (2H, 5.4 (2H, 6.35 (1H, 6.65 (1H, 6.8 (1H, 7.1-7.3 (5H, 7.56 (2H, d) and 7.97 (1H, d).
Step 2: (E)-3-12-[(3-methyl-1H-l-indolvl)methyllphenvl1-2-propenoic acid The hydrolysis of the previous ester (260 mg) was done according to Step 4 of example 1 to yield 212 mg of the title compound.
HRMS calcd. for C 1 9
H,
1 NO, H 292.1337; Found: 292.1337.
Step 3: N2-((E)-3-12-[(3-methvl-1H-1-indolvl)methylphenvll-2-propenoyl)- 2-thiophenesulfonamide (3) WO 99/47497 PCT/CA99/00212 The coupling reaction of the previous acid (196 mg; 0.67 mmol) was done according to step 5 of example 1 to yield 134 mg of the title compound.
'H NMR (acetone-d 6 8 2.39 (3H, 5.57 (2H, 6.65 (2H, m), 7.03 (3H, 7.27 (4H, 7.5 (1H, 7.63 (1H, 7.87 (1H, 7.95 (1H, s) and 8.14 (1H, d).
HRMS calcd. for C 2 3
H
20
N
2 0S 2 H 437.0994; Found: 437.0992.
EXAMPLE 3 N-{(E)-3-[2-(2-NAPHTHYLMETHYL)PHENYL]-2-PROPENOYL}-2- THIOPHENESULFONAMIDE (4) Step 1: Ethyl 2-(2-naphthvlmethvl)phenyll-2-propenoate The benzyl bromide (500 mg) of example 1, step 2 was treated with 2-naphthylboronic acid according to the same procedure previously described to yield 360 mg of the title compound.
'H NMR (CDC1 3 1.30 (3H, 4.27(2H, 4.33 (2H, 6.48 (1H, 7.2-7.4 (4H, 7.45 (2H, 7.55 (1H, 7.62 (1H, 7.8 (3H, m) and 8.15 (1H, d).
Step 2: (E)-3-[2-(2-naphthvlmethvl)phenvll-2-propenoic acid The hydrolysis of the previous ester (300 mg) was done according to Step 4 of example 1 to yield 202 mg of the title compound.
'H NMR (CDC1) 8 4.29 (2H, 6.32 (1H, 7.2-7.4 (6H, m), 7.5 (1H, 7.62 (1H, 7.73 (3H, m) and 8.19 (1H, d).
Step3: [2-(2-naphthvlmethyl)phenvll-2-propenoyll-2thiophenesulfonamide (4) The coupling reaction of the previous acid (100 mg; 0.35 mmol) was done according to step 5 of example 1 to yield 60 mg of the title compound.
1H NMR (CDCI 3 8 4.24 (2H, 6.31 (1H, 7.02 (1H, m), 7.15-7.8 (12H, 7.84 (1H, m) and 8.08 (1H, d).
-76- WO 99/47497 of NaOH.
PCT/CA99/00212 The acid was converted to the sodium salt with 1 equivalent Elemental analysis calcd. for C 24 HiNNaO3S 2
.H
2 0: C, 60.87; H, 4.22; N, 2.96; S, 13.54; Found: C, 60.36; H, 4.25; N, 3.29; S, 12.53.
-77- WO 99/47497 PCT/CA99/00212 EXAMPLE 4 N-((E)-3-[2-(3,4-DICHLOROBENZYL)PHENYL]-2-PROPENOYL)-2- THIOPHENESULFONAMIDE (8) Step 1: Ethyl (E)-3-[2-(3.4-dichlorobenzvl)phenvl-2-propenoate The benzyl bromide (500 mg) of example 1, step 2 was treated with 3,4-dichlorobenzeneboronic acid according to the same procedure described in step 3 of example 1 to yield 410 mg of the title compound.
'H NMR (CDCl,) 8 1.30 (3H, 4.03 (2H, 4.23 (2H, 6.28 (1H, 6.90 (1H, dd), 7.1-7.4 (5H, 7.57 (1H, d) and 7.89 (1H, d).
Step 2: (E)-3-[2-(3.4-dichlorobenzyl)phenvl -2-propenoic acid The hydrolysis of the previous ester (400 mg) was done according to Step 4 of example 1 to yield 296 mg of the title compound.
'H NMR (CDC1 3 8 4.07 (2H, 6.31 (1H, 6.93 (1H, dd), 7.1- 7.4 (5H, 7.50 (1H, d) and 7.99 (1H, d).
Step 3: N-[(E)-3-[2-(3.4-dichlorobenzvl)phenyll-2-propenovyl-2thiophenesulfonamide (8) The coupling reaction of the previous acid (170 mg; 0.55 mmol) was done according to step 5 of example 1 to yield 110 mg of the title compound.
'H NMR (CDC13) 5 4.07 (2H, 6.33 (1H, 6.85 (1H, 7.07 (3H, 7.24 (2H, 7.32 (1H, 7.53 (1H, 7.63 (1H, 7.88 (1H, d) and 7.97 (1H, d).
The acid was converted to the sodium salt with 1 equivalent of NaOH.
Elemental analysis calcd. for C 20
H
14 C1 2 NNaO 3
S
2 .1/2H 2 0: C, 49.7; H, 3.1; N, 2.9; S, 13.27; Found: C, 49.46; H, 2.9; N, 2.86; S, 13.73; -78- WO 99/47497 PCT/CA99/00212 EXAMPLE N-((E)-3-{2-[(2-NAPHTHYLOXY)METHYL]PHENYL)-2-PROPENOYL)-2- THIOPHENESULFONAMIDE Step 1: Ethyl naphthvloxv)methyllphenyll-2-propenoate The benzyl bromide (250 mg, 0.93 mmol) of step 2 in example 1 and 2-naphthol (147 mg) in 5 mL of DMF were treated with cesium carbonate (394 mg) at 40 "C for 12 h. The mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over Na2SO4, filtered and the solvent removed. Purification by silica gel chromatography (10% EtOAc in hexane) yielded 245 mg of the title compound.
'H NMR (CDC1,) 5 1.2 (3H, 4.22 (2H, 5.28 (2H, 6.41 (1H, 7.22 (2H, 7.3-7.5 (4H, 7.55 (1H, 7.64 (1H, 7.75 (3H, m) and 8.05 (1H, d).
Step 2: (E)-3-{2-[naphthvloxv)methvllphenyl)-2-propenoic acid Hydrolysis of the previous ester (245 mg, 0.74 mmol) was done according to step 4 of example 1 to yield 185 mg of the title compound.
'H NMR (CDCl,) 6 5.27 (2H, 6.45 (1H, 7.15-7.25 (2H, m), 7.32 (1H, 7.42 (3H, 7.55 (1H, 7.67 (1H, 7.77 (3H, m) and 8.11 (1H, d).
Step 3: [(2-naphthvloxv)methvllphenvll-2-propenovl)-2thiophenesulfonamide The coupling reaction of the previous acid (150 mg; 0.49 mmol) was done according to step 5 of example 1 to yield 77 mg of the title compound.
'H NMR (CDC13) 5.2 (2H, 6.39 (1H, 7.02 (1H, 7.1- 7.2 (2H, 7.3-7.4 (4H, 7.53 (3H, 7.71 (3H, 7.83 (1H, s) and 8.07 (1H, d).
The product was converted to the sodium salt with 1 equivalent of NaOH.
-79- WO 99/47497 PCT/CA99/00212 Elemental analysis calcd. for C 24
H
2 8 NNaO 4
S
2 .3/2H 2 0: C, 57.82; H,4.21; N, 2.81; Found: C, 58.31; H, 3.96; N, 2.91.
EXAMPLE 6 N-{(E)-3-[2-(2-NAPHTHYLSULFINYL)PHENYL]-2-PROPENOYL)-2- THIOPHENESULFONAMIDE (21) Step 1: 2-(2-naphthylthio)benzaldehvde A mixture of 2-thionaphthol (5.29 g; 33 mmol), 2fluorobenzaldehyde (3.73 g; 33 mmol) and potassium carbonate (4.57 g; 33 mmol) in 28 mL of iso-propanol was heated to reflux for 12 h. The mixture was cooled to diluted with water and filtered. The solution was diluted with EtOAc and washed with water, brine and dry over MgSO 4 The crude product (7.9 g) was used as is for the next step.
1H NMR (CDCl 3 5 7.07 (1H, 7.32 (2H, 7.42 (1H, 7.51 (2H, 7.78 (1H, 7.83 (2H, 7.88 (1H, 7.95 (1H, s) and 10.39 (1H, s).
Step 2: Ethyl (E)-3-[2-(2-naphthvlthio)phenvl-2-propenoate The previous aldehyde (7.72 g; 29.2 mmol) was converted to the ethyl ester according to step 1 of example 1 to furnish 6.36 g of the title compound.
'H NMR (CDC13) 5 1.24 (3H, 4.21 (2H, 6.36 (1H, 7.28 (4H, 7.42 (2H, 7.61 (1H, 7.72 (4H, m) and 8.28 (1H, d).
Step 3: Ethyl (E)-3-[2-(2-naphthylsulfinvl)phenvll-2-propenoate The previous ester (3.00 g; 8.97 mmol) in 45 mL of dichloromethane was treated with 1.1 equivalent of mCPBA at 0 °C for 1 h. The mixture was quenched with sodium thiosulfite and extracted with EtOAc. The organic phase was dry over Na 2
SO
4 and the crude purified by silica gel chromatography (30% EtOAc in hexane) to yield 2.35 g of the title compound.
'H NMR (CDC13) 8 1.34 (3H, 4.27 (2H, 6.26 (1H, 7.42 (2H, 7.53 (4H, 7.77 (2H, 7.88 (2H, 8.07 (2H, 8.22 (1H, s) and 8.28 (2H, m).
WO 99/47497 PCT/CA99/00212 Step 4: Ethyl (E)-3-[2-(2-naphthvlsulfinvl)phenvl-2-propenoic acid The previous ester (1.20 g; 3.43mmol) was hydrolyzed according to the procedure of step 4 of example 1 to yield 1.08 g of the title compound.
'H NMR (methanol-d 6 8 6.23 (1H, 7.33 (1H, dd), 7.45 (3H, 7.53 (1H, 7.62 (1H, 7.8 (3H, 7.98 (1H, 8.05 (1H, d) and 8.27 (1H, s).
Step 5: 2-((E)-3-12-(2-naphthvlsulfinvl)phenvll-2-propenoyvl-2thiophenesulfonamide (21) The coupling reaction of the previous acid (500 mg; 1.55 mmol) was done according to step 5 of example 1 to yield 416 mg of the title compound.
'H NMR (methanol-d 6 5 6.19 (1H, 7.1 (1H, 7.22 (1H, dd), 7.45 (3H, 7.55 (2H, 7.67 (1H, 7.72-7.85 (4H, 7.99 (1H, d), 8.1 (1H, d) and 8.17 (1H, s).
The sodium salt was prepared with 1N NaOH. Elemental analysis calcd. for C 23
H
16 NNaO 4
S
3 .1/2H 2 0: C, 55.36; H,3.40; N, 2.81; S, 19.27; Found: C,55.00; H, 3.62; N, 2.81; S, 18.18.
EXAMPLE 7 N-{(E)-3-[2-(2-NAPHTHYLOXY)PHENYL]-2-PROPENOYL)-2- THIOPHENESULFONAMIDE (28) Step 1: Ethyl 2-(2-naphthyloxv)phenvll-2-propenoate 2-fluoro benzaldehyde (3.0 g; 24.2 mmol), 2-naphthol (24.2 mmol) and potassium carbonate (26.6 mmol) were heated at reflux in dimethyl acetamide for 2 h. The mixture was cooled to diluted with EtOAc and washed with water and brine. The organic phase was dried over Na2SO4, filtered and the solvent removed. Purification by silica gel chromatography (10% EtOAc in hexane) yielded 3.4 g of the title compound.
-81- WO 99/47497 PCT/CA99/00212 'H NMR (CDCl 3 866.93 (1H, 7.17-7.23 (1H, mn), 7.28 (1H, dd), 7.37 (1H, 7.37 (3H, in), 7.7 (1H, 7.84 (2H, in), 7.94 (1H, d) and 10.53 (1H, s).
Step 2: Ethyl r2-(2-naphthvloxv)phenyll -2-p2ropenoate The previous aldehyde (2.00 g; 8.0 inmol) was converted to the title compound according to step 1 of example 1 to yield 2.52 g 1 11 NMR (CDCl 3 6 1.25 (3H, 4.21 (2H, 6.55 (1H, 6.9 (1H, 7.15 (1H, 7.25 (3H, mn), 7.42 (2H, in), 7.65 (2H, in), 7.83 (2H, t) and 8.02 (1H, d).
Step 3: [2-(2-naphthyloxv)pheniyll -2-p2ropenoic acid The previous ester (2.52 g; 7.9 mmol) was hydrolyzed according to the procedure of step 4 of example 1 to yield 1.57 g of the title compound.
'H NMR (CDCl 3 6 6.62 (1H, 7.03 (1H, 7.2-7.5 (6H, in), 7.78 (1H, d) and 7.88-8.03 (4H, mn). HRMS calcd. for C 1 9 H1403 H+ 291.1021; Found: 291.1022.
Step 4: r2-(2-naphthylgxy)phenvfl -2-p2ropenoyl)-2thiophenesulfonainide (28) The coupling reaction of the previous acid (1.00 g; 3.4 inmol) was done according to step 5 of example 1 to yield 790 mng of the title compound.
'H NMR (CDCl 3 6 6.91 (1H, 6.97 (1H, 7.15(1H, dd), 7.24 (111, 7.29 1H, dd), 7.37 (1H, 7.40-7.55 (3H, in), 7.74-7.83 (2H, in), 7.92 (2H, in) and 7.99 (211, in).
The sodium salt was prepared with 1N NaOH. HRMS calcd. for C 23 Hl 6 NNaO 4
S
2 H' 458.0497; Found:458.0497.
EXAMPLE 8 THIOPHENE-2-SULFONYL CARBAMIC ACID NAPHTHYLSULFONYL)PHENYL1 METHYL ESTER (31) Step 1: [2-(2-naphthylthio)phenyll methanol -82- WO 99/47497 PCT/CA99/00212 To 2-(2-naphthylthio) benzaldehyde (7.24 g; 27.4 mmol from Example 6, step 1) in 70 mL of methanol and 30 mL of THF at 0 oC was added NaBH 4 (54.8 mml) portionwise. After lh at 0 oC, the solution was brought to r.t. and quenched with water. After dilution with EtOAc, the solution was washed with water and brine. The organic phase was dry over Na2SO4, filtered and the crude purified by silica gel chromatography to yield 6.71 g of the title compound.
'H NMR (acetone-d e 5 4.29 (1H, 4.7 (2H, 7.29 (2H, m), 7.35-7.52 (4H, 7.71 (2H, 7.77 (1H, m) and 7.83 (2H, m).
Step 2: [2-(2-Naphthvlsulfonvl)phenvllmethanol To the previous sulfide (500 mg; 1.88 mmol) in 8 mL of dichloromethane at 0 °C was added m-CPBA (5.64 mmol) and let stirred for 2 h. The mixture was diluted with EtOAc and washed with NaOH (1N) and brine. The organic phase was dry over Na2SO, filtered and the crude purified by silica gel chromatography (40% EtOAc in hexane) to yield 390 mg of the title compound.
'H NMR (acetone-d 6 8 4.37 (1H, 4,9 (2H, 7.57 (1H, dt), 7.65-7.80 (4H, 7.82 (1H, 8.0-8.1 (2H, 8.2 (2H, m) and 8.63 (1H, s).
Step 3: 2-Thiophenesulfonyl isocyanate A mixture of 2-thiophenesulfonylamide (1.5 g) and oxalyl chloride (6 mL) in 10 mL of 1,2-dichloroethane was refluxed for 14h. The solvent was removed under vacuum and the crude used as is for the next step.
Step 4: To the alcohol of step 2 (250 mg; 0.84 mmol) in ether at 0 °C was added the previous isocyanate (2 equivalent) and let stirred lh at 0 The solution was quenched with water and extracted with EtOAc.
The organic phase dry over Na 2
SO
4 filtered and the crude purified by silica gel chromatography CH3OH in CH 2 C1 2 to yield 300 mg of the title compound.
-83- WO 99/47497 PCT/CA99/00212 'H NMR (CDC1 3 8 5.55 (2H, 7.08 (1H, in), 7.55-7.72 (6H, in), 7.82 (2H, in), 8.0 (1H, 8.07 (1H, 8.2 (2H, m) and 8.66 (1H, s).
The sodium salt was prepared with 1N NaGH.
Elemental analysis calcd. for C 2 2
HI
6 NNaO 6
S
3 .2H 2 0: C, 48.44; H,3.67; N, 2.57; S, 17.63; Found: C,48.86; H, 3.13; N, 2.63; S, 16.46.
-84- WO 99/47497 PCT/CA99/00212 EXAMPLE 9 2-NAPHTHIYLMETHYL)PHENYL] CYCLOPROPYL) CARBONYL-2-THIOPHENESULFONAMIDE Step 1: Ethyl 2- [2-(2-naphthylmethyl )phenvll 1 cclopropanecarboxlate The ethyl ester (300 mg; 0.95 mmol) of step 1 in example 3 and Pd(OAc) 2 (10 mg) were treated with diazomethane at 0' C for lh.
The solvent was removed and the crude oil purified by silica gel chromatography EtOAc in hexane) to yield 300 mg of the title compound.
'H NMR (CDCl 3 81.1 (3H, 1.27 (1H, in), 1.45 (1H, mn), 1.7 (1H, in), 2.53 (1H, mn), 3.98 (2H, in), 4.29 (2H, 7.0 (1H, mn), 7.18 (3H, in), 7.27 (1H, in), 7.39 (2H, in), 7.48 (1H, s) and 7.75 (3H, mn).
Step 2: 2- [2-(2-naphthvlmethyl)phenvll -cyclopropanecarboxvlic acid The previous ester (300 mg; 0.91 mmol) was hydrolyzed according to the procedure of step 4 of example 1 to yield 230 mg of the title compound.
'H NMR (CDCl 3 81.45 (1H, in), 1.6 (1H, mn), 1.8 (1H, in), 2.67 (1H, in), 4.33 (2H, 7.1 (1H, in), 7.24 (4H, in), 7.41 (2H, in), 7.58 (1H, s) and 7.78 (3H, in).
Step 3: F2-(2-naphthylmethyl)phenvll cvclopropvyll carbonvl-2thiophenesulfonamide The coupling reaction of the previous acid (230 ing; 0.76 iniol) was done according to step 5 of example 1 to yield 100 mg of the title compound.
'H NMR (CDC1 3 81.32 (1H, in), 1.48 (1H, mn), 1.63 (1H, in), 2.6 (1H, in), 4.13 (2H, 6.97 (2H, in), 7.12 (4H, in), 7.38 (3H, in), 7.52 (1H, 7.65 (2H, in) and 7.79 (2H, in). The sodium salt was prepared with 1N NaOH. Elemental analysis calcd. for C 25
H
20 NNaO 3
S
2 1/2H 2 0: C, 62.75; H, 4.39; N, 2.93; S, 13.4; Found: 0,62.25; H, 4.24; N, 3.02; S, 12.15.
WO 99/47497 PCT/CA99/00212 EXAMPLE N-((E)-3-(2-(6-BENZYLOXY-2-NAPHTHYL)METHYL)PHENYL)-2- PROPENOYL)-5-BROMO-2-METHOXYBENZENESULFONAMIDE (46) 3 2 6 -benzvloxv-2-naphthyl)methvl)phenvl-2-propenoic acid Step 1: [(6-bromo-2-naphthvl)oxv1(phenvl)methane To a mixture of 6-bromo-2-naphthol (1.99 g, 8.9 mmol) and benzyl bromide (1.2 ml, 1.1 equiv.) in DMF (18 ml) at o0C was added a suspension of NaH 80% in oil (324 mg, 1.2 equiv.) and the mixture was stirred at 0°C for an hour and at r.t. for another hour. After addition of half saturated NH 4 C1, the product was extracted in i-PrOAc, washed with 1 N HC1, dried over Na 2
SO
4 and concentrated to yield 2.84 g of an oil.
Step 2: 6 -benzyloxv-2-naphthaleneboronic acid To a solution of the previous bromide (940 mg, 3.00 mmol) in THF (15 ml) at -78 0 C was added n-BuLi 1.6 M in hexanes (2.2 ml, 1.2 equiv.) and the mixture was stirred at -78 0 C for 15 min. Tri-isopropyl borate (0.97 ml, 1.4 equiv.) was added and the reaction mixture was warmed to r.t. After addition of 2 N HC1, the product was extracted in EtOAc, dried over Na 2
SO
4 and concentrated to yield a solid. This solid was washed with ether:hexane 1:1 to yield 679 mg of pure material.
1 H NMR (Acetone-ds:DMSO-d 6 8 5.27 (2H, 7.22 (1H, dd), 7.33 (1H, dd), 7.40 (3H, 7.54 (2H, 7.63 (2H, 7.72 (1H, 7.83 (1H, 7.90 (1H, 8.36 (1H, s).
Step 3: Ethyl (E)-3-(2-1[6-benzvloxv)-2-naphthvllmethvllphenvl)-2propenoate A mixture of the previous boronic acid (1.05 g, 3.8 mmol), Pd(Ph 3
P)
4 (185 mg), the benzylic bromide of step 2 in example 1 (1.07 g, mmol), 2 M aq. Na 2
CO
3 (4 ml) and toluene (8 ml) was degazed and stirred at 1000 C under nitrogen for 4 h. After addition of half saturated
NH
4 C1, the product was extracted in EtOAc, dried over Na2SO4 and concentrated. Purification by flash chromatography with EtOAc:toluene:hexane 2.5:75:25 yielded 1.17 g of the title compound as an oil.
-86- WO 9-9/47497 WO 9.947497PCT/CA99/00212 Step 4: [6-(benzylox)-2-naphthyll methyl) phenvl)-2-Rppenoic acid The previous ester was hydrolyzed according to the procedure of step 4 of example 1 to yield the title compound.
Step 5: 5-Bromo-2-methoxvbenzenesulfonamide To 5-bromo-2-methoxybenzenesulfonyl chloride (45g; 157.6 mmol, from Lancaster Chemical) at 0 0 C in THF was added concentrated NHQH (42.5 mL) and the reaction mixture was brought to r.t. for 2 h. The reaction mixture was diluted with EtOAc, extracted with NaHCO 3 brine, and the organic phase was dried over MgSO 4 The solvent was removed to give the title compound.
Step 6: 3 2 6 -benzyloxy-2-naphthl)methl)phenl)-2-1propenol).
.5-bromo-2-methoxybenzenesulfonamide (46) To the acid from step 5 (190 mg, 0.482 mmol) in CH 2 C1 2 was added DMF (10 gL) and oxalyl chloride (60 pi) at 00 C and the mixture was warmed to r.t. for an hour and concentrated to dryness. The resulting acid chloride was redissolved in CH 2 Cl 2 :THF 1:1 (10 mL) and bromo-2-methoxybenzenesulfonamide (154 mg, 1.2 equiv., from step 6) and Et 3 N (135 p1, 2 equiv.) were added at 0 0 C. The mixture was then warmed to r.t. for an hour, 0.5 N HCl was added and the product was extracted in i-PrOAc, dried over Na 2
SO
4 and purified by flash chromatography with EtOAc:toluene:acetic acid 20:80:1 to yield 93 mg of a white solid.
'H NMR (CD Cl 3 MS (A-PCI, neg.) 643.3, 641.8, 640.0 393.2.
EXAMPLE 11 [2-NAPHTHYLMETHYL)PHENYL)] BROMO-2-METHOXY-1-BENZENESULFONAVHDE (301) Step 1: f2-napht-hylmethl)pheny )1 -2-propenoyll-5-bromo-2methoxy- 1-benzenesulfonamide (301) -87 WO 99/47497 PCT/CA99/00212 The carboxylic acid (400 mg; 1.22 mmol) of example 3 step 2 was coupled with 5-bromo-2-methoxy-l-benzenesulfonyl chloride according to the procedure of step 5 in example 1 to yield 284 mg of the title compound.
'H NMR (acetone-d 6 -DMSO-d 6 8 3.85 (3H, 4.31 (2H, s), 6.65 (1H, 7.15 (1H, 7.3 (1H, 7.35-7.50 (4H, 7.55-7.65 (2H, m), 7.7-7.9 (5H, m) and 8.01 (1H, d).
The acid was converted to the sodium salt with 1 equivalent of NaOH. Elemental analysis calcd. for C 27
H
21 BrNNaO 4 S.1/2H 2 0: C, 57.15; H,3.88; N, 2.47; Found: C, 56.88; H, 3.73; N, 2.52.
EXAMPLE 12 N-((E)-3-[5-CHLORO-2-(2-NAPHTHYLMETHYL)PHENYL]-2- PROPENOYLI-2-THIOPHENESULFONAMIDE (303) Step 1: 5-chloro-2-methylbenzaldehyde To a solution of 2-bromo-4-chlorotoluene 20.0 g; 97.3 mmol) in 300 mL of THF at -78 °C was added dropwise a 2.5 M solution of n-BuLi (102.2 mmol). After 30 min of stirring at that temperature, 1formylpiperidine (11.4 mL) in 10 mL of THF was added and the solution left for 1 h. It was brought to 0 °C quenched with NH 4 OAc and diluted with EtOAc. The organic phase was dried over Na2SO4, filtered and the solvent removed to yield 13.3 g of the title compound.
1H NMR (CDC1,) 5 2.6 (3H, 7.15 (1H, 7.4 (1H, 7.75 (1H, s) and 10.2 (1H, s).
Step 2: Ethyl (E)-3-(5-chloro-2-methvlphenvl)-2-propenoate The previous aldehyde (13.3 g; 86.0 mmol) was converted to the ethyl cinnamate according to step 1 of example 1 to yield 16.67 g.
'H NMR (CDC1 3 8 1.2 (3H, 2.26 (3H, 4.15 (2H, 6.21 (1H, 6.99 (1H, 7.13 (2H, 7.39 (1H, s) and 7.73 (1H, d).
Step 3: Ethyl (E)-3-[2-(bromomethyl)-5-chlorophenvl -2-propenoate -88- WO 99/47497 PCT/CA99/00212 The previous ester (16.66 g; 74.1 mmol) was converted to the benzylic bromide according to step 2 of example 1 to yield 9.0 g of the title compound.
'H NMR (CDC1) 8 1,2 (3H, 4.25 (2H, 4.5 (2H, 6.4 (1H, 7.28 (2H, 7.55 (1H, s) and 7.95 (1H, d).
Step 4: Ethyl (E)-3-[5-chloro-2-(2-naphthvlmethvl)phenyll-2-propenoate The previous benzylic bromide was coupled in a Suzuki type reaction with 2-naphthylboronic acid according to step 3 of example 1 to yield 1.14 g of the title compound.
1H NMR (CDC1 3 8 1.15 (3H, 4.09 (2H, 4.12 (2H, 6.2 (1H, 7.03 (1H, 7.15 (2H, 7.3 (2H, 7.37 (1H, 7.45 (1H, s), 7.65 (3H, m) and 7.87 (1H, d).
Step 5: (E)-3-[5-chloro-2-(2-naphthylmethyl)phenyll-2-propenoic acid The hydrolysis of the previous ester (1.14 g) was done according to Step 4 of example 1 to yield 0.99 g of the title compound.
1H NMR (CDC1) 5 4.23 (2H, 6.31 (1H, 7.12 (1H, 7.22 (1H, 7.3 (1H, 7.42 (2H, 7.48 (1H, 7.59 (1H, 7.75 (3H, m) and 8.05 (1H, d).
Step 6: N-((E)-3-[5-chloro-2-(2-naphthvlmethvl)phenvl-2-propenoyll-2thiophenesulfonamide (303) The coupling reaction of the previous acid (400 mg; 1.22 mmol) was done according to step 5 of example 1 to yield 272 mg of the title compound.
'H NMR (acetone-d 6 8 4.25 (2H, 6.58 (1H, 7.0 (1H, t), 7.23 (2H, 7.33 (1H, 7.39 (2H, 7.5-7.6 (2H, 7.55 (5H, m) 7.86 (1H, m) and 8.04 (1H, d).
The product was converted to the sodium salt with 1 equivalent of NaOH. Elemental analysis calcd. for
C
2 4 H,1ClNNaO3S2.1/2H 2 O: C, 57.76; H,3.64; N, 2.81; S, 12.84; Found: C, 57.78; H, 3.62; N, 2.86; S, 12.85.
-89- WO 99/47497 PCT/CA99/00212 EXAMPLE 13 (E)-3-{4-CHLORO-2-[6-FLUORO-2-NAPHTHYL)METHYL]PHENYL)-2- PROPENOIC ACID SODIUM SALT (457) Step 1: Ethyl 3 -(5-chloro-2-methvlphenvl)-2-propenoate To 2-bromo-4-chloro toluene 2 0.0g; 97.3 mmol) in 300 mL of THF at -78 oC was added n-BuLi 2.5 M (40.8 mL) dropwise. After min. 1-formylpiperidine (11.4 mL; 103.0 mmol) in 10 mL of THF was added dropwise. After 30 min the reaction mixture was brought to 0 C and quenched with HC1 and diluted with EtOAc. The organic phase was collected, dry and the solvent evaporated to yield 13.3g (89%) of 5-chloro-2-methylbenzaldehyde. This crude aldehyde was mixed with 1.1 equivalent of triethyl phosphonoacetate in THF. Sodium hydride (1.3 equivalent was added portionwise and 1 h later the reaction was quenched with 25% NH4C1. The reaction mixture was diluted with EtOAc and the organic phase collected, dried and the solvent removed.
The crude oil was purified on a short pad of silica gel using 5% EtOAc in hexane to afford 16.67 g of the title compound.
Alternatively, this procedure can be done in one reaction vessel. At the end of the first step, the flask is brought to rt and the phosphonoacetate in THF is added.
1H NMR (CDC13) 8 1.21 (3H, 2.27 (3H, 4.15 (2H, 6.22 (1H, 6.95-7.15 (3H, 7.40 (1H, s) and 7.75 (1H, d).
Step 2: Ethyl(E)-3-12-(bromomethyl)-5-chlorophenvll -2-propenoate The bromination was done according to step 2 of example 1 to provide the title compound in 45% yield.
1H NMR (CDC13) 5 1.32 (3H, 4.27 (2H, 4.52 (2H, 6.43 (1H, 7.30 (2H, 7.55 (1H, s) and 7.93 (2H, d).
Step 3: 6-Fluoro-2-naphthol A solution of 2 -(4-fluorophenyl)acetyl chloride (5.0g; 29 mmol) in CH 2 C1 2 was added to AlC1 3 7 7 3g;58 mmol) in CH 2 C1 2 at -20 °C over 30 min. Trimethylsilyl acetylene 9 9 6g; 101.43 mmol) was added also over 30 min and stirred at -10 OC for lh. The mixture was poured in WO 99/47497 PCT/CA99/00212 ice and extracted with EtOAc. The organic phase was washed with water, NaHCO, and brine. After purification by gel silica chromatography (10% EtOAc in hexane) 2.43 g of 3-(trimethylsilyl)- 6-chloro-2-naphthol was collected. The desylilation was done with TFA in CH 2 C1, at rt overnight. Purification by gel silica chromatography EtOAc in hexane) afforded the title compound in 69% yield.
'H NMR (CDC1 3 6 7.10-7.20 (3H, 7.37 (1H, dd) and 7.65 (2H, m).
Step 4: Ethyl (E)-3-(4-chloro-2-[(6fluoro-2-naphthyl)methvllphenyll-2propenoate The naphthol of Step 3 was converted to the triflate with triflic anhydride/pyridine in CH 2 Cl 2 at 0 OC. This was coupled with the organozinc of the benzyl bromide of step 2 in example 13, with dppf and Pd(dba) 2 This yielded the title compound in 47% yield after purification by silica gel chromatography (10% EtOAc in hexane).
1H NMR (CDC1,) 8 1.25 (3H, 4.20 (2H, 6.30 (1H, 7.10- 7.27 (4H, 7.38 (1H, dd), 7.48 (1H, 7.57 (1H, dd), 7.66 (2H, m) and 7.95 (1H, d).
Step 5: (E)-3-{4-Chloro-2-[(6-fluoro-2-naphthyl)methyllphenvll-2propenoic acid. sodium salt The hydrolysis of the ester of Step 4 (1.03g; 2.7 mmol) was done according to step 4 of example 1 to yield 800mg of the title compound. The sodium salt was prepared with 1N NaOH.
1H NMR (CDC13) 8 4.21 (2H, 6.30 (1H, 7.10-7.40 (4H, 7.38 (1H, dd), 7.45 (1H, 7.58 (1H, 7.68 (2H, m) and 8.05 (1H, d).
LRMS for M-l= 339.
EXAMPLE 14 5-BROMO-N((E)-3-{5-CHLORO-2-[(6-FLUORO-2-NAPHTHYL- 2)METHYL]PHENYL}-2-PROPENOYL)-2- METHOXYBENZENESULFONAMIDE SODIUM SALT (378) -91- WO 99/47497PC/A/O21 PCT/CA99/00212 Step 1: 5-Bromo -N-((E)-3-15-chloro-2-[(6-fluoro-2naphthvl )methyll phenyfl -2-propenoyl)-2-methoxybenzenesulfonamjde The coupling reaction of the acid of Example 1 Step 5 with bromo-2-methoxybenzesulfonamide (500 mg; 1.47 mmol) was done according to step 5 of example 1 to yield 662 mg (7 of the title compound. The sodium salt was prepared with 1N NaOH.
1H NMR (DMSO-d6) 5 3.78 (3H, 4.22 (2H, 6.53 (1H, d), 7.17 (1H, 7.27 (1H, 7.35 (2H, in), 7.47 (1H, dd), 7.51 (1H, 7.58 (1H, 7.64 (1H, dd) and 7.75-7.90 (5H, in).
LRMS for M-1= 588.
EXAMPLE (E)-3-15-CHLORO-2- [(6-CHLORO-2-NAPHTHYL)METHYLIPHENYLI-2- PROPENOIC ACID SODIUM SALT (469) Step 1: 6-Chloro-2-naphthol The title compound was prepared from 2-(4fluorophenyl)acetyl chloride according to step 3 of example 13.
'H NMR (CDC1 3 8 7.10 (2H, in), 7.34 (1H, dd), 7.55-7.67 (2H, m) and 7.72 (1H, s).
Step 2: Ethyl (E)-3-{5-chloro-2- [(6-chloro-2-naphthyl)methvll pheny-1l-2propenoate The title compound was prepared according to step 4 of example 13 in 30% yield.
'H NMR (ODC1 3 8 1.23 (3H, 4.20 (4H, in), 6.29 (1H, 7.10 (1H, 7.22 (2H, in), 7.33 (1H, dd), 7.42 (1H, 7.53 (1H, 7.61 (2H, d), 7.70 (1H, s) and 7.91 (1H, d).
Step 3: {5-Chloro-2- [(6-chloro-2-naphthyl)inethyll phenyll-2propenoic acid, sodium salt The hydrolysis of the ester of Step 2 (620 mg; 1.6 mmol) was done according to step 4 of example 1 to yield 500mg of the title compound.
-92- WO 99/47497 PCT/CA99/00212 'H NMR (CDC1 3 5 4.22 (2H, 6.30 (1H, 7.15 (1H, d), 7.20-7.39 (3H, in), 7.43 (iR, 7.56 (1H, 7.62 (2H, 7.75 (1H, s) and 8.02 (1H, d).
Elemental analysis calcd for C 20
H
13 C1 2 NaO 2
.H
2 0 60.48; H, 3.78; Found C, 60.68, H, 3.63.
-93 WO 99/47497 PCT/CA99/0021 2 EXAMPLE 16 5-BROMO-N((E)-3-(5-CHLORO-2- [(6-CHLORO-2-NAPHTHYL- 2)METHYLIPHENYL}-2-PROPENOYL)-2- METHOXYBENZENESULFONAMVIDE. SODIUM SALT (450) Step 1: 5-Bromo -N-((E)-3-f5-chloro-2-[(6-chloro-2nap~hthyl)methvll phenvil 2 -propenoyl)-2-methoxybenzenesulfonamide The coupling reaction of the acid of Example 15 Step 3 (500 mg; 1.4 mmol) was done according to step 5 of example 1 with 2-methoxybenzesulfonamide to yield 662 mg of the title compound.
The sodium salt was prepared with 1N NaOH.
1H NMR (DMSO-d6) 8 3.78 (3H, 4.22 (2H, 6.53 (1H, d), 7.20 (1H, 7.30-7.40 (2H, in), 7.45 (2H, mn), 7.55 (1H, 7.59 (1H, 7.79 (3H, in), 7.85-7.92 (2H, m) and 7.98 (1H, d).
Elemental analysis calcd for C27H19BrCl2NNaO4S .2H20: C, 49.01; H, 3.33; N, 2.14; Found C, 48.89, H, 3.47; N, 2.11.
EXAMPLE 17 (E)-3-(5-CHLORO-2-{ [6-DIFLUOROMETHOXY)-2- NAPHTHYLIMETHYLIPHENYL-2-PROPENOIC ACID, SODIUM SALT (505)j Step 1: 6-Bromo-2-difluoromethoxvynaphthalene Methyl chlorodifluoroacetate (5.3 inL) was added dropwise to 6-broinonaphthol (10.25 g; 45.9 minol) and potassium carbonate (7.61g; 55.1 iniol) at 90 OC in 160 mL of DMF for 6 h. Purification by gel silica chromatography EtOAc in hexane) gave 4.80 g of the title compound.
1H NMR (CDCl3) 8 6.61 (1H, 7.31 (1H,dd), 7.48 (1H, d), 7.56 (1H, dd), 7.67 (1H, 7.72 (1H, d) and 8.01 (1H, d).
Step 2: Ethyl (E)-3-(5-chloro-2-{ r6-difluorometho,)-2nap~hthyllinethllphenyl)-2-propenoate -94 WO 99/47497 PCT/CA99/00212 The corresponding boronic acid of the previous halide was coupled according to step 3 of example 1 of the title compound in 57% yield.
1H NMR (CDCl3) 8 1.25 (3H, 4.22 (4H, in), 6.28 (1H1, d), 6.53 (1H1, 7.11 (MH) 7.25 (211, in), 7.45 (2H, 7.55 (1H, 7.72 (2H, t) and 7.92 (1H1, d).
Step 3: (E)-3-(5-Chloro-2-{ [6-difluoromethoxvy)-2-naphthvll methyl Iphenvl)-.
2-propenoic acid, sodium salt The hydrolysis of the ester of Step 2 (1.9 g; 4.7 minol) was done according to step 4 of example 1 to yield 6 00mg of the title compound.
1H NMR of sodium salt (DMSO-d6) 8 4.20 (2H, 6.29 (1H1, 7.10-7.40 (611, in), 7.58 (311, m) and 8.84 (2H, t).
HRMS calc'd for C21H1ztO3F2ClNa +11= 411.0575; Found: 411.0577.
EXAMPLE 18 5-BROMO-N-[(E)-3-(5-CHLORO-2-{ [6-DIFLUOROMETHOXY)-2- NAPHTHYLMETHYL)-2-PROPENOYL] -2- METHOXYBENZENESULFONAMIDE, SODIUM SALT (447) Step 1: 5-Bromo [(E)-3-(5-chloro-2-{ I6-difluoromethoxcy)-2naphthyll methvllphenl)-2-propenovll -2-methoxybenzennesulfonamide The coupling reaction of the acid of Example 17 Step 3 (1.00g; 2.57 inmol) was done according to step 5 of example 1 with bromo-2-methoxybenzesulfonamide to yield 915 mng of the title compound. The sodium salt was prepared with IN NaOH.
111 NMR of sodium salt DMSO-d6) 8 3.66 (3H1, 4.18 (211, 6.36 (1H1, 6.92 (1H1, 7.20-7.35 (511, mn), 7.48 (211, in), 7.55-7.65 (311 mn) and 7.80 (311, in).
LRMS for M-1= 634.
WO 99/47497 WO 9947497PCT/CA99/0021 2 EXAMPLE 19 (E)-3-[2-(3,4-DICHLOROBENZYL)-5-CHLOROPHENYL] -2-PROPENOIC ACID, SODIUM SALT (535) Step 1: Ethyl f2-(3 4 -dichlorobenzvb)-5-chlorophenvl)-2-propenoate The benzyl bromide of step 2 of example 13 was treated with 3,4-dichlorobenzeneboronic acid according to the procedure described in step 3 of example 1 to yield the title compound in 67% Yield.
1H NMR (CDCl3) 8 1.30 (3H, 4.00 (2H, 4.23 (2H, 6.30 (1H, 6.90 (1H,dd), 7.09 (1H, 7.15 (1H, 7.28 (1H, in), 7.32 (1H, d), 7.55 (1H, d) and 7.79 (1H, d).
Step 2: 12-(3 4 -Dichlorobenzvl)-5-chlorophenl)-2-,propenoic acid, sodium salt The hydrolysis of the ester of Step 1 (1.00 g; 2.7 inmol) was done according to step 4 of example 1 to yield 907 mg of the title compound.
1H NMR (CDCl3) 8 3.95 (2H, 6.30 (1H, 6.86 (1H, d), 7.08 (2H, in), 7.32 (2H, mn), 7.55 (1H, s) and 7.90 (1H, d).
LRMS for M-1= 339.
EXAMPLE 5-BROMO-N-(E)-3-[5-CHLORO-2-(3,4-DICHLOROBENZYL)pHENYL -2- PROPENOYLI-2-METHOXYBEZENESULFONAMIDE, SODIUM SALT (421) Step 1: 5-Bromo-N-f(E)-3- [5-chloro-2-)3 .4-dichlorobenzvl)p2henyll -2p2ropenoyll-2-methoxybenzenesulfonamide The coupling reaction of the acid of Example 19 Step 2 (0.600 g; 1.75 inmol) was done according to step 5 of example 1 with 5-bromo-2methoxybenzesulfonamide to yield 548 mg of the title compound.
The sodium salt was prepared with 1N NaOH.
-96- WO 99/47497 PCT/CA99/002 12 1H NMR (DMSO-d6) 8 3.85 (3H, 4.10 (2H, 6.54 (1H, s), 7.01 (1H, 7.22 (1H, 7.32 (2H, in), 7.40-7.50 (2H, in), 7.56 (1H, 7.67 (1H, 7.86 (1H, 7.91 (1H, s) and 12.37 (1J, s).
LRMS for M-1= 586.
EXAMPLE 21 5-BROMO-N-I(E)-3- [4-GHLORO-2-(2-NAPHTH-YLMETHYL)PHENYL] -2- PROPENOYLI-2-METHOXYBENZENESULFONAMIDE. SODIUM SALT (449) Step 1: Ethyl (E)-3-{4-chloro-2- R2-naphthylmethyl)phenyll -2-propenoate toluene (20.0 g) was converted to the corresponding aldehyde and then to the cinnamate according to step 1 of example 13. This cinnamate was converted to the benzylic bromide according to step 2 of example 1 and coupled via a Suzuki coupling reaction according to step 3 of example 1 with naphthalene boronic acid to yield the title compound.
'H NMR (ODC1 3 8 1.30 (3H, 4.22 (4H, in), 6.29 (1H, d), 7.15-7.27 (3H, in), 7.42 (2H, in), 7.52 (2H, in), 7.75 (3H, m) and 7.99 (1H, d).
Step 2: (E)-3-14-Chloro-2- [(2-naphthylmethyl)phenvl 1-2-prop~enoic acid (530) The hydrolysis of the ester of Step 1 (0.56 g; 1.57 inmol) was done according to step 4 of example 1 to yield 450 mng of the title compound.
'H NMR (CDCl 3 8 4.24 (2H, 6.30 (1H, 7.20-7.30 (3H, in), 7.42 (2H, in), 7.51 (2H, in), 7.75 (311, in) and 8.09 (1H, d).
LRMS for M-1= 321.
Step 3: 5-Bromo-N-f [(E)-3-[4-chloro-2-(2naphthylmethvl)phenvfl p2rop~enoyll-2-methoxvbenzenesulfonamide The coupling reaction of the acid of Step 2 (0.296 g; 0.89 mmol) was done according to step 5 of example 1 with 5-broino-2inethoxybenzesulfonainide to yield 213 mng of the title compound.
The sodium salt was prepared with 1N NaOH.
-97 WO 99/47497 PCT/CA99/002 12 'H NMR (ACETONE-MEOH-d 6 8 3.70 (3H, 4.20 (2H, s), 6.44 (1H, 6.95 (2H, in), 7.25 (3H, in), 7.40 (2H, mn), 7.55 (3H, in), 7.75 (3H, in), 7.95 (1H, d) and 8.02 (1H, d).
LRMS for M-1= 568.
-98 WO 99/47497 WO 9947497PCT/CA99/002 12 EXAMPLE 22 [5-METHOXY-2-(2-NAPHTHMETHYL)PHENYL] -2-PROPENOIC ACID, SODIUM SALT (534) Step 1: (2-Bromo-4-methoxvphenyl)(2-naphthyl)methanone AIC13 (17.48 g; 131.1 mmol) was added portionwise to a mixture of 3-bromocresol (16.04 g; 87.4 mmol) and 2-naphthoyl chloride (25.00 g; 131.1 mmol) in 50 mL of CHC13 gave 14.0 g of the title compound.
1H NMR (CDCl3) 8 3.78 (3H, 6.92 (1H, dd), 7.19 (1H, d), 7.38 (1H, 7.50 (1H, 7.59 (1H, 7.89 (3H, in), 7.95 (1H, dd) and 8.18 (1H, s).
Step 2: 2-(2-Bromo-4-methoxvbenzvl)naphtalene To the methanone of Step 1 (14.0 g) and triethylsilane mL) in 15 mL of CHC13 was added TFA and was heated to overnight. The solution was cooled and quenched with NaOH (2N) to provide the title compound in 82% yield.
1H NMR (CDC13) 8 3.75 (3H, 4.20 (2H, 6.75 (1H, dd), 7.07 (1H, 7.12 (1H, 7.30 (1H) 7.42 (2H, 7.58 (1H, s) and 7.76 (3H, in).
,Step 3: Ethyl IS-iethoxvy-2-(2-naphthvlinethyl)phenll -2propenoate The naphthalene of Step 2 was converted to the corresponding aldehyde according to the step 1 of example 13 in 98% yield. This aldehyde was then converted to the cinnamate according to step 1 of example 13 in 90% yield.
1H NMR (CDCl3) 8 3.70 (3H, 4.11 (4H, in), 6.20 (1H, d), 6.77 (1H, dd), 6.99 (1H, 7.03 (1H, 7.15 (1H, 7.30 (2H, in), 7.39 (1H, 7.60-7.70 (3H, m) and 7.90 (1H, s).
Step4: E S-Mehox-2-2-nphthmethyb-phenyll -2-propenoic acid -99- WO 99/47497 PCT/CA99/0021 2 The hydrolysis of the ester of Step 3 (2.83 g; 8.2 mmol) was done according to step 4 of example 1 to yield 2.16 g of the title compound. The sodium salt was prepared with 1N NaOH.
1H NMR (CDCl3) 8 3.70 (3H, 4.13 (2H, 6.20 (1H, 6.80 (1H, dd), 7.02 (211, in), 7.15 (1H, 7.29 (2H, in), 7.39 (1H, 7.62 (311, mn) and 8.03 (1H, d).
LRMS calcd for M-1= 317.
EXAMPLE 23 5-BROMO-2-METHOXY-N-{(E)-3- [5-METHOXY-2-(2- NAPHTHYLMETHYL)PHENYLI -2- PROPENOYLIBENZENESULFONAMIDE SODIUM SALT (448) Step? 1: 5-Bromo-2-methoxy-N-I(E)-3- [5-methoxy-2-(2naphthylmethyl)phenyll -2-propenoyIlbenzenesulfonainide The coupling reaction of the acid of Example 22 Step 4 (0.600 g; 1.88 minol) was done according to step 5 of example 1 with 5-bromo-2inethoxybenzesulfonamide to yield 573 mg (5 of the title compound.
The sodium salt was prepared with 1N NaOH.
1H1 NMR (CDCl3) 8 3.72 (3H, 3.77 (3H1, 4.13 (2H, 6.40 (1H1, 6.70 (1H, 6.85 (111, dd), 7.02 (11, 7.10-7.20 (211, in), 7.37 (311, in), 7.57 (1H1, dd), 7.60-7.80 (3H, m),7.95 (1H1, 8.15 (111, d) and 9.12 (111, broad s).
LRMS calcd for M-1= 564.
EXAMPLE 24 [5-CHLORO-2-(4-CHLOROBENZYL)PHENYL -2-PROPENOIC ACID SODIUM SALT (537) Step 1: Ethvl(E)-3- [5-chloro-2-(4-chlorobenzvl)phenyll -2-propenoate 100 WO 99/47497 WO 9947497PCT/CA99/002 12 The benzyl bromide of step 2 of example 13 was coupled in a Suzuki coupling reaction with 4-chlorobenzene boronic acid according to the procedure of step 2 example 1 to yield 69% of the title compound.
1H NMR (CDCl3) 8 1.30 (3H, 4.02 (2H, 4.22 (2H, 6.29 (1H, 6.99 (2H, 7.08 (1H, 7.20-7.30 (3H, in), 7.52 (1H, s) and 7.83 (1H) d).
Step1 2: rS-Chloro-2-(4-chlorobenzylbphenyl] -2-propenoic acid The hydrolysis of the ester of Step 1 14 g; 3.4 minol) was done according to step 4 of example 1 to yield 860 mng of the title compound. The sodium salt was prepared with 1N NaOH.
1H NMR (CDCl3) 8 4.04 (2H, 6.30 (1H, 7.00 (2H, d), 7.10 (1H, 7.23 (2H, 7.29 (1H, 7.55 (1H, s) and 7.95 (1H, d).
LRMS calcd for M-1= 305.
EXAMPLE (E)-3-{2-[(5-(PHENYLMETHOXY)INDOLYL)METHYL FLUOROPHENYL)-N- [(5-BROMO-2-METHOXYPHENYL)SULFONYL] 2-PROPENAMIDE (451) Step 1: Ethyl 3 -(5-fluoro-2-methylphenyl)-2-propenoate 5-Fluoro-2-methylbenzaldehyde (40.58 g; 294 inmol) was converted to the ethyl cinnamate, according to step 1 of example 1 to yield 40.81 g. of the title compound.
'H NMR (acetone-d 6 8 1.29 (3H, 2.40 (3H, 4.23 (2H, q), 6.49 (1H, 7.07 (1H, td), 7.29 (1H, dd), 7.46 (iB, dd) and 7.87 (1H, dd).
Step 2: Ethyl 3 -r 2 -b-romomethyl)-5-fluorophenvlI-2-propenoate The ester of Step 1(40.80 g; 196 minol) was converted to the benzylic bromide according to step 2 of example 1 to yield 24.17 g of the title compound.
'H NMR (acetone-d 6 81.30 (3H, 4.24 (2H, 4.81 (2H, s), 6.62 (1H, 7.18 (1H, td), 7.58 (2H, m) and 8.02 (1H, dd).
101 WO 99/47497 PCT/CA99/00212 Step 3: Ethyl (E)-3-{2-[(5-(phenylmethoxy)indolyl)methyl]-5fluorophenylv-2-propenoate The benzylic bromide of Step 2 (3.16 g; 11.0 mmol) was coupled with 5-(phenylmethoxy)indole according to the same procedure described in step 1 of example 2 to yield 2.27 g of the title compound.
1 H NMR (acetone-d 6 5 1.27 (3H, 4.20 (2H, 5.11 (2H, s), 5.59 (2H, 6.43 (1H, dd), 6.52 (1H, 6.80 (1H, dd), 6.86 (1H, dd), 7.08 (1H, td), 7.19 (1H, 7.22 (1H, 7.31 (2H, 7.38 (2H, 7.50 (2H, m), 7.55 (1H, dd) and 8.01 (1H, dd).
Step 4: (E)-3-{2-[(5-(Phenylmethoxy)indolyl)methyl]-5-fluorophenyl)-2propenoic acid (493) The hydrolysis of the ester of Step 3 (2.27 g) was done according to step 4 of example 1 to yield 2.07 g of the title compound.
1 H NMR (acetone-d 6 5 5.11 (2H, 5.62 (2H, 6.43 (1H, dd), 6.53 (1H, 6.75 (1H, dd), 6.86 (1H, dd), 7.08 (1H, td), 7.19 (1H, 7.25 (1H, 7.31 (2H, 7.38 (2H, 7.50 (2H, 7.56 (1H, dd) and 8.04 (1H, dd). Elemental analysis calcd. for C 25
H
20 FN0 3 .2H20: C, 68.64; H, 5.53; N, 3.20; Found: C, 68.16; H, 4.95; N, 3.06.
Step 5: (E)-3-{2-[(5-(Phenylmethoxy)indolyl)methyl]-5-fluorophenyl)-N- [(5-bromo-2-methoxyphenvl)sulfonvll-2-propenamide The acid of Step 5 (2.06; 5.13 mmol) was coupled with bromo-2-methoxybenzenesulfonamide of example 10, step 5 according to step 5 of example 1 to yield 2.44 g of the title compound.
'H NMR (acetone-d 6 6 3.93 (3H, 5.10 (2H, 5.59 (2H, s), 6.39 (1H, dd), 6.73 (1H, dd), 6.78 (1H, 6.81 (1H, dd), 7.09 (1H, td), 7.18 (1H, 7.24 (3H, 7.32 (1H, 7.39 (3H, 7.49 (2H, 7.82 (1H, dd), 8.01 (1H, dd) and 8.09 (1H, Elemental analysis calcd. for
C
3 2
H
26 BrFN 2 0,S 2 C, 59.17; H, 4.03; N, 4.31; S, 4.94; Found: C, 59.07; H, 4.01; N, 4.34; S, 5.16.
EXAMPLE 26 -102- WO 99/47497 WO 9947497PCT/CA99/0021 2 [2-(BENZO[B]THIOPHEN-2-YLMETHYL)-5-FLUOROPHENYjI-N [(5-BROMO-2-METHOXYPHENYL)SULFONYL] -2-PROPENAMIDE SODIUM SALT (452) Step Ethyl F2-(benzo [hithiophen-2-vlmethyl)-5-fluorophenvll -2propenoate The ester (901 mg, 3.14 mmol) of example 13, step 2 was coupled with benzo[blthiophene-2-boronic acid (from Lancaster Chemical) in DME according to the same procedure described in step 3 of example 10 to yield 657 mg of the title compound.
'H NMR (acetone-l 6 81.22 (3H, 4.16 (2H, 4.43 (2H, s), 6.50 (1H, 7.03 (1H, 7.15-7.35 (3H, in), 7.47 (1H, dd), 7.56 (1H, dd), 7.69 (1H, dd), 7.78 (1H, dd) and 8.00 (1H, dd).
.Step 2: 12-(benzo fbithiophen-2-vlmethvl)-5-fluorophenvll -2propenoic acid (539) The hydrolysis of the ester of Step 1 (657 mg) was done according to step 4 of example 1 to yield 345 mg of the title compound.
1H NMR (acetone-l) 84.45 (2H, 6.51 (1H, 7.04 (1H, cl), 7.2-7.3 (3H, in), 7.49 (1H, dd), 7.57 (1H, dcl), 7.70 (1H, 7.80 (1H, mn) and 8.01 (111, dcl). Elemental analysis calcd. for C ,,Hl 3 F0 2 5: C, 69.21; H, 4.19; Found: C, 68.96; H, 4.15.
Step 3: [2-(Benzo Ib]thiophen-2-ylmethyl)-5-fluorophenyll broino-2-inethoxvp~henvl)sulfonvli -2-prop~enainide The previous acid (264 mng; 0.85 minol) was coupled with bromo-2-methoxybenzenesulfonamicle of example 10, step 5 according to step 5 of example 1 to yield 287 mng of the title compound.
'H NMR (acetone-l 6 8 3.83 (3H, 4.43 (2H, 6.77 (1H, cl), 7.00 (1H, 7.13 (1H, 7.2"7.3 (3H, in), 7.41 (1H, dcl), 7.49 (1H, dd), 7.65 (1H, clcD, 7.78 (2H, in), 7.96 (1K, cld)HH and 8.05 (1K, d).
The acid was converted to the sodium salt with 1 equivalent of NaOH. Elemental analysis calcd. for C 25
K,
8 BrFNNaO 4
S
2
.H
2 0: C, 50.01; K, 3.36; N, 2.33; Found: C, 49.84; H, 3.22; N, 2.41.
103 WO 99/47497 WO 9947497PCT/CA99/002 12 EXAMPLE 27 N-(E)-[(5-BROMO-2-METHOXYPHENYL)SULFONYLI -3-(5-FLUORO-2- I [1-BENZYLINDOL-5-YL]METHYL}PHENYL)-2-PROPENAMIDE SODIUM SALT (453) Step 1: Ethyl [5-fluoro-2-(indol-5-ylmethvl)phenvfll-2-propenoate The ester (1.83 g, 6.37 mmol) of example 13, step 2 was coupled with 5-indolyl boronic acid and NaHCO3 in DME according to the procedure described in step 3 of example 10 to yield 1.08 g of the title compound.
'H NMR (acetone-d 6 81.26 (3H, 4.17 (2H, 4.21 (2H, s), 6.37 (1H, in), 6.44 (1H, 6.94 (1H, dd), 7.14 (1H, td), 7.27-7.37 (4H, in), 7.51 (1H, dd), 8.05 (1H, dd) and 10.13 (1H, s).
Step 2: Ethyl (E)-3-(5-fluoro-2-{ !1-benzylindol-5-yll methyllphenl)-2propenoate The indole of Step 1 (621 mg; 1.92 inmol) was coupled with benzyl bromide according to the procedure described in step 1 of example 2 to yield 678 mng of the title compound.
'H NMR (acetone-d 6 81.26 (3H, 4.17 (4H, in), 5.32 (2H, s), 6.43 (2H, in), 6.95 (1H, dd), 7.1-7.4 (11H, in), 7.49 (1H, dd) and 8.08 (1H, dd).
Step 3: (E)-3-(5-Fluoro-2-I I1-benzylindol-5-vfl methyllphenyl)-2-propenoic acid) (540) The hydrolysis of the ester of Step 2 (678 ing) was done according to step 4 of example 1 to yield 276 mg of the title compound.
'H NMR (acetone-d 6 )8 4.20 (2H, 5.38 (2H, 6.39 (1H, d), 6.45 (1H, 6.95 (1H, 7.1-7.3 (10H, in), 7.48 (1H, d) and 8.04 (1H, dd).
Elemental analysis calcd. for C 25
H
20 FN0 2 C, 77.91; H, 5.23; N, 3.63; Found: C, 78.52; H, 5.46; N, 3.66.
Step 4: I(5-Bromo-2-methoxyphenyl)sulfonyll -3-(5-fluoro-2-{ [1methvllphenvl -2-Dropenamide 104 WO 99/47497 PCT/CA99/00212 The acid of Step 3 (219 mg; 0.57 mmol) was coupled with bromo-2-methoxybenzenesulfonamide of example 10, step 5 according to step 5 of example 1 to yield 149 mg of the title compound.
1H NMR (acetone-d 6 5 3.82 (3H, 4.18 (2H, 5.38 (2H, s), 6.36 (1H, dd), 6.72 (1H, 6.90 (1H, dd), 7.1-7.4 (12H, 7.78 (1H, dd), 7.98 (1H, dd) and 8.05 (1H, d).
The acid was converted to the sodium salt with 1 equivalent of NaOH. Elemental analysis calcd. for C 32 H2 5 BrFN 2 NaO 4 S.1/2H 2 0: C, 57.84; H, 3.94; N, 4.22; Found: C, 57.61; H, 3.86; N, 4.16.
-105- WO 99/47497 WO 9947497PCT/CA99/00212 EXAMPLE 28 N-(E)-[(2,4-DIMETHYL(1,3-THIAZOL-5-YL))SULFONYLI3(3-[(5- CHLOROINDOLYL)METHYL1 (2-PYRIDYL)1-2-PROPENAMIDE (444) Step 1: Ethyl (E)-3-(3-methy-l-2-pvridyl)-2-propenoate To a solution of 2-bromo-3-methylpyridine (10.36 g; 60.2 mmol) in 120 mL of THF at -100' 0 C was added dropwise a 1.6 M solution of n-BuLi (65.6 mmol). After 20 min of stirring at that temperature, 1formylpiperidine (7.65 g) in 10 mL of THF was added and the solution was warmed to After 30 min of stirring at triethyl phosphonoacetate (13.7 mL; 69.1 mmol) was added dropwise below 30 0
C.
After 1 h of stirring, the mixture was quenched with NH 4 OAc and extracted with EtOAc. The solvent was removed and the crude oil was purified by silica gel chromatography (25% EtOAc in hexane) to yield 10.32 g of the title compound.
'H NMR (acetone-d 6 )861.29 (3H, 2.46 (3H, 4.22 (2H, q), 6.99 (1H, 7.27 (1H, dd), 7.64 (11, dt), 7.90 (111 d) and 8.45 (1H, in).
Step 2: Ethyl f3-(bromomethyl)-2-pvridvll -2-propenoate The ester of Step 1 (5.93 g; 31.0 mmol) was converted in benzene to the benzylic bromide according to the procedure described in step 2 of example 1 to yield 1.83 g of the title compound.
'H NMR (acetone-d 6 )861.30 (3H, 4.25 (2H, 4.88 (2H, s), 7.10 (1H, 7.41 (1H, dd), 7.91 (1H, dd), 8.03 (1H, d) and 8.60 (1H, dd).
Step2 3: Ethyl 3- [(5-chloroindolyl)methvll -2-pvridyll-2-propenoate The benzylic bromide of Step 2 (1.33 g; 4.91 mmol) was coupled with 5-chioroindole according to the procedure described in step 1 of example 2 to yield 1.22 g of the title compound.
'H NMR (acetone-d 6 )861.28 (3H, 4.22 (2H, 5.78 (2H, s), 6.57 (1H, 6.94 (1H, 7.04 (1H, 7.11 (1H, dd), 7.27 (1H, dd), 7.43 (2H, in), 7.63 (1H, 7.99 (1H, d) and 8.53 (1H, d).
Step 4: I(5-ChloroindolvLmethyll -2-pyvridvfl)-2-p2rop~enoic acid (542) 106 WO 99/47497 PCT/CA99/00212 The hydrolysis of the ester of Step 3 (283 mg) was done according to step 4 of example 1 to yield 291 mg of the title compound.
'H NMR (acetone-d 6 8 5.81 (2H, 6.57 (1H, 6.88 (1H, d), 7.05 (1H, 7.11 (1H, dd), 7.26 (1H, dd), 7.43 (2H, 7.63 (1H, 8.02 (1H, d) and 8.54 (1H, Elemental analysis calcd. for C1 7 H,,C1N 2 0 2 .1/4H 2 0: C, 64.36; H, 4.29; N, 8.83; Found: C, 64.63; H, 4.43; N, 8.65.
Step 5: [(2.4-Dimethvl(1,3-thiazol-5-vl))sulfonvll-3- 3- chloroindolvl)methyl (2-pyridyl))-2-propenamide The acid of Step 4 (283 mg; 0.90 mmol) was coupled with 2,4dimethyl-1,3-thiazole-5-sulfonamide (from Maybridge Chemical) according to step 5 of example 1 to yield 315 mg of the title compound.
'H NMR (acetone-d 6 8 2.64 (3H, 2.69 (3H, 5.81 (2H, s), 6.56 (1H, 6.84 (1H, 7.09 (1H, dd), 7.26 (1H, dd), 7.31 (1H, 7.41 (2H, 7.62 (1H, 8.05 (1H, d) and 8.51 (1H, Elemental analysis calcd.
for C 22
H,
9 C1N403S2: C, 54.26; H, 3.93; N, 11.50; S, 13.17; Found: C, 54.69; H, 4.03; N, 11.18; S, 12.89.
EXAMPLE 29 N-((E)-3-[5-CHLORO-2-(2-NAPHTHYLMETHYL)PHENYL]-2- PROPENOYL-2-METHOXYBENZENESULFONAMIDE (302) The coupling reaction of the acid (3.00 g; 9.1 mmol) of Step in Example 12 was done with 5-bromo-2-methoxybenzesulfonamide (2.56g; 9.6 mmol) according to Step 5 of Example 1 to yield 4.13g (79 of the title compound. The sodium salt was prepared with 1N NaOH.
'H NMR (DMSO-d 6 d 3.76 (3H, 4.25 (2H, 6.52 (1H, d), 7.15 (1H, 7.26 (1H, 7.36 (1H, 7.41-7.52 (4H, 7.58 (1H, 7.69 (1H, 7.78 (1H, 7.82 (3H, 7.89 (1H, d) and 12.38 (1H, br s).
Elemental analysis: Calcd. for C27H20BrC1NNaO4S.H 2 0: C, 53.08; H, 3.64; N, 2.29; Found: C, 53.25; H, 3.89; N, 2.91.
-107- WO 99/47497 PCT/CA99/00212 These intermediates were prepared according to the literature: 5-fluoro-2-methylbenzaldehyde: Servis, K. Fang, J. Am. Chem. Soc. 1968, 90, 6712- 67 17.
5-indolyl boronic acid: Yang, Martin, A. R. Heterocycles 1992, 34, 1395-1398.
108

Claims (12)

1. A compound represented by formula 1: R I W -'AH A X-B Z or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein: HET represents a member selected from the group consisting of: phenyl, naphthalene, biphenyl, pyridine, qulnoline, isoquinoline, furan, benzofuran, thiophene, benzothiophene, oxazole, thiazole, imidazole, benzothiazole, I .5-thiadiazole, thienopyridine, Indole, tetrazole, imidazole, benzoxazole and pyrrole; A represents a one or two atom moiety and is selected from the group consisting of S. 802, CH2, -OCH-2- -CHOH- C(0I-O(CH3 and -CH2-O-; X represents phenyl optionally substituted with R 14 and R1 5 B is CH=CH; Z is NHSO 2 R 1 9; R' R 2 and R3 independently represent H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkenyl-.HET(Ra)4-.9, -(C(R 4 )2)pSR 5 2 )P0R', CN, N0 2 -(C(R 4 2 )pC(R 7 3 -CO 2 RO,- CON(Rr3) 2 or 2 )pS(O)nR'O, wherein n Is 0.,1 or 2 and p is 0-3; each R4 is independently H, F, CF 3 or lower alkyl, or two R 4 groups are taken in conjunction and represent a ring of up to six atoms, optionally containing one heteroatom selected from 0, S(O)n or N(O)m. wherein m is 0 or I and n is 0, 1 or 2: each R 6 is independently lower alkyl, lower alkenyl, lower alkynyl, OF 3 lower alkyl-HET, lower alkenyl-HET or 8 )z )pPh(R 1 each Re is independently H, lower alkyl, lower alkenyl, lower alkynyl, C17 3 Ph, Bn and when two RW groups are attached to N they may be taken in conjunction and represents a ring of up to 6 atoms, optionally containing an additional heteroatom selected from 0, S(O)n or N(O)m, wherein m and n are as defined above-, A4,- 109 Amended claims VON ZEPA -NUENCHEN 05 ;23- 5- o0 19:06 :51+ 288 8389 +49 89 23994465;# IJ SL amL LL4 23L0U-200 AU~d ~lL. ~am~ CA 009900212 each R 7 is independently H, F, CFa or lower alkyl, and when two groups are presents, they may be taken In conjunction and represent an aromatic or aliphatic ring of 3 to 6 members containing from 0-2 heteroatoms selected from 0, S(O)n and N(O)m, wherein mn and n are as defined above; each R8 represents H or each R9 Is independently H, lower alkyl, lower alkenyl, lower alkynyl Ph or Bn;. each R' 0 is independently lower'alkyl, lower alkenyl, lower alkynyl, CF 3 Ph(R' 1 CH 2 Ph(R' 1 )0-3 or NR) each R 1 Is Independently lower alkyl, SO 2 OR 2 N(R 6 *C0 2 R 2 -CON(R 6 2 -C(O)R' 2 CN, CF3. N0 2 or halogen; each R1 2 1is Independently H, lower alkyl or benzyl; each R 1 3 is independently H, halo, lower alkyl, 0-lower alkenyl, S-lower alkyl, N(R 6 2 C0 2 R' 2 CN, CF 3 or NO 2 R 14 and R1 5 are independently lower alkyl, halogen, CF 3 OR"E, S(OR"or C(R'6) 2 0R 17 each R 1 6 is independently H, lower alkyl, lower alkenyl, Ph, Bn or CF 3 each R IT is independently H, lower alkyl or Bn; each R 1 6 is independently H. F or lower alkyl, and when two R1m groups are present, they may be taken in conjunction and represent a ring of 3 to 6 members comprising carbon atoms and optionally one heteroatom chosen from 0. S(O)n. or N;I R 19 represents a member selected from the group consisting of: lower alkyl and HEr(Ra)3; each R" is Independently H, lower alkyl, lower alkenyl, lower alkynyl, Us~ or Ph(R 13 2 and each Ra is independently selected from the group consisting of: H, OH, halo, CN, N02, amino, Ci.6alkyl. C2-6alkenyl, C2-6alkynyl, C1 6 alkoxy, C2-6alkanyloxy, C2..6alkynyloxy, CI-Salkylamlno, di-CI- 6alkylamino, CF3, C(O)Ci..alkyl, C(O)2.6alkenyt, C(O) C2..6alkynyl, CO2H, C02CI -eakyl, C02C2.6alkenyl, and CO2C2-6alkynyl, said alkyl, alkenyl, alkynyl and the alkyl portions of alkylamino and dialkylamino being optionally substituted with -110- Amended claims CV. VON: C-PA-MUENHEN 05 :23- 6- 0 19106 :61+ 288 8389 +49 89 23994+66:# (3 2 0O 200 0 .JL~I U I Ij CA .009900212 1-3 of: hydroxy. halo, aryl, CI-B alkoxy, C2..6alkernyloxy, C2-6alkynyloxy,' CF3, C(O)Cl1 6alkYl, C(O)C2-6alkenyl, C(O)C2-6alkynyI, CO2H, CO2C 1- 6alkyl, C02C2-6alkenyl, C02C2.6alkynyl, NH2, NHCj-6alkyl and N(Cj.. 68lk4l2.
2. A compound In accordance with claim 1, wherein HET in R' 9 represents a member selected from the group consisting of phenyl, thienyl, naphthyl, furanyl, thiazolyl, imidazolyl and indolyl.
3. A compound in accordance with claim 1 or 2, wherein: HET is selected from the group consisting of: phenyl, biphenyl, naphthyl, indole, thiophene, benzofuran and qulnoline.
4. A compound In accordance with claim 1, 2 or 3, wherein: A Is selected from the group consisting of:: S. S02, C112 and S. A compound in accordance with claim 1, 2, 3 or 4 wherein X represents phenyl and R 1 4 and R 1 5 are absent or represent halo.
6. A compound in accordance with claim 1, 2, 3. 4 or wherein:. B represents CH=CH in the E-Isomeric form.
7. A compound In accordance with claim 1, wherein: Rig represents HET(Ra)3 and HET is selected from the group consisting of: phenyl, thienyl, naphthyl, furanyl, thiazolyl, inildazolyl and indlotyl.
8. A compound in accordance with claim 12 wherein: Z: is NHSO 2 R' and R'9 represents phenyl or thiophene, substituted with (Ra)3.
9. A compound according to claim 1 represented in the following table: Amended claims CV. VON: EPA -ML'CHi4 06
23- 09-2000 *LU:L ;23- 6- 0 19:07 :614 2838 8389 VIIAIS UUJz.1L XUAh, Lft LuJv U.JU3 -+49 89 23994466:w 7 CA 009900212 RIR 2 R1 3 -Het A X B Cpd 3-methylindol CH 2 1,2-Ph CH=CH 2-thlenyl 3 2-ahh OH 2 I 2-Ph CH=CH 2-thionyl4 2-naphthyl S(0) 2 I 2-Ph CH=CH phenyl 3-methylindol, 8(0)2 1,2-Ph *CH=CH 2-thienyll -1-VI_ 2-naphthyl 8S(0)2 1,2-Ph CH=CH 3.5.di-(CF 3 7 3,4-dichloro OHz 1.2-Ph CH=CH 2-thlenyll 8 phony[ 2-naphthyl S(0) 2 1,2-Ph CH=CH 2-thienyl 9 2,4-dichloro CH 2 1,2-Ph CH=CH 2-thienyl phenyl I -naphthyl S(0)7 1 ,2 -Ph CH=CH 11I 1-naphthyl 8(0)2 1.2-Ph CH=CH 3,5-dI-(CF 3 12 phenyl 3,4-chioro CH 2 1,2-Ph CH=CH 2-thlenyl 14 fluoro phenyl__ 1-naphthyl CH 2 _1,2-Ph CI-ICH 2-thienyl 3,4-dichloro S(0) 2 1,2-Ph CH=CH 2-thlenyl 1s phe4 II 4-methylthio CH 2 1.2-Ph CH=CH 2-thienyt 17 phenyl I 4-chlorophenyl CH I r2-Ph CH=CH 2-thienyl 18 2-naphthyl S 1,2-Ph CH=CH 2-thienyl 19 2-nap hthyl O-CH 2 1,2-Ph CH=CH 2-thienyl 2-naphthyl S(O) 1,2-Ph CH=CH 2-thienyl 21 1-naphthyl S(0)2 1,2-Ph CH=CH phenl 22 2-benzofuranyl _21 2 1,2-Ph CH=CH 2-thienyl 23 CH 2 1,2-Ph CI-10H 2-thienyl 24 1-naphthyl S(0)2 1,2-Ph CH=CH 3,&.dl.(CF 3 1-naphthyl S(0) 2 1,2-Ph CHr-CH 2-thienyl 26 3-(1 ,2-(methylene CH 2 1.2-Ph C1-ICH 2-thienyl 27 dioxy)benzene) 2-(6-benzyloxy) OH 2 1,2-Ph CH=CH 2-thienyl 33 naphthyl 2-(O-benzyloxy) CIH2 1,2-Ph CI-iCH 2-methoxy-5- 4 naphthyl bromophenyt -112- Amended claims .CV. VON:EPA-ML'ENCHEN 06 23-06-2000 I*UJ ;23- 13- 0 ;19:07 :5314 288 8389 Ufljj~jh~ VUUAJJ. AUIJ.I ll LJU VJJ +49 89 2399"465: 0 8 I V. I UT CA 009900212 RiR 2 R: 3 -Het A X B I___R19 Cpd 2-naphthyl CH 2 1.2-Ph CH=CH 3,5-I(CF 3 224 2-naphthyi CH 2 I 2-Ph CH=CH 4-isopropyl 225 2-napthyl H 2 12-Ph HCH 23-dphenlo 2 2-naphthyl CH- 2 1,2-Ph .CH=CH 23-diloro 227 2-naphthyl CH 2 1,2-Ph CI-ICH 34-dlorpeo 228 2-naphthyl CH2 1,2-Ph CH=CH 4-lorophenyl 228 2-naphthyl CH 2 1,2-Ph CH=CH 2-dluoro-3-n 220 2-naphthyl CH 2 1,2-Ph CH=CH 2,-chloro--o 231 heanyl 2-naphthyl CH 2 1.2-Ph CH=CH 4-rhooxylur 232 2-naphthyl CH 2 1.2-Ph CH=CH 4-ohx 233 2-naphthyl CH 2 1.2-Ph CH=CH 3-trifluoro 234 _________methyiphenyl 2-naphthyl CH 2 1,2-Ph CHwCH 4-((1-hydroxy-1- 235 methyl)ethyl) phenyl 2-naphthyl CH 2 1,2-Ph CH=CH 4-(methyl 236 ___________sulfonyl~phenyl 2-naphthyl CM 2 1 .2-Ph CH=CH 4-(benzyloxy) 237 ___phenyl 2-naphthyl CH 2 12-Ph CH=CH 2-thiezolyl .240 2-naphthyl 1,2-Ph CH=CH 2-furanyl 241 2-naphthyl CH 2 1,2-Ph CH=CH 2-pyrldinyl 242 2-aht~ CH 2 1.2-Ph CH=CH 4- anopheny 243 2-naphthyl S02 1.2-Ph CH=CH 3,5-di-(CF 3 244 2-na phthyl S02 1,2-Ph CH=CH 4-isopropyl 245 phmnyl 2-naphthyl S02 1.2-Ph OH=CH 2,3-dichloro 246 2-naphhyl SO 1.2-P CH~CH phendyluo 24 2-naphthyl $02 1,2-Ph CH=CH 34-dhlorohey 248 2-naphthyl SO2 1.2-Ph CH=CH 4-fluorophenyl1 249 2-naphthyl 802 1.2-Ph CH=CH 2,5-dichloro-3- 250 1 1 thianyl- -113- Amended claims .C1. VON EPA -MUENCHEN 0.5 -JUV L.UUJZZL 23-05-200 :23- 5- 0 19:07 :514 288 8:389 VIfAU. A -ULf J1 LUU UJUJ 449 89 23994405: 9 CA 009900212 RiR 2 R 3 -Het A X W1 Cpd 2-naphthyl S02 I 2-Ph CH=CH 3-chloro4 251 fluorophenyl 2-naphthyl S0 2 i ,2-Ph CH=CN 4-methoxy 2521 ___phenyl 2-naphthyl S02 1 ,2-Ph CH=CH buyl 253 2-naphthyl S0 2 1,2-Ph CH=CH 3-trifluoro 254 methylphenyl 2-naphthyt $02 1.2-Ph CH=CH 4-((1-hydroxy-1- 255 methyl)ethyl) _______phenyl 2-nap hthyl S02 1,2-Ph CH=CH 4-(methyl 258 _________suffonyI)phenyl 2-naphthyl S0 2 1,2-Ph CH=CH 4-(benzyloxy) 257 phenyl 2-naphthyl SO 2 t 1.2-Ph CH=CH 2-haoy 260 2-naphthy so80 1,2-Ph CH=CH 2-furanyl 261 2-na hthy S 02 1,2-Ph CH=CH 2-pyridinyl 262 2-naphthyl S0 2 1,2-Ph CH=CH 4-cyanophenyl 263 2-naphthyl CH2-O I j2-Ph CH=CH 3,5-di-(CF3) 264 2-naphthyl CH 2 -IO 1.2-Ph CH=CH 4-Isopropyl 265 ___phenyl 2-naphthyl CH2-O 1,2-Ph CH=CH 2,3-dachloro 266 2-naphthyl CHrO 1,2-Ph CHCH 3,4-difluoro 2671 phenyl 2-naphthyl 0-CH 2 1,2-Ph CH=CH 3,5-di.(CF 3 268 phenyl 2-naphthyl 0-CHZ 1,2-Ph CH=CH 4-isopropyl 259 phenylI 2naphthyl 0-CM 2 1 ,2-Ph CH=CH 2,3-dichloro 2701 ___phenyl 2-naphthyl 0-OH 2 1,2-Ph CH=CH 3,4-difluoro 271 2-naphthyl S 1,2-Ph CH=CH 3,5-di-(CF 3 272 2-naphthyl S 1,2-Ph CH=CH 4-I1sopropyl 273 2-naphthyl S 1,2-Ph CH=CH 2,3-dichloro 274 phenyl 2-naphthyl S 1,2-Ph CHCH 3,4-difluoro 2761 -114- Amended claims VONp MIENCHEN 05 I U.lu 23-05-2000 5- 0 :19:08 ;514 288 8380 111nlflL iu LJIL Jot LUU :.J 89 23994-466:010 11W. IU .I CA 009900212 RlR 2 R 3 -IMet A X B Cpd 2-(S-benzyloxy) S502 1,2-Ph CH=CH 2-thienyl 278 naphthyl 2-(6-benzyloxy) $1,2-Ph CH=CH 2-thienyll 277 nophthyl S0 2 I 2-Ph CH=CH 2-thienyl 280 -naphthyl______ S I ,2-Ph' CH=CH 2-thienyl 281 nop hthyl 2-(6-(4-trifuoro S0 2 I 2-Ph CH=CH 2-thienyl 284 methyl)benzyloxy))I naphthyl 28 2-(6-.(4-trifiuoro OH 2 I ,2-Ph CH-CH 2thny28 methyl)benzyloxy)) I -(6-benzyloxy) 8032 1 ,2-Ph CH=CH 2-thienyl 288 naphthyl- I -(6benzyloxy) OH 3 1,2-Ph CH=CH 2-thienyl 289 1naphthyl__ 2-(6-(3,4-dlfluoro SO 2 1.2-Ph CH=CH 2-thienyl 290 benzyloxy)) naphthyl 2-(6-3,4-difluoro OH 2 1,2-Ph CH=CH 2-thienyl 291 benzyloxy)) 2-(7-benzyloxy) SO2 1.2-Ph CH=CH 2-thienyl 293 naphthyl____ 2-(6-(3,4-difluoro SO2 1,2-Ph CH=CH 3,4-difluoro 294 benzyloxy)) phenyl naphth 2-(6-(3,4-difluoro CH 2 1,2-Ph CH=CH 3,4-dlfluoro 295 benzyloxy)) phenyl naphthyl 2-(7-benzyloxy) S02 1.2-Ph CH:CH 3,5-di-(CFs) 297 phenyl. 2-(S-(3,4-difluoro SO 2 1,2-Ph OH-OH 3.5-di-(CF 3 298 benzyloxy)) phenlyl naphthyl 2-(6-(3,4-difluoro OH 2 1,2-Ph CH=CH 3,5-di-(CFa) 299 benzyloxy)) phenlyl naphthy IFC7CH 2-naphthyl OH 2 1,2-Ph C C 0 lbromophell 2-naphthyl CH 2 4-Cl-I 2-Ph CHCQH 2-metthoxy-5- 302 I__I I bromophenyl- -115- Amended claims CV. VON;EPA-MUENCHEN 05 W1 vuu .u.t. 23-05-2d00 :23- 5- 0 19:08 :514 288 8389 UVJUJJ..L VUuIjIL U.I. LU, U~..I -b -149 89 23994485:1111 IV I AU:, .A CA 009900212 RIR 2 R 3 .iet A x X Cpd 2-naphthyl H 2 4-Cl-I .2-Ph CH=CH 2-heny 303 2-nap hthyl so 1,2-Ph CH=CH 2-methoxy-6- 304 ________bromophenyl 2-naphthyl SO 2 1,2-Ph CHCH 2-methoxy-5- 3051 ________bromophenyl CH-2 12-Ph CHCH 2-methoxy-5- 3071 naphthyl S02 1,2-Ph CH=CH 2-methoxy-5- 308 naphthyl _____bromophenyl S 1I 1,2-Ph CH=CH 2-methoxy-5- 309 na hth bromophenyl 2-naphthyl 01-12- 1,2-Ph CFICH 2-methoxy-5- 313 bromophenyl 2-naphthyl is 1,2-Ph CH=CH 2-methoxy-5- 31 4 ________bromophenyt 3-methyl CH 2 -O 1,2-Ph CH=CH 2-mothoxy-5- 317 jnciol-1 -vI- brmophenyl 3-methyl S 1,2-Ph CHCH 2methoxy-5- 3181 bromophenyl 3-methyl CH 2 -O 4-Cl-I .2-Ph CHinCH 2-methoxy-5- 321 bromophenyl 3-methyl S 4-01-1,2-Ph CH=CH 2-methoxy-5- '322 lndol-1 -yl ___________bromophenyl 2-(7-fluoro) S02 4-Cl-I ,2-Ph CH=CH 2-thienyl 347 2-(7-fluoro) S4-Cl-I .2-Ph CH=CH 2-thienyl 3491 na hth I_ 2-(7-fluoro) OH 2 4-Cl-I 2-Ph CH=CH 2-thienyl .350 naphthyl 2-(7-fluoro) OH 2 6-Cl-I ,2-Ph CH=CH 2-thienyl 351 naphthyl 2-(7-fluoro) OH 2 3-Cl-I 2-Ph CHCH 2-thienyl 3531 2-(7-fluoro) S0 2 4-Cl-I ,2-Ph CH=CN 2-methoxy-5- 354 naphthyl ___________bromophenvi 2-(7-fluoro) $4-Cl-I .2-Ph CH&CH 2-methoxy-5- 3565 bromophelYl 2-naphthyl CH 2 4,5-012- CH=CH 2-methoxy-5- 357 12-Ph ____brornophenyl 2-{7-fluoro) CH 2 6-Cl-i .2-Ph CH=CH 2-methoxy-5- 358 naphthyl _____bromophenyl 6 2-(7-luoro) OH 2 3-01-1 .2-Ph CHinCH j2-rnethoxy-5- 36 naphthyl __________Jbromophenyl -116- Amended claims CV. VON:EPA-MI~JENCHEN 05 23-05-2600o :23- 5- 0 ;19:08 ;514 288 8389 .mfj&M4.. =LS %w L jv UV, +49 89 23994465:#12 CA 009900212 RIR2R 3 -Het A X 2-(7-flu oro) S02 4-Ct-I ,2-Ph CH=CH -trittuoro M8 nophthyl chlorophenyl 2.(7-fiuoro) S 4-01-1,2-Ph CHCGH 2-trifluoro 363 naphthyt 2-(7-fluoro) CH 2 4C-,Ph H= 2-trifluoro 384 naphthyl rp henyl 2-(7-fluoro) CH 2 6-Ct-I 2-Ph CH=CH 2-trifluoto 365 naphthyl chioropheflyl 2-(7-fluoro) OH 2 3-Cl-i ,2-Ph CH-CH 2-trifluoro 367 naphthyl chloropheflyl 2-(7-fluoro) SO 2 4-01-1,2-Ph cH-=cH 2-ttiienyl 3.68 riaphthyl______ 2-(7-fluoro) 4-Cl-i .2-Ph C H-OH 2-thionyl 370 naphth 2-(7-fluoro) CH- 2 4-Cl-I .2-Ph CH=CH 2-thlenyl 3711 2-(7-fluoro) OH 2 6-C1-1,2-Ph CH=CH 2-thlenyl 372 n aphthyl 2-(7-fluoro) OH 2 3-Cl-I .2-Ph CH=CH 2-thienyl 374 n aphthyl 2-(7-flu oro) S0 2 4-Cl-I .2-Ph CH=CH 2-methoxy-5- 3751 naphthyl bromophenyl 2-(6-fluoro) S 4-Cl-I .2-Ph CH=CH 2-methoxy-5- 377 naphthyl 2-(6-fluoro) CH 2 4-Cl-I .2-Ph CH-CH 2-methoxy-5- 1378 naphthyl _____bromophenyl 2-{6-fiuoro) CH1 2 8-Cl-I ,2-Ph CH-ICH 2-methoxy-5- 379 naphthyI____ bromophenyl 2-(S-fluoro) CH 2 3-CI-I,2-Ph CH=CH 2-methoxy-5- 381 naphthyl _____bromophell 2-(7-chLoro) S0 2 4-Ct-i .2-Ph CH=CH 2-thlenyl 382 naphthyl, 2-(I-chloro) S 4-01-1,2-Ph CH=CH 2-thienyt 384 2-(7-chloro) CH2 4-01-1,2-Ph OH~zCH 2-thienyl 385 naphthyl 2-(7-chloro) CHz 6-Cl-I .2-Ph CH=CH 2-thienyl 386 naphthyl 1 -117- Amended claims VON EIPA -MUEHEN{~ O5 "An
28-06-2000 :23- 5- 0 19:08 :sit 288 8389 +49 89 23994465:#13 ~i.LUI:,o 4 CA 009900212 RIR 2 R3-Het A X B R'Cpd 2-(7-chloro) 0 CH 2 3-Cl-I .2-Ph CH=CH- 2-thienyl 388 2-(6.7-difluoro) $02 4-Ct-i .2-Ph CH=CH 2-thienyl 389 naphthyl 2-(6,7-difluoro) S 4-CI-I,2-Ph CH-OH 2-thienyl 3911 naphthyl______ 2-(6,7-difluoro) OH 2 .4-Cl-i .2-Ph CH=CH 2-thienyl 392 naphthyl I' 2-(6.7-difluoro) CH 2 6-Cl-I 2-Ph CHCH 2-thienyl 3931 naphthyl T-(6,7-difluoro) CH 2 3-Cl-I .2-Ph CHCH 2-thienyl naphthyl__ 2-(6,7-difluoro) $02 4-Cl-I .2-Ph CH=CH 2-methoxy-5- 3961 naphthyl _____bromophenyl 2-(6.7-difluorc) S 4-Ct-I ,2-Ph CH=CH 2-methoxy-5- 398 naphthyl ____bromophenyl 2-(6.7-difluoro) CH 2 4-Cl-i ,2-Ph CH=CH 2-methoxy-5- 399 bromophenyl 2-(6,7-difluoro) CH 2 6-Cl-I ,2-Ph CH=CH 2-methoxy-5- 400 naphthyl ______bromophenyl 2-(6,7-difluoro) WH 2 3-Cl-I .2-Ph CH=CH 2-methoxy-5- 402 naphthyl bromophenyl 2-(5,7-difluoro) OH 2 4-Cl-I ,2-Ph CH=CH 2-methoxy-5- 403 naphthyl bromophenYl 2-(5,7-difluoro) S 4-Cl-i .2-Ph CHWCH 2-methoxy-5- 404 naphthyl -bromophenyl- 2-(5,7-dluoro) Sol 4-Cl-I .2-Ph CHinCH 2-methoxy,-5- 406 naphthyl _____bromophenYl I 2-(G-fluoro) SOl 4-Ct-I 2-Ph CH=CH 2-methoxy-5- 407 quinolil bomop henyL 2-(6-fluoro) S 4-Cl-I .2-Ph CH=CH 2-methoxy-5- 408 guinoflnyl ___________bromophenYlI 2-(6-fiuoro) CH 2 4-Cl-I .2-Ph CH=CH 2-methoxy-5- 409 g ulnolinyl _____bromophenyl 2-(6-fluoro) OH 2 1.2-Ph CH=CH 2-methoxy-5- 410 bromophenMl 2-(5.7-difiuOro)- $02 4-Cl-i .2-Ph CH=CH 2-mathoxyl 1 guinolinyl____brmhei 2-(5,7-difluoro)- 4-Cl-i .2-Ph CHCH 2-methoxy-5- 4141 quinolinyl 2-(5,7-difluoro)- CH 2 4-Cl-i .2-Ph CH=CH 2-mrethoxy-5- 415 1 uinoliny I bromophenylI -118- Amended claims .NON:hEPA-MUENCHiEN 05 23-05-200 ;23- 5- 0 19:09 :514. 288 8389 WIT a&"A vuaW UU.L&I A, .JL2 LuU u .U.JV +49 89 23s994465;#14 IIU 1 u u 2j A CA 009900212 RI R 2 R 3 -14,t 1A X BB Cpc 2-(5,7-difluoro)- f 1z I 2-Ph CH=CH 2-methoxy-5- 416 quinolinyl _____bromophenyl 3,4-dichloro S02 A-Cl-I ,2-Ph CH=CH 2-methoxy-5- 419 ohenyl _____bromapheflyl 3,4-dichloro S 4-Cl-I .2-Ph CH=CH- 2-methoxy-5- 420 bromophenyl 3,4-dichioro CH 2 4-Cl-I ,2-Ph CH=CH 2-methoxy-5- 421 phenyt bromophenyl 3,4-dichloro CH 2 1.2-Ph CH=CH 2-rnethoxy-5- 422 phenyl bromophenyl 3,4-dichloro CH 2 5-Cl-I 2-Ph CH=CH 2-methoxy-5- 425 phen bromo phenyl 4-chloro S02 4-01-1,2-Ph CH=CH 2-methoxy-5- 4261 phenyl tI C=H b romopheflyl 4-chloro S -$12P HC 2-methoxy-5- 427 phenyl -lIbroropheVy 4-chioro CH 2 4C-9Ph H= 2-methoxy-5- 428 ohen bromophenyl 4-chloro 01-2 1,2-Ph CH=CH 2-methoxy-5- 4219 phenyl _________bromopheflyl 4-chioro CH2 4-CI-1,2-Ph CHCH 2-methoxy-5- 4321 phenyl ______bromophenyl 3,4-dichioro 802 4-Cl-I ,2-Ph CH=CH 2-thienyl 4331 pheny1____ 4,4-dichioro S 4-Cl-I ,2-Ph CH=CH 2-thlenyl 434 ohenm1 3 .4-dichioro CH2 4-CI-I ,2-Ph CH=CH 2-thienyl -4351 phenyl______ 3,4-dichloro CH 2 I 1 2-Ph CH=CH 2-thienyl 436 phenyl_ 3,4-dichloro CH 2 4-Cl-I ,2-Ph CH=CH 2-thienyl 438 phenyl I I n I I AQ 3,4-dichioro phenyl 4-chioro phenyl CH- 2 S. 1-1,242h un=lori V"y I I 2-thienyl ""U 502 4-01-1,2-Ph CH=CH CH=CH 2-thienyl 441 I 4-chioro 4- 1-1,2-Ph 4-u1-~LA 4-chioro .phenyl 4-chioro phenyl C i2 4-ul--ty.-rn vrI Twotty CH~t1 0HZ 11,2-Ph CH=CH I -th' enyl, 4-43 -119- Amended claims VON: EPA-MUENCHEN 05 a .Uu j 23-05-2000 5- 0 ;19:09 :514 288 8389 Ug1MLt VUU&L J-L J1.1 L.u U.1ua +49 89 239S4466:-#16 J'.J L~t S" *A CA 009900212 R1 R2R 3 -Het IA X 15 Cpd CH 2 3,2-Pyr CH=CH 2,4-(Me)2- 444 Indolyl iazoI-B-11 CH2 *3,2-Pyr CH=CH 2-thienyl45 idl-(-4lrO -1 4-F-I .2-Ph CH=CH 3.-chloro-4- 446 phenyl)indol 2-(G6-dffluoro CH 2 4-Cl-I .2-Ph CH=CH 2-methoxy-5- 4471 methoxy) bromopheflyl' naphth I_ 2-naphthyi 082 4-MeO- CH=CH 2-methoxY-5- 448 I.2-Ph ______bromophenll 2-naphthyi CH 2 5-Ct-I ,2-Ph CH=CH- 2-methoxy-5- 449 ,bromopheflyl 2-(6-chloro CH 2 4-C1.1,2-Ph CH=CH 2-methoxy-5- 450 bromophefl CH-2 4-F-i 2-Ph CH=CH 2-methoxy-5- 451 methoxy) bromopheflyl Indolyl,_ 2-(benzolb] CH 2 4-F-I 2-Ph CH=CH 2-methoxy-5- 4521 thiopheny I bromophenyi CH 2 4-F-I 2-Ph CH=CH 2-methoxy-5- 463 bromo henll I -(6-(4-chloro) OH 2 4-F-I 2-Ph CH=CH 2-methoxy-- 454 -phenyI)indov bromophenyl A pharmaceutical composition which is comprised of a compound in accordance with any one of claims I to 9 in combination with a pharmaceutically acceptable carrier. 11. A method of treating or preventing a prostaglandin mediated disease which is comprised of administering to a mammalian patient in need of such treatment a compound in accordance with claim I In an amount which is effective for treating or preventing a prostaglandin mediated disease. 12. A method In accordance with claim 10 wherein the prostaglandin mediated disease is selected from the group consisting of: pain, fever or Inflammation associated with rheumatic fever, influenza or other Viral infections, common cold, low back and neck pain, 120 Amended claims VON: EA-MUENCr4FN o5 ;23- 5- 0 19:10 :514 288 8389 +49 89 23994-465:#16 i pU. ;V%1 .9it a I a J11 's *I'A a'T A 23-05-2000 CA 009900212 skeletal pain, post-partum pain, dysmenorrhea. headache, migraine, toothache, sprains and strains, myositis, neuralgia, synovitis. arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spotidyitis, bursitis, burns including radiation and corrosive chemical injuries, sunburns, pain following surgical and dental procedures, immune and autoimmune diseases; cellular neoplastic transformations or inetastic tumor growth; diabetic retinopathy, tumor angiogenesis; prostanoid-Induced smooth muscle contraction associated with dysmenorrhea, premature labor, asthma or easinophil related disorders; Alzheimer's disease; glaucoma; bone loss; osteoporosiS- promotion of bone formation; Paget' s disease; cytoprotection in peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or other gastrointestinal lesions; GI bleeding and patients undergoing chemotherapy; coagulation disorders selected from hypoprothrombinemia, haemophilia and other bleeding problems; kidney disease; thrombosis; occlusive vascular disease-, presurgery; and anti-coagulation. 13. A method in accordance With claim 11. wherein the prostaglandin mediated disease Is selected from the group consisting of: pain, fever or Inflammation, 14. A method in accordance with claim 11, wherein the prostaglandin mediated disease is dysmenorrhea. -121- Amended claims :v.VONEPANIIENCEN 5 0: 1:10:51- 28 889 +49 89 239944G5: #17 II-MJECEN0 :3 5-U~ 0,S~ UUL: U19:1 :514 288 838J1U.j*J A 23-05-200C CA 009900212 A method In accordance with claim 11, wherein the compound is co-administered with other agents or ingredients. 16. A ri~ethod in accordance With claim 15, wherein the compound I Is co-administered with another agent or ingredient selected from the group consisting qf an analgesic selected from acetamninophen, phenacetin, aspirint a narcotic; a COX-2 selective NSAID and a conventional NSAID; caffeine; an H2-antagonist, aluminum or magnesium hydroxide: simethicone; a decongestant selected from phenylephrine, phenylpropalamlifle, pseudophedrifle, oxymetazolne, ephlnephrine, naphazolifle, xylometazolifle, propyihexedrifle, or levo-desoxyepheddlne;, an antitussive selected from codeine, hydrocodofle, caramiphen, carbetaper'tafle and dextramethorphan; another prostaglandin ligand selected from misoprostol, enprostil, rioprostil, omoprostol and rosaprostol,-a diuretic; and a sedating or non-sedating antihistamine. 17. Use of a compound, salt, hydrate or ester as defined In any one of claims I to 9 In the manufacture of a medicament for treatment or prevention of a prostaglandin mediated disease. 18. A compound, salt, hydrate or ester as defined In any one of claims I to 9 for use in the treatment or prevention of a prostaglandin mediated disease. 19. A prostagiandini antagonist pharmaceutical composition comprising an acceptable prostaglandit' antagonistic amount of a compound, salt, hydrate or ester as defined In any one of claims I to 9, In association with a pharmaceutically acceptable carrier. -122- Amended claims 123 A compound represented by formula I: R' R 2 R 3 -HET X-B I or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein: HET represents a 5-12 membered monocyclic or bicyclic aromatic ring system containing 0-3 heteroatoms selected from O, S(O)n and N(O)m wherein m is 0 or 1 and n is 0, 1 or 2; HET can also represent tetrazole; A is a one or two atom moiety and is selected from the group consisting of: 2 -W-C(R 7 2 -CR(OR 20 -C(R 7 2 -C(R 7 2 -C(OR 2 0 )R 7 -C(R 7 2 or -CR 7 =CR 7 wherein W represents O, S(O)n or NR 17 with n as previously defined and 0 R as defined below; X represents a 5-10 membered monocyclic or bicyclic aryl or heteroaryl group having 1-3 heteroatoms selected from O, S(O)n and N(O)m, and optionally substituted with R 1 4 and R' 1 and A and B are attached to the aryl or heteroaryl group ortho relative to each other; B represents -CH=CH- or 1,2-cyclopropyl; Z is NHSO 2 R 9 R 2 and R 3 independently represent H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkenyl-HET(Ra) 4 9 -(C(R 4 2 )pSR 5 -(C(R 4 2 )pOR 8 -(C(R 4 2 )pN(R 6 2 CN, NO 2 -(C(R 4 2 )pC(R 7 3 -C0 2 R 9 CON(R 6 2 or 20 -(C(R 4 2 )pS(O)n)R lo wherein p is 0-3 and n is as previously defined; Each R 4 is independently H, F, CF 3 or lower alkyl, or two R 4 groups are taken in conjunction and represent a ring of up to six atoms, optionally containing one heteroatom selected from O, S(O)n or N(O)m; each R 5 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 lower alkyl-HET, lower alkenyl-HET or 2 )pPh(R 1 )0-2; each R 6 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF 3 Ph, Bn and when two R 6 groups are attached to N they may be taken in conjunction and represent a ring of up to 6 atoms, optionally containing an additional hetetoatom selected from O, S(O)n or N(O)m; each R 7 is independently H, F, CF 3 or lower alkyl, and when two R 7 groups are present, they may be taken in conjunction and represent an aromatic or aliphatic ring of -AL 3 to 6 members containing from 0-2 heteroatoms selected from O, S(O)n and N(O)m; each R 8 represents H or R 5 [I:\DayLib\LIBXX03235.doc:aak 124 9 each R is independently H, lower alkyl, lower alkenyl, lower alkynyl, Ph or Bn; each R1 0 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 Ph(R') 0 3 CH 2 Ph(R' 1)0-3 or (6)2 each R' is independently lower alkyl, SR" 0 OR 20 N(R 6 2 -CO 2 R 1 2 -CON(R 6 C(O)R' 2 CN, CF 3 NO 2 or halogen; each R I i mdependently lower alkyl or benzyl; each R 1 3 is independently H, halo, lower alkyl, 0-lower alkenyl, S-lower alkyl N(R 6 2 C0 2 R 1 2 CN, CF 3 or NO 2 and R'1 4 and R 1 5 are independently lower alkyl, halogen, CF 3 OR1', S(O) 1 6 or 101 )0 each R 1 6 is independently H, lower alkyl, lower alkenyl, Ph, Bn or- CE 3 each R 1 7 is independently H, lower alkyl or Bn; each R8 is independently H, F or lower alkyl, and when two R8 groups are present, they may be taken in conjunction and represent a ring of 3 to 6 members comprising carhon atoms and optionally one heteroatomn chosen from 0, or N; each R9 is lower alkyl, lower alkenyl, lower alkynyl, CF 3 HET(R 2 4 9 lower alkyl- HET(Ra) 4 9 or lower alkenyl-HET(Ra) 4 9 each R 20IS independently H, lower alkyl, lower alkenyl, lower alky-nyl, CF 3 or Ph(R1 3 2 and each R' is independently selected from the group consisting of: H, OH, halo, CN, NO 2 amino, C 1 oalkyl, C 2 6 alkenyl, C 2 6 a I kynyl, C, 1 6 alkoxy, C 2 6 alkenyloxy, C 2 6 al1kynyloxy, C1- 6 alkylaniino, di-C 1 6 alkylamino, CF 3 C(O)CI- 6 alkyl, 2 6 alkenyl, C(O)C 2 6 alkynyl, CO 2 H, CO 2 CI- 6 alkyl, CO 2 C 2 6 alkenyl, and '*CO 2 C 2 6 alkynyl, said alkyl, alkenyl, alkynyl and the alkyl portions of alkylamino and S 25 dialkylamnino being optionally substituted with 1-3 of: hydroxy, halo, aryl, C 1 -6 alkoxy, C 2 6 alkenyloxy, C2- 6 alkynyloxy, CE 3 C(O)CI- 6 alkyl, C(O)C 2 6 alkenyl, C(O)C 2 6 alkynyl, *CO 2 H, CO 2 CI- 6 alkyl, CO 2 C 2 6 alkenyl, CO 2 C 2 6 alkynyl, NH 2 NHC,- 6 alkyl and N(C 6 alkyl) 2 21. A compound represented by formula 1: R 1 R R -HET or a phanriaceutically acceptable salt, hydrate or ester thereof, wherein: 125 HET represents a member selected from the group consisting of: phenyl, naphthalene, biphenyl, pyridine, quinoline, isoquinoline, furan, benzofuran, thiophene, benzothiophene, oxazole, thiazole, imidazole, benzothiazole, 1,2,5-thiadiazole, thienopyridine, indole, tetrazole, imidazole, benzoxazole and pyrrole; A represents a one atom moiety and is selected from the group consisting of S, SO 2 CH 2 and X represents phenyl optionally substituted with R 14 and R 15 and A and B are attached to the phenyl group ortho relative to each other; B is HC=CH; Z is OH; R R 2 and R 3 independently represent H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkenyl-HET(Ra) 4 -(C(R 4 2 )pSR 5 -(C(R 4 2 )pOR 8 -(C(R 4 2 )pN(R 6 2 CN, NO 2 -(C(R 4 2 )pC(R 7 3 -C0 2 R 9 CON(R 6 2 or -(C(R 4 2 )pS(O)n)R lo wherein p and n are each independently 0-3. 4 4 15 R 4 is independently H, F, CF 3 or lower alkyl, or two R 4 groups are taken in conjunction and represent a ring of up to six atoms, optionally containing one heteroatom selected from O, or N(O)m; each R 5 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 lower alkyl-HET, lower alkenyl-HET or -(C(R")2Ph(R1)0-2; 20 each R 6 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF 3 Ph, Bn and when two R 6 groups are attached to N they may be taken in conjunction and represent a ring of up to 6 atoms, optionally containing an additional heteroatom selected from O, S(O)n or N(O)m; each R 7 is independently H, F, CF 3 or lower alkyl, and when two R 7 groups are present, they may be taken in conjunction and represent an aromatic or aliphatic ring of 3 to 6 members containing from 0-2 heteroatoms selected from O, S(O)n or N(O)m; each R 8 represents H or R 5 each R 9 is independently H, lower alkyl, lower alkenyl, lower alkynyl, Ph or Bn; each R 1 0 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 Ph(R )o-3, CH 2 Ph(R' )o3 or N(R 6 2 each R 1 1 is independently lower alkyl, SR 20 OR 20 N(R 6 2 -CO 2 R 1 2 -CON(R 6 2 -C(O)R 12 CN, CF3, NO2 or halogen; each R 2 is independently H, lower alkyl or benzyl; each R 1 3 is independently H, halo, lower alkyl, O-lower alkenyl, S-lower alkyl, /T N(R 6 2 CO 2 R 12 CN, CF 3 or NO 2 [1:\DayLib\LIBXX]03235.doc:aak 126 R' 4 and R' are independently lower alkyl, halogen, CF 3 OR' 6 S(O)R' 6 or C(R' 6 2 0R each R' 6 is independently H, lower alkyl, lower alkenyl, Ph, Bn or CF 3 each R7 is independently H, lower alkyl or Bn; each R' 8 is independently H, F or lower alkyl, and when two R8 groups are present, they may be taken in conjunction and represent a ring of 3 to 6 members comprising carbon atoms and optionally one heteroatom chosen from S, S(O)n or N; each R 20 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF 3 or Ph(R' 3 2 and Io each R' is independently selected from the group consisting of: H, OH, halo, CN, NO 2 amino, C 1 6 alkyl, C2-6alkenyl, C2-6alkynyl, C 6 salkoxy, C2-6alkenyloxy, C 2 -6al kynyloxy, CI. 6 alkylamino, di-C,. 6 alkylamino, CF 3 C(O)CI 6 alkyl, C(O)C2-6alkenyl, C(O)C2-6alkynyl, CO 2 CO 2 C-6alkyl, CO 2 C2-6alkenyl, and CO2C 2 6 alkynyl, said alkyl, alkenyl, alkynyl and the alkyl portions of alkylamino and is dialkylamino being optionally substituted with 1-3 of: hydroxy, halo, aryl, CI- 6 alkoxy, C 2 -6alkenyloxy, C2-6alkynyloxy, CF 3 C(O)CI- 6 alkyl, C(O)C2-6alkenyl, C(O)C2-6alkynyl, CO 2 H, C0 2 C 1 -6alkyl, CO 2 C2-6alkenyl, CO 2 C 2 6 alkynyl, NH 2 N1Cl-6alkyl and N(C, calkyl) 2 22. A compound in accordance with claim 20 wherein: R19 represents a member selected from the group consisting of: lower alkyl and HET(Ra) 3 23. A compound in accordance with claim 22 wherein: R19 represents HET(Ra) 3 and HET is selected from the group consisting of: phenyl, thienyl, naphyhyl, furanyl, thiazolyl, imidazolyl and indolyl. 24. A compound in accordance with, claim 22 wherein: :R 1 represents benzene or thiophene, substituted with (Ra) 3 25. A compound in accordance with claim 20 wherein: HET represents a member selected from the group consisting of: phenyl, naphthalene, biphenyl, pyridine, quinoline, isoquinoline, furan, benzofuran, thiophene, 30 benzothiophene, oxazole, thiazole, imidazole, benzothiazole, 1,2,5-thiadiazole, thienopyridine, indole, tetrazole, imidazole, benzoxazole and pyrrole; A represents a one or two atom moiety and is selected from the group consisting of S, S02, CH 2 -OCH 2 -CHOH-, -C(OH)CH 3 and -CH 2 X represents phenyl optionally substituted with R' 4 and R' 3 B is CH=CH; [R:\LIBXX)03235.doc:-k 127 Z is NHSO 2 R' 9 and R19 represents a member selected from the group consisting of: lower alkyl and 26. A compound represented in one of the following tables: Table 1 RR R R -HET \A X-B/kNHSO 2 R Iq (Compounds 1-323 and 347-454) RIR)R-Het 1 A I x R I 19 )d I -naphthyl CH2 1,2-Ph CH=CH i 0 5, *5 S S S. CH=CPh(F' I 2-naphthyl S(0) 2 I ,2-Ph CH=CH Ph(F) 5 2 3-rnethylindol-1I-yl CH 2 1,2-Ph CH=CH 2-thienyl 3 2-naphthyl CH 2 1,2-Ph CH=CH 2-thienyl 4 2-naphthyl S(0) 2 1,2-Ph CH=CH 3-n-ethylindol-1I-yl 8(0)2 1,2-Ph CH=CH 2-thienyl 6 2-naphthyl 8(0)2 1,2-Ph CH=CH 3,5-di- 7 (CF 3 )phenyl 3,4-dichiorophenyl CH 2 1,2-Ph CH=CH 2-thienyl 8 2-naphthyl S(0) 2 1,2-Ph CH=CH 2-thienyl 9 2,4-dichlorophenyl CH 2 1,2-Ph CH=CH 2-thienyl I-naphthyl 8(0)2 1,2-Ph CH=CH Ph(F) 3 11 I1-naphthyl 8(0)2 1,2-Ph CH1=CH 3,5-di- 12 (CF) 3 phenyl 2-naphthyl 8(0)2 1,2-Ph l,2-c-propyl 2-thienyl 13 3,4- CH 2 1,2-Ph CH=CH 2-thienyl 14 chlorofluorophenyl I-naphthyl CH 2 1,2-Ph CH=CH 2-thienyl 3,4-dichlorophenyl S(0)2 1,2-Ph CH=CH 2-thienyl 16 4-methylthiophenyl CH 2 1,2-Ph CH=CH 2-thienyl 17 4-chlorophenyl CH 2 1,2-Ph CH=CH 2-thienyl 18 2-naphthyl S 1,2-Ph CH=CH 2-thienyl 19 2-naphthyl 0-CH 2 1,2-Ph CH=CH 2-thienyl 2-naphthyl S(O) 1,2-Ph CH=CH 2-thienyl 21 I -naphthyl 8(0)2 1,2-Ph CH=CH phenyl 22 2-benzofuranyl CH 2 1,2-Ph CH=CH 2-thienyl. 2 t 7 2~$/VT ~<K-R:\LIBXXJ0323 RIR, 2 R3-Het phenyl 1-naphthyl 1-naphthyl 1,2-(methyiene dioxy)benzene) 2-naphthyl RS-2-phenyl RS-2-phenyl 2-naphthyl 3 Qn )vi nyl)) ph enyl 2-(6-benzyloxy) naphthyl 3-((2-(Qn)v-inyl)) phenyl 3-((2-(Qn),vinyl)) phenyl 3-((2-(Qn)vinyl)) phenyl 3-((2-(Qn)vinyl)) phenyl 3 -tolyl-D-3-phenyl 3-((2-(Qn)vinyl)) phenyl 3-((2-(Qn)xrinyl)) phenyl 3-((2-(Qn)vinyl)) phenyl 3-((2-(Qn)vinyl)) phenyl 3-((2-(Qn)vinyl)) phenyl 3 -((2-(Qn)vinyl)) phenyl 2-naphthyl 2-(6-benzyloxy) naphthyl 2-naphthyl 2-naphthyl I A x IA CH 2 S(O)" CH 2 0 CH 2 CH 2 CH, CH 2 so -CHOH 0-CH 2 CH(OH' C=0 0 CH9, CH 2 CH 2 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph -,H=CH CH= C H CH=CH CH=CH -CH=CH CH 2 -0 CH 2 -CH, 2 CHIS-0 CH 2 -o CH=CH CH 2 -0 CH 7 2 -0 CI- 2 z- CH 2 -0 CH9-0 CH 2 -0 CH 2 -0 CH 2 -0 CFH 2 -O C(CH 3 2 -0 CH 2 -0 1 ,2-c-propyl 2-thienyl 3,5-d-C 3 phenyl 2-thienyl 2-thienyl- 2-thienyl 2-thienyl 2-thienyl 2-thienyl 2-thien-yl 2-thienyl 2-thienyl- phen-yl 2-thienyl 2-thieny1 phenyl 2-thienyl phenlyl 2-thienyl 2-thienyl 2-thienyl 2-thienyl Cpd 24 28 29 31 33 34 36 38 39 41 42 43 44 r* C.. C. C C. C C S. C C C. CH=CH l, 2 -c-propyl 1 2 -c-propyl T 2-methoxy-5- brmpenyl 3,4-dichioro phenyvl 4-fluo-ro 46 47 48 phenyI RIR;2R3-Het A Jx B 2-naphthyl 2-naphthyl 2-naphthyl 2-napiithyl 2-naphthyl 2-na ph thyl 2-nap hthy I 2-naphthyl 2-naphthyl 2-naphthyl 2-naphthyl 2-naphthyl 2-naphthyl 2-naphthyl 2-naphthyl 2-na plthyl 2-naphthyl 2-naphthyl 2-naphthyl 2-naphthyl 2-naphthyl 2-naphthyl 2-naphthyl CH 2 CH 2 CH 2 -CH-, CH~, CH2 Cu 2 CH 2 CH2 CH? CH 2 CuH 2 CH 2 C 2 CH 2 CH 2 CH 2 CH 2 CH 2 1,2 P 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1 2 -c-propy 1 2 -c-propy l, 2 -c-prop l, 2 -c-propy l, 2 -c-propy 1 2 -c-propy 1 2 -c-propy 1 2 -c-propy 1 2 -c-propy 1 2 -c-propy 1 2 -c-propy 1 2 -c-propy 1 2 -c-propy] 1 2 -c-propy] 1 2 -c-propy 1 2 -c-propy] 1 2 -c-propyl 1 2 -c-propyl 1 2 -c-propyl 1 2 -c-propyl 1 2 -c-propyl 1 2 -c-propyl T4-chioro--- 49 -phenyl I1 4 -propyl -phenyl 12,5-dichio-ro 51-I thienryl st 1I 52 1 3-chloro-4--5 fluorophenvl 1 4 methoxy 54 phenyl 1 3-brm M phenyl 1 2,5-dimethyl 56 pheny1 1 2 -nitro-4-chlo-o 5-7- 4-bh1e hnyy6 I 2,-difurboeh 64 phenyl 3,5-dichioro 659 phenyl I4-((1-hroy 66 butyl 6t1l 4,-hydroxy 62 mheny1)hel 3-(hydluro 68 methylphenyl ethydilr 69 phefnylphnl__ 3,-methylo phefnyl~pey 4 -(pIhropy l 71 sulfoyl)phenyl 1 2 -c-propyl 130 RPJR2R3 Het JA x I Ix [B z-napntnyi CH 2 CH 2 1,2-Ph 1, 2-Ph 1 2 -c-prop 3 2-naphth 0l 2-npht~l T -H 1,-Ph 1 2 -c-prop 2-naphth-yl H 2 1,2-Ph 1, 2 -c-propy 2-naphthvl 2-naphthyl 2-naphthyl 2-naphth 1 2ahyl- 2-naphthyl 2-naphthy1 2-naphthyt 2-naph t..y 2-naphthyl 2-naphthyl 2-nai hthv1 2-naphthyl 2-naphthyl CR,, 1,2-Ph CLI,, 1,2-Ph CR,, 1,2-Ph CH 1,2-Ph CH, 1,2-Ph- CH 12-Ph CH, 1,2-Ph CH 2 1,2-Ph CH2 1,2-Ph CH 1,2-Ph CH? 1,2-Ph '3(O) 2 1,2-Ph 1,--ro 1 2 -c-propy 1,2-c- ro 1,2-c- ro 2 propy- l,2-c-pro _L,2 c- rop 1 2 -c-propy] 1 2 -c-propyl 1 2 -c-propyl 1 2 -c-propyl 1 2 -c-propyl 1, 2 -c-pro yl 1 2 -c-propyI 7--R' 9 4 4 -((bis-trjfluoro- methyl)-hydrox 3 methy1)phenyl 'I 4 -(benz-yloxy) pheny1 4 thoxy-j. methyl) ethy1)phenyl 1 4-dimethy-l aminophenyl I c clohexyl 1 cyclopentyI 1-morpholinyl I 2 -naphthyl I 2 -thiazolyl I l-imidazol Y-l 3 -(2-'chloro)- furan 1 yridinyl 2 -(4-chloro) yridinyl 3-indolyI 4 -nitro henyl 4 -cyanophenyl 4- -hydrox-1 methyl)ethyl) _hen 1 4-(hydroxy methyl)phenyl 3-(hydroxy methy1)phen i 2 ,5-dimethyl 2 -carbomethoxy 2,4-difluoro phen~ 4-(methyl sulfonyvl)phenyl- 3-(methyl sulfonyl)phenyl- 4 -(propyl 73 74 77 78 7-9- 81 82 83 84 37 88 89 92 a. *0 a a. a a a a a a. 2-naphthyl S9(0) 2 1, 2 -Ph 2 -c-propyl 2-naph ThY S(0) 2 1,2-Ph- l, 2 -c-propyl 2-naphthyl S(O) 2 1,2-Ph l, 2 -c-propyl 2 -naphthyl S(O) 2 :1,2-Ph l, 2 -c-propyl 2-naphthy S(O) 2 1,2'-Ph l 2 cpoy 2-naphthyl 16S(O) 2 I 1,2-Ph 1 2 -c-propyl 2-naphthyl 2-naphthyl (0)2 1,2-Ph I l, 2 -c-propyl 1,2- 1 2 -c--propyl sulfonyl)phenyl I I It KvL4.R-H(e x B x B L-napntnyl 2-naphthyl 2-naphthyl 2-naphthyl 2-naphthyl I I 1,2-Ph I S(O) 2 S(O) 2 1,2-Ph l, 2 -c-propy l, 2 -c-propy 1,2-Ph l 2 cpropy] 1,2-Ph 1,2-Ph 1 2 -c-ropyl 1 2 -c-propy] 2-naphthTI S(O) 2 1,2-Ph l, 2 -c-propyl 2-naphthyl S7 (O) 0 1,2-P Ia-, 2 -c-propyl 2-naphthyl S(O) 2 1,2-Ph l- 2 -c-propyl 2-naphthyl S(O) 2 1,2-Ph- l, 2 -c-prp 2-naphthyl S(O) 2 1,2-Ph l, 2 -c-prpl 2-naphthyl S- (OX, 1,2-P h 1 2 -c.-propyl 2-naphthyl S(O) 2 1,2-Ph l, 2 -c-prop-Yl I4-but 1- henyl I 3,5 -d i (CF 'Phenyl 1 4 -((bis--trifluoro) methyl )-hydrox3 methyl)phenyl 3-bromophenyl 4-(benzy-loxy) phenyvl 2 -nitro-4-chloro _hen-yl 4 -isopropyl _13elurpey 4-(mphoiny-l butyl) p-hnylhny 3 4 -ropylphenyl 2phyl 2 ,5-dlfietoxy phenyl 3-trfluoroey mthypenyl 2,-chlorO-3-ny phenyl Cpd 98 99 112 113 114 117 118 119 12 2-naphthyl 2-naphthyl 2-naphthyl 2-naphthy1 2-naphthyl__ 2-naphthyl 2-naphthyl 2-naphthyl 2-naphthyl 2-naphthyl 2-naphthyl S(O)? S(O) 2 S(O S(O), S(0) 2 S(O) 9 1,2-Ph 1,2-Ph -1,2-Ph 1,2-Ph -1,2-Ph 1,2-Ph I1,2-Ph 1,2-Ph 1,2-Ph -1,2-Ph 1,2-Ph l, 2 -c-propyl l, 2 -c-propyl l,2-c-propyl 1 2 -c-propyl 1 2 -c-propyl 1 ,2-c-prolpyl 1 2 -c-propyl l, 2 -c-propyl l, 2 -c-propyli 1 2 -c-propyl 1 2 -c-propyl S S.. *5 S S S .5 *SS 0* S S. S *5 S e. S S (*5 2-naphthyl I~) 1T,2-Ph l 2 cpoy 2-naphthyl 2-naphthyl 2-naphthyl S(O) 2 S(O), '5(O) 2 1,2-Ph 2 -c-propy 1,2-Ph 1,2-Ph 1, 2 -,-propy 1 2 c-propy 3-2-ury119 13-(2-clor) 12 2-naphthyl I S(O), L2-Ph Ifura nyl 2~1 1 L~-pyrJainyi *1 R-2-aH hAhy 2-naphthyl 2-naphthyl 2-naphthyl 2 -naphthyl 2-naphthyl 2 -naphthyl 2-naphthyl 3-methyli-ndol -l-y 1 I 3-methy-lindol -l-yl 3-methylindol -l-y 1 3 -methylindol- S(OX, S(O) 2 S(O) 9 CH 2 CH 0 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph -1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph B R p l,2-c-pro 1L 2-st 112 l, 2 -c-propyl 3 ,5-difluoro. 1-27 henyl l, 2 -c-propyl 3,5-dichl-oro- 128 heny1 l, 2 -c-propyl 2 -(4-chlo-ro)
129- pridinyI ropy 1 -n o 3 l, 2 -c-propyl 4 -nitrophenyl 131 l,2-c-proPY1 4 -cyanL henYl 132 l, 2 -c-propyl 3-chloro-4- 133 fluorophen'yl l, 2 -c-propyl 3,5-di-(CF 3 13 phenyl l,- 2 -c-propyl 4 -isopropyl 13 DhenyI heyl 2 _c-propyl _L__fuoo 3 _henyI l, 2 -c-propyll 4 -fluorophenyl 138d RH 2 I1,2-Ph a a a a. a a p a. a 1 3-methylindofl 1 3-methy-lindol -1-1 3-methylindofl 1 3-methiylindol 1 3-rnethylindol -1-Y 1 3-methylin-dol 1 lid 3-methyli'ndol 1~ndo 3-methylindol 1 3 -met yln-dol -1-Y I- H 2 -CH 2 CHI 2 CH 2 1,2-Ph 1,2-P 1, 2-Ph 1,2 -Ph 1,2-h 1, 2-Ph 1,2-Ph 1,2-Ph 1,2-Ph l, 2 -c-propyl 1 2 -c-propyl 1 2 -c-propyl 1 2 -c-propyl 4 chloroph-enyl 4 -propylphenyl 2,5-dichloro-3- thieny1 2 -styryl 139 140 141 J1,2-c-propyll 3-chloro-4-fl-uorj 143 CH 2 I 1,2-Ph I KiT-2cp-ropyl 1 2 -c -propyl 1 2 -c-propyl 1 2 -c-p-ropyl 1 2 -c-propyl 1 2 -c-propy h env1 4 -methoxy phen 1 3 -brornophenyl 4,15-d Ir[methyl phenyl 2 -nitro-4-chloro _henyI carb-omethoxy phen 1v 2 ,4-difluoro phenyl 1144 145 147 148 149 RlR2 R3-Het AX B 3-methylindol -1 -yl 3-methylindol -1 -yl 3-methylindol 1 -yl 3-methylindoI.. -1-y] 3-rnethylindol 1 -yl 3-rnethyl indo]- -l-yl 3-mnethyl in dol 3-methyl indo I 1 -YI 3-methylindol 1 -Yl 3-methylindol -l-Y 1 3-methylindol -l-y 1 3-methylindol- -l-yl 3-rnethylindol 1 -yl 3-methylindol 1 -yl 3-methylindol -l-yl 3-methylindol 1 -yl 3-methylindol -l-yl 3-methylindol -l-yl 3-methylin-dol -l-yl 3-methylindol 1 -yl CH 2 CH, CH 2 CH, CH,, -CH, CH., CH, CH 2 CH 2 CH, CH 2 CH 2 CH 2 CH 2 CH 2 CH- 2 1,2-Ph 1T,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2 -PFh 1,2-Ph-i 1,2-Ph 1-T,2-Ph 1,2-Ph 1,2-Ph 1T,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph- 1,2-Ph 1,2-Ph 1,2-Prh l, 2 -c-roy 1 2 -c -ropy] 1, ,--propy] l, 2 -c-propyl 1 2 -c-propyl 1 2 -c-propy 1 2 -c-propyl 1 2 -c-propyl 1 2 -c-propyl 1 2 propyl l, 2 -c-propyl 1 2 -c-propy 1 2 -c-propyl 1 2 -c-propyl 1, 2 -c-propyl 1 2 -c-propyl 1 2 -c-propyl l, 2 -c-propy l, 2 -c-propyll R1 9 I 4 -butylphenyl n-butyl I 2 ,5-dimethoxy phenyl 3 -trifluoro methyiphenyl 3 ,5-difloro phenyl 3,5-dichloro- phenyl 1-hydrox-y- 1- methyl )ethyl) hen I 4-(hydroxy methy1)phenyl 3-(hydroxy methy1)phenyl_ 4-(methyl sulfony1)phenyl 3-(methyl sulfonyl)phenyl 4 -(propyl sulfonyl)phenyl 4 -((bis-trifluoro methyl )hydroxy methyl)phenvl 4-(benzyloxy) pheny 1-methoxy- 1- methyl) ethyl)phenyl 4-dimethyl aminophenyl cyclohexyl cyclopentyl 4 -morpholinyl Cpd 150 151 152 153 154 155 156 157 159 160 161 162 163 164 165 166 S C.. C C. C 0* C. 4@*C CC .C CH 2 1,2 Ph J 1,2-c-propylI 2-naphthyl 169 134 RlR 2 R 3 -Het 3-methylindol -1-yl 3-methylindolI -1-71 3-methylindol -l-yl 3-methylindol -1-71 3-methylindofl -l-yl 3-methylin d-ol -l-yl 3-methylindol -1-71 3-methylind-ol -1-yI 3-rnethyhn-dol 3-rnethyli nd o-l 3-methylindol l-yl 3-methylindol -1-71 3-methylidol -1-yl 3-methylindol- -1-yl 3-methylind ol 1 -yl 3-methylin-dol 1 3-methylindol- -1-yl 3 -methyli'ndol -1-yl 3-methylin-dol 1 -yl 3 -methylindolI 1 -yl 3-methylindol- 1 -yl 3-methyli'ndol -1-yl A eHn 2 CH 2 CH 2 en 2 eHn 2 CH 2 5:02 5- 02 So 2 so 2 5 02 sgo 2 5 02- so 2 50O2 oU 2 x 1,2-PhT 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1, 2 -Ph 1,2-Ph 1,2-Ph 1, 2-Ph- 1,2-Ph 1, 2-Ph 1,2-Ph 1,-2-Ph 1,2- 1,2-Ph 1, 2-Ph 1, 2-Ph 1, 2-Ph 1,2 -P h 1,2-Ph 1, 2-Ph 1,2-Ph B 1 2 -c-prop 1 i, 2 -C-prop 1 2 -c-prop 1 2 -c-prop3 1 2 -c-prop l, 2 -c-propy l, 2 -c-propy l, 2 -c-prop 1, 2 -c-propy 1 2 -c-prop 1 2 c-propy l, 2 -c-propy 1, 2 -c-propy 1 2 -c-propy] 1 2 -c-propyI 1 2 -c-propyl 1 2 -c-propyl l, 2 -c-propyl 1 2 -c-propy l, 2 -c-propyl l, 2 -c-propyl Rl 4l 2 -thiazoly] 1l-irnidaz-olyl 4 2 -furan-yl I1 3 2 -chlloro fu ranyl T 2 -pyridinyl I1 2-(4 -chloro) pyridinyl I 3-indolyl 1 4 -nitrophenyl 1 4 -cyanophenyl 1 ,5-di-(CF 3 phenayl 1 4 -isopropyl phenyl I 3 ,4-dichloro phenyl 3 ,4-difluoro phenyl 4 -fluor-ophenyl 4 -chlorophenyl 4 -propylphenyl 2,5-dichloro-3- thienyl 2 -styryl 3-chloro-4- fluorophenyl 4-methoxy phenyl 3-bromo phenyl phenyl Cpd 170 172 173 1-i74 175 176 178 179 180 181 182 183 184 187 188 190 9 9 9 9 *9 9* 9*S .9. 9 99 .9 9 9. 9 .9 9 9 9*99 9 9999 *999
999. 9 9 99 9 99 9. I RAWIN-Het A A I I I 3-methylindol 1 -y 1 3-methylindol -l-y 1 3-methylin dol -l-yl 3-methylindo1, -1 -YI 3-methylindol 1 -yl -rn -ethyli n-dol 1 -yl 3-rnethylind-ol -l-yl 3-methylindol -l-yl 1- (3-methyl) -indolyl 3-methylin-dol 3-methylindol 3-methylidol 3-methylindol 1 3-methylindol -l-y 1 3-methylinidol 1 -yl 3-methylindol- -l-yl 3-methylindol 3-methylindol 3-methylindol so 2 so0 2 s0 2 sgo 2 so 2 so 2 sgo 2 so, -§2 so 2 so 2 so 2 sgo 2 so0 2 1,2-Ph 1, 2-Ph 1,2-Ph 1,2-Ph 1-i,2-Ph 1,2-Ph 1,2P 1,2-Ph 1,2-Ph 1-T,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1, 2-Ph 1T,2-Ph 1,2-P 1 2 -c-p-ropy 1 i, 2 -c-propyl 1 2 -c-propy] 1 2 -c-propyl 1 2 -c-propyl l, 2 -c-propyl 1, 2 -c--propy l, 2 -c-propyl 1l -p-propyl 1 2 -c-propyl l, 2 -c-propyl 1 2 -c-propyl 1 2 -c-propyl 1, 2 -c-propyl 1 2 -c-propyl 1 2 -c-ppy I 2 -nitro-4-chloro phenyl I 2 -carbomethoxy phenyl 2 ,4 -i fl-uor o phenyl 4-butylphenyl n-b utyl 275-di1nethoxy7 phenyl 3 -trifluorometli_ pheniyl 3 phenyl 3,5-dichio)ro phen-yl 1-hydrox-T1- methyl)ethyl) phenyl 4-(hydroy methy1)pheny1 3 -(hydroxy meth 1) henyl 4-(methyl sulfonlrph enyl 3-(methyl sulfonyl)phenyl 4 -(propyl sulfonyl)phenyl 4-((bis-trifluoro methyl)hydroxy Cpd 192 193 196 1-9 8 200 201 202 203 204 205 .5 S S S *5* S. S S 45 S S 55 S *5*5 S SS S S S 1 2 -c-propyl 1 2 -c-propyl 1 2 -c-propyl l, 2 -c-propyl 4-(benzyloxy) phenyl 4 -((1-methoxy- 1- methyl)ethyl)- phenyl 4-dimethyl am inophenyl cyclohexyl 208 209 210 211 136 RIPR2R 3 -Het 3-methylindol 1 -yl 3-methylindol -l-yl 3-methylindol -l-Y] 3-rnethylindol l-y 1 3-rnethylindol 1 -Y] 3 -rnethyl ind ol 3-methylindol -l-yl 3-m ethyli ndol- 1 -yl 3-rnethylhndol- 1 -yl 3-rnethylindo I -l-yl 3-rnethylindol 3-rneth-yndol 2-naphthryl 2-naphthyl 2-naphthyl 2-naphthyl 2-naphthy 2-naphth-yl 2-naphthyl 2-naphth1yl 2-naphthyl~q 2-naphthyl A so., S O 2 5 02 SgO 2 So 2 502 SO 2 SH2 CH 2 MH 2 OH 2 OH 2 "H 2 I H 2 1 1,xP 1,2-Ph 1,2- 1, 2-Ph 1,2-Ph 1,2-Ph 1,2- Ph 1, 2-PhT 1,2-Ph 1T,2-Ph 1, 2-h 1,2-Ph 1,2 -Ph 1, 2-Ph 1,2-Ph 1,2-Ph 1,2-Ph_ 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph J Bcprpy l, 2 -c-propyl 1 2 propyl l, 2 -c-propyl 1 2 -c-propy 1 2 -c-propyl 1 2 -c-propy 1 2 -c-propyl l, 2 -e-propy 1 i, 2 -c-propyl 1 2 -c-propy 1 2 -c-propy CH CH CH =CH CH CH- CH=CH CH=CH -CH CH CH CH R cyclopentyl 4-mrnrph-oli fl 2-napht-hyl 2 -thi azolyl 2 -fura nyl 3 2-chl-loro furanyl 2 -pyridinyl- 2 -(4-chloro) pyri dinyl 3-indolyl 4 -nitrophey 4 -cyanophenyl 3,5-di--(CF 3 -henyl 4 -isopropyl phenyl 2,311dic h Io ro phenyl 3,4-difluoro phenyl 4 -chlorophenyl 4 -fluorophenyl 2 ,5-dichl-oro-3- thienyl 3 -chloro-4-fluorc phEnyl 4-methoxy butyl 3-trifluoro methyliphenyl Cpd] 212 214 215 21 218 219 220 221 222 223 224 225 226 M3 9. 9. 9 9 .9 "to9 too. RlR2R3-Het A B .x7jB rF1 I z-napntnyi UH2 1,2-Ph CH=CH 4. In 2-nahthy CH 2 1,2-h CHCH 4 2-naphthyl CH 2 1,2-Ph CH=CH 4- 2-nahthy 1,-Ph H=C 2-naphthyl CH2~ 1,2-Ph CH=CH 4. 2-naphthyl C 9 1,2-Ph CH=3 2 2-apthlCHI) ,2P CH=CH 2 2-naphthyl CH2 -1,2-Ph CH-= CH 24- 2-naphthyl CH,, 1,2-Ph CH=CH 4- 2-naphthyl SO, 1,2-Ph CH=CH 3, 2-naphthyl CH, 1,2-Ph CH=CH 4- 2-naphthyl CH0, 1,2-Ph CH=CH 2, -((1-hydroxy-i. Lethyl)ethyl) [ieny1 .ifony1)phenyl (benzyloxy) enyl 7clohexyl *morpholinyl thiazolyl furanyl pyridinyl cyanophenyl 5-di-(C F 3 -ienyl isopropyl ienyI 3-dichloro ienyl 4-difluoro ienyl chiorophenyl Cpd 235 236 237 238 E239 240 241 242 243 244 245 246 247 248 2-naptithyl S02) 1,2-Ph CH=CH 4 3, 4- 2-naphthyl so~ 1 P2-Ph CH=CH 2-naplithyl so~, 1,2-Ph 4 9 ~0 C 9** 9 *9 4* 09 *9 C C a.. *9 .9 cc. 9* C 'S eC 9* 9* C. S *4@C *9Sg C *SCC 9C99 C 9O 4 9* *9 9 CH=c H 2-naphthyl SO 2 1,2-Ph CH=CH 2,5-dichloro-3- 250- thienyl 2-naphthyl 502 1,2-Ph C H=CH 3-chloro-4- 251 fluorophenyl 2-naphthyl SO 2 1,2-Ph CHTT=CH 4-methoxy 252 phenyl 2-naphthyl 09 -1,2-Ph CH=CH buy 253 2-naphthyl S0 2 1,2-Ph CH=CH 3-trifluoro 254 methyiphenyl 2-naphthyl 502 1,2-Ph CH=CH 4-((1-hydroxy-l- 255 methyl)ethyl) p2henyl 2-naphthyl 502 1,2-Ph CH=CH 4-(methyl 256 sufonyl)phenyl 2-naphthyl S0 2 1,2-Ph CH=CH 4-(benzyloxy) 257 phenyl 2-naphthyl -1,2-Ph CH-=CH cyclohexyl 258 2-naphthyl 09 -1,2-Ph CH 7CH 4-morholinyl 259 2-naphthyl 8--9 1,2-Ph CH =CH 2-tazoyl 260 2-naphthyl IS09 1,2-Ph CH-CH 2-furanyl 261 2-naphthyl 1,2-Ph HCH 2prdnl 262 138 R-lR, 2 R 3 -Het 2-naphthyl 2-na ph thyl 2-naphthyl 2-naphthyl 2-naphthyl 2-naphthyl 2-na phthyl 2-naphthyl 2-naphthyl 2-naphthyl 2-naphthyl 2-naphthyl 2-naphthyl 2 -(6-benzyloxy) naphthyl 2 -(6-benzyl-oxy) naphthy1 2 -(6-benzyloxy) 2 -(6-benzy-oxy) naphthyl 2 -(5-benzyloxy) jmphthyl 2 4(5-benzyloxy) naphth LL- 2 -(5-benzyloxy) naphthyAl 2 -(5-benzyloxy) naphthyl 2 4( 6 floro methyl)benzyloxy)) naphthyl_ A CH2-O CH 2 -0 CH 2 -O CH 2 -0 O-CH, O-CH, O-6-CH 2 O-CH 2 S S0 2 S0 2 S02 502 x 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,-2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1, 2-Ph 1,2-Ph C C C. Ci C] 1,2 B R9 H=CH 4-c anophenyl H-C H 3,5-di-(CF) phenyl H=CH 4 -isopropyl HI=CH 2,-3-dichloro phenyl H=CH 3,4-difluoro phenyl phenyl EI=CH 4 -isopropy-l phenyl ffI=CH 2,3-dichioro phenyl [-15HH 5,4-di1fluoro henyl i=CH 3,5-di-(CF 3 phenyl I C 4 T-i s oro py phenyl ~I=CH 2,3-dichioro i=CH 2,-hinlr ~-c-rpy2-henyl i=CHpoy 2-thienyl T= C H 2-thienyl- =CH 2-thienyl -c-propy 2-thienyl ::CHpoy 2-thienyl CH 2-thienyl Cpd 263 264 27 268 2769 270 271 278 *0e S* 00S 0 too* 0* 5@9 S oil S9 139 S RlR 2 R 3 -H-et JA XThL B_ ,'ITT 9 -(rP-A 4- CTj I Ii UU1 v methyl)benzyloxy' naphthyl Ii~) 1, L,-17 11 kr1=kLd1 2-thienyl 285 2f-(6-(4-trifluoro methyl)benzyl .oxy))naphthyl -t i f J. I H,-l 1,2-Ph 1, 2 -c-propyl 2-thyl 286 2-(6-4-trifluoro methyl)benzyl oxy))naphthyl 1-(6-benzyloxy) naphthyl 1-(6-benzylo;6y) naphthyl ,4-difl uoro benzyloxy)) naphthyl ,4-difluoro benzyloxy)) naphthyl 4 1 H24 1,2-Ph 1,2-c-propyl 2-thienyl 87T S0 2 f CH=CH I 2-thienyl 288 CHi I 1,2-Ph CH=CH 2-thienyl I 289 4- 4 L S0 2 1,2-Ph CH=CH I2-thienyl I 290 CH2, 1,2-Ph [CH=CI- 2-thienyl 29 2-(6-(4-fluoro benzyloxy)) naphthyl I 4- Hl 1,2-Ph l, 2 -c-propyl 2-thien-yl 29 2-(7-benzyloxy) naphthyl 4- S0 2 1,2-Ph UH=CH 2-thienyl 19 ,4-difluoro benzyloxy)) naphthyl 2-(6-(3,4-difluoro benzyloxy)) nphthyl 4- I 0i 2 1,2-Ph CH=CH 3 ,4-difluoro phenyl 3 ,4-difluoro phenyl 294 295 1,2-Ph fCH=CH .S.V SO *000 0 SO .00.00 0* 0 S* e. 00 .0. 0 2-(6-4-fluoro CH, 9 1,2-Ph l, 2 -c-prOPYl -3,4-difluoro 296 benzyloxy)) phenyl naphthyl______ 2-(7-benzyloxy) SO 2 1,2-Ph CH=CH 3,5-di-(CF 3 297 naphthyl _____phenyl 2 -(6-(3,4-difluoro SO 2 1,2-Ph CH=CH 3,5-di-(CF 3 298 benzyloxy)) phny naphthyvl 2 -(6-(3,4-difluoro Gil CHC ,-i-C3 9 benzyloxy)) 2p,2Phenyl35di(C 3 naphthyl 2-(7-benzyloxy) SO 2 1,2-Ph l, 2 -c-propyl 3,4-difluoro 300 naphthyl 2-naphthyl CH 2 1,2-Ph CH=CH 2-methoxy-5- 301 bromophenyl RIRV2R3-Het 2-naphthyl 2- naphthyl 2-naphthyl 2-naphthyl 2-naphthyl 2(-ezyloxy) naphthyl 2-(5-benzylox3y) naphthyl naphthyl 2-naphthyl 1,2-Ph 2-naphthyl 2-naphthyl 2-naphthyl 3-methyl indol- l-yl 3-methyl indol-l1-yl 3-methyl indol-1-YI o~oo 3-methyl indol- l.-l 03-methyl indol-1-Yl :3mthyl- indol-1-V1 3-methyl indol-1-v1 3-miethyl indol-1-y1 3-methyl indol-1-yl A C~H, S0 2 0 CH, so,, S CH2 so, 140 x 4-CL-1,2-Pt 4-1,2-P 1,2-Ph 1,2-Ph 1,2-PFh 1,2-P h 1, 2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-Ph 1,2-P h 1,2-Ph 1,2-Ph 4-Cl-1,2-Ph 4-CI-1,-2-Ph 4-Cl-1,2-Ph B ICH=CH CjH=CH If H CH CH =C H CH=CH H C H C H CH~C 1 2 -c-propyl l, 2 -c-propyl 1 2 -c-propy CH=CHL CH=CH 1 2 -c-propyl 1 2 -c-propyl C7H =C H CH CH l, 2 -c-propyl l, 2 -c-propyl CH=CH CH=CH 1 2 -c-propyl R" 2 -methoxy-5- bromophenyl 2-thienyl 2-iimethoxy-5- bromophenyl 2-methoxy-5 bromophenyl 2-met6oxy-5- bromnophenyl bromaophenyl bromo phenyl bromophenyl bromo Phenyl 2-methoxy-5- bromophenyl 2-rnetho-xy-5 bromop henyl 2-methoxy-5 bromophenyl bromophenvl 2 bromophenyl bromophenyl 2-methoxy-5 bromophenyl brornophenyl 2-methoxy-5- bromophenyl bromophenyl 2-methoxy-5- bromophenyl bromophenyl bromophenylI 302 303 304 305 306 3072 303 319 310 311 312 313 314 31 320 P.R,2R3-Het A±.I B Ip 2-(7-fluoro) naphthyl 2-(7-fluoro) naphthyl 2-(7-fluoro) naphthyl 2-(7-fluoro) naphthyl 2-(7-fluoro) naphthyl 2-(7-fluoro) naphthyl 2-(7-fluoro) naphthyl 2-(7-fluoro) naphthyl 7-fluoro) naphthyl 2-(7-fluoro) naphthyl 2-naphthyl I r il bU 2 4- 1-1,2-Ph H=iCH 2-thienyl 347 giT I -I- 4-CI-1,-P-h H 2-thienyl S 4-Cl-1,2-Ph CH=CR- 2-thienyl 349 T CH 2 4-CI-1,2-Ph CH=CH 2-thienyl 350 CH, 6-C1-1,2-Ph CR=CH- 2-thienyl 351I -CR 0 4-Cl-1,2-Ph 1,2-c-Pr 2-thienyl32 CR 0 H- 3-Cl-1,2-PH CjH=CH 2-thienyl 353 SO, 4-Cl-1,2-Ph CH=CH 0 I4-Cl-i 2-P CH=CH S I4-Cl-1,2-Ph -CH 2 S S S 4,5-C12- 1,2-Ph 6-Cl-i ,2-Ph CUH= C H CH=CH CH=CH 2-mi ethoxy-5 bromophenyl 2--methoxy-6- bromophenyl 2-methoxy-5- bromophienyl 2-methoxy-5- bromophenyl -m-ethoxy-5- bromophenyl 2-methoxy-5- broinophenyl 2-methoxy-5- bromoheyl 2-(7-fluoro) CR2 naiphthvl2 354 355 356 357 358 359 360 361 362 2-(7-fluoro) naphthyl 2-(7-fluoro) naphthyl 2-(7-fluoro) naphthyl 2-(7-fluoro) naphthyl 2-(7-fluoro) naphthyl 2-(7-fluoro) naphthyl 2-(7-fluoro) naphthyl H2 4-Cl- 1,2-Ph CR 2 3-Cl-1,2-Ph S0 2 4-Cl-1,2-Ph I1,2-c-Pr CH=CHj CH=CH 0 f 4-Cl-1,2-PhI CH=-CH 2-trifluoro chlorophenyl 2-trifluoro S CR 2 I I /1 -~i chiorophenyl 4-Cl-i ,2-Ph Ch=UH 2-trfluoro chlorophenyl 363 (3H=CH 2-trifluoro chiorophenyl 364 CR 2 6-Cl-1,2-Ph CH=CH 2-trifluoro 365 'ciiou1 op nyi 7 1 IR'LR;4U3-Het 7-fluoro) naphthyl 7-fluoro) naphthyl 6- 'riG 4-UI-1I,2-Ph 1,2-c-Pr GCH, 3-C1-1,2-PH4 CH=CH 2 -trifluor~o rnethoxy-s.. chlorophenyl 2-trifluo-ro chiorophenyl 2-thienyl- 367 I .0 0 2-(7-fluoro) naphthyl 2-(7-fluoro) naphthyl 2-(7-fluoro) n aphthyl 2-(7-fluoro) naphthyl 2-(7-fluoro) naphthyl 7-fluoro) naphthyl 7-fluoro) naphthyl 2-(7-fluoro) naphthyl 2-(6-fluoro) naphthyl 2-(6-fluoro) naphthyl 2-(6-fluoro) naphthyl 2-(6-fluoro) naphthyl 2-(6-fluoro) naphthyl 2-(6-fluoro) naphthyl 2-(7-chloro) naphthyl 7-chioro) naphthvl 2-(7-chloro) naphthyl 2-(7-chloro) naphthyl 2-(7-chloro) naphthyl S0 2 4-01-1,2-Ph CH=CH o 4011,-P CH;TMH 2- thienyl369- S4-01-1,2-Ph CH =CH 2-thienyl 370 TH, 4-01-1,2-Ph CH OH 2-thienyl 371 OH, 6-01-1,2-P C7H=CH 2 thienyl 372 011,, 4-01-1,2-P 1,2-c-Pr 2-thienyl 373 0112 3-01-12-Ph 01=011 2-thiey 374 SO 2 4-01-1,2-P OH=COH 2-methoxy-5- 375 o 4-01-1,2-Ph CH=CH S-g 4-01-1,2- 011-=01 OH 2 4-01-1,2-P 011=011 0112 6-01-1,2- H -=H CH 2 I4-01-1,2-P 1,2-c-Pr bromophenyl 2-methoxy-5- bromophenyl bromophenyl 2-methoxy-5- bromop~henyl 2--methoxy-5- bromnophenyl 2-methoxy-5- 376 378 379 380 0112 3-01-1,2-Ph 011=01 bromophenyl 502 4-01-1,2-Ph o 4-01-1,2-Ph1" S 4-0';112-P 0112 4-01-1,-P 0112 6-01-1,2P CH=CH bromophenyl 2-thienyl 382 T 4 (JI1=CH 2-thienyl 383 I I I :4=011C 2-thienyl 384 T 4 (Jh=CH 2-thienyl T 4 A. (214=011 2-thienyl 386 I 143 I witzRo-Het A nr,1, I naphthyl ti"1 4-131-1,2-Ph 1,2-c-Pr 2-thienyl 2-(7-chloro) CH 2 3-Cl-1,2-Ph CH=CH -2-thienyl naplithyl_____ 2-(6,7-difluoro) S0 2 4-C1-1,2-Ph CH=CH 2-thienyl naphthyl 2-(6,7-difluoro) 0 4-Cl-1,2-Ph CH=CH 2-thienyl naphthyl 2-(6,7-difluoro) S 4-Cl-1,2-Pl CFI=CH 2-thienyl 2-(6,7-difluoro) -C-H 2 4-Cl- 1,2-Ph CH=CH 2-thi'enyll naphthyl 2-(6,7-difluoro) CH 0 6-C1-1,2-Ph CH=CH 2-thienyl naphthyl 387 390 394 naphthyl U1H2 4-C- 1,2-Ph 1,2-c-Pr 2-tinienyl a 2-(6,7-difluoro) CH2 3-C1-1,2-Ph CHi-CH 2-thienyl 395 naphthyl 2-(6,7-difluoro) S0 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 39 n aphthyl __________bromophenyl 2-(6,7-difluoro) 0 4-CI-1,2-Ph CH=CH 2-methoxy-5- 397 naphthyl _________bromophenyl 2-(6,7-difluoro) S 4-C1-1,2-Ph CH=CH 2-methoxy-5- 398 na hthyl _________bromophenyl 2-(6,7-difluoro) CH 2 4-CI-1,2-Ph CH=CH 2-methoxy-5- 399 naphthyl _________bromophenyl 2-(6,7-difluoro) CH 2 6-C1-1,2-Ph CH=CH 2-methoxy-5- 400 naphthyl __________bromophenyl 2-(6,7-difluoro) CH 2 4-C1-1,2-Ph 1,2-c-Pr 2-methoxy-5- 401 naphthyl _________bromophenyl 2-(6,7-difluoro) CH2 3-C1-1,2-Ph CH=CH 2-methoxy-5- 402 naphthyl ______bromophenyl 2-(5,7-difluoro) CH 2 4-C1-1,2-Ph CH=CH 2-methoxy-5- 403 naphthyl _____bromophenyl 2-(5,7-difluoro) S 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 404 naphthyl 2-(5,7-difluoro) 0 4-CII-1,2-Ph CH=CH 2-methoxy-5- 405 naphthyl ____________bromophenyl 2-(5,7-difluoro) S0 2 4-C1-1,2-Ph CH=CH 2-methoxy-5- 406 naphthyl ______bromophenyl 2-(6-fluoro) S0 2 4-C11,2-Ph CJ±=CH 2-methoxy-5- 407 q uinolinyl ____________bromophenyl 2-(6-fluoro) S 4-Cl-1,2-PI CH=CH 2-methoxy-5- 408 quinolinyl bromophenyl I 2-(6-fluoro) quinolinyl 2-(6-fluoro) quinohinyl 2-(6-fluoro) quinolinyl 2-(6-fluoro) quinolinyl ,7-difluoro)- quinolinyl 2-(5,7-difluor-)- quinolinyl ,7-difluoro)- quinolhnyl ,7-difluoro)- quinolinyl 2-(5,7-difluoro)- quinolinyl ,7-difluoro)-- _A X IB1 R 9 U112 4- I-1,2-PhJ CH=CH OH 2 1,2-Ph C H OH- o 4-CJ-1,2-Ph OH=CH CH2 4-01--1,2-P 1,-2-c-Pr SO 2 -012-1,2-PhOH=OH S9- 4-01--1,2-Ph CH=CH OUH 2 4-01-1,2-PI CH ZH- OUH T,-2-Ph c H -O o4-0I1,2-Ph CH=CH OH 2 4-01-1,2-Ph 1,2-c-Pr SO-0 2 4-01-1,2-PE CH=CH S 4-C1-1,2-P CH-=0H OH 2 4-01-1,2-P CH=CH 0* :0 00 0 q uinolinyl 3,4-dichloro phenyl 3 ,4-dichloro phenyl 3 ,4-dichloro phenyl 3,4-dichioro phenyl 3,4-dichioro _henyl 3 ,4-dichloro phenyl 3,4-dichioro phenyl 4-chioro phenyl 4-chioro _phenyl 4-chioro phenyl 4-chioro phenyl 4-chioro phenyl braornohenyl brainophenyl 2-methoxy-5- bromnophenyl 2-rnethoxy-5 brornophenyl 2-rnethoxy-5- bromrophenyl 2-methoxy-5- bromophenyl 2-rnethoxy-5- brornophenyl 2-rnethoxy-5- brornophenyl 2-methoxy-5- bromophenyl 2-meth-oxy-5- bromophenyl 2-rnethoxy-5- brornophenyl 2-meth-oxy-5- brornophenyl 2-methoxy-5- bromnophenyl 2-rnethoxy-5 brornophenyl 2-methoxy-5- brornophenyl 2 -methoxy-5- brornophenyl 2-rnethoxy-5- bromophenyl 2-rnethoxy-5 bromophenyl 2-methoxy-5- bromophenyl 2 -methoxy-5-_ 410 411 412 413 414 415 416 4- 17 418 419 420 421 422 423 424 425 426 427 428 OH 2 1,2-Ph -CH=CH o-G 4-01-1,2-P CH=CHi OH 2 4-01-1,- 1,2-c-Pr- OH- 2 -0-1-1,2-Ph CH=CH S02 4-01-1,2-PE CH=C S 4-01-1,2-P f CH=C H OH 2 4-01-1,2-Ph CH=CHj O H 2 0 1,2-Ph 4-01-1,2-Ph CH=CH bromophenyl 429 429 CH=CH I 2-rnethoxy-5- 430 I -uI-Iiioupnenyi I RlR, 2 R 3 -Het 4-chioro phenyl 4-chloro phenyl 3 ,4-dichloro phenyl 3 ,4-dichloro phenyl 3,4-dichloro phenyl 3, 4-di chi oro ph enylI 3,4-dichlord phenyl 3,4-dichloro phenyl 3,4-dichioro phenyl 4-chloro phenyl 4-chioro phenyl 4-chioro phenyl 4-chloro phenyl indolyl indolyl l-(6-(4-chloro) pheny1)indo l1 2-(6-difluoro methoxy) naphthyl 2-naphthyl- 2-naphthyl 2 -(6-chloro nap hthyl) methoxy) indolyl A CH 2 CH 2 CH, CH 2 -I 2 so 2 CH 2 CH- 2 CH 2 CH 2 Gil 2 x -B 4-Cl-i, 2-Ph 4-Cl-i, 2-Ph 4-CI-1,2-PE 4-Cl-1,2-Ph 4-Cl-1,2-P 1,2-Ph1- 4-Cl-1,2-P i 4-CI-i,2-Ph 5-C l-2-Ph 4-Cl- 1,2-Ph 4-CI-1,2-Ph 4-Cl-1,2-Ph 1,2-P h 3 2 -Pyr 3 2 -Pyr 4-F-1,2-PhT 4-Cl-1,2-PE 4-MeG-- 1,2-Ph 5-Cl-1,2- ClI--1,2 -Ph 4-F- 1,2-Ph p p p p p p p p p. p P p. 1,2-c-Pr CH CH CH CH CfH-=CH -C H=CH CH ZCH CH=CH CH TCH Cf H CH CH=CH C H-=CH CH CH- C H-=CH CH=CH CH=CH -CH CH C-H=CH CH=CH CUH =C H CFL=CHf- C H=CH R -bromophenyl 2-ethoxy-5.. bromophenyl 2-th'enyl- 2 -thienyl 2-thienyl 2-thienyl 2-thienyl 2-thienyl 2-thienyl 2-thienyl- 2T-thienyl 2-thienyl 2 -thienyl 2,4-(Me)2- 2-thienyl 3-chloo-4- fluorophenyl bromophenyl 2-methoxy- bromohenyl bromophenyl bromophenyl 2-methoxy-5- bromophenyl 431 433 44 442 4436 447 435 446) 441 442 443 1,51 146 I WIVZRJ-Het A IA I u-kenzouij thiophenyl U12 4- -1,2-Ph 5-(1-benzyl) CH 2 4-F-1,2-Ph CH=CH 7MH=C H CH=CH 2-methoxy..- bromophenyl bromophenyl 2-methoxy-&- bromophenlyi 454 1-(6-(4-chloro) phenyl )indolyl CH 2 4-F-1,2-Ph L- Table II R 1 R 2 R 3 HET0 0 X- B S S 1-b (Compounds 324-346 and 455-542) RlR2R$3-Het A X B p 2-naphthyl l,2-phenyl CH=CH 324_ 2-naphthyl -S 1,2-phenyl CH=CH 325:T 4-methylthiophenyl CH 9 1,henyl CH=CH 326 3-methylindol-1-yl CH. 1,2-phenyl CH=CH 327 3 -chloro-4-fluorophenyl CHR 9 1 ,2-phenyl CH=CH 328 4-chlorophenyl C 1) 1,2-phenyl CH=CH 329 2-naphthyl _CR 9 1,2-phenyl CH-=CH 330 2-naphthyl 1,2-phenyl l,2-c-propyl 331 2-naphthyl S(0) 9 lhenyl CH,-CH 2 332 2-naphthvl S 1,2-phenyl CII=CH 333 3,4-dichiorophenyl S(O)9 1,2-phenyI CH 9 )-CH 334 3,4-dichlorophenyl C H 1,2-phenyl CH:=CH 335 2 6 -benzyloxynaphthyl CH 9 ,2-phenyl CII=CH 336 2 6 -benzyloxy)naphthyl CR 9 1,2-phenyl l, 2 -c-propyl 337 2-(6-benzylox )naphthy 1 so 9 1,2-pheny 1, 2 -c-poy 3 2 6 -benzyloxy)naphthyl 4CH 9 -O i ,2-PhenvI 1, 2 -c-propyl 339 2 6 -benzyloxy)naphthyl O-CH 2 1,2-penyl l, 2 -c-propyl 340 2 6 -benzyloxy)naphthyl SO 9 1 ,2-phenyl CH=CH 341 2-(6-benzyloxy)naphthyl ut9- 1,2-phenyl CH=CH 342 147 1 1 WWRO-Het A c*~Ii' S I- 4 B /L- 5 -Denzyioy~napttyl 2-(6-benzyloxy)naphthyl 0- H U-UI1~ 1 2-nhen-I I I 2-(7-benzyloxy)naphthyl 2 6 4 -trifluorom-ethyl) benzyloxy))naphthyl 2-(6-fluoro)naphthyl OH 2 1,!2-rheriyl- 1,2-p)henyl 1,2-phe-nyl so 4-CI-1,2-Ph 0 0 I *0* 0* I I* I *0 I I. 0* 0* I I. I I I I. 2-(6-fluoro)naphthy1 2 -(6-fluoro)na'phthyl 6-fluoro )naphthyl 2-(6-fluoro)naphthyl 2 -(6-fluoro)naphthyl 7-fluoro)naphthyl 2-(6-cloro)naphthy1 2 -(7-loro)naphthyl 2 -(6-loro)naphthyl 2 -(6-loro)naphthy1 2 -(7-loro)naphthyl 2-(6-chloro)naphthyl 7-chloro)naphthyl 2 6 ,-dloro)naphthyl 2 -(6,-dloro)naphthyl 2 -(6,-dloro)naphthl 2 6 ,-dloro)naphthyl 2 -(67-dloro)naphthyl 2-(67-dloro)naphthyl 2 -(7-dloro)nahth 1 2-(67-dloro)naphthyl 2 6 7-dloro)naphthyl 2-(6 7-dloro)naphthyl 6, 7-difluoro)naph Iy 7-difluoro)naphthyl 2-meth--fluoroahh 2-(6o- l-ylhhy Is CH? CH,, 0 CH?, s09 s CH? CH., 0 OH 0 so, S CH, 0K, 0 OCH9 S09 S CH9 CHI? CH9, CH 2 so CH 2 CH 2 CH2 CRH CR 2 CH, CH 9 CH, CH 2 CH~ s o 2 4 4-01 2 -Ph 4-C1-1,2-Ph 4-1,2-h- 4-1,2-h 4-01-1,2-Ph 4-Cl- 1,2-Ph 4-Cl- 1,2-Ph 4-01-1,2-Ph 4-1, 2-Ph 4-1,2-Ph 4-Cl- 1,2-Ph 4-CI-1,2-Ph 4-01-1,2-Ph 4-01--1,2-Ph 4-1,2-Ph 4-1,2-Ph 4-01-1,2-Ph 4-Cl- 1,2-Ph 4-01-1,2-Ph 4-01-1,2-Ph 4-C1-1,2-Ph 4-01-1,2-Ph 4-Cl- 12P 4-01-1,-2-Ph 4-01-1,2-Ph 4-01-1,2-Ph 4-Cl-i ,2-Ph CH TCH CH=O H CR =CH OH=CH CHR=CH CH =CH OH=CH 1,2-c-Pr CR=CH CR=CR CR=CH CR=CR 1,2-c-Pr CR=CR OR=CR OR=CR CR-=CH CHc=CR CR=CR CR=CH CH=CH CH=CH 343 344 345 346 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 4-01-1,2-Ph CR=CH 482 4-01-12-Ph 483C 4-Ul-I Z-Jvh 483 1,2-c-Pr48 -2- 4-U 1-1,2-Ph 4-01-1,-2-Ph 1,2-Ph 4-01-1,2-Ph 4-01-1,2-Ph H= H 485 CH=CH CR=OR CR=CH CR=CH OR=CH 1,2-c-Pr CH=CH 486 487 488 489 491 i. L 148 RlIR 2 R 3 -Het I AIy 73-methyl-5-fluoro indol-1-yl i ndol- l-yvl 2-(6h--fluoro ioi 2n-(-lo ioi in-(-loqioi 2 6 -fluoro)guinolin I 2-(6-fluoro) uinoljn I 2 6 -fluoro)quinolinyl 2 -(6-fluorometoiyy naphtylooqioi 2 6 -difluoromethoxy)- naphthyl 2 -(6-difluorom ethoxyy- naphthyl 2 -(6-difluoromethoxy)- na phthyl 2 -(-diflur-omethoxyy- na hthyl 2 6 -difluoromethoxyy- naphthyl 2 -(6-difluoromethoixv>) s1 4-C1-1,2-Ph I CH= Cnf::1 q C -1-1,2-Ph CH=CH 4 93 CH 2 1,2-PhCHC49 CH 2 4-C1-1,2-Ph CH=C7 H 495 CH 2 4-Cl-1,2-ph CJJH 49-6 CH?, 0 CH,. s0 2 4-CI-1,2-Ph 4-C1-1,2-Ph 4-C1-1,2-Ph 4-Cl-1,2-Ph 4-CI-1,2-Ph 4-Cl- 1,2-Ph 4-CI-1,2-Ph CH =CH CH=CHF CH=CHl CH=CH- CH=CHF CH=CH 4-97 498 499 500 501 502 S S *5S S. S S 0* S S *5 S S *5 S 2 4-CI-1,2-Ph C HCH S 2 4-CI-1,2-Ph CH=CH0 5-902 4-Cl-i,2-Ph CCH 56 S0 2 -CI-1,2-Ph CH CH 507 SO 2 -Cl-,2-Ph CH =CH 508 SO; 4-Cl -i,2-Ph CH=CH- 509 naphthyl 2 7 -difluoromethoxy)- naphthyl 2 -(7-difluoromethoxy). naphthyl 2 7 -difluoromethoxy). naphthyl 2 7 -difluoromethoxy). aphthyl 2 7 -difluoronetoxy). naphthyl 2-(6;-methoxy)na hthy1 2-(6-methoxY)naphth 1 2 -(6-methoxy)naphthyl 2 6 -meth-ox:ynah yl' S 4-Cl-i,2-Ph CH=CH51 -CH' 2 4-ClT-12-Ph CH=CHf- 511 CRH 2 4-CI--,2-Ph CH=CH 512 0 4-C1-i1,2-Ph CH=CH 513 CH 2 4-CJ-1,2-,Ph CH=CH 514 CH, 4-CI-192ph CH=CH 515 516 4-Cl-i ,2-Ph- 4-Cl-i ,2- CH=CH CH=CH 516 5187 4-Cl-i ,2-Ph CH=CH 518 149 Table 1 continued R 1 R 2 R 3 -HET I X OH l b (Compounds 324-346 and 455-542) R'R 2 R 3 -Het A X B Cpd 2-(6-i-ethoxy)naphthyl 0 4-C1-1,2-Ph CH=CH 519 2 -(6-i-ethoxy)naphthyl CH 2 4-Cl- 1,2-Ph CH=CH 520 2 -(6-flUoro)naphthyl CH 2 4-Cl-I ,2-Ph CH==CH 521 2-(6-fluoro)naphthyl CH, 4-CI-1,2-Ph CT-=CH 522 2 -(6-fl uoro)naphthyl CH') 4-CI-1,2-Ph CH=CH 523 2 -(6-fluoro)naphthyl CH 2 4-Cl- 1,2-Ph CH=CH 524 2-(6-fluoro)naphthy1 CH 2 4-CI-1,2-Ph CH=CH 525 2-(6-fluoro)naphthyI CH 2 4-Cl-I,2-Ph CH=CH 526 2-(6-fluoro)naphthyl CH 2 4-Cl- 1,2-Ph CH=CH 527 :92-(7-fluoro)naphthyl CH 2 4-Cl- 1,2-Ph CH=CH 528 2-(7-fluoro)naphthyl CH 2 4-Cl- 1,2-Ph CH=CH 529 ::*2-(7-fluoro)naphthy1 CH 2 4-Cl- 1,2-Ph CH=CH 530 V.2-(7-fluoro)naphthy1 CH 2 4-C1-1,2-Ph CH=CH 531 2 -(7-fluoro)naphthyI CH 2 4-Cl-1,2-Ph CH=CH 532 *.-apty CH a.I-52P HC 3 2-naphthy1 CH 2 4-C- 1,2-Ph CH=CH 533 q2-naphthy1 CH 2 4-Cl- 1,2-Ph CH=CH 534 34-chorophenyl CH 2 4-Cl-I1,2-Ph CH=CH 535 -na -(-hth 1 tixyido Cl- 2 4-C-l,2-Ph CH=CH 536 2-(benzo[b]thioplienyl) CH 2 4-F-1,2-Ph CH=CH 539 5-(1-benzy1 indolyI CH 2 4-F-1,2-Ph CH=CH 540 1 6 4 -chloro)phenyl)indolyl CH 2 4-F- 1,2-Ph CH=CH 541 CH 2 3,2-Py CH=CH 542 where D=-O-(CH 2 3 Qn=7-chloroquinolin-2-y1, 1 ,2-Ph= 1,2-benzenediyl, CH 2 SCH 2 CH 2 Ph, Pry=pyridinediyl, c-pr--cyclopropyl and Bn=benzyl. 27. A method of treating or preventing a prostaglandin mediated disease which is of administering to a mammalian patient in need of such treatment a 150 compound in accordance with claim 20 in an amount which is effective for treating or preventing a prostaglandin mediated disease. 28. A method in accordance with claim 27 wherein the prostaglandin mediated disease is selected from the group consisting of: pain, fever or inflammation associated with rheumatic fever, influenza or other viral infections, common cold, low back and neck pain, skeletal pain, post-partum pain, dysmenorrhea, headache, migraine, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, bums including radiation and corrosive chemical injuries, sunburns, pain following surgical and dental procedures, immune and autoimmune diseases; cellular neoplastic transformations or metastic tumor growth; diabetic retinopathy, tumor angiogenesis; prostanoid-induced smooth muscle contraction associated with dysmenorrhea, premature labor, asthma or eosinophil related disorders; Alzheimer's disease; glaucoma; bone loss; osteoporosis; 20 promotion of bone formation; Paget's disease; cytoprotection in peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or other gastrointestinal lesions; GI bleeding and patients undergoing chemotherapy; 25 coagulation disorders selected from hypoprothrombinemia, hemophilia and other bleeding problems; kidney disease; thrombosis; occlusive vascular disease; presurgery; and anti-coagulation. 29. A method in accordance with claim 27 wherein the prostaglandin mediated disease is selected from the group consisting of: pain, fever or inflammation. A method in accordance with claim 27 wherein the prostaglandin mediated disease is dysmenorrhea. 151 31. A method in accordance with claim 27 wherein the compound is co- administered with other agents or ingredients. 32. A method in accordance with claim 31 wherein the compound I is co- administered with another agent or ingredient selected from the group consisting of: an analgesic selected from acetaminophen, phenacetin, aspirin, a narcotic; a COX-2 selective NSAID and a conventional NSAID; caffeine; an H 2 -antagonist; aluminium or magnesium hydroxide; simethicone; a decongestant selected from phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levodesoxyephedrine; an antiitussive selected from codeine,hydrocodone, caramiphen, 15 carbetapentane and dextramethorphan; another prostaglandin ligand selected from misoprostol, enprostil, rioprostil, ornoprostol and rosaprostol; a diuretic; and a sedating or non-sedating antihistamine. 33. A pharmaceutical composition which is comprised of a compound in 20 accordance with claim 20 in combination with a pharmaceutically acceptable carrier. 0: 0. 34. A pharmaceutical composition which is comprised of a compound represented by formula I: 0 a R 1 R 2 R 3 -HET -B Z I or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein: HET represents a member selected from the group consisting of: phenyl, naphthalene, biphenyl, pyridine, quinoline, isoquinoline, furan, benzofuran, thiophene, benzothiophene, oxazole, thiazole, imidazole, benzothiazole, 1,2,5-thiadiazole, thienopyridine, indole, tetrazole, imidazole, benzoxazole and pyrrole; A represents a one or two atom moiety and is selected from the group consisting of S, SO 2 CH 2 -OCH 2 -CHOH-, -C(OH)CH 3 and -CH 2 X represents phenyl optionally substituted with R 14 and R 15 and A and B are RAL iqattached to the phenyl group ortho relative to each other; B is HC=CH; [I:\DayLib\LIBXX]03235.doc:aak Z is OH; R 2 and R 3 independently represent H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkenyl-HET(Ra) 4 9 -(C(R 4 2 )pSR 5 -(C(R 4 2 )pOR 8 -(C(R 4 2 )pN(R 6 2 CN, NO 2 -(C(R 4 2 )pC(R) 3 -C0 2 R 9 CON(R 6 2 or -(C(R 4 2 )pS(O)n)R o 1 wherein p and n are each independently 0-3. R 4 is independently H, F, CF 3 or lower alkyl, or two R 4 groups are taken in conjunction and represent a ring of up to six atoms, optionally containing one heteroatom selected from O, S(O)n or N(O)m; each R 5 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 lower alkyl-HET, lower alkenyl-HET or 8 2 Ph(R1)0-2; each R 6 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF 3 Ph, Bn and when two R 6 groups are attached to N they may be taken in conjunction and represent a ring of up to 6 atoms, optionally containing an additional heteroatom selected from O, S(O)n or N(O)m; s15 each R 7 is independently H, F, CF 3 or lower alkyl, and when two R 7 groups are present, they may be taken in conjunction and represent an aromatic or aliphatic ring of 3 to 6 members containing from 0-2 heteroatoms selected from O, S(O)n or N(O)m; each R represents H or R each R 9 is independently H, lower alkyl, lower alkenyl, lower alkynyl, Ph or Bn; S 20 each R 1 0 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 Ph(R' 0 3, CH 2 Ph(R')o-3 or N(R6)2; each R" is independently lower alkyl, SR 20 OR 20 N(R 6 2 -CO 2 R 1 2 -CON(R 6 2 -C(O)R 2 CN, CF 3 NO 2 or halogen; each R 12 is independently H, lower alkyl or benzyl; each R 1 3 is independently H, halo, lower alkyl, O-lower alkenyl, S-lower alkyl, N(R6)2, C0 2 R 1 2 CN, CF 3 or NO 2 R 1 4 and R 15 are independently lower alkyl, halogen, CF 3 OR 1 6 S(O)nR' 6 or C(R6) 2 OR17; each R 16 is independently H, lower alkyl, lower alkenyl, Ph, Bn or CF 3 each R 17 is independently H, lower alkyl or Bn; each R 1 8 is independently H, F or lower alkyl, and when two R 18 groups are present, they may be taken in conjunction and represent a ring of 3 to 6 members comprising carbon atoms and optionally one heteroatom chosen from S, or N; RAL each R 20 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF 3 or Ph(R13) 2 and [I:\DayLb\LIBXX03235.doc:aak 153 each Ra is independently selected from the group consisting of: H, OH, halo, CN, NO 2 amino, Cl-6alkyl, C2-6alkenyl, C 2 -6alkynyl, C 1 6 alkoxy, C 2 -6alkenyloxy, C 2 6 alkynyloxy, Cl -6alkylamino, di-C I. 6 alkylamino, CF 3 C(O)C 6 alkyl, C(O)C 2 6 alkenyl, C(O)C2- 6 alkynyl, CO 2 H, C0 2 C -6alkyl, CO 2 C 2 6 alkenyl, and s CO 2 C 2 6 alkynyl, said alkyl, alkenyl, alkynyl and the alkyl portions of alkylamino and dialkylamino being optionally substituted with 1-3 of: hydroxy, halo, aryl, C 1 6 alkoxy, C2- 6 alkenyloxy, C2-6alkynyloxy, CF 3 C(O)CI-6alkyl, C(O)C2- 6 alkenyl, C(O)C2- 6 alkynyl, CO 2 H, C0 2 C 1 6 alkyl, CO 2 C 2 6 alkenyl, CO 2 C 2 6 alkynyl, NH 2 NHC 1 -6alkyl and N(CI- 6 alkyl) 2 in combination with a pharmaceutically acceptable carrier. to 35. A method of treating or preventing a prostaglandin mediated disease which is comprised of administering to a mammalian patient in need of such treatment, a compound represented by formula I: R'R 2 R 3 -HET O A 0I X-Z or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein: HET represents a member selected from the group consisting of: phenyl, naphthalene, biphenyl, pyridine, quinoline, isoquinoline, furan, benzofuiran, thiophene, benzothiophene, oxazole, thiazole, imidazole, benzothiazole, 1,2,5-thiadiazole, thienopyridine, indole, tetrazole, imidazole, benzoxazole and pyrrole; A represents a one or two atom moiety and is selected from the group consisting of 20 S, SO2, CH 2 -OCH 2 -CHOH-, -C(OH)CH 3 and -CH 2 X represents phenyl optionally substituted with R' 4 and R' 1 5 and A and B are attached to the phenyl group ortho relative to each other; B is HC=CH; Z is OH; R 2 and R 3 independently represent H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkenyl-HET(Ra) 4 9 -(C(R 4 2 )pSR', -(C(R 4 2 )pOR, -(C(R 4 2 )pN(R 6 2 CN, NO 2 -(C(R 4 2 3 -C0 2 R 9 CON(R 6 2 or -(C(R 4 2 wherein p and n are each independently 0-3. R 4 is independently H, F, CF 3 or lower alkyl, or two R 4 groups are taken in conjunction and represent a ring of up to six atoms, optionally containing one heteroatom selected from O, S(O)n or N(O)m; ALI each R 5 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 lower alkyl-HET, lower alkenyl-HET or 8 2 Ph(R' [I:\DayLib\LIBXX]03235.doc:aak 154 each R 6 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF 3 Ph, Bn and when two R 6 groups are attached to N they may be taken in conjunction and represent a ring of up to 6 atoms, optionally containing an additional heteroatom selected from O, or N(O)m; each R 7 is independently H, F, CF 3 or lower alkyl, and when two R 7 groups are present, they may be taken in conjunction and represent an aromatic or aliphatic ring of 3 to 6 members containing from 0-2 heteroatoms selected from O, or N(O)m; each R 8 represents H or R 5 each R 9 is independently H, lower alkyl, lower alkenyl, lower alkynyl, Ph or Bn; each R 1 0 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 Ph(R' )o-3, CH 2 Ph(R' 1 )o3 or N(R 6 2 each R" is independently lower alkyl, SR 20 OR 20 N(R 6 2 -CO 2 R 12 -CON(R 6 2 -C(O)R' 2 CN, CF 3 NO 2 or halogen; each R 1 2 is independently H, lower alkyl or benzyl; 15 each R 3 is independently H, halo, lower alkyl, O-lower alkenyl, S-lower alkyl, N(R 6 2 CO 2 R 1 2 CN, CF 3 or NO 2 R 1 4 and R 1 5 are independently lower alkyl, halogen, CF 3 OR' 6 S(O)nR' 6 or C(RI6) 2 OR7; each R 16 is independently H, lower alkyl, lower alkenyl, Ph, Bn or CF 3 20 each R 1 7 is independently H, lower alkyl or Bn; each R 18 is independently H, F or lower alkyl, and when two R' 8 groups are present, they may be taken in conjunction and represent a ring of 3 to 6 members comprising carbon atoms and optionally one heteroatom chosen from S, S(O)n or N; each R 20 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF 3 or Ph(R' 3 2 and each Ra is independently selected from the group consisting of: H, OH, halo, CN, NO 2 amino, Ci- 6 alkyl, C 2 -6alkenyl, C2-6alkynyl, CI-6alkoxy, C2-6alkenyloxy, C 2 6 alkynyloxy, CI. 6 alkylamino, di-Cl.6alkylamino, CF 3 C(O)Ci- 6 alkyl, C(O)C2- 6 alkenyl, C(O)C 2 6 alkynyl, CO 2 H, CO 2 Ci.6alkyl, CO 2 C 2 6 alkenyl, and CO 2 C 2 6 alkynyl, said alkyl, alkenyl, alkynyl and the alkyl portions of alkylamino and dialkylamino being optionally substituted with 1-3 of: hydroxy, halo, aryl, CI- 6 alkoxy, C 2 6 alkenyloxy, C2- 6 alkynyloxy, CF 3 C(O)C1- 6 alkyl, C(O)C2- 6 alkenyl, C(O)C2- 6 alkynyl, CO 2 H, CO 2 C1- 6 alkyl, CO 2 C 2 6 alkenyl, C02C 2 6 alkynyl, NH 2 NHC- 6 alkyl and N(Ci- 6 alkyl)2, in an amount which is effective for treating or preventing a prostaglandin mediated disease. [I:\DayLib\LIBXX]03235.doc:aak 155 36. A compound of claim 1, substantially as herein described with reference to the examples. 37. A compound of claim 20 or 21, substantially as herein described with reference to the examples. 38. A pharmaceutical composition for treating or preventing a prostaglandin mediated disease in a mammal in need thereof comprising a compound of claim 36 or 37 together with a pharmaceutically acceptable carrier. 39. A process of making a compound of claim 1 which process is substantially as herein described with reference to the examples. 40. A process of making a compound of claim 20 or 21 which process is substantially as herein described with reference to the examples. 41. A method of treating or preventing a prostaglandin mediated disease in a mammal in need thereof comprising administering to the mammal a compound of claim 36 or 37 or a composition of claim 38. s 42. A compound of claim 36 or 37 or a composition of claim 38 when used to treat or prevent a prostaglandin mediated disease in a mammal in need thereof. 43. A compound of any one of claims 1 and 20 when used to treat or prevent a S° °prostaglandin mediated disease in a mammal in need thereof. ~44. A compound represented by the formula (I) R 2R-HET o *BI 20 X- Z I or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein: HET represents a member selected from the group consisting of: phenyl, naphthalene, biphenyl, pyridine, quinoline, isoquinoline, furan, benzofuran, thiophene, benzothiophene, oxazole, thiazole, imidazole, benzothiazole, 1,2,5-thiadiazole, thienopyridine, indole, tetrazole, imidazole, benzoxazole and pyrrole; A represents a one or two atom moiety and is selected from the group consisting of S, SO 2 CH 2 -OCH 2 -CHOH-, -C(OH)CH 3 and -CH 2 X represents phenyl optionally substituted with R 1 4 and R 1 5 and A and B are attached to the phenyl group ortho relative to each other; B is HC=CH; Z is OH; [I:\DayLib\LIBXX]03235.doc:aak 156 R 2 and R 3 independently represent H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkenyl-HET(Ra) 4 9 -(C(R 4 2 )pSR 5 -(C(R 4 2 )pOR 8 -(C(R 4 2 )pN(R 6 2 CN, NO 2 -(C(R 4 2 )pC(R 7 3 -C0 2 R 9 CON(R 6 2 or -(C(R 4 2 )pS(O)n)R' 0 wherein p and n are each independently 0-3. R 4 is independently H, F, CF 3 or lower alkyl, or two R 4 groups are taken in conjunction and represent a ring of up to six atoms, optionally containing one heteroatom selected from O, S(O)n or N(O)m; each R 5 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 lower alkyl-HET, lower alkenyl-HET or 2 Ph(R11)02; each R 6 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF 3 Ph, Bn and when two R 6 groups are attached to N they may be taken in conjunction and represent a ring of up to 6 atoms, optionally containing an additional heteroatom selected from O, S(O)n or N(O)m; each R 7 is independently H, F, CF 3 or lower alkyl, and when two R 7 groups are 15 present, they may be taken in conjunction and represent an aromatic or aliphatic ring of 3 to 6 members containing from 0-2 heteroatoms selected from O, or N(O)m; each R represents H or Rs; each R 9 is independently H, lower alkyl, lower alkenyl, lower alkynyl, Ph or Bn; each R 1 0 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 Ph(R' 1 o-3, 11 6 20 CH 2 Ph(R 0 3 or N(R 6 2 each R" is independently lower alkyl, SR 20 OR 20 N(R6) 2 -CO 2 R' 2 -CON(R6)2, -C(O)R 1 2 CN, CF 3 NO 2 or halogen; each R 12 is independently H, lower alkyl or benzyl; each R 1 3 is independently H, halo, lower alkyl, O-lower alkenyl, S-lower alkyl, N(R 6 2 CO 2 R' 2 CN, CF 3 or NO 2 R 1 4 and R 1 5 are independently lower alkyl, halogen, CF 3 OR 1 6 S(O)nR' 6 or C(R16) 2 0R17; each R 16 is independently H, lower alkyl, lower alkenyl, Ph, Bn or CF 3 each R 17 is independently H, lower alkyl or Bn; each R 8 is independently H, F or lower alkyl, and when two R' 8 groups are present, they may be taken in conjunction and represent a ring of 3 to 6 members comprising carbon atoms and optionally one heteroatom chosen from S, S(O)n or N; each R 20 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF 3 or yf^ 7 Ph(R 3 2 and [I:\DayLib\LIBXX]03235.doc:aak 157 each Ra is independently selected from the group consisting of: H, OH, halo, CN, NO 2 amino, Cl-6alkyl, C2- 6 alkenyl, C 2 6 alkynyl, Cl-6alkoxy, C2-6alkenyloxy, C 2 -6alkynyloxy, C 1 -6alkylamino, di-C 1 6 alkylamino, CF 3 C(O)C l-6alkyl, C(O)C2- 6 alkenyl, C(O)C2-6alkynyl, CO 2 H, CO 2 C1- 6 alkyl, CO 2 C 2 6 alkenyl, and C02C 2 6 alkynyl, said alkyl, alkenyl, alkynyl and the alkyl portions of alkylamino and dialkylamino being optionally substituted with 1-3 of: hydroxy, halo, aryl, C 1 6 alkoxy, C 2 -6alkenyloxy, C2-6alkynyloxy, CF 3 C(O)Cl-6alkyl, C(O)C2- 6 alkenyl, C(O)C 2 6 alkynyl, CO 2 H, CO 2 CI-6alkyl, CO 2 C 2 6 alkenyl, C0 2 C 2 6 alkynyl, NH 2 NHC 1 -6alkyl and N(CI-6alkyl) 2 when used to treat or prevent a prostaglandin mediated disease in a to mammal in need thereof 45. A composition of any one of claims 10, 33 or 34 when used to treat or prevent a prostaglandin mediated disease in a mammal in need thereof. 46. Use of a compound represented by the formula (I) R 1 R 2 R 3 -HET O I X-B/kZ I S Is or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein: HET represents a member selected from the group consisting of: phenyl, naphthalene, biphenyl, pyridine, quinoline, isoquinoline, furan, benzofuran, thiophene, benzothiophene, oxazole, thiazole, imidazole, benzothiazole, 1,2,5-thiadiazole, thienopyridine, indole, tetrazole, imidazole, benzoxazole and pyrrole; A represents a one or two atom moiety and is selected from the group consisting of S, SO 2 CH 2 -OCH 2 -CHOH-, -C(OH)CH 3 and -CH 2 X represents phenyl optionally substituted with R 14 and R' 5 and A and B are attached to the phenyl group ortho relative to each other; B is HC=CH; Z is OH; R 2 and R 3 independently represent H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkenyl-HET(Ra) 4 -(C(R 4 2 )pSR 5 -(C(R 4 2 )pOR, -(C(R 4 2 )pN(R 6 2 CN, NO 2 -(C(R 4 2 )pC(R) 3 -C0 2 R 9 CON(R 6 2 or -(C(R 4 2 )pS(O)n)R'o, wherein p and n are each independently 0-3. R 4 is independently H, F, CF 3 or lower alkyl, or two R 4 groups are taken in conjunction and represent a ring of up to six atoms, optionally containing one heteroatom Sselected from O, S(O)n or N(O)m; [1:\DayLib\LIBXX03235.doc:aak 158 each R 5 is independently lower alkyl; lower alkenyl, lower alkynyl, CF 3 lower alkyl-HET, lower alkenyl-HET or 2 Ph(R 1)0-2; each R 6 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF 3 Ph, Bn and when two R 6 groups are attached to N they may be taken in conjunction and represent a ring of up to 6 atoms, optionally containing an additional heteroatom selected from 0, S(O)n or N(O)m; each R 7 is independently H, F, CF 3 or lower alkyl, and when two R 7 groups are present, they may be taken in conjunction and represent an aromatic or aliphatic ring of 3 to 6 members containing from 0-2 heteroatoms selected from O, S(O)n or N(O)m; each R 8 represents H or each R 9 is independently H, lower alkyl, lower alkenyl, lower alkynyl, Ph or Bn; :each R is independently lower alkyl, lower alkenyl, lower alkynyl, CF3, Ph(R)3, each R 10 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 Ph(R CH 2 Ph(R')0-3 or N(R 6 2 each R" is independently lower alkyl, SR 20 OR 2 0 N(R 6 2 -CO2R 2 -CON(R 6 2 15 -C(0)R 1 2 CN, CF 3 NO 2 or halogen; each R 12 is independently H, lower alkyl or benzyl; each R 13 is independently H, halo, lower alkyl, O-lower alkenyl, S-lower alkyl, N(R 6 2 CO 2 R 2 CN, CF 3 or NO 2 R 1 4 and R 1 5 are independently lower alkyl, halogen, CF 3 OR 16 S(O)nR' 6 or 20 C(RI6) 2 0R7; each R' 6 is independently H, lower alkyl, lower alkenyl, Ph, Bn or CF 3 17 each R' 7 is independently H, lower alkyl or Bn; each R 18 is independently H, F or lower alkyl, and when two R 18 groups are present, they may be taken in conjunction and represent a ring of 3 to 6 members comprising carbon atoms and optionally one heteroatom chosen from S, S(O)n or N; each R 20 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF 3 or Ph(RI3) 2 and each Ra is independently selected from the group consisting of: H, OH, halo, CN, NO 2 amino, Ci- 6 alkyl, C2- 6 alkenyl, C 2 -6alkynyl, CI- 6 alkoxy, C2- 6 alkenyloxy, C 2 6 alkynyloxy, C 1 6 alkylamino, di-C -6alkylamino, CF 3 C(O)C 6 alkyl, C(O)C 2 6 alkenyl, C(O)C2-6alkynyl, CO 2 H, C0 2 C1- 6 alkyl, C02C 2 6 alkenyl, and CO 2 C 2 6 alkynyl, said alkyl, alkenyl, alkynyl and the alkyl portions of alkylamino and dialkylamino being optionally substituted with 1-3 of: hydroxy, halo, aryl, CI- 6 alkoxy, l C2- 6 alkenyloxy, C2-6alkynyloxy, CF 3 C(O)Cl.6alkyl, C(O)C2- 6 alkenyl, C(O)C 2 6 alkynyl, [I:\DayLib\LIBXX03235.doc:aak 159 CO 2 H, CO 2 C1. 6 alkyl, C0 2 C 2 6 alkenyl, CO 2 C 2 6 alkynyl, NH 2 NHC 1 6 alkyl and N(Cl-6alkyl) 2 in the preparation of a medicament for treating or preventing a prostaglandin mediated disease in a mammal in need thereof. 47. Use of a compound of any one of claims 1 and 20 in the preparation of a medicament for treating or preventing a prostaglandin mediated disease in a mammal in need thereof. 48. Use of a compound of claim 36 or 37 in the preparation of a medicament for treating or preventing a prostaglandin mediated disease in a mammal in need thereof. 49. The method of any one of claims 11 to 16, 27 to 32 or 41 wherein the 0o mammal is a human. :50. The compound when used according to any one of claims 42 to 44 wherein S" the mammal is a human. 000 51. The composition when used according to claim 45 wherein the mammal is a 00 human. 5 Dated 25 October, 2002 o Merck Frosst Canada Co. •0 00 0000 Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 0 0 00 00 0 00° [I:\DayLib\LIBXX]03235.doc:aak
AU27086/99A 1998-03-13 1999-03-12 Carboxylic acids and acylsulfonamides, compositions containing such compounds and methods of treatment Ceased AU756333B2 (en)

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US7960567B2 (en) * 2007-05-02 2011-06-14 Amgen Inc. Compounds and methods useful for treating asthma and allergic inflammation
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