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AU687558B2 - Substituted sulfonamides as selective beta 3 agonists for the treatment of diabetes and obesity - Google Patents
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AU687558B2 - Substituted sulfonamides as selective beta 3 agonists for the treatment of diabetes and obesity - Google Patents

Substituted sulfonamides as selective beta 3 agonists for the treatment of diabetes and obesity Download PDF

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AU687558B2
AU687558B2 AU23937/95A AU2393795A AU687558B2 AU 687558 B2 AU687558 B2 AU 687558B2 AU 23937/95 A AU23937/95 A AU 23937/95A AU 2393795 A AU2393795 A AU 2393795A AU 687558 B2 AU687558 B2 AU 687558B2
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Australia
Prior art keywords
ethyl
amino
hydroxy
phenyl
pyridinyl
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AU23937/95A
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AU2393795A (en
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Michael H. Fisher
Elisabeth M Naylor
Dong Ok
Hyun Ok
Thomas Shih
Ann E. Weber
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Merck and Co Inc
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Merck and Co Inc
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    • 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
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    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/47—Y being a hetero atom
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    • 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
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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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    • 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
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    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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Description

WO 95/29159 PCT/US95/10956 -1- TITLE OF THE INVENTION SUBSTITUTED SULFONAMIDES AS SELECTIVE 133 A mS9rNIS FOR THE TREATMENT OF DIABETES AND OB fY CROSS REFERENCE This ontinuation-in-part of co-pending application U.S.S 33,166 filed April 26, 1994, which is hereby incorporated y reference in its entirety. BACKGROUND OF THE INVENTION P-Adrenoceptors have been subclassified as 11 and 32 since 1967. Increased heart rate is the primary consequence of P1-receptor stimulation, while brorichodilation and smooth muscle relaxation typically result from 12 stimulation. Adipocyte lipolysis was initially thought to be solely a Pi-mediated process. However, more recent results indicate that the receptor-mediating lipolysis is atypical in nature. These atypical receptors, later called 33-adrenoceptors, are found on the cell surface of both white and brown adipocytes where their stimulation promotes both lipolysis (breakdown of fat) and energy expenditure.
Early developments in this area produced compounds with greater agonist activity for the stimulation of lipolysis (13 activity) than for stimulation of atrial rate (P1) and tracheal relaxation These early developments disclosed in Ainsworth et al., U.S. Patents 4,478,849 and 4,396,627, were derivatives of phenylethanolamines.
Such selectivity for p3-adrenoceptors could make compounds of this type potentially useful as antiobesity agents. In addition, these compounds have been reported to show antihyperglycemic effects in animal models of non-insulin-dependent diabetes mellitus.
A major drawback in treatment of chronic diseases with 33 agonists is the potential for stimulation of other -receptors and subsequent side effects. The most likely of these include muscle tremor (13P2) and increased heart rate Although these phenylethanolamine WO 95/29159 PCTIUS95104956 -2derivatives do possess some 13 selectivity, side effects of this type have been observed in human volunteers. It is reasonable to expect that these side effects resulted from partial P 1 and/or 32 agonism.
More recent developments in this area are disclosed in Ainsworth et al., U.S. Patent 5,153,210, Caulkett et al., U.S. Patent 4,999,377, Alig et al., U.S. Patent 5,017,619, Lecount etal., European Patent 427480 and Bloom et al., European Patent 455006.
Even though these more recent developments purport to describe compounds with greater p3 selectivity over the 11 and 32 activities, this selectivity was determined using rodents, in particular, rats as the test animal. Because even the most highly selective compounds, as determined by these assays, still show signs of side effects due to residual 11 and p2 agonist activity when the compounds are tested in humans, it has become apparent that the rodent is not a Sgood model for predicting human p3 selectivity.
Recently, assays have been developed which more accurately predict the effects that can be expected in humans. These assays utilize cloned human p3 receptors which have been expressed in Chinese hamster ovary cells. See Emorine et al, Science, 1989, 245:1118-1121; and Liggett, Mol. Pharmacol., 1992, 42:634-637. The agonist and antagonist effects of the various compounds on the cultivated cells provide an indication of the antiobesity and antidiabetic effects of the compounds in humans.
2 SUMMARY OF THE INVENTION The instant invention is concerned with substituted sulfonamides which are useful as antiobesity and antidiabetic compounds. Thus, it is an object of this invention to describe such compounds. It is a further object to describe the specific preferred stereoisomers of the substituted sulfonamides. A still further object is to describe processes for the preparation of such compounds. Another object is to describe methods and compositions which use the compounds as the active ingredient thereof. Further objects will become apparent from reading the following description.
WO 95/29159 PC'TIUS95/04956 -3- DESCRIPTION OF THE INVENTION The present invention provides compounds having the formula I: OH H R 2 4
-CHCH
2
N-SO
2
(CH
2 )r-R I I
R
3
R
5
R
6 (R)n
R
I
where n is m is r is A is 0 to 0 or 1; 0 to 3; a 5 or 6--membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, phenyl, or a benzene ring fused to a C3-C8 cycloalkyl ring; hydroxy, oxo, halogen, cyano,
NR
8 R8, R1 is I WO 95/29159 WO 9/9159Pt1US95/0,4956 -4
SR
8 trifluoromethyl, Cl-GbO alkyl,
OR
8 S02R9, (11) OCOR 9 (12) NR 8 COR9, (13) COR 9 (14) NR 8 SO2R 9 (15) NR 8 002R 8 or (16) CIj-Clo alkyl substituted by hydroxy, halogen, cyano, NR8R8, SR 8 trifluoromethyl, OR 8 C3-C8 cycloalkyl, phenyl, NR 8 COR9, COR 9 S02R 9
OCOR
9
NR
8 SO2R9 or
NR
8 CO2R 8
SR
2 and R3 are independently hydrogen, Cl-ClO alkyl or C 1-Ci10 alkyl with 1 to 4 substituents selected from hydroxy, CI-Cio alkoxy, and halogen; Xis -CH2-, -CH2-CH2-, -CH=CH- or -CH2O-; 4 and R5 are independently (1)hydrogen, Cj-Clm alkyl, halogen,
NHR
8 (5)0OR 8 S02R 9 or NHSO2R9; R6 is hydrogen or Cl-ClO alkyl; R7 is Z-(Rla)n; I WO 95/29159 PCT1US95/04956 Rla is Z is
R
1 with the proviso that when A is phenyl, R a is not C 1-C10 alkyl, C3-C8 cycloalkyl, phenyl optionally substituted with up to 4 groups independently selected from R 8
NR
8
R
8
OR
8
SR
8 and halogen, or 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, R 8
NR
8
R
8
OR
8
SR
8 and halogen; phenyl, naphthyl, a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a benzene ring fused to a C3-C8 cycloalkyl ring, a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-C8 cycloalkyl ring; hydrogen, C1-C10 alkyl, C3-C8 cycloalkyl, Z optionally having 1 to 4 substituents selected from halogen, nitro, oxo, NR 10
R
10 Cl-C10 alkyl, alkoxy, C1-C10 alkylthio, and C1-C10 alkyl having 1 to 4 substituents selected from hydroxy, halogen, CO2H, C02- C1-C10 alkyl, S02-C1-C10 alkyl, C3-C8 cycloalkyl, C1- R8 is -L 'WO 95/29159 PCT/US95/04956 -6alkoxy, and Z optionally substituted by from 1 to 3 of halogen, C1-C10 alkyl or CI-C10 alkoxy, or C1-C10 alkyl having 1 to 4 substituents selected from hydroxy, halogen, CO2H, C02-Cl-C10 alkyl, S02-Cl-C10 alkyl, C3-Cg cycloalkyl, C1-C10 alkoxy, C1-C10 alkyl, and Z optionally substituted by from 1 to 4 of halogen, C1-C10 alkyl or CI-C10 alkoxy; R9 is R8 or NR8R 8 R10 is C1-C10 alkyl, or two R 10 groups together with the N to which they are attached formed a 5 or 6-membered ring optionally substituted with C1-C10 alkyl; or a pharmaceutically acceptable salt thereof.
In one embodiment of the instant invention A is a 5 or 6membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen.
In another embodiment of the instant invention A is phenyl or benzene fused to a C3-C8 cycloalkyl ring.
Preferred compounds of the instant invention are realized when in the above structural formula I: R2 and R 3 are hydrogen or methyl; X is -CH2-; nis 0 to 3; m is 1; r is 0 to 2; and
R
4
R
5 and R 6 are hydrogen.
Other preferred compounds of the instant invention are realized when in the above structural formula I: *WO 95/29159 PCTIUS95/04956 A is R1 is r is -7phenyl or a 6-membered heterocyclic ring with 1 or 2 heteroatoms selected from nitrogen and sulfur; hydroxy, halogen, cyano, trifluoromethyl, NR8R8,
NR
8 SO2R 9 NR8COR9, NR8CO2R8, C1-C6 alkyl optionally substituted by hydroxy; and 0 or 2.
More preferred compounds are represented by the formula OH H R 2 (R)n f CHCH 2 N-C-(X)m NH- S02- Z-(Ra) NJ
R
Ia whereir n is m is
R
1 is
R
2
R
3
R
l a is 0 to 3; 1 halogen or
NR
8
R
8 are independently hydrogen or methyl; halogen, Cl-C10 alkyl,
NR
8
R
8
NR
8
COR
9
NR
8 CO2R 8
COR
9
OCOR
9 or a 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, halogen, R 8
NR
8
R
8
OR
8 and SR 8 phenyl, naphthyl, Z is I L 'WO 95/29159 PCT/US95/04956 -8- X is
R
8 and
R
9 a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, or a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-C8 cycloalkyl ring; -CH2-; and are as defined under formula I.
Even more preferred compounds are those represented by formula Id: OH H R 2
B
I IIHCH -CH1 a (R1)n -,CHCH2N-C-CH2 NH-SO- )(R1a)n N *1 -R 3 1
R
3 n is
R
1 is
R
2 and B is 0 or 1;
NR
8
R
8 R3 are independently hydrogen, or methyl; hydrogen, u-enzene fused to the benzene ring to form naphthyl, or a 5 or 6-membered heterocycle with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atom fused to the benzene ring; halogen, C1-C10 alkyl,
NR
8
R
8
NR
8
COR
9
NR
8 CO2R 8 Rlais 'WO 95/29159 ICPtrSF95/04.195 -9-
COR
9 or a 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently s selected from oxo, R 8
SR
8
OR
8 and NR 8
R
8 when B and the benzene ring form a fused ring system, Rla is attached to either ring;
R
8 is hydrogen, C1-C10 alkyl, Z optionally having 1 to 4 substituents selected from nitro, oxo, and NR 1 ORIO, or Cl-C10 alkyl having 1 to 4 substituents selected from hydroxy, halogen, C1-C10 alkyl, C3-C8 cycloalkyl, and Z optionally substituted by from 1 to 4 of halogen, alkyl or CI-C10 alkoxy;
R
9 is R 8 or NR8R 8
R
1 0 is C1-CIJ alkyl, or two R 10 groups together with the N to which they are attached formed a 5 or 6-membered ring optionally substituted with C1-C10 alkyl; and Z is phenyl, a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-C8 cycloalkyl ring.
Other more preferred compounds are represented by formula Ib: WO 95/29159 9/29159I'(M1IUS95/04950 10 OH H R 2 (R)n 2 CHCH 2 N-CKm N H-SO 2 Z-(Rla )n lb wherein n is 0Oto 3; mnis
I
R1 is hydroxy, cyano,
NR
8
R
8 or Rlis halogren; Ra is halogen,
NR
8
R
8
NR
8
COR
9
NR
8 CO2R 8
OCOR
9 or a 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to three groups independently selected from oxo, halogen, R 8
NR
8
R
8
OR
8 and SR 8 is phenyl, naphthyl or benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; X is and 2 and R 3 are independently hydrogen or methyl.
Representative antiobesity and antidiabetic compounds of the present invention include the following: N- 2-hy droxy-2- (6-ami nopyri din- 3-y) ethyl] amino] ethyl] phenyl] 4-(hexylaminocarbonylamino)benzenesulfonamide WO 95/29159 WO 95/2 159 ICrUS95/04956 IIl- [2-hiydrcixy-2-( 6-aminiopyridi n-3-yl )ethiyl Iamiinojcthlyl]phienyl]- 4-iodobenzenesulfonai-ide [2-hydroxy-2-(6-am-inopyridin-3-yl )etliyI amino] ethyl] phenyl 1 benzenesulfonamide N- [-hIydroxy-2-(6-aminopyridiin-3-yl )ethiylI amino] ethyl Iphenyl I 2-naphthalenesulfonamide Nj-[4- [2-hydroxy-2-(6-arninopyri din-3-yl)ethyl ]amino] ethyl] phenyl] 3-quinolinesulfonamide N0h- [2-hydroxy-2-(6-aminopyridin-3-yI )ethyl] amino] ethyl] phenyl] 105-benzisoxazolesulfonamide [2-hydroxy-2- (6-aminopyridin-3 y)ethyl] amino] ethyl] phenyl 4- [(hexylmethyl ani nocarbonyl) amino] benzenesulfo namide [2-hydroxy-2- (6-ami nopyrid in -3-yl) ethyl] amino] ethyl] phenyl] 154- [(dimethyl ami noc arbonyl) amino] benzenesulfonamide [[2-hydroxy-2-(6-aminopyridin -3-y)ethyl] amino] ethyl] phenyl] 4-(3-hexyl-2-imidazolidon- 1 -yl)benzenesulfonamide [3 [2-hydrox y-2- (6-aminopyridin-3 -yl) ethyl] am ino] propylphenyl] -4-(hexylaminocarbonylamino)benzenesulfonamide [3 [2-hydroxy-2-(6- amin opyri din- 3-yl) ethyl] aniino]propyl] 20phenyl]-4-iodobenzenesulfonamide N- [[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl] aminoipropyl] phenyllbenzenesulfonamide N- [2-hydroxy-2-(6-aminopyridin-3 -yl)ethyl] amino] propyl] phenyl]-2-naphthalenesulfonamide [3 [2-hydroxy-2- (6-aminopyridin-3 -yl) ethyl] amino] propyl] phenyl]-3-quinolinesulfonamide Nj- [2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl] -4- (hexylaminocarbonylamino)benzenesulfonamide N- [2-hy droxy-2- (3 -pyridinyl)ethyl] amino] ethyl] phenyl -4isopropylbenzenesulfonamide j- [[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] plelyl]- 2 naphthalenesulfonamide N- [[2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl] -3quinolinesulfonamide I wo 95/29159 WO 95/9159 CTIUS95/04956 [[2-hydroxy-2-(3 -pyridinyl)ethyl] amino)ethyl] phenyl] -4- [(hexylmethyl aminocarbonyl) amino] benzenesulIfonami de N- [2-[[2-hydroxy-2-(3-pyridinyl)ethyl]ami no]ethyl]phenyl]-4-(3hexyl-2-imidazolidinon- 1 -yl)benzenesulfonamide N- [[2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl iodobenzenesulfonamide N- hydroxy-2- (3 -pyridinyl) ethyl] amino) ethyl] phenyl] 1-4- 5- (3cyclopentyipropyl)- [1,2 ,4]-oxadiazol-3 -yl] benzensulfonamide [2-hydroxy-2- (3 -pyridinyl. )ethyl] amino]ethyl]phenyl]-4- oxoheptyl)amino] benzenesulfonamide N- [2-[[2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyljphenyl] oxo-4-phenylbutyl)amino]benzenesulfonarnide [[2-hydroxy-2.1(3-pyridinyl)ethiyl] amino] ethyl]phenyl] -4- [(propoxyb arbonyl) amino] benzenesulfonamide N- [[2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyl] phenyl] 2-ylmethyl)amino]carbonyl] amino]benzenesulfonamide N- [2-hydroxy-2- (3 -pyri dinyl) ethyl] amino] ethyl] phenyl] phenylethyl) amino] carbonyl] amino) benzenesulfonamide N- [2-hydroxy-2- 3 -pyridinyl)ethyl] amino] ethyl] ph enyl] indol-3 -ylethyl)amino] carbonyl] amino] benzenesulfonamide N- hydroxy-2-(3-pyridinyl)ethyl] amino) ethyl] phenyl] -4- [[(octylarnino)carbonyl] amino~benzenesulfonamide N- [[2-hydroxy-2-(3 -pyridinyl)ethyl] amino] ethyl] phenyl]- 1 N- [[2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl] 1- Nj- [[2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl] [[2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl] -1 -l 30oxononyl)-5-indolinesulfonamide N- [2-hydroxy-2- (3 -pyridiiiyl) ethyl] amino] ethyl] phenyl 1 methylthiazol-2-yl)- [[>-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl]- 1 -indolinesulfonamiLc ,Wo 95/29159 WO 95/9159 CI/US95/04956 13 N- [[2-hydroxy-2-(3-pyridinyl)ethyl]ai-ninio]ethyljphenyl]-l 1-(4ethyl-5-methylthiazol-2-yl)-5-indolinesulfonarnide N N- [[2-hydroxy-2-(Q3-pyridinyl)ethyl] amino] ethyl] phenyl]-4- (3 octyl-2-imidazolidinon- 1- yl) benzenes ul fonami de N- [4-12- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl]-4- [3 (4,4,4-trifluorobutyl)-2-imidazolidinon- I -yl]benzenesulfonamide N- [2-hydroxy-2-(3-pyridinyl) ethyl] amino] ethyl] phenyl]-4- phenylpropyl) -2-imi dazolidi non- Il-yl] benzenesu ifonamide N- [[2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyl ]phenyl [3 5-pentafluoropentyl)-2-imidazolidinon- 1 yl]benzenesulfonamide N- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl [3 cyclohexy Iethyl)-2-imidazolidinon- 1 -yl]benzenesulfonamide [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl [3- (4-chlorophenyl)propyl]-2-imidazolidinon- 1 -yl]benzenesulfonamide N [[2-hydroxy-2- (3 -pyridinyl)ethyl] amino] ethyl] phenyl] pentyl-2-imidazolidinon- I -yl)benzenesulfonamide N- [2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl]phenyl]-4- (3cyclopentylpropyl)-2..-imidazolidinon- 1 -yl]benzenesulfonamide N- [2-hydroxy-2-(3 -pyridinyl)ethyll amino] ethyl] phenyl] (2cyclopentylethyl)-2-imidazolidinon- 1-yl]benzenesulfonamide j- [2-hydroxy-2- (3 -pyridinyl)ethyl] amino] ethyl] phenyl] [3 cyclohexylpropyl)-2-imidazolidinon- 1 -yl]benzenesulfonamide [[2-hydroxy-2- (3-pyridinyi)ethyl] aminolethyl]phenyl]-4- dimethylhexyl)-2-imidazolidinon- i-yl]benzenesulfonamide N- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl] (3 hexyl-2-imidazolon- 1 -yl)benzenesulfonainide j- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl] [3 30(4,4,4-trifluorobutyl)-2-imidazolon- 1 -yl]benzenesulfonamide 30N-[4- [[2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyl] phenyl] octyl-2-imidazolon- 1-yl)benzenesulfonamide.
Nj [2-hydroxy-2 (3 -pyridinyl)ethyl] amino] ethyllphenyl] [3 cyclopentylpropyl)-2-imidazolon- 1 -y'i]benzenesulfonamide WO 95/29159 WO 9529159V(~1IMS95/04956 14 Ni-[4- [[2-hydroxy-2-(3-pyridinyl)ethylj amino] ethyl] phenyl]-4- (2octyl-3-oxo-[ 1,2,4]-triazol-4-yl)benzenesulfonamide [[2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl (4- 1 -yl)benzenesulfonamide [2-hydroxy- 2- (3-pyridinyl) ethyl] amino] ethyl] ph enyl] (4- 1 -yl)benzenesulfonarnide N- [[2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyl] phenyl]-4- -tetrazolon- 1l-yl] benzenesulfonamide N- [2-hydroxy- 2- pyri dinyl) ethyl] amino] ethyl] ph enyl (2- N- [[2-hydroxy-2- (3-pyridiriyl) ethyl] amino] ethyl] phenyl 4- (2- N- [2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] (2- N- [2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] ph enyl] ethyl- 5 -methylthiazol-2-yl) amino] benzenesulfonamide N- [2-hydroxy- 2- (3-pyridinylI)ethyl] amino] ethyl]phenyl1]-4tetrahydrobenzothiazol-2-yl) amino] benzenesulfonamide, N- [[2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl]-4- (2hexylimidazol-4-yl)benzenesulfonamide N- [[2-hydroxy-2-(3-pyridinyl) ethyl] amino] ethyl]phenyl] (1 N- [[2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyl]phenyl] 1methyl-2-(2-cyclopentylethyl)imidazol-5-yl]benzenesulfonamide N- [2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl]phenyll-4- [1 methyl-2- [2-(4-fluorophenyl)ethyl]imidazol-5-yl]benzenesulfonamide N- [[2-hydroxy-2- (3-pyri dinyl)ethyl] amino] ethyl]pheny1]- 4- (5 pentyl- -oxadiazol-3-yl)benzenesulfonamide N- [[2-hydroxy-2- (3 -pyridinyl)ethyl] amino] ethyl] phenyl] 5- (2- -oxadiazol-3-yl]benzenesulfonamide N- [2-hydroxy-2- (3-pyridiny1) ethyl] amino] ethyl] phenyl] (5 heptyl- [1 ,2,4]-oxadiazol-3 -yl)benzenesulfonamide N- [[2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl] octyl- -oxadiazol-3-yl)benzenesulfonamide WO 95/29159 WO 9529159PCI/US95/04956 15 [[2-hydroxy-2-(3-pyridinyl)ethyljaminolethyl]phenyl]-4-(5hexylthio-[ 1,2,4] -triazol-3-yl)benzeiiesulfonamide [[2-hydroxy-2- (3 -pyridinyl)ethyl] amino] ethyl] phenyl]-4- propylpipericdin- l-yl)- 1, 1-dioxo-[ [1,2,5]-thiadi azol-3yl]amino] benzenesulfonamide N- [[2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyl] pheny [4- (hexylmethyl.amino)- 1, 1-dioxo- 5]-thiadiazol- 3yl] amino]benzenesulfonamide N- [2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyl] phenyl (Nheptyl, N-methylamino)- 1,1 -dioxo-[ 1,2,5]-thiadiazol-3yl] amino]benzenesulfonamide [2-h ydroxy-2- (3 -pyri dinyl) ethyl] amino] ethyl] pheny1] 1octyl-2,4-imidazolidinedion-3-yl)benzenesulfonamide N- [2-hydroxy-2- (3 -pyridinyl)etfiyl] amino] ethyl] phenyl] [3 (3 nitrophenyl)-5-pyrazolon- 1-yl]benzenesulfonamide [2-hydroxy-2- (3 -pyridinyl)ethyl] amino] ethyl]phenyl] (1 -triazol-2-yl] benzenesulfonami-de N- [[2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyl] phenyl] 1hydroxyheptyl)-5-methyl- -triazol-2-yl]benzenesulfonamide N- [2-hydroxy-2- (3-pyridinyl) ethyl] amino] -2-methyipropyl]1 phenyl] -4-(3-hexyl-2-imidazolidinon- 1 -yl)benzenesulfonamide N- [2-hydroxy-2-(3-pyridinyl)ethyl] amino] -2-methyipropyl] phenyl]-4-iodobenzenesulfonamide N- [[2-hydroxy-2-(3 -pyridinyl)ethyl] amino] -2-methyipropyl] phenyl] [(hexylamino)carbonyl] amino] benzenesulfonamide N- [(2-hydroxy- 2-phenylethyl) amino] ethylphenyl] iodobenzenesulfonamide [(2-hydroxy-2-phenylethyl) amino] ethyl] phenyl] -2-naph th alenesulfonamide N- [2-[(2-hydroxy-2-phenylethyl) amino] ethyl] phenyl -quinolinesulfonamide N- [[2-hydroxy-2- (3 -chlorophenyl) ethyl] amino] ethyl] phenyl] -3 isopropylbenzenesulfonamide
I
'WO 95/29159 WO 95/2159 rcrUS95/04956 16 N- [2-hydroxy-2-(Q3-chl orophenyl) ethyl] amino] ethyl] phenyl]1-2naphthalenesulfonamide N- [[2-hydroxy-2 -chlorophenyl) ethyl] amino] ethyl] phenyl] -3 quinolinesulfonamide N- [[2-hydrox y-2- amino- 3,5 -dichlorophenyl) ethyl] amino] ethyl)]phenyl] -4-(hexylaminocarbonylamino)benzenesulfonami de [[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl]amino] ethyl]phenyl]- 1 [[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl] amino] ethyl]- 10phenyl]-4-(3-hexyl-2-imidazolidinon-l1 -yl)benzenesulfonamide N- [[2-hydroxy-2- (4-amino-3 ,5-dichlorophenyl)ethyl] amino] ethyl] phenyl]-4-(3-octyl-2-imidazolidinon- 1 -yl)benzenesulfonamide N- [2-hydroxy-2- (4-hydroxyphenyl)ethyll amino] ethyl] phen yl] benzenesulfonamide [[2-hydroxy-2- (4-hydroxyphenyl)ethyl] amino] ethyl] phenyl] -4iodobe-nzenesulfonamide N- [[2-hydroxy-2-(3 -cy anophenyl)ethyl] amino] ethyl) phenyll -4- (hexylaminocarbonylamino)benzenesulfonamide [[2-hydroxy-2-(3-cyanophenyl)ethyl] amino] ethyl] phenyl] -3- N- [[2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyl] phenyl] hexyl-[1 ,2,4]-oxadiazol-3-yl)benzenesulfonamide N- [2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyl] phenyl)]-4- (4heptyl-5-methyl- [1 ,2,3]-triazol-2-yl)benzenesuifonamide N- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl] (3 hexyl-2,4-imidazolidinedion- 1 -yl)benzenesulfonamide N- [2-hydroxy-2- (3 -pyridinyl)ethyl] amino] ethyl] phenyl] (3 octy1-2,4-imidazolid.,nedion- 1 -yl)benzenesulfonamide [2-hydroxy-2- (3 -pyridinyl)ethyl] amino] ethyl] phenyl] [3 30cyclopentylpropyl)-2 ,4-imidazolidinedion- 1 -yl]benzenesulfonamide N- [[2-hydroxy-2- Q3-pyridinyl) ethyl) amino] ethyl]phenyl] (3 pentyl- [1 ,2,4]-oxadiazol-5-yl)benzenesulfonamide N- [2-hydroxy- 2- (3-pyri dinyl) ethyl] amino] ethyl] pheny1] (3 hexyl- [1,2 ,4]-oxadiazol-5 -yl)benzenesulfonamide WO 95/29159 WO 9529159ICIUS95/04956 17 N- [2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl (3 heptyl- [1 ,2,4]-oxadiazol-5-yl)benzenesulfonamide N- [[2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl] octyl-[ 1 ,2,4]-oxadiazol-5-yl)benzenesulfohamide N- [2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyllphenyl]-4- cyclopentylethyl)-[ [1,2,4]-oxadiazol-5-yl]benzenesulfonam-ide N- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl] 3 cyclopentylpropyl)-[ 1,2,4] -oxadiazol-5 -yl]benzenesulfonamide N- [2-hydroxy-2-(3 -pyridinyl) ethyl] amino] ethyl) phenyl pentyl- -thiadiazol-5 -yl)benzenesulfonami de N- [[2-hydroxy-2-(3 -pyridinyl)ethyl] amino] ethyl] phenyl] hexyl- [1 ,2,4]-thiadiazol-5-yl)benzenesulfonamide Nj- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl -4-(Q3heptyl- [1 ,2,4]-thiadiazol-5 -yl)benzenesulfonamide N- [2-hydroxy-2- (3 -pyridinyl) ethyl] ami no] ethyl] phenyl] (3 octyl-[ 1,2,4] N- [2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl]phenyl] cyclopentylethyl)-[ 1,2,4] -thiadiazol-5 -yl]benzenesulfonamide N- [2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl]phenyl]-4- cyclopentyipropyl)- [1 ,2,4]-thiadiazol-5-yl]benzenesulfonamide N- [2-hydroxy- 2- (3-pyridinyl)ethyl] amino] ethyl] phenyl]-4- (5 pentyl- [1 ,2,4]-thiadiazol- 3-yl)benzenesulfonamide N- hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] hexyl- [1 ,2,4]-thiadiazol-3- yl)benzenesulfonamide [2-hydroxy-2-(3 -pyridinyl)ethyl] amino] ethyl] phenyl] heptyl-[ 1,2,4]-thiadiazol-3-yl)benzenesulfonamide N- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl] (5 octyl-[ 1 ,2,4]-thiadiazol-3-yl)benzenesulfonamide N- [2-hydroxy-2- (3 -pyridinyl)ethyl] amino] ethyl] phenyl] [5 (2cyclopentylethyl)- -thiadiazol-3-yl]benzenesulfonamide Nj- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl] [5 cyclope.ntylpropyl)-[ 1,2,4]-thiadiazol-3-yl]benzenesulfonamide N- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl] (4pentyl-3-oxo- -triazol-2-yl)benzenesulfonamide Iwo 95/29159 WO 95/9 159PCT11JS95/04956 18 [[2-hydroxy-2-(3-pyridinyl)ethyl jal-ino] ethyljphenyl hexyl-3-oxo- 1, 2,4] -tri azol-2-yl) benzenes ulfo nami de N- 2 -hydroxy-2- (3-pyridin yl)ethyl]ami no] ethyl] phenyly4-(4heptyl-3-oxo- 1, 2 ,4]-triazol-2-yl)benzenesulfonamide N- [2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyl] phenyl]-4-(4octyl-3-oxo-[1 ,2,4]-triazol-2-yl)benzenesulfonamide N- [2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl (2cyclopentylethyl)-3-oxo-[ [1, 2 4 ]-triazol-2-yl]benzenesulfonamide N- [2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl] (3 cyclopentylpropyl)-3-oxo- [1 ,2,4]-triazol-2-yl]benzenesulfonamide N- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phen yl] (5 pentyloxazol-2-yl)benzenesulfonamide N- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] ph enyl (5 15hexyloxazol-2-yl)benzenesulfonamide N- [2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] (5 heptyloxazol-2-yl)benzenesulfonamide N- [[2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl octyloxazol-2-yl)benzenesulfonamid-, [2-hydroxy-2-(3 -pyridiriyl)ethyl] amino] ethyl] ph enyl] (2- 20cyclopentylethiyl)oxazol-2-yl]benzenesulfonamjde N- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl] (3 cyclopentylpropyl)oxazol-2-yl]benzenesulfonamide N- [[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] (4- 25pentyloxazol-2-yl)benzenesulfonamide [[2-hydroxy-2-(3 -pyridinyl)ethyl] amino]ethyl]phenyl]-4-(4hexyloxazol-2-yl)benzenesulfonamide N- [[2-1L ydroxy-2- (3-pyridinyl)ethyl] amino] ethyl]phenyl] heptyloxazol-2--yl)benzenesulfonamide [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl] (4- 30octyloxazol-2-yl)benzenesulfonamide N- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl]phenyl] (2cyclopentylethyl)oxazol-2-yl]benzenesulfonamide N- [2-hydroxy-2- (3 -pyridinyl)ethyl] amnino] ethyl] phenyl] (3 cyclopentylpropyl)oxazol -2-yl] benzenes ulfonainide VO 95/29159 W0 52159P,T/US95/04950 19 N- [[2-hydroxy-2-(3-pyridinyl)ethiyl] amino] ethyl]phenyl] N- [2-hydroxy-2- (3 -pyri di nyl) ethyl] amino] ethyl] phenyl] -yl)benzenesulfonamide N- [2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl] (3- N- [2-hydroxy-2-(3 -pyridinyl) ethyl] amino] ethyl] phenyl] (4- Nj- [2-hydroxy-2-(3 -pyridinyl)ethyl] amino] ethyl] phenyl] [2- (4-fluorophenyl) ethyl] ox ao..5 yl] benzenesufonamide N- [2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl pentyloxazol-4-yl)benzenesulfonamide N- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl] (2hexyloxazol-4-yl)benzenesulfonamide N- [2-hydroxy-2- (3 -pyri dinyl)ethyl] amino] ethyl] phenyl (2heptyloxazol-4-yl)benzenesulfonamide N- [2-hydroxy-2- (3 -pyridinyl)ethyl] amino] ethyl] phenyl] (2octyloxazol-4-yl)benzenesulfonamide N0h- [2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyl] phenyl] 20cyclopentylethyl)oxazol-4-yl]benzenesulfonamide N- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl] (3 cyclopentylpropyl)oxazol-4-yl]benzenesulfonamide N- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl (5 25pentylthiazol-2-yl)benzenesulfonamide [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl (5 hexylthiazol-2-ylbenzenesulfonamide N- r2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl] (5 heptylthiazol-2-yl)benzenesulfonamide [[2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl] (5 30octylthiazol-2-yl)benzenesnilfonamide N- [[2-hydroxy-2-(3 -pyridinyl)ethyl] amino] ethyl] phenyl] cyclopentylethyl)thiazol-2-ylbenzenesulfonamide N- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyllphenyl] [5 cyclopentylpropyl)thiazol-2-yl]benzenesulfonarmide WO 95129159 'WO 9529159PCT/US95/04950 20 Nj-[4- [2-hydroxy-2-(3 -pyridinyl)ethyl] amnino] ethyl] phenyl pen tylthi azol-2- yl)benzenesulfon amide N- [[2-hydroxy-2- (3-pyridinyl)ethyl] amino)jethyl] phenyl] (4hexylthiazol-2-yl)benzenesulfonamide N- [2-hydroxy (3 -pyri dinyl) ethyl] amino] ethyl.]ph enyl (4heptylthiazol-2-yl)benzenesulfonamide N- [[2-hydroxy-2-(3 -pyri dinyl) ethyl] amino] ethyl] phenyl] octylthiazol-2-yl)benzenesulfonamide N- [[2-hydrox y-2- (3 -pyridinyl) ethyl] amino] ethyl ]phenyl] cyclopentylethyl)thiazol-2-yl]benzenesulfonamide N- hydroxy- 2- (3-pyridinyl)ethyl] amino] ethyl] phenyl] (3cyclopentylpropyl)thiazol-2-yl]benzenesulfonamide Nj- [[2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl] pentylthiazol-4-yl)benzenesulfonamide [[2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyl] phenyl] hexylthiazol-4-yl)benzenesulfonamide N- [2-[[2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl] heptylthiazol-4-yl)benzenesulfonamide N- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl (2octylthiazol-4-yl)benzenesulfonamide N- [2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyl ]phenyl]-4- (2cyclopentylethyl)thiazol-4-yl]benzenesulfonamide N- [2-hydroxy-2- (3 -pyridinyl)ethyl] amino] ethyllphenyl] (3 cyclopentylpropyl)thiazol-4-yl]benzenesulfonamid-- N- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl] (2- N- [[2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl] (2- N- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl] (2- N- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl] (2- N- [2-hydroxy-2- (3 -pyridinyl)ethyl] amino] ethyl] phenyl] (2- I wo 95/29159 W0952919 1YUVIS9.5/04956 21 N- [[2-hydroxy-2-(3-pyridinyl)ethyllaminojethyjphenyll-4- N- [2-hydroxy-2- (3 -pyridinyl)ethyl] arn inolethyl] phenyl] 1 N- [[2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl] 1 pentylthiazol-2-y1)-5 -indolinesulfon amide N- [[2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyl] phenyl]- 1 N0 [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl] 1 10heptylthiazol-2-yl)-5-indolinesulfonamide N- [2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl]- 1 N- [2-hydroxy-2- (3 -pyridinyl)ethyl] amino] ethyl] phenyl] 1 ethyl) thiazol-2-yl] -5 -indolinesulfonamide, N- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl]iphenyl] 1- cyclopentylpropyl)thiazol-2-yl] N- [[2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyl] phenyl] 1-(4- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl.] 1-(4- 20hexylthiazol-2-yl)-5-indolinesulfonamide N- [2-hydroxy-2- (3-pyridinylI)ethyl] amino] ethyl] pheny1] 1 N- [2-hydroxy-2- (3 -pyridinyl)ethyl] amino] ethyl] phenyl] (2- N- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl] 1 cyclopentylpropyl)thiazol-2-yl] N- [[2-hydroxy- 2- (3-pyridinyl)ethyl] amino] ethyl] phenyl] 1 [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl] 1- 30pentyloxazol-2-yl)-5 -indolinesulfonamide N- [2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] N- F[2-hydroxy-2- Q3-pyridinyl) ethyl] amino] ethyl] phenyl] -1 (5 WO 95/29159 WO 95/9159IVUS951041950 22 [2-[[2-hiydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl- I N- [[2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenylj- 1- N- hydroxy-2- pyridi nyl) ethyl] amino] ethyl] phenyl] 1 N- [[2-hydroxy-2-(3-pyridinyl)ethyl amino] ethyl] phenyl]- 1 N- [[2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyl] phenyl]- 1 N- [[2-hydroxy-2- (3-pyridinyl)ethiyl] amino] ethyl] phenyl]- 1 exyloxazo1-2-y)-5-indolinesulfonamide N- [[2-hydroxy-2-(3-pyridinyl) ethyl] amino] ethyl] phenyl]- 1 N- [[2-hydroxy-2-(3-pyridinyl) ethyl] amino] ethylphenyl- 1- (4- N- [[2-hydroxy-2-(3-pyridinyl)ethyl] aminojethyljphenyl]- 1- cyclopentylethyl)oxazo1-2-yl]-5-indolinesulfonamide N- [[2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyllphenyl]- 1- N- [[2-hydroxy-2- (3-pyridiny1) ethyl) amino] ethyllphenyl] 1-(3methyl- [1 ,2,4]-oxadiazol-5-yl)-5-indolinesulfonamide N- [[2-hydroxy-2- (3-pyridinyl)ethyll amino] ethyl]phenyl] 1- (3pentyl- -oxadiazol-5 [[2-hydroxy-2-(3-pyridinyl)ethyl] amiir, ,y1]phenyl] hexyl- [1 ,2,4]-oxadiazol- 5-yl)-5 -indolinesulfonamide N- hy droxy- 2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] 1-(3heptyl- [1 ,2,4]-oxadiazol-5-yl)-5-indolinesulfonamide N- [[2-hydroxy-2-(3-pyri dinyl)ethvl] amino] ethyl] phenyl]- 1-(3octyl- N- [2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl cyclopentylethyl)- -oxadiazol-5-yl] -5 -indolinesulfonaimide N- [2-hydroxy-2- (3 -pyridinyl)ethyl] amino] ethyl] phenyl] 1 [3 cyclope ntyipropyl)- [1 ,2,4]-oxadiazol-5 -yl] WO 95/29159 PCP('US95/04956 -23- N- 2--hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl phenyl methyl-[1,2,4]-oxadiazol-3-yl)-5-indolinesu Ifonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- pentyl-[ 1,2,4]-oxadiazol-3-yl)-5-indolinesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- hexyl-[1,2,4]-oxadiazol-3-yl)-5-indolinesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethylaminojethyl]phenyl]- heptyl-[1,2,4]-oxadiazol-3-yl)-5-indolinesulfonamide [2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amno]ethyl]phenyl- octyl-[1,2,4]-oxadiazol-5-yl)-3-indolinesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]- 1 cyclopentylethyl)-[1,2,4J-oxadiazol-3-yl]-5-indolinesulfonamide [[2-hydroxy-2-(3-pyridinyl)ethyl] amino]ethyl]phenyl]- 1 cyclopentylpropyl)-[1,2,4]-oxadiazol-3-yl]-5-indolinesulfonamide The compounds of the instant invention all have at least one asymmetric center as noted by the asterisk in structural Formula I.
Additional asymmetric centers may be present on the molecule depending upon the nature of the various substituents on the molecule, in particular, R 2 and R 3 Each such asymmetric center will produce two optical isomers and it is intended that all such optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof, be included within the ambit of the instant invention.
In the case of the asymmetric center represented by the asterisk in Formula I, it has been found that the compound in which the hydroxy substituent is above the plane of the structure, as seen in Formula Ic, is more active and thus more preferred over the compound in which the hydroxy substituent is below the plane of the structure.
The following stereospecific structure represents the preferred stereoisomers of the instant invention: WO 95/29159 PCT/US95/04956 24 H OH H R 2 R 4 I I 11 7 A CCH 2 m NS0 2
(CH
2 )rR I I (R)n R R 5
R
6 where n, m, r, A, R 1
R
2
R
3
R
4
R
5
R
6
R
7 and X are as defined above under formula I.
Throughout the instant application, the following terms have the indicated meanings: The alkyl groups specified above are intended to include those alkyl groups of the designated length in either a straight or branched configuration. Exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
The alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a straight or branched configuration. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
The term "halogen" is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.
Examples of 5 and 6-membered heterocycles and fused heterocycles f A, Z and R la include pyridyl, quinolinyl, pyrimidinyl, pyrrolyl, thienyl, imidazolyl, thiazolyl, benzimidazolyl, thiadiazolyl, benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl, benzoxazinyl, benzisoxazolyl, benzothiazolyl, tetrahydronaphthyl, dihydrobenzofuranyl, tetrahydroquinolinyl, furopyridine and thienopyridine.
The preferred values of A and Z are phenyl, naphthyl, benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or WO 95/29159 CI'/US95/04956 25 heterocycles with from 1 to 4 heteroatoms independently selected from one of oxygen or sulfur, and/or 1 to 4 nitrogen atoms.
The more preferred values of A are phenyl, pyridyl, quinolinyl, pyrimidinyl, pyrrolyl, thienyl, imidazolyl, and thiazolyl.
The more preferred values of Z are phenyl, naphthyl, quinolinyl, thienyl, benzimidazolyl, thiadiazolyl, benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl, benzoxazinyl, benzisoxazolyl, benzothiazolyl, tetrahydronaphthyl, dihydrobenzofuranyl, triazolyl, tetrazolyl, oxadiazolyl, imidazolyl, oxazolyl, thiazolyl, imidazolidinyl, pyrazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazolyl, tetrahydrobenzothiazolyl and tetrahydroquinolinyl. When Z is attached to -NSO2(CH2)r-, it is preferably phenyl, naphthyl or a benzene ring fused to a 5 or 6membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen. When Z is part of the definition of R 8 it is preferably phenyl, a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or a 5 or 6membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-CS cycloalkyl ring.
The preferred heterocycles of R 1 a are thienyl, thiadiazolyl, triazolyl, tetrazolyl, oxadiazolyl, imidazolyl, oxazolyl, thiazolyl, imidazolidinyl, pyrazolyl, isoxazolyl, pyridyl, pyrimidyl, and pyrazolyl.
Certain of the above defined terms may occur more than once in the above formula and upon such occurrence each term shall be defined independently of the other; thus for example, NR 8
R
8 may represent NH2, NHCH3, N(CH3)CH2CH3, and the like.
The following abbreviations are used throughout the specification: Boc tert-butyloxycarbonyl Cbz carbobenzyloxy DIP-Cl diisopinocampheylchloroborane DMF dimethylformamide
II,
WO 95/29159 PCT/US95/04956 -26- DMSO dimethylsulfoxide HPLC high pressure liquid chromatography Me methyl MPLC medium pressure liquid chromatography Ms methanesulfonyl (mesyl) NBS N-bromosuccinimide NCS :N-chlorosuccinimide nHex n-hexyl TBAF tetrabutylammonium fluoride TBS (TBDMS) t-butyldimethylsilyl TFA :trifluoroacetic acid THF tetrahydrofuran The compounds of the present invention can be prepared from epoxide intermediates such as those of formula II and amine intermediates such as those of formula III. The preparation of these intermediates is described in the following schemes.
0
R
2
R
4 I I- 4 0 A H 2 N-C-(X m NSO 2
(CH
2 )r-R 7
A
3 R6 Rs (R1)n I III where n, m, r, A, R 1
R
2
R
3
R
4
R
5
R
6
R
7 and X are as defined above.
Compounds II are known in the literature or may be conveniently prepared by a variety of methods familiar to those skilled in the art. One common route is illustrated in Scheme 1. Acid chloride 1, which may be commercially available or readily prepared from the corresponding acid by treatment with, for example, thionyl chloride or oxalyl chloride, is treated with diazomethane in a solvent such as diethyl ether. The resultant diazoketone is then treated with hydrogen chloride to give chloroketone 2 (X Cl). The haloketone 2 is then reduced with a reducing agent such as sodium borohydride. The resultant alcohol 3 is I WO 95/29159 PCTIUS95/04956 -27treated with base such as potassium carbonate in refluxing acetone to provide the desired epoxide II. The enantiomerically enriched and epoxides II are readily available by asymmetric reduction of haloketones 2 using chiral reducing agents such as or (+)-DIP-C1, or (S)-Alpine borane or or (S)-tetrahydro-l-methyl-3,3diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole-borane or
OAB-BH
3 SCHEME 1 1) CH 2
N
2 2) HCI (R)nv 1
[H]
B
2 (X Cl, Br) base
OA
3 (X CI, Br) An alternate route to the desired haloketones 2 is illustrated in Scheme 2. Methylketone 4 may be converted to the corresponding haloketone using a variety of reagents known to those in the art and summarized in Larock Comprehensive Organic Transformations; VCH: New York, 1989, 369-372. Conveniently, methylketone 4 is treated I I WO 95/29159 PCTIUS95/04956 -28with chlorine or N-chlorosuccinimide in acetic acid with an additional acid source such as hydrogen chloride or aluminum chloride. For the synthesis of 2 (X Br), bromine, dibromobarbituric acid or NBS with hydrogen bromide or aluminum bromide may be used. In some cases, the chloro or bromoketones 2 may be commercially available.
SCHEME 2
O
0 0 A CH 3 CI2 or Br 2
X
(R')n 4 2 (X CI, Br) Many of the methylketones 4 are commercially available or readily prepared by methods described in the literature and known to those skilled in the art. Rl substituents on the acid chlorides 1 or methylketones 4 may need to be protected during the subsequent procedures. A description of such protecting groups may be found in: Protective Groups in Organic Synthesis, 2nd Ed., T. W. Greene and P.
G. M. Wuts, John Wiley and Sons, New York, 1991.
Compounds III can be conveniently prepared by a variety of methods familiar to those skilled in the art. A convenient route for their preparation when R 6 is hydrogen is illustrated in Scheme 3.
Compound 5 is selectively protected as a suitable carbamate derivative 6 with, for example, di-tert-butyl dicarbonate or carbobenzyloxy chloride. This compound is then treated with a sulfonyl halide, preferably the sulfonyl chloride 7, and a base such as pyridine in an anhydrous solvent such as dichloromethane or chloroform for 0.5 to 24 hours at temperatures of -20 to 50 0 C, preferably 0°C, to provide the sulfonamide 8. The protecting group is then removed with, for 1 7 1 111-1 'WO 95/29159 PCT/US95/04956 -29example, trifluoracetic acid in the case of Boc or catalytic hydrogenation in the case of Cbz, to give the desired amine 9.
SCHEME 3.
R2
H
2 N-C-(X)m
R
3 or CbzCI/base
R
2 GNH-C-X)m -NH 2
R
6G G Boc or Cbz
R
7
(CH
2 )rSO 2 CI (Z) f.
pyridine, CH2C1 2 TFA, CH2C1 2 or H 2 /Pd catalyst R2 n GNH-C-(X)m
NSO
2
(CH
2 ),r 8 HN--3(X)m/ NSO 2
(CH
2 )r-R 7 R3
H
9 Compounds III where R6 is not hydrogen may be conveniently prepared as illustrated in Scheme 4. Sulfonamide 8, prepared as described above, is alkylated with an appropriate alkylating agent 10 in the presence of base to provide sulfonamide 11. Removal of the protecting group as above gives the desired compound 9a.
g WO 95/29159 PCT/US95/04956 SCHEME 4 2 R 4 Alk-Y GNH-CX)m NSO 2
(CH
2 )r-R 7
R
3 8 R 5 H base R2 GNH-C-(X)m NSO 2
(CH
2 )r-R 7 TFA, CH 2
CI
2 R3 Alk
R
5 or H 2 /Pd catalyst 11
R
4 R2
II
H2N-(X)NSO(CH,)R 7 G Boc or Cbz R s Alk Y= CI, Br, or I AIk C1-C6 alkyl 9a The sulfonyl chlorides 2, many of which are commercially available, can also be readily prepared by a number of methods familiar to those skilled in the art. One suitable method involves the addition of an organolithium reagent or a Grignard reagent to sulfuryl chloride following the procedure of S. N. Bhattacharya, et. al., J. Chem. Soc.
1265-1267 (1969). Another convenient method involves the treatment of a thiol with sulfuryl chloride and a metal nitrate according to the procedure of Y. J. Park, et. al., Chemistry Letters, 1483-1486 (1992). Sulfonic acids are also conveniently converted to the corresponding sulfonyl chloride by treatment with PCl5, PCl3 or SOC12 March, Advanced Organic Chemistry, 4th Ed., John Wiley and Sons, New York: 1992, p 12 9 7 and references sited therein). Aromatic and heteroaromatic compounds may be chlorosulfonylated directly by treatment with Vilsmeier's reagent or chorosulfonic acid (Organic Synthesis, I, 8).
II
WO 95/29159 O f1US95/01956 -31 The diamines 5 are commercially available or readily prepared by methods described in the literature or known to those skilled in the art. Compound 5 where R2 or R3 is methyl can be prepared from the corresponding amino acid following the method of J.
D. Bloom, et. al., J. Med. Chem., 35, 3081-3084 (1992). As illustrated in Scheme 5 for R3 methyl, the appropriate amino acid 12 is esterified, conveniently by treatment with methanolic hydrochloric acid, and then treated with di-tert-butyl dicarbonate to give compound 13.
The ester group is reduced with a hydride source such as lithium borohydride and the resultant alcohol is converted to a leaving group such as a mesylate. Removal of the Boc protecting groups gives diamine 14. This compound is subjected to catalytic hydrogenation in the presence of base such as sodium acetate to give the desired c-methyl amine 15. The other enantiomer is available through an analogous 1 sequence starting with the corresponding amino acid.
I II 'WO 95/29159 PCT/US95/04956 -32- SCHEME
H
2 N (X)m /R4 12C 5
NH
2 BocNH (X)m R4 MeO 2 C
I-
H
2 N 4 MsO/ R NH 2 1A *2CF 3 C02 1) MeOH, HCI 2) Boc20, NaHCO 3 1) LiBH 4 2) MeSO 2 CI, Et 3
N
oc 3) TFA,
CH
2
CI
2
H
2 NaOAc cat. Pd
H
2 N (X)m R4 Me
NH
2 Diamines 5 or sulfonamide amines 9 where X is and m is 1 are also readily prepared by methods described in the literature or known to those skilled in the art. For example, as shown in Scheme 6, the sodium salt of 4-nitrophenol 16 is alkylated with 1bromo-2-chloroethane, conveninetly in refluxing 2-butanone with a base such as potassium carbonate to give chloro derivative 17. The chloride is converted to the corresponding amine by treatment with lithium azide followed by reduction with, for example, triphenylphosphine in aqueous tetrahydrofuran. Protection of the resultant amine, conveniently as its t-butyl carbamate by treatment with di-tert-butyldicarbonate, gives derivative 18. The nitro group is then reduced, for example, by -e e VO 95/29159 'WO 95/2159 PCTUS95/04956 33 catalytic hydrogenation to provide amine 19. Acylation of intermediate 19 with sulfonyl chloride 7, followed by deprotection with acid such as trifluoroacetic acid gives the desired intermediate SCHEME 6 N a O a N 0 2
K
2 00 3 2-butanone, reflux, 24h C1 O a NO 2 17 1. LIN 3 DMF, 600 2. PPh 3
THF/H
2
O,
3. Boc anhydride, 0H 2 C1 2 BocNH" 0 a N0
INO
2
H
2 Pd/C BocNH 01 1. R 7
(CH
2 )rSO 2 CI pyridine, CH 2 01 2
NH
2 2. TFAICH 2
CI
2 (1:3) 1 NHSO 2
(CH
2 )r-R 7 Alternatively, diamine 5 where X is -CH2O- and mn is 1 is available from intermediate 19 by treatment with trifluoroacetic acid.
This diamine may then be modified as illustrated in Scheme 3.
'WO 95/29159 PCT/US95/04956 -34- Diamines 5 and sulfonamide amines 9 where X is -CH2CH2- and m is 1 are also readily prepared by methods described in the literature or known to those skilled in the art. For example, as shown in Scheme 7, bromo derivative 21 is treated with sodium cyanide to provide nitrile 22. The nitro group is selectively reduced by treatment with hydrogen and catalytic palladium to provide amine 23.
Amine 23 is acylated with sulfonyl chloride 7 to give the corresponding sulfonamide 24. Reduction of compound 24 with cobalt chloride and sodium borohydride provides the desired amine SCHEME 7 Br
NO
2 21 N 2
H
2 Pd/C N C MeOH NaCN
DMSO
RT, 6h NC N 22 NO,
R
7
(CH
2 )rSO 2 C (7) pyridine, CH 2 C1 2
'NH
2 23 NC N A NHSO 2
(CH
2 )r-R 7 CoC12"6H 2 0 NaBH 4 MeOH
H
2 N NHS(CHR7
NHSO
2
(CH
2
)-R
7 WO 95/29159 PCT/US95/04956 35 Alternatively, diamine 5 where X is -CH2CH2- and m is 1 is available from intermediate 23 by reduction of the nitrile group with, for example, cobalt chloride and sodium borohydride. This diamine may then be modified as illustrated in Scheme 3.
Intermediates II and III are coupled by heating them neat or as a solution in a polar solvent such as methanol, acetonitrile, tetrahydrofuran, dimethylsulfoxide or N-methyl pyrrolidinone for 1 to 24 hours at temperatures of 30 to 150 0 C to provide compounds I as shown in Scheme 8. The reaction is conveniently conducted in refluxing methanol. Alternatively, a salt of amine III, such as the trifluoroacetate or hydrochloride salt, may be used. In these cases, a base such as sodium bicarbonate or diethylisopropylamine is added to the reaction mixture. The product is purified from unwanted side products by recrystallization, trituration, preparative thin layer Schromatography, flash chromatography on silica gel as described by W.
C. Still, et. al., J. Org. Chem. 43, 2923 (1978), medium pressure liquid chromatography, or HPLC. Compounds which are purified by HPLC may be isolated as the corresponding salt. Purification of intermediates is achieved in the same manner.
S WO 95/29159 PCT/US95/04956 36 SCHEME 8
O
A
(R
1 )n R4
I-
H
2 N-9-(X)m NSO 2
(CH
2 )r-R R3 R6
III
R4 OH HR 2 4 j(RCHCH 2 N-C'(X)m NSO 2
(CH
2 )r-R 7
(R
1
R
3
R
6
I
In some cases, the coupling product I from the reaction described in Scheme 8 may be further modified, for example, by the removal of protecting groups or the manipulation of substituents on, in particular, R1 and R7. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art.
An alternate method for the synthesis of compound I is illustrated in Scheme 9. Epoxide II is coupled to amine 5 as described above for coupling intermediates II and III (Scheme 8) to give aniline derivative 27. The secondary amine is selectively protected, for example, as a carbamate by treatment with di-tert-butyldicarbonate to provide carbamate 29. Alternatively, nitro amine 26 is used in the coupling reaction to provide 28. Following protection as described above, the nitro group is reduced, for example, by catalytic hydrogenation with palladium catalyst or raney nickel, to provide intermediate 29. In some cases, other group may be reduced concomitantly. For example, if R1 is halogen in intermediate 28, it may WO 95/29159 P ("IC11S95/104956 -37be converted to hydrogen in intermediate 29. Treatment with a sulfonyl chloride in the presence of a base such as pyridine followed by removal of the protecting group with, in the case of a tert-butylcarbamate, acid such as trifluoroacetic acid or methanolic hydrogen chloride, provides the sulfonamide I.
SCHEME 9
O
A
(R
1 )n
R
4
H
2 N-C(X)m -Z 1
R
i NH 2 S(Z N0 2
R
4 OH HR2 1 1 HN /I I BocO or A CHCH 2 N-C.(X)m Z R3 1) (Rn
R
5 2) H 2 Pd/C 27 (Z NH 2 2 (Z NO 2 OH BocR 2
R
(Rn CHCH 2 N- (X)m NH 2 (R1) R 3 n 2R 1) R (CH 2 )r-SO 2 CI, base
I
2) TFA or HCI/MeOH In some cases, compound I from the reaction sequence illustrated in Scheme 9 may be further modified, for example, by the _I 'WO 95/29159 I'T/IUS95/04956 38 removal of protecting groups or the manipulation of substituents on, in particular, R1 and R7, as described above. In addition, manipulation of substituents on any of the intermediates in the reaction sequence illustrated in Scheme 9 may occur, One such example is illustrated in Scheme 10. Compound which is prepared as outlined in Scheme 9 from the corresponding epoxide, is subjected to reduction using tin(II) chloride to provide compound 31. Other examples of substituents on compound I which may be reduced to the corresponding amine by methods commonly known to those skilled in the art include nitro groups, nitriles, and azides.
SCHEME OH Boc R NC- (X)m NS 2
(CH
2 )n-R 7
R
2 R
R
4
N--N
SnCI 2 aq. HCI-MeOH OH H R S R 2 R
R
4
H
2 N N 31 The compounds of the present invention can also be prepared from amine intermediates such as those of formula III and haloketone intermediates such as those of formula 2, as shown in Scheme 11. Amine III is alkylated with haloketone derivative 2, conveniently by treatment of a mixture of III and 2 with base such as potassium carbonate or triethylamine in a polar solvent such as acetonitrile, acetone or dimethylformamide. The resultant aminoketone 'WO 95/29159 PCT/1US95/04956 -39- 32 is reduced with, for example, sodium borohydride in methanol to give the desired aminoalcohol I.
SCHEME 11 0 x
(R
1 2 (X CI, Br) 2
R
2
H
2 N-C-(X)m NS0 2
(CH
2 )rR R3 R6
III
0
HR
2 R4 (RCCH2N-C'(X)3 NSO 2
(CH
2 )r-R (R)n
R
5 6 32
[H]
I
In some cases, the product I from the reaction described in Scheme 11 may be further modified, for example, by the removal of protecting groups or the manipulation of substituents on, in particular, R1 and R7. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art.
An alternate synthesis of key intermediate 29 is shown is Scheme 12. The alcohol of intermediate 3 is protected, for example, as its t-butyldimethylsilyl ether to give TBS derivative 33. This compound is then treated with amine 5 and a base such as diisopropylethylamine in a solvent, typically polar aprotic such as acetonitrile, at temperatures of
L
WO 95/29159 PCIT/US95/0495( to 150 °C for 1 to 72 hours. Typically, an iodide source such as sodium iodide is added to facilitate the reaction. The protecting group is then removed, in the case of silyl ether, by treatment of the resultant amine 34 with a fluoride source such as tetrabutylammonium fluoride.
Protection of the secondary amine as before gives key intermediate 29.
SCHEME 12
OR
X
A
9 3 (R H, X CI, Br) n 33 (R SiMe 2 tBu)
R
4 1 2
H
2 N-C
/)NH
2
R
R
4 20 OTBS H R 2
,-R
4 S I 1)TBAF A CHCH 2 N-C-(X)m NH2 R3 2)Boc20 (R )n 34 R 5 OH BocR 2
R
4 CHCH2N- -X)m NH2 3 R 3 Il 29 In some cases, compound I may be synthesized directly from intermediate 27 without protection of the secondary amine. For example, when R 2 and R 3 are both methyl, aniline derivative 27 is treated with sulfonyl chloride 7 and a base such as pyridine in a solvent WO 95/29159 PC'/YU895/0495O -41 such as dichloromethane at a temperature of -30 to 50 oC, typically 0 to provide compound I.
In some cases, the product I from the reaction described in Scheme 13 may be further modified, for example, by the removal of protecting groups or the manipulation of substituents on, in particular, R1 and R7, as described above.
SCHEME 13 R4 OH H R 2 (R CHCH2N-C-(X)m-\
NH
2 (R n 3 27 (R 2
,R
3 Me)
R
7
(CH
2 )r-SO 2 CI (Z)
I
base The compounds of the present invention where R 2 and
R
3 are hydrogen can also be prepared from acid intermediates of formula 36 and aminoalcohols of formula 37, as shown in Scheme 14.
Acid 36 is available from the corresponding ester 35, typically a methyl or ethyl ester, by treatment with sulfonyl chloride 7 and a base such as pyridine, followed by hydrolysis of the ester with aqueous acid or base.
Acid 36 is coupled to amine 37, which is known in the literature or readily prepared by methods known to those skilled in the art, using a coupling agent such as benzotriazolyl-N-oxytris(dimethylamino)phosphonium hexafluorophosphate or 1-(3dimethylaminopropyl)-3-ethylcarbodiimide methiodide to provide the amide 38. This is treated with a reducing agent, typically borane, to provide the desired compound I.
-I
'WO 95/29159 PCT/US95/04956 -42- SCHEME 14
R
4 RO-C(X)m NH 1) CISO 2
(CH
2 )r-R 7 base R6
R
5 2) aqueous acid or base R Me or Et, etc.
R
4 HO-C-(X)m NSO 2
(CH
2 )r-R 7
R
36
OH
O
(R ANH
(R
1 3 7 OH HO CCH2N- /NSO 2
(CH
2
)-R
7 38
R
[H]
I
Compounds of the general Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof. The pair of enantiomers thus obtained
I
WO 95/29159 I'CT/US95/049S56 43 may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent.
Alternatively, any enantiomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials of known configuration.
The instant compounds can be isolated in the form of their pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic and the like. In addition, certain compounds containing an acidic function such as a carboxy or tetrazole, can be isolated in the form of their inorganic salt in which the counterion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases.
As previously indicated, the compounds of the present invention have valuable pharmacological properties.
The present invention also provides a compound of the general Formula I or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance.
In one aspect, the present invention provides a compound of the general Formula I or a pharmaceutically acceptable ester thereof: or a pharmaceutically acceptable salt thereof for use in the treatment of obesity in human or non-human animals.
The present invention further provides a compound of the general Formula I, or a pharmaceutically acceptable ester thereof; or pharmaceutically acceptable salt thereof, for use in the treatment of hyperglycemia (diabetes) in human or non-human animals.
The disease diabetes mellitus is characterized by metabolic defects in production and utilization of glucose which result in the failure to maintain appropriate blood sugar levels. The result of these defects is elevated blood glucose or hyperglycemia. Research on the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Treatments have included parenteral I I 'WO 95129159 PCI'T'US95/04956 44 administration of exogenous insulin, oral administration of drugs and dietary therapies.
Two major forms of diabetes mellitus are now recognized.
Type I diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone which regulates glucose utilization. Type II diabetes, or insulin-independent diabetes, often occurs in the face of normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most of the Type II diabetics are also obese.
In addition the compounds of the present invention lower triglyceride levels and cholesterol levels and raise high density lipoprotein levels and are therefore of use in combatting medical conditions wherein such lowering (and raising) is thought to be beneficial. Thus they may be used in the treatment of hypertriglyceridaemia, hypercholesterolaemia ind conditions of low HDL (high density lipoprotein) levels in addition to the treatment of atherosclerotic disease such as of coronary, cerebrovascular and peripheral arteries, cardiovascular disease and related conditions.
Accordingly, in another aspect the present invention provides a method of lowering triglyceride and/or cholesterol levels and/or increasing high density lipoprotein levels which comprises administering, to an animal in need thereof, a therapeutically effective amount of a compound of the formula or pharmaceutically acceptable salt thereof. In a further aspect the present invention provides a method of treating atherosclerosis which comprises administering, to an animal in need thereof; a therapeutically effective amount of a compound of the formula or pharmaceutically acceptable salt thereof. The compositions are formulated and administered in the same general manner as detailed below for treating diabetes and obesity. They may also contain other active ingredients known for use in the treatment of atherosclerosis and related conditions, for example fibrates such as clofibrate, bezafibrate and gemfibrozil; inhibitors of cholesterol biosynthesis such as HMG-CoA reductase inhibitors for example lovastatin, simvastatin and pravastatin; inhibitors WO95129159 JPCT/US95/04956 of cholesterol absorption for example beta-sitosterol and (acyl CoA:cholesterol acyltransferase) inhibitors for example melinamide; anion exchange resins for example cholestyramine, colestipol or a dialkylaminoalkyl derivatives of a cross-linKed dextran; nicotinyl alcohol, nicotinic acid or a salt thereof; vitamin E; and thyromimetics.
The compounds of the instant invention also have the effect of reducing intestinal motility and thus find utility as aiding in the treatment of various gastrointestinal disorders such as irritable bowel syndrome. It has been proposed that the motility of non-sphincteric smooth muscle contraction is mediated by activity at 33 adrenoreceptors. The availability of a 33 specific agonist, with little activity at 13 and 12 receptors will assist in the pharmacologic control of intestinal motility without concurrent cardiovascular effects. The instant compounds are administered generally as described below with dosages similar to those used for the treatment of diabetes and obesity.
It has also been found unexpectedly that the compounds which act as agonists at B3 adrenoreceptors may be useful in the treatment of gastrointestinal disorders, especially peptic ulcerations, esophagitis, gastritis and duodenitis, (including that induced by H.
pylori), intestinal ulcerations (including inflammatory bowel disease, ulcerative colitis, Crohn's disease and proctitis) and gastrointestinal ulcerations.
In addition, 33 receptors have been indicated to have an effect on the inhibition of the release of neuropeptides in certain sensory fibers in the lung. As sensory nerves may play an important role in the neurogenic inflammation of airways, including cough, the instant specific 33 agonists may be useful in the treatment of neurogenetic inflammation, such as asthma, with minimal effects on the cardiopulmonary system.
33 adrenoreceptors are also able to produce selective antidepressant effects by stimulating the 33 receptors in the brain and thus an additional contemplated utility of the compounds of this invention are as antidepressant agents.
C I-~ SWO 95/29159 11IA18TU95/04956 -46- The active compounds of the present invention may be orally administered as a pharmaceutical composition, for example, with an inert diluent, or with an assimilable edible carrier, or they may be enclosed in hard or soft shell capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
For oral therapeutic administration, which includes sublingual administration, these active compounds may be incorporated with excipients and used in the form of tablets, pills, capsules, ampules, sachets, elixirs, suspensions, syrups, and the like. Such compositions and preparations should contain at least 0.1 percent of active compound.
The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated.
When treating diabetes mellitus and/or hyperglycemia generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligrams to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
When treating obesity, in conjunction with diabetes and/or hyperglycemia, or alone, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily
-=I
'WO 95129159 W C'lktUS95/04956 -47dosage of from 1 milligram to about 1000 milligrams per kilogram of animal body weight, preferably given in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 10 milligrams to about 10,000 milligrams, preferably from about 10 milligrams to about 500 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 70 milligrams to about 3500 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
These active compounds may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the
I--
*W )95/29159 )'9II US95O1i)956 -48contaminating action of microorganisms such as bacteria and fungi.
The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
The following examples are provided so that the invention might be more fully understood. They should not be construed as limiting the invention in any way.
0 EXAMPLE 1
OH
H
N- N
NH
2 Il
N
N
(R)-N-[2-[4-(aminophenyl)]ethyl]-2-hydroxy-2- (tetrazolo[1,5-a]pyrid-6yl)ethylamine A solution of 1.62 g (10 mmol) of (R)-2-(tetrazolo[1,5..
a]pyrid-6-yl)oxirane (See Fisher and Wyvratt, European Patent Application 0 318 092 A2 for the synthesis of this compound.) and 4.1 g mmol) of 2-(4-aminophenyl)ethylamine in 30 mL of methanol was heated at reflux for 5h. The reaction mixture was concentrated and the residue chromatographed on silica gel methanol/98% methylene chloride) to give 1.69 g of the title compound: 1H NMR (400 MHz, CD30D) 8 9.01 1H, J =1.3 Hz), 8.02 (d,l H, J 9.2 Hz), 7.82 (dd, 1H, J 1.3, 9.2 Hz), 6.94 2H, J 6.3 Hz), 6.63 2H, J 6.3 Hz), 4.91 1H), 2.82 4H), 2.67 2 H, J 7.1Hz).
WO 95/291599 49 EXAMPLE 2
OH
N
N N NNH 2
N=N
(R)-N-[2-[4-(aminophenyl)]ethyl]-2-hydroxy-2-(tetrazolo[1,5-a]pyrid-6yl)ethylcarbamic acid 1,1-dimethylethyl ester A solution of 1.69 g (56.7 mmol) of the amine from Example 1 and 1.23 g (56.7 mmol) of di-tert-butyl dicarbonate in mL of tetrahydrofuran (THF) at 0° C was stirred for 2 h. The reaction mixture was concentrated and the residue chromatographed on silica gel methanol/96% methylene chloride) to afford 2.2 g of the 1 title compound: 1 H NMR (400 MHz, CD30D) 8 8.96 1H), 8.05 (m, 2H), 7.85 2H), 6.93 (dd, 2H, J 7.7, 8.3 Hz), 6.66 2H, J 8.
Hz), 4.99 1H), 3.49 4H), 2.70 2H, J =6.5 Hz), 1.26 9H).
EXAMPLE 3 0 KS02CI nHex-NH N
H
4-(Hexylaminocarbonvlamino)benzenesulfonyl chloride Hexylamine, 12.15 ml (9.2 mmol), was added dropwise to a solution of 10 ml (9.2 mmol) of phenyl isocyanate in THF (150 ml) at 0°C, and stirring was continued for 1 h. The solvent was removed in vacuo, and the resultant hexyl phenyl urea was used without further purification.
A 6-g (2.7 mmol) portion was added over 20 min to chlorosulfonic acid at 0°C, followed by heating at 60 0 C for 2h. After cooling, the mixture was added to ice/water (100ml) and the aqueous
I
WO 95/29159 'lCTI/U95/0,4956 phase extracted with EtOAc (3x100 ml). The combined organic phase was washed with brine (50 ml), dried with MgSO4, concentrated, and purified by flash chromatography (silica gel, 75% hexane/ 25% ethyl acetate) to give 6 g of the title compound: 1 H NMR (CDC13) 7.85 2H, J 9.6 Hz), 7.54 2H, J 9.6 Hz), 6.79 (br.s, 1H), 4.71(br. s, 1H), 3.23 2H, J 8 Hz), 1.54-1.44 2H), 1.33-1.20 (m, 6H1), 0.91-0.79 3H).
EXAMPLE 4
OH
OH Boc
N
N N NH N=N 0 SO2 nHex-NH N
H
(R)-N-[4-[2-[N-(1,1-dimethylethoxycarbonyl)-N-[2-hydroxy-2-(tetrazolo[1,5-a]pyrid-6-yl)]ethyl]amino]ethyl]phenyl]-4-(hexylaminocarbonylamino)benzenesulfonamide To a stirred solution of 0.200 g (0.502 mmol) of the Boccompound from Example 2 in 3 mL of methylene chloride was added 80 mg (1.00 mmol) of pyridine followed by 0.16 g (0.75 mmol) of the sulfonyl chloride from Example 3. After being stirred for 5h, the reaction mixture was concentrated and the residue chromatographed on silica gel (10% methanol/90% methylene chloride) to afford 0.303 g of the title compound: 1 H NMR (400 Hz, CD30D) 5 8.95 (s, 1H), 8.0-8.08 1H), 7.75-7.87 1H), 7.40-7.62 4H), 7.00 (m, 4H), 4.95 2H), 3.47 2H), 3.15 2H), 2.75 2H), 1.52 (t, 2H, J 6.0 Hz), 1.33 8H), 1.21 9H), 0.90 3H, J 6.0 Hz).
L~
I_
'WO 95/29159 I't°1IS9.I/0.95( -51 EXAMPLE OH H
N
H
2 N N
NH
O 0
S
0 2 nHex-NH N
H
[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenvll-4-(hexvlaminocarbonvlamino)benzenesulfonamide A mixture of 0.302 g (0.44 mmol) of the tetrazine from Example 4, 0.20 g (0.88mol) of tin(II) chloride dihydrate and 0.3 ml of concentrated aqueous hydrochloric acid in 2 mL of methanol was heated at reflux for 5 h. The reaction mixture was concentrated and the residue purified by reverse-phase MPLC (C8, 47%methanol/53 0.1% trifluoroacetic acid buffer) to give 0.32 g of the title compound 2 as its bistrifluoroacetate salt: 1H NMR (400 MHz, CD30D) 8 7.96 (dd, 1H, J 2.0, 9.2 Hz), 7.86 1H, J 2.0 Hz), 7.59 2H, J 8.8 Hz), 7.43 2H, J 8.8 Hz), 7.14 2H, J 8.4 Hz), 7.07 2H, J 8.4 Hz), 7.03 1H, J 9.2 Hz), 4.92 1H), 3.23 2H), 3.15 2H), 2.93 2H, 4.0 Hz), 1.49 2H, J 6.0Hz), 1.32 8H), 0.91 3H, J 6.0 Hz); CI MS m/z 555(M+1).
Following the procedures outlined for Examples 1-5, the compounds listed in Table 1 were prepared.
VO 95/29159 'WO 95/91591107118U95/04950 52 TAB3LE I
H
N 0 N R' HO0
H
2
N
Example Selected I H NMR (CD3OD) Data 6 Ph, trifluoroacetate salt 7.74 7.53 (mn, 11H), 7.45 2H).
7 2-naphthyl, 7.93 (in, 4H), 7.75 1H, J 1.7 ________trifluoroacetate. salt Hz), 7.61 (in, 2H) 8 3-quinolinyl, 9.00 1H, J 2.3 Hz), 8.06 (in, trifluoroacetate salt 2H), 7.94 (mn, 2H), 7.72 IlH, J= 7.2 Hz) 9 1,2-benzisoxazol-5-yl, 9.02 1H), 8.30 1H, J 1.3 trifluoroacetate salt Hz), 7.90 1H), 7.77 (mn, lH) 4-iodophenyl, 7.83 2H, J 8.6 Hz), 7.46 (d, _________trifluoroacetate salt 2H, J 8.6 Hz) 11I 4-[(N-hexyl,N-methyl- 7.62 2H, J 4.6 Hz), 7.48 (d, aininocarbonyl)aininoj- 2H, J 4.6Hz), 2.99 3H) phenyl, trifluoro acetate salt 12 4- ,N-dim ethylaininocarbonyl) amino]phenyl, trifl uoro acetate salt 3.0 6H) 13 4-(3-hexyl-2- 3.88-3.83 (in, 2H), 3.57-3.50 (in, imidazolidinon-1- 2H), 2.89-2.95 (in, 2H), 1.61-1.52 yl)phenyl, (in, 2H), 1.37-1.30 (mn, 6H), and _________trifluoroacetate, salt 0.93-0.88 (in,3H) 'WO 95/29159 PCT/US95/04956 53 EXAMPLE 14 0 d^ c i
CI
N
3-(2-Chloroacetyl)pyridine hydrochloride To a solution of 12 g (11 mL, 100 mmol) of 3acetylpyridine in 100 mL of ethyl ether was added 100 mL of 1 M ethereal hydrogen chloride. The resultant precipitate was filtered and 15.0 g (95.2 mmol) was collected and placed in a 500-mL round bottom flask equipped with a magnetic stir bar. To this was added 95 mL of 1 M hydrogen chloride in acetic acid. After the mixture was stirred until all the solid had dissolved, 12.7 g (95.2 mmol) of N-chlorosuccinimide (NCS) was added in one portion. The solution turned yellow and the NCS gradually dissolved. After 4 h, a white precipitate had formed.
The mixture was allowed to stir for 2.5 days. It was then filtered. The solid collected was washed with 10 mL of acetic acid and 200 mL of ethyl ether to give 15.2 g of the title compound as a white solid: 1H NMR (200 MHz, d6-DMSO) 5 9.22 1H, J 1 Hz), 8.29 (dd, 1H, J 1.6, 5.1 Hz), 8.55 (td, 1H, J 2, 8.1 Hz), 7.82 (ddd, 1H, J 0.8, 5.1, 8.1 Hz), 5.27 2H).
EXAMPLE
OH
N
(R)-a-Chloromethyl-3-pyridinemethanol To a stirred solution of 3.67 g (11.5 mmol) of (-)-B-chlorodiisopinocampheylborane in 11 mL of THF at °C was added a slurry of 1.00 g (5.21 mmol) of the product from
L'
'WO 95/29159 1'C''/US95/04956 -54- Example 14 in 5 mL of THF via a cannula. Following the addition of 0.80 mL (5.79 mmol) of triethylamine, the reaction mixture was stirred at -25 °C for 4 days. To the mixture was added 10 mL of water which was then allowed to warm to room temperature. To the mixture was added 20 mL of ethyl acetate and the organic phase separated. The aqueous phase was neutralized with saturated NaHCO3 solution then extracted six times with ethyl acetate. The combined organic phase was concentrated in vacuo to afford a yellow oil. Flash chromatography (silica gel, 75 100% ethyl acetate-hexanes) afforded 561 mg of the title compound as a pale yellow oil: 1 H NMR (400 MHz, CD30D) 8 8.58 1H, J 1.8 Hz), 8.46 (dd, 1H, J 4.9, 1.5 Hz), 7.90 1H, J 7.9 Hz), 7.44 (dd, 1H, J 7.9, 4.9 Hz), 4.93 1H), 3.75 2H).
EXAMPLE 16 0
N
(R)-(Pyrid-3-yl)oxirane To a solution of 557 mg (3.55 mmol) of the product from Example 15 in 16 mL of acetone was added 1.80 g of potassium carbononate. The mixture was heated at reflux for 20 h then cooled to room temperature. The mixture was filtered and the filtrate evaporated in vacuo. Flash chromatography (silica gel, 2% methanol-methylene chloride) afforded 262 mg of the title compound as a pale yellow oil: 1 H NMR (200 MHz, CDC13) 8 8.54 2H), 7.52 1H), 7.24 1H), 3.86 (dd, 1H, J 4.0, 2.5 Hz), 3.17 (dd, 1H, J 5.4, 4.0 Hz), 2.80 (dd, 1H, J 5.4, 2.5 Hz).
I
WO 95/29,159 PC'IU(" S95/04956 EXAMPLE 17
OH
NNH
(R)-N-r2-[4-(Aminophenvl)]ethyll-2-hydroxy-2-(pyrid-3-yl)ethylamine To a stirred solution of 377 mg (2.44 mmol) of 4-aminophenethylamine in 10 mL of methanol was added a solution of 300 mg (2.48 mmol) of the product from Example 16 in 15 mL of methanol. The mixture was heated at reflux for 16 h then cooled to room temperature. The methanol was removed in vacuo and the residue chromatographed (silica gel, 6 8% methanol, 1% ammonia-methylene Schloride) to afford 101 mg of the title compound together with 279 mg of a mixture that was rechromatographed methanol, 1% ammonia-methylene chloride) to give a further 54 mg of the title compound as an off-white solid: IH NMR (500 MHz, CD30D) 6 8.52 1H, J 1.8 Hz), 8.43 (dd, 1H, J 4.8, 1.4 Hz), 7.81 1H), 7.40 1H), 6.95 2H, J 8.3 Hz), 6.67 2H, J 8.3 Hz), 4.81 (m, 1H), 2.90-2.65 6H).
EXAMPLE 18
OH
N
f Boc N NH 2 (R)-N-[2-[4-(aminophenyl)]ethyl]-2-hydroxy-2-(pyrid-3yl)ethylcarbamic acid 1,1-dimethylethyl ester A solution of 386 mg (1.77 mmol) of di-tert-butyl dicarbonate in 3.5 mL of THF was added, via a cannula, to a stirred slurry of 456 mg (1.77 mmol) of the product from Example 17 in 3.6 WO 95/29159 PCT/US95/04956 56mL of THF cooled to 0 The yellow solution was stirred at 0 °C for 3 h, then the THF was removed in vacuo. Flash chromatography (silica gel, 10% methanol, 1% ammonia-methylene chloride) afforded 549 mg of the title compound as an off white solid: H NMR (500 MHz, CD30D, mixture of rotomers) 5 8.45 2H), 7.83 0.6H, J 7.4 Hz), 7.78 0.4H, J 6.9 Hz), 7.41 1H), 6.94 0.8H, J Hz), 6.89 1.2H, J 7.8 Hz), 6.66 2H, J 7.3 Hz), 4.89 1H), 3.42-3.21 4H), 2.67 2H), 1.39 5.4H), 1.36 3.6H).
An alternative synthesis of the aniline derivative in Example 18 is illustrated in Examples 19-23: EXAMPLE 19 0 ClBr CI N 2-Chloro-5-(2-bromoacetyl)pyridine hydrochloride A solution of 784 mg of 2-chloro-5-acetylpyridine in mL of THF was added via canula to a solution of 1.44 g of dibromobarbituric acid (DBBA) in 10 mL of THF. The resultant solution was heated at 50-55 °C for 12 h, and then an additional 0.72 g DBBA was added. After stirring at 50-55 oC for 2.5 more hours, 0.36 g DBBA was added. The mixture was allowed to stir for 2 h at which point NMR analysis of an aliquot indicated 87% conversion. The reaction mixture was cooled, diluted with ethyl acetate, washed with two portions of saturated aqueous sodium bicarbonate, water, and brine, dried over magnesium sulfate and concentrated. Purification by flash chromatography (silica gel, 15% ethyl acetate/hexane) provided 0.86 g of the title compound as a white solid: 1H NMR (400 MHz, CDC13) 6 8.96 1H, J 2.6 Hz), 8.21 (dd, 1H, J 2.5, 8.3 Hz), 7.46 1H, J 8.4 Hz), 4.37 2H). The NMR also indicated the presence
I
WO 9)5/29,159 PC'I/US95/0()495 -57 of the corresponding 2-bromo derivative, The ~4:1 mixture was carried on through the synthesis.
EXAMPLE
OH
Br CI N (R)-oa-Bromomethyl-3-(6-chloropyridine)methanoI To a solution of 602 mg (1.88 mmol) of (-)-DIP-Cl in mL of THF at -25 °C-was added via canula 200 mg of ketone from Example 19 in 1.5 mL of THF at -25 The reaction mixture was allowed to stir at -25 °C for 17 h. It was then quenched by the addition of water and extracted with ether. The ether phase was diluted with ethyl acetate, washed with two portions of saturated aqueous sodium bicarbonate, water, and brine, dried over magnesium sulfate and concentrated. Purification by flash chromatography (silica gel, 15 and 25% ethyl acetate/hexane) gave 170 mg of the title compound: 1 H NMR (400 MHz, CDC13) 5 8.38 1H), 7.70 (dd, 1H), 7.32 (d, 1H), 4.97 1H), 3.61 (dd, 1H), 3.50 (dd, 1H), 2.85 1H).
EXAMPLE 21
O
CI N To a solution of 100 mg of bromoalcohol from Example in 2 mL of 1:1 THF:water was added 1 mL of 5 N aqueous sodium hydroxide solution. The mixture was allowed to stir for 10 min. It was then extracted with three portions of dichloromethane. The combined
I
WO 95/29159 PCT/US95/04956 -58organic phases were washed with two portions of water and brine, dried over magnesium sulfate, and concentrated to give 98 mg of the title compound which was used without further purification: 1 H NMR (400 MHz, CDC13) 5 8.34 1H), 7.48 (dd, 1H), 7.29 1H), 3.86 (dd, 1H), 3.18 (dd, 1H), 2.78 (dd, 1H).
EXAMPLE 22 o1 OH Boc CI N NO 2 (R)-N-[2-[4-(Nitrophenyl)] ethyl]-2-hydroxy-2-(2-chloropyrid-5yl)ethylcarbamic acid 1.1-dimethylethyl ester Following the procedure outlined in Examples 17 and 18, the title compound was prepared from the epoxide from Example 21 and 4-nitrophenylethylamine: 1H NMR (400 MHz, CDC13) 6 8.32 (d, 1H, J 1.3 Hz), 8.13 2H, J 8.6 Hz), 7.66 (br m, 1H), 7.30 2H, J 8.1 Hz), 7.27 (br m, 1H), 4.94 (br 3.38 (br m, 4H), 2.84 (br m, 2H), 1.40 9H).
EXAMPLE 23 OH Boc
N
aN
NH
2 3 (R)-N-[2-[4-(aminophenyl)]ethyl]-2-hydroxy-2-(pyrid-3yl)ethylcarbamic acid 1,1-dimethylethyl ester To a solution of 80 mg (0.19 mmol) of the nitro compound from Example 22 in 2 mL of ethanol was added 0.114 mL (0.57 mmol) of 5 N aqueous sodium hydroxide solution and 20 mg of raney nickel.
.WO 95/29159 1'CT/US95/04956 -59- The reaction mixture was shaken at room temperature under 45 psi hydrogen for 16 h. The mixture was neutralized with saturated aqueous sodium phosphate monobasic and extracted with three portions of ethyl acetate. The combined organic phases were washed with water and brine, dried (magnesium sulfate), and concentrated to give 40 mg (59%) of the title compound which was identical to the sample prepared in Example 18.
EXAMPLE 24 0 S02CI nHex NW.. N 4-(3-Hexyl-2-imidazolon-1 -l)phenylsulphonyl chloride Hexyl iodide (50mmol, 7.38ml) was added to a mixture of 2-amino acetaldehyde dimethyl acetal (100mmol, lml) and potassium carbonate (50mmol, 6.9g) in DMF (10ml) at 0°C. Stirring was continued for 16h before diluting with ethyl acetate (200ml), and filtering the solution through a plug of celite. Concentration in vacuo was follwed by column chromatography (eluant ethyl acetate) to give Nhexyl 2-amino acetaldehyde dimethyl acetal (7.39g, 78%) as a colourless oil.
To the amine (38.6mmol, 7.3g) in methylene chloride (100ml) at 0°C was added 4-(chlorosulphonyl) phenyl isocyanate (38.6mmol, 8.4g). The reaction mixture was stirred for 20mins until a clear solution had formed, and 1:1 water: trifluoroacetic acid (100ml total) was added. Vigorous stirring was continued for 16h., the layers separated, the organic layer was diluted with ethyl acetate (500ml) and washed with saturated sodium bicarbonate solution (4x50ml), brine dried with anhydrous magnesium sulphate, and concentrated in vacuo. Column chromatrography (eluant 3 hexane/ 1 ethyl acetate) yielded the title compound as pale yellow crystals (8.8g, 67%).
I
WO 95/29159 iPCT/JUS95/04956 60 EXAMPLE
OH
H
N NH nHex-NH N 0
H
[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino] ethyl]phenyl]-4- (hexylaminocarbonvlamino)benzenesulfonamide To a solution of 302 mg (0.845 mmol) of the product from Example 18 and 137 mL (1.69 mmol) of pyridine in 10 mL of methylene chloride was added 296 mg (0.928 mmol) of 4-(hexylaminocarbonylamino)benzenesulfonyl chloride from Example 3. The reaction was stirred for 12 h then the solvent removed in vacuo.
Flash chromatography (silica gel, 6% methanol, 0.5% ammoniamethylene chloride) afforded 468 mg of the BOC-protected title compound.
A solution of 468 mg (0.731 mmol) of BOC-protected title compound in 5 mL of methylene chloride and 5 mL of trifluoroacetic acid was stirred for 30 min then the volatile components removed in vacuo. The residue was azeotroped twice with 10% methanol/toluene, twice with methanol, then dried in vacuo to give 521 mg of the title compound as its trifluroracetate salt: IH NMR (400 MHz, 8 8.88 1H), 8.79 1H, J 5.5 Hz), 8.53 1H, J 8.2 Hz), 7.99 1H), 7.59 (dd, 2H, J 6.9, 1.9 Hz), 7.43 (dd, 2H, J 6.9, 1.9 Hz), 7.15 (dd, 2H, J 8.6, 2.1 Hz 7.08 (dd, 2H, J 8.6, 2.1 Hz), 5.23 (m, 1H), 3.40-3.10 6H), 2.94 2H), 1.49 2H), 1.32 6H), 0.90 2H).
'WO 95/29159 WO 9529 19 1)P '/(t95/04956 61 EXAMPLE 26 CbzNH
NH
NCS2 '11 N) [(phenylmethoxycarbonyl) amino] ethyl] phenylj-4cyanobenzensulfonamide Following the procedure outlined in Example 4, the title compound was prepared from 2-(4-aminophenyl)ethylcarbamic acid phenylmethyl ester (see Fisher, et. al., Eur. Pat. Appl. 0 611 003 Al, 1994) and 4-cyanobenzenesulfonyl chloride: IH NMR (400 MHz,
CD
3 OD) 8 1 H NMR (400 MHz, CDCl3) 8 7.81 2H, J=8.7Hz), 7.69 2H, J=8.7Hz), 7.32 (mn, 5H), 7.06 2H, J=8.4Hz), 6.96 2H, J=8.4Hz), 6.75 1H), 5.06 2H), 4.71 br, 1H), 3.38 2H, J=6.9Hz), 2.74 2H, EXAMPLE 27 CbzNH N
H
~S02
H
2 N -r
HO'
[(phenylmethoxycarbonyl) amino] ethyl] phenyl] -4aminooximi domethyl)benzensulfonami de A mi"'ture of the nitrile. from Example 26 (2.71g, 6.23mmol), absolute ethanol (65m1), finely divided K2C03 (5,17g) WO 95/29159s 'PC'I"/US95/01956 62- 37.4mmol), and hydroxylamine hydrochloride (2.17g, 31.2mmol) was refluxed for 6 h. The ethanol was removed under reduced pressure.
The resulting solid was dissolved in ethyl acetate and washed with water 3 times. The organic phase was concentrated in vacuo to 2.87g of the title compound as a white powder which was of sufficient purity to be used in subsequent steps: 1H NMR (400 MHz, CD30D) 8 7.71 (s, 4H), 7.31 5H), 7.04 2H, J=8.4Hz), 6.99 2H, J=8.4Hz), 5.02 2H), 3.25 2H, J=6.8Hz), 2.67 2H, J=6.7Hz).
EXAMPLE 28 CbzNH
NH
N
SO2 (N)-[4-[2-[(phenylmethoxycarbonyl)amino]ethyl]phenyl]-4-[5-(3cyclopentylpropyl)-[ 1 ,2.41-oxadiazol-3-yllbenzensulfonamide To a solution of compound from Example 27 (0.468g, 1.00mmol) in dry pyridine (5.0ml) was added 4-cyclopentylbutyryl chloride (0.175g, 1.00mmol). The mixture was refluxed for 3.5 h. The pyridine was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (35% ethyl acetate in hexanes) to give 0.152g of the title compound: 1H NMR (400 MHz, CDCL3) 5 8.12 2H, J=8.7Hz), 7.81 2H, J=8.7Hz), 7.31 (m, 7.03 2H, J=8.1Hz), 6.97 2H, J=8.4Hz), 6.67 1H), 5.05 (s, 2H), 4.70 br, 1H), 3.37 2H, J=6.5Hz), 2.91 2H, J=7.6Hz), 2.72 2H, 1.90-1.70 5H), 1.65-1.30 6H), 1.06 2H).
WO 95/2159 P("I/US95/(O96 63- EXAMPLE 29
H
2
N
NN
N-[4-(2-aminoethyl)phenyl]-4-[5-(3-cyclopentylpropyl)-[1,2,4]oxadiazol-3-yllbenzensulfonamide A mixture of Cbz amine from Example 28 (0.145g, 0.246mmol), palladium hydroxide on carbon (0.02g), and glacial acetic acid (5.0ml) was hydrogenated for 2 h. The acetic acid was removed under reduced pressure. The residue was purified by silica gel chromatography (1 9 of 10% ammonium hydroxide in methanol methylene chloride) to give 0.058g of the title compound: 1H NMR (400 MHz, CD30D) 8 8.11 2H, J=8.6Hz), 7.87 2H, 7.06 2H, J=8.6Hz), 7.02 2H, J=8.7Hz), 2.97 2H, 2.84 2H, J=6.9Hz), 2.67 2H, J=7.5Hz), 1.90-1.75 (m, 5H), 1.70-1.40 6H), 1.12 2H).
wo 95/29 159 W0959159PIINS95/04950 64 EXAMPLE
OHH
N N N )"NH ON [[2-Hydroxy-2-(pyridin-3-yl)ethyl] amino] ethyl]phenyl] -4- [5-(3-cyclopentvlpropvl)-[ 1.2,4]-oxadiazol-3-vl lbenzensulfonamide To a solution of amine from Exar, de 29 (0.053g, 0.l1l7mmol) in dry methanol (30.Oml) was added 3-pyridine epoxide from Example 16 (0.021g, 0.l75mrnlol). The resulting solution was refluxed overnight. After concentration, the residue was purilied by silica gel chromatography (13% methanol in methylene chioriL 0 give 0.Olg of the title compound: 1H NMR (400 MHz, CD3OD) 8 8.52 1H, J=1.9Hz), 8.42 (dd, lH, J=1.5, 4.8Hz), 8.13 2H, 1=8.6Hz), 7.85 (in, 3H), 7.40 (dd, 1H, J=4.8, 7.8Hz), 7.10 1H, J=8.6Hz), 7.03 2H, 1=8.6Hz), 4.81 (dd, 1H, J=4.9, 8.1Hz), 2.96 (t, 2H, J=7.5Hz), 2.93-2.70 (in, 6H), 1.90-1.72 (in, 5H), 1.68-2.48 (in, 4H), 1.42 (in, 2H), 1. 11 (mn, 2H).
I wo 95/29159 W095/2159 r/1S9$A/O4956 65 EXAMPLE 31 OH
H
NN
N NH HO N-N a R
-N
R =nHex
M
R=H M L [2-Hydroxy-2-(pyridin- 3-yl)ethyl] amino] ethyljjphenylj-4- [4-(l1-hydroxy- 1-hexylheptyl)-5-methyl-[ 1,2, 31-triazol-2yl]benzenesulfonamide and [2-Hydroxy-2-(pyridin-3 yl) ethyl] amino] ethyl]ph enyl] (1 -(RS)-hydroxvhetyl r 1,2,31-triazol-2-yllbenzenesulfonamide To a solution of 180 mg of (R)-jN-[4-[2?-[[2-Hydroxy-2- (pyridin- 3-yl)ethyl] amino] ethyl] phenyl] (4-metho xycarbon yl-5 methyl- -triazol-2-yl)benzenesulfonamide (prepared according to the procedures outlined in examples 14-19) in 2 mL of distilled THF under argon at OOC was added, dropwise, 2 mL of a 2.OM solution of n-hexylmagnesium bromide in ether. After 5 min, the reaction was quenched with cautious addition of 5 mL of aqueous ammonium chloride followed by ethyl acetate extraction of the aqueous layer. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude products. Preparative layer chromatography (PLC) on 2X0.5 mmn thick silica gel plates eluted in 9:1 (vlv) dichloromethane: methanol gave two bands A (20 mg) and B IH NMR (500 MHz, CD 3 OD) of A: 8 8.51 1H, J=2 Hz), 8.41 (dd, 1H, J=1.5, 5 Hz), 8.01 (dd, 2H, J=2.5, 6.5Hz), 7.81 (in, 11-), 7.78 (dd, 2H, J=2.0, 9.0 Hz), 7.37 (in, 1H), 7.07;7.02 (ABq, 4H, Jab= Hz), 4.86 CD3OH), 4.79 (dd, 1H, J= 7.5, 8 Hz), 2.9-2.7 (mn, 614), 2.44 3H), 1.85 (in, 4H), 1.40-1.15 (in, 16H), 0.83 6H, 1=7 Hz) WO 95/29159 W095/9159IA950,19S( 66 indicating the dihexyl tertiary alcohol adduct, mass spec. expected 677 found 677. 1 H NMR (500 MHz, CD3OD) of B: 8.51 I H, J=2' Hz), 8.41 (dd, 1H, J=1.5, 5 Hz), 8.03 2H, J=9 Hz), 7.78 2H, J=9 Hz), 7.37 (dd, 1H, J= 4.8, 7.7 Hz), 7.07;7.02 (ABq, 4H, Jab=8 Hz), 4.86 (s, CD3OH), 4.80 (in, 2H), 2.9-2.7 (in, 6H), 2.38 3H), 1.87 (mn, 2H), 1.44 (in, 1H), 1.4-1.2 (mn, 7H), 0.87 3H, J=7 Hz) indicating the mono-hexyl adduct. Mass spec expected 591 (for the hexyl ketone) found 593 (hexyl alcohol, intermediate ketone reduced by Grignard reagent in situ).
Following the procedures outlined for Examples 14-3 1, the compounds listed in Table 2 were prepared.
TABLE 2
OH
H
N
0
IS"
N 11 R HO0 Example Selected lH NMR (CD3OD) Data 32 4-isopropyiphenyl 7.64 2H, J 8.0 Hz), 7.33 (d, 2H, J 8.0 Hz), 4.80 (mn, 1H), 2.95- 2.70 (in, 7H), 1.22 6H, J 6.7 Hz) 33 4-iodophenyl, 7.84 2H, J 8.6 Hz), 7.47 (d, bistrifluoroacetate salt 2H, J 8.6 Hz), 5.19 (dd, 1H, J 10.1, 3.0 Hz), 3.40-3.20 (mn, 4H), 2.96 (mn, 2H) 34 2-ahhl8.28 lH), 7.94 (in, 3H), 7.72 2-napthyl(dd, I1H, J 8.7, 1.9 Hz), 7.60 (in, 2H) 3-quinolinyl, 9.01 1H, J 2.3 Hz), 8.76 (d, bistrifluoroacetate salt 1H, 1.8 Hz), 8.08 1H, J 8.7 Hz), 8.04 1H, J 8.0 Hz), 7.93 (in, 114), 7.73 (in, 1H) 0 I WO 95/29159 W095/9159 ITIM/S95/0O4956 67 36 4-[(N-hexyl,N-methyl- 5.12 I1H, J 8.7 Hz), 3.40-3. aminocarbonyl)- (in, 6H), 2.99 3H), 2.95 (mn, 2H), amin~pheyl,1.56 (in, 2H), 1.31 (mn, 6H), 0.88 b bistrifluoro acetate salt 37 4-(3-hexyl-2- 5.15 (mn, 11H), 3.85 (in, 2H), 3.53 imidazolidinon-1- (mn, 2H), 3.40-3.15 (mn, 6H), 2.94 yl)phenyl, (in, 2H), 1.55 (in, 2H), 1.32 (mn, _________bistrifluoroacetate salt 611), 0.89 (in, 314).
38 4-[(1-oxoheptyl)- 2.35 (tr, 2H, J=7.5 Hz), 1.65 aininoiphenyl, (quint., 2H, J=7.1 Hz), 1.32 (in, bistrifluoroacetate salt 6H), 0.892 (tr, 3H, J=6.8Hz).
39 4-[(l-oxo-4-phenyl- 7.34-7.25 (mn, 4H), 7.15-7.05 (mn, butyl)amino]phenyl, 5H), 2.71 (tr, 2H, J=7.7Hz), 2.36 bistriftu oro acetate salt (tr, 2H, J-7.4 Hz), 1.96 (mn, 2H).
4-[(propoxycarbonyl)- 4.07 (tr, 2H, J=6.6 Hz), 1.67 aininoiphenyl (sextet, 2H, J=7.0 Hz). 0.968 (tr, J=7.4 Hz).
41 7.40 1H, J 0.9 Hz), 6.32 (dd, ylinethyl)amino]car- 1 H, J 2.9, 1.8 Hz), 6.23 I1H, J bonyl]arnino]phenyl, =2.9 Hz), 4.34 2H) __________bistrifluoroacetate salt 42 7.38-7.02 (mn, 9H), 3.50-3.15 (in, phenylethyl1) amino] car- 6H), 2.80 (mn, 2H) bonyl]amino]phenyl, __________bistrifluoroacetate salt 43 4-[[[(2-indol-3- 7.58-7.53 (in, 3 7.42-7.30 (in, 4 ylethyl) amino] carbon- 7.08-6.94 (in, 7H), 3.48 (tr, 2 yl]amino]phenyl H, J=6.9 Hz) 2.94 (tr, 2H, J=6.8 Hz).
44 4- 2.94 (mn, 2H), 1.51 (tr, 2H, J=6-8 [[(octylamnino)carbonyl] Hz), 1.30 (mn, IGH), 0.884 (tr, 3H, ainino]phenyl, J=6.9 Hz).
bistrifluoro acetate salt I WO 95/29159 W05/2159ICI/7US95/04956 68 1- 7.83 2H, J 9.2 Hz), 7.48 (in, [(hexyllamino)carbonyl] 2H), 3.92 2H, J 8.8 Hz), 3.1 3.2 (two overlap-ping t, 4H), 1.54 (mn, 1.30 (mn, 6H), 0.90 3H, J 6.8 Hz).
46 1-7.83 2H, J 9.2 Hz), 7.48 (in, [(octylamino)carbonyl]- 2H), 3.92 2H, J 8.8 Hz), 3.1 3.2 (two overlap-ping t, 4H), 1.63 (mn, 2H), 1.30 (mn, 10H), 0.89 3H, 6.9 Hz).
47 1-[(N-methyl-N- 7.53 (mn, 2H), 6.90 1H, J 8.3 octylamino)carbonyl]- Hz), 3.89 2H, J 8.4 Hz), 3.26 2H, J 7.6 Hz), 3.04 2H, J 8.4 Hz), 2.91 3H), 1.60 (mn, 2H), 1.27 (mn, IGH), 0.87 3H, J 6.8).
48 1-(1-oxononyl)indolin- 7.49 (in, 2H), 8.09 I H, J=9.1), 4.04 2H, 3.07 2H, 2.41 2H, 1.62 (in, 2H), 1.30 (in, 10H), 0.88 3H, J=6.8) 49 1-(4-methylthiazol-2- 7.87 1H, J= 8.6 Hz), 7.58 (1H, dd, J 2.0, 8.6 Hz), 7.52 1H, J 2.0 Hz), 6.48 1H), 4.08 2H, J 8.7 Hz), 3.25 2H, J 8.7 Hz), 2.30 3H).
1-(4-octylthiazol-2- 7.97 1H, 1= 8.6 Hz), 7.57 (1H, dd, J 2.0, 8.6 Hz), 7.5 3 1 H, J 2.0 Hz), 6.49 1H), 4.06 2H, J 8.8 Hz), 3.24 2H, J 8.8 Hz), 2.62 2H, J 7.5 Hz), 1.68 (in, 2H), 1.2-1.4 (mn, IGH), 0.88 3H, =7.0 Hz).
'WO 95/29J59 11CIMS95/0,1956 69 51 1-(4-ethyl-5- 7.87 1H, J= 8.5 Hz), 7.54 (1H, methylthiazol-2- dd, J 2.0, 8.5 Hz), 7.50 JH, J 2.0 Hz), 4.02 2H, J 8.7 Hz), 3.20 2H, J 8.7 Hz), 2.56 (q, 2H, J 7.7 Hz), 2.26 3H), 1.20 3H, J 7.7 Hz).
52 4-(3-octyl-2- 4.78 (in, 1H), 3.83 (mn, 2H), 3.52 iinidazolidinon-1- (mn, 3.24 2H, 8Hz), 1.60yl)phenyl 1.51 (mn, 2H), 1.35-1.25 (in, IOH), 0.88 2H, 8Hz).
53 3.86 (mn, 2H), 3.54 (in, 2H), 3.40trifluorobutyl)-2- 3.20 (in, 6H), 2.19 (in, 2H), 1.82 iinidazolidinon-lI- (quin, J 7.9 Hz, 2H) yl]phenyl, strifluoro acetate salt 54 4-[3-(3-phenylpropyl)- 7.20 (mn, 4H), 7.10 (in, 1H), 5.15 2-iinidazolidinon-1- (dd, 1H, 9.6,4Hz), 3.75 (mn, 2H), yl]phenyl, 3.46 (mn, 2H), 3.36-3.20 (in, 6H), bistrifluoroacetate salt 2.95-2.9 1 (in, 2H), 2.65 2H, 1.90 (gu, 2H, 8Hz).
3.87 (mn, 2H), 3.56 (in, 2H), 3.40pentafluoropentyl)-2- 3.20 (in, 6H), 2.14 (mn, 2H), 1.86 imidazolidinon-1- (quin, J 7.8 Hz, 2H) yl]phenyl, bistrifluoroacetate salt 56 3.82 (in, 2H), 3.50 (mn, 2H), 2.87cyclohexylethyl)-2- 2.70 (in, 6H), 1.78-1.63 (mn, iinidazolidinon-1- 1.41 (quartet, 2H, J=7.2 Hz), 1.30yl]phenyl, 1.18 (mn, 4H), 0.949 (mn, 2H).
__________bistrifluoroacetate salt 57 7.19 4H), 4.79 (in, 1H), 3.74 (mn, chlorophenyl)propyl]- 2H), 3.47 (mn, 2H), 3.30 (mn, 2H), 2-im-idazolidinon-1- 2.63 2H, 7.6Hz), 1.91-1.83 (in, f2H).
WO 95/29159 WO 95/2 159 (IM/S95/04950 70 58 4-(3-pentyl-2- 3.82 (in, 2 3.53 (in, 2H), 2.94 iinidazolidinon-1- (in, 2H), 1.57 (quintet, 2H, J=7.4 yl)phenyl, Hz), 1.39-1.28 (in, 0.916, (tr, bi strifluoro acetate salt 3H, J=7. 1 Hz).
59 3.81 (in, 2H), 3.51 (in, 2H), 3.23 (t, cyclopentylpropyl)-2- J 7.3 Hz, 2H), 1.78 (in, 3H), 1.57 iinidazolidinon-1- (in, 6H), 1.33 (in, 21-I), 1.17 (in, _______yllphenyl 2H) 60 4-113-(2cyclopentylethyl)-2imidazolidinon- 1yllphenyl, bistrifluoroacetate salt cyclohexylpropyl)-2imidazolidin on-ilphenyl 3.83 (in. 2H), (in, 2H), 1.81 (in, 5H), 1. 16 3.53 (in, 2H), 2.94 (in, 4H), 1.65-1.53 (in, 2H).
61 3.83 (in, 2H), 3.51 (in, 2H), 3.22 (t, J 7.3 Hz, 2H), 1.71 (in, 5H), 1.56 (in, 2H), 1.20 (in, 6H), 0.88 (in, 2H) 62 3.82 (in, 2H), 3.60 (in, 2H), 3.03 (s, diinethylhexyl)-2- 211), 1.28 (in, 6H), 0.93 (in, 3H), imidazolidinon-1- 0.91 611) yl]Ehenyl__ 63 4-(3-hexyl-2- 6.93 1H, 4Hz), 6.70 1H, imidazolon- 1-yl)phenyl 4Hz), 4.79 (in,1H), 3.64 2H, 8Hz), 1.7 1-1.64 (in, 2H), L.35-1.28 (in, 6H1), 0.91-0.86 (in, 3H).
64 6.97 1H, 3Hz), 6.73 1H, trifluorobutyl)-2- 3H4z), 3.73 2H, 7Hz), 2.23-2.19 _________iiidazolon-1-yllphenyl (in, 2H), 1.98-1.92 (in, 211).
4-(3-octyl-2- 6.93 111H, 4Hz), 6.69 111, imidlazolon- 1-yI)phenyl 4H4z), 3.64 211, 7Hz), 1.70-1.63 (in, 211), 1.33-1.23 (in, 1011), 0.90- (in, 3H).
I
I WO 95/29159 WO 95/29159 PcTUS95/04956 71 66 6.93 1H, 3Hz), 6.69 1H, cyclopentylpropyl)-2- 3Hz), 3.63 7Hz), 1,80-1.47 imidazolon-1-y1]phenyl (in, 11H), 1.35-1.29 (in, 2H), 1.13- 1.02 (in, 2H).
67 4-(2-octyl-3-oxo- 8.25 1H), 3.79 2H, 7Hz), [1,2,4]-triazol-4- 1.80-1.70 (in, 2H), 1.36-1.25 (in, _______yl)phenyl 10H), 0.91-0.86 (in, 3H).
68 4-(4-hexyl-5- 3.98 2H, J=7.lHz), 2.9-2.7 (in, tetrazolon-1I-yl)phenyl 6H), 1.82 2H, J=7 Hz), 1.4-1.27 (in, 6H), 0.89 3H, J=7Hz) 69 4-(4-octyl-5-tetrazolon- 3.98 2H, J=7.lHz), 2.9-2.7 (in, 1-yl)phenyl 6H), 1.83 (in, 2H), 1.4-1.2 (in, 1OH), 0.87 3H, J=7 Hz) 3.97 2H, J=7.lHz), 2.9-2.7 (in, 9H), 1.9-1.7 (mn, 5H), 1.6 (mn, 1H), tetrazolon- 1-yllphenyl 1.5 (mn, 1H), 1.37(m, 2H), 1.07(m,
H)
71 4-(2-pentyloxazol-5- 7.48 1H), 4.82 (mn, 1H), 2.92yl)phenyl 2.70 (in, 8H), 1.80 (in, 2H), 1.39 4H), 0.92 (in, 4H) 72 4-(2-octyloxazol-5- 7.52 1H), 5.09 (in, 1H), 3.01yl)phenyl 2.82 (mn, 8H), 1.77 (in, 2H), 1.37- 1.27 (in, 10H), 0.87 (in, 1H) 73 7.52 4.80 (mn, 1H), 2.94cyclopentylethyl)oxazol 2.70 (mn, 8H), 1.79 (mn, 5H), 1.62 (in, 2H), 1.54 (mn, 2H), 1.12 (in, 2H) 74 4-[(4-ethyl-5- 7.62 2H, J 9 Hz), 7.58 2H, methylthiazol-2- J 9 Hz), 2.53 2H, J 7.5 Hz), yl)amino]phenyl 2.23 3H), 1.18 3H, J Hz)
I
I wo 95129159 WO9~i'9I59 CI71JS95/04956 72 f7.54 2H, J 9 Hz), 7.48 2H, tetrahydrobenzo- J =9 Hz), 2.54 (in, 2H), 2.50 (in, thiazol-2- 1.75 (mn, 4H) amino] phenyl 76 4-(2-hexylimidazol-4yl)phenyl 7.75 11H), 5.04 (in, 1H), 3.29- 3.20 (in, 4H), 2,97-2.90 (mn, 4H), 1.82 (mn, 2H1), 1.40-1.30 (mn, 6H), 0.9 (in, 3H) 7 1-methyl-2phenyl 7.92 1H), 5.30 (in, 11H), 4.84 (s, 3H), 3.48-3.25 (in, 4H), 3.05-2.95 1.80 (mn, 2H), 1.50-1.26 i1OH), 0.89 (mn, 3H) 78 4-[1-inethyl-2-(2- 7.41 1H), 3.64 3H), 2.96-2.68 cyclopentylethyl)- (mn, 8H), 1.90-1.79 (in, 9H), 1.16 (mn, 2H) 79 4-[1-methyl-2-[2-(4- 7.40 1H), 7.10-6.95 (in, 4H), fluorophenyl) ethyl] 4.91 (in, 1H), 3.39 3H), 3.0 (bs, 4H) 4-(5-pentyl-[1,2,4]- 2.96 2H, J=7.6Hz), 1.84 2H, oxadiazol-3-yl)phenyl J=7.4Hz), 1.39 (in, 4H), 0.92 3H, J=7. 1) 81 2.98 2H, J=7.5Hz), 1.84 (mn, cyclopentylethyl)- 1.70-1.50 (mn, 4H), 1.16 (in, 2H) [1 ,2,4]-oxadiazol-3yl]phenyl__ 82 4-(5-hexyl-[1,2,4]- 2.96 2H, J=7.5Hz), 1.84 (quin, oxadiazol-3-yl)phenyl 2H-, 1=7.4Hz), 1.48-1.28 (in, 6H), 0.90 3H, J=7.OHz) 83 4-(5-heptyl-[1,2,4]- 2.96 2H, 1=7.5Hz), 1.84 (quin, oxadiazol-3-yl)pheryl 2H, J=7.OHz), 1.46-1.26 (mn, 8H), 3H, J=6.9Hz) WO 95/29159 WO 9/2919 11AS95/04956 73 84 4-(5-hexylthio-[ 3.11 (t,2H,J=7.3Hz), 2.98-2.84 triazol-3-yl)phenyl (rn,4H), 2.76 (t,2H,J=7.3Hz), 1.65 (q,2H,J=7.3Hz), 1.37 (q,2H,J=7.lHz), 1.28-1.23 (m,4H), 0.84 (t,3H,J=6.9Hz) 8.84 1H), 8.75(d, 1H, J=5.07 propylpiperidin-1-yl)- Hz), 8.46(d, 1H, J=8Hz), 7.15 1,1-dioxo-[1,2,5]- 7.08 each 2H, J=8Hz), 0.92(t, thiadiazol-3- 3H, 1=7Hz) yl] amino] phenyl 86 7.15(d, 2H, J=8.5Hz), 7.12(d, 2H, (hexylmethylamino)- J=8.5Hz), 5.19(dd, 1H, 3.1Hz, 9Hz), 1,1-dioxo-[1,2,5]- 2.93(m, 2H), 0.90(t, 3H, 6.8Hz) thiadiazol-3 amino] ph enyl 87 7.16(d, 2H, 1=8.8Hz), 7.11 2H, (heptylmethylamino)- J=8.8 Hz), 5.01 (dd, 1=3.2Hz, 1,1-dioxo-[1,2,5]- 9.9Hz), 2.92(m, 2H), 1.68(m, 2H) thiadiazol-3amino] phenyl____ 88 4-(1-octyl-2,4- 4.09 2H), 3.41 2H, 7hz), imidazolidinedion-3- 1.65-1.56 (in, 2H), 1.30-1.25 (in, _______yl)phenyl 10H), 0.9 1-0.86 (mn, 3H).
89 4-[3-(3-nitrophenyl)-5- 8.55 (t,1H,J=1.9Hz), 8.47 (d, pyrazolon- 1 -yl]phenyl 1H,J=2.OHz), 8.37 (dd, 1H, 1=3.2Hz), 8.14 (d,2H,J=8.9Hz), 8.08 (t,2H,1=8.5Hz), 7.74(d, 3H,1=8.9Hz), 7.56 1H,J=8.0 Hz), 7.33 (dd,1H,J=4.8Hz), 7.04 (dd,4H,J=6.6Hz), 4.75 (t, 1H,J=2.lHz), 2.83-2.69 (in,6H) m wo 9 9/29oq WO 95/9159 CItS95IO4950 74 Starting with commercially available (T)-styrene epoxide and following the procedures outlined for Examples 17,18 and 25, the compounds listed in Table 3 were prepared.
TABLE 3
H
N
0 11 N I I HO0 Example R Selected I H NMR (CD3OD) Data 4-iodophenyl, 7.84 2H, J 8.6 Hz), 7.45 (d, ________trifluoroaceta te salt 2H, J 8.5 Hz) 91 2-naphthyl, 8.31 1H), 7.96-7.90 (in, 3H), trifluoroacetate salt 7.74 (dd, 1H, J 1.8, 8.7 Hz), 7.63 1H), 7.58 III) 92 3-quinolinyl, 9.01 1H, J 2.2 Hz), 8.75 (d, trifluoroacetate salt 1H, J 2.1 Hz), 8.07 IH, J 8.4 Hz), 8.03 1H, J 8.3 Hz), 7.92 1H, J =7.0 Hz), 7.72 lH, J 7.1 Hz) EXAMPLE 93 nHex-N JN
M
WO 95/29159 PC("I/LS95/01956 (R)-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]-2methylpropyl]phenyl]-4-(3-hexyl-2-imidazolidinon- yl)benzenesulfonamide A solution of pyridine epoxide (160mg,1.32 mmol) from example 16 and 4-amino-a,a-dimethylphenethylamine (1.2g, 7.3 mmol), prepared according to J. Biol. Chem. 1981, 256, 11944-50, in methanol (8 ml) was warmed at reflux for 16 hours. After cooling, the reaction mixture was concentrated and purified by flash chromatography (silica gel, 95:5 CH2C12: 10% NH40H/CH30H) to give 23 mg (0.080 mmol) of product as an oil.
The above product (18 mg, 0.063 mmol) was dissolved in CH2C12 (1 mL) and pyridine (0.05 mL). The resulting solution was cooled to 0°C and treated with 4-(3-hexyl-2-imidazolidinon-1yl)benzenesulfonyl chloride (22 mg, 0.063 mmol). The mixture was 1 5 allowed to stir at 0°C for 20 hours and was then purified by flash chromatography (silica gel, 95:5 CH2Cl2: 10% NH40H/CH30H) to give the desired product (21 mg, 0.035mmol) as an oil: 1 HNMR (CD30D) 8 8.53 1H), 8.44 (d,lH, 7.83 1H, 7.63 4H), 7.40 (dd, 1H, J=5.0, 6.98 4H), 4.72 (dd, 1H, J=4.0, 3.80 (m, 2H), 3.49 2H), 3.22 2H, 2.78 2H), 2.62 2H), 1.55 2H), 1.31 6H), 1.01 3H), 0.99 3H), 0.89 3H).
Following the procedure outlined above, the compounds in Table 4 were prepared.
TABLE 4
OH
N 0 Me Me 'R
HO
Examle I R I Selected 1H NMR (CD30D) Data am R I -b WO 95/29159 WQ 95/29159 ''1'/S95/04956 76 94 4-iodophenyl 7.82 2H, 7.42 2H, J=8 .6) 4-[[(hexylamino)car- 7.55 2H, 7.42 2H, 3.11 2H, 1.49 (in, 1.30 (in, 6H), .089 (in, 3H) EXAMPLE 96 0 Si(tBu)Me 2 C I Br
H
2
N
C 1 (R)-4-amino-x- (bromomethyl)-3 ,5 -dichlorobenzenemethanol, dimethyl- 1,1 -dimethylethylsilvi ether A solution of t-butyldimethylsilyl chloride 67 g, 11. 1 mmol) in DMF (15 mL) was added slowly to a stirred solution of amino-a-(bromomethyl)-3 ,5-dichlorobenzenemethanol (2.1 g, 7.4 mmol, see Judkins, et. al, European Patent Application 0 460 924) and imidazole (0.75 g, 11. 1 minol) in DMF (6 mL) with an ice-water bath cooling. After being stirred at RT for 3h, the reaction mixture was poured into water (300 mL) and the product was extracted with ether.
The organic phase was washed with saturated aqueous sodium bicarbonate solution, brine, dried(MgSO4) and evaporated to dryness.
The crude product was purified on silica (95/5 hexane/ethyl acetate) to give the title compound (2.73 g, 93 IH NMR (400 MHz, CDCl3) 8 7.14 2H), 4.67 (dd, 1H, J=2.1, 6.4 Hz), 3.33 (in, 2H), 0.87 9H), 0.89(s, 6H)
I
WO 95/29159 W095IT.5 P171JS95/04950 77 EXAMPLE 97 0 Si(tBu)Me 2
H
CI N
H
2 N NH 2 C1 [2-[4-(Aminophenyl)]ethyll-2- [(dimethyl- 1,1 dimethylethylsilyl)oxy]-2-(4-amino-3. O-TBDMS bro.nio compound from Example 96 (2.73g, 6.86 mmol) was dissolved in CH3CN (50 mL) and 4-aminophenethylamine (1.86 g, 13.72 mmol) was added, followed by the addition of N,N'-diisopropylethylamine (3.58 mL, 20.6 mmol) and sodium iodide (1.03 g, 6.86 mmol). After being heated at reflux for 48 h, the reaction mixture was concentrated and the residue chromatographed on silica (50/50 ethyl U-cetate/hexane) to provide the title compound (2.3 g, 75 1H NMR (400 MHz, CDCl3) 8 7.08 (s, 2H), 6.94 (AAN, 2H, J=8.4 Hz), 6.60 2H, J=8.4 Hz), 4.63 (in, IH), 4.37 2H), 3.53 (br s, 2H), 2.87-2.60 (mn, 6H), 0.80 9H), -0.03 (s, 6H) EXAMPLE 9-8
OHH
C1 N
H
2 N NH 2 .01 [4-(Aminophenyl)] ethyl] -2-hydroxy-2-(4-amino-3 ,5 dichlorophen i) ethvl amine To a stirred solution of silyl compound from Example 97 (2.2 g, 4.8 mmol) in THF (20 inL) at RT was added WO 95/29159 WO 9529159I'C'i1117SWO4956 -78.
tetrabutylammonium fluoride (1 0 rnL of 1 .0 M solution in THF) in one portion. After being stirred at RT for 2h, the reaction mixture was concentrated and chromatographed on silica (10/9(0 ClI3OH/CH2-CI2) to give the title compound (1.59 g, 97 lIH NMR (400) MHz, CD3OD) 57.15 2H), 6,92 (AA t 2H-, J=8.3 Hz), 6.60 21H, 8.3 Hz), 4.J8 283-2.65 (in, 6H) EXAMPLE 99 OH
H
CI N C1 0 SO 2 nHey-N Nj [2-[[2-Hydroxy-2- (4-amino-3 dichlorophenyl) ethyl) amino] ethyl] -phenyl 1-4- (hexylaminocarbonylamino)benzenesulfonami de Following the procedure outlined in Example 18 and the title compound was prepared from the aniline derivative from Example 98: NMR (400 MHz, CD3OD) 7.57 2H, J=2.7 Hz), 7.42 2H, J=2.7 Hz), 7.16 2H). 7.04 2H, 1=2.0 Hz), 7.00 (BB', 2H, J=2.0 Hz), 4.58 1H, j=7.1 Hz), 3.14 1H, J=7.0 Hz), 2.80 (mn, 2H), 2.73 (in, 4H), 1.49 (in, 2H), 1.32 (mn, 6H), 0.90 3H, J=6.7 Hz).
ESI MS rn/z 622 Following the procedure outlined in Examples 96-99, the compounds in Table 5 were prepared.
wo 95/29159 WO 9519159 I VIt 9510495b -79-
H
2
N
N0 HO0 Selected IH NMR (CD3OD) Data Example 11 100
I-
[(octylamino)carbonyl]- 7.82 I H, J=9.2 Hz), 7.47 (m, 2H), 3.93 Ct, 211, J=9.0 Hz), 3.18 (in, 411), 1.53 (mn, 21H), 1.31 Cm, 101-I). 0.88 3H,. J=7.1 Hz) 101 4-(3-hexyl-2- 7.68-7.60 (AA'BB t 4H), 3.82l (t, imidazolidinon-l- 2H1, J=6.2 Hz), 3.52 (t,2H, J=6.2 yl)phenyl Hz), 3.30 2H, J=6.0 Hz), 1.54 (mn, 2H), 1.31 (in, 6H), 0,89 3H J=6.0 Hz) 102 4-(3-octyl-2- 7.65-7.60 (AA'BB', 4H), 3.82 (t, iinidazolidinon-1- 2H1, J=6.2 Hz), 3.52 211, J=6.2 yl)phenyl Hz), 3.29 Ct, 211, J=6.0 Hz), 1.54 Cm, 211), 1.30 Cm, 1011), 0,87 311, J=6. 1 HZ) EXAMPLE 103
OH
N NH
NSO
2 WO 95/29159 PI'CTI I95/I 4956 2-Hydroxy-2-(4hydroxyphenvl)et yl]amino]ethyl Iphenyl]-benzenesulfonamide A solution of 5 g of 4-aminophenethyl alcohol in 50 mL of DMF .vas silylated with 5.5 g of t-butyldimethylsilyl chloride (TBDMS- Cl) and 2.5 g of imidazole overnight at room temperature. Extraction of the product following an aqueous ammonium chloride workup afforded 6.6 g of the O-TBDMS ether. This aniline derivative was then coupled to benzenesulfonyl chloride in pyridine-dichloromethane to give the sulfonamide in greater than 80% yield after chromatographic purification. The TBDMS group of the sulfonamide was removed with methanolic HCI at room temperature for 30 min. The crude alcohol was oxidized to the corresponding carboxylic acid with Jones reagent in acetone (RT 30 min, ethyl acetate extraction).
To a solution of 180 mg of (R)-octopamine and 300 mg of the resultant 4-N-benzenesulfonamidophenylacetic acid in 7 mL of DMF was added 0.5 mL of triethylamine and 490 mg of benzotriazolyl-Noxy-tris(dimethylamino)phosphonium hexafluorophosphate. The reaction mixture was stirred at RT 2h, flash chromatography over silica gel eluting with 95:5 chloroform-methanol gave 322 mg of purified amide.
A solution of 220 mg of this amide in 13 mL of 1.0 M borane-THF was refluxed under argon for 2h followed by the addition of 3 mL of N,N-dimethylaminoethanol and further reflux for another hour. The solvent and excess volatiles were removed in vacuo and the residual solid was taken up in acetone and purified by PLC on silica gel (9:1 ethyl acetate:methanol) to yield 61 mg of the title compound: 1
H
NMR (500 MHz, CD30D) 8 7.73 (dt, 2H, J=2.1, 8.2Hz), 7.53 (tt, 1H, J=1.4, 7.6Hz), 7.44 2H, J=8 Hz), 7.18 2H, J=8.4 Hz), 7.05 (ABq, 4H, Jab=8.5 Hz), 6.76 2H, J=8.4Hz), 4.75 (dd, 1H, J=7.5, 7.6 Hz), 3.05-2.90 4H), 2.81 2H, J=7.6 Hz). Mass spec calcd. 412.5 found 413.2.
II
WO 95/291$9 WO 91291$9PCIATS95/0495( 81 EXAMPLE 104 (i&-N-[4-[2-[I[2-Hydroxy-2-(4hydroxyphenyl) ethyl) amino) ethyl) phenyl) -4-i odobenzenesul fo nami de Following the procedure outlined in Example 103, the title compound was prepared: IH NMR (500 MHz, CD3OD) 5 7.77 2H, Hz), 7.43 2H, j=8.5 Hz), 7.15 2H, J=8.5 Hz), 7.02 (ABq, 4H, Jab=8.7 Hz), 6.75 2H, J=8.5 Hz), 4.67 (dd, 1H, J=4.4, 6.6 Hz), 2.90-2.66 (in, 6H). Mass sp.-c calcd. 538.4 found 538.9.
EXAMPLE 105 3-(2-bromoacetyl)benzonitril e To a solution of 1.02 g (7.04 inmol) of 3-acetylbenzonitrile in 70 mL of ethyl ether was added 1.02 g (3.52 inmol, 0.5 equiv) of dibromobarbituric acid. The mixture was allowed to stir at room temperature overnight. The resultant white slurry was filtered and the filtrate was concentrated. Purification by flash chromotography (silica gel, 20% ethyl acetate/hexane) gave 1.28 g (8 of the title compound as a white solid: IH NMR (400 MHz, CDC13) 8 .8.26 1H, J 1.4 'WO 95/29159 'PC/US95/04956 82 Hz), 8.20 (td, 1H, J 1.5, 8.0 Hz), 7.87 (dd, 1 H, J 1.3, 7.8 Hz), 7.64 1H, J 7.9 Hz), 4.40 2H).
EXAMPLE 106
OH
NC Br romomethyl-3-cyanophenvlmethanol To a suspension of 181 mg (0.623 mmol) of tetrahydro-l-methyl-3,3-diphenyl- 1H,3Hpyrrolo[1,2g][1,3,2]oxazaborole-borane (R-OAB catalyst) in 6 mL of THF at 0 °C was added dropwise 6.24 mL (6.24 mmol) of a 1 M solution of borane in THF. The resultant clear solution was allowed to stir for 5 min, and then a solution of 1.27 g (5.67 mmol) of bromoketone from Example 105 in 6 mL of THF was added slowly over 1 h. After the reaction was allowed to stir for 30 min more, it was quenched by the dropwise addition of 6 mL of methanol and concentrated. Purification by flash chromatography (silica gel, 20-25% ethyl acetate/hexane) provided 944 mg of the title compound as a clear oil which crystallized: 1H NMR (400 MHz, CDC13) 8 7.70 1H, J 1.5 Hz), 7.62-7.60 2H), 7.48 1H, J 7.7 Hz), 4.95 (dd, 1H, J 3.4, 8.4 Hz), 3.63 (dd, 1H, J 3.4 Hz), 3.49 (dd, 1H, J 8.4 Hz).
EXAMPLE 107
N
NC. -<J (R)-(3-cvanophenyl')oxirane
I
WO 95/2159 PC(T/US95)04956 83 To a solution of 937 mg (4.14 mmol) of bromohydrin from Example 106 in 8 mL of methanol was added 601 mg (4.35 mmol, 1.05 equiv) of potassium carbonate. The reaction mixture was allowed to stir at room temperature for 7 h. It was then diluted with ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated. Purification by flash chromatography (silica gel, ethyl acetate/hexane) provided 573 mg of the title compound: 1
H
NMR (400 MHz, CDC13) .7.59-7.55 2H), 7.49 (dd, 1H, J 1.6, 7.9 Hz), 7.44 1H, J 7.7 Hz), 3.87 (dd, 1H, J 2.5, 4.0 Hz), 3.17 (dd, 1H, J 4.1, 5.5 Hz), 2.74 (dd, 1H, J 2.5, 5.4 Hz).
EXAMPLE 108 OHBoc NC N N, (R)-N-[2-[4-(aminophenyl)]ethyl]-2-hydroxy-2-(3cyanophenyl)ethylcarbamic acid 1,1-dimethylethyl ester Following the procedures outlined in Examples 17 and 18, the title compound was prepared from the epoxide from Example 107: 1H NMR (400 MHz, CDC13) 8 7.58-7.52 (br m, 3H), 7.41 1H, J Hz), 6.89 (br d, 2H, J 7.6 Hz), 6.65 (br d, 2H, J 7.8 Hz), 4.82 (br dd, 1H, J 2.7, 7.9 Hz), 3.42-3.05 (br m, 4H), 2.75-2.55 (br m, 2H).
"II-
WO 95129 159 W0959159PTIUS9,5/04956 84.- EXAMPLE 109 OH
H
NC N nHex-NH J N
H
[[2-Hydroxy-2-(3-cyanophenyl)ethyljamino]ethylphenylj-4- (hexylaminocarbonylamino)benzenesul fonamide Following the procedure outlined in Example 25, the title compound was prepared from the Boc aniline derivative from Example 108: IH NMR (400 MHz, CD3OD) 8 7.70 IH), 7.63-7.57 4H), 7.48 1H, J 7.7 Hz), 7.43 2H, J 8.9 Hz), 7.06 2H, J Hz), 6.99 2H, J 8.5 Hz), 4.77 (dd, I H, J 3.9, 8.5 Hz), 3.15 (t, 2H-, J 7.0 Hz), 2.86-2.69 (in, 6H), 1.49 (br mn, 2H), 1.31 (br m, 6H), 0.90 (br t, 3H).
EXAMPLE 110 OH
H
NC NN NH S021 [[2-Hy droxy-2- (3-cyanophenyl)ethyll amino] ethyl] phenyl] 3guinolinesulfonamide Following the procedure outlined in Example 25, the title compound was prepared from the Boc aniline derivative from Example wo 95/29159 WO 95/9159 (IIIIS95/04956 85 108 and 3-quinolinesulfonyl chloride: 1 H NMR (400 MHz, CD3C)D) 8 9.02 1H, J 2.3 Hz), 8.68 1H, J3 1.9 Hz), 8.06 111, J3 8.3 Hz), 8.02 1H, J 7.9 Hz), 7.90 (ddd, 1H, J =1 7.0, 8.4 Hz), 7.72- 7.69 (mn, 7.62-7.5 8 (mn, 2H), 7.47 1H, J =7.7 Hz), 7.07 2H, J 8.7 Hz), 7.03 2H, J 8.7 Hz), 4.76 (dd, I H, J 4.0, 8.5 Hz), 2.85- 2.68 (in, 6H).
Following the procedures outlined for Examples 14-3 1, the compounds listed in Table 6 were prepared, TABLE 6
OH
0~ 1. 1105 S., N N-1 R HO0 Example Selected 1H NMR (CD30D) Data i1l 4-(3-hexyl-2,4- 4.40 3.54 (in, 2H), 1.68iinidazolidinedion-1- 1.59 (in, 2H), 1.37-1.28 (mn, 6H), _______yl)phenyl 0.91 (mn, 3H).
112 4-(3-octyl-2,4- 4.40 3.52 (in, 2H), 1.68iinidazolidinedion-1- 1.59 (in, 2H), 1.38-1.23 (mn, 1OH), ______yl)phenyl 0.89 (in, 3H). 113 7.66 1H), 5.35 (in, 1H), 3.22cyclohexylbutyl)- 3.32 (in, 5H), 2.95 (in, 2H), 2.90 (t, J=6.5Hz, 2H), 1.8 (in, 2H), 1.69 (in, trihydrochioride 5H), 1.45 (in, 2H), 1.24 (mn, 6H), 0.89 (in. 2H) 114 7.49 1H), 7.2 (in, 2H), 6.99 (in, fluorophenyl) ethyl] 2H), 4.90 (mn, 1H), 3.05 (mn, 4H), oxazol-5-ylilphenyl 12.70-2.85 (mn, 6H)
I
wo 95/29159 W095/2915911,185/04956 86 115 7.51 111), 4.90 (in, IH), 2.65cycl open tyl propyl)- 2.90 8H), 1.80 (mn, 5H), 1.46- 1.62 (mn, 4H), 1.05 (mn, 2H) 116 4-(4-hexyl-3-oxo- 8.04 1H), 3.69 (in 2H), 1.78- [1,2,4]-triazol-2- 1.69 Cm, 2H), 1.39-1.28 (mn, 6H4), yl)phenyl 0.90 3H).
117 4-(4-octyl-3-oxo- 8.03 Cs, 1H), 3.69 (mn 2H), 1.77- [1,2,4]-triazol-2- 1.69 Cm, 2H), 1.38-1.25 (mn, 1OH), 0.89 (in, 3H).
118 4-(4-heptyl-5-inethyl- 2.28 1.67 2H, J=6.9 Hz), [1,2,3]-triazol-2- 1.36-1.34 (mn, 4H), 1.31-1.29 (in, yl)phenyl 2H), 1,18 4H, J=2.5 Hz), 0.88 (t, 3H, J=7.0 Hz)

Claims (6)

1. A compound having the formula 1: where n is m is r is A is OH H R 2 4 SHCH 2 N-C-(X)m N-SO,(CH 2 )r-R 7 I I SR R 5 R 6 n I 0 to 0 or 1; 0 to 3; a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, phenyl, or a benzene ring fused to a C3-C8 cycloalkyl ring; hydroxy, oxo, halogen, cyano, NR 8 R 8 SR 8 trifluoromethyl, R1 is WO 95/29 159 WO 9529159PC'I1US95/04956 Ci-Clo alkyl, OR 8 S02R9, (11) OCOR 9 (12) NR 8 COR9, (13) COR 9 (14) NR 8 SO2R 9 NR 8 CO2R 8 or (16) Ci-CIO alkyl substituted by hydroxy, halogen, cyano, NR8R8, SR 8 1 trifluoromethyl, OR 8 C3-C8 cycloalkyl, phenyl, NR 8 COR9, COR 9 S02R9, OCOR 9 NR 8 SO2R9 or NR 8 CO2R 8 R2 and R3 are independently hydrogen, Cj--Gb alkyl or CI-Cio alkyl with I to 4 substituents selected from hydroxy, CI-ClO alkoxy, and halogen; X is -CH2-, -CH2-CH2-, -CH::CH- or -CH2O-; R 4 and R5 are independently (1)hydrogen, Ci-CiG alkyl, halogen, NHR 8 OR 8 S02R 9 or NHSO2R9; R 6 is hydrogen or Ci-ClO alkyl; R7 is Z-(Rla)n; Rlais R 1 with the proviso that when A is phenyl, RIaI is not Cl-CIO alkyl, WO 95/29159 PCTIUS95/04956 89 Z is R8is C3-C8 cycloalkyl, phenyl optionally substituted with up to 4 groups independently selected from R 8 NR 8 R 8 OR 8 SR 8 and halogen, or 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, R 8 NR 8 R 8 OR 8 SR 8 and halogen; phenyl, naphthyl, a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a benzene ring fused to a C3-C8 cycloalkyl ring, a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-C8 cycloalkyl ring; hydrogen, C1-C10 alkyl, C3-C8 cycloalkyl, Z optionally having 1 to 4 substituents selected from halogen, nitro, oxo, NR 10 R 10 C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, and C1-C10 alkyl having 1 to 4 substituents selected from hydroxy, halogen, CO2H, C02- C1-C10 alkyl, S02-C1-C10 alkyl, C3-C8 cycloalkyl, C1- alkoxy, and Z optionally substituted by from 1 to 3 of halogen, C1-C10 alkyl or C1-C10 alkoxy, or WO 95/29159 PCT/US95/04956 C1-C10 alkyl having 1 to 4 substituents selected from hydroxy, halogen, CO2H, C02-Cl-C10 alkyl, S02-Cl-C10 alkyl, C3-C8 cycloalkyl, C1-C10 alkoxy, C1-C10 alkyl, and Z optionally substituted by from 1 to 4 of halogen, alkyl or CI-C10 alkoxy; R9 is R8 or NR8R8; R 10 is C1-C10 alkyl, or two R 10 groups together with the N to which they are attached formed a 5 or 6-membered ring optionally substituted with C1-C10 alkyl; or a pharmaceutically acceptable salt thereof n is m is r is A is X is
2. A )mpound of Claim 1 where 0 to 3; 1; 0 to 2; phenyl or a 5- or 6-membered heterocyclic ring with from 1 to 4 nitrogen atoms; -CH2-; RI is hydroxy, halogen, cyano, trifluoromethyl, NR 8 R 8 NR 8 SO2R 9 NR 8 COR 9 NR 8 CO2R 8 or C1-C10 alkyl optionally substituted by hydroxy; 0 R 2 R 3 are independently hydrogen or methyl; R 4 R 5 and R 6 are each hydrogen; R 7 is Z-(Rla)n; and WO 95/29159 PCT/S95/04956 -91 R 8 R 9 Z and Rla are as defined in Claim 1, and when RI is part of the definition of Rla has the meaning defined in Claim 1.
3. A compound of Claim I having the formula la: OH H R 2 (R)n HCH 2 N-C-(X)m /-NH-SO-Z-(Ra)n N R 3 wherein n is 0 to 3; mis 1 R1 is halogen nr NR 8 R8; R 2 R 3 are independently hydrogen or methyl; Rla is halogen, C1-C10 alkyl, NR 8 R 8 NR 8 COR 9 NR 8 CO2R 8 COR 9 OCOR 9 or a 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, halogen, R 8 NR 8 R 8 OR 8 and SR 8 Zis phenyl, naphthyl, a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, 0 wo 95/29159 WO 959159P17US95/04956 92 benzene ring fused to a 5 or 6-membered heterocyclic ring with from I to 3 heteroatoms selected from oxygen, sulfur and nitrogen, or a 5 or 6-membered heterocyclic ring with from I to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-C8 cycloalkyl ring; and are as defined in Claim 1.
4. A compound of Claim 3 wherein R 2 and R 3 are each X is R8 and R 9 hydrogen. A compound of Claim 1 having the formula lb: OH HR 2 (I)e -j I I HS2 -R ni KCHCH2N-Cm NHS 2 Z(~)n 1R 3 M wherein is m is R1 is Rla is 0Oto 3; 1 hydroxy, cyano, NR 8 R 8 or halogen; halogen, NR 8 R 8 NR 8 00R 9 NR 8 CO2R 8 OCOR 9 or IWO 95/29159 W'CVIS95/0)4956 93 a 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to three groups independently selected from oxo, halogen, R 8 NR 8 R 8 OR 8 and SR 8 Z is phenyl, naphthyl or benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; Xis -CH2-; and R 2 and R 3 are independently hydrogen or methyl.
6. A compound of Claim 1 having the formula Id OH HR 2 B (R -CHCH 2 N-C-CH2- NH-SO 2 (R )n R 3 Id nis 0 or 1; R 1 is NR 8 R 8 R 2 and R 3 are independently hydrogen, or methyl; B is hydrogen, benzene fused to the benzene ring to form naphthyl, or a 5 or 6-membered heterocycle with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atom fused to the benzene ring; R l a is halogen, C1-C10 alkyl, NR 8 R 8 NR 8 COR 9 WO 95/29159 P("T'AuS95/04956
94- R 8 is R9 is R 10 is NR 8 CO2R 8 COR 9 or a 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, R 8 SR 8 OR 8 and NR 8 R 8 when B and the benzene ring form a fused ring system, Rla is attached to either ring; hydrogen, C1-CIO alkyl, Z optionally having 1 to 4 substituents selected from nitro, oxo, and NR 1 ORO 1 or C1-C10 alkyl having 1 to 4 substituents selected from hydroxy, halogen, C1-C10 alkyl, C3-C8 cycloalkyl, and Z optionally substituted by from 1 to 4 of halogen, alkyl or C1-C10 alkoxy; R8 or NR8R8; C1-CQ1 alkyl, or two R 10 groups together with the N to which they are attached formed a 5 or 6-membered ring optionally substituted with C1-C10 alkyl; and phenyl, a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-C8 cycloalkyl ring. 7. A compound of Claim 1 selected from the group Z is consisting of: WO 95/29159 WO 95/29159 (rAvS'5/04956 95 N- [(2-hydroxy-2-phenylethyl)ami no) ethyl] phenyl] -4- iodobenzenesulfonamide; hN- [(2-hydroxy-2-phenylethyl)amino ]ethyl lphenyl 1-2- naphthalenesulfonamide; and N- 4- [(2-hydroxy-2-phenylethyl)aminoj ethyl] phenyl] -3 quinolinesulfonamide. N- [[2-hydroxy-2-(4-amino-3 ,5-dichlorophenyl)ethyl] amino]- ethyl)]-phenyl] (hexylarninocarb onyl amino)benzenesulfon amide N-[4-[2-[[2-hydroxy-2-(4-amino-3 ,5-dichlorophenyl )ethyl] amino]- ethyl] -phenyl] 1 [(octyl amino)carbonylamino] -5 -indoli nesulfonamide Nj-[4- [[2-hydroxy-2-(4-amino-3 ,5-dichlorophenyl)ethyl] amino]- ethyl)]-ph enyl] (3 -hexyl-2-imi dazoli don- I -yI)benzenesulfonamide N- 2- [[2-hy droxy-2- (4-amino-3,5- dichlorophenyl) ethyl] amino] ethyl] -phenyl] octyl-2-imidazolidon- I -yl)benzenesulfonamide N- [[2-hydroxy-2-(4-hydroxyphenyl)etliyl] amino] -ethyl] phenyl] benzenesulfonamide N- [2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -ethyl]phenyl] -4- iodobenzenesulfonamnide, N- [[2-hydroxy-2-(3-cyanophenyl)ethyl] amino] ethyl] phenyl]-4- (hexylaminocarbonylamino)benzenesulfonamide, and N- [[2-hy droxy-2- cyanophenyl)ethyl] amino] ethyl] phenyl]- 3- quinolinesulfonamide 8. A compound of Claim 1 selected from the group consisting of: N- [[2-hydroxy-2-(6-arninopyridin-3-yl)ethyl]amino] ethyl] phenyl]- 4-(hexylaminocarbonylamino)benzenesulfonamide; N- [[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl] amino] ethyl] phenyl]- 4-iodobenzenesulfonamide; N- [4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl] amino] ethyl] phenyl] benzenesulfonamide; [[2-hydroxy-2- aminopyridin-3 -yl) ethyl] amino] ethyl] phenyl] 2-niaphthalenesulfonamide; N- [[2-hydroxy-2-(6-am-inopyridin-3-yl)ethyl] amino] ethyl] phenyl] 3-quinolinesulfonamide; WO 95/29159 PCTIUS95/04 956 96 hj- [2-hydroxy-2-(6-aminopyridin-3-yl) ethyl I amino] ethyl Iphenyl]- AN- [[2-hydroxy-2-(6-aminopyri din-3-yl)ethyl] amino) ethyl] phenyl] 4- [(hexylmethyl amino-.,arbonyl)aminio]benzenesulfonamide; N- [2-hydroxy-2- aminopyridi n- 3-y1) ethyl] amino] ethyl] phenyl] 4- [(dimethylaminoc arbonyl) amino] benzenesulfonamide-, N-[4-[2-[[2-hydroxy-2--(6-aminopyridin-3-yI)ethyl] arin lethyllphenyl]- 4-(3-hexyl-2-imidazolidon- 1-yl)benzenesulfonamide; N- [[(2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyl] phenyl] -4- (hexylaminocarbonylamino)benzenesulfonamide; N- [2-hydroxy-2- (3-pyri dinyl)ethyl] amino] ethyl] phtny1] -4- isopropylbenzenesulfonamide; hl-[4- [[2-hydlroxy-2-(3 -pyridinyl)ethyll amino] ethyl] phen)y1j-2- naphthalenesulfonamide; N- [2-[[2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyl]phenyl]- 3- quinolinesulfonamide; N- [2-hydroxy-2-(3 -pyridinyl) ethyl] amino] ethyl] phenyl] -4- [(hexylmethylaminocarbonyl)amino]benzenesulfonamide; N- [[2-hydroxy-2-(3-pyridinyl)ethyl] amino]ethyljphenyl]-4- (3- hexyl-2-imidazolidon- 1-yl)benzenesulfonamide; [2-[[2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl]-4- iodobenzenesulfonamide; N- [[2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyl] phenyl] [3 cyclopentylpropyl) -2-imidazoli don- Il-yl] benzenesulfonamide N- [2-hydroxy-2-(3 -pyridinyl) ethyl] amino] ethyl] phenyl] (3 octyl-2-imidazolidinon- 1-yl)benzenesulfonamide N- [2-hy droxy-2- (3-pyri dinyl) ethyl] amino] ethyl] phenyl] (3 hexyl-2-imidazolon- 1-yl)benzenesulfonamide N- [[2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl]-4-(3 octyl-2-imidazolon- 1-yl)benzenesulfonamide N- [[2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] (3 cyclopentylpropyl)-2-imidazolon- I -yl]benzenesulfonamide N- [[2-hydroxy-2-(3-pyridinyl)ethyl] amino) ethyl] phenyl] 1-(4- WO 095/29159)IC/S9/4$ 11MV.S95/04956 97 [[2-hlydroxy-2-(3-pyridinyl)etlhylj amino] ethyl] pentyl- [1 ,2,4]-oxadiazol-3-yl)benzenesulfonamide N- [[2-hydroxy-2-(3-pyridinyl)ethyl] ami no]jethyl] phenyl]-4- hexyl-[ 1 ,2,4]-oxadiazol-3-yl)benzenesulfonamide NA- [2-hydroxy-2- (3-pyri dinyl) ethyl] amino] ethyl] phen yl1]-4- (5 heptyl-El ,2,4]-oxadiazol-3-yl)benzenesulfonaimide N- [[2-hydroxy-2-(3-pyridinyl)ethyl ]amnino] ethyl] octyl-[ 1,2,4]-oxadiazol-3-yl)benzenesulfonamide E- hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] ph enyl] (2- cyclopentylethyl)- [1 ,2,4]-oxadiazol-3-yl]benzenesulfonamide N- [2-hydroxy-2- (3-pyridinyl) ethyl] amino] ethyl] phenyl] (3- cyclopentyipropyl)- [1 ,2,4]-oxadiazol-3-yl]benzensulfonamide N- [[2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl] phenyl]-4-(2- N- [[2-hydroxy-2- (3-pyri dinyl) ethyl] amino] ethyl] phenyl (2- N- [[2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyllphenyl]1-4- (2- .heptyloxazol-5-y1)benzenesulfonamide N- [[2-hydroxy-2- (3-pyridinyl)ethyll amino] ethyl] phenyl] (2- [[2-hydroxy-2- (3-pyridinyl)ethyl] amino] ethyl]phenyl] (2- N- [2-hy droxy-2- (3-pyridinyl)ethyl] amino] ethylI]phenyl] (3- N- [2-hydroxy-2-(3-pyri dinyl) ethyl] amino] ethyl] pheny1] 1-yl)benzenesulfonamide N- [2-hydroxy-2- (3 -pyridinyl) ethyl] amino] ethyl] phenyl1] (4- 1 -yl)benzenesulfonamide N- [[2-hydroxy-2-(3-pyridinyl)ethyl] amino] ethyl]phenyl] cyclopentylpropyl)-5 -tetrazolon- 1 -yl]benzenesulfonamide 9. A compound of Claim I with the structural formnula 2 H R where n, m, r, A, R 1 R 2 R 3 R 4 R 5 R 6 R 7 and X are as defined in Claim 1. A selective P3 agonistic substituted sulfonamide derivative which is useful in the treatment of obesity and diabetes, substantially as hereinbefore described with reference to any one of the Examples. 11. A pharmaceutical composition which comprises an inert carrier and an effective amount of a compound of any one of Claims 1 to 12. A method for the treatment of diabetes which comprises administering to a diabetic patient an effective amount of a compound of any one of Claims 1 to 10 or of a 10 composition of Claim 11. 13. A method for the treatment of obesity which comprises administering to an obese patient an effective amount of a compound of any one of Claims 1 to 10 or of a composition of Claim 11. 14. A method for lowering triglyceride levels and cholesterol levels or raising 15 high density lipoprotein levels which comprises administering to a patient needing lower triglyceride and cholesterol levels or higher high density lipoprotein levels an effective amount of a compound of any one of Claims 1 to 10 or of a composition of Claim 11. A method for decreasing gut motility which comprises administering to a patient in need of decreased gut motility, an effective amount of a compound of any one of Claims 1 to 10 or of a composition of Claim 11. 16. A method for reducing neurogenic inflammation of airways which comprises administering to a patient in need of reduced neurogenic inflammation, an effective amount of a compound of any one of Claims 1 to 10 or of a composition of Claim 11. 17. A method for reducing depression which comprises administering to a depressed patient an effective amount of a compound of any one of Claims 1 to 10 or of a composition of Claim 11. 18. A method for treating gastrointestinal disorders, which comprises administering to a patient with gastrointestinal disorders an effective amount of a compound of any one of Claims 1 to 10 or of a composition of Claim 11. Dated 3 December, 1997 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person I^ SPRUSON FERGUSON [n:\libc](X)573:MCN INTERNATIONAL S]EAILCI[ RZEPOirr Inta m AppilitinNi PCT/US 95/04956 (7I.ASSII*IC*A I ION 01,D SUIlIJI CI MA I'I I It. IPC 6 C07D213/30 C070413/12 C07D401/12 C07D417/14 C07C311/21 C070417/12 C070209/08 C07D233/36 C070215/36 A61K31/44 A61K31/47 A61K31/18 According to International I'aicnt, classification II110 or t) both national (lassiiation and Minimum documentation searched (clasification sy~tcm followed by clai;sificatiuin symbols) IPC 6 C07D C07C A61K D~ocumentation scarched olhcr than minimum dscumeintation to the extent that such documents arc included in thc Acids starched Electronic data base conwltcd during the intcmational -search (namc of data basc and, where practical, Ncarch terms used) C. 1)0OLMflNTIS CONSIIWRPiI)T II II RFiI.INVA N C:ategory Citation of document, with indication, where appropriate, of thc relevant passages Relev~ant to claim No, XP EP-A-O 611 003 (MERCK CO INC) 17 August 1-17 1994 see the whole document A EP-A-O 091 749 (BEECHAM GROUP PLC) 19 1-17 October 1983 see the whole document Furt~hcr documcnts arc listcd in the continuation or box c. rv I Patent family mcmbcrs are listed in annex. Special categories of cited documents: -1 later documcnt puhlishcd after- the interniational filing date 'A dcumnt eliing he encal tatcof he rt hichis ot r pionty date and not in conflict with thc application hut 'A oeonde in to h ealsae of parhcla rcc ancc cic s o ted to undersiand the principIc or theory undcrlying ihc consdere tobe o paticuar elevnceinvention 'l earlier document but published on or aftcr thc intcrnational *xdocument of patclar rclcvance; the claimed invention iling datc cannot he consdrd novel or cannot he considcred to documcnt which may throw diiuhts on prionty claim(s) or involvc an inventivestcp when the document is taken alone which is cited to cstablish thc publication date of another y document of particular relevance,, the claimed invention citation or othcr special reason (as specificd) cannot be considered to involve an invcntive step when thc documcnt rcferring to an oral disclosurc, ttne, exhibition or documcnt is combined with one or morc othcr such docu- other means menits, such combhination being obvious to a person skilled rP document published poor to the intcmational filing date hut in the art. later than the pnrity date claimed W& document member of the same patent family Date of the actual completion of the international search IDate of mailing of the intcmational search report 4 August 1995 11. 08. Name and mailing address of the ISA Authoitzed officer lEuropran Patent Office, PA.L. 5818 Platentlaan 2 NI, 2280 1IIV R9ilswelk 'ret. 1I 31.70) 340.2040, Txe. 31 651 cpo ril,Bos a P Var. tI 31-70) 340-3016 B sa Formi PCT'ISA!210 (second sheet) (July 1992) INTERNATIONAL SE~ARCHI REPORT i nter lAM Application No eiflitnon pritent lamnily rncinlcri PCT/US 95/04956 Patent documnrl Publication Patnt hirrnaly Publicaton cstcd in scarch rcport date 7 incrmber(s) datc EP-A-0611003 17-08-94 AU-B- 5498694 29-06-95 CA-A- 2114712 10-08-94 JP-A- 7010827, 13-01-95 WO-A- 9418161 18-08-94 EP-A-0091749 19-10-83 JP-A- 58185554 29-10-83 I'nrm PCT/ISA/1210 (patent family annex) (July 1992)
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