WO1996039390B1

WO1996039390B1 - Benzimidazole derivatives as inhibitors of smooth muscle cell proliferation

Info

Publication number: WO1996039390B1
Application number: PCT/US1996/008353
Authority: WO
Filing date: 1996-06-03
Publication date: 1997-01-09
Anticipated expiration: 1997-12-06

Abstract

Disclosed herein are compounds and pharmaceutically acceptable salts of compounds of formula (I) or (II), wherein R is alkyl, phenyl or substituted phenyl; R2 is hydrogen, halogen, alkoxy or alkyl; R1 is hydrogen, alkyl, aryl, arylalkyl, or substituted benzyl; which are useful as inhibitors of smooth muscle cell proliferation.

Claims

-27-

AMENDED CLAIMS

[received by the International Bureau on 27 November 1996 (27.11.96); original claims 1-15 replaced by amended claims 1-17 (8 pages)]

( 1 ) A pharmaceutically acceptable salt of a compound of formula I or II:

i π wherein

R is alkyl of 1 to 6 carbon atoms, phenyl, benzyl, phenyl or benzyl substituted with one or more of hydroxyl, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, trifluoromethyl or alkyl of 1 to 6 carbon atoms; R2 is hydrogen, halogen, alkoxy of 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms;

Rl is hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms, arylalkyl of 7 to 12 carbon atoms, or benzyl substituted with one or more of halogen, carboxyl, alkoxycarbonyl of 2 to 6 carbon atoms or aryloxycarbonyl of 7 to 12 carbon atoms; provided that the pharmaceutically acceptable salt of the compound of formula II is not α-(3-fluorophenyl)-2-methyl-lH-benzimidazole- 5-methanol monohydrochloride or 2-methyl-α-phenyl-lH-benzimidazole-5- methanol hydrochloride or sulphate.

(2) A compound of formula I :

wherein

Rl is hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms, aiylalkyl of 7 to 12 carbon atoms, or benzyl substituted with one or more of halogen, carboxyl, alkoxycarbonyl of 2 to 6 carbon atoms or aryloxycarbonyl of 7 to 12 carbon atoms, or a pharmaceutically acceptable salt thereof; provided that when Ri and R2 are hydrogen, R is not methyl, phenyl, p-chlorophenyl or p-methoxy-phenyl; and provided that when R is methyl and R2 is hydrogen, then Ri is not ethyl or phenyl; and provided that the compound of formula I is not 3-fiuorophenyl-(2-methyl-lH- benzimidazol-5-yl)methanone.

(3) A compound of formula I or II:

wherein

R is alkyl of 1 to 6 carbon atoms, substituted phenyl or substituted benzyl in which the substituents are one or more of hydroxyl, alkoxy of 1 to 6 carbon atoms, trifluoromethoxy, or alkyl of 1 to 6 carbon atoms;

R2 is hydrogen;

Rl is hydrogen, benzyl or benzyl substituted with one or more of halogen, carboxyl, alkoxycarbonyl of 2 to 6 carbon atoms or aryloxycarbonyl of 7 to 12 carbon atoms, or a pharmaceutically acceptable salt thereof; provided that in formula I when Ri and R2 are hydrogen, R is not p-methoxy-phenyl.

(4) A compound according to claim 1, 2 or 3 wherein R is alkyl of 1 to 6 carbon atoms, phenyl, phenyl or benzyl substituted with one or more of hydroxyl, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, or alkyl of 1 to 6 carbon atoms; R2 is hydrogen; R i is hydrogen or benzyl substituted with one or more of halogen, carboxyl, or alkoxycarbonyl of 2 to 6 carbon atoms. -29-

(5) A compound of formula II:

II

wherein

R is alkyl of 3 to 6 carbon atoms; dialkoxyphenyl in which each alkoxy group has, independently, 1 to 6 carbon atoms; alkoxy-hydroxy-phenyl in which the alkoxy group has 1 to 6 carbon atoms; trifluoromethoxyphenyl or substituted benzyl, in which the substituents are hydroxyl, alkoxy of 1 to 6 carbon atoms, trifluoromethoxy or alkyl of 1 to 6 carbon atoms;

R2 is hydrogen;

R _l is hydrogen, benzyl or benzyl subsituted with halogen, carboxyl, alkoxycarbonyl of 2 to 6 carbon atoms or aryloxycarbonyl of 7 to 12 carbon atoms, or a pharmaceutically acceptable salt thereof.

(6) A compound according to any of the preceding claims in which the groups

^R

are in the 5- or 6- position of the benzimidazole group.

(7) A compound which is :

phenyl-(2-propyl-lH-benzoimidazol-5-yl)-methanone or a pharmaceutically acceptable salt thereof;

4-(5-benzoyl-2-propyl-benzoimidazol-l-ylmethyl)-benzoic acid ethyl ester or a pharmaceutically acceptable salt thereof; -30-

4-(6-benzoyl-2-propyl-benzoimidazol-l-ylmethyl)-benzoic acid ethyl ester or a pharmaceuticaUy acceptable salt thereof;

4-(6-benzoyl-2-propyl-benzoimidazol-l-ylmethyl) benzoic acid or a pharmaceutically acceptable salt thereof;

4-(5-benzoyl-2-propyl-benzoimidazol-l-ylmethyl)-benzoic acid or a pharmaceutically acceptable salt thereof;

4- [5-(hydroxy-(phenyl)-methyl)-2-propyl-benzoimidazol-l-ylmethyl] -benzoic acid or a pharmaceutically acceptable salt thereof;

[ 1 -(3,4-dichloro-benzyl)-2-propyl- lH-benzoimidazol-5yl]-phenyl-methanone or a pharmaceutically acceptable salt thereof;

[2-(4-hydroxy-3-methoxy-phenyl)- lH-benzoimidazol-5-yl] -pheny 1-methanone or a pharmaceutically acceptable salt thereof;

[2-(4-hexyloxy-3-methoxy-phenyl)- lH-benzoimidazol-5-yl]-phenyl-methanone or a pharmaceutically acceptable salt thereof; phenyl- [2- (4-trifluoromethoxy-phenyl)- lH-benzoimidazol-5-yl]-methanone or a pharmaceutically acceptable salt thereof;

[2-(3,4-dimethoxybenzyl)- lH-benzoimidazol-5-yl]-phenyl-methanone or a pharmaceutically acceptable salt thereof.

(8) A pharmaceutical composition comprising a compound of formula I or II:

i π wherein

Rl is hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms, arylalkyl of 7 to 12 carbon atoms, or benzyl substituted- with one or more of -31-

halogen, carboxyl, alkoxycarbonyl of 2 to 6 carbon atoms or aryloxycarbonyl of 7 to 12 carbon atoms, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable caπier.

(9) A method of treatment of a mammal which comprises administering to that mammal, orally or parenterally, a compound of formula I or II:

i n wherein

R is alkyl of 1 to 6 carbon atoms, phenyl, benzyl, phenyl or benzyl substituted with hydroxyl, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, trifluoromethyl or alkyl of 1 to 6 carbon atoms; R2 is hydrogen, halogen, alkoxy of 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms;

R l is hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms, arylalkyl of 7 to 12 carbon atoms, or benzyl substituted with one or more of halogen, carboxyl, alkoxycarbonyl of 2 to 6 carbon atoms or aryloxycarbonyl of 7 to 12 carbon atoms, or a pharmaceutically acceptable salt thereof.

(10) A method according to claim 9 in which the method of treatment is for preventing smooth muscle cell proliferation in a mammal.

(11) A method according to Claim 10 wherein said smooth muscle cell proliferation manifests itself as restenosis following angioplasty.

(12) A compound of formula I or II -32-

i π wherein

R is alkyl of 1 to 6 carbon atoms, phenyl, benzyl, phenyl or benzyl substituted with hydroxyl, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, trifluoromethyl or alkyl of 1 to 6 carbon atoms;

R2 is hydrogen, halogen, alkoxy of 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms;

Rl is hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms, arylalkyl of 7 to 12 carbon atoms, or benzyl substituted with one or more of halogen, carboxyl, alkoxycarbonyl of 2 to 6 carbon atoms or aryloxycarbonyl of 7 to 12 carbon atoms, or a pharmaceutically acceptable salt thereof, for use in the treatment of mammals.

(13) A compound as claimed in claim 12 for use in the treatment of diseases or conditions related to smooth muscle cell proliferation.

(14) A compound according to any of claims 2 to 7 for use in the treatment of mammals.

(15) A compound according to claim 14 for use in the treatment of diseases or conditions related to smooth muscle cell proliferation.

(16) A compound according to Claim 13 or 15 wherein said smooth muscle cell proliferation manifests itself as restenosis following angioplasty.

(17) A process for the preparation of a compound of formula I or π -33-

i π wherein

R is alkyl of 1 to 6 carbon atoms, phenyl, phenyl or benzyl substituted with hydroxyl, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, trifluoromethyl or alkyl of 1 to 6 carbon atoms;

R2 is hydrogen, halogen, alkoxy of 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms; Rl is hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms, arylalkyl of 7 to 12 carbon atoms, or benzyl substituted with one or more of halogen, carboxyl, alkoxycarbonyl of 2 to 6 carbon atoms or aryloxycarbonyl of 7 to 12 carbon atoms, which comprises

(a) reacting a nitrile of formula RCN with an alcohol and hydrogen chloride to form a compound of formula (1) in which R is as previously defined:

(b) reacting the compound of formula 1 and a 3,4-diaminobenzophenone of formula

in which R2 is as previously defined, in refluxing alcohol to give the corresponding compound of formula (2) -34-

(c) and optionally alkylating the compound of formula (2) with an alkyl, aryl or arylalkyl halide in the presence of a base affords the isomers (3a, 3b)

(d) and optionally separating the isomers by recrystallization and chromatography;

(e) and optionally further reacting the compounds of formula (I) with a reducing agent to obtain the corresponding compound of formula (II).