Derivatives of benzimidazole and their use as medicaments

1. A compound of the formula

in racemic, enantiomeric form or any combinations of these forms wherein:

A is —CH 2 —;

X is —CH—,

R 1 is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl optionally substituted by hydroxy or at least one halo; (C 2 -C 6 )alkenyl and —(CH 2 ) n —X 1 ;

R 2 is selected from the group consisting of (C 1 -C 8 )alkyl optionally substituted by hydroxy or at least halo; (C 2 -C 6 )alkenyl, alkenyl and —(CH 2 ) n —X 1 ;

each X 1 independently is selected from the group consisting of (C 1 -C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, adamantyl, heterocycloalkyl, aryl and heteroaryl,

the (C 3 -C 7 )cycloalkyl, heterocycloalkyl, aryl and heteroaryl being substituted by at least one member selected from the group consisting of:

—(CH 2 ) n′ —V 1 —Y 1 , halo, nitro, cyano and aryl;

V 1 is selected from the group consisting of —O—, —S— and covalent bond;

Y 1 is (C 1 -C 6 )alkyl optionally substituted by at least one halo;

n is an integer from 0 to 6 and n′ is an integer from 0 to 2 (it being understood that when n is equal to 0, then X 1 is not alkoxy);

or R 1 and R 2 form together with the nitrogen atom to which they are attached, a heterobicycloalkyl or a heterocycloalkyl optionally substituted by at least one member selected from the group consisting of hydroxy, (C 1 -C 6 )alkyl, optionally substituted by hydroxy, (C 1 -C 6 )alkoxy-carbonyl, heterocycloalkyl and —C(O)NV 1 ′Y 1 ′ with V 1 ′ and Y 1 ′ independently are hydrogen or (C 1 -C 6 )alkyl; or R 1 and R 2 together form a member selected from the group consisting of

R 3 is selected from the group consisting of -Z 3 , —C(R Z3 )(R′ Z3 )-Z 3 , —C(R Z3 )(R′ Z3 )—(CH 2 ) p -Z 3 and —C(O)-Z′ 3

R Z3 and R′ Z3 are independently hydrogen or (C 1 -C 6 )alkyl,

Z 3 is selected from the group consisting of Z 3a , Z 3b , Z 3c , Z 3d , or Z 3e ;

Z 3a is (C 1 -C 6 )alkyl;

Z 3b is selected from the group consisting of (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylamino and di((C 1 -C 6 )alkyl)amino;

Z 3c is aryl or heteroaryl;

Z 3d is selected from the group consisting of (C 1 -C 6 ) alkoxy-carbonyl, amino-carbonyl, (C 1 -C 6 )alkylamino-carbonyl, di((C 1 -C 6 )alkyl)amino-carbonyl, (C 1 -C 6 )alkyl-C(O)—NH—, (C 3 -C 7 )cycloalkyl and heterocycloalkyl;

(C 3 -C 7 )cycloalkyl and heterocycloalkyl being optionally substituted by at least one member selected from the group consisting of halo, nitro, (C 1 -C 6 )alkoxy optionally substituted by at least one halo, (C 1 -C 6 )alkyl optionally substituted by at least one halo, (C 1 -C 6 )alkyl-carbonyl, (C 1 -C 6 )alkoxy-carbonyl, amino-carbonyl, (C 1 -C 6 )alkylamino-carbonyl, di((C 1 -C 6 )alkyl)amino-carbonyl and oxy,

the aryl and heteroaryl being optionally substituted by at least one member selected from the group consisting of halo, cyano, nitro, azido, oxy, (C 1 -C 6 )alkoxy-carbonyl-(C 1 -C 6 )alkenyl, (C 1 -C 6 )alkylamino-carbonyl-(C 1 -C 6 )alkenyl, —SO 2 —NR 31 R 32 , heterocycloalkyl, heteroaryl and —(CH 2 ) p′ —V 3 Y 3 ;

R 31 and R 32 form together with the nitrogen to which they are attached, a heterocycloalkyl;

V 3 is selected from the group consisting of —O—, —S—, —C(O)—, —C(O)—O—, —O—C(O)—, —SO 2 —, —SO 2 NH—, —NR′ 3 —SO 2 —, —NR′ 3 —, —NR′ 3 —C(O), —C(O)—NR′ 3 ,

—NH—C(O)—NR′ 3 — and a covalent bond;

Y 3 is selected from the group consisting of hydrogen; (C 1 -C 6 )alkyl optionally substituted by at least one halo; aryl optionally substituted by at least one member selected from the group consisting of halo, nitro, (C 1 -C 6 )alkyl (C 1 -C 6 )alkoxy; aryl-(C 1 -C 6 )alkyl optionally substituted by at least one member selected from the group consisting of halo, nitro, (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy;

Z 3e is

Z′ 3 is aryl optionally substituted by at least one member selected from the group consisting of halo, nitro and —(CH 2 ) p″ —V′ 3 —Y′ 3 ;

V′ 3 is selected from the group consisting of —O—, —C(O)—, —C(O)—, —C(O)—O—, —C(O)—O—, —C(O)—NR′ 3 —, —NH—C(O)—NR′ 3 — and a covalent bond;

Y′ 3 is hydrogen or (C 1 -C 6 )alkyl optionally substituted by at least one halo;

R′ 3 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy;

p is an integer from 1 to 4; p′ and p″, are independently, an integer from 0 to 4;

R 4 is —(CH 2 ) s —R′ 4 ,

R′ 4 is selected from the group consisting of guanidine; heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C 1 -C 6 )alkyl or aralkyl; heteroaryl containing at least one nitrogen and optionally substituted by (C 1 -C 6 )alkyl; and —NW 4 W′ 4 ;

W 4 is hydrogen or (C 1 -C 8 )alkyl;

W′ 4 is —(CH 2 ) s′ -Z 4 ;

Z 4 is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl optionally substituted by at least one member selected from the group consisting of (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, hydroxy; (C 2 -C 6 )alkenyl; (C 3 -C 7 )cycloalkyl optionally substituted by at least one (C 1 -C 6 )alkyl; cyclohexene; heteroaryl and aryl;

the aryl and heteroaryl being optionally substituted by at least one member selected from the group consisting of —(CH 2 ) s″ —V 4 —Y 4 , hydroxy, halo, nitro and cyano;

V 4 is selected from the group consisting of —O—, —S—, —NH—C(O)—, —NV 4 ′— and a covalent bond;

Y 4 is hydrogen or (C 1 -C 6 )alkyl optionally substituted by at least;

V 4 ′ is hydrogen or (C 1 -C 6 )alkyl;

s″ is an integer from 0 to 4;

or Z 4 is

s and s′ are independently, an integer from 0 to 6;

and i) when R 3 is —C(O)-Z′ 3 and R 4 is —(CH 2 ) s —NW 4 W′ 4 and W 4 and W′ 4 are independently, hydrogen or (C 1 -C 6 )alkyl, then —(CH 2 ) s is neither ethylene nor —(CH 2 )—CH((C 1 -C 4 )alkyl)- and ii) when R 3 is -Z 3c and Z 3c is phenyl or naphthyl, then phenyl and naphthyl are not substituted by cyano; and it being understood that when R 3 is -Z 3d then Z 3d only is (C 3 -C 7 ) cycloalkyl or heterocycloalkyl;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 wherein

R 1 and R 2 are independently, (C 1 -C 8 )alkyl;

R 3 is selected from the group consisting of -Z 3c , —C(R Z3 )(R′ Z3 )-Z 3c , —C(R Z3 )(R′ Z3 )-Z 3d , and —C(R Z3 )(R′ Z3 )—(CH 2 ) p -Z 3d ;

R 4 is —(CH 2 ) s —R′ 4 ;

R′ 4 is heterocycloalkyl containing at least one nitrogen and optionally substituted by (C 1 -C 6 )alkyl; or —NW 4 W′ 4 ;

W 4 is hydrogen or (C 1 -C 8 )alkyl;

W′ 4 is —(CH 2 ) s′ -Z 4 ;

Z 4 is hydrogen;

s is an integer from 2 to 4; s′ is an integer from 0 to 4;

or a pharmaceutically acceptable salt thereof.

3. A compound of claim 2 wherein

the heterocycloalkyl of R′ 4 is piperidine;

R Z3 and R′ Z3 are hydrogen;

Z 3c is selected from the groups consisting of thienyl, furyl or phenyl unsubstituted or

substituted by at least one halo or —(CH 2 ) p′ —V 3 —Y 3 ;

V 3 is selected from the group consisting of —O—, —C(O)—, —C(O)—O—, —C(O)—NR′ 3 — and a covalent bond;

R′ 3 is hydrogen or (C 1 -C 6 )alkyl;

Y 3 is hydrogen or (C 1 -C 6 )alkyl optionally substituted by at least one halo;

Z 3d is (C 1 -C 6 )alkoxy-carbonyl or imidazolidine;

or a pharmaceutically acceptable salt thereof.

4. A process for the preparation of a compound of claim 1 comprising reacting a compound of the formula

in which A, X, R 1 , R 2 , R 4 have the meaning of claim 1 , with an isothiocyanate of the formula R 3 N═C═S in which R 3 has the meaning indicated in claim 1 , in the presence of a coupling agent or yellow mercury (II) oxide in the presence of sulfur, for a period of 3 to 48 hours, in a protic or aprotic solvent, at a temperature of 50 to 80° C.