US 7,501,525 B2
Derivatives of benzimidazole and their use as medicaments
Lydie Poitout, Le Kremlin Bicetre (France); Valerie Brault, Saint-Arnoult-En-Yvelines (France); Carole Sackur, Paris (France); Pierre Roubert, Paris (France); and Pascale Plas, Chatillon (France)
Assigned to Societe de Conseils de Recherches et d'Applications Scientifiques (S.C.R.A.S.), Paris (France)
Filed on Jan. 31, 2008, as Appl. No. 12/12,184.
Application 12/012184 is a division of application No. 10/504033, granted, now 7,355,052, previously published as PCT/FR2004/000418, filed on Feb. 25, 2004.
Claims priority of application No. 03 02320 (FR), filed on Feb. 26, 2003.
Prior Publication US 2008/0139619 A1, Jun. 12, 2008
Int. Cl. C07D 235/00 (2006.01); A61K 31/44 (2006.01)
U.S. Cl. 548—307.4  [514/323] 4 Claims
 
1. A compound of the formula

OG Complex Work Unit Drawing
in racemic, enantiomeric form or any combinations of these forms wherein:
A is —CH2—;
X is —CH—,
R1 is selected from the group consisting of hydrogen, (C1-C8)alkyl optionally substituted by hydroxy or at least one halo; (C2-C6)alkenyl and —(CH2)n—X1;
R2 is selected from the group consisting of (C1-C8)alkyl optionally substituted by hydroxy or at least halo; (C2-C6)alkenyl, alkenyl and —(CH2)n—X1;
each X1 independently is selected from the group consisting of (C1-C6)alkoxy, (C3-C7)cycloalkyl, adamantyl, heterocycloalkyl, aryl and heteroaryl,
the (C3-C7)cycloalkyl, heterocycloalkyl, aryl and heteroaryl being substituted by at least one member selected from the group consisting of:
—(CH2)n′—V1—Y1, halo, nitro, cyano and aryl;
V1 is selected from the group consisting of —O—, —S— and covalent bond;
Y1 is (C1-C6)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 X1 is not alkoxy);
or R1 and R2 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, (C1-C6)alkyl, optionally substituted by hydroxy, (C1-C6)alkoxy-carbonyl, heterocycloalkyl and —C(O)NV1′Y1′ with V1′ and Y1′ independently are hydrogen or (C1-C6)alkyl; or R1 and R2 together form a member selected from the group consisting of

OG Complex Work Unit Drawing
R3 is selected from the group consisting of -Z3, —C(RZ3)(R′Z3)-Z3, —C(RZ3)(R′Z3)—(CH2)p-Z3 and —C(O)-Z′3
RZ3 and R′Z3 are independently hydrogen or (C1-C6)alkyl,
Z3 is selected from the group consisting of Z3a, Z3b, Z3c, Z3d, or Z3e;
Z3a is (C1-C6)alkyl;
Z3b is selected from the group consisting of (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkylamino and di((C1-C6)alkyl)amino;
Z3c is aryl or heteroaryl;
Z3d is selected from the group consisting of (C1-C6) alkoxy-carbonyl, amino-carbonyl, (C1-C6)alkylamino-carbonyl, di((C1-C6)alkyl)amino-carbonyl, (C1-C6)alkyl-C(O)—NH—, (C3-C7)cycloalkyl and heterocycloalkyl;
(C3-C7)cycloalkyl and heterocycloalkyl being optionally substituted by at least one member selected from the group consisting of halo, nitro, (C1-C6)alkoxy optionally substituted by at least one halo, (C1-C6)alkyl optionally substituted by at least one halo, (C1-C6)alkyl-carbonyl, (C1-C6)alkoxy-carbonyl, amino-carbonyl, (C1-C6)alkylamino-carbonyl, di((C1-C6)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, (C1-C6)alkoxy-carbonyl-(C1-C6)alkenyl, (C1-C6)alkylamino-carbonyl-(C1-C6)alkenyl, —SO2—NR31R32, heterocycloalkyl, heteroaryl and —(CH2)p′—V3Y3;
R31 and R32 form together with the nitrogen to which they are attached, a heterocycloalkyl;
V3 is selected from the group consisting of —O—, —S—, —C(O)—, —C(O)—O—, —O—C(O)—, —SO2—, —SO2NH—, —NR′3—SO2—, —NR′3—, —NR′3—C(O), —C(O)—NR′3,
—NH—C(O)—NR′3— and a covalent bond;
Y3 is selected from the group consisting of hydrogen; (C1-C6)alkyl optionally substituted by at least one halo; aryl optionally substituted by at least one member selected from the group consisting of halo, nitro, (C1-C6)alkyl (C1-C6)alkoxy; aryl-(C1-C6)alkyl optionally substituted by at least one member selected from the group consisting of halo, nitro, (C1-C6)alkyl and (C1-C6)alkoxy;
Z3e is

OG Complex Work Unit Drawing
Z′3 is aryl optionally substituted by at least one member selected from the group consisting of halo, nitro and —(CH2)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 (C1-C6)alkyl optionally substituted by at least one halo;
R′3 is selected from the group consisting of hydrogen, (C1-C6)alkyl and (C1-C6)alkoxy;
p is an integer from 1 to 4; p′ and p″, are independently, an integer from 0 to 4;
R4 is —(CH2)s—R′4,
R′4 is selected from the group consisting of guanidine; heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C1-C6)alkyl or aralkyl; heteroaryl containing at least one nitrogen and optionally substituted by (C1-C6)alkyl; and —NW4W′4;
W4 is hydrogen or (C1-C8)alkyl;
W′4 is —(CH2)s′-Z4;
Z4 is selected from the group consisting of hydrogen, (C1-C8)alkyl optionally substituted by at least one member selected from the group consisting of (C1-C6)alkoxy, (C1-C6)alkylthio, hydroxy; (C2-C6)alkenyl; (C3-C7)cycloalkyl optionally substituted by at least one (C1-C6)alkyl; cyclohexene; heteroaryl and aryl;
the aryl and heteroaryl being optionally substituted by at least one member selected from the group consisting of —(CH2)s″—V4—Y4, hydroxy, halo, nitro and cyano;
V4 is selected from the group consisting of —O—, —S—, —NH—C(O)—, —NV4′— and a covalent bond;
Y4 is hydrogen or (C1-C6)alkyl optionally substituted by at least;
V4′ is hydrogen or (C1-C6)alkyl;
s″ is an integer from 0 to 4;
or Z4 is

OG Complex Work Unit Drawing
s and s′ are independently, an integer from 0 to 6;
and i) when R3 is —C(O)-Z′3 and R4 is —(CH2)s—NW4W′4 and W4 and W′4 are independently, hydrogen or (C1-C6)alkyl, then —(CH2)s is neither ethylene nor —(CH2)—CH((C1-C4)alkyl)- and ii) when R3 is -Z3c and Z3c is phenyl or naphthyl, then phenyl and naphthyl are not substituted by cyano; and it being understood that when R3 is -Z3d then Z3d only is (C3-C7) cycloalkyl or heterocycloalkyl;
or a pharmaceutically acceptable salt thereof.