Human papilloma virus inhibitors and pharmaceutical compositions containing same

1. A compound of formula (I):

as well as its stereoisomers and its pharmaceutically acceptable salts,

wherein:

G 1 represents a group

wherein n is an integer comprised between 1 and 4,

R1 and R2 either identical or different, each represent independently of each other a group selected from a hydrogen atom, a halogen atom, a hydroxyl, thio, alkoxy, haloalkoxy, alkylthio, haloalkylthio, amino, monoalkylamino, dialkylamino, cycloakyl, alkyl or haloalkyl group,

R3 represents:

a group

wherein:

W represents an oxygen, sulfur atom or NH,

m is an integer comprised between 0 and 5 and

R4 and R5 represent independently of each other a hydrogen atom, a linear or branched alkyl group or an alkoxy group,

or one of the following groups:

wherein:

R6 represents a hydrogen atom or a linear or branched alkyl group,

R7 represents a hydrogen atom, a linear of branched alkyl group, acyl, —COCH 2 OH, —CH 2 COOH or —(CH 2 ) 2 NH 2 ,

m is an integer comprised between 0 and 5,

the groups indicated above have the following meaning:

represents a monocyclic cycloalkyl with 3, 4, 5 or 6 apices;

represents a monocyclic heterocycle with 3, 4, 5 or 6 apices including a nitrogen atom;

represents a monocyclic heterocycle with 3, 4, 5 or 6 apices including two nitrogen atoms;

A represents an aryl group, optionally substituted:

in the meta or para position with:

a halogen atom or an alkyl, haloalkyl, cyano, acyl, alkoxy, haloalkoxy, acylaminoalkyl group or a group —XR wherein X represents —O—, —NH—, —N(Alk)-, —N(COCH 3 )—, —S—, —SO—, —SO 2 —, —CO— or —CONH— and R represents an arylalkyl, cycloalkyl or aryl group, each optionally substituted with one or two substituents, either identical or different, or

a cycloalkyl, aryl, arylalkyl, or heterocycle group, each being optionally substituted with one or two substituents, either identical or different,

and/or in the ortho or meta position with an alkyl group, and

B represents an aryl group:

substituted in the ortho position with a N-cycloalkyl group, or with a cyclohexyl, each optionally substituted with one or more substituents, either identical or different, selected from an alkyl, haloalkyl, alkoxy, haloalkoxy, oxo, —X′-aryl group wherein X′ represents —O—, —NH—, —N(Alk)-, —N(COCH 3 )—, —S—, —SO—, —SO 2 —, —CO— or —CONH—, and/or

optionally substituted with a halogen atom or with an alkyl or haloalkyl group.

2. The compound according to claim 1 , wherein:

R1 represents an alkoxy group,

R2 represents a hydrogen or halogen atom, or an alkyl group, and

R3, A and B are as defined in claim 1 .

3. The compound according to claim 1 , wherein:

R3 represents:

a group:

wherein:

W represents an oxygen atom or NH,

m is an integer comprised between 0 and 2, and

R4 and R5 represent independently of each other a hydrogen atom, a linear or branched alkyl group, or an alkoxy group,

or the group:

wherein R7 is as defined as in claim 1 , and m is an integer between 0 and 2,

and R1, R2, A and B are as defined in claim 1 .

4. The compound according to claim 1 , wherein:

A represents an aryl group, optionally substituted:

in the meta or para position with:

a halogen atom or a cyano, acyl, alkoxy, haloalkoxy, acylaminoalkyl or —XR group wherein X represents —O—, —S—, —SO—, —SO 2 — or —CO— and R represents an arylalkyl, cycloalkyl or aryl group, each optionally substituted with one or two substituents, either identical or different, a halogen atom, an alkoxy or acyl group or

a cycloalkyl, aryl or arylalkyl group, each optionally substituted with one or two substituents, either identical or different, and/or

in the ortho or meta position with an alkyl group, and

B represents an aryl group,

substituted in the ortho position with a heterocycle, and/or

substituted in the ortho' position with an alkyl group,

and R1, R2 and R3 are as defined in claim 1 .

5. The compound according to claim 1 , wherein:

R1 represents an alkoxy group,

R2 represents a halogen atom,

R3 represents:

a group:

wherein:

W represents an oxygen atom or NH,

m is an integer comprised between 0 and 2, and

R4 and R5 represent independently of each other a hydrogen atom, a linear or branched alkyl group, or an alkoxy group,

or the group:

wherein R7 is as defined in claim 1 and m is an integer comprised between 0 and 2,

A represents an aryl group, optionally substituted in the para position with an alkoxy or acyl group, and

B represents an aryl group,

substituted in the ortho position with a heterocycle, and/or

substituted in the ortho position with an alkyl group.

6. The compound according to claim 1 , selected from the following group:

1) 5-Bromo-2-methoxy-4-[N′-(4-methoxy-phenyl)-N′-(2-methyl-6-piperidin-1-yl -phenyl)-hydrazinocarbonylmethyl]-benzamide;

2) 5-Bromo-2-methoxy-4-[N′-(4-methoxy-phenyl)-N′-(2-methyl-6-piperidin-1-yl -phenyl)-hydrazinocarbonylmethyl]-N,N-dimethyl-benzamide;

3) [2-Bromo-5-methoxy-4-(4-methyl-piperazine-1-carbonyl)-phenyl]-acetic acid N′-(4-methoxy-phenyl)-N′-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazide;

4) 4-[N′-(4-Acetyl-phenyl)-N′-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazino -carbonylmethyl]-5-bromo-2-methoxy-benzamide;

5) (4-Acetyl-2-bromo-5-methoxy-phenyl)-acetic acid N′-(4-methoxy-phenyl)-N′-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazide;

6) 5-Bromo-2-N-dimethoxy-4-[N′-(4-methoxy-phenyl)-N′-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-N-methyl-benzamide; and

7) 5-Bromo-N-tert-butyl-2-methoxy-4-[N′-(4-methoxy-phenyl)-N′-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl]-benzamide.

7. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient.

8. A method of treating an infection by the papilloma virus or of inhibiting the replication of the papilloma virus comprising the administration to a person in need thereof of a compound of formula (I) according to claim 1 or of a pharmaceutically acceptable salt thereof.

9. A method for treating a pathology related to the papilloma virus comprising the administration to a person in need thereof of a compound of formula (I) according to claim 1 or of a pharmaceutically acceptable salt thereof.

10. The method according to claim 8 , wherein said pathology is selected from ano-genital verrucas, laryngeal, conjunctival or buccal papillomas and other epithelial lesions.

11. The method according to claim 10 , wherein the ano-genital verrucas are selected from acuminated condylomas and planar condylomas and the epithelial lesions are selected from recurrent respiratory papillomatoses and low grade and high grade intra-epithelial neoplasias, bowenoid papuloses, verrucas, verruciform epidermaldysplasias, carcinomas, and all the lesions which are associated with the papilloma virus.

12. The method according to claim 11 , wherein the verrucas are selected from vulgar, plantar, myrmecias, superficial and flat verrucas and the carcinomas are ano-genital carcinomas.

13. The compound according to claim 1 , wherein n has the value 1.

14. The compound according to claim 1 , wherein A represents an aryl group, optionally substituted:

in the meta or para position with:

a halogen atom or an alkyl, haloalkyl, cyano, acyl, alkoxy, haloalkoxy, acylaminoalkyl group or a group —XR wherein X represents —O—, —NH—, —N(Alk)-, —N(COCH 3 )—, —S—, —SO—, —SO 2 —, —CO— or —CONH— and R represents an arylalkyl, cycloalkyl or aryl group, each optionally substituted with one or two substituents, either identical or different, selected from a halogen atom, an alkoxy, alkyl, haloalkyl, cyano, acyl, amino, monoalkylamino or dialkylamino group, or

a cycloalkyl, aryl, arylalkyl, or heterocycle group, each being optionally substituted with one or two substituents, either identical or different, selected from a halogen atom, an alkoxy, alkyl, haloalkyl, cyano, acyl, amino, monoalkylamino, or dialkylamino, acid, ester, amide, mono- or di-alkylamide group, or a group —SOnR′, —OCOR′, —NR′COR″, or —NR′ SO 2 R″, wherein R′ and R″ each represent independently of each other a hydrogen atom, an alkyl or haloalkyl group, and n has the value 1 or 2,

and/or in the ortho or meta position with an alkyl group.

15. The compound according to claim 2 , wherein R1 is in the ortho position relative to R3.

16. The compound according to claim 2 , wherein R2 is in the meta position relative to R3.

17. The compound according to claim 4 , wherein A represents an aryl group, optionally substituted:

in the meta or para position with:

a halogen atom or a cyano, acyl, alkoxy, haloalkoxy, acylaminoalkyl or —XR group wherein X represents —O—, —S—, —SO—, —SO 2 — or —CO— and R represents an arylalkyl, cycloalkyl or aryl group, each optionally substituted with one or two substituents, either identical or different, selected from a halogen atom, an alkoxy or acyl group, or

a cycloalkyl, aryl or arylalkyl group, each optionally substituted with one or two substituents, either identical or different, selected from an acyl or alkoxy group, and/or

in the ortho or meta position with an alkyl group.