IP Library › Granted Patent US 8,889,678

Granted Patent B2

US 8,889,678 · App. 13/386,782 · Granted Nov 18, 2014

Acyl guanidine derivatives modulating the hedgehog protein signaling pathway

Inventors: Martial Ruat (Orsay, FR); Hélène Faure (Gif-sur-Yvette, FR); Elisabeth Traiffort (Paris, FR); Hermine Roudaut (Marly-la-Ville, FR); André Mann (Ostwald, FR); Angèle Schoenfelder (Lampertheim, FR); Maurizio Taddei (Monteriggioni, IT); Fabrizio Manetti (Castelnuovo Berardenga, IT); Antonio Solinas (Siena, IT)

Assignees: Centre National de la Recherche Scientifique; Universite de Strasbourg

C07C279/22 C07D209/08 A61K31/155 C07D317/68 C07D213/56 C07D513/04 C07D307/68 C07D209/14 C07D295/155 C07D213/81 C07C2101/14

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Quick Facts

Patent No.: US 8,889,678
App. No.: 13/386,782
Granted: Nov 18, 2014
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention relates to acyl guanidine derivatives modulating the hedgehog protein signaling pathway to be used as drugs, in particular for treating diseases involving a tissue dysfunction associated with a deregulation of the hedgehog protein signaling pathway, as well as to pharmaceutical compositions containing same. The present invention also relates to novel acyl guanidine derivatives as such.

Claims (218)

1. Compounds corresponding to formula (I) below:

in which:

R 1 , R 2 and R 3 , which may be identical or different, and independently of one another, are selected from the group consisting of:

a hydrogen or halogen atom,

a hydroxyl radical,

an alkyl group,

a perfluoroalkyl group,

an optionally substituted alkoxy group,

an alkylthio group,

a nitrile group, and

a heterocycle obtained from two of R 1 , R 2 and R 3 which are fused with two adjacent carbon atoms of the phenyl ring to which they are bonded;

Y is selected in the group consisting of:

a monocyclic or polycyclic heteroaryl group chosen from indole or imidazole fused to a thiazole group,

—NH—(C═O)—R 6 ,

—(C═O)—NH—R 6 and

—NH—(C═O)—NH—R 6 ,

in which R 6 is selected from the group consisting of:

an unsubstituted monocyclic or polycyclic aryl group;

an aryl group comprising one or more substituents selected from the group consisting of a halogen atom, an alkyl radical, an alkoxy radical, an alkoxyaryl radical, monoalkylamino or dialkylamino radical, an aryl group, an heteroaryl group and a heterocycle;

monocyclic or polycyclic heteroaryl group;

a linear or branched alkyl radical; and

a saturated or unsaturated, monocyclic or polycyclic hydrocarbon-based group;

R 4 and R 5 , which may be identical or different, and independently of one another, are selected from the group consisting of a hydrogen atom, a halogen atom, an alkoxy group, an alkylthio group, an alkyl group, a perfluoroalkyl group, a nitrile group and a nitro group,

as medicaments.

2. The compounds of formula (I) as claimed in claim 1 , wherein the compounds are chosen from those in which:

R 1 , R 2 and R 3 , which may be identical or different, represent a hydrogen atom, a methyloxy or ethyloxy radical, or a dioxolane fused with two adjacent carbon atoms of the phenyl ring to which they are bonded;

R 4 and R 5 , which may be identical or different, represent a hydrogen, chlorine, bromine or fluorine atom, or a methyl or methoxy radical; and

Y represents a monocyclic or polycyclic heteroaryl group, —NH—(C═O)—R 6 , —(C═O)—NH—R 6 or —NH—(C═O)—NH—R 6 in which R 6 represents:

a phenyl group, optionally substituted with a halogen atom, an alkyl, diaminoalkyl or alkoxy radical, a cycloalkyl group, or an aryl group;

a cycloalkyl group;

a pyridinyl group;

a naphthyl group;

a furyl group;

a thiophenyl group; or

an isopropyl radical.

3. The compounds of formula (I) as claimed in claim 2 , wherein said group Y is chosen from indole or imidazole fused to a thiazole group, when said group Y represents a monocyclic or polycyclic heteroaryl group.

4. The compounds of formula (I) as claimed in claim 2 , wherein R 6 represents:

a phenyl group, optionally substituted with a chlorine atom, a methoxy radical, a morpholine, or a phenyl or phenoxy group;

a cyclohexyl group;

a pyridinyl group;

a naphthyl group; or

a furyl group,

when said group Y represents an —NH—(C═O)—R 6 , —(C═O)—NH—R 6 or —NH—(C═O)—NH—R 6 group.

5. The compounds of formula (I) as claimed in claim 1 , wherein the compounds are selected from the group consisting of:

3,4,5-trimethoxy-N—(N-(3-(4-methoxybenzamido)phenyl)carbamimidoyl)benzamide:

N—(N-(3-(2-chlorobenzamido)phenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide:

3,4,5-trimethoxy-N—(N-(3-(3-methoxybenzamido)phenyl)carbamimidoyl)benzamide:

N-(3-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)biphenyl-4-carboxamide:

N—(N-(3-(cyclohexanecarboxamido)phenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide:

N-(3-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)-2-naphthamide:

N-(3-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)isonicotinamide:

N-(3-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)furan-2-carboxamide:

N—(N-(3-benzamidophenyl)carbamimidoyl)-3,5-dimethoxybenzamide:

N—(N-(3-benzamidophenyl)carbamimidoyl)-4-ethoxy-3,5-dimethoxybenzamide:

N—(N-(3-benzamidophenyl)carbamimidoyl)-3,4-diethoxy-5-methoxybenzamide:

N—(N-(3-benzamidophenyl)carbamimidoyl)-7-methoxybenzo[d][1,3]dioxole-5-carboxamide:

N—(N-(3-benzamidophenyl)carbamimidoyl)-2,4-dimethoxybenzamide:

N—(N-(3-benzamido-4-fluorophenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide:

N—(N-(3-benzamidophenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide:

N—(N-(3-benzamido-4-chlorophenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide:

N-(2-chloro-5-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)biphenyl-4-carboxamide:

3,4,5-trimethoxy-N—(N-(3-(4-morpholinobenzamido)phenyl)carbamimidoyl)benzamide:

N—(N-(3-(1H-indol-2-yl)phenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide:

N—(N-(4-chloro-3-(4-methoxyphenylcarbamoyl)phenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide:

N—(N-(4-chloro-3-(phenylcarbamoyl)phenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide:

3,4,5-trimethoxy-N—(N-(4-methyl-3-(phenylcarbamoyl)phenyl)carbamimidoyl)benzamide:

4′-fluoro-N-(3-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)biphenyl-4-carboxamide:

N-(2-methyl-5-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)biphenyl-4-carboxamide:

N-(2-methyl-5-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)biphenyl-3-carboxamide:

N-(2-chloro-5-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)biphenyl-3-carboxamide:

N—N-(3-benzamido-4-methylphenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide:

N—N-(3-(imidazo[2,1-b]thiazol-6-yl)phenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide:

N—(N-(3-(1H-indol-1-yl)phenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide:

4′-fluoro-N-(2-methyl-5-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)biphenyl-4-carboxamide:

3,4,5-trimethoxy-N—(N-(4-methyl-3-(4-(pyridin-4-yl)benzamido)phenyl)carbamimidoyl)-benzamide:

N—(N-(4-chloro-3-(4-phenoxybenzamido)phenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide:

N-(3-(3-benzoylguanidino)phenyl)biphenyl-4-carboxamide:

N-(2-methyl-3-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)biphenyl-4-carboxamide:

N-(4-methyl-3-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)biphenyl-4-carboxamide:

N—(N-(3-benzamidophenyl)carbamimidoyl)benzamide:

N—(N-(3-(3-biphenyl-4-ylureido)phenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide:

N—(N-(4-chloro-3-(3-phenylureido)phenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide:

6. The compounds as claimed in claim 5 , wherein the compounds are chosen from:

3,4,5-trimethoxy-N—(N-(3-(4-methoxybenzamido)phenyl)carbamimidoyl)benzamide (Compound 1);

N—(N-(3-(2-chlorobenzamido)phenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide (Compound 2);

3,4,5-trimethoxy-N—(N-(3-(3-methoxybenzamido)phenyl)carbamimidoyl)benzamide (Compound 3);

N-(3-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)-2-naphthamide (Compound 6);

N-(3-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)furan-2-carboxamide (Compound 8);

N—(N-(3-benzamidophenyl)carbamimidoyl)-3,5-dimethoxybenzamide (Compound 9);

N—(N-(3-benzamidophenyl)carbamimidoyl)-7-methoxybenzo[d][1,3]dioxole-5-carboxamide (Compound 12);

N—(N-(3-benzamidophenyl)carbamimidoyl)-2,4-dimethoxybenzamide (Compound 13);

N—(N-(3-benzamidophenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide (Compound 15);

N-(2-chloro-5-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)biphenyl-4-carboxamide (Compound 17);

N—(N-(3-(1H-indol-2-yl)phenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide (Compound 19);

N—(N-(4-chloro-3-(phenylcarbamoyl)phenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide (Compound 21);

4′-fluoro-N-(3-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)biphenyl-4-carboxamide (Compound 23);

N-(2-methyl-5-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)biphenyl-4-carboxamide (Compound 24);

N—(N-(3-(1H-indol-1-yl)phenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide (Compound 29);

4′-fluoro-N-(2-methyl-5-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)biphenyl-4-carboxamide (Compound 30);

N—(N-(4-chloro-3-(4-phenoxybenzamido)phenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide (Compound 32);

N—(N-(4-chloro-3-(3-phenylureido)phenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide (Compound 38).

7. The compounds of formula (I) as claimed in claim 1 wherein the compounds are in the form of salts.

8. The compounds of formula (I) as claimed in claim 7 , wherein said salts are formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, alkanesulfonic acids, such as methanesulfonic acid and ethanesulfonic acid, arylsulfonic acids, such as benzenesulfonic acid and para-toluenesulfonic acid or arylcarboxylic acids.

9. The compounds of formula (I) as claimed in claim 8 , wherein said salts are formed with hydrochloric acid.

10. The compounds of formula (I) as claimed in claim 1 , for use as a medicament intended for the treatment of tumors associated with hyperactivation of the Hedgehog protein signaling pathway.

11. The compounds of formula (I) as claimed in claim 10 , for use as a medicament for the treatment of tumors selected from the group consisting of nervous tissue tumors, skin tumors, muscle tumors, bone tissue tumors, kidney tumors, bladder tumors, prostate tumors, lung tumors, stomach tumors, pancreas tumors, breast tumors, and liver tumors.

12. The compounds of formula (I) as claimed in claim 1 , for use as a medicament intended for the treatment of neurodegenerative pathological conditions.

13. The compounds of formula (I) as claimed in claim 12 , for use as a medicament for the treatment of Parkinson's disease, Huntington's chorea, Alzheimer's disease, multiplesclerosis and motoneuron disease.

14. The compounds of formula (I) as claimed in claim 1 , for use as a medicament intended for the treatment of diseases linked to brain development, for the treatment of strokes and cardiovascular events, and also for diseases of oligodentrocytes and Schwann cells.

15. The compounds of formula (I) as claimed in claim 14 , for use in vitro for controlling and modulating the renewal of human or animal stem cells.

16. The compounds of formula (I) as claimed in claim 1 , for use as a medicament intended for the treatment of diabetes.

17. The compounds of formula (I) as claimed in claim 1 , as markers for detecting the presence of proteins, such as the Smoothened, Patched (Patched 1 and Patched 2), Dispatched (Dispatched 1 and Dispatched 2) and HIP proteins, in tissues or cell lines.

18. The compounds of formula (I) as claimed in claim 1 , as diagnostic tools for screening for proteins, such as the Smoothened, Patched (Patched 1 and Patched 2), Dispatched (Dispatched 1 and Dispatched 2) and HIP proteins, in tissues or cell lines.

19. A pharmaceutical composition comprising as active ingredient, at least one compound of formula (I) as defined according to claim 1 , and at least one pharmaceutically acceptable excipient.

20. Compounds corresponding to formula (I) below:

in which:

R 1 , R 2 and R 3 , which may be identical or different, and independently of one another, are selected from the group consisting of:

a hydrogen or halogen atom,

a hydroxyl radical,

an alkyl group,

a perfluoroalkyl group,

an optionally substituted alkoxy group,

an alkylthio group,

a nitrile group, and

a heterocycle obtained from two of R 1 , R 2 and R 3 which are fused with two adjacent carbon atoms of the phenyl ring to which they are bonded;

Y is selected from the group consisting of:

a monocyclic or polycyclic heteroaryl group chosen from indole or imidazole fused to a thiazole group,

—NH—(C═O)—R 6 ,

—(C═O)—NH—R 6 and

—NH—(C═O)—NH—R 6

in which R 6 represents is selected from the group consisting of:

an unsubstituted monocyclic or polycyclic aryl group;

an aryl group comprising one or more substituents selected from the group consisting of a halogen atom, an alkyl radical, an alkoxy radical, an alkoxyaryl radical, a monoalkylamino or dialkylamino radical, an aryl group, an heteroaryl group, and a heterocycle;

a monocyclic or polycyclic heteroaryl group;

a linear or branched alkyl radical; and

a saturated or unsaturated, monocyclic or polycyclic hydrocarbon-based group;

R 4 and R 5 , which may be identical or different, and independently of one another, are selected from the group consisting of a hydrogen atom, a halogen atom, or an alkoxy group, an alkylthio group, an alkyl group, a perfluoroalkyl group, a nitrile, and a nitro group.

21. The compounds of formula (I) as claimed in claim 20 , wherein the compounds are chosen from those in which:

R 4 and R 5 , which may be identical or different, represent a hydrogen, chlorine, bromine or fluorine atom, or a methyl or methoxy radical; and

Y represents:

a monocyclic or polycyclic heteroaryl group selected from the group consisting of an indole, an imidazole fused to a thiazole group; or

an —NH—(C═O)—R 6 , or —(C═O)—NH—R 6 or —NH—(C═O)—NH—R 6 group in which R 6 represents:

a phenyl group optionally substituted with a halogen atom, an alkyl, diaminoalkyl or alkoxy radical, a cycloalkyl group, or an aryl group;

a cycloalkyl group;

a pyridinyl group;

a naphthyl group;

a furyl group;

a thiophenyl group; or

an isopropyl radical.

22. The compounds of formula (I) as claimed in claim 21 , wherein R 6 represents:

a phenyl group optionally substituted with a chlorine atom, a methoxy radical, a morpholine, or a phenyl or phenoxy group;

a cyclohexyl group;

a pyridinyl group;

a naphthyl group; or

a furyl group,

when said group Y represents an —NH—(C═O)—R 6 , —(C═O)—NH—R 6 or —NH—(C═O)—NH—R 6 group.

23. The compounds of formula (I) as claimed in claim 20 , wherein the compounds are selected from the group consisting of: