Acyl guanidine derivatives modulating the hedgehog protein signaling pathway

• US 8,889,678 B2
• Filed: 07/19/2010
• Issued: 11/18/2014
• Est. Priority Date: 07/24/2009
• Status: Expired due to Fees

• Current Assignee: Centre National De La Recherche Scientifique, Universite De Strasbourg (Financière Meeschaert SA)
• Original Assignee: Centre National De La Recherche Scientifique, Universite De Strasbourg (Financière Meeschaert SA)
• Inventors: Ruat, Martial, Faure, Hlne, Traiffort, Elisabeth, Roudaut, Hermine, Mann, Andr, Schoenfelder, Angle, Taddei, Maurizio, Manetti, Fabrizio, Solinas, Antonio
• Primary Examiner(s): SHTERENGARTS, SAMANTHA L
• Application Number:
  US13/386,782
• Publication Number:
  US 20120196865A1
• Time in Patent Office: 1,583 Days
• Field of Search: 514/239.5, 514/354, 514/368, 514/415, 514/466, 514/471, 514/616, 544/165, 546/323, 548/155, 548/511, 549/436, 549/487, 564/157
• US Class Current: 514/239.5
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 279/22 Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 209/14 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 213/81 Amides; Imides
• CPC Class Codes: C07D 295/155 with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 307/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 317/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

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

1. Compounds corresponding to formula (I) below:

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

R₁, R₂ and R₃, 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;

R₄ and R₅, 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)—

R₆, —

(C═

O)—

NH—

R₆ or —

NH—

(C═

O)—

NH—

R₆ in which R₆ 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 R₆ 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)—

R₆, —

(C═

O)—

NH—

R₆ or —

NH—

(C═

O)—

NH—

R₆ 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;

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:

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

R₁, R₂ and R₃, 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;

R₄ and R₅, 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)—

R₆, or —

(C═

O)—

NH—

R₆ or —

NH—

(C═

O)—

NH—

R₆ group in which R₆ 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 R₆ 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)—

R₆, —

(C═

O)—

NH—

R₆ or —

NH—

(C═

O)—

NH—

R₆ group.

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

3,4,5-trimethoxy-N—

(N-(3-(4-methoxybenzamido)phenyl)carbamimidoyl)benzamide;

24. The compounds as claimed in claim 23, 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).

25. The compounds of formula (I) as claimed in claim 20, wherein the compounds are in the form of salts.

26. The compounds of formula (I) as claimed in claim 25, 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, arylsulfonic acids, or arylcarboxylic acids.

27. The compounds of formula (I) as claimed in claim 26, wherein said salts are formed with hydrochloric acid.