N-acylthiourea and N-acylurea inhibitors of the Hedgehog protein signalling pathway

• US 9,073,835 B2
• Filed: 04/16/2009
• Issued: 07/07/2015
• Est. Priority Date: 04/24/2008
• 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, Schoenfelder, Angle, Mann, Andr, Taddei, Maurizio, Solinas, Antonio, Manetti, Fabrizio
• Primary Examiner(s): JEAN-LOUIS, SAMIRA JM
• Application Number:
  US12/988,975
• Publication Number:
  US 20110275663A1
• Time in Patent Office: 2,273 Days
• US Class Current: 1/1
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 275/54 Y being a carbon atom of a six-membered aromatic ring, e.g. benzoylureas
• CPC Class Codes: C07C 335/08 of a saturated carbon skeleton
• CPC Class Codes: C07C 335/26 Y being a hydrogen or a carbon atom, e.g. benzoylthioureas
• 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 213/81 Amides; Imides
• CPC Class Codes: C07D 235/14 Radicals substituted by nitrogen atoms by nitro radicals C07D235/10
• CPC Class Codes: C07D 235/18 with aryl radicals directly attached in position 2
• 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 319/18 Ethylenedioxybenzenes, not substituted on the hetero ring
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

The present invention relates to the use of acylthiourea or acylurea derivatives for the treatment of pathologies involving a tissue dysfunction associated with a deregulation of the Hedgehog protein signalling pathway, and also to novel acylthiourea or acylurea derivatives as such, to their use as a medicinal product, and to pharmaceutical compositions containing them.

Claims

1. A method for manufacturing a drug, said method comprising mixing at least one pharmaceutically acceptable excipient and at least one compound with the following formula (I):

3. The method as claimed in claim 1, characterized in that the compound is selected from those in which, in the formula (I):

R₁, R₂, and R₃, which are identical or different, represent a hydrogen atom or a methyloxy or ethyloxy radical,

X represents a sulfur or oxygen atom;

Y represents a or a —

NH—

(C═

O)—

R₆, or —

(C═

O)—

NH—

R₆ group, wherein R₆ represents a group selected from phenyl groups;

phenyl substituted with a radical methoxy or dimethylamino, with a chlorine atom, with a phenyl group, with a benzyl, cyclohexyl, isopropyl, pyridinyl, naphthyl, furfuryl or thiophene group; and

R₄ and R₅, which are identical or different, are selected from hydrogen, chlorine, bromine, fluorine, methyl and methoxy.

4. The method as claimed in claim 1, characterized in that the compound with formula (I) is selected from the group consisting of:

N-[[[3-(4-methoxy-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (I-a) with the following formula;

6. The method as claimed in claim 1, characterized in that the drug is for treating tumors characterized by a hyperactivation of Hedgehog protein signaling pathway.

7. The method as claimed in claim 1, characterized in that the drug is for treating neuro-degenerative type pathology characterized by a hyperactivation of Hedgehog protein signaling pathway.

2. A method for manufacturing a drug, said method comprising mixing at least one pharmaceutically acceptable excipient and at least one compound with the following formula (I):

5. The method as claimed in claim 2, characterized in that the compounds with formula (I) are selected from the group consisting of:

N-[[[3-(4-methoxy-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     1);

N-[[[3-(2-chloro-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     2);

N-[[[3-(3-methoxy-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     3);

N-[[[3-(2-methoxy-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     4);

N-[[[3-(4-methoxy-benzoylamino)phenyl]amino]oxomethyl]-3,4,5-methoxy-benzamide (compound

     6);

N-[[[3-(4-pyridocarboxylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     11);

N-[[[3-(4-chloro-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     13);

N-[[[3-(isopropoylcarboxylamino))phenyl]amino]oxomethyl]-3,4,5-methoxy-benzamide (compound

     17);

N-[[[3-(benzoylamino)phenyl]amino]thioxomethyl]-3,5-methoxy-benzamide (compound

     18);

N-[[[3-(benzoylamino)phenyl]amino]thioxomethyl]-3,5-methoxy-4-ethoxy-benzamide (compound

     19);

N-[[[3-(benzoylamino)phenyl]amino]thioxomethyl]-3,4-ethoxy-5-methoxy-benzamide (compound

     20);

N-[[[3-(benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-ethoxy-benzamide (compound

     23);

N-[[[4-fluoro-3-(benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     24);

N-[[[4-chloro-3-(phenylamino)carbonyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     25);

N-[[[3-(benzoylamino)phenyl]amino]oxomethyl]-3,4,5-methoxy-benzamide (compound

     31);

N-[[[4-chloro-3-(benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     34);

N-[[[3-(benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     38);

N-[[[4-chloro-3-(4-dimethylamino-phenylamino)carbonyl]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     39);

N-[[[4-chloro-3-(4-chloro-phenylamino)]carbonyl]phenylamino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     43);

N-[[[2-methyl-3-(benzoylamino)phenyl]amino]oxomethyl]-3,4,5-methoxy-benzamide (compound

     45);

N-[[[-3-(4-chloro-benzoylamino)phenyl]amino]oxomethyl]-3,4,5-methoxy-benzamide (compound

     47).

8. Compounds with the following formula (I′

);

9. The compounds as claimed in claim 8, characterized in that they are selected from the group consisting of:

N-[[[3-(4-methoxy-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (I-a) with the following formula;

10. The compounds as claimed in claim 8, characterized in that they are selected from the group consisting of:

N-[[[3-(4-methoxy-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     1);

N-[[[3-(2-chloro-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     2);

N-[[[3-(3-methoxy-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     3);

N-[[[3-(2-methoxy-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     4);

N-[[[3-(4-pyridocarboxylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     11);

N-[[[3-(4-chloro-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     13);

N-[[[3-(benzoylamino)phenyl]amino]thioxomethyl]-3,5-methoxy-benzamide (compound

     18);

N-[[[3-(benzoylamino)phenyl]amino]thioxomethyl]-3,5-methoxy-4-ethoxy-benzamide (compound

     19);

N-[[[3-(benzoylamino)phenyl]amino]thioxomethyl]-3,4-ethoxy-5-methoxy-benzamide (compound

     20);

N-[[[3-(benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-ethoxy-benzamide (compound

     23);

N-[[[4-fluoro-3-(benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     24);

N-[[[4-chloro-3-(benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     34);

N-[R3-(benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     38).

11. A pharmaceutical composition, characterized in that it comprises, as active principle, at least one compound as defined in claim 8, and at least one pharmaceutically acceptable excipient.

12. A method for treating tumors characterized by a hyperactivation of Hedgehog protein signaling pathway or neuro-degenerative type pathologies characterized by a hyperactivation of Hedgehog protein signaling pathway, comprising a step of administering at least one compound of formula (I):

14. The method of claim 12, wherein the compounds are selected from those in which, in the formula (I):

R₁, R₂, and R₃, which are identical or different, represent a hydrogen atom or a methyloxy or ethyloxy radical,

X represents a sulfur or oxygen atom;

Y represents or a —

NH—

(C═

O)—

R₆ or —

(C═

O)—

NH—

R₆ group wherein R₆ represents a group selected from phenyl groups;

phenyl substituted with a radical methoxy or dimethylamino, with a chlorine atom, with a phenyl group, with a benzyl, cyclohexyl, isopropyl, pyridinyl, naphthyl, furfuryl or thiophene group; and

R₄ and R₅, which are identical or different, are selected from hydrogen, chlorine, bromine, fluorine, methyl and methoxy.

15. The method of claim 12, wherein the compounds with formula (I) are selected from the group consisting of:

N-[[[3-(4-methoxy-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (I-a) with the following formula;

16. The method of claim 12, wherein the compounds with formula (I) are selected from the group consisting of:

N-[[[3-(4-methoxy-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     1);

N-[[[3-(2-chloro-benzoyl amino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     2);

N-[[[3-(3-methoxy-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     3);

N-[[[3-(2-methoxy-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     4);

N-[[[3-(4-methoxy-benzoylamino)phenyl]amino]oxomethyl]-3,4,5-methoxy-benzamide (compound

     6);

N-[[[3-(4-pyridocarboxylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     11);

N-[[[3-(4-chloro-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     13);

N-[[[3-(isopropoylcarboxylamino))phenyl]amino]oxomethyl]-3,4,5-methoxy-benzamide (compound

     17);

N-[[[3-(benzoylamino)phenyl]amino]thioxomethyl]-3,5-methoxy-benzamide (compound

     18);

N-[[[3-(benzoylamino)phenyl]amino]thioxomethyl]-3,5-methoxy-4-ethoxy-benzamide (compound

     19);

N-[[[3-(benzoylamino)phenyl]amino]thioxomethyl]-3,4-ethoxy-5-methoxy-benzamide (compound

     20);

N-[[[3-(benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-ethoxy-benzamide (compound

     23);

N-[[[4-fluoro-3-(benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     24);

N-[[[4-chloro-3-(phenylamino)carbonyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     25);

N-[[[3-(benzoylamino)phenyl]amino]oxomethyl]-3,4,5-methoxy-benzamide (compound

     31);

N-[[[4-chloro-3-(benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     34);

N-[[[3-(benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     38);

N-[[[4-chloro-3-(4-dimethylamino-phenylamino)carbonyl]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     39);

N-[[[4-chloro-3-(4-chloro-phenylamino)]carbonyl]phenylamino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     43);

N-[[[2-methyl-3-(benzoylamino)phenyl]amino]oxomethyl]-3,4,5-methoxy-benzamide (compound

     45);

N-[[[-3-(4-chloro-benzoylamino)phenyl]amino]oxomethyl]-3,4,5-methoxy-benzamide (compound

     47).

17. The method of claim 12, wherein:

Y represents a —

NH—

(C═

O)—

R₆ group wherein R₆ represents a non-substituted aryl group;

an aryl group comprising one or more substituents selected from a halogen atom and an alkyl, alkoxy or mono- or dialkylamino radical;

a mono- or polycyclic heteroaryl group;

a linear or branched alkyl radical;

or a saturated or unsaturated mono- or polycyclic hydrocarbon group; and

when Y represents a —

NH—

(C═

O)—

R₆, X represents a sulfur atom.

18. The method of claim 12, wherein the compounds with formula (I) are selected from the group consisting of:

N-[[[3-(4-methoxy-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (I-a) with the following formula;

19. The method of claim 12, wherein the compounds with formula (I) are selected from the group consisting of:

N-[[[3-(4-methoxy-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     1);

N-[[[3-(2-chloro-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     2);

N-[[[3-(3-methoxy-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     3);

N-[[[3-(2-methoxy-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     4);

N-[[[3-(4-pyridocarboxylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     11);

N-[[[3-(4-chloro-benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     13);

N-[[[3-(benzoylamino)phenyl]amino]thioxomethyl]-3,5-methoxy-benzamide (compound

     18);

N-[[[3-(benzoylamino)phenyl]amino]thioxomethyl]-3,5-methoxy-4-ethoxy-benzamide (compound

     19);

N-[[[3-(benzoylamino)phenyl]amino]thioxomethyl]-3,4-ethoxy-5-methoxy-benzamide (compound

     20);

N-[[[3-(benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-ethoxy-benzamide (compound

     23);

-N-[[[4-fluoro-3-(benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     24);

N-[[[4-chloro-3-(benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     34);

N-[[[3-(benzoylamino)phenyl]amino]thioxomethyl]-3,4,5-methoxy-benzamide (compound

     38).

13. A method for treating tumors characterized by a hyperactivation of Hedgehog protein signaling pathway or neuro-degenerative type pathologies characterized by a hyperactivation of Hedgehog protein signaling pathway, comprising a step of administering at least one compound of formula (I):