Compounds modulating the hedgehog protein signaling pathway, marked forms thereof, and applications

• US 8,981,149 B2
• Filed: 09/21/2012
• Issued: 03/17/2015
• Est. Priority Date: 09/23/2011
• 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, Roudaut, Hermine, Hoch, Lucile, Schoenfelder, Angle, Taddei, Maurizio, Mann, Andr
• Primary Examiner(s): Kumar, Shailendra
• Application Number:
  US14/346,538
• Publication Number:
  US 20140228441A1
• Time in Patent Office: 907 Days
• Field of Search: 564/158, 564/176, 514/616, 514/622
• US Class Current: 564/158
• 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 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 279/22 Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
• CPC Class Codes: C07C 279/24 Y being a hetero atom
• CPC Class Codes: G01N 33/5011 for testing antineoplastic activity
• CPC Class Codes: G01N 33/5041 involving analysis of members of signalling pathways
• CPC Class Codes: G01N 33/57492 involving compounds localized on the membrane of tumor or cancer cells

Abstract

The invention relates to compounds of formula (I), and the use thereof as a drug, particularly for the treatment of tumors associated with hyperactivation of the hedgehog protein signaling pathway, treatment of neurodegenerative diseases, treatment of diseases related to cerebral development (holoprosencephaly), for stem cell monitoring treatment of cerebrovascular accidents and cardiovascular accidents, treatment of diseases involving oligodendrocytes and diseases involving neurolemmocytes, for application thereof in vitro for modulating human or animal stem cell renewal, and for the treatment of diabetes. The invention also relates to pharmaceutical compositions having a compound of formula (I). The invention also relates to a method for radio-marking compounds having formula (I), the marked compounds, and the use of the compounds as research tools, and method for screening and/or identifying ligands in the Smoothened receptor (Smo) binding sites, methods for identifying agonists and antagonists of the Smoothened receptor, and a method for identifying cells.

Claims

1. A compound, characterized in that it corresponds to the following formula (I):

2. The compound of formula (I) as claimed in claim 1, characterized in that R₁, R₂ and R₃ represent an alkoxy radical, and preferably a methoxy radical.

3. The compound of formula (I) as claimed in claim 1, characterized in that X is NH.

4. The compound of formula (I) as claimed in claim 1, characterized in that R₄ and R₇ represent a hydrogen or chlorine atom, a methyl, ethyl or isopropyl group.

5. The compound of formula (I) as claimed in claim 1, characterized in that R₆ represents a halogen atom or an alkoxy or aminoalkyl group.

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

N—

(N-(3-(4-benzoylbenzamido)-4-methylphenyl)carbamimidoyl)-3,4,5-trimethoxybenzamide hydrochloride of the following formula;

7. A medicinal product comprising the compound of formula (I) as claimed in claim 1.

8. A method for treating tumors associated with hyperactivation of the Hedgehog protein signalling pathway, the method comprising the step of administering the medicinal product as claimed in claim 7, wherein the tumors associated with hyperactivation of the Hedgehog protein signalling pathway are nerve tissue tumors (medulloblastomas, neuroectodermal primary tumors, glioblastomas, meningiomas and oligodendrogliomas), skin tumors (basal cell carcinomas, trichoepitheliomas), tumors of muscle and bone tissues (rhabdomyosarcomas, osteosarcomas) or tumors of other tissues (kidney, bladder, prostate, lung, stomach, pancreas).

9. A method for treating disorders of the neurodegenerative type comprising the step of administering the medicinal product as recited in claim 7, wherein the disorders of the neurodegenerative type are Parkinson'"'"'s disease, Huntington'"'"'s chorea, Alzheimer'"'"'s disease, multiple sclerosis or motor neuron disease.

10. A method for treating diseases connected with cerebral development (holoprosencephaly), for treating cerebrovascular accident and cardiovascular accidents, as well as for diseases of the oligodendrocytes and Schwann cells, the method comprising the step of administering the medicinal product as recited in claim 7.

11. A method for in vitro modulating the renewal of human or animal stem cells, the method comprising the step of administering the medicinal product as recited in claim 7.

12. A method for treating diabetes, the method comprising the step of administering the medicinal product as recited in claim 7.

13. A pharmaceutical composition comprising as active principle, at least one compound of formula (I) as claimed in claim 1 and at least one pharmaceutically acceptable excipient.