Quinolinone derivatives

• US 9,061,997 B2
• Filed: 11/15/2011
• Issued: 06/23/2015
• Est. Priority Date: 11/16/2010
• Status: Expired due to Fees

• Current Assignee: Centre National De La Recherche Scientifique
• Original Assignee: Centre National De La Recherche Scientifique
• Inventors: Ruat, Martial, Faure, Hlne, Mann, Andr, Taddei, Maurizio, Solinas, Antonio, Gorojankina, Tatiana, Manetti, Fabrizio
• Primary Examiner(s): Seaman, D M
• Application Number:
  US13/885,089
• Publication Number:
  US 20130267559A1
• Time in Patent Office: 1,316 Days
• Field of Search: 546/159, 546/163, 514/312, 514/338
• US Class Current: 1/1
• CPC Class Codes: A61K 31/4704 2-Quinolinones, e.g. carbostyril
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• 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 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/18 of the parathyroid hormones
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07D 215/22 attached in position 2 or 4
• CPC Class Codes: C07D 215/56 with oxygen atoms in position 4

Abstract

The present invention relates to compounds which are quinolinone derivatives of general formula (I) capable of modulating the activity, in particular of inducing the differentiation, of stem and progenitor cells; these compounds are of use in the treatment of disorders related to a stem differentiation defect; the invention also relates to novel compounds among these quinolinone derivatives and to pharmaceutical compositions containing the same.

Claims

1. A method for the treatment of diseases caused by one or more of the dysregulation of osteoblast function or differentiation, or by a functional imbalance between osteoblasts and osteoclasts, the method causing inducement of cellular differentiation of stem or progenitor cells, said method comprising the step of administering a compounds of general formula (I):

3. The method according to claim 1, wherein said R³ radical is an alkyl radical having from 3 to 8 carbon atoms;

the R² radical is a hydrogen atom or an alkyl radical having from 1 to 3 carbon atoms; and

the R⁴, R⁵, R⁶ and R⁷ radicals represent a hydrogen atom or an alkyl radical having from 1 to 3 carbon atoms.

4. The method according claim 1, wherein the compound is chosen from:

propyl 4-(1-hexyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido)benzoate (compound 1);

ethyl 4-(1-benzyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3carboxamido)benzoate (compound 2);

ethyl 4-(1-hexyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido)benzoate (compound 3);

4-(1-hexyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido)benzoic acid (compound 4);

butyl 4-(1-hexyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido)benzoate (compound 5);

tert-butyl 4-(1-hexyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido)benzoate (compound 6);

benzyl 4-(1-hexyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido)benzoate (compound 7);

N-(4-(butylcarbamoyl)phenyl)- 1 -hexyl-4-hydroxy-2-oxo- 1 ,2-dihydroquinoline-3- carboxamide (compound 8);

or

isopropyl 4-(1-hexyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido)benzoate (compound 9).

2. A method for preparing implants of autologous cells differentiated into osteoblasts for remedying bone tissue losses subsequent to injuries and/or to surgical operations, comprising a step of inducing the differentiation of mesenchymal cells into osteoblasts by a compound of general formula (I):

5. Compounds of general formula (Ia):

6. The compounds of general formula (Ia) as claimed in claim 5, as a medicament.

7. A pharmaceutical composition comprising as an active ingredient, at least one compound of general formula (Ia) as claimed in claim 5, and at least one pharmaceutically acceptable excipient.

8. A method for the treatment of diseases caused by dysregulation of osteoblast function or differentiation and/or by a functional imbalance between osteoblasts and osteoclasts, said method making it possible to induce the cellular differentiation of stem or progenitor cells, the method comprising the step of administering a compound of general formula (Ia) according to claim 5, and wherein the disease is selected from the group consisting of osteoporosis, brittleness of the skeleton, bone rarefaction, embrittlement of bone tissue resulting from osteopenia, osteogenesis imperfect, hypercalcemia, bone resorption associated with hyperparathyroidism, osteomalacia, osteonecrosis, bone resorption associated with Paget'"'"'s disease of bone (osteitis deformans), rheumatoid arthritis, inflammatory arthritis, osteomyelitis, paradontitis, and bone resorption associated with bone metastases, and combinations thereof.

9. A method for preparing implants of autologous cells differentiated into osteoblasts for remedying bone tissue losses subsequent to injuries and/or to surgical operations, comprising a step of inducing the differentiation of mesenchymal cells into osteoblasts by a compound of general formula (Ia) according to claim 5.