Quinolinone Derivatives

• US 20130267559A1
• Filed: 11/15/2011
• Published: 10/10/2013
• Est. Priority Date: 11/16/2010
• Status: Active Grant

• Current Assignee: Centre National De La Recherche Scientifique
• Original Assignee: Centre National De La Recherche Scientifique
• Inventors: Ruat, Martial, Faure, Helene, Gorojankina, Tatiana, Mann, Andre, Taddei, Maurizio, Solinas, Antonio, Manetti, Fabrizio
• Granted Patent: US 9,061,997 B2
• Time in Patent Office: Days
• US Class Current: 514/312
• 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. Compounds of general formula (I):

2. The compounds as claimed in claim 1, for the treatment of osteoporosis;

and disorders such as brittleness of the skeleton and/or bone rarefaction and/or embrittlement of bone tissue resulting from osteopenia;

osteogenesis imperfecta;

hypercalcemia;

hyperparathyroidism;

osteomalacia;

osteonecrosis;

Paget'"'"'s disease of bone (osteitis deformans);

rheumatoid arthritis;

inflammatory arthritis;

osteomyelitis;

paradontitis;

bone metastases.

4. The compound as claimed in 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.

5. The compound as claimed in claim 1, wherein the compound is 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-3-carboxamido)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).

6. A method for preparing osteoblast cells from adult stem cells or from progenitor cells, comprising a step consisting in incubating, for a sufficient period of time, said cells in a liquid nutritive medium allowing the development of said cells, said nutritive medium containing in solution at least one compound of general formula (I) as defined in claim 1.

3. Compounds of general formula (I):

7. Compounds of general formula (Ia):

8. The compounds of general formula (Ia) as claimed in claim 7, as a medicament.

9. A pharmaceutical composition comprising as an active ingredient, at least one compound of general formula (Ia) as claimed in claim 8, and at least one pharmaceutically acceptable excipient.

10. A method for the treatment of a condition selected from the group consisting of osteoporosis;

osteopenia;

osteogenesis imperfecta;

hypercalcemia;

hyperparathyroidism;

osteomalacia;

osteonecrosis;

Paget'"'"'s disease of bone (osteitis deformans);

rheumatoid arthritis;

inflammatory arthritis;

osteomyelitis;

paradontitis; and

bone metastases, the method comprising the step of administering as an active ingredient a compound of general formula (I);

11. The method of claim 10 wherein the compound is selected from the group consisting of

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-3-carboxamido)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); and

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

     9).

12. A method of inducing cellular differentiation of stem or progenitor cells comprising the step of administering a compound of general formula (I) to a patient in need thereof, wherein the compound of general formula (I) is as follows: