Tetrahydropyridines, preparation method and pharmaceutical compositions containing same

• US 6,689,797 B2
• Filed: 10/15/2002
• Issued: 02/10/2004
• Est. Priority Date: 01/06/2000
• Status: Expired due to Fees

• Current Assignee: Sanofi-Aventis (Sanofi-Synthélabo SA)
• Original Assignee: Sanofi-Synthelabo Incorporated (Sanofi-Aventis U.S., LLC)
• Inventors: Bourrie, Bernard, Baroni, Marco, Casellas, Pierre, Cardamone, Rosanna
• Primary Examiner(s): DENTZ, BERNARD I
• Application Number:
  US10/169,528
• Publication Number:
  US 20030083347A1
• Time in Patent Office: 483 Days
• Field of Search: 546/256, 546/281.1, 546/284.1, 514/333, 514/337
• US Class Current: 514/333
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• 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 25/00 Drugs for disorders of the nervous system
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• 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: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention relates to compounds of formula (I):

in which

R₁ represents a hydrogen or halogen atom, or a group CF₃;

R₂ and R₃ represent, independently, a hydrogen atom or a methyl group;

n and n′ each represent, independently, 0 or 1;

* represents the positions of attachment;

A represents N or CH;

X represents a sulfur or oxygen atom;

R₄ and R₅ represent, independently, a hydrogen atom or a (C₁-C₆) alkyl group;

and also their salts or solvates, to a method for the preparation thereof and to the pharmaceutical compositions containing them.

Claims

1. A compound of formula (I):

in which

R₁ represents a hydrogen or halogen atom, or a group CF₃;

R₂ and R₃ represent, independently, a hydrogen atom or a methyl group;

n and n′

each represent, independently, 0 or 1;

* represents the positions of attachment;

A represents N or CH;

X represents a sulfur or oxygen atom;

R₄ and R₅ represent, independently, a hydrogen atom or a (C₁-C₆) alkyl group;

and their salts or solvates.

2. The compound as claimed in claim 1, in which n is zero.

3. The compound as claimed in claim 1, in which R₁ is in position 3 of the benzene.

4. The compound as claimed in claim 1, in which R₂ and R₃ are each a hydrogen atom.

5. The compound as claimed in claim 1, in which R₁ is a group CF₃.

6. The compound as claimed in claim 1, in which R₄ and R₅ are each a methyl group.

7. A method for preparing a compound of claim 1 wherein

(a) the compound of formula (II):

 

in which A and R₁ are defined as in claim 1, is reacted with a functional derivative of the acid of formula (III);

 

in which R₂, R₃, R₄, R₅, n and X are as defined in claim 1,

(b) the carbonyl group of the compound of formula (IV);

 

is reduced,

(c) the intermediate piperidinol of formula (V);

 

is dehydrated,

(d) the compound of formula (I) thus obtained is isolated and, optionally, it is transformed into one of its salts or solvates, or its N-oxide.

8. A method for preparing a compound of claim 1 wherein a tetrahydropyridine of formula (VI):

in which A and R₁ are as defined in claim 1, is condensed with a compound of formula (VII);

in which R₂, R₃, R₄, R₅, n and X are as defined above and Q is a leaving group, the compound of formula (I) thus obtained is isolated and is optionally transformed into one of its salts or solvates, or into its N-oxide.

9. A pharmaceutical composition containing, as active principle, a compound of formula (I) as claimed in claim 1, or one of its pharmaceutically acceptable salts or solvates.

10. The composition as claimed in claim 9 wherein it contains from 0.01 to 50 mg of active principle.

11. A pharmaceutical composition containing, as active principle, a compound of formula (I) as claimed in claim 2, or one of its pharmaceutically acceptable salts or solvates.

12. A pharmaceutical composition containing, as active principle, a compound of formula (I) as claimed in claim 3, or one of its pharmaceutically acceptable salts or solvates.

13. A pharmaceutical composition containing, as active principle, a compound of formula (I) as claimed in claim 4, or one of its pharmaceutically acceptable salts or solvates.

14. A pharmaceutical composition containing, as active principle, a compound of formula (I) as claimed in claim 5, or one of its pharmaceutically acceptable salts or solvates.

15. A pharmaceutical composition containing, as active principle, a compound of formula (I) as claimed in claim 6, or one of its pharmaceutically acceptable salts or solvates.

16. A method for the treatment of diseases related to immune and inflammatory disorders which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim 1.

17. A method for the treatment of diseases related to immune and inflammatory disorders which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim 2.

18. A method for the treatment of diseases related to immune and inflammatory disorders which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim 3.

19. A method for the treatment of diseases related to immune and inflammatory disorders which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim 4.

20. A method for the treatment of diseases related to immune and inflammatory disorders which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim 5.

21. A method for the treatment of diseases related to immune and inflammatory disorders which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim 6.

22. A method according to claim 16 for the treatment of atherosclerosis, autoimmune diseases, diseases which lead to the demyelinization of neurons, asthma, rheumatoid arthritis, fibrotic diseases, idiopathic pulmonary fibrosis, cystic fibrosis, glumerulonephritis, rheumatoid spondylitis, osteoarthritis, gout, bone and cartilage resorption, osteoporosis, Paget'"'"'s disease, multiple myeloma, uveoretinitis, septic shock, septicemia, endotoxic shock, graft-versus-host reaction, graft rejection, adult respiratory distress syndrome, silicosis, asbestosis, pulmonary sarcoidosis, Crohn'"'"'s disease, ulcerative colitis, amyotrophic lateral sclerosis, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, lupus erythematosus disseminatus, hemodynamic shock, ischemic pathological conditions, postischemic reperfusion injuries, malaria, mycobacterial infections, meningitis, leprosy, viral infections, AIDS-related opportunistic infections, tuberculosis, psoriasis, atopic and contact dermatosis, diabetes, cachexia, cancer and radiation-mediated damage.