Piperidine derivatives and their use as modulators of chemokine receptor activity (especially ccr5)

• US 20050014788A1
• Filed: 11/12/2002
• Published: 01/20/2005
• Est. Priority Date: 11/15/2001
• Status: Abandoned Application

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Tucker, Howard, Cumming, John
• Application Number:
  US10/495,405
• Publication Number:
  US 20050014788A1
• Time in Patent Office: Days
• US Class Current: 514/317
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• 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 25/06 Antimigraine agents
• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• 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 31/18 for HIV
• 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 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/16 : for decreasing, blocking or antagonising the activity of the thyroid hormones
• 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 211/58 : attached in position 4
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Compounds of formula (I): compositions comprising them, processes for preparing them and their use in medical therapy (for example modulating CCR5 receptor activity in a warm blooded animal).

Claims

1. A compound of formula (I):

2. A compound as claimed in claim 1 wherein R¹ is phenyl {para-substituted by:

halo, S(O)_k(C_1-6 alkyl), S(O)₂NH₂, S(O)₂NH(C_1-6 alkyl), S(O)₂N(C_1-6 alkyl)₂, cyano, NH₂, NH(C_1-6 alkyl), N(C_1-6 alkyl)₂, CO₂(C_1-6 alkyl), NHC(O)(C_1-6 alkyl), NHC(O)O(C_1-6 alkyl), NHS(O)₂(C_1-6 alkyl), NHC(O)phenyl, NHC(O)heteroaryl, NHC(O)(C_1-4 alkyl)phenyl, NHC(O)(C_1-4 alkyl)heteroaryl, NHS(O)₂phenyl, NHS(O)₂heteroaryl, NHS(O)₂(C_1-4 alkyl)phenyl, NHS(O)₂(C_1-4 alkyl)heteroaryl, NHC(O)NH(C_1-6 alkyl), NHC(O)NH(C_3-7 cycloalkyl), NHC(O)NHphenyl, NHC(O)NHheteroaryl, NHC(O)NH(C_1-4 alkyl)phenyl or NHC(O)NH(C_1-4 alkyl)heteroaryl;

wherein the foregoing phenyl and heteroaryl groups are optionally substituted by halo, hydroxy, nitro, S(O)_k(C_1-4 alkyl), S(O)₂NH₂, S(O)₂NH(C_1-4 alkyl), S(O)₂N(C_1-4 alkyl)₂, cyano, C_1-4 alkyl, C_1-4 alkoxy, C(O)NH₂, C(O)NH(C_1-4 alkyl), C(O)N(C_1-4 alkyl)₂, CO₂H, CO₂(C_1-4 alkyl), NHC(O)(C_1-4 alkyl), NHS(O)₂(C_1-4 alkyl), C(O)(C_1-4 alkyl), CF₃ or OCF₃}; and

k is 2.

3. A compound as claimed in claim 1 wherein R² is phenyl, mono-fluorophenyl, difluorophenyl, mono-chlorophenyl or mono-(C_1-4 alkoxy)phenyl.

4. A compound as claimed in claim 1 wherein R³ is hydrogen.

5. A compound as claimed in claim 1 wherein R⁴ is ethyl.

6. A compound as claimed in claim 1 wherein R⁵ is hydrogen, halo, hydroxy, nitro, cyano, C_1-4 alkyl, C_1-4 alkoxy, CF₃ or OCF₃.

7. A compound as claimed in claim 1 wherein R⁶ is C_1-4 alkyl and wherein the S(O)₂R⁶ group of formula (I) is para disposed to the remainder of the structure of formula (I).

8. A process for the preparation of a compound as claimed in claim 1, the process comprising:

a) reductive amination of a compound of formula (II) or (IIa);

with a compound of formula (III);

in the presence of NaBH(OAc)₃ (wherein Ac is C(O)CH₃) and acetic acid, in a suitable solvent at room temperature;

or,

b) coupling a compound of formula (IV) or (IVa);

with a compound of formula (V);

in the presence of a suitable coupling agent, in the presence of a suitable base, in a suitable solvent and at room temperature.

9. A pharmaceutical composition which comprises a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof or solvate thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.

12. A method of treating a CCR5 mediated disease state comprising administering to a patient in need of such treatment an effective amount of a compound as claimed in claim 1.

13. The method of claim 8 wherein the temperature during step b) is from 10°

C. to 30°

C.

10-11. -11. (Cancelled)