Pharmaceutically active piperidine derivatives, in particular as modulators of chemokine receptor activity

• US 20040006081A1
• Filed: 12/10/2002
• Published: 01/08/2004
• Est. Priority Date: 05/17/2000
• Status: Abandoned Application

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Cooper, Anne, Burrows, Jeremy, McInally, Thomas, Tucker, Howard, Cumming, John
• Application Number:
  US10/276,430
• Publication Number:
  US 20040006081A1
• Time in Patent Office: Days
• US Class Current: 514/238.2
• 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 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• 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 25/00 Drugs for disorders of the nervous system
• 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 31/08 for leprosy
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• 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 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 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

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 heteroaryl is pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl, indolyl, benzimidazolyl, benzo[b]furyl, benzo[b]thienyl, phthalazinyl, indanyl, oxadiazolyl or benzthiazolyl.

3. A compouind as claimed in claim 1 or 2 wherein aryl is phenyl.

4. A compound as claimed in claim 1, 2 or 3 wherein heterocyclyl is piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl or tetrahydrofuryl.

5. A compound as claimed in claim 1, 2, 3 or 4 wherein R⁴, R⁵, R⁶ and R⁷ are all hydrogen.

6. A compound as claimed in claim 1, 2, 3, 4, or 5 wherein X is C(O).

7. A compound as claimed in claim 1, 2, 3, 4, 5 or 6 wherein m and p are both 1.

8. A compound as claimed in claim 1, 2, 3, 4, 5, 6 or 7 wherein R² is methyl, ethyl, allyl, cyclopropyl or propargyl.

9. A compound as claimed in claim 1, 2, 3, 4, 5, 6, 7 or 8 wherein R³ is NR⁴⁵R⁴⁶, aryl, heteroaryl, aryl(C_1-4)alkyl or heteroaryl(C_1-4)alkyl;

R⁴⁵ is hydrogen or C_1-6 alkyl;

R⁴⁶ is aryl, heteroaryl, aryl(C_1-4)alkyl or heteroaryl(C_1-4)alkyl;

wherein the aryl and heteroaryl groups of R³ and R⁴⁶ are independently substituted by S(O)_qR²⁵, OC(O)NR²⁶R²⁷, NR³²C(O)NR³³R³⁴ or C(O)R⁴¹, and optionally further substituted by one or more of halo, cyano, nitro, hydroxy, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy(C_1-6)alkyl, S(O)_qR²⁵, OC(O)NR²⁶R²⁷, NR²⁸R²⁹, NR³⁰C(O)R³¹, NR³²C(O)NR³³R³⁴, S(O)₂NR³⁵R³⁶, NR³⁷S(O)₂R³⁸, C(O)NR³⁹R⁴⁰, C(O)R⁴¹, CO₂R⁴², NR⁴³CO₂R⁴⁴, C_3-10 cycloalkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, phenyl, phenyl(C_1-4)alkyl, phenoxy, phenylthio, phenyl(C_1-4)alkoxy, heteroaryl, heteroaryl(C_1-4)alkyl, heteroaryloxy or heteroaryl(C_1-4)alkoxy;

wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halo, hydroxy, nitro, S(O)_kC_1-4 alkyl, S(O)₂NH₂, cyano, C_1-4 alkyl, C_1-4 alkoxy, C(O)NH₂, C(O)NH(C_1-4 alkyl), 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;

wherein q, k, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³ and R⁴⁴ are as defined in claim 1.

10. A compound as claimed in claim 1, 2, 3, 4, 5, 6, 7, 8 or 9 wherein R¹ is 2,6-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4-dimethoxy-6-hydroxybenzyl, 3-(4-dimethylamino-phenyl)prop-2-enyl, (1-phenyl-2,5-dimethylpyrrol-3-yl)methyl, 2-phenylethyl, 3-phenylpropyl, 3-R/S-phenylbutyl, 3-cyano-3,3-diphenylpropyl, 3-cyano-3-phenylpropyl, 4-(N-methylbenzamido)-3-phenylbutyl or 3,3-diphenylpropyl.

11. A pharmaceutical composition which comprises a compound of the formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof or solvate thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.

15. A method of treating a patient comprising administering a compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof or solvate thereof, or a composition as claimed in claim 11.

16. A process for the preparation of a compound of formula (I) as claimed in claim 1 comprising:

a. reductively aminating a compound of formula (II);

with an aldehyde R³CHO;

or

b. where R¹ is optionally substituted alkyl, reacting a compound of formula (III);

with an alkyl halide, in the presence of a base.

12. A compound of the formula (I), or a pharmaceutically acceptable salt thereof or solvate thereof, for use as a medicament.

13. A compound of formula (I), or a pharmaceutically acceptable salt thereof or solvate thereof, in the manufacture of a medicament for use in therapy.

14. A compound of formula (I), or a pharmaceutically acceptable salt thereof or solvate thereof, in the manufacture of a medicament for use in modulating CCR5 receptor activity in a warm blooded animal.