Chemical compounds

• US 6,958,350 B2
• Filed: 02/18/2002
• Issued: 10/25/2005
• Est. Priority Date: 02/19/2001
• Status: Expired due to Fees

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: McInally, Thomas, Brough, Stephen, Springthorpe, Brian, Perry, Matthew
• Primary Examiner(s): Huang, Evelyn Mei
• Application Number:
  US10/468,179
• Publication Number:
  US 20040102483A1
• Time in Patent Office: 1,345 Days
• Field of Search: 546/209, 546/210, 546/211, 546/208, 546/207, 546/194, 514/318, 514/321, 514/326
• US Class Current: 514/318
• 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 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 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 21/04 for myasthenia gravis
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• 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 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 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : 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 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

The invention provides a compound of formula (I): wherein R¹, R², R³, R⁴, R⁵, N, X and Y are as defined in the specification, processes, for their preparation, pharmaceutical compositions containing them, and their use in therapy, especially for the treatment of chemokine receptor related diseases and conditions.

Claims

1. A compound of formula (I):

wherein;

R¹ is phenyl which is optionally substituted by halogen, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, nitro or cyano;

R², R³ and R⁴ are, independently, hydrogen or C_1-4 alkyl;

R⁵ is C_1-6 alkyl, aryl, heteroaryl, aryl(C_1-4)alkyl, heteroaryl(C_1-4)alkyl or C_3-8 cycloalkyl;

wherein the aryl and heteroaryl moieties of R⁵ are optionally substituted by halogen, C_1-6 alkyl (optionally substituted by halogen, C_1-6 alkoxy or phenyl (itself optionally substituted by halogen, C_1-4 alkyl, C_1-4 alkoxy or CF₃)), OR⁶, S(O)_mR⁷, S(O)₂NR⁸R⁹, NR¹⁰S(O)₂R¹¹, C(O)R¹², C(O)NR¹³R¹⁴, NR¹⁵C(O)R¹⁶, NR¹⁷R¹⁸, NR¹⁹C(O)NR²⁰R²¹, methylenedioxy, nitro or cyano;

X is (CH₂)_n, where n is 1, 2, 3 or 4;

Y is a 2,4-, 2,5- or 3,5-linking 5-membered heteroaryl ring having 2 or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur, wherein Y is optionally substituted by C_1-4 alkyl;

R⁶, R⁸, R⁹, R¹⁰, R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are independently, hydrogen or C_1-6 alkyl (optionally substituted by C_1-6 alkoxy (provided no acetal or aminal is formed) or phenyl (itself optionally substituted by halogen, C_1-4 alkyl, C_1-4 alkoxy or CF₃));

R⁷ and R¹¹ are, independently, C_1-6 alkyl (optionally substituted by C_1-6 alkoxy (provided no thioacetal is formed) or phenyl (itself optionally substituted by halogen, C_1-4 alkyl, —

C_1-4 alkoxy or CF₃));

R¹² is hydrogen, C_1-6 alkyl (optionally substituted by C_1-6 alkoxy (provided no acetal is formed) or phenyl (itself optionally substituted by halogen, C_1-4 alkyl, C_1-4 alkoxy or CF₃)) or C_1-6 alkoxy (unsubstituted or mono-substituted by C_1-6 alkoxy or phenyl (itself optionally substituted by halogen, C_1-4 alkyl, C_1-4 alkoxy or CF₃));

or a pharmaceutically acceptable salt thereof.

2. A compound as claimed in claim 1 wherein R¹ is phenyl optionally substituted by C_1-4 alkyl, C_1-4 alkoxy or halogen.

3. A compound as claimed in claim 1 wherein R², R³ and R⁴ are all hydrogen.

4. A compound as claimed in claim 1 wherein R⁵ is C_1-6 alkyl, C_3-8 cycloalkyl, phenyl, monocyclic heteroaryl, benzyl or monocyclic heteroarylmethyl, wherein the phenyl and heteroaryl moieties of R⁵ are optionally substituted by halogen, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 haloalkyl, methylenedioxy, C(O)(C_1-4 alkyl), C_1-4 thioalkyl, cyano, N(C_1-4 alkyl)₂, NHC(O)(C_1-4 alkyl), C(O)N(C_1-4 alkyl)₂ or S(O)₂(C_1-4 alkyl).

5. A compound as claimed in claim 1 wherein X is (CH₂)₂.

6. A compound as claimed in claim 1 wherein Y is 2,5-linked thiazolyl ring (optionally substituted with C_1-4 alkyl), or a 3,5-linked 1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or 1,3,4-thiadiazolyl ring.

7. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, and a pharmaceutically acceptable diluent or carrier therefor.

8. A process for preparing a compound as claimed in claim 1 which comprises:

A. coupling a compound of formula (II);

with a compound of formula (III);

in a suitable solvent, in the presence of a suitable coupling agent and at a temperature in the range 0-50°

C.;

or,

B. where R² is hydrogen, reacting a compound of formula (IV);

with an aldehyde of formula R¹CHO in a suitable solvent and in the presence of a suitable acid; and

reducing the product so formed;

or,

C. where Y is 1,3,4-oxadiazolyl and R⁴ is hydrogen, heating a compound of formula (V);

at a suitable temperature, in a suitable solvent and in the presence of a suitable ring-closure chemical.