Chemical Compounds

• US 20080153855A1
• Filed: 02/28/2008
• Published: 06/26/2008
• Est. Priority Date: 07/19/2001
• Status: Abandoned Application

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Reynolds, Rachel Heulwen, Ingall, Anthony Howard
• Application Number:
  US12/039,204
• Publication Number:
  US 20080153855A1
• Time in Patent Office: Days
• US Class Current: 514/260.1
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/08 Bronchodilators
• 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 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

Abstract

The invention relates to a compound of formula (1)

in which Q is —CO— or —C(R⁴)(R⁵)—, where R⁴ is a hydrogen atom or C_1-4alkyl and

• • R⁵ is a hydrogen atom or hydroxy group; and Ar is a 5- to 10-membered aromatic ring system where up to 4 ring atoms may be heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring system being optionally substituted by one or more substituents as defined in the specification. It also relates to methods of preparing, pharmaceutical compositions containing and methods of using the compound of the formula (1), particularly in the modulation of autoimmune disease.

Claims

1. A method of inhibiting the proliferation of T cells, comprising administering to a patient a therapeutically effective amount of a compound of formula (1)

2. The method of claim 1, wherein R² is methyl or ethyl.

3. The method of claim 1, wherein R¹ is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl, cyclopropylmethyl, trifluoromethyl 2,2,2-trifluoroethyl, 2-chloroethyl, 2-chloropropyl or 3,3,3-trifluoropropyl.

4. The method of claim 1, wherein Q is —

CO—

or —

CH₂—

.

5. The method of claim 1, wherein R¹⁰ is C_1-4alkyl optionally substituted by hydroxy.

6. The method of claim 1, wherein R¹¹ is C_1-4alkyl optionally substituted by hydroxy.

7. The method of claim 1, wherein Y is O.

8. The method of claim 1, wherein R³ is —

CON(Me)OMe, —

CON(Et)OMe, —

CON(OEt)Me, —

CON(Et)OEt, —

CON(CH₂CH₂OH)OEt, —

CON(CH₂CH₂OH)Me, —

CON(OCH₂CH₂OH)Me, or —

CON(OCH₂CH₂OH)Et.

9. The method of claim 1, wherein Ar contains at least 1 ring nitrogen.

10. The method of claim 1, wherein Ar contains at least 2 ring nitrogen.

11. The method of claim 1, wherein Ar is selected from the group consisting of imidazolyl, pyrazolyl, pyrrolyl, isoxazolyl, phenyl, quinolyl, indolyl, benzimidazolyl, indazolyl, benztriazolyl, 2,3-dihydrothiazolyl, 2,3-dihydrobenzoxazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, 2,3-dihydrothiazolo[5,4-b]pyridyl, 2,3-dihydropyrazinyl, 2,3-dihydrobenzothiazolyl and 2,3-dihydrobenzimidazolyl, each ring system being optionally substituted according to claim 1.

12. The method of claim 1, wherein Ar is substituted by 1, 2 or 3 substituents independently selected from the group consisting of C_1-4alkyl optionally substituted by 1 or 2 hydroxy groups, C_1-4alkoxy, halogen, trihaloalkyl, C_1-4alkylthio, C_1-4alkoxycarbonyl, C_2-4alkanoyl, oxo, thioxo, cyano, —

NHR⁷, —

(CH₂)pN(R⁸)R⁹ wherein p is 1 or 2, hydroxy, C_1-4alkylsulphonyl, carbamoyl, C_1-4alkylcarbamoyl, di-(C_1-4alkyl)carbamoyl, carboxy, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur.

13. A method of effecting immunosuppression, comprising administering to a patient a therapeutically effective amount of a compound of formula (1)

14. The method of claim 13, wherein R² is methyl or ethyl.

15. The method of claim 13, wherein R¹ is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl, cyclopropylmethyl, trifluoromethyl 2,2,2-trifluoroethyl, 2-chloroethyl, 2-chloropropyl or 3,3,3-trifluoropropyl.

16. The method of claim 13, wherein Q is —

CO—

or —

CH₂—

.

17. The method of claim 13, wherein R¹⁰ is C_1-4alkyl optionally substituted by hydroxy.

18. The method of claim 13, wherein R¹¹ is C_1-4alkyl optionally substituted by hydroxy.

19. The method of claim 13, wherein Y is O.

20. The method of claim 13, wherein R³ is —

CON(Me)OMe, —

CON(Et)OMe, —

CON(OEt)Me, —

CON(Et)OEt, —

CON(CH₂CH₂OH)OEt, —

CON(CH₂CH₂OH)Me, —

CON(OCH₂CH₂OH)Me, or —

CON(OCH₂CH₂OH)Et.

21. The method of claim 13, wherein Ar contains at least 1 ring nitrogen.

22. The method of claim 13, wherein Ar contains at least 2 ring nitrogen.

23. The method of claim 13, wherein Ar is selected from the group consisting of imidazolyl, pyrazolyl, pyrrolyl, isoxazolyl, phenyl, quinolyl, indolyl, benzimidazolyl, indazolyl, benztriazolyl, 2,3-dihydrothiazolyl, 2,3-dihydrobenzoxazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, 2,3-dihydrothiazolo[5,4-b]pyridyl, 2,3-dihydropyrazinyl, 2,3-dihydrobenzothiazolyl and 2,3-dihydrobenzimidazolyl, each ring system being optionally substituted according to claim 13.

24. The method of claim 13, wherein Ar is substituted by 1, 2 or 3 substituents independently selected from the group consisting of C_1-4alkyl optionally substituted by 1 or 2 hydroxy groups, C_1-4alkoxy, halogen, trihaloalkyl, C_1-4alkylthio, C_1-4alkoxycarbonyl, C_2-4alkanoyl, oxo, thioxo, cyano, —

NHR⁷, —

(CH₂)pN(R⁸)R⁹ wherein p is 1 or 2, hydroxy, C_1-4alkylsulphonyl, carbamoyl, C_1-4alkylcarbamoyl, di-(C_1-4alkyl)carbamoyl, carboxy, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur.

25. A method of treating or reducing the risk of a reversible obstructive airways disease in a patient suffering from, or at risk of, the disease, comprising administering to the patient a therapeutically effective amount of a compound of formula (1)

26. The method of claim 25, wherein the obstructive airways disease is chronic obstructive pulmonary disease (COPD).

27. The method of claim 25, where in the obstructive airways disease is asthma.

28. The method of claim 25, wherein R² is methyl or ethyl.

29. The method of claim 25, wherein R¹ is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl, cyclopropylmethyl, trifluoromethyl 2,2,2-trifluoroethyl, 2-chloroethyl, 2-chloropropyl or 3,3,3-trifluoropropyl.

30. The method of claim 25, wherein Q is —

CO—

or —

CH₂—

.

31. The method of claim 25, wherein R¹⁰ is C_1-4alkyl optionally substituted by hydroxy.

32. The method of claim 25, wherein R¹¹ is C_1-4alkyl optionally substituted by hydroxy.

33. The method of claim 25, wherein Y is O.

34. The method of claim 25, wherein R³ is —

CON(Me)OMe, —

CON(Et)OMe, —

CON(OEt)Me, —

CON(Et)OEt, —

CON(CH₂CH₂OH)OEt, —

CON(CH₂CH₂OH)Me, —

CON(OCH₂CH₂OH)Me, or —

CON(OCH₂CH₂OH)Et.

35. The method of claim 25, wherein Ar contains at least 1 ring nitrogen.

36. The method of claim 25, wherein Ar contains at least 2 ring nitrogen.

37. The method of claim 25, wherein Ar is selected from the group consisting of imidazolyl, pyrazolyl, pyrrolyl, isoxazolyl, phenyl, quinolyl, indolyl, benzimidazolyl, indazolyl, benztriazolyl, 2,3-dihydrothiazolyl, 2,3-dihydrobenzoxazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, 2,3-dihydrothiazolo[5,4-b]pyridyl, 2,3-dihydropyrazinyl, 2,3-dihydrobenzothiazolyl and 2,3-dihydrobenzimidazolyl, each ring system being optionally substituted according to claim 25.

38. The method of claim 25, wherein Ar is substituted by 1, 2 or 3 substituents independently selected from the group consisting of C_1-4alkyl optionally substituted by 1 or 2 hydroxy groups, C_1-4alkoxy, halogen, trihaloalkyl, C_1-4alkylthio, C_1-4alkoxycarbonyl, C_2-4alkanoyl, oxo, thioxo, cyano, —

NHR⁷, —

(CH₂)pN(R⁸)R⁹ wherein p is 1 or 2, hydroxy, C_1-4alkylsulphonyl, carbamoyl, C_1-4alkylcarbamoyl, di-(C_1-4alkyl)carbamoyl, carboxy, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur.

39. A method of treating or reducing the risk of cancer in a patient suffering from, or at risk of, the cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (1)

40. The method of claim 39, wherein R² is methyl or ethyl.

41. The method of claim 39, wherein R² is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl, cyclopropylmethyl, trifluoromethyl 2,2,2-trifluoroethyl, 2-chloroethyl, 2-chloropropyl or 3,3,3-trifluoropropyl.

42. The method of claim 39, wherein Q is —

CO—

or —

CH₂—

.

43. The method of claim 39, wherein R¹⁰ is C_1-4alkyl optionally substituted by is hydroxy.

44. The method of claim 39, wherein R¹¹ is C_1-4alkyl optionally substituted by hydroxy.

45. The method of claim 39, wherein Y is O.

46. The method of claim 39, wherein R³ is —

CON(Me)OMe, —

CON(Et)OMe, —

CON(OEt)Me, —

CON(Et)OEt, —

CON(CH₂CH₂OH)OEt, —

CON(CH₂CH₂OH)Me, —

CON(OCH₂CH₂OH)Me, or —

CON(OCH₂CH₂OH)Et.

47. The method of claim 39, wherein Ar contains at least 1 ring nitrogen.

48. The method of claim 39, wherein Ar contains at least 2 ring nitrogen.

49. The method of claim 39, wherein Ar is selected from the group consisting of imidazolyl, pyrazolyl, pyrrolyl, isoxazolyl, phenyl, quinolyl, indolyl, benzimidazolyl, indazolyl, benztriazolyl, 2,3-dihydrothiazolyl, 2,3-dihydrobenzoxazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, 2,3-dihydrothiazolo[5,4-b]pyridyl, 2,3-dihydropyrazinyl, 2,3-dihydrobenzothiazolyl and 2,3-dihydrobenzimidazolyl, each ring system being optionally substituted according to claim 39.

50. The method of claim 39, wherein Ar is substituted by 1, 2 or 3 substituents independently selected from the group consisting of C_1-4alkyl optionally substituted by 1 or 2 hydroxy groups, C_1-4alkoxy, halogen, trihaloalkyl, C_1-4alkylthio, C_1-4alkoxycarbonyl, C_2-4alkanoyl, oxo, thioxo, chicano, —

NHR⁷, —

(CH₂)pN(R⁸)R⁹ wherein p is 1 or 2, hydroxy, C_1-4alkylsulphonyl, carbamoyl, C_1-4alkylcarbamoyl, di-(C_1-4alkyl)carbamoyl, carboxy, and a 5 or 6 membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulphur.