Serine hydrolase inhibitors

• US 20080161290A1
• Filed: 09/20/2007
• Published: 07/03/2008
• Est. Priority Date: 09/21/2006
• Status: Active Grant

• Current Assignee: Kyorin Pharmaceutical Company Limited (Kyorin Holdings Incorporated)
• Original Assignee: Kyorin Pharmaceutical Company Limited (Kyorin Holdings Incorporated)
• Inventors: Hu, Yi, Ishiyama, Junichi, Shreder, Kevin, Kohno, Yasushi, Fraser, Allister, Kojima, Akihiko
• Granted Patent: US 7,879,846 B2
• Time in Patent Office: Days
• US Class Current: 514/218
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 31/04 Antibacterial agents
• 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: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• 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 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 containing three or more hetero rings

Abstract

Provided herein are benzoxazinone compounds of formula I and compositions containing the compounds. The compounds and compositions are useful in the methods of inhibiting the action of serine hydrolase, including neutrophil elastase. In certain embodiments, the compounds and compositions are useful in the prevention, amelioration or treatment of serine hydrolase-mediated diseases.

Claims

1. A compound of formula I:

2. The compound of claim 1, wherein R¹ is —

OR³, —

SR³ or NR⁴R⁵.

3. The compound of claim 1, wherein A is a 5-7 membered heterocyclyl or heteroaryl ring.

4. The compound of claim 1, wherein A is a 5-7 membered heterocyclyl ring.

5. The compound of claim 1, wherein A is a 5-7 membered heteroaryl ring.

6. The compound of claim 1, wherein A is pyridinyl.

7. The compound of claim 1, wherein A is 3-pyridinyl.

8. The compound of claim 1, wherein A is 2-pyridinyl.

9. The compound of claim 1, wherein A is 4-pyridinyl.

10. The compound of claim 1, wherein A is 2-thienyl.

11. The compound of claim 1, wherein R² is halo, alkyl, haloalkyl or alkoxy.

12. The compound of claim 1, wherein R² is chloro, bromo, methyl, ethyl, trifluoromethyl or methoxy.

13. The compound of claim 1, wherein R¹ is —

OR³ or —

NR⁴R⁵.

14. The compound of claim 1, wherein R¹ is —

NR⁴R⁵.

15. The compound of claim 1, wherein R³ is alkyl, haloalkyl, heteroalkyl, aryl, haloaryl, alkoxyalkyl, alkylaryl or arylsulfonylalkyl.

16. The compound of claim 1, wherein R³ is methyl, ethyl, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-tolyl, phenylsulfonylethyl, 3,4-methylenedioxybenzyl or dimethoxyamino ethyl.

17. The compound of claim 1, wherein R⁴ is hydrogen, lower alkyl or alkoxyalkyl.

18. The compound of claim 1, wherein R⁴ is hydrogen, methyl or methoxyethyl.

19. The compound of claim 1, wherein R⁵ is aralkyloxycarbonylalkyl, dialkylaminoalkyl, heterocyclylalkyl, alkylheterocyclyl or alkoxyalkyl.

20. The compound of claim 1, wherein R⁵ is benzyloxycarbonylmethyl, dimethylaminoethyl, 4-morpholinoethyl, N-methylpyrrolidin-3-yl or methoxyethyl.

21. The compound of claim 1, wherein R⁴ and R⁵ together with the nitrogen atom on which they are substituted form a 5 or 6 membered heterocyclyl or heteroaryl ring.

22. The compound of claim 1, wherein R⁴ and R⁵ together with the nitrogen atom on which they are substituted form a 5 or 6 membered heterocyclyl ring.

23. The compound of claim 1, wherein R¹ is

24. The compound of claim 23, wherein R is hydrogen, methyl, ethyl, isopropyl, 2-propenyl, 2-propynyl, 3-butynyl, phenyl, cyclopropylmethyl, 2-hydroxyethyl, hydroxycarbonylethyl, hydroxycarbonylpropyl, ethoxycarbonylethyl, methoxymethyl, ethoxymethyl, cyanoethyl, 3-cyanopropyl, dimethylaminomethyl, dimethylaminoethyl, 4-morpholinoethyl, 2-pyrimidinyl, 3-pyrimidinyl, 4-pyrimidinyl, 2-thiazolyl, 4-fluorophenylmethyl, 4-methoxyphenylmethyl, pyrrolidin-1-ylmethyl, tetrahydrofunan-2-ylmethyl, 1,3-dioxolan-2-ylmethyl, N-methylpiperidin-4-yl, ethoxycarbonylmethyl, hydroxycarbonylmethyl, morpholin-4-ylcarbonylmethyl, t-butlyoxycarbonylaminoethyl, hydroxyethoxyethyl, aminocarbonylmethyl, 2-propynyloxycarbonylaminoethyl, or —

C(NH)NH₂.

25. The compound of claim 23, wherein Q¹ is methyl, ethyl, propyl, isopropyl, phenyl, dimethylamino, diethylamino, dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl, hydroxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, phenylmethyl, hydroxycarbonylpropyl, hydroxyalkyl, hydroxyalkoxyalkyl, 1-imidazolyl, 4-morpholino, morpholin-4-ylmethyl, morpholin-4-ylethyl, —

N(CH₃)₃⁺, methylsulfinylmethylcarbonyl, cycloalkylaminoalkyl, fluoro, di(hydroxyethyl)amino, dialkylaminoalkylcarbonyl, pyrrolidin-1-ylmethyl, pyrrolidin-1-ylethyl, cyclopropylaminomethyl, 2-oxo-piperazin-4-yl, 1,1-dioxo-thiomorpholin-4-yl, N-methyl-N-(methoxyethyl)amino, N-methyl-piperazin-4-ylcarbonyl, N,N-dimethylaminoethylamino(methyl)carbonyl, —

SO₃H or —

(CH₂)₃SO₃H.

26. The compound of claim 23, wherein R⁶ is hydrogen, methyl, methoxymethyl or cyclopropylmethyl;

R⁷ is hydrogen;

Q¹ is methyl, dimethylamino, tert-butyloxycarbonyl or methoxycarbonyl;

n₁ is 1 or 2; and

n₂ is 1 or 2.

27. The compound of claim 1, wherein R¹ is

28. The compound of claim 27, wherein R is hydrogen, methyl, methoxyethyl or cyclopropylmethyl.

29. The compound of claim 27, wherein n₂ is 1 and Q¹ is methyl, dimethylamino, tert-butyloxycarbonyl or methoxycarbonyl.

30. The compound of claim 1, wherein R¹ is

31. The compound of claim 1, having formula:

32. The compound of claim 1, having formula:

33. The compound of claim 1, having formula:

34. The compound of claim 1, having formula:

35. The compound of claim 23 having formula:

36. The compound of claim 35 having formula:

37. The compound of claim 35 having formula:

38. The compound of claim 30 having formula:

39. The compound of claim 38 having formula:

40. The compound of claim 39 having formula:

41. The compound of claims 39, wherein R² is alkyl, haloalkyl, alkoxy, amino, halo, alkylcarbonyl or alkylsulfenyl.

42. The compound of any of claims 36-38, wherein R¹ is methyl, ethyl, isopropyl, trifluoromethyl, methoxy, hydroxy, amino, chloro, acyl or methylsulfenyl.

43. The compound of claim 40, wherein R⁸ is alkoxy, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl.

44. The compound of claim 1, having formula:

45. The compound of claim 44, wherein n₃ is 3 or 4.

46. The compound of claim 44, wherein R⁹ is hydrogen, methyl, phenyl or 3-carboxypyridin-2-yl.

47. The compound of claim 1, having formula:

48. The compound of claim 47 having formula:

53. A compound of claim 1, selected from:

54. A compound of claim 1, selected from:

55. A pharmaceutical composition comprising a compound of claim 1 or 49, and a pharmaceutically acceptable carrier.

59. A method for treatment of a serine hydrolase-mediated disease comprising administering a compound of claim 1.

60. A method of inhibiting an action of a serine hydrolase comprising administering a compound of claim 1.

66. The method of claim 59, wherein the disease is selected from pulmonary emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome, idiopathic interstitial pneumonia, cystic pulmonary fibrosis, chronic interstitial pneumonia, chronic bronchitis, chronic sinopulmonary infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, hepatic failure, chronic rheumatoid arthritis, joint scleroma, osteoarthritis, psoriasis, periodontitis, atherosclerosis, rejection against organ transplant, premature amniorrhexis, bullous dermatosis, shock, sepsis, systemic lupus erythematosus, Crohn'"'"'s disease, disseminated intracapillary coagulation, tissue injury after ischemia-reperfusion, formation of cornea cicatricial tissue and myelitis.

67. An article of manufacture, comprising a packaging material, the compound of claim 1, or pharmaceutically acceptable derivative thereof contained within packaging material, which is used for treatment, prevention or amelioration a serine hydrolase-mediated disease, and a label that indicates that the compound or the pharmaceutically acceptable derivative thereof is used for treatment, prevention or amelioration of a serine hydrolase-mediated disease.

49. A compound of formula:

50. A compound of claim 49 having formula:

51. The compound of claim 49 having formula:

52. The compound of claim 51, wherein n4 is 4.

56. A method of inhibiting an action of a serine hydrolase comprising administering a compound of Formula I:

58. The method of claim 56 or 57, wherein R¹ is R³, —

SR³;

or NR⁴R⁵.

61. The method of any of claims 56, 57, 59, and 60, wherein the serine hydrolase is neutrophil elastase.

62. The method of claim 61, wherein the neutrophil elastase is human neutrophil elastase.

63. The method of claim 58, wherein the serine hydrolase is neutrophil elastase.

64. The method of claim 63, wherein the neutrophil elastase is human neutrophil elastase.

65. The method of claim 58, wherein the disease is selected from pulmonary emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome, idiopathic interstitial pneumonia, cystic pulmonary fibrosis, chronic interstitial pneumonia, chronic bronchitis, chronic sinopulmonary infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, hepatic failure, chronic rheumatoid arthritis, joint scleroma, osteoarthritis, psoriasis, periodontitis, atherosclerosis, rejection against organ transplant, premature amniorrhexis, bullous dermatosis, shock, sepsis, systemic lupus erythematosus, Crohn'"'"'s disease, disseminated intracapillary coagulation, tissue injury after ischemia-reperfusion, formation of cornea cicatricial tissue and myelitis.

57. A method for treatment of a serine hydrolase-mediated disease comprising administering a compound of Formula I: