Serine hydrolase inhibitors

• US 7,879,846 B2
• Filed: 09/20/2007
• Issued: 02/01/2011
• Est. Priority Date: 09/21/2006
• Status: Expired due to Fees

• 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
• Primary Examiner(s): HABTE, KAHSAY
• Application Number:
  US11/903,483
• Publication Number:
  US 20080161290A1
• Time in Patent Office: 1,230 Days
• Field of Search: 544/90, 514/230.5
• US Class Current: 514/230.5
• 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 3-pyridinyl.

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

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

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

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

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

OR³ or —

NR⁴R⁵.

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

NR⁴R⁵.

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

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

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

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

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

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

16. 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.

17. 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.

18. The compound of claim 1, wherein R¹ is

19. The compound of claim 18, wherein R⁶ 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.

20. The compound of claim 18, 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.

21. The compound of claim 18, 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.

22. The compound of claim 1, wherein R¹ is

23. The compound of claim 22, wherein R⁶ is hydrogen, methyl, methoxyethyl or cyclopropylmethyl.

24. The compound of claim 22, wherein n₂ is 1 and Q¹ is methyl, dimethylamino, tert-butyloxycarbonyl or methoxycarbonyl.

25. The compound of claim 1, wherein R¹ is

26. The compound of claim 1, having formula:

27. The compound of claim 1, having formula:

28. The compound of claim 1, having formula:

29. The compound of claim 1, having formula:

30. The compound of claim 18 having formula:

31. The compound of claim 30 having formula:

32. The compound of claim 30 having formula:

33. The compound of claim 25 having formula:

34. The compound of claim 33 having formula:

35. The compound of claim 34 having formula:

36. The compound of claims 34, wherein R² is alkyl, haloalkyl, alkoxy, amino, halo, alkylcarbonyl or alkylsulfenyl.

37. The compound of any of claims 31-33, wherein R² is methyl, ethyl, isopropyl, trifluoromethyl, methoxy, hydroxy, amino, chloro, acyl or methylsulfenyl.

38. The compound of claim 35, wherein R⁸ is alkoxy, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl.

39. The compound of claim 1, having formula:

40. The compound of claim 39, wherein n₃ is 3 or 4.

41. The compound of claim 39, wherein R⁹ is hydrogen, methyl, phenyl or 3-carboxypyridin-2-yl.

42. The compound of claim 1, having formula:

43. The compound of claim 42 having formula:

44. A compound of claim 1, selected from:

45. A compound of claim 1, selected from:

46. A pharmaceutical composition comprising a compound of claim 1, and a pharmaceutically acceptable carrier.

47. A method for the treatment of a serine hydrolase-mediated disease comprising administering a compound of claim 1 to a patient in need thereof, 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.

48. 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 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.

49. The compound of claim 1 selected from

50. A pharmaceutical composition comprising the compound of claim 49 and a pharmaceutically acceptable carrier.