Substituted 2-quinolyl-oxazoles useful as PDE4 inhibitors

• US 20060106062A1
• Filed: 05/16/2005
• Published: 05/18/2006
• Est. Priority Date: 05/18/2004
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Shih, Neng-Yang, Huang, Ying, Chen, Xiao, Kuang, Rongze, Cao, Jianhua, Ting, Pauline C., Xiao, Li, Wong, Shing-Chun, Gu, Danlin, Schwerdt, John H., Blythin, David, Shue, Ho-Jane
• Granted Patent: US 7,511,062 B2
• Time in Patent Office: Days
• US Class Current: 514/314
• 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 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• 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 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 27/14 Decongestants or antiallergics
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• 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 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• 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
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

The invention claims compounds of the formula
wherein is a 5-membered heteroaryl; X is S or O;

• • R¹ is H, alkyl, cycloalkyl, cylcoalkylalkyl-, —CH₂F, —CHF₂, —CF₃, —C(O)alkyl or —C(O)NR¹⁸R¹⁹;
  • R³ and R⁴H, alkyl, hydroxyalkyl or —C(O)Oalkyl;
  • R⁵ and R⁶ are H, alkyl, hydroxyalkyl, alkoxyalkyl, mercaptoalkyl, —CH₂F, —CHF₂, —CF₃, —C(O)OH or —C(O)Oalkyl;
  • R⁷ is H, alkyl, alkenyl, hydroxyalkyl, cycloalkyl, alkoxyalkyl, aminoalkyl, (R¹⁷-phenyl)alkyl or —CH₂—C(O)—O-alkyl; and R⁸ comprises alkyl, heteroaryl, phenyl or cycloalkyl, or heterocycloalkyl, all optionally substituted, or a cycloalkyl- or heterocycloalkyl-substituted amide; or
  • R⁷ and R⁸ and the nitrogen to which they are attached together form an optionally substituted ring; and the remaining variables are as defined in the specification. Also claimed are pharmaceutical compositions, the use of the compounds as PDE4 inhibitors, and combinations with other actives.

Claims

1. A compound represented by the structural formula

2. A compound of claim 1 wherein X is O.

3. A compound of claim 2 wherein

4. A compound of claim 3 wherein R¹⁰, R¹¹ and R¹³ are each H;

R¹ is H, alkyl, cycloalkyl or —

CF₃; and

R⁹ is H, alkyl or —

CF₃.

5. A compound of claim 4 wherein R¹⁰, R¹¹ and R¹³ are each H, R¹ is alkyl, and R⁹ is —

CF₃

6. A compound of claim 5 wherein t is 1, R⁵ is H, R⁶ is H, alkyl or hydroxyalkyl, and R³ and R⁴ are each H or alkyl.

7. A compound of claim 6 wherein R⁷ is H, alkyl, cycloalkyl, hydroxyalkyl or alkoxyalkyl, and R⁸ is R¹²-cycloalkyl, (R¹²-cycloalkyl)alkyl, R⁴⁵-hydroxyalkyl, R¹⁷-phenyl, (R¹⁷-phenyl)alkyl, R²³-heteroaryl, (R²³-heteroaryl)alkyl, -alkyl-N(R³⁰)—

C(O)—

NR¹⁸R¹⁹, -alkyl-N(R³⁰)—

C(O)alkyl, -alkyl-N(R³⁰)—

C(O)—

(R¹⁷-phenyl), -alkyl-N(R³⁰)—

C(O)—

(R²³-heteroaryl), -alkyl-N(R³⁰)—

(R²³-heteroaryl),

8. A compound of claim 7 wherein R⁸ is R¹²-cycloalkyl, R⁴⁵-hydroxyalkyl, (R¹⁷-phenyl)alkyl, R²³-heteroaryl, (R²³-heteroaryl)alkyl, -alkyl-N(R³⁰)—

(R²³-heteroaryl), -alkyl-N(R³⁰)—

C(O)alkyl,

9. A compound of claim 8 wherein R¹² is OH, —

(CH₂)_n—

N(R³⁰)—

C(O)-cycloalkyl or —

(CH₂)_n—

N(R³⁰)—

(R²³-heteroaryl), R⁴⁵ is R¹⁷-phenyl, or R²⁹ is heteroaryl, —

C(O)alkyl or —

C(O)cycloalkyl.

10. A compound of claim 6 wherein R⁷ and R⁸ and the nitrogen to which they are attached form

11. A compound of claim 10 wherein R⁷ and R⁸ form

12. A compound of claim 10 wherein R⁷ and R⁸ form

13. A compound of claim 10 wherein R⁷ and R⁸ form

14. A compound of claim 10 wherein R⁷ and R⁸ form

15. A compound of claim 7 wherein R⁷ is H or alkyl and R⁸ is (R¹⁷-phenyl)alkyl, R⁴⁵-hydroxyalkyl or -alkyl-N(R³⁰)—

(R²³-heteroaryl), wherein R⁴⁵ is R¹⁷-phenyl;

heteroaryl is pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzothienyl or benzofuranyl;

R¹⁷ is 1 to 3 substituents independently selected from the group consisting of halogen, OH, alkoxy and alkyl; and

R²³ is 1 or 2 substituents Independently selected from the group consisting of H, alkyl, alkoxy and halogen.

16. A compound of claim 1 selected from the group consisting of

17. The compound of claim 1 having the formula

18. The compound of claim 1 having the formula

19. The compound of claim 1 having the formula

20. The compound of claim 1 having the formula

21. The compound of claim 1 having the formula

22. The compound of claim 1 having the formula

23. The compound of claim 1 having the formula

24. The compound of claim 1 having the formula

25. The compound of claim 1 having the formula

26. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

27. A method of treating a PDE4 mediated disease comprising administering an effective amount of a compound of claim 1 to a patient In need of such treatment.

28. The method of claim 27 wherein the PDE4 mediated disease is selected from the group consisting of allergic and inflammatory diseases, CNS diseases, and diabetes.

29. The method of claim 28 for treating COPD, asthma, inflammatory bowel disease, dermatitis, multiple sclerosis, arthritis, Parkinson'"'"'s disease, Alzheimer'"'"'s disease, mild cognitive impairment, depression or anxiety.

30. The method of claim 27 for treating dermatitis in dogs or recurrent airway disease In horses.

31. The method of claim 27 further comprising administering to said patient the compound of formula I in combination with at least one other medicament selected from the group consisting of disease modifying antirheumatic drugs, nonsteroidal anitinflammatory drugs, COX-2 selective inhibitors, COX-1 inhibitors, Immunosuppressives, steroids, biological response modifiers and other anti-inflammatory agents or therapeutics useful for the treatment of PDE4 mediated diseases.