Benzodioxanyl-hydroxyethyleneamino-piperidinyl acetanilides, ketones, esters and carbamates which effect immunity and calcium entry and .beta.-blockade

• US 4,499,100 A
• Filed: 05/18/1983
• Issued: 02/12/1985
• Est. Priority Date: 05/18/1983
• Status: Expired due to Fees

• Current Assignee: Syntec Incorporated (Atos SE)
• Original Assignee: Syntec Incorporated (Atos SE)
• Inventors: Kluge, Arthur F., Clark, Robin D.
• Primary Examiner(s): Schwartz, Richard A.
• Application Number:
  US06/495,902
• Time in Patent Office: 636 Days
• Field of Search: 546/197, 542/430, 542/439, 424/267
• US Class Current: 514/321
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links

Abstract

Novel compounds of the general formula: ##STR1## and the pharmaceutically acceptable acid addition salts thereof, wherein: R¹, R², R³ and R⁴ are each independently hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl or lower alkyl sulfonyl;

R⁵ is hydrogen or lower alkyl;

m is 0 or 1;

W is alkylene, --CH═CH--, --O--, or --N(R⁶)--, where R⁶ is lower alkyl or hydrogen;

n is 0 or 1; and

Q is lower alkyl, cycloalkyl or optionally substituted phenyl.

These compounds combine β-blockade and calcium entry blockade properties in the same compound and therefore are useful in therapy in the treatment of cardiovascular diseases, including myocardial infarction, hypertension, arrhythmia and variant and exercise induced angina. The compounds are also useful in immunosuppressant therapy for immune diseases, such as rheumatoid arthritis.

Claims

1. A compound of the formula:

##STR18## or a pharmaceutically acceptable acid addition salt thereof, wherein;

R¹, R², R³ and R⁴ are each independently hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl or lower alkyl sulfonyl;

R⁵ is hydrogen or lower alkyl;

m is 0 or 1;

W is alkylene, --CH═

CH--, --O--, or --N(R⁶)--, where R⁶ is lower alkyl or hydrogen;

n is 0 or 1; and

Q is lower alkyl, cycloalkyl of 3-8 carbon atoms or optionally substituted phenyl of the formula ##STR19## wherein each of R⁷, R⁸, R⁹, R¹⁰ and R¹¹ is independently chosen from hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl or lower alkyl sulfonyl, aminosulfonyl or hydroxyl or R⁸ and R⁹ together form a --OCH₂ O-- linkage.

2. The compound of claim 1 wherein two substituents of R¹, R², R³ or R⁴ are hydrogen.

3. The compound of claim 1 wherein R¹, R², R³ and R⁴ are each hydrogen.

4. The compound of claim 3 wherein m is 1 and R⁵ is hydrogen.

5. The compound of claim 4 wherein n is 1.

6. The compound of claim 5 wherein W is --N(R⁶)-- and R⁶ is hydrogen.

7. The compound of claim 6 wherein Q is optionally substituted phenyl of the formula:

##STR20##

8. The compound of claim 7 wherein three substituents of R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are hydrogen.

9. The compound of claim 8 wherein Q is 2,6-dimethylphenyl, i.e., 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}-1-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperidine, or a pharmaceutically acceptable acid addition salt thereof.

10. The compound of claim 8 wherein Q is 3,4-methylenedioxyphenyl, i.e., 4-{[2-(1,4-benzodioxan-2-yl)-2hydroxyethyl]amino}-1-(3,4-methylenedioxyphenyl)aminocarbonylmethyl]piperidine, and the pharmaceutically acceptable salts thereof.

11. The compound of claim 8 wherein Q is 2,6-dichlorophenyl, i.e., 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}-1-[(2,6-dichlorophenyl)aminocarbonylmethyl]piperidine, and the pharmaceutically acceptable acid addition salts thereof.

12. The compound of claim 7 wherein four substituents of R⁷, R⁸, R⁹, R¹⁰ or R¹¹ are hydrogen.

13. The compound of claim 12 wherein Q is 4-methylphenyl, i.e., 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}-1-[(4-methylphenyl)aminocarbonylmethyl]piperidine, or a pharmaceutically acceptable acid addition salt thereof.

14. The compound of claim 12 wherein Q is 3-methylthiophenyl, i.e., 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}-1-[(4-methylthiophenyl)aminocarbonyl-1-methyl]piperidine, or a pharmaceutically acceptable acid addition salt thereof.

15. The compound of claim 12 wherein Q is 4-n-butylphenyl, i.e. 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}-1-[(4-n-butylphenyl)aminocarbonylmethyl]piperidine, or a pharmaceutically acceptable acid addition salt thereof.

16. The compound of claim 12 wherein Q is 4-fluorophenyl, i.e., 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}-1-[(4-fluorophenyl)aminocarbonylmethyl]piperidine, or a pharmaceutically acceptable acid addition salt thereof.

17. The compound of claim 12 wherein Q is 4-chlorophenyl, i.e. 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}-1-[(4-chlorophenyl)aminocarbonylmethyl]piperidine, or a pharmaceutically acceptable acid addition salt thereof.

18. The compound of claim 12 wherein Q is 3-trifluoromethylphenyl, i.e., 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}-1-[(3-trifluoromethylphenyl)aminocarbonylmethyl]piperidine, or a pharmaceutically acceptable acid addition salt thereof.

19. The compound of claim 12 wherein Q is 4-trifluoromethylphenyl, i.e. 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}-1-[(4-trifluoromethylphenyl)aminocarbonylmethyl]piperidine, or a pharmaceutically acceptable acid addition salt thereof.

20. The compound of claim 12 wherein Q is 4-methoxyphenyl, i.e., 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}-4-[(4-methoxyphenyl)aminocarbonylmethyl]piperidine, or a pharmaceutically acceptable acid addition salt thereof.

21. The compound of claim 12 wherein Q is 4-hydroxyphenyl, i.e., 4-{[(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}-1-[(4-hydroxyphenyl)aminocarbonylmethyl]piperidine, or a pharmaceutically acceptable acid addition salt thereof.

22. The compound of claim 12 wherein Q is 4-aminosulfonylphenyl, i.e., 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}-1-[(4-aminosulfonylphenyl)aminocarbonylmethyl)]piperidine, or a pharmaceutically acceptable acid addition salt thereof.

23. The compound of claim 7 wherein Q is phenyl, i.e., 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}-1-(phenylaminocarbonylmethyl)piperidine, or a pharmaceutically acceptable acid addition salt thereof.

24. The compound of claim 3 wherein m is 0, W is --N(R)⁶ --, and n is 1.

25. The compound of claim 24 wherein R⁶ is hydrogen.

26. The compound of claim 25 wherein Q is phenyl, i.e., 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}-1-[(phenyl)aminocarbonyl]piperidine, or a pharmaceutically acceptable acid addition salt thereof.

27. The compound of claim 25 wherein Q is isopropyl, i.e. 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}-1-[isopropylaminocarbonyl]piperidine, or a pharmaceutically acceptable acid addition salt thereof.

28. The compound of claim 25 wherein Q is cyclohexyl, i.e., 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}-1-[cyclohexylaminocarbonyl]piperidine, or a pharmaceutically acceptable acid addition salt thereof.

29. The compound of claim 3 wherein m and n are each 0.

30. The compound of claim 29 wherein Q is phenyl, i.e., 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}-1-(benzoyl)piperidine, or a pharmaceutically acceptable acid addition salt thereof.

31. The compound of claim 29 wherein Q is 4-fluorophenyl, i.e., 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}-1-(4-fluorobenzoyl)piperidine, or a pharmaceutically acceptable acid addition salt thereof.

32. The compound of claim 29 wherein Q is 3,4-methylenedioxyphenyl, i.e. 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}-1-(3,4-methylenedioxybenzoyl)piperidine, or a pharmaceutically acceptable acid addition salt thereof.

33. The compound of claim 29 wherein Q is methyl, i.e., 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}-1-(methylcarbonyl)piperidine, or a pharmaceutically acceptable acid addition salt thereof.

34. The compound of claim 3 wherein m is 0, W is --CH═

CH-- and n is 1.

35. The compound of claim 34 wherein Q is 3,4,5-trimethoxyphenyl, i.e., 4-{[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]amino}-1-[3-(3,4,5-trimethoxyphenyl)propenoyl]piperidine, or a pharmaceutically acceptable acid addition salt thereof.

36. A pharmaceutical composition useful for treating a cardiovascular disease in a mammal which comprises a therapeutically effective amount of a compound of claim 1 in admixture with a pharmaceutically acceptable excipient.

37. A pharmaceutical composition of claim 36 wherein said mammal is a human being.

38. A pharmaceutical composition useful for treating an autoimmune disease in a mammal which comprises a therapeutically effective amount of a compound of claim 1 in admixture with a pharmaceutically acceptable excipient.

39. A pharmaceutical composition of claim 36 wherein said mammal is a human being.

40. A method for treating a cardiovascular disease in a mammal which method comprises administering to a subject in need of such treatment a therapeutically effective amount of the compound of claim 1.

41. A method of claim 40 wherein said mammal is a human being.

42. The method of claim 41 wherein said cardiovascular disease is myocardial infarction.

43. The method of claim 41 wherein said cardiovascular disease is variant angina.

44. The method of claim 41 wherein said cardiovascular disease is exercise-induced angina.

45. The method of claim 41 wherein said cardiovascular disease is hypertension.

46. The method of claim 41 wherein said cardiovascular disease is arrhythmia.

47. A method for treating an autoimmune disease in a mammal which method comprises administering to a subject in need of such treatment a therapeutically effective amount of the compound of claim 1.

48. A method of claim 47 wherein said mammal is a human being.

49. The method of claim 47 wherein said autoimmune disease is rheumatoid arthritis.