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Claims for Patent: 5,019,583

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Claims for Patent: 5,019,583

Title: N-phenyl-N-(4-piperidinyl)amides useful as analgesics
Abstract:N-Phenyl-N-(4-piperdinyl)amide derivatives are disclosed having the general formula (I): ##STR1## wherein X is a member selected from the group consisting of alkoxy-carbonyl-lower alkyl, lower alkyl-carbonyloxy-lower alkyl, alkenyloxy-carbonyl-lower alkyl, and (C.sub.1-2)alkoxy-(C.sub.1-2)-alkoxy-carbonyl-lower alkyl, and Ar, R, R.sup.1 and R.sup.2 are defined hereinafter, including isomeric forms thereof and acid addition salts thereof. The compounds exhibit analgesic activity having relatively short durations of analgesic action. The invention embraces the compounds (I), pharmaceutical compositions of (I) and methods of providing analgesia with (I). Also included are certain novel intermediates for making (I).
Inventor(s): Feldman; Paul L. (Durham, NC), James; Michael K. (Raleigh, NC), Brackeen; Marcus F. (Durham, NC), Johnson; Michael R. (Chapel Hill, NC), Leighton; Harry J. (Chapel Hill, NC)
Assignee: Glaxo Inc. (Research Triangle Park, NC)
Application Number:07/448,497
Patent Claims: 1. A compound having the formula (I): ##STR15## wherein X is a member selected from the group consisting of: alkoxy-carbonyl-lower alkyl, lower alkyl-carbonyloxy-lower alkyl, alkenyloxy-carbonyl-lower alkyl, and (C.sub.1-2)alkoxy-(C.sub.1-2)alkoxy-carbonyl-lower alkyl

Ar is a member selected from the group consisting of phenyl and mono- di- and tri-substituted phenyl, wherein each substituent is independently selected from the group consisting of halo, lower alkyl, lower alkoxy and trifluoromethyl;

R is a member selected from the group consisting of lower alkyl, and lower alkoxy-lower alkyl;

R.sup.1 is a member selected from the group consisting of hydrogen, lower alkoxy-carbonyl, and methoxymethyl; and

R.sup.2 is a member selected from the group consisting of hydrogen and methyl;

and the diastereomeric and enantiomeric isomers thereof, and the pharmaceutically acceptable acid addition salts of said compounds and isomers.

2. The compound of claim 1 wherein X is alkoxy-carbonyl-lower alkyl.

3. The compound of claim 1 wherein X is lower alkyl-carbonyl-oxy-lower alkyl.

4. The compound of claim 1 wherein X is alkenyloxy-carbonyl-lower alkyl.

5. The compound of claim 1 wherein X is (C.sub.1-2)alkoxy-(C.sub.1-2)-alkoxy-carbonyl-lower alkyl.

6. The compound of claim 1 wherein Ar is phenyl or 2-fluorophenyl.

7. The compound of claim 1 wherein R is ethyl.

8. The compound of claim 1 wherein R.sup.1 is methoxycarbonyl.

9. The compound of claim 1, wherein said compound is:

5-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]pentanoic acid, methyl ester;

2-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]ethyl acetate;

3-[4-[(1-oxopropyl)-2-fluorophenylamino]-1-piperidine]propanoic acid, methyl ester; or

3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid, vinyl ester,

or pharmaceutically acceptable acid addition salt thereof.

10. 3-[4-Methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-pi peridine]propanoic acid, alkyl ester, and the pharmaceutically acceptable acid addition salts thereof.

11. The compound of claim 10, wherein in the alkyl portion of the said alkyl ester, the carbon directly attached to the oxygen is a methylene or methyl group.

12. The compound of claim 10, wherein said alkyl of said alkyl ester is of about 1 to 10 carbons.

13. The compound of claim 10, wherein said alkyl ester is the methyl ester.

14. A diastereomer or enantiomer of a compound as claimed in claim 1.

15. A pharmaceutical analgesic composition comprising an effective analgesic amount of a compound having the formula (I): ##STR16## wherein: X is a member selected from the group consisting of: alkoxy-carbonyl-lower alkyl, lower alkyl-carbonyloxy-lower alkyl, alkenyloxy-carbonyl-lower alkyl, and (C.sub.1-2)alkoxy-(C.sub.1-2)alkoxy-carbonyl-lower alkyl;

Ar is a member selected from the group consisting of phenyl and mono-, di- and tri-substituted phenyl, wherein each substituent is independently selected from the group consisting of halo, lower alkyl, lower alkoxy and trifluoromethyl;

R is a member selected from the group consisting of lower alkyl, and lower alkoxy-lower alkyl;

R.sup.1 is a member selected from the group consisting of hydrogen, lower alkoxy-carbonyl, and methoxymethyl; and

R.sup.2 is a member selected from the group consisting of hydrogen and methyl;

and the diastereomeric and enantiomeric isomers thereof, and the pharmaceutically acceptable acid addition salts of said compounds and isomers;

and a pharmaceutically acceptable carrier.

16. The composition of claim 15 wherein X is alkoxy-carbonyl-lower alkyl.

17. The composition of claim 15 wherein X is lower alkyl-carbonyloxy-lower alkyl.

18. The composition of claim 15 wherein X is alkenyloxy-carbonyl-lower alkyl.

19. The composition of claim 15 wherein X is (C.sub.1-2)alkoxy-(C.sub.1-2)-alkoxy-carbonyl-lower alkyl.

20. The composition of claim 15 wherein Ar is phenyl or 2-fluorophenyl.

21. The composition of claim 15 wherein R is ethyl.

22. The composition of claim 15 wherein R.sup.1 is methoxycarbonyl.

23. The composition of claim 15 wherein said compound is:

5-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]pentanoic acid, methyl ester;

2-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]ethyl acetate;

3-[4-(1-oxopropyl)-2-fluorophenylamino]-1-piperidine]propanoic acid, methyl ester;

3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid, vinyl ester;

or the pharmaceutically acceptable acid addition salt thereof.

24. 3-[4-Methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperi dine]propanoic acid, alkyl ester, and the pharmaceutically acceptable acid addition salt thereof.

25. The composition of claim 24 wherein in the alkyl portion of the said alkyl ester, the carbon directly attached to the oxygen is a methylene or methyl group.

26. The composition of claim 24, wherein said alkyl of said alkyl ester is of about 1 to 10 carbons.

27. The composition of claim 24, wherein said alkyl ester is the methyl ester.

28. The composition of claim 15, wherein said compound is a diastereomer or enantiomer.

29. The composition of claim 15, wherein said pharmaceutically acceptable carrier is suitable for parenteral administration.

30. A method of providing analgesia in a mammal comprising administering to such mammal an analgesically effective amount of a compound having the formula (I): ##STR17## wherein: X is a member selected from the group consisting of: alkoxy-carbonyl-lower alkyl, lower alkyl-carbonyloxy-lower alkyl, alkenyloxy-carbonyl-lower alkyl, and (C.sub.1-2)alkoxy-(C.sub.1-2)alkoxy-carbonyl-lower alkyl;

Ar is a member selected from the group consisting of phenyl and mono-, di- and tri-substituted phenyl, wherein each substituent is independently selected from the group consisting of halo, lower alkyl, lower alkoxy and trifluoromethyl;

R is a member selected from the group consisting of lower alkyl, and lower alkoxy-lower alkyl;

R.sup.1 is a member selected from the group consisting of hydrogen, lower alkoxy-carbonyl, and methoxy-methyl; and

R.sup.2 is a member selected from the group consisting of hydrogen and methyl;

and the optically active and cis-trans isomers thereof, and the pharmaceutically acceptable acid addition salts of said compounds and isomers.

31. The method of claim 30 wherein X is alkoxy-carbonyl-lower alkyl.

32. The method of claim 30 wherein X is lower alkyl-carbonyloxy-lower alkyl.

33. The method of claim 30 wherein X is alkenyloxy-carbonyl-lower alkyl.

34. The method of claim 30 wherein X is (C.sub.1-2)alkoxy-(C.sub.1-2)-alkoxy-carbonyl-lower alkyl.

35. The method of claim 30 wherein Ar is phenyl or 2-fluorophenyl.

36. The method of claim 30 wherein R is ethyl.

37. The method of claim 30 wherein R.sup.1 is methoxycarbonyl.

38. The method of claim 30 wherein said compound is

5-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]pentanoic acid, methyl ester;

2-[4-methoxycarbonyl-4-(1-oxopropyl)phenylamino]-1-piperidine]ethyl acetate;

3-[4-[(1-oxopropyl)-2-fluorophenylamino]-1-piperidine]propanoic acid, methyl ester; or

3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid, vinyl ester;

or a pharmaceutically acceptable acid addition salt thereof.

39. 3-[4-Methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-pipe ridine]propanoic acid, methyl ester, and the pharmaceutically acceptable acid addition salts

40. The method of claim 30, wherein in the alkyl portion of the said alkyl ester, the carbon directly attached to the oxygen is a methylene or methyl group.

41. The method of claim 30, wherein said alkyl of said alkyl ester is of about 1 to 10 carbons.

42. The method of claim 30, wherein said alkyl ester is the methyl ester.

43. The method of claim 30, wherein said compound is a diastereomer or enantiomer.

44. A compound having the formula (A): ##STR18## wherein: X.sub.a is carboxyloweralkyl;

Ar is a member selected from the group consisting of phenyl and mono-, di- and tri-substituted phenyl, wherein each substituent is independently selected from the group consisting of halo, lower alkyl, lower alkoxy and trifluoromethyl;

R is a member selected from the group consisting of lower alkyl, and lower alkoxy-lower alkyl;

R.sup.1 is a member selected from the group consisting of hydrogen, lower alkoxy-carbonyl, and methoxymethyl; and

R.sup.2 is a member selected from the group consisting of hydrogen and methyl.

45. A compound of claim 44 wherein X.sub.a is carboxyethyl.

46. A compound having the formula (I): ##STR19## wherein: X is a member selected from the group consisting of: alkoxy-carbonyl-lower alkyl, lower alkyl-carbonyloxy-lower alkyl, alkenyloxy-carbonyl-lower alkyl, and (C.sub.1-2)alkoxy-(C.sub.1-2)alkoxy-carbonyl-lower alkyl;

Ar is a member selected from the group consisting of phenyl and mono-, di- and tri-substituted phenyl, wherein each substituent is independently selected from the group consisting of halo, lower alkyl, lower alkoxy and trifluoromethyl;

R is a member selected from the group consisting of lower alkyl, and lower alkoxy-lower alkyl;

R.sup.1 is a member selected from the group consisting of hydrogen, lower alkoxy-carbonyl, and methoxymethyl; and

R.sup.2 is a member selected from the group consisting hydrogen and methyl;

and the diastereomeric and enantiomeric isomers thereof, and the acid addition salts of said compounds and isomers.

47. A compound having the formula: ##STR20## wherein: X is a member selected from the group consisting of: lower alkoxy-carbonyl-lower alkyl, lower alkyl-carbonyloxy-lower alkyl, lower alkenyloxy-carbonyl-lower alkyl, and (C.sub.1-2)alkoxy -(C.sub.1-2)alkoxy-carbonyl-lower alkyl;

Ar is a member selected from the group consisting of phenyl and mono-, di- and tri-substituted phenyl, wherein each substituent is independently selected from the group consisting of halo, lower alkyl, lower alkoxy and trifluoromethyl;

R is a member selected from the group consisting of lower alkyl, and lower alkoxy-lower alkyl;

R.sup.1 is a member selected from the group consisting of hydrogen, lower alkoxy-carbonyl, and methoxymethyl; and

R.sup.2 is a member selected from the group consisting of hydrogen and methyl;

and the diastereomeric and enantiomeric isomers thereof, and the pharmaceutically acceptable acid addition salts of said compounds and isomers.
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