N-aryl-N-[4-(1-heterocyclicalkyl)piperidinyl]amides and pharmaceutical compositions and methods employing such compounds

Abstract

This invention pertains to novel substituted N/aryl-N-[4-(1-heterocyclicalkyl)piperidinyl]amides useful as analgesics, and methods of administering analgesia, which comprises the systemic administration to mammals of such compounds, and pharmaceutical compositions containing such compounds, wherein the novel compounds have the general formula: ##STR1## including optically active isomeric forms, and the pharmaceutically acceptable acid addition salts thereof, wherein R, R 1 , R 2 , R 3 and R 4 are defined in the disclosure.

We claim: 
     
       1. A compound having the formula: ##STR22## optically active isometric forms thereof, and pharmaceutically acceptable acid addition salts thereof, wherein: R is selected from the group consisting of phenyl and substituted phenyl, wherein said substituents are members independently selected from the group consisting .[.one or more of halogen.]. .Iadd.of one or more of halo and lower alkoxy.Iaddend.;   R 1  is selected form the group consisting of lower alkyl, lower-alkenyl, and a lower-alkoxy lower-alkyl group having from 2 to 6 carbon atoms;   R 2  is a .[.quniazolyl.]. .Iadd.quinazolinyl .Iaddend.lower-alkyl group or a purinyl lower-alkyl group, the lower-alkyl portion of said groups containing from 1 to 7 carbon atoms and the heterocyclic portion thereof being unsubstituted or substituted with one or more substituents selected from the group consisting of .[.halogen.]. .Iadd.halo, oxo.Iaddend., hydroxyl, nitro, amino, lower-alkoxy carbonyl, lower-alkyl, lower-cycloalkyl, lower alkoxy, halogenated lower-alkyl, aryl and halogenated aryl; and   R 3  is lower-alkoxy carbonyl or lower-alkoxy methyl.   
     
     
       2. A compound according to claim 1, wherein R is selected from the group consisting of phenyl, 2-fluorophenyl and 2-methoxyphenyl. 
     
     
       3. A compound according to claim 1, wherein R 1  is selected from the group consisting of ethyl, ethenyl, methoxymethyl and 1-methoxyethyl. 
     
     
       4. A compound according to claim 1, wherein R 2  is selected from the group consisting of substituted or unsubstituted quinazolin-3-yl lower-alkyl, purin-1-yl lower-alkyl and purin-7-yl lower-alkyl groups. 
     
     
       5. A compound according to claim 1, wherein R 3  is methoxy carbonyl or methoxymethyl. 
     
     
       6. A compound according to claim 1, wherein R is a phenyl group; R 2  is a substituted or unsubstituted .Iadd.quinazolinyl .Iaddend.lower-alkyl group or purinyl lower-alkyl group; and   R 3  is a lower-alkoxy carbonyl group.   
     
     
       7. A compound according to claim 6, wherein R 1  is ethyl. 
     
     
       8. A compound according to claim 6, wherein R 2  is selected from the group consisting of substituted or unsubstituted quinazolin-3-yl lower-alkyl, purin-1-yl lower-alkyl and purin-7-yl lower alkyl groups. 
     
     
       9. A compound according to claim 1, wherein R is a phenyl group; R 2  is a substituted or unsubstituted quinazolinyl lower-alkyl group or purinyl lower-alkyl group; and   R 3  is a lower-alkoxy methyl group.   
     
     
       10. A compound according to claim 9, wherein R 1  is ethyl and R 3  is methoxymethyl. 
     
     
       11. A compound in accordance with claim 6, which .[.comprises.]. .Iadd.consists of .Iaddend.N-(phenyl-N-[1-(2-(1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-pyrin-7-yl)ethyl))-4-methoxycarbonyl-4-piperidinyl]propanamide or a pharmaceutically acceptable acid addition salt thereof. 
     
     
       12. A compound in accordance with claim .[.6.]. .Iadd.10.Iaddend., which .[.comprises.]. .Iadd.consists of .Iaddend.N-(phenyl)-N-[1-(2-(2-methyl-3,4-dihydro-4-oxo-3H-quinazolin-3-yl)ethyl))-4-methoxymethyl-4-piperidinyl]propanamide or a pharmaceutically acceptable acid addition salt thereof. 
     
     
       13. A compound according to claim 9, wherein R 2  is selected from the group consisting of substituted or unsubstituted quinazolin-3-yl lower alkyl, purin-1-yl lower-alkyl and purin-7-yl lower-alkyl groups. 
     
     
       14. An analgesic composition comprising a non-toxic pharmaceutically acceptable carrier and an analgesically effective amount of a compound as defined in claim 1. 
     
     
       15. The composition according to claim 14, wherein R is selected from the group consisting of phenyl, 2-fluorophenyl and 2-methoxyphenyl. 
     
     
       16. The composition according to claim 14, wherein R 1  is selected from the group consisting of ethyl, ethenyl, methoxymethyl and 1-methoxyethyl. 
     
     
       17. A composition according to claim 14, wherein R 2  is selected from the group consisting of substituted or unsubstituted quinazolinyl-3-yl lower-alkyl, purin-1-yl, lower-alkyl and purin-7-yl lower-alkyl groups. 
     
     
       18. A composition according to claim 14, wherein R 3  is methoxy carbonyl or methoxymethyl. 
     
     
       19. A composition according to claim 14, wherein R is a phenyl group; R 2  is .[.substituted or.]. .Iadd.selected from the group consisting of substituted and .Iaddend.unsubstituted quinazolinyl lower-alkyl group or purinyl lower-alkyl group; and   R 3  is lower-alkoxy carbonyl group.   
     
     
       20. A composition according to claim 19, wherein R 1  is ethyl. 
     
     
       21. A composition according to claim 19, wherein R 3  is methoxy carbonyl. 
     
     
       22. A composition according to claim 19, wherein R 2  is selected from the group consisting of substituted or unsubstituted quinazolin-3-yl lower-alkyl, purin-1-yl lower-alkyl and purin-7-yl lower-alkyl groups. 
     
     
       23. A composition in accordance with claim 14, wherein the compound comprises N-(phenyl)-N-[1-(2-(1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purin-7-yl)ethyl))-4-methoxy-carbonyl-4-piperidinyl]propanamide or a pharmaceutically acceptable acid addition salt thereof. 
     
     
       24. A composition in accordance with claim 14, wherein the compound comprises N-(phenyl)-N-[1-(2-(2-methyl-3,4-dihydro-4-oxo-3H-quinazolin-3-yl)ethyl))-4-methoxymethyl-4-piperidinyl]propanamide or a pharmaceutically acceptable acid addition salt thereof. 
     
     
       25. A method for producing analgesia in a mammal in need thereof comprising administering to the mammal an analgesically effective amount of a compound as defined in claim 1. 
     
     
       26. A method according to claim 25, wherein R is selected from the group consisting of phenyl, 2-fluorophenyl and 2-methoxyphenyl. 
     
     
       27. A method according to claim 25, wherein R 1  is selected from the group consisting of ethyl, ethenyl, methoxymethyl and 1-methoxyethyl. 
     
     
       28. A method according to claim 25, wherein R is a phenyl group; R 2  is selected from the group consisting of substituted .[.or.]. .Iadd.and .Iaddend.unsubstituted quinazolinyl lower-alkyl and purinyl lower-alkyl groups; and   R 3  is a lower-alkoxy carbonyl group.   
     
     
       29. A method according to claim 25, wherein R 2  is selected from the group consisting of substituted or unsubstituted quinazolin-3-yl lower-alkyl, purin-1-yl lower-alkyl and purin-7-yl lower-alkyl. 
     
     
       30. A method according to claim 28, wherein R 2  is selected from the group consisting of substituted or unsubstituted quinazolin-3-yl lower-alkyl, purin-1-yl lower-alkyl and purin-7-yl lower-alkyl groups.