Claims
- 1. A compound according to the formula ##STR8## or an optical isomer thereof or a pharmaceutically acceptable acid addition salt thereof, wherein:
- n is an integer of 1 to 6;
- R.sub.1 is hydrogen or alkyl of 1 to 4 carbons;
- R.sub.2 is hydrogen or R.sub.1 and R.sub.2 are combined to form an oxo group;
- R.sub.3 is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl, hydroxy lower alkyl or an aliphatic acylate thereof of 1 to 6 carbon atoms or an aryl acylate thereof of 7 to 12 carbon atoms, carbamoyl alkyl, carboxyalkyl, alkoxycarbonylalkyl or an .alpha.-amino acid side chain;
- R.sub.4 is hydrogen, alkyl of 1 to 6 carbons, benzyl, or hydroxy lower alkyl;
- Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy;
- A is NR.sub.5 R.sub.6 wherein R.sub.5 an R.sub.6 are independently selected from the group consisting of: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms or an aliphatic acylate thereof of 1 to 6 carbon atoms or an aryl acylate thereof of 7 to 12 carbon atoms; cycloalkyl of 3 to 8 carbon atoms or cycloalkyl lower alkyl of 4 to 12 carbon atoms wherein the cycloalkyl ring is unsubstituted or substituted with a lower alkyl, lower alkoxy, --OH, --OCOR.sub.7, halo, --NH.sub.2, --N(R.sub.7).sub.2, --NHCOR.sub.7, --COOH, or --COO(R.sub.7) group wherein R.sub.7 is lower alkyl; phenyl or phenyl lower alkyl wherein phenyl is unsubstituted or substituted with at least one lower alkyl, halo or lower alkoxy group or an --NH.sub.2, --N(R.sub.7).sub.2, --NHCOR.sub.7, --COOH, or --COOR.sub.7 group wherein R.sub.7 is lower alkyl; or wherein N, R.sub.5 and R.sub.6 are combined to form a selected from the group consisting of morpholinyl, piperidinyl, perhexylenyl, N-loweralkylpiperazinyl, pyrrolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, (.+-.)-decahydroquinolinyl, and indolinyl.
- 2. A compound according to the formula ##STR9## or an optical isomer thereof or a pharmaceutically acceptable acid addition salt thereof, wherein:
- n is an integer of 1 to 6;
- R.sub.1 is hydrogen or alkyl of 1 to 4 carbons;
- R.sub.2 is hydrogen or R.sub.1 and R.sub.2 are combined to form an oxo group;
- R.sub.3 is an aliphatic hydroxy lower alkyl acylate of 1 to 6 carbon atoms or an aryl hydroxy lower alkyl acylate of 7 to 12 carbon atoms, carbamoyl alkyl, carboxyalkyl, alkoxycarbonylalkyl or an .alpha.-amino acid side chain;
- R.sub.4 is hydrogen, alkyl of 1 to 6 carbons, benzyl, or hydroxy lower alkyl;
- Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy;
- A is NR.sub.5 R.sub.6 wherein R.sub.5 and R.sub.6 are independently selected from the group consisting of: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms or an aliphatic acylate thereof of 1 to 6 carbon atoms or an aryl acylate thereof of 7 to 12 carbon atoms; cycloalkyl of 3 to 8 carbon atoms or cycloalkyl lower alkyl of 4 to 12 carbon atoms wherein the cycloalkyl ring is unsubstituted or substituted with a lower alkyl, lower alkoxy, --OH, --OCOR.sub.7, halo, --NH.sub.2, --N(R.sub.7).sub.2, --NHCOR.sub.7, --COOH, or --COO(R.sub.7) group wherein R.sub.7 is lower alkyl; and phenyl or phenyl lower alkyl wherein phenyl is unsubstituted or substituted with 1 or more lower alkyl, halo or lower alkoxy groups or an --NH.sub.2, --N(R.sub.7).sub.2, --NHCOR.sub.7, --COOH, or --COOR.sub.7 group wherein R.sub.7 is lower alkyl; or where N, R.sub.5 and R.sub.6 together form a group selected from the group consisting of morpholinyl, piperidinyl, perhexylenyl, N-loweralkylpiperazinyl, pyrrolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, (.+-.)-decahydroquinolinyl, and indolinyl.
- 3. A compound according to the formula ##STR10## or an optical isomer thereof or a pharmaceutically acceptable acid addition salt thereof, wherein:
- n is 3 or 4;
- R.sub.4 is hydrogen or methyl;
- Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy;
- A is NR.sub.5 R.sub.6 wherein the nitrogen substituents are independently selected from the group consisting of: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms or an aliphatic acylate thereof of 1 to 6 carbon atoms or an aryl acylate thereof of 7 to 12 carbon atoms; cycloalkyl of 3 to 8 carbon atoms or cycloalkyl lower alkyl of 4 to 12 carbon atoms wherein the cycloalkyl ring is unsubstituted or substituted with a lower alkyl, lower alkoxy, --OH, --OCOR.sub.7, halo, --NH.sub.2, --N(R.sub.7).sub.2, --NHCOR.sub.7, --COOH, or --COO(R.sub.7) group wherein R.sub.7 is lower alkyl; phenyl or phenyl lower alkyl wherein phenyl is unsubstituted or substituted with at least one lower alkyl, halo or lower alkoxy group or an --NH.sub.2, --N(R.sub.7).sub.2, --NHCOR.sub.7, --COOH, or --COOR.sub.7 group wherein R.sub.7 is lower alkyl; or N, R.sub.5, and R.sub.6 together form a group selected from the group consisting of morpholinyl, piperidinyl, perhexylenyl, N-loweralkylpiperazinyl, pyrrolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, (.+-.)-decahydroquinolinyl, and indolinyl.
- 4. A compound according to claim 3 wherein R.sub.4 is hydrogen; and wherein the R.sub.5 and R.sub.6 substituents are independently selected from the group consisting of: alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms or an aliphatic acylate thereof of 1 to 6 carbon atoms or an aryl acylate thereof of 7 to 12 carbon atoms; and cycloalkyl of 3 to 8 carbon atoms or cycloalkyl lower alkyl of 4 to 12 carbon atoms.
- 5. A compound according to claim 3 wherein n is 3; and wherein R.sub.5 is alkyl of 1 to 6 carbon atoms and R.sub.6 is cycloalkyl of 3 to 8 carbon atoms.
- 6. The compound of claim 5 which is N-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-9-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 7. The compound of claim 5 which is N-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-8-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 8. The compound of claim 5 which is N-cyclohexyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-6-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 9. The compound of claim 5 which is N-cyclooctyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 10. The compound of claim 5 which is N-cyclopentyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 11. The compound of claim 5 which is N-cyclohexyl-N-ethyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 12. The compound of claim 5 which is N-cyclohexyl-N-isopropyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 13. The compound of claim 5 which is N-cyclohexyl-N-2-methoxyethyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 14. The compound of claim 5 which is N-cyclohexyl-N-n-butyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 15. The compound of claim 5 which is N-cycloheptyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 16. A compound according to claim 4 wherein n is 3; and wherein the R.sub.5 and R.sub.6 substitutents are independently selected from the group consisting of: hydroxyalkyl of 1 to 6 carbon atoms or an aliphatic acylate thereof of 1 to 6 carbon atoms or an aryl acylate thereof of 7 to 12 carbon atoms; cycloalkyl of 3 to 8 carbon atoms; and cycloalkyl lower alkyl of 4 to 12 carbon atoms.
- 17. The compound of claim 16 which is N-cyclohexyl-N-t-butyryloxyethyl-4-(2-oxo-1,2,3,5-tetra-hydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable acid addition salt thereof.
- 18. The compound of claim 16 which is N-cyclohexyl-N-isopropionyloxyethyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable acid addition salt thereof.
- 19. A compound according to the formula ##STR11## or an optical isomer thereof or a pharmaceutically acceptable acid addition salt thereof, wherein:
- R.sub.3 is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl, hydroxy lower alkyl or an aliphatic acylate thereof of 1 to 6 carbon atoms or an aryl acylate thereof of 7 to 12 carbon atoms, carbamoyl alkyl, carboxyalkyl, alkoxycarbonylalkyl or an .alpha.-amino acid side chain;
- A is NR.sub.5 R.sub.6 wherein the nitrogen is substituted with alkyl of 1 to 6 carbon atoms and cycloalkyl of 3 to 8 carbon atoms.
- 20. The compound of claim 19 which is N-cyclohexyl-N-methyl-4-(2-oxo-3-D-hydroxymethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 21. The compound of claim 19 which is N-cyclohexyl-N-methyl-4-(2-oxo-3-L-hydroxymethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 22. The compound of claim 19 which is N-cyclohexyl-N-methyl-4-(2-oxo-3-D-methyl-1,2,3,5-tetra-hydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 23. The compound of claim 19 which is N-cyclohexyl-N-methyl-4-(2-oxo-3-L-methyl-1,2,3,5-tetra-hydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 24. The compound of claim 19 which is N-cyclohexyl-N-methyl-4-(2-oxo-3-D-ethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 25. The compound of claim 19 which is N-cyclohexyl-N-methyl-4-(2-oxo-3-L-ethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 26. The compound of claim 19 which is N-cyclohexyl-N-methyl-4-(2-oxo-3-D-(1-hydroxyethyl)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 27. The compound of claim 19 which is N-cyclohexyl-N-methyl-4-(2-oxo-3-L-(1-hydroxyethyl)-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 28. The compound of claim 19 which is N-cyclohexyl-N-methyl-4-(2-oxo-3-D-isopropyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 29. The compound of claim 19 which is N-cyclohexyl-N-methyl-4-(2-oxo-3-L-isopropyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 30. The compound of claim 19 which is N-cyclohexyl-N-methyl-4-(2-oxo-3-D-benzyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 31. The compound of claim 19 which is N-cyclohexyl-N-methyl-4-(2-oxo-3-L-benzyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 32. The compound of claim 19 which is N-cyclohexyl-N-methyl-4-(2-oxo-3-D-phenyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 33. The compound of claim 19 which is N-cyclohexyl-N-methyl-4-(2-oxo-3-L-phenyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable addition salt thereof.
- 34. A compound according to claim 3, wherein n is 4.
- 35. The compound of claim 34 which is N-cyclohexyl-N-methyl-5-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-7-yl)oxypentamide or a pharmaceutically acceptable acid addition salt thereof.
- 36. A compound according to claim 3, wherein R.sub.4 is hydrogen; n is 3; and wherein R.sub.5 and R.sub.6 are independently selected from the group consisting of: alkyl of 1 to 6 carbon atoms; phenyl; and phenyl lower alkyl.
- 37. The compound of claim 36 which is N-diphenylmethyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable acid addition salt thereof.
- 38. The compound of claim 36 which is N,N-dibenzyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable acid addition salt thereof.
- 39. The compound of claim 36 which is N-benzyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydro-imidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable acid addition salt thereof.
- 40. The compound of claim 36 which is N-phenyl-N-methyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable acid addition salt thereof.
- 41. The compound according to claim 1 wherein n is 1; Y, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; and wherein R.sub.5 is alkyl of 1 to 6 carbon atoms and R.sub.6 is cycloalkyl of 3 to 8 carbon atoms.
- 42. The compound of claim 41 which is N-cyclohexyl-N-methyl-2-(2oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-7-yl)oxyacetamide or a pharmaceutically acceptable acid addition salt thereof.
- 43. A compound according to claim 1 wherein n is 5; Y, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; and R.sub.5 and R.sub.6 are independently alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 8 carbon atoms.
- 44. The compound of claim 43 which is N-cyclohexyl-N-methyl-6-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-7-yl)oxyhexanamide or a pharmaceutically acceptable acid addition salt thereof.
- 45. A compound according to claim 1, wherein n is 6; Y, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; and R.sub.5 and R.sub.6 are independently alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 8 carbon atoms.
- 46. The compound of claim 45 which is N-cyclohexyl-N-methyl-7-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-b]quinazolin-7-yl)oxyheptanamide or a pharmaceutically acceptable acid addition salt thereof.
- 47. A compound according to claim 1, wherein n is 3; Y, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are all hydrogen; and R.sub.6 is a cycloalkyl group of 3 to 8 carbon atoms.
- 48. The compound of claim 47 which is N-cyclohexyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable acid addition salt thereof.
- 49. A compound according to claim 1, wherein n is 3; and Y, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are all hydrogen; or a pharmaceutically acceptable acid addition salt thereof.
- 50. A compound according to claim 1, wherein n is 3; R.sub.1 and R.sub.2 are combined to form an oxo group; and Y, R.sub.3 and R.sub.4 are hydrogen.
- 51. The compound of claim 50 which is N-cyclohexyl-N-methyl-4-(2,5-dioxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramide or a pharmaceutically acceptable acid addition salt thereof.
- 52. A compound according to claim 1, wherein n is 3; Y, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; and A is tetrahydroquinolinyl or a pharmaceutically acceptable acid addition salt thereof.
- 53. A compound according to claim 1, wherein n is 3; Y, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; and A is perhexylenyl or a pharmaceutically acceptable acid addition salt thereof.
- 54. A compound according to claim 1, wherein n is 3; Y, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; and A is indolinyl or a pharmaceutically acceptable acid addition salt thereof.
- 55. A compound according to claim 1, wherein n is 3; Y, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; and A is piperidinyl or a pharmaceutically acceptable acid addition salt thereof.
- 56. A compound according to claim 1, wherein n is 3; Y, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; and A is pyrrolidinyl or a pharmaceutically acceptable acid addition salt thereof.
- 57. A compound according to claim 1, wherein n is 3; Y, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; and A is (.+-.)-decahydroquinolinyl or a pharmaceutically acceptable acid addition salt thereof.
- 58. A compound according to claim 1, wherein n is 3; Y, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; and A is tetrahydroisoquinolinyl, or a pharmaceutically acceptable acid addition salt thereof.
- 59. A compound according to claim 1, wherein n is 3; Y, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; and A is morpholinyl, or a pharmaceutically acceptable acid addition salt thereof.
- 60. A compound according to claim 1, wherein n is 3; Y, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are all hydrogen; R.sub.5 is cyclohexyl; and R.sub.6 is 2-morpholinylethyl; or a pharmaceutically acceptable acid addition salt thereof.
- 61. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of the formula ##STR12## or an optical isomer thereof or a pharmaceutically acceptable acid addition salt thereof wherein
- n is an integer of 1 to 6;
- R.sub.1 is hydrogen or alkyl of 1 to 4 carbons;
- R.sub.2 is hydrogen or R.sub.1 and R.sub.2 are combined to form an oxo group;
- R.sub.3 is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl, hydroxy lower alkyl or an aliphatic acylate thereof of 1 to 6 carbon atoms or an aryl acylate thereof of 7 to 12 carbon atoms, carbamoyl alkyl, carboxyalkyl, alkoxycarbonylalkyl or an .alpha.-amino acid side chain;
- R.sub.4 is hydrogen, benzyl, hydroxy lower alkyl or alkyl of 1 to 6 carbons;
- Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy;
- A is NR.sub.5 R.sub.6 wherein R.sub.5 and R.sub.6 are independently selected from the group consisting of: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms or an aliphatic acylate thereof of 1 to 6 carbon atoms or an aryl acylate thereof of 7 to 12 carbon atoms; cycloalkyl of 3 to 8 carbon atoms or cycloalkyl lower alkyl of 4 to 12 carbon atoms wherein the cycloalkyl ring is unsubstituted or substituted with a lower alkyl, lower alkoxy, --OH, --OCOR.sub.7, halo, --NH.sub.2, --N(R.sub.7).sub.2, --NHCOR.sub.7, --COOH, or --COO(R.sub.7) group wherein R.sub.7 is lower alkyl; and phenyl or phenyl lower alkyl wherein phenyl is unsubstituted or substituted with 1 or more lower alkyl, halo or lower alkoxy groups or an --NH.sub.2, --N(R.sub.7).sub.2, --NHCOR.sub.7, --COOH, or --COOR.sub.7 group wherein R.sub.7 is lower alkyl; or wherein N, R.sub.5 and R.sub.6 are combined to form a group selected from the group consisting of morpholinyl, piperidinyl, perhexylenyl, N-loweralkylpiperazinyl, pyrrolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, (.+-.)-decahydroquinolinyl and indolinyl.
- 62. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of the formula ##STR13## or an optical isomer thereof or a pharmaceutically acceptable acid addition salt thereof wherein
- n is an integer of 1 to 6;
- R.sub.1 is hydrogen or alkyl of 1 to 4 carbons;
- R.sub.2 is hydrogen or R.sub.1 and R.sub.2 are combined to form an oxo group;
- R.sub.3 is an aliphatic hydroxy lower alkyl acylate of 1 to 6 carbon atoms or an aryl hydroxy lower alkyl acylate of 7 to 12 carbon atoms, carbamoyl alkyl, carboxyalkyl, alkoxycarbonylalkyl or an .alpha.-amino acid side chain;
- R.sub.4 is hydrogen, benzyl, hydroxy lower alkyl or alkyl of 1 to 6 carbons;
- Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy;
- A is NR.sub.5 R.sub.6 wherein R.sub.5 and R.sub.6 are independently selected from the group consisting of: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms or an aliphatic acylate of 1 to 6 carbon atoms or an aryl acylate of 7 to 12 carbon atoms; cycloalkyl of 3 to 8 carbon atoms or cycloalkyl lower alkyl of 4 to 12 carbon atoms wherein the cycloalkyl ring is unsubstituted or substituted with a lower alkyl, lower alkoxy, --OH, --OCOR.sub.7, halo, --NH.sub.2, --N(R.sub.7).sub.2, --NHCOR.sub.7, --COOH, or --COO(R.sub.7) group wherein R.sub.7 is lower alkyl; phenyl or phenyl lower alkyl wherein phenyl is unsubstituted or substituted with 1 or more lower alkyl, halo or lower alkoxy groups or an --NH.sub.2, --N(R.sub.7).sub.2, --NHCOR.sub.7, --COOH, or --COOR.sub.7 group wherein R.sub.7 is lower alkyl; or wherein R.sub.5 and R.sub.6 are combined to form a group selected from the group consisting of morpholinyl, piperidinyl, perhexylenyl, N-loweralkylpiperazinyl, pyrrolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, (.+-.)-decahydroquinolinyl, and indolinyl.
- 63. A method for inhibiting 3',5'-cyclic AMP phosphodiesterase which method comprises administering a cyclic AMP phosphodiesterase inhibiting amount of a compound of the formula ##STR14## or an optical isomers thereof or a pharmaceutically acceptable acid addition salt thereof either alone or in admixture with a a pharmaceutically acceptable excipient wherein
- n is an integer of 1 to 6;
- R.sub.1 is hydrogen or alkyl of 1 to 4 carbons;
- R.sub.2 is hydrogen or R.sub.1 and R.sub.2 are combined to form an oxo group;
- R.sub.3 is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl, hydroxy lower alkyl or an aliphatic acylate thereof of 1 to 6 carbon atoms or an aryl acylate thereof of 7 to 12 carbon atoms, carbamoyl alkyl, carboxyalkyl, alkoxycarbonylalkyl or an .alpha.-amino acid side chain;
- R.sub.4 is hydrogen, benzyl, hydroxy lower alkyl or alkyl of 1 to 6 carbons;
- Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy;
- A is NR.sub.5 R.sub.6 wherein R.sub.5 and R.sub.6 are independently selected from the group consisting of: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms or an aliphatic acylate of 1 to 6 carbon atoms or an aryl acylate of 7 to 12 carbon atoms; cycloalkyl of 3 to 8 carbon atoms or cycloalkyl lower alkyl of 4 to 12 carbon atoms wherein the cycloalkyl ring is unsubstituted or substituted with a lower alkyl, lower alkoxy, --OH, --OCOR.sub.7, halo, --NH.sub.2, --N(R.sub.7).sub.2, --NHCOR.sub.7, --COOH, or --COO(R.sub.7) group wherein R.sub.7 is lower alkyl; phenyl or phenyl lower alkyl wherein phenyl is unsubstituted or substituted with 1 or more lower alkyl, halo or lower alkoxy groups or an --NH.sub.2, --N(R.sub.7).sub.2, --NHCOR.sub.7, --COOH, or --COOR.sub.7 group wherein R.sub.7 is lower alkyl; or wherein N, R.sub.5 and R.sub.6 are combined to form a group selected from the group consisting of morpholinyl, piperidinyl, perhexylenyl, N-loweralkylpiperazinyl, pyrrolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, (.+-.)-decahydroquinolinyl, and indolinyl.
- 64. A method of inhibiting 3',5'-cyclic AMP phosphodiesterase which method comprises administering a cyclic AMP phosphodiesterase inhibiting amount of a compound of the formula ##STR15## or an optical isomer thereof or a pharmaceutically acceptable acid addition salt thereof either alone or in admixture with a a pharmaceutically acceptable excipient wherein
- n is an integer of 1 to 6;
- R.sub.1 is hydrogen or alkyl of 1 to 4 carbons;
- R.sub.2 is hydrogen or R.sub.1 and R.sub.2 are combined to form an oxo group;
- R.sub.3 is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl, hydroxy lower alkyl or an aliphatic acylate thereof of 1 to 6 carbon atoms or an aryl acylate thereof of 7 to 12 carbon atoms, carbamoyl alkyl, carboxyalkyl, alkoxycarbonylalkyl or an .alpha.-amino acid side chain;
- R.sub.4 is hydrogen, benzyl, hydroxy lower alkyl or alkyl of 1 to 6 carbons;
- Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy;
- A is NR.sub.5 R.sub.6 wherein R.sub.5 and R.sub.6 are independently selected from the group consisting of: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms or an aliphatic acylate of 1 to 6 carbon atoms or an aryl acylate of 7 to 12 carbon atoms; cycloalkyl of 3 to 8 carbon atoms or cycloalkyl lower alkyl of 4 to 12 carbon atoms wherein the cycloalkyl ring is unsubstituted or substituted with a lower alkyl, lower alkoxy, --OH, --OCOR.sub.7, halo, --NH.sub.2, --N(R.sub.7).sub.2, --NHCOR.sub.7, --COOH, or --COO(R.sub.7) group wherein R.sub.7 is lower alkyl; phenyl or phenyl lower alkyl wherein phenyl is unsubstituted or substituted with 1 or more lower alkyl, halo or lower alkoxy groups or an --NH.sub.2, --N(R.sub.7).sub.2, --NHCOR.sub.7, --COOH, or --COOR.sub.7 group wherein R.sub.7 is lower alkyl; or wherein N, R.sub.5 and R.sub.6 are combined to form a group selected from the group consisting of morpholinyl, piperidinyl, perhexylenyl, N-loweralkylpiperazinyl, pyrrolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, (.+-.)-decahydroquinolinyl, and indolinyl.
- 65. A method for inhibiting tumor growth in cases of spontaneous metastases or melanoma which method comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of the formula ##STR16## or an optical isomer thereof or a pharmaceutically acceptable acid addition salt thereof either alone or in admixture with a a pharmaceutically acceptable excipient wherein
- n is an integer of 1 to 6;
- R.sub.1 is hydrogen or alkyl of 1 to 4 carbons;
- R.sub.2 is hydrogen or R.sub.1 and R.sub.2 are combined to form a oxo group;
- R.sub.3 is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl, hydroxy lower alkyl or an aliphatic acylate thereof of 1 to 6 carbon atoms or an aryl acylate thereof of 7 to 12 carbon atoms, carbamoyl alkyl, carboxyalkyl, alkoxycarbonylalkyl or an .alpha.-amino acid side chain;
- R.sub.4 is hydrogen, benzyl, hydroxy lower alkyl or alkyl of 1 to 6 carbons;
- Y is hydrogen, alkyl of 1 to 4 carbon atoms, halo or lower alkoxy;
- A is NR.sub.5 R.sub.6 wherein R.sub.5 and R.sub.6 are independently selected from the group consisting of: hydrogen; alkyl of 1 to 6 carbon atoms; hydroxyalkyl of 1 to 6 carbon atoms or an aliphatic acylate of 1 to 6 carbon atoms or an aryl acylate of 7 to 12 carbon atoms; cycloalkyl of 3 to 8 carbon atoms or cycloalkyl lower alkyl of 4 to 12 carbon atoms wherein the cycloalkyl ring is unsubstituted or substituted with a lower alkyl, lower alkoxy, --OH, --OCOR.sub.7, halo, --NH.sub.2, --N(R.sub.7).sub.2, --NHCOR.sub.7, --COOH, or --COO(R.sub.7) group wherein R.sub.7 is lower alkyl; phenyl or phenyl lower alkyl wherein phenyl is unsubstituted or substituted with 1 or more lower alkyl, halo or lower alkoxy groups or an --NH.sub.2, --N(R.sub.7).sub.2, --NHCOR.sub.7, --COOH, or --COOR.sub.7 group wherein R.sub. 7 is lower alkyl; or wherein N, R.sub.5 and R.sub.6 are combined to form a group selected from the group consisting of morpholinyl, piperidinyl, perhexylenyl, N-loweralkylpiperazinyl, pyrrolidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, (.+-.)-decahydroquinolinyl, and indolinyl.
BACKGROUND OF THE INVENTION
This patent application is a continuation-in-part of U.S. Pat. No. 4,551,459, issued Nov. 5, 1985 (filed Apr. 13, 1984 as U.S. Ser. No. 06/599,858), which in turn is a continuation-in-part of U.S. Pat. No. 4,490,371, issued Dec. 25, 1984 (filed Feb. 16, 1983 as U.S. Ser. No. 06/467,125).
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Continuation in Parts (2)
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Number |
Date |
Country |
Parent |
599858 |
Apr 1984 |
|
Parent |
467125 |
Feb 1983 |
|