Patent EA-002746-B1 (EA)
Title: Growth hormone secretagogues
Inventor: DODGE JEFFREY ALAN
IPC: C07D233/88
Filed: 1998-08-19
Abstract: 1. A compound of formula I   wherein: A is C1-C6alkyl, aryl, C1-C6alkylaryl, C1-C6alkyl (O)C1-C6alkylaryl, C1-C6alkyl (S)C1-C6alkylaryl, indolyl, indolinyl, thienyl, (C1-C6alkyl)thienyl, benzothienyl, benzofuranyl, naphthanyl, cyclohexyl, (C1-C6alkyl)indolyl, (C1-C6alkyl)benzothienyl, (C1-C6alkyl)naphthanyl, (C1-C6alkyl)benzofuranyl, and (C1-C6alkyl)cyclohexyl; B is NH2, NHR1, C1-C6alkyl NH2, C1-C6alkyl NHR1, C1-C6alkylaryl NH2, C1-C6alkylaryl NHR1, C1-C6a1kylcyclohexyl NH2, C1-C6alkylcyclohexyl NHR1, R1-piperidin-3-yl(C1-C6alkyl), R1-piperidin-2-yl(C1-C6alkyl), R1-piperidin-4-yl(C1-C6alkyl), R1-quinolin-2-yl(C1-C6alkyl), R1-(2,4-dihydroquinolin-2-yl(C1-C6alkyl), R1-isoquinolin-2-yl(C1-C6alkyl), and R1-(2,4-dihydroisoquinolin-2-yl(C1-C6alkyl); R1 is hydrogen, C1-C6alkyl, C1-C6alkyl(OH), or C1-C6alkylidenyl(OH)R2; R2 is C1-C6alkyl, C1-C6alkenyl, C1-C6alkyl(O)C1-C6 alkyl, C(O)O-C1-C6 alkyl, aryl, or C1-C6alkylaryl; X is C1-C6alkylidenyl, O, S, NH, or N(C1-C6alkyl); V is selected from the group consisting of   W is S, O, NH, or CH2; Y is N or CH; Z is N or CH; Y' is N or CH; Z' is N or CH; R4 and R5 are independently hydrogen, C1-C6alkyl, aryl, C1-C6alkylaryl, C(O)O(C1-C6alkyl), C(O)N(C1-C6alkyl)2, or C1-C6alkylCOR7; R7 is hydrogen, C1-C6alkyl, pyrrolidinyl, piperidinyl, homoproline, or proline; D is hydrogen, C1-C6alkyl, C1-C6alkyl(O)(CO)C1-C6alkyl, C1-C6alkyl(O)(CO)N(C1-C6alkyl)2, C1-C6alkylaryl, C(O)R6, C1-C6alkyl(O)R6, C1-C6alkyl(OH), C1-C6 alkylC(O)R6, C1-C6alkylR6, aryl, (C1-C6alkyl)NHSO2(C1-C6alkyl), (C1-C6alkyl)NHSO2(aryl); R6 is H, C1-C6alkyl, aryl, naphthyl, C1-C6alkylaryl, acetyl, NH2, NH (C1-C6alkyl), NH(C1-C6alkyl)O(C1-C6alkyl), NH(C1-C6alkyl)S(C1-C6alkyl), NH(C1-C6alkylidenyl)OCH3, NH(C1-C6alkyl)aryl, NH(C3-C6cycloalkyl), NH(C1-C6alkyl)C(O)(C1-C6alkyl), NH(C1-C6alkyl)NH(C1-C6alkyl), NH(C1-C6alkyl)NH(C1-C6alkylaryl), NHSO2(C1-C6alkylaryl), NH(C1-C6alkyl)C(O)O(C1-C6alkyl), NH(naphthyl), N(C1-C6alkyl)2, N(C1-C6alkyl)(aryl), N(C1-C6alkyl)(C1-C6alkylaryl), O(C1-C6alkyl), O(aryl), O(C1-C6alkylaryl), piperidinyl, piperidinyl-C(O)NH(C1-C6alkyl), piperidinyl-C(O)NH(C1-C6alkylaryl), piperidinyl-C(O)N(C1-C6alkyl)2, piperidinyl-C(O)N(C1-C6alkyl)(aryl), pyrrolidinyl, pyrrolidinyl C(O)NH(aryl), pyrrolidinyl C(O)NH(C1-C6alkyl), pyrrolidinyl C(O)N(C1-C6alkyl)2, pyrrolidinyl C(O)NH(C1-C6alkylaryl), pyrrolidinyl C(O)NH(C1-C6alkyl)(aryl), pyrrolinyl, morpholino, hexamethyleneimino, heptamethyleneimino, quinolinyl, 2,4-dihydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,4-dihydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, indolinyl, an amino acid selected from the group consisting of proline, homoproline, glycine, alanine, valine, leucine, isoleucine, tyrosine, tryptophan, phenylalanine, serine, threonine, asparagine, glutamic acid, aspartic acid, lysine, arginine, glutamine, histidine, cysteine, and methionine, or a nitrogen-containing heterocycle selected from the group consisting of     E is hydrogen, C1-C6alkyl, C(O)C1-C6alkyl, aryl, (aryl)C(O)NR6, (aryl) (C1-C6alkyl)C(O)R6, C1-C6alkylaryl, C(O) aryl, C1-C6 alkylC(O)aryl, naphthyl, C1-C6alkylnaphthyl, C(O)naphthyl, C1-C6alkylC(O)naphthyl, heteroaryl, C1-C6alkylheteroaryl, C(O)heteroaryl, C1-C6alkylC(O)heteroaryl, indanyl, C1-C6alkylindanyl, C(O)indanyl, C1-C6alkylC(O)indanyl, cycloalkyl; or D and E combine to form indanyl, fluorenyl, or cycloalkyl; G is hydrogen, C1-C6alkyl, aryl, C1-C6alkylaryl, and C1-C6alkenyl; J is hydrogen, C1-C6alkyl, aryl, and C1-C6alkylaryl; L is hydrogen, C1-C6alkyl, C(O)OC1-C6alkyl, aryl, C1-C6alkylaryl, C(O)OC1-C6alkylaryl, C1-C6alkenyl, -F, and -CN, C1-C6alkyl-OH, C1-C6alkyl-O-C1-C6alkyl, C1-C6alkyl-C(O)R6; or a pharmaceutically acceptable salt or solvate thereof. 2. A compound according to Claim 1 wherein A is selected from the group consisting of   3. A compound according to Claim 1 wherein B is    4. A compound according to Claim 1 wherein X is NH. 5. A compound according to Claim 1 wherein V is selected from the group consisting of   6. A compound according to Claim 1 wherein D is -C(O)R6, and R6 is 1-pyrrolidinyl, 1-piperidinyl, 4-methyl-1-piperidinyl,   7. A compound according to Claim 1 wherein E is    8. A compound according to Claim 1 wherein G is H. 9. A compound according to Claim 1 wherein J is H. 10. A compound according to Claim 1 wherein L is H or CH3. 11. A compound of formula IA:   or a pharmaceutically acceptable salt or solvate thereof. 12. A compound of formula IB:   or a pharmaceutically acceptable salt or solvate thereof. 13. A compound of formula Ia':   wherein E is selected from the group consisting of hydrogen, C1-C6alkyl, C(O)C1-C6alkyl, aryl, (aryl)C(O)NR6, (aryl) (C1-C6alkyl)C(O)R6, C1-C6alkylaxyl, C(O)aryl, C1-C6 alkylC(O)aryl, naphthyl, C1-C6alkylnaphthyl, C(O)naphthyl, C1-C6alkylC(O)naphthyl, heteroaryl, C1-C6alkylheteroaryl, C(O)heteroaryl, C1-C6 alkylC(O)heteroaryl, indanyl, C1-C6alkylindanyl, C(O)indanyl, C1-C6alkylC(O)indanyl, cycloalkyl; or a pharmaceutically acceptable salt or solvate thereof. 14. A compound of formula ZZ:   wherein E is selected from the group consisting of hydrogen, C1-C6alkyl, C(O)C1-C6alkyl, aryl, C1-C6alkylaryl, C(O)aryl, C1-C6 alkylC(O)aryl, naphthyl, C1-C6alkylnaphthyl, C(O)naphthyl, C1-C6alkylC(O)naphthyl, heteroaryl, C1-C6alkylheteroaryl, C(O)heteroaryl, C1-C6alkylC(O)heteroaryl, indanyl, C1-C6alkylindanyl, C(O)indanyl, C1-C6alkylC(O)indanyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 15. A compound of formula ZZZ:   wherein E is selected from the group consisting of hydrogen, C1-C6alkyl, C(O)C1-C6alkyl, aryl, C1-C6alkylaryl, C(O)aryl, C1-C6alkylC(O)aryl, naphthyl, C1-C6alkylnaphthyl, C(O)naphthyl, C1-C6alkylC(O)naphthyl, heteroaryl, C1-C6alkylheteroaryl, C(O)heteroaryl, C1-C6 alkylC(O)heteroazyl, indanyl, C1-C6alkylindanyl, C(O)indanyl, C1-C6alkylC(O)indanyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 16. A method for increasing the level of endogenous growth hormone in a human or an animal which comprises administering to said human or animal an effective amount of a compound of formula Id:   or a pharmaceutically acceptable salt or solvate thereof. 17. A pharmaceutical formulation which comprises as an active ingredient a compound of Claim 1, or a pharmaceutically acceptable salt or solvate thereof, associated with one or more pharmaceutically acceptable carriers, diluents, or excipients. 18. A compound according to Claim 1 wherein A is selected from the group consisting of   B is    J is H; G is H; X is NH; V is    E is    D is -C(O)R6, and R6 is 1-pyrrolidinyl, 1-piperidinyl, 4-methyl-1-piperidinyl,   L is H or CH3; or a pharmaceutically acceptable salt or solvate thereof. 19. A compound according to claim 1, which is a compound of formula   or a pharmaceutically acceptable salt or solvate thereof. 20. A compound according to claim 1, which is a compound of formula   or a pharmaceutically acceptable salt or solvate thereof. 21. A compound according to claim 1, which is a compound of formula   or a pharmaceutically acceptable salt or solvate thereof. 22. A compound according to claim 1, which is a compound of formula   or a pharmaceutically acceptable salt or solvate thereof. 23. A compound according to claim 1, which is a compound of formula   or a pharmaceutically acceptable salt or solvate thereof. 24. A compound according to claim 1, which is a compound of formula   or a pharmaceutically acceptable salt or solvate thereof. 25. A compound according to claim 1, which is a compound of formula   or a pharmaceutically acceptable salt or solvate thereof. 26. A compound according to claim 1, which is a compound of formula   or a pharmaceutically acceptable salt or solvate thereof. 27. A compound according to claim 1, which is a compound of formula   or a pharmaceutically acceptable salt or solvate thereof. 28. A compound according to claim 1, which is a compound of formula   or a pharmaceutically acceptable salt or solvate thereof. 29. A compound according to claim 1, which is a compound of formula   or a pharmaceutically acceptable salt or solvate thereof. 30. A compound according to claim 1, which is a compound of formula   or a pharmaceutically acceptable salt or solvate thereof. 31. A compound according to claim 1, which is a compound of formula   or a pharmaceutically acceptable salt or solvate thereof. 32. A compound according to claim 1, which is a compound of formula   or a pharmaceutically acceptable salt or solvate thereof.