Patent EA-002643-B1 (EA)
Title: Tartrate salt of a substituted dipeptide as growth hormone secretagogue
Inventor: CARPINO PHILIP ALBERT
IPC: C07K5/02
Filed: 1998-06-05
Abstract: 1. The (L)-(+)-tartaric acid salt of the compound of Formula I   2. The (L)-(+)-tartaric acid salt of the compound of formula I according to Claim 1 wherein the stereochemical configuration is 3a-S, 1-R. 3. The (L)-(+)-tartaric acid salt of the compound of formula I according to Claim 1 wherein the stereochemical configuration is 3a-S, 1-S. 4. The (L)-(+)-tartaric acid salt of the compound of formula i according to Claim 1 wherein the stereochemical configuration is 3a-R, 1-S. 5. The (L)-(+)-tartaric acid salt of the compound of formula I according to Claim 1 wherein the stereochemical configuration is 3a-R, 1-R. 6. A process for the preparation of the (D)-tartaric acid or the (L)tartaric acid salt of the compound of formula (E),   which comprises reacting the compound of formula (D),   with (D)-tartaric acid or (L)-tartaric acid in about 8:1 to about 9:1 mixture of acetone: water at a temperature between about 0 degree C to room temperature. 7. A process according to Claim 6 wherein (D)-tartaric acid is reacted with the compound of formula (D) and the compound of formula (E) has the R-configuration. 8. A process for the preparation of the compound of formula (J),   which comprises reacting the compound of formula (E),   with the compound of formula (X),   where Prt is an amine protecting group and X is OH, -O(C1-C4)alkyl or halo, in the presence of an organic base and a peptide coupling reagent at a temperature between about -78 degree C to about -20 degree C. 9. A process according to Claim 8 where the peptide coupling reagent is 1-propane phosphonic acid cyclic anhydride and the compound of formula X has the R-configuration and the compound of formula E has the R-configuration. 10. A process according to Claim 9 wherein Prt is tert-butoxycarbonyl. 11. A process for the preparation of the (L)-(+)-tartaric acid salt of the compound of formula I,   which comprises reacting the compound of formula (E),   with the compound of formula (X),   where Prt is an amine protecting group and X is OH, -O(C1-C4)alkyl or halo, in the presence of an organic base and a peptide coupling reagent at a temperature between about -78 degree C to about -20 degree C, to yield the compound of formula (J),   deprotecting the compound of formula (J) under appropriate deprotecting conditions to yield the compound of formula (K),   reacting the compound of formula (K) with (L)-(+)-tartaric acid in a reaction inert solvent to yield the (L)-(+)-tartaric acid salt of the compound of formula I. 12. A process according to Claim 11 where Prt is tert-butoxycarbonyl. 13. A process according to Claim 12 where the peptide coupling reagent is 1-propane phosphonic acid cyclic anhydride and the compound of formula I has the absolute and relative configuration 3a-(R), 1-(R). 14. A method for increasing levels of endogenous growth hormone in a human or other animal which comprises administering to such human or animal an effective amount of the (L)-(+)-tartaric acid salt of the compound of formula I according to Claim 1. 15. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an amount of the (L)-(+)-tartaric acid salt of the compound of formula I according to Claim 1. 16. A pharmaceutical composition useful for increasing the endogenous production or release of growth hormone in a human or other animal which comprises a pharmaceutically acceptable carrier, an effective amount of the (L) (+)-tartaric acid salt of the compound of formula I according to Claim 1 and a growth hormone secretagogue selected from the group consisting of GHRP-6, Hexarelin, GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2 and B-HT920 or an analog thereof. 17. A method for treating or preventing osteoporosis which comprises administering to a human or other animal in need of such treatment or prevention an amount of the (L)-(+)-tartaric acid salt of the compound of formula I according to Claim 1 which is effective in treating or preventing osteoporosis. 18. A method for treating or preventing diseases or conditions which may be treated or prevented by growth hormone which comprises administering to a human or other animal in need of such treatment or prevention an amount of the (L)-(+)-tartaric acid salt of the compound of formula I according to Claim 1 which is effective in promoting release of endogenous growth hormone. 19. A method according to Claim 18 wherein the disease or condition is congestive heart failure, obesity or frailty associated with aging. 20. A method according to Claim 19 wherein the disease or condition is congestive heart failure. 21. A method according to Claim 19 wherein the disease or condition is frailty associated with aging. 22. A method for accelerating bone fracture repair, attenuating protein catabolic response after a major operation, reducing cachexia and protein loss due to chronic illness, accelerating wound healing, or accelerating the recovery of burn patients or patients having undergone major surgery, which method comprises administering to a mammal in need of such treatment an amount of the (L)-(+)-tartaric acid salt of the compound of formula I according to Claim 1 which is effective in promoting release of endogenous growth hormone. 23. A method according to Claim 22 wherein the method is for accelerating the recovery of patients having undergone major surgery. 24. A method according to Claim 22 wherein the method is for accelerating bone fracture repair. 25. A method for improving muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis or renal homeostasis, which method comprises administering to a human or other animal in need of such treatment an amount of the (L)-(+)-tartaric acid salt of the compound of formula I according to Claim 1 which is effective in promoting release of endogenous growth hormone. 26. A method for the treatment or prevention of osteoporosis which comprises administering to a human or other animal with osteoporosis effective amounts of a bisphosphonate compound and the (L)-(+)-tartaric acid salt of the compound of formula I according to Claim 1. 27. A method for the treatment of osteoporosis according to Claim 26 wherein the bisphosphonate compound is ibandronate. 28. A method for the treatment of osteoporosis according to Claim 26 wherein the bisphosphonate compound is alendronate. 29. A method to increase IGF-1 levels in a human or other animal deficient in IGF-1 which comprises administering to a human or other animal with IGF-1 deficiency an effective amount of the (L)-(+)-tartaric acid salt of the compound of formula I according to Claim 1. 30. A method for increasing muscle mass, which method comprises administering to a human or other animal in need of such treatment an effective amount of the (L)-(+)-tartaric acid salt of the compound of formula I according to Claim 1. 31. A method for promoting growth in growth hormone deficient children which comprises administering to a growth hormone deficient child an effective amount of the (L)-(+)-tartaric acid salt of the compound of formula I according to Claim 1. 32. A method for treating insulin resistance in a mammal, which comprises administering to said mammal an effective amount of the (L)-(+)-tartaric acid salt of the compound of formula I according to Claim 1. 33. A method according to Claim 32 wherein the condition associated with insulin resistance is type I diabetes, type II diabetes, hyperglycemia, impaired glucose tolerance or an insulin resistant syndrome. 34. A method according to Claim 32 wherein the condition associated with insulin resistance is associated with obesity or old age. 35. The R,S-enantiomeric mixture, the R-enantiomer or the S-enantiomer of the compound of the formula   36. The (D)-tartaric acid or the (L)-tartaric acid salt of the compound according to Claim 35. 37. The 3a-(R,S),1-(R) diastereomeric mixture, the 3a-(R),1-(R) diastereomer or the 3a-(S),1-(R) diastereomer of the compound of the formula   where Prt is an amine protecting group selected from the group consisting of tert-BOC, FMOC and CBZ. 38. The R,S-enantiomeric mixture, the R-enantiomer or the S-enantiomer of the compound of the formula   39. The R,S-enantiomeric mixture, the R-enantiomer or the S-enantiomer of the compound of the formula   where X is OH, -O(C1-C4)alkyl or halo and Prt is an amine protecting group. 40. The compound according to Claim 39 where X is OH, Prt is BOC and the stereocenter is in the R-configuration. 41. A method of treating sleep disorders in a mammal suffering from sleep disorders comprising administering to said mammal an effective amount of the (L)-(+)-tartaric acid salt of the compound of formula I according to Claim 1.