Patent EA-000528-B1 (EA)
Title: Polymorphic forms of a growth hormone secretagogue
Inventor: DRAPER JEROME P
IPC: C07K5/062
Filed: 1996-10-23
Abstract: 1. A polymorphic form of the compound N-[1(R)-[(1,2-dihydro-1-methanesulfonyl-spiro[3H-indole-3,4'-piperidin]-1'-yl)-carbonyl]-2-(phenylmethyl-oxy)ethyl]-2-amino-2-methylpropanamide methanesulfonate designated Form I, characterized by an X-ray powder diffraction pattern with principal reflections at approximately: 6.5, 14.7, 16.9, 17.1, 17.9, 19.5, 21.1, 21.7, and 22.0 degree  (2 theta). 2. The polymorphic form of Claim 1 characterized by an endothern of melting with an extrapolated onset temperature of about 170 degree C when heated in a differential scanning calorimetric cell at a rate of 10 degree C/min under a nitrogen atmosphere. 3. The polymorphic form of Claim 1 characterized in that solubility in isopropanol 4,6 mg/ml. 4. The polymorphic form of Claim 1 characterized by a double refraction in polirized light. 5. The polymorphic form of the compound N-[1(R)-[(1,2-dihydro- l-methanesulfonyl-spiro[3H-indole-3,4'-piperidin]-1'-yl)-carbonyl]-2-(phenylmethyl-oxy)ethyl]-2-amino-2-methylpropanamide methanesulfonate designated Form IV, characterized by an X-ray powder diffraction pattern with principal reflections at approximately: 16.0, 16.2, 18.3, 20.1, 21.0, and 24.2 degree  (2 theta). 6. The polymorphic form of Claim 5 characterized by a water loss endothenn at a temperature of about 45 degree C followed by an endothern with an extrapolated onset temperature of about 129 degree C when heated in a differential scanning calorimetric cell at a rate of 10 degree C/min under a nitrogen atmosphere. 7. The polymorphic form of Claim 5 which contains approximately 3.5 moles of water per mole of N-[l(R)-[(l,2-dihydro-l-methanesulfonyl-spiro[3H-indole-3,4'-piperidin]- 1'-yl)carbonyl]-2-(phenylmethyl-oxy)ethyl]-2-amino-2-methylpropanamide methanesulfonate. 8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the polymorphic form of Claim 1. 9. The pharmaceutical composition useful for the treatment of osteoporosis which comprises a combination of a bisphosphonate compound and the polymorphic form of Claim 1. 10. The pharmaceutical composition of Claim 9 wherein the bisphosphonate compound is alendronate. 11. The pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the polymorphic form of Claim 5. 12. A pharmaceutical composition useful for the treatment of osteoporosis which comprises a combination of a bisphosphonate compound and the polymorphic form of Claim 5. 13. The pharmaceutical composition of Claim 12 wherein the bisphosphonate compound is alendronate. 14. A method for increasing levels of endogenous growth hormone in a human or an animal which comprises administering to such human or animal an effective amount of the polymorphic form of Claim 1. 15. A method for increasing levels of endogenous growth hormone in a human or an animal which comprises administering to such human or animal an effective amount of the polymorphic form of Claim 1 and an additional growth hormone secretagogue. 16. The method of Claim 15 wherein the additional growth hormone secretagogue is selected from the group consisting of: growth hormone releasing peptide GHRP-6; growth hormone releasing peptide GHRP-2; growth hormone releasing peptide GHRP-1; B-HT920; growth hormone releasing factor; an analog of growth hormone releasing factor; IGF-1 and IGF-2. 17. A method for increasing feed efficiency, promoting growth, increasing milk production and improving the carcass quality of livestock which comprises administering to such livestock an effective amount of the polymorphic form of Claim 1. 18. A method of treating or preventing a condition selected from the group consisting of: osteoporosis; catabolic illness; immune deficiency, including that in individuals with a depressed T4/T8 cell ratio; hip fracture; musculoskeletal impairment in the elderly; growth hormone deficiency in adults or in children; obesity; cachexia and protein loss due to chronic illness such as AIDS or cancer; and treating patients recovering from major surgery, wounds or bums, in a patient in need thereof which comprises the administration to the patient of an effective amount of the polymorphic form of Claim 1. 19. A method for the treatment of osteoporosis which comprises administering to a patient with osteoporosis a combination of a bisphosphonate compound and the polymorphic form of Claim 1. 20. The method of Claim 19 wherein the bisphosphonate compound is alendronate. 21. A method for increasing levels of endogenous growth hormone in a human or an animal which comprises administering to such human or animal an effective amount of the polymorphic form of Claim 5. 22. A method for increasing levels of endogenous growth hormone in a human or an animal which comprises administering to such human or animal an effective amount of the polymorphic form of Claim 1 and an additional growth hormone secretagogue. 23. The method of Claim 22 wherein the additional growth hormone secretagogue is selected from the group consisting of: growth hormone releasing peptide GHRP-6; growth hormone releasing peptide GHRP-2; growth hormone releasing peptide GHRP-1; B-HT920; growth hormone releasing factor; an analog of growth hormone releasing factor; IGF-1 and IGF-2. 24. A method for increasing feed efficiency, promoting growth, increasing milk production and improving the carcass quality of livestock which comprises administering to such livestock an effective amount of the polymorphic form of Claim 5. 25. A method of treating or preventing a condition selected from the group consisting of: osteoporosis; catabolic illness; immune deficiency, including that in individuals with a depressed T4/T8 cell ratio; hip fracture; usculoskeletal impairment in the elderly; growth hormone deficiency in adults or in children; obesity; cachexia and protein loss due to chronic illness such as AIDS or cancer; and treating patients recovering from major surgery, wounds or bums, in a patient in need thereof which comprises the administration to the patient of an effective amount of the polymorphic form of Claim 5. 26. A method for the treatment of osteoporosis which comprises administering to a patient with osteoporosis a combination of a bisphosphonate compound and the polymorphic form of Claim 5. 27. The method of Claim 26 wherein the bisphosphonate compound is alendronate. 28. A process for the preparation of the polymorphic form of Claim 1 designated Form I which comprises: stirring a solution of Form II of N-[l(R)-[(l,2-dihydro-1 -methanesulfonyl-spiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethyl-oxy)ethyl]-2-amino-2-methylpropanamide methane-sulfonate in isopropanol at approximately 25 degree C for about 2-24 hours.