Patent EA-004937-B1 (EA)
Title: Sodium-hydrogen exchanger type 1 inhibitor crystals
Inventor: BROSTROM LYLE ROBINSON
IPC: C07D401/04
Filed: 2000-10-09
Abstract: 1. A crystalline form of a salt having the Formula I which is anhydrous N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine, monomesylate salt. 2. A crystalline of claim 1 which is anhydrous N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine, monomesylate salt (D) having the following X-ray diffraction pattern (Form D) Interplanar spacing d( angstrom )	Relative intensity l	Interplanar spacing d( angstrom )	Relative intensity l	Interplanar spacing d( angstrom )	Relative intensity l 27.24671	2.8	5.99091	6.0	4.00874	26.0 23.73093	2.2	5.63525	25.5	3.92839	6.2 16.16249	100.0	5.47164	11.5	3.69629	10.3 13.22989	1.7	5.27699	39.9	3.60428	7.4 11.97180	1.5	5.17064	18.3	3.55640	23.3 8.70523	1.2	5.03666	22.4	3.47039	9.6 8.06940	6.9	4.81802	24.0	3.40872	12.2 7.82513	7.2	4.46748	17.0	3.35011	12.3 7.25205	8.4	4.17294	62.7	3.26503	3.6 6.70670	10.2	4.06613	10.7		 Interplanar spacing d( angstrom )	Relative intensity l	Interplanar spacing d( angstrom )	Relative intensity l 3.21953	5.2	2.58367	2.4 3.13686	4.7	2.55540	2.3 3.09315	2.5	2.51395	3.1 2.98181	10.2	2.46750	2.4 2.91078	4.2	2.40342	2.1 2.85527	3.6	2.36976	2.5 2.73317	3.4	2.33468	4.3 2.68209	5.6	2.30520	2.6 2.64423	2.6	2.26652	1.5 3. A crystal of claim 1 which is the anhydrous N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine, monomesylate salt (A) having the following X-ray diffraction pattern (FORM A) Interplanar spacing d( angstrom )	Relative intensity l	Interplanar spacing d( angstrom )	Relative intensity l	Interplanar spacing d( angstrom )	Relative intensity l 12.78805	75.6	5.98486	14.5	4.40968	9.1 10.11984	0.9	5.74817	7.7	4.26077	35.9 9.54998	1.0	5.44162	25.8	3.99060	100.0 8.48106	10.5	5.17467	6.2	3.70101	9.6 8.06059	32.3	4.88694	19.8	3.56895	10.0 7.40035	3.7	4.80505	6.4	3.45647	18.9 6.90891	9.9	4.71329	12.3	3.39599	4.3 6.78458	7.1	4.64163	8.3	3.28501	14.3 6.39441	37.1	4.47485	17.2	3.19673	8.2 Interplanar spacing d( angstrom )	Relative intensity l	Interplanar spacing d( angstrom )	Relative intensity l 3.13360	28.1	2.64749	3.2 3.05819	7.2	2.58618	5.7 2.98863	6.2	2.55874	3.4 2.92559	4.5	2.51058	3.5 2.90063	3.7	2.44154	3.9 2.87377	3.5	2.37704	2.5 2.80412	3.0	2.31951	3.9 2.67941	5.6	2.29666	3.1 4. A crystal of claim 1 which is N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine, monomesylate hemihydrate. 5. A method for making the crystal of claim 2 comprising combining an acetone solution of N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine and N-methyl pyrrolidinone with methanesulfonic acid at a temperature of about 30 degree C to about 60 degree C, followed by cooling to a temperature of about ambient to about 35 degree C. 6. A method for making the crystal of claim 3 comprising repulping the Form (D) anhydrous crystal in acetone at a temperature of about 20 degree C to about 25 degree C. 7. A method for making the crystal of claim 4 comprising repulping the anhydrous Form A crystal in ethanol or iso-propanol/water at a temperature of about 20 degree C to about 25 degree C. 8. The method of claim 7 wherein the range is about 85% to about 95% ethanol and about 5% to about 15% water. 9. [5-Cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl]guanidine, monomesylate hemihydrate. 10. A method of reducing tissue damage resulting from ischemia or hypoxia comprising administering to a mammal in need of such treatment a therapeutically effective amount of a pharmaceutical composition wherein said composition comprises a crystal of claim 1 and a pharmaceutically acceptable carrier, vehicle or diluent. 11. A method as recited in claim 10 wherein the tissue is cardiac, brain, liver, kidney, lung, gut, skeletal muscle, spleen, pancreas, nerve, spinal cord, retina tissue, the vasculature, or intestinal tissue. 12. A method as recited in claim 11 wherein the amount of the Formula I crystal is about 0.01 mg/kg/day to about 10 mg/kg/day. 13. A method as recited in claim 12 wherein the mammal is a female or male human. 14. A method as recited in claim 13 wherein said tissue is heart tissue. 15. A method as recited in claim 13 wherein said tissue is brain tissue. 16. A method as recited in claim 13 wherein said tissue is liver tissue. 17. A method as recited in claim 13 wherein said tissue is kidney tissue. 18. A method as recited in claim 13 wherein said tissue is lung tissue. 19. A method as recited in claim 13 wherein said tissue is gut tissue. 20. A method as recited in claim 15 wherein said tissue is skeletal muscle tissue. 21. A method as recited in claim 13 wherein said tissue is spleen tissue. 22. A method as recited in claim 13 wherein said tissue is pancreas tissue. 23. A method as recited in claim 13 wherein said tissue is retina tissue. 24. A method as recited in claim 13 wherein the compound is administered prophylactically. 25. A method as recited in claim 13 wherein the pharmaceutical composition is administered prior to surgery. 26. A method as recited in claim 13 wherein the pharmaceutical composition is administered prior to cardiac surgery. 27. A method as recited in claim 13 wherein the pharmaceutical composition is administered during surgery. 28. A method as recited in claim 13 wherein the pharmaceutical composition is administered during cardiac surgery. 29. A method as recited in claim 13 wherein the pharmaceutical composition is administered within twenty-four hours after surgery. 30. A method as recited in claim 13 wherein the pharmaceutical composition is administered within twenty four hours after cardiac surgery. 31. A method as recited in claim 13 wherein the tissue damage resulting from ischemia is ischemic damage and is incurred during organ transplantation. 32. A method as recited in claim 13 wherein the pharmaceutical composition is administered to prevent perioperative myocardial ischemic injury. 33. A pharmaceutical composition which comprises a therapeutically effective amount of a crystal of claim 1 and a pharmaceutically acceptable carrier, vehicle or diluent. 34. A pharmaceutical composition for the reduction of tissue damage resulting from ischemia or hypoxia which comprises a therapeutically effective amount of a crystal of claim 1 and a pharmaceutically acceptable carrier, vehicle or diluent. 35. A method as recited in claim 13 wherein the pharmaceutical composition is administered prior to, during and after surgery. 36. A method as recited in claim 13 wherein the pharmaceutical composition is administered prior to, during and after cardiac surgery.