Details for Patent: 8,501,698

Title:	Crystal structures of SGLT2 inhibitors and processes for preparing same
Abstract:	The present invention relates to physical crystal structures of a compound of the formula I: ##STR00001## wherein R.sup.1, R.sup.2, R.sup.2a, R.sup.3 and R.sup.4 are as defined herein, especially ##STR00002## pharmaceutical compositions containing structures of compound I or II, processes for preparing same, intermediates used in preparing same, and methods of treating diseases such as diabetes using such structures.
Inventor(s):	Gougoutas; Jack Z. (Princeton, NJ), Lobinger; Hildegard (Princeton, NJ), Ramakrishnan; Srividya (Princeton, NJ), Deshpande; Prashant P. (Princeton, NJ), Bien; Jeffrey T. (Princeton, NJ), Lai; Chiajen (Princeton, NJ), Wang; Chenchi (Princeton, NJ), Riebel; Peter (Princeton, NJ), Grosso; John Anthony (Princeton, NJ), Nirschl; Alexandra A. (Princeton, NJ), Singh; Janak (Princeton, NJ), DiMarco; John D. (Princeton, NJ)
Assignee:	Bristol-Myers Squibb Company (Princeton, NJ)
Filing Date:	Mar 16, 2011
Application Number:	13/049,712
Claims:	1. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline (S)-propylene glycol ((S)-PG) solvate of the structure (form SC-3) Ia ##STR00066## characterized by a powder x-ray diffraction pattern comprising the following 2.theta.values (CuK.alpha..lamda.=1.5418.ANG.): 3.8.+-.0.1, 7.6.+-.0.1, 8.1.+-.0.1, 8.7.+-.0.1, 15.2.+-.0.1, 15.7.+-.0.1, 17.1.+-.0.1, 18.9.+-.0.1 and 20.1.+-.0.1, measured at at room temperature. 2. The pharmaceutical composition according to claim 1, wherein the crystalline (S)-propylene glycol ((S)-PG) solvate is characterized by one or more of the following: a) unit cell parameters substantially equal to the following: Cell dimensions: a=11.2688(8).ANG. b=4.8093(3).ANG. c=46.723(3).ANG. .alpha.=90 degrees .beta.=90 degrees .gamma.=90 degrees Space group =P2.sub.12.sub.12.sub.1 Molecules/asymmetric unit =1 wherein measurement of said crystalline structure is at room temperature and which is characterized by fractional atomic coordinates substantially as listed in Table 4; b) a solid state .sup.13C NMR spectrum having substantially similar peak positions at 16.2, 17.6, 39.3, 60.9, 63.3, 69.8, 76.9, 78.7, 79.4, 113.8, 123.6, 129.3, 130.5, 132.0, 135.7, 139.1 and 158.0 ppm, as determined on a 400 MHz spectrometer relative to TMS at zero; c) a differential scanning calorimetry thermogram having an endotherm in the range of about 50.degree. C. to 78.degree. C. or as shown in FIG. 7; or d) a thermal gravimetric analysis curve with about 18.7% weight loss from about room temperature up to about 240.degree. C. or as shown in FIG. 5. 3. A pharmaceutical composition according to claim 1 further comprising one or more therapeutic agents selected from the group consisting of an antidiabetic agent, an anti-obesity agent, an anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent. 4. A pharmaceutical composition according to claim 1, further comprising a pharmaceutically acceptable carrier or diluent. 5. The pharmaceutical composition according to claim 1, wherein the crystalline (S)-propylene glycol ((S)-PG) solvate is in substantially pure form. 6. The pharmaceutical composition according to claim 1, wherein the crystalline (S)-propylene glycol ((S)-PG) solvate has substantially pure phase homogeneity. 7. The pharmaceutical composition according to claim 1, wherein the crystalline (S)-propylene glycol ((S)-PG) solvate is characterized by unit cell parameters substantially equal to the following: Cell dimensions: a=11.2688(8).ANG. b=4.8093(3).ANG. c=46.723(3).ANG. .alpha.=90 degrees .beta.=90 degrees .gamma.=90 degrees Space group =P2.sub.12.sub.12.sub.1 Molecules/asymmetric unit =1, wherein measurement of the crystalline structure is at room temperature. 8. A pharmaceutical composition according to claim 7, further comprising one or more therapeutic agents selected from the group consisting of an antidiabetic agent, an anti-obesity agent, an anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent. 9. A pharmaceutical composition according to claim 7, further comprising a pharmaceutically acceptable carrier or diluent. 10. The pharmaceutical composition according to claim 7, wherein the crystalline (S)-propylene glycol ((S)-PG) solvate is in substantially pure form. 11. The pharmaceutical composition according to claim 7, wherein the crystalline (S)-propylene glycol ((S)-PG) solvate has substantially pure phase homogeneity. 12. The pharmaceutical composition according to claim 1, wherein the crystalline (S)-propylene glycol ((S)-PG) solvate is characterized by a solid state .sup.13C NMR spectrum having substantially similar peak positions at 16.2, 17.6, 39.3, 60.9, 63.3, 69.8, 76.9, 78.7, 79.4, 113.8, 123.6, 129.3, 130.5, 132.0, 135.7, 139.1 and 158.0 ppm, as determined on a 400 MHz spectrometer relative to TMS at zero. 13. A pharmaceutical composition according to claim 12, further comprising one or more therapeutic agents selected from the group consisting of an antidiabetic agent, an anti-obesity agent, an anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent. 14. A pharmaceutical composition according to claim 12, further comprising a pharmaceutically acceptable carrier or diluent. 15. The pharmaceutical composition according to 12, wherein the crystalline (S)-propylene glycol ((S)-PG) solvate is in substantially pure form. 16. The pharmaceutical composition according to claim 12, wherein the crystalline (S)-propylene glycol ((S)-PG) solvate has substantially pure phase homogeneity. 17. The pharmaceutical composition according to claim 1, wherein the crystalline (S)-propylene glycol ((S)-PG) solvate is characterized by a differential scanning calorimetry thermogram having an endotherm in the range of about 50.degree. C. to 78.degree. C. or as shown in FIG. 7. 18. A pharmaceutical composition according to claim 17, further comprising one or more therapeutic agents selected from the group consisting of an antidiabetic agent, an anti-obesity agent, an anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent. 19. A pharmaceutical composition according to claim 17, further comprising a pharmaceutically acceptable carrier or diluent. 20. The pharmaceutical composition according to claim 17, wherein the crystalline (S)-propylene glycol ((S)-PG) solvate is in substantially pure form. 21. The pharmaceutical composition according to claim 17, wherein the crystalline (S)-propylene glycol ((S)-PG) solvate has substantially pure phase homogeneity. 22. A method of treating diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, dyslipidemia, obesity, hypertriglyceridemia, Syndrome X, diabetic complications, atherosclerosis or hypertension, or for increasing high density lipoprotein levels in a mammal comprising administering to the mammal a therapeutically-effective amount of the pharmaceutical composition according to claim 1. 23. A method of treating Type II diabetes in a mammal comprising administering to the mammal a therapeutically-effective amount of the pharmaceutical composition according to claim 1. 24. A method of treating diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, dyslipidemia, obesity, hypertriglyceridemia, Syndrome X, diabetic complications, atherosclerosis or hypertension, or for increasing high density lipoprotein levels in a mammal comprising administering to the mammal a therapeutically-effective amount of the pharmaceutical composition according to claim 7. 25. A method of treating type II diabetes in a mammal comprising administering to the mammal a therapeutically-effective amount of the pharmaceutical composition according to claim 7. 26. A method of treating diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, dyslipidemia, obesity, hypertriglyceridemia, Syndrome X, diabetic complications, atherosclerosis or hypertension, or for increasing high density lipoprotein levels in a mammal comprising administering to the mammal a therapeutically-effective amount of the pharmaceutical composition according to claim 12. 27. A method of treating type II diabetes in a mammal comprising administering to the mammal a therapeutically-effective amount of the pharmaceutical composition according to claim 12. 28. A method of treating diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, dyslipidemia, obesity, hypertriglyceridemia, Syndrome X, diabetic complications, atherosclerosis or hypertension, or for increasing high density lipoprotein levels in a mammal comprising administering to the mammal a therapeutically-effective amount of the pharmaceutical composition according to claim 17. 29. A method of treating type II diabetes in a mammal comprising administering to the mammal a therapeutically-effective amount of the pharmaceutical composition according to claim 17.