Crystal forms of saxagliptin and processes for preparing same
View Patent ↗Physical crystal structures of a compound of the formula I: are provided including the free base monohydrate thereof (form H-1) and the hydrochloric acid salt thereof, including hydrochloric acid salt containing 0.75 equivalent of H 2 O (form H0.75-3) and hydrochloric acid salt containing 2 equivalents of H 2 O (form H2-1), and hydrochloric acid salt Pattern P-5, preferably in substantially pure form, and other forms as described herein, pharmaceutical compositions containing structures of compound I or IA, processes for preparing same, intermediates used in preparing same, and methods of treating diseases such as diabetes using such structures.
1. A method for treating diabetes, insulin resistance, hyperglycemia, dyslipidemia or elevated blood levels of free fatty acids or glycerol, obesity, Syndrome X, dysmetabolic syndrome, retinopathy, neuropathy, nephropathy, cataracts, hypertriglyceridemia, hyperinsulinemia, atherosclerosis, impaired glucose homeostasis, impaired glucose tolerance, infertility, polycystic ovary syndrome, arthritis, allograft rejection in transplantation, scleroderma, multiple sclerosis, necrotizing enteritis, microvillus inclusion disease, celiac disease, inflammatory bowel syndrome, anorexia nervosa, osteoporosis, lupus erythematosis, psoriasis, Crohn's disease, or ulcerative colitis, which comprises administering to a mammalian species in need of treatment or an effective amount of a crystalline compound in a form selected from H2-1 (1HCl), H2-1 (2HCl), H0.75-3, H1.67-1, P-5, N-3, H-1 (1H 2 O), H-1 (1PhCO 2 H/1H 2 O), N-1, and mixtures thereof,
wherein the crystalline compound of form H2-1 (1HCl) has structure
and has powder x-ray diffraction peaks at 2θ values (CuKα λ−1.5418 Å) of 6.8±0.1, 11.1±0.1, 13.7±0.1, 14.6±0.1, 15.2±0.1, 16.4±0.1, 17.0±0.1, 20.2±0.1, and 21.1 ±0.1;
wherein the crystalline compound of form H2-1 (2HCl) has structure
and has powder x-ray diffraction peaks at 2θ values (CuKα λ−1.5418 Å) of 7.2±0.1, 8.6±0.1, 11.6±0.1, 14.3±0.1, 15.7±0.1, 19.5±0.1, and 22.5±0.1;
wherein the crystalline compound of form H0.75-3 has structure
and has powder x-ray diffraction peaks at 2θ values (CuKα λ−1.5418 Å) of 5.0±0.1, 7.0±0.1, 8.1±0.1, 11.4±0.1, 13.4±0.1, 14.0±0.1, 14.5±0.1, 18.6±0.1, 19.4±0.1, and 20.0±0.1;
wherein the crystalline compound of form H1.67-1 has structure
and has powder x-ray diffraction peaks at 2θ values (CuKα λ−1.5418 Å) of 5.4±0.1, 7.0±0.1, 13.8±0.1, 14.2±0.1, 14.6±0.1, 16.1±0.1, 16.6±0.1, 18.6±0.1, 19.0±0.1, and 20.3±0.1;
wherein the crystalline compound of form P-5 has structure
and has powder x-ray diffraction peaks at 2θ values (CuKα λ−1.5418 Å) of 6.2±0.1, 10.7±0.1, 14.5±0.1, 15.0±0.1, 15.6±0.1, 16.2±0.1, 18.1±0.1, 18.7±0.1, and 21.1 ±0.1;
wherein the crystalline compound of form N-3 has structure
and has powder x-ray diffraction peaks at 2θ values (CuKα λ−1.5418 Å) of 5.2±0.1, 7.9±0.1, 10.8±0.1, 11.5±0.1, 13.0±0.1, 14.6±0.1, 15.6±0.1, 15.9±0.1, and 16.5±0.1;
wherein the crystalline compound of form H-1 (1H 2 O) has structure
and has powder x-ray diffraction peaks at 2θ values (CuKα λ−1.5418 Å) of 12.4±0.1, 13.3±0.1, 13.6±0.1, 14.7±0.1, 16.2±0.1, 18.2±0.1, 19.9±0.1, 20.9±0.1, 21.9 ±0.1, and 22.4±0.1;
wherein the crystalline compound of form H-1 (1PhCO 2 H/1H 2 O) has structure
and has powder x-ray diffraction peaks at 2θ values (CuKα λ−1.5418 Å) of 6.6±0.1, 8.3±0.1, 15.3±0.1, 16.1±0.1, 16.9±0.1, 17.5±0.1, 17.8±0.1, 18.6±0.1, and 21.3±0.1; and
wherein the crystalline compound of form N-1 has structure
and has powder x-ray diffraction peaks at 2θ values (CuKα λ−1.5418 Å) of 5.5±0.1, 7.0±0.1, 11.1±0.1, 14.4±0.1, 15.1±0.1, 15.7±0.1, 16.4±0.1, 16.8±0.1, and 19.6±0.1,
alone or in combination with a therapeutic agent.
2. The method according to claim 1 , wherein the method is a method for treating type II diabetes.
3. The method according to claim 1 , wherein the crystalline compound is in a form selected from H2-1 (1HCl), H2-1 (2HCl), H0.75-3, H1.67-1, P-5, and mixtures thereof.
4. The method according to claim 3 , wherein the crystalline compound is in a form H2-1 (1HCl).
5. The method according to claim 4 , wherein the crystalline compound of form H2-1 (1HCl) has an observed powder x-ray diffraction pattern as shown in FIG. 6 .
6. The method according to claim 3 , wherein the crystalline compound is in a form H2-1 (2HC 1 ).
7. The method according to claim 3 , wherein the crystalline compound is in a form H0.75-3.
8. The method according to claim 7 , wherein the crystalline compound of form H0.75-3 has an observed powder x-ray diffraction pattern as shown in FIG. 11 .
9. The method according to claim 3 , wherein the crystalline compound is in a form H1.67-1.
10. The method according to claim 9 , wherein the crystalline compound of form H1.67-1 has an observed powder x-ray diffraction pattern as shown in FIG. 16 .
11. The method according to claim 3 , wherein the crystalline compound is in a form P-5.
12. The method according to claim 11 , wherein the crystalline compound of form P-5 has an observed powder x-ray diffraction pattern as shown in FIG. 28 .
13. The method according to claim 1 , wherein the crystalline compound is in a form selected from N-3, H-1 (1H 2 O), H-1 (1PhCO 2 H/1H 2 O), and N-1, and mixtures thereof.
14. The method according to claim 13 , wherein the crystalline compound is of form N-3.
15. The method according to claim 11 , wherein the crystalline compound of form N-3 has an observed powder x-ray diffraction pattern as shown in FIG. 25 .
16. The method according to claim 13 , wherein the crystalline compound is of form H-1 (1H 2 O).
17. The method according to claim 16 , wherein the crystalline compound of form H-1 (1H 2 O) has an observed powder x-ray diffraction pattern as shown in FIG. 1 .
18. The method according to claim 13 , wherein the crystalline compound is of form H-1 (1PhCO 2 H/1H 2 O).
19. The method according to claim 18 , wherein the crystalline compound of form H-1 (1PhCO 2 H/1H 2 O) according to claim 18 has an observed powder x-ray diffraction pattern as shown in FIG. 22 .
20. The method according to claim 13 , wherein the crystalline compound is of form N-1.
21. The method according to claim 20 , wherein the crystalline compound of form N-1 has an observed powder x-ray diffraction pattern as shown in FIG. 21 .
22. The method according to claim 1 , wherein the crystalline compound is administered in combination with at least one or more antidiabetic agent(s) other than a DPP4 inhibitor for treating diabetes.
23. The method according to claim 22 wherein the antidiabetic agent is a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ agonist, a CTEP inhibitor, a PPAR α/γ dual agonist, an SGLT2 inhibitor, an aP2 inhibitor, a glycogen phosphorylase inhibitor, an AGE inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1) or mimetic thereof, insulin and/or a meglitinide.
24. The method according to claim 22 wherein the antidiabetic agent is metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, dapagliflozin, rosiglitazone, insulin, G1-262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, APR-HO39242, GW-409544, KRP297, AC2993, Exendin-4, LY307161, NN2211, and/or LY315902.
25. The method according to claim 22 wherein the antidiabetic agent is metformin, glyburide, glipizide, or dapagliflozin.
26. The method according to claim 22 wherein the antidiabetic agent is metformin or dapagliflozin.
27. The method according to claim 22 wherein the antidiabetic agent is dapagliflozin.
28. The method according to claim 1 , wherein the crystalline compound is administered in combination with an anti-obesity agent.
29. The method according to claim 28 , wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, famoxin, and/or mazindol.
30. The method according to claim 1 , wherein the crystalline compound is administered in combination with a lipid modulating agent.
31. The method according to claim 30 , wherein the lipid modulating agent is pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, ZD-4522, fenofibrate, gemfibrozil, clofibrate, implitapide, CP-529,414, avasimibe, TS-962, MD-700, and/or LY295427.