Crystal forms of saxagliptin and processes for preparing same

• US 8,236,847 B2
• Filed: 04/06/2011
• Issued: 08/07/2012
• Est. Priority Date: 04/20/2007
• Status: Expired due to Fees

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Gougoutas, Jack Z., Malley, Mary F., DiMarco, John D., Yin, Xiaotian S., Wei, Chenkou, Yu, Jurong, Vu, Truc Chi, Jones, Gregory Scott, Savage, Scott A.
• Primary Examiner(s): Anderson, Rebecca
• Assistant Examiner(s): SHTERENGARTS, SAMANTHA L
• Application Number:
  US13/081,341
• Publication Number:
  US 20110257085A1
• Time in Patent Office: 489 Days
• Field of Search: 514/412, 548/452
• US Class Current: 514/412
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 : for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 209/52 : condensed with a ring other than six-membered

Abstract

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 H₂O (form H0.75-3) and hydrochloric acid salt containing 2 equivalents of H₂O (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.

Claims

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 (1H₂O), H-1 (1PhCO₂H/1H₂O), N-1, and mixtures thereof,

wherein the crystalline compound of form H2-1 (1HCl) has structure

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 (2HC1).

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 (1H₂O), H-1 (1PhCO₂H/1H₂O), 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 (1H₂O).

17. The method according to claim 16, wherein the crystalline compound of form H-1 (1H₂O) 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 (1PhCO₂H/1H₂O).

19. The method according to claim 18, wherein the crystalline compound of form H-1 (1PhCO₂H/1H₂O) 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.