Crystal forms of saxagliptin and processes for preparing same

• US 8,802,715 B2
• Filed: 12/27/2013
• Issued: 08/12/2014
• Est. Priority Date: 04/20/2007
• Status: Expired due to Fees

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• 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): SHTERENGARTS, SAMANTHA L
• Application Number:
  US14/142,081
• Publication Number:
  US 20140121155A1
• Time in Patent Office: 228 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 crystalline compound of the structure

2. The crystalline compound according to claim 1, in the form of the hydrated HBr salt in the H2-1 form containing 2 equiv. H₂O, characterized by unit cell parameters substantially equal to the following:

3. The crystalline compound according to claim 1, in the form of the hydrated HBr salt in the H1-2 form containing 1 equiv. H₂O, characterized by unit cell parameters substantially equal to the following:

a=23.30(1) Å

b=6.77(1) Å

c=12.90(2) Å

α

=90°

β

=102.2(1)°

γ

=90°

Space group C2

Molecules/asymmetric unit 1

wherein said crystalline form is at about 22°

C.

4. The crystalline compound according to claim 1, in the form of the hydrated HI salt in the form H2-1 containing 2 equiv. H₂O, characterized by unit cell parameters substantially equal to the following:

a=11.267(1) Å

b=7.006(4) Å

c=13.22(2) Å

α

=90°

β

=93.96(9)°

γ

=90°

Space group P2₁

Molecules/asymmetric unit 1

wherein said crystalline form is at about −

20°

C.

5. The crystalline compound according to claim 1, in the form of the hydrated ammonium sulfate salt in the H3-1 form containing 3 equiv. H₂O, characterized by unit cell parameters substantially equal to the following:

a=31.671(1) Å

b=6.685(1) Å

c=11.394(1) Å

α

=90°

β

=103.15(1)°

γ

=90°

Space group C2

Molecules/asymmetric unit 1

wherein said crystalline form is at about −

50°

C.

6. The crystalline compound according to claim 1, in the form of the nitrate (NO₃) salt in the N−

1 form, characterized by unit cell parameters substantially equal to the following;

a=20.615(1) Å

b=25.214(1) Å

c=7.034(1) Å

α

=90°

β

=90°

γ

=90°

Space group P2₁2₁2₁

Molecules/asymmetric unit 2

wherein said crystalline form is at about +22°

C.

7. The crystalline compound according to claim 6, having powder X-ray diffraction pattern characteristic peak positions at the following 2θ

values (CuKα

λ

−

1.5418 Å

) 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 at about room temperature.

8. The crystalline compound according to claim 1, in the form of the hydrated benzoate salt in the H-1 form containing 1 equiv. H₂O, characterized by unit cell parameters substantially equal to the following:

9. The crystalline compound according to claim 8, having powder X-ray diffraction pattern characteristic peak positions at the following 2θ

values (CuKα

λ

−

1.5418 Å

) 6.6±

1, 8.3±

1, 15.3±

1, 16, 1±

1, 16.9±

1, 17.5±

1, 17.8±

1, 18.6±

1 and 21.3±

1 at about room temperature.

10. The crystalline compound according to claim 1, in the form of the hydrated R—

H-tartrate salt in the H.5-1 form containing 0.5 equiv. of H₂O characterized by unit cell parameters substantially equal to the following

a=7.070(1) Å

b=16.400(1) Å

c=19.640(1) Å

α

=90°

β

=97.69(2)°

γ

=90°

Space group P2₁

Molecules/asymmetric unit 2

wherein said crystalline form is at −

173°

C.

11. The crystalline compound according to claim 1, in the form of the hydrated fumarate salt in the H4-1 form containing 4 equiv. H₂O, characterized by unit cell parameters substantially equal to the following:

a=11.429(1) Å

b=26.979(2) Å

c=6.803(2) Å

α

=90°

β

=90.32(2)°

γ

=90°

Space group P2₁

Molecules/asymmetric unit 2

wherein said crystalline form is at about +22°

C.

12. 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 thereof an effective amount of a crystalline compound according to claim 1.

13. A method for treating type II diabetes which comprises administering to a mammalian species in need of treatment thereof an effective amount of a crystalline compound according to claim 1.

14. A pharmaceutical composition which comprises a crystalline compound as defined in claim 1 and a pharmaceutically acceptable carrier therefor.

15. The pharmaceutical composition according to claim 14, further comprising one or more antidiabetic agents selected from 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 LY315902.

16. The pharmaceutical composition according to claim 15 wherein the antidiabetic agent is metformin.

17. The pharmaceutical composition according to claim 15 wherein the antidiabetic agent is dapagliflozin.

18. The pharmaceutical composition according to claim 14, further comprising an anti-obesity agent selected from orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, famoxin, and mazindol.

19. The pharmaceutical composition according to claim 14, further comprising a lipid modulating agent selected from pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, ZD-4522, fenofibrate, gemfibrozil, clofibrate, implitapide, CP-529,414, avasimibe, TS-962, MD-700, and LY295427.