WO2017162168A1 - 一种dppiv抑制剂的盐型及其制备方法 - Google Patents

一种dppiv抑制剂的盐型及其制备方法 Download PDF

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WO2017162168A1
WO2017162168A1 PCT/CN2017/077679 CN2017077679W WO2017162168A1 WO 2017162168 A1 WO2017162168 A1 WO 2017162168A1 CN 2017077679 W CN2017077679 W CN 2017077679W WO 2017162168 A1 WO2017162168 A1 WO 2017162168A1
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crystal
another preferred
glycolate
salt
maleate
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PCT/CN2017/077679
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English (en)
French (fr)
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柳红
王江
李建
李佳
李静雅
蒋华良
罗小民
陈凯先
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中国科学院上海药物研究所
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Priority to US16/087,318 priority Critical patent/US10611774B2/en
Priority to EP17769445.2A priority patent/EP3434678B1/en
Priority to JP2018549826A priority patent/JP6871941B2/ja
Priority to CA3018800A priority patent/CA3018800C/en
Priority to RU2018137020A priority patent/RU2734549C2/ru
Priority to KR1020187030139A priority patent/KR102238364B1/ko
Publication of WO2017162168A1 publication Critical patent/WO2017162168A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl-3 a salt form of 4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylic acid, a preparation method thereof and use thereof.
  • Diabetes is a metabolic disease caused by insufficient insulin secretion in the human body and dysfunction of pancreatic ⁇ cells, which leads to metabolic disorders of sugar, fat and protein.
  • Hyperglycemia caused by diabetes can cause damage to body tissues and lead to microvascular disease and macrovascular disease, such as retinopathy, kidney disease, neuropathy, stroke and coronary atheroma, and other complications that seriously damage human health and threaten human life. .
  • Diabetes can be divided into type 1 diabetes (T1DM) and type 2 diabetes (T2DM).
  • DPP-IV inhibitors saxagliptin
  • GLP-1 endogenous active glucagon-like peptide-1
  • GIP glucose-dependent insulinotropic peptide
  • DPP IV inhibitors can significantly reduce blood glucose levels in the body, increase glucose tolerance, promote insulin secretion, reduce glucagon levels, delay insulin resistance, and increase insulin response in patients with type 2 diabetes.
  • DPP IV inhibitors have the following characteristics compared with existing oral diabetes drugs: (1) DPP IV inhibitors do not require injection, and continue to reduce glycosylated hemoglobin levels by oral administration; (2) long-term application of DPP IV inhibitors Has good drug resistance; (3) can enhance insulin secretion and increase glucagon release; (4) improve insulin sensitivity, while increasing islet ⁇ cell function; (5) low incidence of hypoglycemia, will not Causes weight gain, no nausea and vomiting and gastrointestinal dysfunction; (6) DPP IV inhibitors have synergistic effects in combination with other type 2 diabetes drugs. However, such drugs may cause side effects such as pancreatitis, urticaria, and angioedema.
  • a salt form of a compound of formula I selected from the group consisting of hydrochloride, maleate, phosphate and glycolate
  • the salt form is a crystal.
  • the hydrochloride salt is a crystal.
  • the X-ray powder diffraction pattern of the hydrochloride crystals includes 3 or more 2 ⁇ values selected from the group consisting of: 7.43 ⁇ 0.2°, 11.06 ⁇ 0.2°, 11.70 ⁇ 0.2°, 13.46. ⁇ 0.2°, 15.03 ⁇ 0.2°, 15.34 ⁇ 0.2°, 18.32 ⁇ 0.2°, 21.96 ⁇ 0.2°, 24.01 ⁇ 0.2°, 27.20 ⁇ 0.2°, 29.32 ⁇ 0.2°, 30.26 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the hydrochloride crystals includes 3 or more 2 ⁇ values selected from the group consisting of 7.43°, 11.06°, 11.70°, 18.32°, 21.96°, 24.01. °, 27.20 °, 29.32 °, 30.26 °.
  • the X-ray powder diffraction pattern of the hydrochloride crystals includes 3 or more 2 ⁇ values selected from the group consisting of: 7.43 ⁇ 0.2°, 11.06 ⁇ 0.2°, 11.70 ⁇ 0.2°, 13.46. ⁇ 0.2°, 15.03 ⁇ 0.2°, 15.34 ⁇ 0.2°, 15.84 ⁇ 0.2°, 16.35 ⁇ 0.2°, 17.59 ⁇ 0.2°, 18.32 ⁇ 0.2°, 19.54 ⁇ 0.2°, 20.13 ⁇ 0.2°, 21.24 ⁇ 0.2°, 21.96 ⁇ 0.2°, 22.46 ⁇ 0.2°, 22.74 ⁇ 0.2°, 23.67 ⁇ 0.2°, 24.01 ⁇ 0.2°, 24.83 ⁇ 0.2°, 25.19 ⁇ 0.2°, 26.63 ⁇ 0.2°, 27.20 ⁇ 0.2°, 29.32 ⁇ 0.2°, 30.26 ⁇ 0.2°, 32.15 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the hydrochloride crystals is substantially characterized as in Figure 1.
  • the X-ray powder diffraction pattern of the hydrochloride crystal crystal has a deviation of ⁇ 0.5° from a characteristic absorption peak represented by a 2 ⁇ value, preferably a deviation of ⁇ 0.3°, more preferably ⁇ 0.1 ° deviation.
  • the differential scanning calorimetry (DSC chart) of the hydrochloride crystal has no melting peak prior to decomposition.
  • the hydrochloride crystals have a DSC pattern substantially as shown in FIG.
  • the TG pattern of the hydrochloride crystal crystal has a characteristic absorption peak at 272 ⁇ 2 °C.
  • the TG image of the hydrochloride crystal crystal has a characteristic absorption peak at 272.6 °C.
  • thermogravimetric analysis (TG map) of the hydrochloride crystals is substantially characterized as in Figure 2.
  • the hydrochloride salt crystals have a thermal weight loss at 400 ° C of from 64 to 65 wt%, preferably 64.33 wt%.
  • the hydrochloride crystals are taken out in a desiccator having a humidity of 50% and taken out after 24 hours, and the weight gain is calculated to be ⁇ 3%, preferably ⁇ 1%, more preferably ⁇ 0.3%.
  • the hydrochloride crystal has a DVS pattern substantially as shown in FIG.
  • the IR pattern of the hydrochloride crystals includes 3 or more characteristic absorption peaks represented by the wavelength ⁇ selected from the group consisting of: 3429 ⁇ 2 cm -1 , 2951 ⁇ 2 cm -1 , 2827 ⁇ 2cm -1 , 2225 ⁇ 2cm -1 , 1720 ⁇ 2cm -1 , 1687 ⁇ 2cm -1 , 1560 ⁇ 2cm -1 , 1533 ⁇ 2cm -1 , 1446 ⁇ 2cm -1 , 1385 ⁇ 2cm -1 , 1261 ⁇ 2cm -1 , 1064 ⁇ 2 cm -1 , 771 ⁇ 2 cm -1 .
  • the hydrochloride crystal has an IR pattern substantially as shown in FIG.
  • the hydrochloride crystal has a Raman diagram substantially as shown in FIG.
  • the maleate salt is a crystal.
  • the X-ray powder diffraction pattern of the maleate crystals includes 3 or more 2 ⁇ values selected from the group consisting of 7.55 ⁇ 0.2°, 12.41 ⁇ 0.2°, 15.45 ⁇ 0.2°, 17.50 ⁇ 0.2°, 20.89 ⁇ 0.2°, 26.59 ⁇ 0.2°, 26.93 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the maleate crystals includes 3 or more 2 ⁇ values selected from the group consisting of 7.55 ⁇ 0.2°, 12.41 ⁇ 0.2°, 15.45 ⁇ 0.2°, 17.50 ⁇ 0.2°, 20.89 ⁇ 0.2°, 26.59 ⁇ 0.2°, 26.93 ⁇ 0.2°, 27.10 ⁇ 0.2°, 28.21 ⁇ 0.2°, 30.53 ⁇ 0.2°, 32.96 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the maleate crystals includes 3 or more 2 ⁇ values selected from the group consisting of 7.55 ⁇ 0.2°, 10.83 ⁇ 0.2°, 12.41 ⁇ 0.2°, 13.22 ⁇ 0.2°, 14.38 ⁇ 0.2°, 14.75 ⁇ 0.2°, 15.45 ⁇ 0.2°, 15.80 ⁇ 0.2°, 17.50 ⁇ 0.2°, 18.30 ⁇ 0.2°, 19.40 ⁇ 0.2°, 20.43 ⁇ 0.2°, 20.89 ⁇ 0.2°, 21.85 ⁇ 0.2°, 22.87 ⁇ 0.2°, 23.25 ⁇ 0.2°, 25.04 ⁇ 0.2°, 26.59 ⁇ 0.2°, 26.93 ⁇ 0.2°, 27.10 ⁇ 0.2°, 28.21 ⁇ 0.2°, 30.53 ⁇ 0.2°, 32.96 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the maleate crystals is substantially characterized as in Figure 7.
  • the X-ray powder diffraction pattern of the maleate crystal crystal has a deviation of ⁇ 0.5° from a characteristic absorption peak represented by a 2 ⁇ value, preferably a deviation of ⁇ 0.3°, more preferably ⁇ 0.1° deviation.
  • the differential scanning calorimetry (DSC chart) of the maleate crystals has a characteristic absorption peak at 113 ⁇ 5 °C.
  • the differential scanning calorimetry (DSC chart) of the maleate crystals has a characteristic absorption peak at 113.8 °C.
  • the maleate crystals have a DSC pattern substantially as shown in FIG.
  • the TG map of the maleate crystals comprises a characteristic absorption peak selected from the group consisting of 77 ⁇ 2 ° C, 180 ⁇ 5 ° C, and 284 ⁇ 5 ° C.
  • the TG map of the maleate crystals comprises a characteristic absorption peak selected from the group consisting of 77.3 ° C, 179.6 ° C, and 283.6 ° C.
  • thermogravimetric analysis map (TG map) of the maleate crystals is substantially characterized as in Figure 8.
  • the maleate crystals have a thermal weight loss at 400 ° C of 42 to 43 wt%, preferably 42.58 wt%.
  • the initial value of the endothermic transition temperature of the maleate crystal is 110 ⁇ 2 ° C, preferably 110.37 ° C.
  • the maleate crystals are taken out in a desiccator having a humidity of 50% and taken out after 24 hours, and the weight gain is calculated to be ⁇ 3%, preferably ⁇ 1%, more preferably ⁇ 0.3%.
  • the maleate crystals have a DVS pattern substantially as shown in FIG.
  • the IR pattern of the maleate salt comprises 3 or more characteristic absorption peaks represented by the wavelength ⁇ selected from the group consisting of: 3429 ⁇ 2 cm -1 , 3062 ⁇ 2 cm -1 , 2954 ⁇ 2cm -1 , 2862 ⁇ 2cm -1 , 2224 ⁇ 2cm -1 , 1720 ⁇ 2cm -1 , 1676 ⁇ 2cm -1 , 1558 ⁇ 2cm -1 , 1531 ⁇ 2cm -1 , 1469 ⁇ 2cm -1 , 1354 ⁇ 2cm -1 , 1290 ⁇ 2 cm -1 , 1219 ⁇ 2 cm -1 , 1063 ⁇ 2 cm -1 , 864 ⁇ 2 cm -1 , 775 ⁇ 2 cm -1 , 654 ⁇ 2 cm -1 .
  • the maleate crystals have an IR pattern substantially as shown in FIG.
  • the maleate crystals have a Raman diagram substantially as shown in FIG.
  • the phosphate is a crystal.
  • the X-ray powder diffraction pattern of the phosphate crystal comprises 3 or more 2 ⁇ values selected from the group consisting of 11.99 ⁇ 0.2°, 12.20 ⁇ 0.2°, 14.80 ⁇ 0.2°, 20.11 ⁇ 0.2°, 20.46 ⁇ 0.2°, 24.18 ⁇ 0.2°, 24.68 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the phosphate crystal comprises 3 or more 2 ⁇ values selected from the group consisting of 11.99 ⁇ 0.2°, 12.20 ⁇ 0.2°, 14.80 ⁇ 0.2°, 20.11 ⁇ 0.2°, 20.46 ⁇ 0.2°, 23.15 ⁇ 0.2°, 24.18 ⁇ 0.2°, 24.68 ⁇ 0.2°, 25.63 ⁇ 0.2°, 26.15 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the phosphate crystal comprises 3 or more 2 ⁇ values selected from the group consisting of 6.23 ⁇ 0.2°, 11.99 ⁇ 0.2°, 12.20 ⁇ 0.2°, 14.80 ⁇ 0.2°, 15.16 ⁇ 0.2°, 16.04 ⁇ 0.2°, 16.56 ⁇ 0.2°, 17.90 ⁇ 0.2°, 20.11 ⁇ 0.2°, 20.46 ⁇ 0.2°, 22.74 ⁇ 0.2°, 23.15 ⁇ 0.2°, 24.18 ⁇ 0.2°, 24.68 ⁇ 0.2°, 25.63 ⁇ 0.2°, 26.15 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the phosphate crystal is substantially as shown in FIG. Sign.
  • the X-ray powder diffraction pattern of the phosphate crystal has a deviation of ⁇ 0.5° from a characteristic absorption peak represented by a 2 ⁇ value, preferably a deviation of ⁇ 0.3°, more preferably ⁇ 0.1°. Deviation.
  • the differential scanning calorimetry (DSC chart) of the phosphate crystal has a characteristic absorption peak at 155 ⁇ 5 ° C, preferably 154.8 ° C.
  • the phosphate crystal has a DSC pattern substantially as shown in FIG.
  • the TG image of the phosphate crystal has a characteristic absorption peak at 361 ⁇ 2 ° C, preferably 361.0 ° C.
  • the phosphate crystals have a thermal weight loss at 400 ° C of 47 to 48 wt%, preferably 47.57 wt%.
  • thermogravimetric analysis (TG map) of the phosphate crystals is substantially characterized as in Figure 14.
  • the initial value of the endothermic transition temperature of the phosphate crystal is 148 ⁇ 2 ° C, preferably 148.0 ° C.
  • the phosphate crystals are taken out in a desiccator having a humidity of 50% and taken out after 24 hours, and the weight gain is calculated to be ⁇ 3%, preferably ⁇ 1%, more preferably ⁇ 0.3%.
  • the phosphate crystal has a DVS pattern substantially as shown in FIG.
  • the IR pattern of the phosphate crystal comprises 3 or more characteristic absorption peaks represented by the wavelength ⁇ selected from the group consisting of: 3408 ⁇ 2 cm -1 , 2951 ⁇ 2 cm -1 , 2860 ⁇ 2cm -1, 2225 ⁇ 2cm -1, 1716 ⁇ 2cm -1, 1684 ⁇ 2cm -1, 1601 ⁇ 2cm -1, 1556 ⁇ 2cm -1, 1531 ⁇ 2cm -1, 1450 ⁇ 2cm -1, 1379 ⁇ 2cm - 1 , 1282 ⁇ 2 cm -1 , 1238 ⁇ 2 cm -1 , 1124 ⁇ 2 cm -1 , 1064 ⁇ 2 cm -1 , 947 ⁇ 2 cm -1 , 868 ⁇ 2 cm -1 , 758 ⁇ 2 cm -1 , 521 ⁇ 2 cm -1 .
  • the phosphate crystal has an IR pattern substantially as shown in FIG.
  • the phosphate crystal has a Raman diagram substantially as shown in FIG.
  • the glycolate salt is a crystal.
  • the X-ray powder diffraction pattern of the glycolate crystals includes 3 or more 2 ⁇ values selected from the group consisting of: 8.92 ⁇ 0.2°, 10.20 ⁇ 0.2°, 13.35 ⁇ 0.2°, 16.89 ⁇ 0.2°, 19.37 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the glycolate crystals includes 3 or more 2 ⁇ values selected from the group consisting of: 8.92 ⁇ 0.2°, 10.20 ⁇ 0.2°, 13.35 ⁇ 0.2°, 16.89 ⁇ 0.2°, 19.37 ⁇ 0.2°, 20.51 ⁇ 0.2°, 21.22 ⁇ 0.2°, 21.78 ⁇ 0.2°, 23.00 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the glycolate crystals includes 3 or more 2 ⁇ values selected from the group consisting of: 8.92 ⁇ 0.2°, 10.20 ⁇ 0.2°, 13.35 ⁇ 0.2°, 16.89 ⁇ 0.2°, 19.37 ⁇ 0.2°, 20.51 ⁇ 0.2°, 21.22 ⁇ 0.2°, 21.78 ⁇ 0.2°, 23.00 ⁇ 0.2°, 23.87 ⁇ 0.2°, 24.08 ⁇ 0.2°, 24.37 ⁇ 0.2°, 25.52 ⁇ 0.2°, 33.81 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the glycolate crystals includes 3 or more 2 ⁇ values selected from the group consisting of 6.66 ⁇ 0.2°, 8.92 ⁇ 0.2°, 9.91 ⁇ 0.2°, 10.20. ⁇ 0.2°, 13.35 ⁇ 0.2°, 13.92 ⁇ 0.2°, 15.78 ⁇ 0.2°, 16.71 ⁇ 0.2°, 16.89 ⁇ 0.2°, 17.41 ⁇ 0.2°, 18.70 ⁇ 0.2°, 19.37 ⁇ 0.2°, 20.12 ⁇ 0.2°, 20.51 ⁇ 0.2°, 21.22 ⁇ 0.2°, 21.78 ⁇ 0.2°, 22.75 ⁇ 0.2°, 23.00 ⁇ 0.2°, 23.87 ⁇ 0.2°, 24.08 ⁇ 0.2°, 24.37 ⁇ 0.2°, 25.52 ⁇ 0.2°, 26.44 ⁇ 0.2°, 27.02 ⁇ 0.2°, 27.48 ⁇ 0.2°, 28.23 ⁇ 0.2°, 28.63 ⁇ 0.2°, 28.84 ⁇ 0.2°, 29.68 ⁇ 0.2°, 30.14 ⁇ 0.2°, 30.51 ⁇ 0.2°, 31.41 ⁇ 0.2°, 31.76 ⁇
  • the X-ray powder diffraction pattern of the glycolate crystals is substantially characterized as in Figure 19.
  • the X-ray powder diffraction pattern of the glycolate crystal has a deviation of ⁇ 0.5° from the characteristic absorption peak represented by the 2 ⁇ value, preferably ⁇ 0.3° deviation, more preferably ⁇ 0.1 ° deviation.
  • the differential scanning calorimetry (DSC chart) of the glycolate crystals has a characteristic absorption peak at 189 ⁇ 5 °C.
  • the glycolate crystals have a DSC pattern substantially as shown in FIG.
  • the initial value of the endothermic transition temperature of the glycolate crystals is 148 ⁇ 2 ° C, preferably 148.0 ° C.
  • the TG image of the glycolate crystal has a characteristic absorption peak at 192 ⁇ 2 ° C and 268 ⁇ 2 ° C, preferably 192.5 ° C, 268.0 ° C.
  • the glycolate crystals have a TG map substantially as shown in FIG.
  • the glycolate crystals have a thermal weight loss at 400 ° C of 53 to 54 wt%, preferably 53.41 wt%.
  • the glycolate crystals are taken out in a desiccator having a humidity of 50% and taken out after 24 hours, and the weight gain is calculated to be ⁇ 3%, preferably ⁇ 1%, more preferably ⁇ 0.3%.
  • the glycolate crystals have a DVS pattern substantially as shown in FIG.
  • the IR pattern of the glycolate crystals includes 3 or more characteristic absorption peaks represented by the wavelength ⁇ selected from the group consisting of 3462 ⁇ 2 cm -1 , 2958 ⁇ 2 cm -1 , 2837 ⁇ 2cm -1 , 2227 ⁇ 2cm -1 , 1720 ⁇ 2cm -1 , 1674 ⁇ 2cm -1 , 1558 ⁇ 2cm -1 , 1533 ⁇ 2cm -1 , 1450 ⁇ 2cm -1 , 1350 ⁇ 2cm -1 , 1282 ⁇ 2cm -1 , 1223 ⁇ 2 cm -1 , 1072 ⁇ 2 cm -1 , 928 ⁇ 2 cm -1 , 760 ⁇ 2 cm -1 , 692 ⁇ 2 cm -1 .
  • the glycolate salt has an IR pattern substantially as shown in FIG.
  • the glycolate salt has a Raman diagram substantially as shown in FIG.
  • a salt type combination comprising one or more salt forms of a hydrochloride, a maleate, a phosphate, a glycolate or the like according to the first aspect of the present invention.
  • a salt form of a hydrochloride, a maleate, a phosphate or a glycolate as described in the first aspect of the invention is provided.
  • the total mass percentage of the hydrochloride, maleate, phosphate, glycolate is from 60 to 99.999%, preferably based on the total weight of the salt composition. 80-99.999%, more preferably 90-99.999%.
  • the salt form combination further comprises: (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl
  • a method of preparing a salt form of a compound of formula I according to the first aspect of the invention comprising the steps of:
  • step (3) The solid obtained in the step (2) is filtered and/or dried to obtain the salt form of the first aspect of the invention.
  • the solvent is selected from the group consisting of alcohols, ethers, ketones, esters, or a combination thereof.
  • the alcohol is a C1-C10 alcohol, preferably a C1-C8 alcohol, more preferably a C1-C5 alcohol.
  • the alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol, or a combination thereof.
  • the ether is a C2-C8 ether, preferably a C2-C5 ether.
  • the ether is selected from the group consisting of diethyl ether, tetrahydrofuran or a combination thereof.
  • the ester is a C1-C10 ester, preferably a C1-C7 ester, more preferably a C1-C5 ester.
  • the ester is selected from the group consisting of methyl formate, ethyl acetate, isobutyl formate, or a combination thereof.
  • the molar ratio of the free base to the acid is 1:0.8-1:1.5, preferably 1:0.9-1:1.3, more preferably It is 1:1.0-1:1.1.
  • the temperature ranges from 10 to 80 ° C, preferably from 30 to 50 ° C.
  • the reaction time is from 0.1 to 10 h, preferably from 0.5 to 6 h.
  • the drying temperature is from 10 to 90 ° C, preferably from 20 to 80 ° C, more preferably from 40 to 70 ° C.
  • the drying pressure is 0-20 KPa, preferably 0-10 Kpa, more preferably 5-10 KPa.
  • the drying time is from 5 to 150 hours, preferably from 30 to 100 hours, more preferably from 60 to 80 hours.
  • the crystallization is carried out at 0 to 50 ° C, preferably 0 to 40 ° C, more preferably 20 to 30 ° C.
  • the crystallization is carried out under agitation.
  • the yield of the method is from 50% to 99.9%, preferably from 75% to 99.9%, more preferably from 85% to 99.9%.
  • a pharmaceutical composition comprising:
  • the excipient is selected from the group consisting of a filler, a disintegrant, a binder, a lubricant, or a combination thereof.
  • the filler is selected from the group consisting of starch, lactose, microcrystalline cellulose, dextrin, mannitol, magnesium oxide, calcium sulfate, or a combination thereof.
  • the disintegrant is selected from the group consisting of carboxymethylcellulose and salts thereof, croscarmellose and salts thereof, crospovidone, sodium carboxymethyl starch, and low Substituting hydroxypropyl cellulose, or a combination thereof.
  • the binder is selected from the group consisting of povidone, hydroxypropyl methylcellulose, starch slurry, or a combination thereof.
  • the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, or a combination thereof.
  • the complication of type II diabetes is selected from the group consisting of coronary artery disease, stroke, hypertension, kidney disease, peripheral vascular disease, neurological disease, and retinopathy.
  • a method for treating or preventing a complication of type 2 diabetes and/or type II diabetes wherein a therapeutically effective amount of the hydrochloride salt of the compound of formula I according to the first aspect of the invention, A maleate, a phosphate, a glycolate, or a combination thereof, or a salt combination according to the second aspect of the invention or a pharmaceutical composition according to the fourth aspect of the invention.
  • Figure 1 is an XRD chart of the hydrochloride salt of Example 1 of the present invention.
  • Figure 2 is a TG diagram of the hydrochloride salt of Example 1 of the present invention.
  • FIG. 3 is a differential scanning calorimetry (DSC) chart of the hydrochloride salt of Example 1 of the present invention.
  • Figure 4 is a graph showing the hygroscopicity analysis (DVS) of the hydrochloride salt of Example 1 of the present invention.
  • Figure 5 is an infrared spectrum (IR) chart of the hydrochloride salt of Example 1 of the present invention.
  • Figure 6 is a Raman spectrum diagram of the hydrochloride salt of Example 1 of the present invention.
  • Figure 7 is an XRD pattern of the maleate salt of Example 2 of the present invention.
  • Figure 8 is a TG diagram of the maleate salt of Example 2 of the present invention.
  • Figure 9 is a differential scanning calorimetry (DSC) chart of the maleate salt of Example 2 of the present invention.
  • Figure 10 is a graph showing the hygroscopicity analysis (DVS) of the maleate salt of Example 2 of the present invention.
  • Figure 11 is an infrared spectrum (IR) chart of the maleate salt of Example 2 of the present invention.
  • Figure 12 is a Raman spectrum of the maleate salt of Example 2 of the present invention.
  • Figure 13 is an XRD pattern of the phosphate of Example 3 of the present invention.
  • Figure 14 is a TG diagram of the phosphate of Example 3 of the present invention.
  • Figure 15 is a differential scanning calorimetry (DSC) chart of the phosphate of Example 3 of the present invention.
  • Figure 16 is a graph showing the hygroscopicity analysis (DVS) of the phosphate of Example 3 of the present invention.
  • Figure 17 is an infrared spectrum (IR) chart of the phosphate of Example 3 of the present invention.
  • Figure 18 is a Raman spectrum of the phosphate of Example 3 of the present invention.
  • Figure 19 is an XRD chart of the glycolate salt of Example 4 of the present invention.
  • Figure 20 is a TG diagram of the glycolate salt of Example 4 of the present invention.
  • Figure 21 is a differential scanning calorimetry (DSC) chart of the glycolate salt of Example 4 of the present invention.
  • Figure 22 is a graph showing the hygroscopicity analysis (DVS) of the glycolate salt of Example 4 of the present invention.
  • Figure 23 is an infrared spectrum (IR) chart of the glycolate salt of Example 4 of the present invention.
  • Figure 24 is a Raman spectrum diagram of the glycolate salt of Example 4 of the present invention.
  • the inventors have unexpectedly prepared (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyano) with better pharmaceutical properties through long-term and intensive research. Salt form of benzyl)-4-carbonyl-3,4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylic acid. Based on the above findings, the inventors completed the present invention.
  • the compound of the formula I according to the invention is (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl-3,4-di Hydrothiophene [3,2-d]pyrimidine-6-carboxylic acid.
  • the compound of formula I is effective in inhibiting DPP IV activity in normal mouse and rat plasma, and its DPP IV inhibitory activity is superior to the marketed drug alogliptin.
  • the compound of formula I can increase the oral glucose tolerance of normal ICR mice in a dose-dependent manner, and the effective dose is only 0.1 mg/kg, which is superior to alogliptin; the compound can be effectively administered to ob/ob mice.
  • the fasting blood glucose of ob/ob mice was lower than that of the positive control drug alogliptin; the chronic administration of the compound reduced the fasting blood glucose of the gene-deficient db/db mice, which was comparable to the positive control drug alogliptin.
  • hypoglycemic effect of this compound in vivo is superior to the currently used DPPIV inhibitor.
  • the free base (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl) is obtained by the preparation method described in Patent Application No. CN201210262331.3. a 4-carbonyl-3,4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylic acid powder.
  • the present invention provides a hydrochloride salt of a compound of formula I.
  • the hydrochloride salt is a crystal.
  • the X-ray powder diffraction pattern of the hydrochloride crystals includes 3 or more 2 ⁇ values selected from the group consisting of: 7.43 ⁇ 0.2°, 11.06 ⁇ 0.2°, 11.70 ⁇ 0.2°, 13.46. ⁇ 0.2°, 15.03 ⁇ 0.2°, 15.34 ⁇ 0.2°, 18.32 ⁇ 0.2°, 21.96 ⁇ 0.2°, 24.01 ⁇ 0.2°, 27.20 ⁇ 0.2°, 29.32 ⁇ 0.2°, 30.26 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the hydrochloride crystals includes 3 or more 2 ⁇ values selected from the group consisting of 7.43°, 11.06°, 11.70°, 18.32°, 21.96°, 24.01. °, 27.20 °, 29.32 °, 30.26 °.
  • the X-ray powder diffraction pattern of the hydrochloride crystals includes 3 or more 2 ⁇ values selected from the group consisting of: 7.43 ⁇ 0.2°, 11.06 ⁇ 0.2°, 11.70 ⁇ 0.2°, 13.46. ⁇ 0.2°, 15.03 ⁇ 0.2°, 15.34 ⁇ 0.2°, 15.84 ⁇ 0.2°, 16.35 ⁇ 0.2°, 17.59 ⁇ 0.2°, 18.32 ⁇ 0.2°, 19.54 ⁇ 0.2°, 20.13 ⁇ 0.2°, 21.24 ⁇ 0.2°, 21.96 ⁇ 0.2°, 22.46 ⁇ 0.2°, 22.74 ⁇ 0.2°, 23.67 ⁇ 0.2°, 24.01 ⁇ 0.2°, 24.83 ⁇ 0.2°, 25.19 ⁇ 0.2°, 26.63 ⁇ 0.2°, 27.20 ⁇ 0.2°, 29.32 ⁇ 0.2°, 30.26 ⁇ 0.2°, 32.15 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the hydrochloride crystals is substantially characterized as in Figure 1.
  • the X-ray powder diffraction pattern of the hydrochloride crystal crystal has a deviation of ⁇ 0.5° from a characteristic absorption peak represented by a 2 ⁇ value, preferably a deviation of ⁇ 0.3°, more preferably ⁇ 0.1 ° deviation.
  • the differential scanning calorimetry (DSC chart) of the hydrochloride crystal has no melting peak prior to decomposition.
  • the hydrochloride crystals have a DSC pattern substantially as shown in FIG.
  • the TG pattern of the hydrochloride crystal crystal has a characteristic absorption peak at 272 ⁇ 2 °C.
  • the TG image of the hydrochloride crystal crystal has a characteristic absorption peak at 272.6 °C.
  • thermogravimetric analysis (TG map) of the hydrochloride crystals is substantially characterized as in Figure 2.
  • the hydrochloride salt crystals have a thermal weight loss at 400 ° C of from 64 to 65 wt%, preferably 64.33 wt%.
  • the hydrochloride crystals are taken out in a desiccator having a humidity of 50% and taken out after 24 hours, and the weight gain is calculated to be ⁇ 3%, preferably ⁇ 1%, more preferably ⁇ 0.3%.
  • the hydrochloride crystal has a DVS pattern substantially as shown in FIG.
  • the IR pattern of the hydrochloride crystals includes 3 or more characteristic absorption peaks represented by the wavelength ⁇ selected from the group consisting of: 3429 ⁇ 2 cm -1 , 2951 ⁇ 2 cm -1 , 2827 ⁇ 2cm -1 , 2225 ⁇ 2cm -1 , 1720 ⁇ 2cm -1 , 1687 ⁇ 2cm -1 , 1560 ⁇ 2cm -1 , 1533 ⁇ 2cm -1 , 1446 ⁇ 2cm -1 , 1385 ⁇ 2cm -1 , 1261 ⁇ 2cm -1 , 1064 ⁇ 2 cm -1 , 771 ⁇ 2 cm -1 .
  • the hydrochloride crystal has an IR pattern substantially as shown in FIG.
  • the hydrochloride crystal has a Raman diagram substantially as shown in FIG.
  • the present invention provides a maleate salt of a compound of formula I.
  • the maleate salt is a crystal.
  • the X-ray powder diffraction pattern of the maleate crystals includes 3 or more 2 ⁇ values selected from the group consisting of 7.55 ⁇ 0.2°, 12.41 ⁇ 0.2°, 15.45 ⁇ 0.2°, 17.50 ⁇ 0.2°, 20.89 ⁇ 0.2°, 26.59 ⁇ 0.2°, 26.93 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the maleate crystals includes 3 or more 2 ⁇ values selected from the group consisting of 7.55 ⁇ 0.2°, 12.41 ⁇ 0.2°, 15.45 ⁇ 0.2°, 17.50 ⁇ 0.2°, 20.89 ⁇ 0.2°, 26.59 ⁇ 0.2°, 26.93 ⁇ 0.2°, 27.10 ⁇ 0.2°, 28.21 ⁇ 0.2°, 30.53 ⁇ 0.2°, 32.96 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the maleate crystals includes 3 or more 2 ⁇ values selected from the group consisting of 7.55 ⁇ 0.2°, 10.83 ⁇ 0.2°, 12.41 ⁇ 0.2°, 13.22 ⁇ 0.2°, 14.38 ⁇ 0.2°, 14.75 ⁇ 0.2°, 15.45 ⁇ 0.2°, 15.80 ⁇ 0.2°, 17.50 ⁇ 0.2°, 18.30 ⁇ 0.2°, 19.40 ⁇ 0.2°, 20.43 ⁇ 0.2°, 20.89 ⁇ 0.2°, 21.85 ⁇ 0.2°, 22.87 ⁇ 0.2°, 23.25 ⁇ 0.2°, 25.04 ⁇ 0.2°, 26.59 ⁇ 0.2°, 26.93 ⁇ 0.2°, 27.10 ⁇ 0.2°, 28.21 ⁇ 0.2°, 30.53 ⁇ 0.2°, 32.96 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the maleate crystals is substantially characterized as in Figure 7.
  • the X-ray powder diffraction pattern of the maleate crystal is represented by a 2 ⁇ value.
  • the characteristic absorption peak has a deviation of ⁇ 0.5°, preferably a deviation of ⁇ 0.3°, and more preferably a deviation of ⁇ 0.1°.
  • the differential scanning calorimetry (DSC chart) of the maleate crystals has a characteristic absorption peak at 113 ⁇ 5 °C.
  • the differential scanning calorimetry (DSC chart) of the maleate crystals has a characteristic absorption peak at 113.8 °C.
  • the maleate crystals have a DSC pattern substantially as shown in FIG.
  • the TG map of the maleate crystals comprises a characteristic absorption peak selected from the group consisting of 77 ⁇ 2 ° C, 180 ⁇ 5 ° C, and 284 ⁇ 5 ° C.
  • the TG map of the maleate crystals comprises a characteristic absorption peak selected from the group consisting of 77.3 ° C, 179.6 ° C, and 283.6 ° C.
  • thermogravimetric analysis map (TG map) of the maleate crystals is substantially characterized as in Figure 8.
  • the maleate crystals have a thermal weight loss at 400 ° C of 42 to 43 wt%, preferably 42.58 wt%.
  • the initial value of the endothermic transition temperature of the maleate crystal is 110 ⁇ 2 ° C, preferably 110.37 ° C.
  • the maleate crystals are taken out in a desiccator having a humidity of 50% and taken out after 24 hours, and the weight gain is calculated to be ⁇ 3%, preferably ⁇ 1%, more preferably ⁇ 0.3%.
  • the maleate crystals have a DVS pattern substantially as shown in FIG.
  • the IR pattern of the maleate salt comprises 3 or more characteristic absorption peaks represented by the wavelength ⁇ selected from the group consisting of: 3429 ⁇ 2 cm -1 , 3062 ⁇ 2 cm -1 , 2954 ⁇ 2cm -1 , 2862 ⁇ 2cm -1 , 2224 ⁇ 2cm -1 , 1720 ⁇ 2cm -1 , 1676 ⁇ 2cm -1 , 1558 ⁇ 2cm -1 , 1531 ⁇ 2cm -1 , 1469 ⁇ 2cm -1 , 1354 ⁇ 2cm -1 , 1290 ⁇ 2 cm -1 , 1219 ⁇ 2 cm -1 , 1063 ⁇ 2 cm -1 , 864 ⁇ 2 cm -1 , 775 ⁇ 2 cm -1 , 654 ⁇ 2 cm -1 .
  • the maleate crystals have an IR pattern substantially as shown in FIG.
  • the maleate crystals have a Raman diagram substantially as shown in FIG.
  • the present invention provides a phosphate of a compound of formula I.
  • the phosphate is a crystal.
  • the X-ray powder diffraction pattern of the phosphate crystal comprises 3 or more 2 ⁇ values selected from the group consisting of 11.99 ⁇ 0.2°, 12.20 ⁇ 0.2°, 14.80 ⁇ 0.2°, 20.11 ⁇ 0.2°, 20.46 ⁇ 0.2°, 24.18 ⁇ 0.2 °, 24.68 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the phosphate crystal comprises 3 or more 2 ⁇ values selected from the group consisting of 11.99 ⁇ 0.2°, 12.20 ⁇ 0.2°, 14.80 ⁇ 0.2°, 20.11 ⁇ 0.2°, 20.46 ⁇ 0.2°, 23.15 ⁇ 0.2°, 24.18 ⁇ 0.2°, 24.68 ⁇ 0.2°, 25.63 ⁇ 0.2°, 26.15 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the phosphate crystal comprises 3 or more 2 ⁇ values selected from the group consisting of 6.23 ⁇ 0.2°, 11.99 ⁇ 0.2°, 12.20 ⁇ 0.2°, 14.80 ⁇ 0.2°, 15.16 ⁇ 0.2°, 16.04 ⁇ 0.2°, 16.56 ⁇ 0.2°, 17.90 ⁇ 0.2°, 20.11 ⁇ 0.2°, 20.46 ⁇ 0.2°, 22.74 ⁇ 0.2°, 23.15 ⁇ 0.2°, 24.18 ⁇ 0.2°, 24.68 ⁇ 0.2°, 25.63 ⁇ 0.2°, 26.15 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the phosphate crystals is substantially characterized as in Figure 13.
  • the X-ray powder diffraction pattern of the phosphate crystal has a deviation of ⁇ 0.5° from a characteristic absorption peak represented by a 2 ⁇ value, preferably a deviation of ⁇ 0.3°, more preferably ⁇ 0.1°. Deviation.
  • the differential scanning calorimetry (DSC chart) of the phosphate crystal has a characteristic absorption peak at 155 ⁇ 5 ° C, preferably 154.8 ° C.
  • the phosphate crystal has a DSC pattern substantially as shown in FIG.
  • the TG image of the phosphate crystal has a characteristic absorption peak at 361 ⁇ 2 ° C, preferably 361.0 ° C.
  • the phosphate crystals have a thermal weight loss at 400 ° C of 47 to 48 wt%, preferably 47.57 wt%.
  • thermogravimetric analysis (TG map) of the phosphate crystals is substantially characterized as in Figure 14.
  • the initial value of the endothermic transition temperature of the phosphate crystal is 148 ⁇ 2 ° C, preferably 148.0 ° C.
  • the phosphate crystals are taken out in a desiccator having a humidity of 50% and taken out after 24 hours, and the weight gain is calculated to be ⁇ 3%, preferably ⁇ 1%, more preferably ⁇ 0.3%.
  • the phosphate crystal has a DVS pattern substantially as shown in FIG.
  • the IR pattern of the phosphate crystal comprises 3 or more characteristic absorption peaks represented by the wavelength ⁇ selected from the group consisting of: 3408 ⁇ 2 cm -1 , 2951 ⁇ 2 cm -1 , 2860 ⁇ 2cm -1 , 2225 ⁇ 2cm -1 , 1716 ⁇ 2cm -1 , 1684 ⁇ 2cm -1 , 1601 ⁇ 2cm -1 , 1556 ⁇ 2cm -1 , 1531 ⁇ 2cm -1 , 1450 ⁇ 2cm -1 , 1379 ⁇ 2cm - 1 , 1282 ⁇ 2 cm -1 , 1238 ⁇ 2 cm -1 , 1124 ⁇ 2 cm -1 , 1064 ⁇ 2 cm -1 , 947 ⁇ 2 cm -1 , 868 ⁇ 2 cm -1 , 758 ⁇ 2 cm -1 , 521 ⁇ 2 cm -1 .
  • the phosphate crystal has an IR pattern substantially as shown in FIG.
  • the phosphate crystal has a Raman diagram substantially as shown in FIG.
  • the present invention provides a glycolate salt of a compound of formula I,
  • the glycolate salt is a crystal.
  • the X-ray powder diffraction pattern of the glycolate crystals includes 3 or more 2 ⁇ values selected from the group consisting of: 8.92 ⁇ 0.2°, 10.20 ⁇ 0.2°, 13.35 ⁇ 0.2°, 16.89 ⁇ 0.2°, 19.37 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the glycolate crystals includes 3 or more 2 ⁇ values selected from the group consisting of: 8.92 ⁇ 0.2°, 10.20 ⁇ 0.2°, 13.35 ⁇ 0.2°, 16.89 ⁇ 0.2°, 19.37 ⁇ 0.2°, 20.51 ⁇ 0.2°, 21.22 ⁇ 0.2°, 21.78 ⁇ 0.2°, 23.00 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the glycolate crystals includes 3 or more 2 ⁇ values selected from the group consisting of: 8.92 ⁇ 0.2°, 10.20 ⁇ 0.2°, 13.35 ⁇ 0.2°, 16.89 ⁇ 0.2°, 19.37 ⁇ 0.2°, 20.51 ⁇ 0.2°, 21.22 ⁇ 0.2°, 21.78 ⁇ 0.2°, 23.00 ⁇ 0.2°, 23.87 ⁇ 0.2°, 24.08 ⁇ 0.2°, 24.37 ⁇ 0.2°, 25.52 ⁇ 0.2°, 33.81 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the glycolate crystals includes 3 or more 2 ⁇ values selected from the group consisting of 6.66 ⁇ 0.2°, 8.92 ⁇ 0.2°, 9.91 ⁇ 0.2°, 10.20. ⁇ 0.2°, 13.35 ⁇ 0.2°, 13.92 ⁇ 0.2°, 15.78 ⁇ 0.2°, 16.71 ⁇ 0.2°, 16.89 ⁇ 0.2°, 17.41 ⁇ 0.2°, 18.70 ⁇ 0.2°, 19.37 ⁇ 0.2°, 20.12 ⁇ 0.2°, 20.51 ⁇ 0.2°, 21.22 ⁇ 0.2°, 21.78 ⁇ 0.2°, 22.75 ⁇ 0.2°, 23.00 ⁇ 0.2°, 23.87 ⁇ 0.2°, 24.08 ⁇ 0.2°, 24.37 ⁇ 0.2°, 25.52 ⁇ 0.2°, 26.44 ⁇ 0.2°, 27.02 ⁇ 0.2°, 27.48 ⁇ 0.2°, 28.23 ⁇ 0.2°, 28.63 ⁇ 0.2°, 28.84 ⁇ 0.2°, 29.68 ⁇ 0.2°, 30.14 ⁇ 0.2°, 30.51 ⁇ 0.2°, 31.41 ⁇ 0.2°, 31.76 ⁇
  • the X-ray powder diffraction pattern of the glycolate crystals is substantially characterized as in Figure 19.
  • the X-ray powder diffraction pattern of the glycolate crystal has a deviation of ⁇ 0.5° from the characteristic absorption peak represented by the 2 ⁇ value, preferably ⁇ 0.3° deviation, more preferably ⁇ 0.1 ° deviation.
  • the differential scanning calorimetry (DSC chart) of the glycolate crystals has a characteristic absorption peak at 189 ⁇ 5 °C.
  • the glycolate crystals have a DSC pattern substantially as shown in FIG.
  • the initial value of the endothermic transition temperature of the glycolate crystals is 148 ⁇ 2 ° C, preferably 148.0 ° C.
  • the TG pattern of the glycolate crystal is characterized by 192 ⁇ 2 ° C and 268 ⁇ 2 ° C.
  • the absorption peak is preferably 192.5 ° C and 268.0 ° C.
  • the glycolate crystals have a TG map substantially as shown in FIG.
  • the glycolate crystals have a thermal weight loss at 400 ° C of 53 to 54 wt%, preferably 53.41 wt%.
  • the glycolate crystals are taken out in a desiccator having a humidity of 50% and taken out after 24 hours, and the weight gain is calculated to be ⁇ 3%, preferably ⁇ 1%, more preferably ⁇ 0.3%.
  • the glycolate crystals have a DVS pattern substantially as shown in FIG.
  • the IR pattern of the glycolate crystals includes 3 or more characteristic absorption peaks represented by the wavelength ⁇ selected from the group consisting of 3462 ⁇ 2 cm -1 , 2958 ⁇ 2 cm -1 , 2837 ⁇ 2cm -1 , 2227 ⁇ 2cm -1 , 1720 ⁇ 2cm -1 , 1674 ⁇ 2cm -1 , 1558 ⁇ 2cm -1 , 1533 ⁇ 2cm -1 , 1450 ⁇ 2cm -1 , 1350 ⁇ 2cm -1 , 1282 ⁇ 2cm -1 , 1223 ⁇ 2 cm -1 , 1072 ⁇ 2 cm -1 , 928 ⁇ 2 cm -1 , 760 ⁇ 2 cm -1 , 692 ⁇ 2 cm -1 .
  • the glycolate salt has an IR pattern substantially as shown in FIG.
  • the glycolate salt has a Raman diagram substantially as shown in FIG.
  • the crystalline composition comprises the hydrochloride, maleate, phosphate, glycolate or the hydrochloride, maleate, phosphate, glycolate salt to make.
  • the hydrochloride, maleate, phosphate, glycolate is present in an amount of from 60 to 99.999%, preferably 80% by weight based on the total weight of the crystalline composition. 99.999%, more preferably 90-99.999%.
  • the crystalline composition further comprises: (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl -3,4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylic acid hydrochloride, maleate, phosphate, glycolate, free base (R)-methyl-2-( 3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl-3,4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylic acid.
  • step (3) The solid obtained in the step (2) is filtered and/or dried to obtain the salt form of the first aspect of the invention.
  • the solvent is selected from the group consisting of alcohols, ethers, ketones, esters, or a combination thereof.
  • the alcohol is a C1-C10 alcohol, preferably a C1-C8 alcohol, more preferably a C1-C5 alcohol.
  • the alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol, or a combination thereof.
  • the ether is a C2-C8 ether, preferably a C2-C5 ether.
  • the ether is selected from the group consisting of diethyl ether, tetrahydrofuran or a combination thereof.
  • the ester is a C1-C10 ester, preferably a C1-C7 ester, more preferably a C1-C5 ester.
  • the ester is selected from the group consisting of methyl formate, ethyl acetate, isobutyl formate, or a combination thereof.
  • the molar ratio of the free base to the acid is 1:0.8-1:1.5, preferably 1:0.9-1:1.3, more preferably It is 1:1.0-1:1.1.
  • the temperature ranges from 10 to 80 ° C, preferably from 30 to 50 ° C.
  • the reaction time is from 0.1 to 10 h, preferably from 0.5 to 6 h.
  • the drying temperature is from 10 to 90 ° C, preferably from 20 to 80 ° C, more preferably from 40 to 70 ° C.
  • the drying pressure is 0-20 KPa, preferably 0-10 Kpa, more preferably 5-10 KPa.
  • the drying time is from 5 to 150 hours, preferably from 30 to 100 hours, more preferably from 60 to 80 hours.
  • the crystallization is carried out at 0 to 50 ° C, preferably 0 to 40 ° C, more preferably 20 to 30 ° C.
  • the crystallization is carried out under agitation.
  • the yield of the method is from 50% to 99.9%, preferably from 75% to 99.9%, more preferably from 85% to 99.9%.
  • the present invention provides a pharmaceutical composition comprising the pharmaceutical composition
  • the excipient is not particularly limited and may be selected from conventional materials in the art, or obtained by a conventional method, or commercially available.
  • the excipients include, but are not limited to, fillers, disintegrants, binders, lubricants, or combinations thereof.
  • the filler includes, but is not limited to, starch, lactose, microcrystalline cellulose, dextrin, mannitol, magnesium oxide, calcium sulfate, or a combination thereof.
  • the disintegrant includes, but is not limited to, carboxymethylcellulose and salts thereof, croscarmellose and salts thereof, crospovidone, sodium carboxymethyl starch, low Substituting hydroxypropyl cellulose, or a combination thereof.
  • the binder includes, but is not limited to, povidone, hydroxypropyl methylcellulose, starch slurry, or a combination thereof.
  • the lubricant includes, but is not limited to, magnesium stearate, calcium stearate, or a combination thereof.
  • Also provided in the invention is a (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl-3,4 - the use of dihydrothiophene [3,2-d]pyrimidine-6-carboxylic acid hydrochloride, maleate, phosphate, and glycolate or the salt composition or the pharmaceutical composition thereof, A medicament for the preparation of a prophylactic or therapeutic complication of type 2 diabetes and/or type II diabetes.
  • Type II diabetes complications of Type II diabetes include, but are not limited to, coronary artery disease, stroke, hypertension, kidney disease, peripheral vascular disease, neurological disease, retinopathy.
  • Also provided in the invention is a method of treating or preventing a complication of type 2 diabetes and/or type II diabetes, administering to the patient a therapeutically effective amount of said (R)-methyl-2-(3-aminoperazine) Hydrochloride of the crystal of pyridin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl-3,4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylate, Malay An acid salt, a phosphate salt, and a glycolate or a salt type composition or the pharmaceutical composition.
  • the amount of the hydrochloride, maleate, phosphate, and glycolate of the present invention or a pharmaceutical composition thereof varies depending on the age, sex, race, condition, and the like of the patient.
  • the compounds of the invention may be administered alone or in combination or in combination with other drugs or active ingredients.
  • the mode of application of the crystalline form or pharmaceutical composition of the present invention is not particularly limited. It can be selected from the conventional (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl-3,4-dihydrothiophene [3, 2-d]pyrimidine-6-carboxylic acid in the same or similar manner of administration, including but not limited to: oral, transdermal, intravenous Internal, intramuscular, topical administration, etc.
  • hydrochloride, maleate, phosphate, and glycolate of the present invention have higher purity
  • hydrochloride, maleate, phosphate and glycolate of the present invention have superior stability, especially stability in water, enhance oral absorption capacity, and improve bioavailability;
  • hydrochloride, maleate, phosphate and glycolate crystal forms of the present invention have lower hygroscopicity, and when the relative humidity is less than 50%, the hydrochloride, maleate, phosphate And the hygroscopicity of the glycolate is ⁇ 0.3%;
  • hydrochloride, maleate, phosphate and glycolate salts of the present invention are not easily degraded under conventional conditions;
  • the preparation method of the hydrochloride, maleate, phosphate and glycolate of the invention is simple in operation, easy to control, good in reproducibility, and suitable for industrial production;
  • the salt type compound of the present invention has superior oral hypoglycemic activity in preventing or treating type II diabetes.
  • the crystal is subjected to the following series of general tests.
  • X-ray Diffraction is a structural analysis method in which a substance is spatially distributed in a space by X-ray diffraction formed by a crystal.
  • X-rays having a certain wavelength are irradiated onto a crystalline substance, X-rays are scattered by encountering regularly arranged atoms or ions in the crystal, and the scattered X-rays are phase-enhanced in some directions to exhibit and crystallize.
  • the characteristic diffraction phenomenon corresponding to the structure.
  • test parameters of XRD are as follows: instrument model: Bruker D8advance; target: Cu-K ⁇ (40 kV, 40 mA); sample to detector distance: 30 cm; scanning range: 3 ° to 40 ° (2 theta value); Scanning step: 0.1s.
  • Thermo Gravimetric Analysis is an analytical technique for determining the mass of a substance as a function of temperature under program temperature control conditions. Thermogravimetric analysis can obtain the heat generated by the thermal change of the sample. It is suitable for checking the loss of crystal solvent or crystal water molecule in the crystal form or the process and quantity of sample sublimation and decomposition. It can also effectively distinguish whether the substance contains crystal solvent or Crystal water component.
  • test parameters of the TGA are as follows: instrument model: Netzsch TG 209F3; crucible: alumina crucible; temperature range: 30 to 400 ° C; scanning rate: 10 K / min; purge gas: 25 mL / min; : 15 mL/min.
  • DSC Differential Scanning Calorimeter
  • test parameters of the DSC are as follows: instrument model: Perkin Elmer DSC 8500; crucible: aluminum crucible; scanning from 50 ° C to 280 ° C at a heating rate of 10 ° C / min under a nitrogen purge.
  • the dynamic vapor absorption (DVS) test/water absorption test is a high sensitivity and high stability of the sample placed in a self-suspended state by rapidly measuring the increase and loss of moisture caused by the flow carrier gas set to the relative humidity (RH). On the digital microbalance, the adsorption/desorption of water vapor is then measured by measuring the increase/decrease in the mass of the material to determine the hygroscopicity of the sample.
  • test parameters of DVS are as follows: instrument model: SMS DVS Intrinsic; anhydrate: 0 to 95% - 0% RH; temperature: 25 ° C; hydrate: 40 to 95% - 0% RH, temperature: 25 ° C.
  • IR Infra-red Spectrometry
  • the IR test parameters are as follows: instrument model: Nicolet 6700 Fourier transform infrared spectrometer; single point ATR method, resolution 4.0 cm -1 .
  • Raman Spectroscopy is a method based on the Raman effect to study molecular vibration. In contrast to infrared absorption spectroscopy, Raman spectroscopy is the study of the scattering of light from molecules and light interactions. frequency. The absorption of Raman spectra of non-polar groups with insignificant infrared absorption is obvious.
  • test parameters of the RM are as follows: instrument model: Thermo DXR Raman Microscope confocal micro-Raman spectrometer; laser wavelength: 532 nm; exposure time: 1.0 sec; number of exposures: 10.
  • the hydrochloride salt prepared in Example 1 was subjected to XRD, TGA, DSC, DVS, IR and Raman tests.
  • Figure 1 is an XRD pattern of the hydrochloride salt of Example 1, and it can be seen from Figure 1 that the hydrochloride salt is at 7.43 °, 11.06 °, 11.70 °, 13.46 °, 15.03 °, 15.34 °, 15.84 °, 16.35 °, 17.59 °. , 18.32°, 19.54°, 20.13°, 21.24°, 21.96°, 22.46°, 22.74°, 23.67°, 24.01°, 24.83°, 25.19°, 26.63°, 27.20°, 29.32°, 30.26°, 32.15° Absorption peak.
  • Figure 2 is a TG diagram of the hydrochloride salt of Example 1, and it can be seen from Figure 2 that the hydrochloride salt has a weight loss of 64.33% at 210-400 °C.
  • FIG. 3 is a differential scanning calorimetry (DSC) chart of the hydrochloride salt of Example 1, from which it can be seen that the hydrochloride salt has no melting peak prior to decomposition.
  • Figure 4 is a graph showing the hygroscopicity analysis (DVS) of the hydrochloride salt of Example 1. It can be seen from Figure 4 that the hydrochloride salt has a slight hygroscopicity, and the humidity variation range is small, less than 3.0% in the conventional storage humidity range. At 80% RH, it absorbs 2.54% of water.
  • DVD hygroscopicity analysis
  • IR infrared spectrum
  • the maleic acid salt prepared in Example 2 was subjected to XRD, TGA, DSC, DVS, IR and Raman tests.
  • Figure 7 is an XRD pattern of the maleate salt of Example 2. It can be seen from Figure 7 that the maleate salt is 7.55°, 10.83°, 12.41°, 13.22°, 14.38°, 14.75°, 15.45°, 15.80°, 17.50. There are absorption peaks at °, 18.30, 19.40, 20.43, 20.89, 21.85, 22.87, 23.25, 25.04, 26.59, 26.93, 27.10, 28.21, 30.53, 32.96.
  • Figure 8 is a TG diagram of the maleate salt of Example 2. It can be seen from Figure 8 that the maleate salt has a weight loss of 42.56% at 210-400 °C.
  • Figure 9 is a differential scanning calorimetry (DSC) chart of the maleate salt of Example 2. It can be seen from Figure 9 that the corresponding DSC of the maleate salt shows a melting point of 113.80 °C.
  • Figure 10 is a graph showing the hygroscopicity analysis (DVS) of the maleate salt of Example 2. It can be seen from Figure 10 that the Malay has a slightly hygroscopicity, and the humidity variation range is small, less than 2.0% in the conventional storage humidity range. At 80% RH, it absorbs 1.57% of water.
  • Figure 11 is an infrared spectrum (IR) diagram of the maleate salt of Example 2. It can be seen from Figure 11 that the maleate salt is at 3429, 3062, 2954, 2862, 2224, 1720, 1676, 1558, 1531, 1469, 1354. There are characteristic absorption peaks at 1290, 1219, 1063, 864, 775, and 654 cm -1 .
  • the phosphates prepared in Example 3 were tested by XRD, TGA, DSC, DVS, IR and Raman.
  • Figure 13 is an XRD pattern of the phosphate of Example 3, and it can be seen from Figure 13 that the phosphate salts are at 6.23 °, 11.99 °, 12.20 °, 14.80 °, 15.16 °, 16.04 °, 16.56 °, 17.90 °, 20.11 °, There are absorption peaks at 20.46°, 22.74°, 23.15°, 24.18°, 24.68°, 25.63°, and 26.15°.
  • Figure 14 is a TG diagram of the phosphate of Example 3, and it can be seen from Figure 14 that the phosphate has a weight loss of 47.57% at 210-400 °C.
  • Figure 15 is a differential scanning calorimetry (DSC) chart of the phosphate of Example 3, from which it can be seen that the phosphate corresponding DSC shows a melting point of 154.80 °C.
  • Figure 16 is a graph showing the hygroscopicity analysis (DVS) of the phosphate of Example 3. From Fig. 16, it can be seen that the phosphate is slightly hygroscopic, and the humidity variation range is small in the conventional storage humidity range.
  • DVD hygroscopicity analysis
  • Figure 17 is an infrared spectrum (IR) diagram of the phosphate of Example 3, from which it can be seen that the phosphates are at 3408, 2951, 2860, 2225, 1716, 1684, 1601, 1556, 1531, 1450, 1379, 1282. There are characteristic absorption peaks at 1238, 1124, 1064, 947, 868, 758, and 521 cm -1 .
  • the glycolate prepared in Example 4 was subjected to XRD, TGA, DSC, DVS, IR and Raman tests.
  • Figure 19 is an XRD pattern of the glycolate salt of Example 4. From Figure 19, it can be seen that the glycolate is 6.66 °, 8.92 °, 9.91 °, 10.20 °, 13.35 °, 13.92 °, 15.78 °, 16.71 °, 16.89 °.
  • Figure 20 is a TG diagram of the glycolate salt of Example 4. From Figure 20, it can be seen that the glycolate has a weight loss of 53.41% at 210-400 °C.
  • Figure 21 is a differential scanning calorimetry (DSC) chart of the glycolate salt of Example 4, and it can be seen from Figure 21 that the DSC of the glycolate salt shows a melting point of 188.75 °C.
  • Figure 22 is a graph showing the hygroscopicity analysis (DVS) of the glycolate salt of Example 4. From Fig. 22, it can be seen that the glycolate has a slight hygroscopicity, and the humidity variation range is small, less than 2.0% in the conventional storage humidity range. At 80% RH, it absorbs 1.23% of water.
  • Figure 23 is an infrared spectrum (IR) diagram of the glycolate salt of Example 4, and it can be seen from Figure 23 that the glycolate is at 3462, 2958, 2837, 2227, 1720, 1674, 1558, 1533, 1450, 1350, 1282. There are characteristic absorption peaks at 1223, 1072, 928, 760, and 692 cm -1 .

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Abstract

本发明涉及(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸的盐型及其制备方法。本发明还公开了所述式I化合物盐型的药物组合物。本发明的盐型具有较强的体内降糖活性，有望成为新型的治疗或预防II型糖尿病和/或II型糖尿病的并发症的药物活性成分.

Description

一种DPPIV抑制剂的盐型及其制备方法 技术领域
本发明涉及药物化学领域，具体地，涉及一种(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸的盐型、其制备方法及用途。
背景技术
糖尿病是由于人体内胰岛素分泌不足和胰腺β细胞的功能障碍，从而导致糖，脂肪和蛋白质代谢障碍而引起的一种代谢性疾病。糖尿病造成的高血糖会导致身体组织的损坏并导致微血管病变和大血管病变，如视网膜病，肾病，神经病，中风和冠状动脉粥样化，等并发症严重损害人类的健康，威胁人类的生命安全。
糖尿病可分为Ⅰ型糖尿病(T1DM)和Ⅱ型糖尿病(T2DM)。DPP-Ⅳ抑制剂(沙格列汀)通过增加内源性活性胰高血糖素样肽-1(GLP-1)及葡萄糖依耐性促胰岛素肽(GIP)水平，改善α及β细胞功能障碍。DPP IV抑制剂能够显著降低体内的血糖浓度、增加葡萄糖耐受、促进胰岛素分泌、降低胰高血糖素水平、延缓胰岛素抵抗、提高II型糖尿病病人血糖增加时胰岛素的应答水平。DPP IV抑制剂与现有的口服糖尿病药物相比较，具有如下特点：(1)DPP IV抑制剂无需注射，通过口服给药方式持续降低糖基化血红蛋白水平；(2)DPP IV抑制剂长期应用具有良好的耐药性；(3)可以增强胰岛素分泌并提高胰高血糖素的释放；(4)改善胰岛素敏感性，同时增加胰岛β细胞功能；(5)低血糖发生率较低，不会引起体重增加，不会出现恶心呕吐及胃肠道功能不良；(6)DPP IV抑制剂与其它II型糖尿病药物联合使用具有协同作用。但该类药物可能引起胰腺炎、荨麻疹、血管性水肿等副作用。
(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸(式I化合物)为新型DPP IV抑制剂，具有较强的体内降糖活性。但是，现有的(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸的综合性能尚难以令人满意。
因此，本领域迫切需要开发一种高效、低毒、长效的(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸的新盐型，以获得具有更优性能的药物活性成分。
发明内容
本发明的目的在于提供一种高效、低毒、长效的式I化合物的多种盐型。
本发明的第一方面，提供了一种式I所示化合物的盐型，所述盐型选自下组：盐酸盐、马来酸盐、磷酸盐和乙醇酸盐
Figure PCTCN2017077679-appb-000001
在另一优选例中，所述的盐型为晶体。
在另一优选例中，所述的盐酸盐为晶体。
在另一优选例中，所述盐酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：7.43±0.2°、11.06±0.2°、11.70±0.2°、13.46±0.2°、15.03±0.2°、15.34±0.2°、18.32±0.2°、21.96±0.2°、24.01±0.2°、27.20±0.2°、29.32±0.2°、30.26±0.2°。
在另一优选例中，所述盐酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：7.43°、11.06°、11.70°、18.32°、21.96°、24.01°、27.20°、29.32°、30.26°。
在另一优选例中，所述盐酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：7.43±0.2°、11.06±0.2°、11.70±0.2°、13.46±0.2°、15.03±0.2°、15.34±0.2°、15.84±0.2°、16.35±0.2°、17.59±0.2°、18.32±0.2°、19.54±0.2°、20.13±0.2°、21.24±0.2°、21.96±0.2°、22.46±0.2°、22.74±0.2°、23.67±0.2°、24.01±0.2°、24.83±0.2°、25.19±0.2°、26.63±0.2°、27.20±0.2°、29.32±0.2°、30.26±0.2°、32.15±0.2°。
在另一优选例中，所述盐酸盐晶体的X射线粉末衍射图谱基本如图1所表征。
在另一优选例中，所述盐酸盐晶体的X射线粉末衍射图谱用2θ值表示的特征吸收峰存在±0.5°的偏差，较佳地存在±0.3°的偏差，更佳地存在±0.1°的偏差。
在另一优选例中，所述盐酸盐晶体的差示扫描量热法分析图谱(DSC图)在分解前无熔融峰。
在另一优选例中，所述盐酸盐晶体具有基本如图3所示的DSC图。
在另一优选例中，所述盐酸盐晶体的TG图在272±2℃存在特征吸收峰。
在另一优选例中，所述盐酸盐晶体的TG图在272.6℃存在特征吸收峰。
在另一优选例中，所述盐酸盐晶体的热重分析图谱(TG图)基本如图2所表征。
在另一优选例中，所述盐酸盐晶体在400℃的热失重为64-65wt％，较佳地为64.33wt％。
在另一优选例中，所述盐酸盐晶体放置于湿度为50％的干燥器中24小时后取出，计算增重≤3％，较佳地≤1％，更佳地≤0.3％。
在另一优选例中，所述盐酸盐晶体具有基本如图4所示的DVS图。
在另一优选例中，所述盐酸盐晶体的IR图包括3个或3个以上选自下组的用波长λ表示的特征吸收峰：3429±2cm-1、2951±2cm-1、2827±2cm-1、2225±2cm-1、1720±2cm-1、1687±2cm-1、1560±2cm-1、1533±2cm-1、1446±2cm-1、1385±2cm-1、1261±2cm-1、1064±2cm-1、771±2cm-1。
在另一优选例中，所述盐酸盐晶体具有基本如图5所示的IR图。
在另一优选例中，所述盐酸盐晶体具有基本如图6所示的Raman图。
在另一优选例中，所述的马来酸盐为晶体。
在另一优选例中，所述马来酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：7.55±0.2°、12.41±0.2°、15.45±0.2°、17.50±0.2°、20.89±0.2°、26.59±0.2°、26.93±0.2°。
在另一优选例中，所述马来酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：7.55±0.2°、12.41±0.2°、15.45±0.2°、17.50±0.2°、20.89±0.2°、26.59±0.2°、26.93±0.2°、27.10±0.2°、28.21±0.2°、30.53±0.2°、32.96±0.2°。
在另一优选例中，所述马来酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：7.55±0.2°、10.83±0.2°、12.41±0.2°、13.22±0.2°、14.38±0.2°、14.75±0.2°、15.45±0.2°、15.80±0.2°、17.50±0.2°、18.30±0.2°、19.40±0.2°、20.43±0.2°、20.89±0.2°、21.85±0.2°、22.87±0.2°、23.25±0.2°、25.04±0.2°、26.59±0.2°、26.93±0.2°、27.10±0.2°、28.21±0.2°、30.53±0.2°、32.96±0.2°。
在另一优选例中，所述马来酸盐晶体的X射线粉末衍射图谱基本如图7所表征。
在另一优选例中，所述马来酸盐晶体的X射线粉末衍射图谱用2θ值表示的特征吸收峰存在±0.5°的偏差，较佳地存在±0.3°的偏差，更佳地存在±0.1°的偏差。
在另一优选例中，所述马来酸盐晶体的差示扫描量热法分析图谱(DSC图)在113±5℃存在特征吸收峰。
在另一优选例中，所述马来酸盐晶体的差示扫描量热法分析图谱(DSC图)在113.8℃存在特征吸收峰。
在另一优选例中，所述马来酸盐晶体具有基本如图9所示的DSC图。
在另一优选例中，所述马来酸盐晶体的TG图包括选自下组的特征吸收峰：77±2℃、180±5℃、284±5℃。
在另一优选例中，所述马来酸盐晶体的TG图包括选自下组的特征吸收峰：77.3℃、179.6℃、283.6℃。
在另一优选例中，所述马来酸盐晶体的热重分析图谱(TG图)基本如图8所表征。
在另一优选例中，所述马来酸盐晶体在400℃的热失重为42-43wt％，较佳地为42.58wt％。
在另一优选例中，所述马来酸盐晶体的吸热转变温度的起始值为110±2℃，较佳地为110.37℃。
在另一优选例中，所述马来酸盐晶体放置于湿度为50％的干燥器中24小时后取出，计算增重≤3％，较佳地≤1％，更佳地≤0.3％。
在另一优选例中，所述马来酸盐晶体具有基本如图10所示的DVS图。
在另一优选例中，所述马来酸盐的IR图包括3个或3个以上选自下组的用波长λ表示的特征吸收峰：3429±2cm-1、3062±2cm-1、2954±2cm-1、2862±2cm-1、2224±2cm-1、1720±2cm-1、1676±2cm-1、1558±2cm-1、1531±2cm-1、1469±2cm-1、1354±2cm-1、1290±2cm-1、1219±2cm-1、1063±2cm-1、864±2cm-1、775±2cm-1、654±2cm-1。
在另一优选例中，所述马来酸盐晶体具有基本如图11所示的IR图。
在另一优选例中，所述马来酸盐晶体具有基本如图12所示的Raman图。
在另一优选例中，所述的磷酸盐为晶体。
在另一优选例中，所述磷酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：11.99±0.2°、12.20±0.2°、14.80±0.2°、20.11±0.2°、20.46±0.2°、24.18±0.2°、24.68±0.2°。
在另一优选例中，所述磷酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：11.99±0.2°、12.20±0.2°、14.80±0.2°、20.11±0.2°、20.46±0.2°、23.15±0.2°、24.18±0.2°、24.68±0.2°、25.63±0.2°、26.15±0.2°。
在另一优选例中，所述磷酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：6.23±0.2°、11.99±0.2°、12.20±0.2°、14.80±0.2°、15.16±0.2°、16.04±0.2°、16.56±0.2°、17.90±0.2°、20.11±0.2°、20.46±0.2°、22.74±0.2°、23.15±0.2°、24.18±0.2°、24.68±0.2°、25.63±0.2°、26.15±0.2°。
在另一优选例中，所述磷酸盐晶体的X射线粉末衍射图谱基本如图13所表 征。
在另一优选例中，所述磷酸盐晶体的X射线粉末衍射图谱用2θ值表示的特征吸收峰存在±0.5°的偏差，较佳地存在±0.3°的偏差，更佳地存在±0.1°的偏差。
在另一优选例中，所述磷酸盐晶体的差示扫描量热法分析图谱(DSC图)在155±5℃存在特征吸收峰，较佳地为154.8℃。
在另一优选例中，所述磷酸盐晶体具有基本如图15所示的DSC图。
在另一优选例中，所述磷酸盐晶体的TG图在361±2℃存在特征吸收峰，较佳地为361.0℃。
在另一优选例中，所述磷酸盐晶体在400℃的热失重为47-48wt％，较佳地为47.57wt％。
在另一优选例中，所述磷酸盐晶体的热重分析图谱(TG图)基本如图14所表征。
在另一优选例中，所述磷酸盐晶体的吸热转变温度的起始值为148±2℃，较佳地为148.0℃。
在另一优选例中，所述磷酸盐晶体放置于湿度为50％的干燥器中24小时后取出，计算增重≤3％，较佳地≤1％，更佳地≤0.3％。
在另一优选例中，所述磷酸盐晶体具有基本如图16所示的DVS图。
在另一优选例中，所述磷酸盐晶体的IR图包括3个或3个以上选自下组的用波长λ表示的特征吸收峰：3408±2cm-1、2951±2cm-1、2860±2cm-1、2225±2cm-1、1716±2cm-1、1684±2cm-1、1601±2cm-1、1556±2cm-1、1531±2cm-1、1450±2cm-1、1379±2cm-1、1282±2cm-1、1238±2cm-1、1124±2cm-1、1064±2cm-1、947±2cm-1、868±2cm-1、758±2cm-1、521±2cm-1。
在另一优选例中，所述磷酸盐晶体具有基本如图17所示的IR图。
在另一优选例中，所述磷酸盐晶体具有基本如图18所示的Raman图。
在另一优选例中，所述乙醇酸盐为晶体。
在另一优选例中，所述乙醇酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：8.92±0.2°、10.20±0.2°、13.35±0.2°、16.89±0.2°、19.37±0.2°。
在另一优选例中，所述乙醇酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：8.92±0.2°、10.20±0.2°、13.35±0.2°、16.89±0.2°、19.37±0.2°、20.51±0.2°、21.22±0.2°、21.78±0.2°、23.00±0.2°。
在另一优选例中，所述乙醇酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：8.92±0.2°、10.20±0.2°、13.35±0.2°、16.89±0.2°、19.37±0.2°、 20.51±0.2°、21.22±0.2°、21.78±0.2°、23.00±0.2°、23.87±0.2°、24.08±0.2°、24.37±0.2°、25.52±0.2°、33.81±0.2°。
在另一优选例中，所述乙醇酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：6.66±0.2°、8.92±0.2°、9.91±0.2°、10.20±0.2°、13.35±0.2°、13.92±0.2°、15.78±0.2°、16.71±0.2°、16.89±0.2°、17.41±0.2°、18.70±0.2°、19.37±0.2°、20.12±0.2°、20.51±0.2°、21.22±0.2°、21.78±0.2°、22.75±0.2°、23.00±0.2°、23.87±0.2°、24.08±0.2°、24.37±0.2°、25.52±0.2°、26.44±0.2°、27.02±0.2°、27.48±0.2°、28.23±0.2°、28.63±0.2°、28.84±0.2°、29.68±0.2°、30.14±0.2°、30.51±0.2°、31.41±0.2°、31.76±0.2°、33.00±0.2°、33.81±0.2°、34.13±0.2°、35.21±0.2°、25.83±0.2°、36.37±0.2°、37.70±0.2°、37.93±0.2°。
在另一优选例中，所述乙醇酸盐晶体的X射线粉末衍射图谱基本如图19所表征。
在另一优选例中，所述乙醇酸盐晶体的X射线粉末衍射图谱用2θ值表示的特征吸收峰存在±0.5°的偏差，较佳地存在±0.3°的偏差，更佳地存在±0.1°的偏差。
在另一优选例中，所述乙醇酸盐晶体的差示扫描量热法分析图谱(DSC图)在189±5℃存在特征吸收峰。
在另一优选例中，所述乙醇酸盐晶体具有基本如图21所示的DSC图。
在另一优选例中，所述乙醇酸盐晶体的吸热转变温度的起始值为148±2℃，较佳地为148.0℃。
在另一优选例中，所述乙醇酸盐晶体的TG图在192±2℃、268±2℃存在特征吸收峰，较佳地为192.5℃、268.0℃。
在另一优选例中，所述乙醇酸盐晶体具有基本如图20所示的TG图。
在另一优选例中，所述乙醇酸盐晶体在400℃的热失重为53-54wt％，较佳地为53.41wt％。
在另一优选例中，所述乙醇酸盐晶体放置于湿度为50％的干燥器中24小时后取出，计算增重≤3％，较佳地≤1％，更佳地≤0.3％。
在另一优选例中，所述乙醇酸盐晶体具有基本如图22所示的DVS图。
在另一优选例中，所述乙醇酸盐晶体的IR图包括3个或3个以上选自下组的用波长λ表示的特征吸收峰：3462±2cm-1、2958±2cm-1、2837±2cm-1、2227±2cm-1、1720±2cm-1、1674±2cm-1、1558±2cm-1、1533±2cm-1、1450±2cm-1、1350±2cm-1、1282±2cm-1、1223±2cm-1、1072±2cm-1、928±2cm-1、760±2cm-1、692±2cm-1。
在另一优选例中，所述乙醇酸盐具有基本如图23所示的IR图。
在另一优选例中，所述乙醇酸盐具有基本如图24所示的Raman图。
本发明第二方面，提供一种盐型组合，所述盐型组合包含一种或多种本发明第一方面所述的盐酸盐、马来酸盐、磷酸盐、乙醇酸盐等盐型或由本发明第一方面所述的盐酸盐、马来酸盐、磷酸盐、乙醇酸盐等盐型构成。
在另一优选例中，以所述盐型组合物的总重量计，盐酸盐、马来酸盐、磷酸盐、乙醇酸盐的总质量百分含量为60-99.999％，较佳地为80-99.999％，更佳地为90-99.999％。
在另一优选例中，所述盐型组合还包括：(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸的其他盐型、游离碱(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸。
本发明第三方面，提供一种制备本发明第一方面所述的式I化合物的盐型的方法，所述方法包括如下步骤：
(1)将式I化合物的游离碱溶于溶剂中，加入一定量的酸；
(2)将步骤(1)所得的溶液在一定温度下放置一段时间进行反应，搅拌下析晶，得到固体；
(3)过滤和/或干燥步骤(2)所得固体，制得本发明第一方面所述的盐型。
在另一优选例中，所述步骤(1)中，所述溶剂选自下组：醇类、醚类、酮类、酯类或其组合。
在另一优选例中，所述醇类为C1-C10的醇，较佳地为C1-C8的醇，更佳地为C1-C5的醇。
在另一优选例中，所述醇类选自下组：甲醇、乙醇、正丙醇、异丙醇、正丁醇、新戊醇、或其组合。
在另一优选例中，所述醚类为C2-C8的醚，较佳地为C2-C5的醚。
在另一优选例中，所述醚类选自下组：乙醚、四氢呋喃或其组合。
在另一优选例中，所述酯类为C1-C10的酯，较佳地为C1-C7的酯，更佳地为C1-C5的酯。
在另一优选例中，所述酯类选自下组：甲酸甲酯、乙酸乙酯、甲酸异丁酯、或其组合。
在另一优选例中，所述步骤(1)中，所述游离碱与所述酸的摩尔比为1：0.8-1：1.5，较佳地为1:0.9-1:1.3，更佳地为1:1.0-1:1.1。
在另一优选例中，所述步骤(1)中，所述温度范围为10-80℃，较佳地为30-50℃。
在另一优选例中，所述步骤(1)中，所述反应时间为0.1-10h，较佳地为0.5-6h。
在另一优选例中，所述步骤(2)中，干燥的温度为10-90℃，较佳地为20-80℃，更佳地为40-70℃。
在另一优选例中，所述步骤(2)中，干燥的压力为0-20KPa，较佳地为0-10Kpa，更佳地为5-10KPa。
在另一优选例中，所述步骤(2)中，干燥的时间为5-150小时，较佳地为30-100小时，更佳地为60-80小时。
在另一优选例中，所述步骤(2)中，所述析晶在0-50℃下进行，较佳地为0-40℃，更佳地为20-30℃。
在另一优选例中，所述析晶在搅拌下进行。
在另一优选例中，所述步骤(3)中，所述方法的产率为50％-99.9％，较佳地为75％-99.9％，更佳地为85％-99.9％。
本发明第四方面，提供一种药物组合物，所述药物组合物包含：
(1)本发明第一方面所述的式I化合物的盐酸盐、马来酸盐、磷酸盐、乙醇酸盐、或其组合；以及
(2)药学上可接受的赋形剂。
在另一优选例中，所述赋形剂选自下组：填充剂、崩解剂、粘合剂、润滑剂、或其组合。
在另一优选例中，所述填充剂选自下组：淀粉、乳糖、微晶纤维素、糊精、甘露醇、氧化镁、硫酸钙、或其组合。
在另一优选例中，所述崩解剂选自下组：羧甲基纤维素及其盐、交联羧甲基纤维素及其盐、交联聚维酮、羧甲基淀粉钠、低取代羟丙基纤维素、或其组合。
在另一优选例中，所述粘合剂选自下组：聚维酮、羟丙基甲基纤维素、淀粉浆、或其组合。
在另一优选例中，所述润滑剂选自下组：硬脂酸镁、硬脂酸钙、或其组合。
本发明第五方面，提供一种本发明第一方面所述的盐型或本发明第二方面所述的盐型组合或本发明第四方面所述的药物组合物的用途，用于制备预防或治疗II型糖尿病和/或II型糖尿病的并发症的药物。
在另一优选例中，所述II型糖尿病的并发症选自下组：冠状动脉性疾病、中风、高血压、肾病、周围血管性疾病、神经性疾病、视网膜病。
本发明第六方面，提供一种治疗或预防II型糖尿病和/或II型糖尿病的并发症的方法，向患者给予治疗有效量的本发明第一方面所述的式I化合物的盐酸盐、马来酸盐、磷酸盐、乙醇酸盐、或其组合或本发明第二方面所述的盐型组合或本发明第四方面所述的药物组合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1是本发明实施例1盐酸盐的XRD图。
图2是本发明实施例1盐酸盐的TG图。
图3是本发明实施例1盐酸盐的差示扫描量热分析(DSC)图。
图4是本发明实施例1盐酸盐的吸湿性分析(DVS)图。
图5是本发明实施例1盐酸盐的红外光谱(IR)图。
图6是本发明实施例1盐酸盐的拉曼光谱(Raman)图。
图7是本发明实施例2马来酸盐的XRD图。
图8是本发明实施例2马来酸盐的TG图。
图9是本发明实施例2马来酸盐的差示扫描量热分析(DSC)图。
图10是本发明实施例2马来酸盐的吸湿性分析(DVS)图。
图11是本发明实施例2马来酸盐的红外光谱(IR)图。
图12是本发明实施例2马来酸盐的拉曼光谱(Raman)图。
图13是本发明实施例3磷酸盐的XRD图。
图14是本发明实施例3磷酸盐的TG图。
图15是本发明实施例3磷酸盐的差示扫描量热分析(DSC)图。
图16是本发明实施例3磷酸盐的吸湿性分析(DVS)图。
图17是本发明实施例3磷酸盐的红外光谱(IR)图。
图18是本发明实施例3磷酸盐的拉曼光谱(Raman)图。
图19是本发明实施例4乙醇酸盐的XRD图。
图20是本发明实施例4乙醇酸盐的TG图。
图21是本发明实施例4乙醇酸盐的差示扫描量热分析(DSC)图。
图22是本发明实施例4乙醇酸盐的吸湿性分析(DVS)图。
图23是本发明实施例4乙醇酸盐的红外光谱(IR)图。
图24是本发明实施例4乙醇酸盐的拉曼光谱(Raman)图。
具体实施方式
本发明人经过长期而深入的研究，意外地制备了一种具有更优药学性能的(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸的盐型。基于上述发现，发明人完成了本发明。
式I化合物
本发明所述的式I化合物即(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸。
Figure PCTCN2017077679-appb-000002
(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸(式I)为新型DPP IV选择性、可逆竞争型抑制剂，具有较强的体内降糖活性。其抑制活性达纳摩尔级，体外DPP IV抑制活性和选择性优于上市药物西他列汀和维格列汀。
在动物体内，式I化合物能有效抑制正常小鼠和大鼠血浆中DPP IV活性，其DPP IV抑制活性优于上市药物阿格列汀。式I化合物可以剂量依赖性地提高正常ICR小鼠的口服糖耐量，起效剂量仅为0.1mg/kg，效果优于阿格列汀；该化合物慢性给药ob/ob小鼠，能有效地降低ob/ob小鼠的空腹血糖，优于阳性对照药阿格列汀；该化合物慢性给药降低基因缺陷型db/db小鼠的空腹血糖，与阳性对照药阿格列汀相当。
药代动力学和安全性研究结果表明，式I化合物在大鼠和犬的药代动力学性质以及安全性良好，在大鼠和犬中的半衰期和AUC0-t优于上市药物阿格列汀。该化合物安全性良好，ICR小鼠急性毒性实验表明，300mg/kg给药组未见动物死亡； 比格犬急性毒性实验表明，1g/kg给药组未见动物死亡；大鼠亚急性毒性实验表明，大鼠经口给予150mg/kg组无明显的毒性反应。
综合体外药效学评价、体内药理学评价、药代动力学研究、以及安全性评价等研究结果，该化合物体内降糖作用优于目前临床使用的DPPIV抑制剂。
式I化合物的游离碱
本发明中，采用专利申请号CN201210262331.3中所述制备方法制得游离碱(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸粉末。1H NMR(CDCl3):δ7.76(s,1H),7.610(d,1H),7.493(t,1H),7.320(t,1H),7.180(d,1H),5.500(quartet,2H),3.895(s,3H),3.680(d,2H),3.355(m,1H),3.010(m,2H),2.150(m,1H),1.894(m,2H),1.644(m,1H)；LC-MS m/z 424.1[M+H]+。
盐酸盐
本发明提供了一种式I所示化合物的盐酸盐。
在另一优选例中，所述的盐酸盐为晶体。
在另一优选例中，所述盐酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：7.43±0.2°、11.06±0.2°、11.70±0.2°、13.46±0.2°、15.03±0.2°、15.34±0.2°、18.32±0.2°、21.96±0.2°、24.01±0.2°、27.20±0.2°、29.32±0.2°、30.26±0.2°。
在另一优选例中，所述盐酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：7.43°、11.06°、11.70°、18.32°、21.96°、24.01°、27.20°、29.32°、30.26°。
在另一优选例中，所述盐酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：7.43±0.2°、11.06±0.2°、11.70±0.2°、13.46±0.2°、15.03±0.2°、15.34±0.2°、15.84±0.2°、16.35±0.2°、17.59±0.2°、18.32±0.2°、19.54±0.2°、20.13±0.2°、21.24±0.2°、21.96±0.2°、22.46±0.2°、22.74±0.2°、23.67±0.2°、24.01±0.2°、24.83±0.2°、25.19±0.2°、26.63±0.2°、27.20±0.2°、29.32±0.2°、30.26±0.2°、32.15±0.2°。
在另一优选例中，所述盐酸盐晶体的X射线粉末衍射图谱基本如图1所表征。
在另一优选例中，所述盐酸盐晶体的X射线粉末衍射图谱用2θ值表示的特征吸收峰存在±0.5°的偏差，较佳地存在±0.3°的偏差，更佳地存在±0.1°的偏差。
在另一优选例中，所述盐酸盐晶体的差示扫描量热法分析图谱(DSC图)在分解前无熔融峰。
在另一优选例中，所述盐酸盐晶体具有基本如图3所示的DSC图。
在另一优选例中，所述盐酸盐晶体的TG图在272±2℃存在特征吸收峰。
在另一优选例中，所述盐酸盐晶体的TG图在272.6℃存在特征吸收峰。
在另一优选例中，所述盐酸盐晶体的热重分析图谱(TG图)基本如图2所表征。
在另一优选例中，所述盐酸盐晶体在400℃的热失重为64-65wt％，较佳地为64.33wt％。
在另一优选例中，所述盐酸盐晶体放置于湿度为50％的干燥器中24小时后取出，计算增重≤3％，较佳地≤1％，更佳地≤0.3％。
在另一优选例中，所述盐酸盐晶体具有基本如图4所示的DVS图。
在另一优选例中，所述盐酸盐晶体的IR图包括3个或3个以上选自下组的用波长λ表示的特征吸收峰：3429±2cm-1、2951±2cm-1、2827±2cm-1、2225±2cm-1、1720±2cm-1、1687±2cm-1、1560±2cm-1、1533±2cm-1、1446±2cm-1、1385±2cm-1、1261±2cm-1、1064±2cm-1、771±2cm-1。
在另一优选例中，所述盐酸盐晶体具有基本如图5所示的IR图。
在另一优选例中，所述盐酸盐晶体具有基本如图6所示的Raman图。
马来酸盐
本发明提供了一种式I所示化合物的马来酸盐。
在另一优选例中，所述的马来酸盐为晶体。
在另一优选例中，所述马来酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：7.55±0.2°、12.41±0.2°、15.45±0.2°、17.50±0.2°、20.89±0.2°、26.59±0.2°、26.93±0.2°。
在另一优选例中，所述马来酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：7.55±0.2°、12.41±0.2°、15.45±0.2°、17.50±0.2°、20.89±0.2°、26.59±0.2°、26.93±0.2°、27.10±0.2°、28.21±0.2°、30.53±0.2°、32.96±0.2°。
在另一优选例中，所述马来酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：7.55±0.2°、10.83±0.2°、12.41±0.2°、13.22±0.2°、14.38±0.2°、14.75±0.2°、15.45±0.2°、15.80±0.2°、17.50±0.2°、18.30±0.2°、19.40±0.2°、20.43±0.2°、20.89±0.2°、21.85±0.2°、22.87±0.2°、23.25±0.2°、25.04±0.2°、26.59±0.2°、26.93±0.2°、27.10±0.2°、28.21±0.2°、30.53±0.2°、32.96±0.2°。
在另一优选例中，所述马来酸盐晶体的X射线粉末衍射图谱基本如图7所表征。
在另一优选例中，所述马来酸盐晶体的X射线粉末衍射图谱用2θ值表示的 特征吸收峰存在±0.5°的偏差，较佳地存在±0.3°的偏差，更佳地存在±0.1°的偏差。
在另一优选例中，所述马来酸盐晶体的差示扫描量热法分析图谱(DSC图)在113±5℃存在特征吸收峰。
在另一优选例中，所述马来酸盐晶体的差示扫描量热法分析图谱(DSC图)在113.8℃存在特征吸收峰。
在另一优选例中，所述马来酸盐晶体具有基本如图9所示的DSC图。
在另一优选例中，所述马来酸盐晶体的TG图包括选自下组的特征吸收峰：77±2℃、180±5℃、284±5℃。
在另一优选例中，所述马来酸盐晶体的TG图包括选自下组的特征吸收峰：77.3℃、179.6℃、283.6℃。
在另一优选例中，所述马来酸盐晶体的热重分析图谱(TG图)基本如图8所表征。
在另一优选例中，所述马来酸盐晶体在400℃的热失重为42-43wt％，较佳地为42.58wt％。
在另一优选例中，所述马来酸盐晶体的吸热转变温度的起始值为110±2℃，较佳地为110.37℃。
在另一优选例中，所述马来酸盐晶体放置于湿度为50％的干燥器中24小时后取出，计算增重≤3％，较佳地≤1％，更佳地≤0.3％。
在另一优选例中，所述马来酸盐晶体具有基本如图10所示的DVS图。
在另一优选例中，所述马来酸盐的IR图包括3个或3个以上选自下组的用波长λ表示的特征吸收峰：3429±2cm-1、3062±2cm-1、2954±2cm-1、2862±2cm-1、2224±2cm-1、1720±2cm-1、1676±2cm-1、1558±2cm-1、1531±2cm-1、1469±2cm-1、1354±2cm-1、1290±2cm-1、1219±2cm-1、1063±2cm-1、864±2cm-1、775±2cm-1、654±2cm-1。
在另一优选例中，所述马来酸盐晶体具有基本如图11所示的IR图。
在另一优选例中，所述马来酸盐晶体具有基本如图12所示的Raman图。
磷酸盐
本发明提供了一种式I化合物的磷酸盐。
在另一优选例中，所述的磷酸盐为晶体。
在另一优选例中，所述磷酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：11.99±0.2°、12.20±0.2°、14.80±0.2°、20.11±0.2°、20.46±0.2°、 24.18±0.2°、24.68±0.2°。
在另一优选例中，所述磷酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：11.99±0.2°、12.20±0.2°、14.80±0.2°、20.11±0.2°、20.46±0.2°、23.15±0.2°、24.18±0.2°、24.68±0.2°、25.63±0.2°、26.15±0.2°。
在另一优选例中，所述磷酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：6.23±0.2°、11.99±0.2°、12.20±0.2°、14.80±0.2°、15.16±0.2°、16.04±0.2°、16.56±0.2°、17.90±0.2°、20.11±0.2°、20.46±0.2°、22.74±0.2°、23.15±0.2°、24.18±0.2°、24.68±0.2°、25.63±0.2°、26.15±0.2°。
在另一优选例中，所述磷酸盐晶体的X射线粉末衍射图谱基本如图13所表征。
在另一优选例中，所述磷酸盐晶体的X射线粉末衍射图谱用2θ值表示的特征吸收峰存在±0.5°的偏差，较佳地存在±0.3°的偏差，更佳地存在±0.1°的偏差。
在另一优选例中，所述磷酸盐晶体的差示扫描量热法分析图谱(DSC图)在155±5℃存在特征吸收峰，较佳地为154.8℃。
在另一优选例中，所述磷酸盐晶体具有基本如图15所示的DSC图。
在另一优选例中，所述磷酸盐晶体的TG图在361±2℃存在特征吸收峰，较佳地为361.0℃。
在另一优选例中，所述磷酸盐晶体在400℃的热失重为47-48wt％，较佳地为47.57wt％。
在另一优选例中，所述磷酸盐晶体的热重分析图谱(TG图)基本如图14所表征。
在另一优选例中，所述磷酸盐晶体的吸热转变温度的起始值为148±2℃，较佳地为148.0℃。
在另一优选例中，所述磷酸盐晶体放置于湿度为50％的干燥器中24小时后取出，计算增重≤3％，较佳地≤1％，更佳地≤0.3％。
在另一优选例中，所述磷酸盐晶体具有基本如图16所示的DVS图。
在另一优选例中，所述磷酸盐晶体的IR图包括3个或3个以上选自下组的用波长λ表示的特征吸收峰：3408±2cm-1、2951±2cm-1、2860±2cm-1、2225±2cm-1、1716±2cm-1、1684±2cm-1、1601±2cm-1、1556±2cm-1、1531±2cm-1、1450±2cm-1、1379±2cm-1、1282±2cm-1、1238±2cm-1、1124±2cm-1、1064±2cm-1、947±2cm-1、868±2cm-1、758±2cm-1、521±2cm-1。
在另一优选例中，所述磷酸盐晶体具有基本如图17所示的IR图。
在另一优选例中，所述磷酸盐晶体具有基本如图18所示的Raman图。
乙醇酸盐
本发明提供了一种式I化合物的乙醇酸盐，
在另一优选例中，所述乙醇酸盐为晶体。
在另一优选例中，所述乙醇酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：8.92±0.2°、10.20±0.2°、13.35±0.2°、16.89±0.2°、19.37±0.2°。
在另一优选例中，所述乙醇酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：8.92±0.2°、10.20±0.2°、13.35±0.2°、16.89±0.2°、19.37±0.2°、20.51±0.2°、21.22±0.2°、21.78±0.2°、23.00±0.2°。
在另一优选例中，所述乙醇酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：8.92±0.2°、10.20±0.2°、13.35±0.2°、16.89±0.2°、19.37±0.2°、20.51±0.2°、21.22±0.2°、21.78±0.2°、23.00±0.2°、23.87±0.2°、24.08±0.2°、24.37±0.2°、25.52±0.2°、33.81±0.2°。
在另一优选例中，所述乙醇酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：6.66±0.2°、8.92±0.2°、9.91±0.2°、10.20±0.2°、13.35±0.2°、13.92±0.2°、15.78±0.2°、16.71±0.2°、16.89±0.2°、17.41±0.2°、18.70±0.2°、19.37±0.2°、20.12±0.2°、20.51±0.2°、21.22±0.2°、21.78±0.2°、22.75±0.2°、23.00±0.2°、23.87±0.2°、24.08±0.2°、24.37±0.2°、25.52±0.2°、26.44±0.2°、27.02±0.2°、27.48±0.2°、28.23±0.2°、28.63±0.2°、28.84±0.2°、29.68±0.2°、30.14±0.2°、30.51±0.2°、31.41±0.2°、31.76±0.2°、33.00±0.2°、33.81±0.2°、34.13±0.2°、35.21±0.2°、25.83±0.2°、36.37±0.2°、37.70±0.2°、37.93±0.2°。
在另一优选例中，所述乙醇酸盐晶体的X射线粉末衍射图谱基本如图19所表征。
在另一优选例中，所述乙醇酸盐晶体的X射线粉末衍射图谱用2θ值表示的特征吸收峰存在±0.5°的偏差，较佳地存在±0.3°的偏差，更佳地存在±0.1°的偏差。
在另一优选例中，所述乙醇酸盐晶体的差示扫描量热法分析图谱(DSC图)在189±5℃存在特征吸收峰。
在另一优选例中，所述乙醇酸盐晶体具有基本如图21所示的DSC图。
在另一优选例中，所述乙醇酸盐晶体的吸热转变温度的起始值为148±2℃，较佳地为148.0℃。
在另一优选例中，所述乙醇酸盐晶体的TG图在192±2℃、268±2℃存在特征 吸收峰，较佳地为192.5℃、268.0℃。
在另一优选例中，所述乙醇酸盐晶体具有基本如图20所示的TG图。
在另一优选例中，所述乙醇酸盐晶体在400℃的热失重为53-54wt％，较佳地为53.41wt％。
在另一优选例中，所述乙醇酸盐晶体放置于湿度为50％的干燥器中24小时后取出，计算增重≤3％，较佳地≤1％，更佳地≤0.3％。
在另一优选例中，所述乙醇酸盐晶体具有基本如图22所示的DVS图。
在另一优选例中，所述乙醇酸盐晶体的IR图包括3个或3个以上选自下组的用波长λ表示的特征吸收峰：3462±2cm-1、2958±2cm-1、2837±2cm-1、2227±2cm-1、1720±2cm-1、1674±2cm-1、1558±2cm-1、1533±2cm-1、1450±2cm-1、1350±2cm-1、1282±2cm-1、1223±2cm-1、1072±2cm-1、928±2cm-1、760±2cm-1、692±2cm-1。
在另一优选例中，所述乙醇酸盐具有基本如图23所示的IR图。
在另一优选例中，所述乙醇酸盐具有基本如图24所示的Raman图。
盐型组合
在本发明中，所述晶体组合物包含所述的盐酸盐、马来酸盐、磷酸盐、乙醇酸盐或由所述的盐酸盐、马来酸盐、磷酸盐、乙醇酸盐制成。
在另一优选例中，以所述晶体组合物的总重量计，盐酸盐、马来酸盐、磷酸盐、乙醇酸盐的重量百分含量为60-99.999％，较佳地为80-99.999％，更佳地为90-99.999％。
在另一优选例中，所述晶体组合物还包括：(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸的盐酸盐、马来酸盐、磷酸盐、乙醇酸盐、游离碱(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸。
盐型化合物的制备方法
在本发明中，提供了所述式I化合物盐型的制备方法，所述方法包括如下步骤：
(1)将式I化合物的游离碱溶于溶剂中，加入一定量的酸；
(2)将步骤(1)所得的溶液在一定温度下放置一段时间进行反应，搅拌下析晶，得到固体；
(3)过滤和/或干燥步骤(2)所得固体，制得本发明第一方面所述的盐型。
在另一优选例中，所述步骤(1)中，所述溶剂选自下组：醇类、醚类、酮类、酯类或其组合。
在另一优选例中，所述醇类为C1-C10的醇，较佳地为C1-C8的醇，更佳地为C1-C5的醇。
在另一优选例中，所述醇类选自下组：甲醇、乙醇、正丙醇、异丙醇、正丁醇、新戊醇、或其组合。
在另一优选例中，所述醚类为C2-C8的醚，较佳地为C2-C5的醚。
在另一优选例中，所述醚类选自下组：乙醚、四氢呋喃或其组合。
在另一优选例中，所述酯类为C1-C10的酯，较佳地为C1-C7的酯，更佳地为C1-C5的酯。
在另一优选例中，所述酯类选自下组：甲酸甲酯、乙酸乙酯、甲酸异丁酯、或其组合。
在另一优选例中，所述步骤(1)中，所述游离碱与所述酸的摩尔比为1：0.8-1：1.5，较佳地为1:0.9-1:1.3，更佳地为1:1.0-1:1.1。
在另一优选例中，所述步骤(1)中，所述温度范围为10-80℃，较佳地为30-50℃。
在另一优选例中，所述步骤(1)中，所述反应时间为0.1-10h，较佳地为0.5-6h。
在另一优选例中，所述步骤(2)中，干燥的温度为10-90℃，较佳地为20-80℃，更佳地为40-70℃。
在另一优选例中，所述步骤(2)中，干燥的压力为0-20KPa，较佳地为0-10Kpa，更佳地为5-10KPa。
在另一优选例中，所述步骤(2)中，干燥的时间为5-150小时，较佳地为30-100小时，更佳地为60-80小时。
在另一优选例中，所述步骤(2)中，所述析晶在0-50℃下进行，较佳地为0-40℃，更佳地为20-30℃。
在另一优选例中，所述析晶在搅拌下进行。
在另一优选例中，所述步骤(3)中，所述方法的产率为50％-99.9％，较佳地为75％-99.9％，更佳地为85％-99.9％。
药物组合物
本发明提供了一种药物组合物，所述药物组合物包含
(1)本发明第一方面所述的式I化合物的盐酸盐、马来酸盐、磷酸盐、乙醇酸盐、 或其组合；以及
(2)药学上可接受的赋形剂。
应理解，在本发明中，所述赋形剂没有特别限制，可以选用本领域常规材料，或用常规方法制得，或从市场购买得到。
代表性地，所述赋形剂包括(但并不限于)：填充剂、崩解剂、粘合剂、润滑剂、或其组合。
代表性地，所述填充剂包括(但并不限于)：淀粉、乳糖、微晶纤维素、糊精、甘露醇、氧化镁、硫酸钙、或其组合。
代表性地，所述崩解剂包括(但并不限于)：羧甲基纤维素及其盐、交联羧甲基纤维素及其盐、交联聚维酮、羧甲基淀粉钠、低取代羟丙基纤维素、或其组合。
代表性地，所述粘合剂包括(但并不限于)：聚维酮、羟丙基甲基纤维素、淀粉浆、或其组合。
代表性地，所述润滑剂包括(但并不限于)：硬脂酸镁、硬脂酸钙、或其组合。
用途
本发明中还提供了一种所述的(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸盐酸盐、马来酸盐、磷酸盐以及乙醇酸盐或所述的盐型组合物或所述的药物组合物的用途，用于制备预防或治疗II型糖尿病和/或II型糖尿病的并发症的药物。
代表性地，所述II型糖尿病的并发症包括(但并不限于)：冠状动脉性疾病、中风、高血压、肾病、周围血管性疾病、神经性疾病、视网膜病。
本发明中还提供了一种治疗或预防II型糖尿病和/或II型糖尿病的并发症的方法，向患者给予治疗有效量的所述的(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸晶体的盐酸盐、马来酸盐、磷酸盐以及乙醇酸盐或所述的盐型组合物或所述的药物组合物。
本发明的盐酸盐、马来酸盐、磷酸盐以及乙醇酸盐或其药物组合物的给药量随患者的年龄、性别、种族、病情等的不同而不同。
本发明化合物可以单独给药，也可以与其他的药物或活性成分一起或联合给药。
在本发明中，本发明的晶型或药物组合物的施用方式没有特别限制。可以选用与常规(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸相同或相近的给药方式，其中包括(但并不限于)：口服、经皮、静脉 内、肌內、局部给药等。
本发明具有以下主要优点：
(1)本发明的盐酸盐、马来酸盐、磷酸盐以及乙醇酸盐具有更高的纯度；
(2)本发明的盐酸盐、马来酸盐、磷酸盐以及乙醇酸盐具有更优的稳定性，尤其是水中的稳定性，增强口服吸收能力，提高生物利用度；
(3)本发明盐酸盐、马来酸盐、磷酸盐以及乙醇酸盐晶型具有更低的吸湿性，当相对湿度小于50％时，所述盐酸盐、马来酸盐、磷酸盐以及乙醇酸盐的吸湿性≤0.3％；
(4)本发明的盐酸盐、马来酸盐、磷酸盐以及乙醇酸盐在常规条件下不易降解；
(5)本发明盐酸盐、马来酸盐、磷酸盐以及乙醇酸盐的制备方法操作简单，容易控制，重现性好，适合工业化生产；
(6)本发明的盐型化合物在预防或治疗II型糖尿病方面具有更优的口服降糖活性。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
通用测试方法和测试参数
在本发明中，对所述晶体进行如下一系列通用测试。
粉末X射线衍射分析(X-ray Diffraction,XRD)是利用晶体形成的X射线衍射，对物质进行内部原子在空间分布状况的结构分析方法。将具有一定波长的X射线照射到结晶性物质上时，X射线因在结晶内遇到规则排列的原子或离子而发生散射，散射的X射线在某些方向上相位得到加强，从而显示与结晶结构相对应的特有的衍射现象。
在本发明中，XRD的测试参数如下：仪器型号：Bruker D8advance；靶：Cu-Kα (40kV，40mA)；样品到检测器距离：30cm；扫描范围：3°～40°(2theta值)；扫描步径：0.1s。
热重分析法(Thermo Gravimetric Analysis,TGA)是在程序控温条件下，测定物质的质量随温度变化的一种分析技术。热重分析法可获得样品热变化产生的热量，适用于检查晶型物质中的结晶溶剂或结晶水分子的丧失或样品升华、分解的过程和量值，也可有效区分物质是否含有结晶溶剂或结晶水成分。
在本发明中，TGA的测试参数如下：仪器型号：Netzsch TG 209F3；坩锅：氧化铝坩埚；温度范围：30～400℃；扫描速率：10K/min；吹扫气：25mL/min；保护气：15mL/min。
差示扫描量热法(Differential Scanning Calorimeter,DSC)是采用程序控制升温或降温，测量样品与惰性参比物(常用α-Al2O3)之间的热量差随温度变化的技术。DSC检测适用于分析样品的熔融分解状态、混晶物质状态、转晶物质状态等。
在本发明中，DSC的测试参数如下：仪器型号：Perkin Elmer DSC 8500；坩锅：铝坩埚；在氮气吹扫下以10℃/min的升温速率，从50℃扫描到280℃。
动态蒸汽吸收(DVS)测试/吸水性测试是通过快速测量设定了相对湿度(RH)的流动载气所引起的样品水分的增加和流失，样品置于自悬挂状态下的高灵敏度，高稳定性的数字微量天平上，然后，通过测量材料质量的增加/减少来检测水蒸气的吸附/解吸附，从而确定样品的吸湿性。
在本发明中，DVS的测试参数如下：仪器型号：SMS DVS Intrinsic；无水合物：0～95％-0％RH；温度：25℃；水合物：40～95％-0％RH，温度：25℃。
红外光谱(Infra-red Spectrometry,IR)是最早用于晶型物质识别与鉴定的分析方法。由于不同晶型分子共价键的电环境不一样，共价键强度也可能会有变化，共价键强度的改变必然会导致不同晶型的IR光谱的不同。
在本发明中，IR的测试参数如下：仪器型号：Nicolet 6700型傅里叶变换红外光谱仪；单点ATR方法，分辨率4.0cm-1。
拉曼光谱(Raman Spectroscopy,RM)是以拉曼效应为基础研究分子震动的一种方法，与红外吸收光谱相反，拉曼光谱是研究分子和光相互作用发生散射光的 频率。一般红外吸收不明显的非极性基团拉曼光谱吸收很明显。
在本发明中，RM的测试参数如下：仪器型号：Thermo DXR Raman Microscope共聚焦显微拉曼光谱仪；激光波长：532nm；曝光时间：1.0sec；曝光次数：10。
实施例1：制备(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸的盐酸盐(No.1)
将200mg的(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸溶于溶剂THF-MeOH(1:1,v/v)中，加入等当量的盐酸[(浓度0.02M，溶剂THF-MeOH(1:1,v/v)]，将上述所得的溶液于40℃条件下放置1h反应搅拌下析晶，过滤得盐酸盐，再将盐酸盐加入丙酮-水(1:1,v/v)重结晶，将所得固体物料置于真空干燥箱中，于50℃、5KPa条件下真空干燥70个小时，得到(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸盐酸盐150mg。
结果
对实施例1所制得盐酸盐进行XRD、TGA、DSC、DVS、IR和Raman等测试。
图1为实施例1盐酸盐的XRD图，从图1中可以看出盐酸盐在7.43°、11.06°、11.70°、13.46°、15.03°、15.34°、15.84°、16.35°、17.59°、18.32°、19.54°、20.13°、21.24°、21.96°、22.46°、22.74°、23.67°、24.01°、24.83°、25.19°、26.63°、27.20°、29.32°、30.26°、32.15°处有吸收峰。
图2为实施例1盐酸盐的TG图，从图2中可以看出盐酸盐在210-400℃有64.33％的失重。
图3为实施例1盐酸盐的差示扫描量热分析(DSC)图，从图3中可以看出盐酸盐在分解之前无熔融峰。
图4为实施例1盐酸盐的吸湿性分析(DVS)图，从图4中可以看出盐酸盐略有引湿性，在常规储存湿度范围内，湿度变化幅度小，小于3.0％。在80％RH吸收水分2.54％。
图5为实施例1盐酸盐的红外光谱(IR)图，从图5中可以看出盐酸盐在3429、2951、2827、2225、1720、1687、1560、1533、1446、1385、1261、1064、771cm-1处有特征吸收峰。
实施例2：制备(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸的马来酸盐(No.2)
将200mg的(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸溶于溶剂THF-MeOH(1:1,v/v)中，加入等当量的马来酸[(浓度0.02M，溶剂THF-MeOH(1:1,v/v)]，将上述所得的溶液于40℃条件下放置1h反应搅拌下析晶，过滤得马来酸盐，再将马来酸盐加入丙酮-水(1:1,v/v)重结晶，将所得固体物料置于真空干燥箱中，于50℃、5KPa条件下真空干燥70个小时，得到(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸马来酸盐170mg。
结果
对实施例2所制得马来酸酸盐进行XRD、TGA、DSC、DVS、IR和Raman等测试。
图7为实施例2马来酸盐的XRD图，从图7中可以看出马来酸盐在7.55°、10.83°、12.41°、13.22°、14.38°、14.75°、15.45°、15.80°、17.50°、18.30°、19.40°、20.43°、20.89°、21.85°、22.87°、23.25°、25.04°、26.59°、26.93°、27.10°、28.21°、30.53°、32.96°处有吸收峰。
图8为实施例2马来酸盐的TG图，从图8中可以看出马来酸盐在210-400℃有42.56％的失重。
图9为实施例2马来酸盐的差示扫描量热分析(DSC)图，从图9中可以看出马来酸盐对应的DSC显示熔点为113.80℃。
图10为实施例2马来酸盐的吸湿性分析(DVS)图，从图10中可以看出马来略有引湿性，在常规储存湿度范围内，湿度变化幅度小，小于2.0％。在80％RH吸收水分1.57％。
图11为实施例2马来酸盐的红外光谱(IR)图，从图11中可以看出马来酸盐在3429、3062、2954、2862、2224、1720、1676、1558、1531、1469、1354、1290、1219、1063、864、775、654cm-1处有特征吸收峰。
实施例3：制备(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸的磷酸盐(No.3)
将200mg的(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸溶于溶剂THF-MeOH(1:1,v/v)中，加入等当量的磷酸[(浓度 0.02M，溶剂THF-MeOH(1:1,v/v)]，将上述所得的溶液于40℃条件下放置1h反应搅拌下析晶，过滤得磷酸盐，再将磷酸盐加入丙酮-水(1:1,v/v)重结晶，将所得固体物料置于真空干燥箱中，于50℃、5KPa条件下真空干燥70个小时，得到(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸磷酸盐152mg。
结果
对实施例3所制磷酸盐进行XRD、TGA、DSC、DVS、IR和Raman等测试。
图13为实施例3磷酸盐的XRD图，从图13中可以看出磷酸酸盐在6.23°、11.99°、12.20°、14.80°、15.16°、16.04°、16.56°、17.90°、20.11°、20.46°、22.74°、23.15°、24.18°、24.68°、25.63°、26.15°处有吸收峰。
图14为实施例3磷酸盐的TG图，从图14中可以看出磷酸盐在210-400℃有47.57％的失重。
图15为实施例3磷酸盐的差示扫描量热分析(DSC)图，从图15中可以看出磷酸盐对应的DSC显示熔点为154.80℃。
图16为实施例3磷酸盐的吸湿性分析(DVS)图，从图16中可以看出磷酸盐略有引湿性，在常规储存湿度范围内，湿度变化幅度小。
图17为实施例3磷酸盐的红外光谱(IR)图，从图17中可以看出磷酸盐在3408、2951、2860、2225、1716、1684、1601、1556、1531、1450、1379、1282、1238、1124、1064、947、868、758、521cm-1处有特征吸收峰。
实施例4：制备(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸的乙醇酸盐(No.4)
将200mg的(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸溶于溶剂THF-MeOH(1:1,v/v)中，加入等当量的乙醇酸[(浓度0.02M，溶剂THF-MeOH(1:1,v/v)]，将上述所得的溶液于40℃条件下放置1h反应搅拌下析晶，过滤得乙醇酸盐，再将乙醇酸盐加入丙酮-水(1:1,v/v)重结晶，将所得固体物料置于真空干燥箱中，于50℃、5KPa条件下真空干燥70个小时，得到(R)-甲基-2-(3-氨基哌啶-1-基)-3-(2-氰基苄基)-4-羰基-3,4-二氢噻吩[3,2-d]嘧啶-6-羧酸乙醇酸盐165mg。
结果
对实施例4所制得乙醇酸盐进行XRD、TGA、DSC、DVS、IR和Raman等测试。
图19为实施例4乙醇酸盐的XRD图，从图19中可以看出乙醇酸盐在6.66°、8.92°、9.91°、10.20°、13.35°、13.92°、15.78°、16.71°、16.89°、17.41°、18.70°、19.37°、20.12°、20.51°、21.22°、21.78°、22.75°、23.00°、23.87°、24.08°、24.37°、25.52°、26.55°、27.02°、27.48°、28.23°、28.63°、28.84°、29.68°、30.14°、30.51°、31.41°、31.76°、33.00°、33.81°、34.13°、35.21°、35.83°、36.37°、37.70°、37.93°。处有吸收峰。
图20为实施例4乙醇酸盐的TG图，从图20中可以看出乙醇酸盐在210-400℃有53.41％的失重。
图21为实施例4乙醇酸盐的差示扫描量热分析(DSC)图，从图21中可以看出乙醇酸盐对应的DSC显示熔点为188.75℃。
图22为实施例4乙醇酸盐的吸湿性分析(DVS)图，从图22中可以看出乙醇酸盐略有引湿性，在常规储存湿度范围内，湿度变化幅度小，小于2.0％。在80％RH吸收水分1.23％。
图23为实施例4乙醇酸盐的红外光谱(IR)图，从图23中可以看出乙醇酸盐在3462、2958、2837、2227、1720、1674、1558、1533、1450、1350、1282、1223、1072、928、760、692cm-1处有特征吸收峰。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式I所示化合物的盐型，其特征在于，所述盐型选自下组：盐酸盐、马来酸盐、磷酸盐和乙醇酸盐
    Figure PCTCN2017077679-appb-100001
  2. 如权利要求1所述的盐型，其特征在于，所述的盐型为晶体。
  3. 如权利要求1所述的盐型，其特征在于，所述的盐酸盐具有选自下组的一个或多个特征：
    (1)所述的盐酸盐为晶体；和/或
    (2)所述盐酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：7.43±0.2°、11.06±0.2°、11.70±0.2°、13.46±0.2°、15.03±0.2°、15.34±0.2°、18.32±0.2°、21.96±0.2°、24.01±0.2°、27.20±0.2°、29.32±0.2°、30.26±0.2°；和/或
    (3)所述盐酸盐晶体的差示扫描量热法分析图谱(DSC图)在分解前无熔融峰；和/或
    (4)所述盐酸盐晶体的TG图在272±2℃存在特征吸收峰；和/或
    (5)所述盐酸盐晶体在400℃的热失重为64-65wt％；和/或
    (6)所述盐酸盐晶体放置于湿度为50％的干燥器中24小时后取出，计算增重≤3％，较佳地≤1％，更佳地≤0.3％；和/或
    (7)所述盐酸盐晶体的IR图包括3个或3个以上选自下组的用波长λ表示的特征吸收峰：3429±2cm-1、2951±2cm-1、2827±2cm-1、2225±2cm-1、1720±2cm-1、1687±2cm-1、1560±2cm-1、1533±2cm-1、1446±2cm-1、1385±2cm-1、1261±2cm-1、1064±2cm-1、771±2cm-1。
  4. 如权利要求1所述的盐型，其特征在于，所述的马来酸盐具有选自下组的一个或多个特征：
    (1)所述的马来酸盐为晶体；和/或
    (2)所述马来酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：7.55±0.2°、12.41±0.2°、15.45±0.2°、17.50±0.2°、20.89±0.2°、26.59±0.2°、26.93±0.2°；和/或
    (3)所述马来酸盐晶体的差示扫描量热法分析图谱(DSC图)在113±5℃存在特征吸收峰；和/或
    (4)所述马来酸盐晶体的TG图包括选自下组的特征吸收峰：77±2℃、180±5℃、284±5℃；和/或
    (5)所述马来酸盐晶体在400℃的热失重为42-43wt％；和/或
    (6)所述马来酸盐晶体的吸热转变温度的起始值为110±2℃；和/或
    (7)所述马来酸盐晶体放置于湿度为50％的干燥器中24小时后取出，计算增重≤3％，较佳地≤1％，更佳地≤0.3％；和/或
    (8)所述马来酸盐的IR图包括3个或3个以上选自下组的用波长λ表示的特征吸收峰：3429±2cm-1、3062±2cm-1、2954±2cm-1、2862±2cm-1、2224±2cm-1、1720±2cm-1、1676±2cm-1、1558±2cm-1、1531±2cm-1、1469±2cm-1、1354±2cm-1、1290±2cm-1、1219±2cm-1、1063±2cm-1、864±2cm-1、775±2cm-1、654±2cm-1。
  5. 如权利要求1所述的盐型，其特征在于，所述的磷酸盐具有选自下组的一个或多个特征：
    (1)所述的磷酸盐为晶体；和/或
    (2)所述磷酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：11.99±0.2°、12.20±0.2°、14.80±0.2°、20.11±0.2°、20.46±0.2°、24.18±0.2°、24.68±0.2°；和/或
    (3)所述磷酸盐晶体的差示扫描量热法分析图谱(DSC图)在155±5℃存在特征吸收峰；和/或
    (4)所述磷酸盐晶体的TG图在361±2℃存在特征吸收峰；和/或
    (5)所述磷酸盐晶体在400℃的热失重为47-48wt％；和/或
    (6)所述磷酸盐晶体的吸热转变温度的起始值为148±2℃；和/或
    (7)所述磷酸盐晶体放置于湿度为50％的干燥器中24小时后取出，计算增重≤3％，较佳地≤1％，更佳地≤0.3％；和/或
    (8)所述磷酸盐晶体的IR图包括3个或3个以上选自下组的用波长λ表示的特征吸收峰：3408±2cm-1、2951±2cm-1、2860±2cm-1、2225±2cm-1、1716±2cm-1、1684±2cm-1、1601±2cm-1、1556±2cm-1、1531±2cm-1、1450±2cm-1、1379±2cm-1、1282±2cm-1、1238±2cm-1、1124±2cm-1、1064±2cm-1、947±2cm-1、868±2cm-1、758±2cm-1、521±2cm-1。
  6. 如权利要求1所述的盐型，其特征在于，所述的乙醇酸盐具有选自下组的一个或多个特征：
    (1)所述乙醇酸盐为晶体；和/或
    (2)所述乙醇酸盐晶体的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：8.92±0.2°、10.20±0.2°、13.35±0.2°、16.89±0.2°、19.37±0.2°；和/或
    (3)所述乙醇酸盐晶体的差示扫描量热法分析图谱(DSC图)在189±5℃存在特征吸收峰；和/或
    (4)所述乙醇酸盐晶体的吸热转变温度的起始值为148±2℃；和/或
    (5)所述乙醇酸盐晶体的TG图在192±2℃、268±2℃存在特征吸收峰；和/或
    (6)所述乙醇酸盐晶体在400℃的热失重为53-54wt％；和/或
    (7)所述乙醇酸盐晶体放置于湿度为50％的干燥器中24小时后取出，计算增重≤3％，较佳地≤1％，更佳地≤0.3％；和/或
    (8)所述乙醇酸盐晶体的IR图包括3个或3个以上选自下组的用波长λ表示的特征吸收峰：3462±2cm-1、2958±2cm-1、2837±2cm-1、2227±2cm-1、1720±2cm-1、1674±2cm-1、1558±2cm-1、1533±2cm-1、1450±2cm-1、1350±2cm-1、1282±2cm-1、1223±2cm-1、1072±2cm-1、928±2cm-1、760±2cm-1、692±2cm-1。
  7. 一种制备如权利要求1所述的式I化合物的盐型的方法，其特征在于，所述方法包括如下步骤：
    (1)将式I化合物的游离碱溶于溶剂中，加入一定量的酸；
    (2)将步骤(1)所得的溶液在一定温度下放置一段时间进行反应，搅拌下析晶，得到固体；
    (3)过滤和/或干燥步骤(2)所得固体，制得权利要求1所述的盐型。
  8. 如权利要求7所述的方法，其特征在于，所述醇类为C1-C10的醇。
  9. 一种药物组合物，其特征在于，所述药物组合物包含
    (1)如权利要求1所述的式I化合物的盐酸盐、马来酸盐、磷酸盐、乙醇酸盐、或其组合；以及
    (2)药学上可接受的赋形剂。
  10. 一种权利要求1所述的盐型或权利要求9所述的药物组合物的用途，其特征在于，用于制备预防或治疗II型糖尿病和/或II型糖尿病的并发症的药物。
PCT/CN2017/077679 2016-03-22 2017-03-22 一种dppiv抑制剂的盐型及其制备方法 WO2017162168A1 (zh)

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RU2018137020A RU2734549C2 (ru) 2016-03-22 2017-03-22 Соляная форма ингибитора дипептидилпепдидазы iv и способ получения солевой формы
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