WO2016127898A1 - 一种化合物的a晶型及其制备方法 - Google Patents

一种化合物的a晶型及其制备方法 Download PDF

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Publication number
WO2016127898A1
WO2016127898A1 PCT/CN2016/073386 CN2016073386W WO2016127898A1 WO 2016127898 A1 WO2016127898 A1 WO 2016127898A1 CN 2016073386 W CN2016073386 W CN 2016073386W WO 2016127898 A1 WO2016127898 A1 WO 2016127898A1
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Prior art keywords
crystal
methyl
pyrimidine
carbonyl
aminopiperidin
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PCT/CN2016/073386
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English (en)
French (fr)
Inventor
柳红
王江
李建
李佳
李静雅
周圣斌
苏明波
蒋华良
罗小民
陈凯先
Original Assignee
中国科学院上海药物研究所
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Application filed by 中国科学院上海药物研究所 filed Critical 中国科学院上海药物研究所
Priority to CA2976408A priority Critical patent/CA2976408C/en
Priority to EP16748699.2A priority patent/EP3257856B1/en
Priority to KR1020177024861A priority patent/KR102029728B1/ko
Priority to US15/549,918 priority patent/US10392401B2/en
Priority to RU2017130691A priority patent/RU2699030C2/ru
Priority to JP2017542114A priority patent/JP6574843B2/ja
Publication of WO2016127898A1 publication Critical patent/WO2016127898A1/zh

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    • 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
    • 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
    • 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
    • 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 (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl-3, Form A of 4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylic acid crystal and a preparation method thereof.
  • Diabetes Mellitus is a multi-pathogenic metabolic disease caused by absolute or relative deficiency of human insulin secretion, or a series of metabolism of proteins, fats, water and electrolytes caused by decreased sensitivity of target tissues to insulin.
  • Disorder syndrome Acute complications of diabetes include: diabetic ketoacidosis, diabetic hyperosmolar coma, various acute infections, and lactic acidosis.
  • hypoglycemia which occurs during the treatment of diabetes, is one of the most common acute complications.
  • Chronic complications of diabetes include diabetic eye disease, diabetic nephropathy, diabetic neuropathy, diabetic heart and brain limb vascular disease, diabetic foot and skin lesions.
  • Type II diabetes is a type of metabolic syndrome caused by the inability to control blood glucose levels in the body.
  • the main features of type 2 diabetes are hyperglycemia, insulin resistance, and insulin secretion deficiency, which are often associated with dyslipidemia, hypertension, and obesity.
  • Type II diabetes is a global epidemic disease.
  • insulin can be secreted in the body but the amount is relatively insufficient, or the insulin produced cannot function effectively due to decreased tissue sensitivity or insulin resistance, and thus the blood glucose is aggregated and the level is increased. Because these patients with diabetes can secrete insulin, they generally do not need to be treated with insulin. Blood sugar can be controlled only by dietary adjustment or oral hypoglycemic agents.
  • the therapeutic drugs for type II diabetes mainly include insulin, sulfonylureas, metformin, thiazolidinediones, PPAR ⁇ / ⁇ dual agonists, DPP IV inhibitors, and GLP-1 analogs.
  • existing drugs can control blood sugar levels and reduce the incidence of complications, most of them have more serious side effects, such as gastrointestinal toxicity, weight gain, edema, hypoglycemia, etc., which cannot fundamentally control and cure type 2 diabetes. .
  • traditional diabetes treatments have limited efficacy and poor tolerance, as well as obvious side effects, research and development of safe and effective diabetes treatment drugs has important research significance from the perspective of human health and economic benefits.
  • 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.
  • the object of the present invention is to provide a highly efficient, low toxicity, long-acting (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4- Form A of the crystal of carbonyl-3,4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylate.
  • a (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl group of formula I A crystalline form of a crystal of -3,4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylate, the XRD pattern of the crystalline form A comprising the following characteristic absorption peaks expressed by the interplanar spacing d:
  • the XRD pattern of the Form A includes the following characteristic absorption peaks expressed by the crystal plane distance d:
  • the XRD pattern of the Form A includes the following characteristic absorption peaks expressed by the crystal plane distance d:
  • the XRD pattern of the Form A includes the following characteristic absorption peaks expressed by the crystal plane distance d:
  • the XRD pattern of the Form A includes the following characteristic absorption peaks expressed by the crystal plane distance d:
  • the XRD pattern of the Form A includes the following characteristic absorption peaks expressed by the crystal plane distance d:
  • the XRD pattern of the Form A includes the following characteristic absorption peaks expressed by the crystal plane distance d:
  • the XRD pattern of the Form A includes the following characteristic absorption peaks expressed by the crystal plane distance d:
  • the Form A crystal has an XRD pattern substantially as shown in FIG.
  • the XRD pattern of the A crystal form has a deviation of ⁇ 0.5 from the characteristic absorption peak represented by the crystal plane distance d, preferably a deviation of ⁇ 0.3, and more preferably a deviation of ⁇ 0.1.
  • the Form A crystal has one or more characteristics selected from the group consisting of:
  • the TG pattern of the A crystal form has a characteristic absorption peak at 261 ⁇ 2 ° C;
  • the TG pattern of the Form A crystal has a characteristic absorption peak at 262.1 °C.
  • the TG pattern of the A crystal form has a characteristic absorption peak at 323 ⁇ 5 ° C;
  • the TG pattern of the Form A crystal has a characteristic absorption peak at 324 °C.
  • the A crystal form has a thermal weight loss at 77 ° C of 77.65 wt%.
  • the Form A crystal has a TG pattern substantially as shown in FIG.
  • the DSC pattern of the A crystal form has a characteristic absorption peak at 135 ⁇ 5 ° C;
  • the DSC pattern of the Form A crystal has a characteristic absorption peak at 135.67 °C.
  • the initial value of the endothermic transition temperature of the Form A crystal is 131 ⁇ 2 °C.
  • the initial value of the endothermic transition temperature of the Form A crystal is 131.84 °C.
  • the Form A crystal has a DSC pattern substantially as shown in FIG.
  • the A crystal form has a hygroscopicity of less than 1%.
  • the A crystal form has a hygroscopicity of less than 0.3% when the relative humidity RH is less than 50%.
  • the Form A crystal has a DVS pattern substantially as shown in FIG.
  • the IR pattern of the A crystal form includes the following characteristic absorption peaks expressed by the wavelength ⁇ : 3368 ⁇ 2 cm -1 , 2940 ⁇ 2 cm -1 , 2848 ⁇ 2 cm -1 , 2222 ⁇ 2 cm -1 , 1729 ⁇ 2cm -1 , 1672 ⁇ 2cm -1 , 1564 ⁇ 2cm -1 , 1529 ⁇ 2cm -1 , 1470 ⁇ 2cm -1 , 1454 ⁇ 2cm -1 , 1387 ⁇ 2cm -1 , 1298 ⁇ 2cm -1 , 1203 ⁇ 2 cm -1 , 1105 ⁇ 2 cm -1 , 1075 ⁇ 2 cm -1 , 921 ⁇ 2 cm -1 , 781 ⁇ 2 cm -1 , 709 ⁇ 2 cm -1 .
  • the IR pattern of the Form A includes the following characteristic absorption peaks expressed by the wavelength ⁇ : 3368, 2940, 2848, 2222, 1729, 1672, 1564, 1529, 1470, 1454, 1387, 1298, 1203, 1105, 1075, 921, 781, 709 cm -1 .
  • the Form A crystal has an IR pattern substantially as shown in FIG.
  • the Form A crystal has a Raman diagram substantially as shown in FIG.
  • a crystal composition comprising the first aspect of the present invention
  • the A crystal form crystal of the aspect is made of the crystal form A crystal of the first aspect of the invention.
  • the A crystal form crystal has a weight percentage of 60-99.999%, preferably 80-99.999%, more preferably 90-99.999%, based on the total weight of the crystal composition. .
  • the crystalline composition further comprises: (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl) of non-A crystalline form --4-carbonyl-3,4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylic acid crystal, amorphous (R)-methyl-2-(3-aminopiperidin-1-yl) 3-(2-Cyanobenzyl)-4-carbonyl-3,4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylic acid.
  • a (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl) group according to the first aspect of the invention.
  • the first solvent is a good solvent selected from the group consisting of alcohols, ketones, esters, chlorinated alkanes, or combinations 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 ketone is a C2-C8 ketone, preferably a C3-C5 ketone.
  • the ketone is selected from the group consisting of acetone, isobutanol butanone, 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 chloroalkane is dichloromethane, chloroform, or a combination thereof, preferably dichloromethane.
  • the (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl-3,4-di Hydrothiophene [3,2-d]pyrimidine-6-carboxylic acid is an amorphous compound.
  • the second solvent is a poor solvent selected from the group consisting of water, ethers, alkanes, tetrahydrofuran, 1,4-dioxane, or a combination thereof.
  • the ether is a C1-C10 ether, preferably a C1-C8 ether, more preferably a C1-C6 ether.
  • the ether is selected from the group consisting of petroleum ether, tert-butyl methyl ether, diethyl ether, diisopropyl ether, diethyl ether, or a combination thereof.
  • the alkane is a C2-C15 alkane, preferably a C3-C10 alkane, more preferably a C4-C8 alkane.
  • the alkane is selected from the group consisting of n-pentane, n-hexane, n-heptane, or a combination thereof.
  • step 2) the following steps are further included:
  • the drying temperature is from 10 to 70 ° C, preferably from 20 to 80 ° C, more preferably from 25 to 40 ° 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 yield of the process is from 50% to 99%, preferably from 75% to 99%, more preferably from 85% to 99%.
  • the solute (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4- in the first solution The concentration of carbonyl-3,4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylic acid was 0.1 g/L-saturated.
  • the solute (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4- in the first solution The concentration of carbonyl-3,4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylic acid is from 0.1 g/L to 100 g/L, preferably from 1 g/L to 870 g/L, more preferably 10g/L-70g/L, optimally 10g/L-50g/L.
  • the solute (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4- in the first solution The concentration of carbonyl-3,4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylic acid is unsaturated concentration.
  • the crystallization is carried out at 0-50 °C.
  • the crystallization is carried out at 0-40 ° C, preferably at 20-30 ° C; preferably at room temperature.
  • the crystallization is carried out under agitation.
  • a pharmaceutical composition comprising (R)-methyl-2-(3-aminopiperidin-1-yl)- of the first aspect of the invention Form A of 3-(2-cyanobenzyl)-4-carbonyl-3,4-dihydrothiophene[3,2-d]pyrimidine-6-carboxylic acid crystals and a pharmaceutically acceptable excipient.
  • 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.
  • a (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl) group according to the first aspect of the invention.
  • Form A of the crystal of 4-carbonyl-3,4-dihydrothiophene[3,2-d]pyrimidine-6-carboxylate or the crystalline composition of the second aspect of the invention or the fourth aspect of the invention Use of a pharmaceutical composition for the preparation of a medicament for the prevention or treatment of complications of type 2 diabetes and/or type II diabetes.
  • 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 of treating or preventing a complication of type 2 diabetes and/or type II diabetes wherein a therapeutically effective amount of the (R)-methyl group of the first aspect of the invention is administered to a patient -2-(3-Aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl-3,4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylic acid Form A of the crystal or the crystalline composition of the second aspect of the invention or the pharmaceutical composition of the fourth aspect of the invention.
  • Figure 1 is a polarized photograph of Form A of a crystal of Example 1 of the present invention.
  • Figure 2 is an XRD pattern of Form A of the crystal of Example 1 of the present invention.
  • Figure 3 is a TG diagram of Form A of the crystal of Example 1 of the present invention.
  • Figure 4 is a differential scanning calorimetry (DSC) chart of Form A of the crystal of Example 1 of the present invention.
  • Fig. 5 is a graph showing the hygroscopicity analysis (DVS) of the crystal form A of the crystal of Example 1 of the present invention.
  • Figure 6 is an infrared spectrum (IR) chart of Form A of the crystal of Example 1 of the present invention.
  • Fig. 7 is a Raman spectrum diagram of Form A of the crystal of Example 1 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.
  • the compound is a selective, reversible competitive inhibitor of DPP IV, inhibiting the activity of Danamol, and the DPP IV inhibitory activity and selectivity in vitro is superior to the marketed drugs sitagliptin and vildagliptin; in animals, the compound It can effectively inhibit DPP IV activity in normal mouse and rat plasma, and its DPP IV inhibitory activity is better than the marketed drug alogliptin; it can increase the oral glucose tolerance of normal ICR mice in a dose-dependent manner, and the effective dose is only 0.1.
  • the effect is better than alogliptin; the compound is chronically administered to ob/ob mice, which can effectively reduce the fasting blood glucose of ob/ob mice, which is better than the positive control drug alogliptin; The drug reduced the fasting blood glucose of the gene-deficient db/db mice, which was comparable to the positive control drug alogliptin.
  • Pharmacokinetic and safety studies have shown that the compound has good pharmacokinetic properties and safety in rats and dogs. Among them, the half-life and AUC 0-t of the compound in rats and dogs are superior to the marketed drug alogliptin. Safety experiments showed that the compound was safe.
  • the acute toxicity test of ICR mice showed that there was no animal death in the 300 mg/kg administration group.
  • the acute toxicity test of Beagle dogs showed that there was no animal death in the 1 g/kg administration group.
  • the subacute toxicity test of rats showed that there was no obvious toxicity in the rats administered orally in the 150 mg/kg group.
  • the hypoglycemic effect of this compound is superior to the currently used DPPIV inhibitor. Therefore, the compound is expected to be developed into a new one.
  • Type II diabetes treatment is a new one.
  • Drug Polymorphism refers to the presence of two or more different crystalline forms of a drug.
  • solid chemical drugs due to their different molecular arrangement and symmetry, the same drug can form a variety of different crystalline solid state.
  • the different crystalline solid state of the same substance is often called "polymorph”. phenomenon”. Polymorphism is ubiquitous in solid drugs, and polymorphism is one of the important factors affecting the quality and efficacy of solid drugs.
  • the present invention provides a (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl-3,4- represented by the formula I.
  • the XRD pattern of the Form A includes the following characteristic absorption peaks expressed by the crystal plane distance d:
  • the XRD pattern of the Form A comprises the following characteristic absorption peaks expressed by the crystal plane distance d:
  • the XRD pattern of the Form A includes the following characteristic absorption peaks expressed by the crystal plane distance d:
  • the XRD pattern of the Form A includes the following characteristic absorption peaks expressed by the crystal plane distance d:
  • the XRD pattern of the Form A includes the following characteristic absorption peaks expressed by the crystal plane distance d:
  • the XRD pattern of the Form A includes the following characteristic absorption peaks expressed by the crystal plane distance d:
  • the XRD pattern of the Form A includes the following characteristic absorption peaks expressed by the crystal plane distance d:
  • the Form A crystal has an XRD pattern substantially as shown in FIG.
  • the XRD pattern of the A crystal form has a deviation of ⁇ 0.5 from the characteristic absorption peak represented by the crystal plane distance d, preferably a deviation of ⁇ 0.3, and more preferably a deviation of ⁇ 0.1.
  • the Form A crystal has one or more characteristics selected from the group consisting of:
  • the TG pattern of the A crystal form has a characteristic absorption peak at 261 ⁇ 2 ° C;
  • the TG pattern of the Form A crystal has a characteristic absorption peak at 262.1 °C.
  • the TG pattern of the A crystal form has a characteristic absorption peak at 323 ⁇ 5 ° C;
  • the TG pattern of the Form A crystal has a characteristic absorption peak at 324 °C.
  • the A crystal form has a thermal weight loss at 77 ° C of 77.65 wt%.
  • the Form A crystal has a TG pattern substantially as shown in FIG.
  • the DSC pattern of the A crystal form has a characteristic absorption peak at 135 ⁇ 5 ° C;
  • the DSC pattern of the Form A crystal has a characteristic absorption peak at 135.67 °C.
  • the initial value of the endothermic transition temperature of the Form A crystal is 131 ⁇ 2 °C.
  • the initial value of the endothermic transition temperature of the Form A crystal is 131.84 °C.
  • the Form A crystal has a DSC pattern substantially as shown in FIG.
  • the A crystal form has a hygroscopicity of less than 1%.
  • the A crystal form has a hygroscopicity of less than 0.3% when the relative humidity RH is less than 50%.
  • the Form A crystal has a DVS pattern substantially as shown in FIG.
  • the IR pattern of the A crystal form includes the following characteristic absorption peaks expressed by the wavelength ⁇ : 3368 ⁇ 2 cm -1 , 2940 ⁇ 2 cm -1 , 2848 ⁇ 2 cm -1 , 2222 ⁇ 2 cm -1 , 1729 ⁇ 2cm -1 , 1672 ⁇ 2cm -1 , 1564 ⁇ 2cm -1 , 1529 ⁇ 2cm -1 , 1470 ⁇ 2cm -1 , 1454 ⁇ 2cm -1 , 1387 ⁇ 2cm -1 , 1298 ⁇ 2cm -1 , 1203 ⁇ 2 cm -1 , 1105 ⁇ 2 cm -1 , 1075 ⁇ 2 cm -1 , 921 ⁇ 2 cm -1 , 781 ⁇ 2 cm -1 , 709 ⁇ 2 cm -1 .
  • the IR pattern of the Form A includes the following characteristic absorption peaks expressed by the wavelength ⁇ : 3368, 2940, 2848, 2222, 1729, 1672, 1564, 1529, 1470, 1454, 1387, 1298, 1203, 1105, 1075, 921, 781, 709 cm -1 .
  • the Form A crystal has an IR pattern substantially as shown in FIG.
  • the Form A crystal has a Raman diagram substantially as shown in FIG.
  • the A crystalline form compound of the present invention has superior oral hypoglycemic activity in preventing or treating type II diabetes, and the A crystal form can improve the dissolution of the compound.
  • the crystal composition comprises or is made of the crystal form A of the crystal.
  • the A crystal form crystal has a weight percentage of 60-99.999%, preferably 80-99.999%, more preferably 90-99.999%, based on the total weight of the crystal composition. .
  • the crystalline composition further comprises: (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl) of non-A crystalline form --4-carbonyl-3,4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylic acid crystal, amorphous (R)-methyl-2-(3-aminopiperidin-1-yl) 3-(2-Cyanobenzyl)-4-carbonyl-3,4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylic acid.
  • the first solvent is a good solvent selected from the group consisting of alcohols, ketones, esters, chlorinated alkanes, or combinations thereof;
  • the alcohol, the ketone, and the ester are not particularly limited, and may be selected from materials conventional in the art, or prepared by a conventional method, or commercially available.
  • the alcohol is a C1-C10 alcohol, preferably a C1-C8 alcohol, more preferably a C1-C5 alcohol.
  • the alcohols include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol, or combinations thereof.
  • the ketone is a C2-C8 ketone, preferably a C3-C5 ketone.
  • the ketones include, but are not limited to, acetone, isobutanol butanone, or a combination thereof.
  • the ester is a C1-C10 ester, preferably a C1-C7 ester, more preferably a C1-C5 ester. ester.
  • the esters include, but are not limited to, methyl formate, ethyl acetate, isobutyl formate, or combinations thereof.
  • the chlorinated alkane includes, but is not limited to, dichloromethane, chloroform, or a combination thereof, preferably dichloromethane.
  • the (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl-3,4-di Hydrothiophene [3,2-d]pyrimidine-6-carboxylic acid is an amorphous compound.
  • the second solvent is a poor solvent selected from the group consisting of water, ethers, alkanes, tetrahydrofuran, 1,4-dioxane, or a combination thereof.
  • the ether is a C1-C10 ether, preferably a C1-C8 ether, more preferably a C1-C6 ether.
  • the ethers include, but are not limited to, petroleum ether, tert-butyl methyl ether, diethyl ether, diisopropyl ether, diethyl ether, or a combination thereof.
  • the alkane is a C2-C15 alkane, preferably a C3-C10 alkane, more preferably a C4-C8 alkane.
  • the alkane includes, but is not limited to, n-pentane, n-hexane, n-heptane, or a combination thereof.
  • step 2) the following steps are further included:
  • step 2) Filtration and/or drying of the solid obtained in step 2) to give the (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)- Form A of 4-carbonyl-3,4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylic acid crystal.
  • drying conditions are not particularly limited.
  • the drying temperature is from 10 to 70 ° C, preferably from 20 to 80 ° C, more preferably from 25 to 40 ° 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 yield of the method is from 50% to 99%, preferably from 75% to 99%, more preferably 85%-99%.
  • concentration of 3,4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylic acid was 0.1 g/L-saturated.
  • the solute (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4- in the first solution The concentration of carbonyl-3,4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylic acid is from 0.1 g/L to 100 g/L, preferably from 1 g/L to 870 g/L, more preferably 10g/L-70g/L, optimally 10g/L-50g/L.
  • the solute (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4- in the first solution The concentration of carbonyl-3,4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylic acid is an unsaturated concentration.
  • the crystallization is carried out at 0-50 °C.
  • the crystallization is carried out at 0-40 ° C, preferably at 20-30 ° C; preferably at room temperature.
  • the crystallization time is not particularly limited, and is preferably 0.05 to 72 hours (or longer), preferably 0.1 to 48 hours, more preferably 1 to 24 hours, most preferably It is 2-12 hours.
  • the crystallization is carried out under agitation.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl) Form A of 4-carbonyl-3,4-dihydrothiophene[3,2-d]pyrimidine-6-carboxylic acid crystals and a pharmaceutically acceptable excipient.
  • 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, lake A slip, 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 Form A of the crystal of dihydrothiophene [3,2-d]pyrimidine-6-carboxylate or the use of said crystalline composition or said pharmaceutical composition for the preparation or prevention of type 2 diabetes and/or Or a drug for the complications of type 2 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) Form A of the crystal of the crystal of pyridin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl-3,4-dihydrothiophene [3,2-d]pyrimidine-6-carboxylate or Crystal composition or the pharmaceutical composition.
  • the amount of the A crystal form 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 A or the 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,
  • the same or similar modes of administration of 2-d]pyrimidine-6-carboxylic acid include, but are not limited to, oral, transdermal, intravenous, intramuscular, topical, and the like.
  • the present invention has the following main advantages:
  • a crystal form prepared by the method of the present invention has higher purity
  • the crystalline form A of the invention has better stability, especially thermal stability
  • the crystalline form A of the present invention has a lower hygroscopicity, and when the relative humidity RH is less than 50%, the hygroscopicity of the crystalline form A is less than 0.3%;
  • the preparation method of the crystal form A of the present invention is simple in operation, easy to control, and has good reproducibility, and is suitable for industrial production.
  • 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 ° ⁇ 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.
  • 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 frequency of scattered light from molecular and optical interactions. 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.
  • 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 .
  • 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.
  • the crystal form A of the crystal obtained in Example 1 was subjected to polarization, XRD, TGA, DSC, DVS, IR, and Raman tests.
  • Fig. 1 is a polarized photograph of Form A of the crystal of Example 1, and it can be seen from Fig. 1 that Form A is a powder crystal.
  • Example 2 is an XRD pattern of the crystal form A of the crystal of Example 1, and it can be seen from FIG. 2 that the A crystal form is There is an absorption peak.
  • Figure 3 is a TG diagram of Form A of the crystal of Example 1, from which it can be seen that Form A has a weight loss of 77.65% at 210-400 °C.
  • DSC differential scanning calorimetry
  • Figure 5 is a graph showing the hygroscopicity analysis (DVS) of the crystal form A of the crystal of Example 1, and it can be seen from Fig. 5 that the A crystal form has a slight wettability, and the humidity change range is small, less than 2.0% in the conventional storage humidity range. .
  • the moisture content in the 40% RH is 0.26%
  • the moisture in the 65% RH is 0.42%
  • the moisture in the 80% RH is 0.57%.
  • FIG. 6 is an infrared spectrum (IR) diagram of the crystal form A of the crystal of Example 1, and it can be seen from FIG. 6 that the A crystal form is 3368, 2940, 2848, 2222, 1729, 1672, 1564, 1529, 1470, 1454, There are characteristic absorption peaks at 1387, 1298, 1203, 1105, 1075, 921, 781, and 709 cm -1 .
  • Figure 7 is a Raman diagram of Form A of the crystal of Example 1, and it can be seen from Figure 7 that Form A is 3375.5, 3300.3, 3081.8, 3074.7, 2961.9, 2839.7, 2224.1, 1711.9, 1676.6, 1596.8. Characteristic absorption peaks at 1554.5, 1521.6, 1474.6, 1373.5, 1267.8, 1209.1, 1157.4, 1039.9, 917.7, 812.0, 755.6, 633.4 cm -1 .

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Abstract

本发明涉及一种化合物的A晶型。本发明还公开了所述A晶型的制备方法和药物组合物。所述A晶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

一种化合物的A晶型及其制备方法 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-羧酸晶体的A晶型及其制备方法。
背景技术
糖尿病(Diabetes Mellitus,DM)是一种多病因的代谢性疾病，是由于人体胰岛素分泌绝对或相对不足，或靶组织细胞对胰岛素敏感性降低而引起的蛋白质、脂肪、水和电解质等一系列代谢紊乱综合症。糖尿病的急性并发症包括：糖尿病酮症酸中毒、糖尿病高渗性昏迷、各种急性感染及乳酸酸中毒等。另外在糖尿病治疗过程中出现的低血糖症也是最常见的急性并发症之一。糖尿病慢性并发症包括糖尿病眼病、糖尿病肾病、糖尿病神经病变、糖尿病心脑肢体大血管病变、糖尿病足部及皮肤病变等。
II型糖尿病是一类由于不能控制体内血糖水平而引起的代谢综合症。II型糖尿病的主要特征是高血糖、胰岛素抵抗和胰岛素分泌缺乏，通常与血脂障碍、高血压和肥胖症相关。II型糖尿病是全球流行性疾病，目前全世界6％的人口患有II型糖尿病，已成为全球第三位威胁人类健康的慢性非传染性疾病。II型糖尿病病人体内可分泌产生胰岛素但数量相对不足，或产生的胰岛素由于组织敏感性降低或胰岛素抵抗而不能有效发挥作用，因而血液内葡萄糖聚集，水平升高。由于这类糖尿病患者能够分泌胰岛素，一般不需要用胰岛素治疗，仅用饮食调整或口服降糖药即可控制血糖。
2000年，全球约有1.71亿糖尿病患者；预计，如不采取有效的治疗措施，在2030年，全球糖尿病患者将达到3亿6千万，其中超过90％的糖尿病患者都属于II型糖尿病患者。中国糖尿病治疗费用每年高达1734亿元人民币，糖尿病所致的直接医疗开支已经占到中国医药总开支的13％。预计2028年美国糖尿病病人数量达到五千万，每年增长速率为5％。而我国糖尿病患者高达9250万，预计2028年中国糖尿病病人数量达到1亿，每年增长速率为4％。作为一种复杂性疾病，II型糖尿病患者异质性强，且东方人与西方人相比具有更高的II型糖尿病易感性，个性化治疗需求高。
目前II型糖尿病的治疗药物主要包括胰岛素、磺酰脲类、二甲双胍类、噻唑烷二酮类、PPARα/γ双重激动剂、DPP IV抑制剂以及GLP-1类似物。虽然现有药物能控制血糖水平，减少并发症的发生几率，但大多数具有比较严重的副作用，例如胃肠道毒性、体重增加、水肿、低血糖等，不能从根本上控制、治愈II型糖尿病。由于传统的糖尿病治疗药物效果有限且耐受性不佳，同时还有明显的副作用，因此，从人类健康和经济利益的角度来考虑，研究开发安全、高效的糖尿病治疗药物具有重要的研究意义。
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。
(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抑制剂，具有较强的体内降糖活性。但是，现有的各晶型的(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-羧酸的新的晶型，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(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A晶型。
本发明的第一方面，提供了一种式I所示(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A晶型，所述A晶型的XRD图谱包括用晶面距d表示的以下特征吸收峰：
Figure PCTCN2016073386-appb-000001
Figure PCTCN2016073386-appb-000002
Figure PCTCN2016073386-appb-000003
在另一优选例中，所述A晶型的XRD图谱包括用晶面距d表示的以下特征吸收峰：
Figure PCTCN2016073386-appb-000004
在另一优选例中，所述A晶型的XRD图谱包括用晶面距d表示的以下特征吸收峰：
Figure PCTCN2016073386-appb-000005
Figure PCTCN2016073386-appb-000006
在另一优选例中，所述A晶型的XRD图谱包括用晶面距d表示的以下特征吸收峰：
Figure PCTCN2016073386-appb-000007
Figure PCTCN2016073386-appb-000008
在另一优选例中，所述A晶型的XRD图谱包括用晶面距d表示的以下特征吸收峰：
Figure PCTCN2016073386-appb-000009
Figure PCTCN2016073386-appb-000010
在另一优选例中，所述A晶型的XRD图谱包括用晶面距d表示的以下特征吸收峰：
Figure PCTCN2016073386-appb-000011
Figure PCTCN2016073386-appb-000012
在另一优选例中，所述A晶型的XRD图谱包括用晶面距d表示的以下特征吸收峰：
Figure PCTCN2016073386-appb-000013
Figure PCTCN2016073386-appb-000014
在另一优选例中，所述A晶型的XRD图谱包括用晶面距d表示的以下特征吸收峰：
Figure PCTCN2016073386-appb-000015
Figure PCTCN2016073386-appb-000016
在另一优选例中，所述A晶型具有基本如图2所示的XRD图。
在另一优选例中，所述A晶型的XRD图谱的用晶面距d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A晶型具有选自下组的一个或多个特征：
1)所述A晶型的TG图在261±2℃存在特征吸收峰；
在另一优选例中，所述A晶型的TG图在262.1℃存在特征吸收峰。
2)所述A晶型的TG图在323±5℃存在特征吸收峰；
在另一优选例中，所述A晶型的TG图在324℃存在特征吸收峰。
3)所述A晶型在400℃的热失重为77-78wt％；
在另一优选例中，所述A晶型在400℃的热失重为77.65wt％。
在另一优选例中，所述A晶型具有基本如图3所示的TG图。
4)所述A晶型的DSC图在135±5℃存在特征吸收峰；
在另一优选例中，所述A晶型的DSC图在135.67℃存在特征吸收峰。
在另一优选例中，所述A晶型的吸热转变温度的起始值为131±2℃。
在另一优选例中，所述A晶型的吸热转变温度的起始值为131.84℃。
在另一优选例中，所述A晶型具有基本如图4所示的DSC图。
5)所述A晶型的吸湿性小于1％。
在另一优选例中，当相对湿度RH小于50％时，所述A晶型的吸湿性小于0.3％。
在另一优选例中，所述A晶型具有基本如图5所示的DVS图。
在另一优选例中，所述A晶型的IR图包括用波长λ表示的以下特征吸收峰：3368±2cm-1、2940±2cm-1、2848±2cm-1、2222±2cm-1、1729±2cm-1、1672±2cm-1、1564±2cm-1、1529±2cm-1、1470±2cm-1、1454±2cm-1、1387±2cm-1、1298±2cm-1、1203±2cm-1、1105±2cm-1、1075±2cm-1、921±2cm-1、781±2cm-1、709±2cm-1。
在另一优选例中，所述A晶型的IR图包括用波长λ表示的以下特征吸收峰：3368、2940、2848、2222、1729、1672、1564、1529、1470、1454、1387、1298、1203、1105、1075、921、781、709cm-1。
在另一优选例中，所述A晶型具有基本如图6所示的IR图。
在另一优选例中，所述A晶型具有基本如图7所示的Raman图。
本发明的第二方面，提供了一种晶体组合物，所述晶体组合物包含本发明第一 方面所述的A晶型晶体或由本发明第一方面所述的A晶型晶体制成。
在另一优选例中，以所述晶体组合物的总重量计，A晶型晶体的重量百分含量为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：非A晶型的(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、无定形(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。
本发明的第三方面，提供了一种本发明第一方面所述的(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A晶型的制备方法，所述方法包括如下步骤：
1)提供第一溶液，所述第一溶液含有第一溶剂和溶于所述第一溶剂中的(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，其中，
所述第一溶剂为良溶剂，选自下组：醇类、酮类、酯类、氯代烷烃、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，所述酮类为C2-C8的酮，较佳地为C3-C5的酮。
在另一优选例中，所述酮类选自下组：丙酮、异丁醇丁酮、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，所述氯代烷烃为二氯甲烷、三氯甲烷、或其组合，优选为二氯甲烷。
在另一优选例中，所述(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-羧酸为无定形化合物。
2)添加第二溶剂至所述第一溶液中，析晶得到本发明第一方面所述的(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A晶型，其中，
所述第二溶剂为不良溶剂，选自下组：水、醚类、烷烃类、四氢呋喃、1,4-二氧六环、或其组合。
在另一优选例中，所述醚类为C1-C10的醚，较佳地为C1-C8的醚，更佳地为C1-C6的醚。
在另一优选例中，所述醚类选自下组：石油醚、叔丁基甲基醚、乙醚、异丙醚、二乙醚、或其组合。
在另一优选例中，所述烷烃类为C2-C15的烷烃，较佳地为C3-C10的烷烃，更佳地为C4-C8的烷烃。
在另一优选例中，所述烷烃类选自下组：正戊烷、正己烷、正庚烷、或其组合。
在另一优选例中，在步骤2)之后还包括如下步骤：
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(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A晶型。
在另一优选例中，所述干燥的温度为10-70℃，较佳地为20-80℃，更佳地为25-40℃。
在另一优选例中，所述干燥的压力为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，所述方法的产率为50％-99％，较佳地为75％-99％，更佳地为85％-99％。
在另一优选例中，在所述第一溶液中，溶质(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-羧酸的浓度为0.1g/L-饱和浓度。
在另一优选例中，在所述第一溶液中，溶质(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-羧酸的浓度为0.1g/L-100g/L，较佳地为1g/L-870g/L，更佳地为10g/L-70g/L，最佳地为10g/L-50g/L。
在另一优选例中，在所述第一溶液中，溶质(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-羧酸的浓度为非饱和 浓度。
在另一优选例中，所述析晶在0-50℃下进行。
在另一优选例中，所述析晶在0-40℃下进行，较佳地为20-30℃下进行；优选为室温。
在另一优选例中，所述析晶在搅拌下进行。
本发明的第四方面，提供了一种药物组合物，所述药物组合物包含本发明第一方面所述的(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A晶型以及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。
本发明的第五方面，提供了一种本发明第一方面所述的(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A晶型或本发明第二方面所述的晶体组合物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。
本发明的第六方面，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本发明第一方面所述的(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A晶型或本发明第二方面所述的晶体组合物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晶体的A晶型的偏光照片。
图2是本发明实施例1晶体的A晶型的XRD图。
图3是本发明实施例1晶体的A晶型的TG图。
图4是本发明实施例1晶体的A晶型的差示扫描量热分析(DSC)图。
图5是本发明实施例1晶体的A晶型的吸湿性分析(DVS)图。
图6是本发明实施例1晶体的A晶型的红外光谱(IR)图。
图7是本发明实施例1晶体的A晶型的拉曼光谱(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-羧酸晶体的A晶型。基于上述发现，发明人完成了本发明。
无定形粉末
(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抑制剂，具有较强的体内降糖活性。该化合物是DPP IV的选择性、可逆竞争型抑制剂，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，该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；能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，该化合物在大鼠的和犬的药代动力学性质以及安全性良好。其中该化合物在大鼠和犬种的半衰期和AUC0-t优于上市药物阿格列汀。安全性实验表明该 化合物安全性良好，其中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，因此，该化合物有望开发成为新的II型糖尿病治疗药物。
Figure PCTCN2016073386-appb-000017
药物多晶型(Drug Polymorphism)是指药物存在两种或两种以上的不同晶型物质状态。对于固体化学药物，由于其分子的排列形式以及对称规律不同，同一种药物可以形成多种不同的晶型固体物质状态，这种同一物质的不同晶型固体状态通常被称之为“多晶型现象”。多晶型现象在固体药物中普遍存在，多晶型是影响固体药物质量和疗效的重要因素之一。
采用专利申请号CN201210262331.3中所述制备方法制得无定形(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]+。
A晶型
本发明提供了一种式I所示(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A晶型，所述A晶型的XRD图谱包括用晶面距d表示的以下特征吸收峰：
Figure PCTCN2016073386-appb-000018
Figure PCTCN2016073386-appb-000019
Figure PCTCN2016073386-appb-000020
在另一优选例中，所述A晶型的XRD图谱包括用晶面距d表示的以下特征吸收峰：
Figure PCTCN2016073386-appb-000021
典型地，所述A晶型的XRD图谱包括用晶面距d表示的以下特征吸收峰：
Figure PCTCN2016073386-appb-000022
在另一优选例中，所述A晶型的XRD图谱包括用晶面距d表示的以下特征吸收峰：
Figure PCTCN2016073386-appb-000023
Figure PCTCN2016073386-appb-000024
在另一优选例中，所述A晶型的XRD图谱包括用晶面距d表示的以下特征吸收峰：
Figure PCTCN2016073386-appb-000025
Figure PCTCN2016073386-appb-000026
在另一优选例中，所述A晶型的XRD图谱包括用晶面距d表示的以下特征吸收峰：
Figure PCTCN2016073386-appb-000027
Figure PCTCN2016073386-appb-000028
在另一优选例中，所述A晶型的XRD图谱包括用晶面距d表示的以下特征吸收峰：
Figure PCTCN2016073386-appb-000029
Figure PCTCN2016073386-appb-000030
在另一优选例中，所述A晶型的XRD图谱包括用晶面距d表示的以下特征吸收峰：
Figure PCTCN2016073386-appb-000031
Figure PCTCN2016073386-appb-000032
在另一优选例中，所述A晶型具有基本如图2所示的XRD图。
在本发明中，所述A晶型的XRD图谱的用晶面距d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。
具体地，所述A晶型具有选自下组的一个或多个特征：
1)所述A晶型的TG图在261±2℃存在特征吸收峰；
在另一优选例中，所述A晶型的TG图在262.1℃存在特征吸收峰。
2)所述A晶型的TG图在323±5℃存在特征吸收峰；
在另一优选例中，所述A晶型的TG图在324℃存在特征吸收峰。
3)所述A晶型在400℃的热失重为77-78wt％；
在另一优选例中，所述A晶型在400℃的热失重为77.65wt％。
在另一优选例中，所述A晶型具有基本如图3所示的TG图。
4)所述A晶型的DSC图在135±5℃存在特征吸收峰；
在另一优选例中，所述A晶型的DSC图在135.67℃存在特征吸收峰。
在另一优选例中，所述A晶型的吸热转变温度的起始值为131±2℃。
在另一优选例中，所述A晶型的吸热转变温度的起始值为131.84℃。
在另一优选例中，所述A晶型具有基本如图4所示的DSC图。
5)所述A晶型的吸湿性小于1％。
在另一优选例中，当相对湿度RH小于50％时，所述A晶型的吸湿性小于0.3％。
在另一优选例中，所述A晶型具有基本如图5所示的DVS图。
在另一优选例中，所述A晶型的IR图包括用波长λ表示的以下特征吸收峰：3368±2cm-1、2940±2cm-1、2848±2cm-1、2222±2cm-1、1729±2cm-1、1672±2cm-1、1564±2cm-1、1529±2cm-1、1470±2cm-1、1454±2cm-1、1387±2cm-1、1298±2cm-1、1203±2cm-1、1105±2cm-1、1075±2cm-1、921±2cm-1、781±2cm-1、709±2cm-1。
在另一优选例中，所述A晶型的IR图包括用波长λ表示的以下特征吸收峰：3368、2940、2848、2222、1729、1672、1564、1529、1470、1454、1387、1298、1203、1105、1075、921、781、709cm-1。
在另一优选例中，所述A晶型具有基本如图6所示的IR图。
在另一优选例中，所述A晶型具有基本如图7所示的Raman图。
与无定形(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-羧酸粉末相比，本发明A晶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，且A晶型能够提高化合物的溶解性，增强口服吸收能力，提高生物利用度，在预防或治疗II型糖尿病方面效果更佳。
晶体组合物
在本发明中，所述晶体组合物包含所述的A晶型晶体或由所述的A晶型晶体制成。
在另一优选例中，以所述晶体组合物的总重量计，A晶型晶体的重量百分含量为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：非A晶型的(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、无定形(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。
A晶型的制备方法
在本发明中，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-羧酸晶体的A晶型的制备方法，所述方法包括如下步骤：
1)提供第一溶液，所述第一溶液含有第一溶剂和溶于所述第一溶剂中的(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，其中，
所述第一溶剂为良溶剂，选自下组：醇类、酮类、酯类、氯代烷烃、或其组合；
在本发明中，所述醇类、酮类、酯类没有特别限制，可选用本领域常规的材料，或用常规的方法制备，或从市场购买得到。
典型地，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。
代表性地，所述醇类包括(但并不限于)：甲醇、乙醇、正丙醇、异丙醇、正丁醇、新戊醇、或其组合。
典型地，所述酮类为C2-C8的酮，较佳地为C3-C5的酮。
代表性地，所述酮类包括(但并不限于)：丙酮、异丁醇丁酮、或其组合。
典型地，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。
代表性地，所述酯类包括(但并不限于)：甲酸甲酯、乙酸乙酯、甲酸异丁酯、或其组合。
代表性地，所述氯代烷烃包括(但并不限于)：二氯甲烷、三氯甲烷、或其组合，优选为二氯甲烷。
在另一优选例中，所述(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-羧酸为无定形化合物。
2)添加第二溶剂至所述第一溶液中，析晶得到所述的(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A晶型，其中，
所述第二溶剂为不良溶剂，选自下组：水、醚类、烷烃类、四氢呋喃、1,4-二氧六环、或其组合。
典型地，所述醚类为C1-C10的醚，较佳地为C1-C8的醚，更佳地为C1-C6的醚。
代表性地，所述醚类包括(但并不限于)：石油醚、叔丁基甲基醚、乙醚、异丙醚、二乙醚、或其组合。
典型地，所述烷烃类为C2-C15的烷烃，较佳地为C3-C10的烷烃，更佳地为C4-C8的烷烃。
代表性地，所述烷烃类包括(但并不限于)：正戊烷、正己烷、正庚烷、或其组合。
在另一优选例中，在步骤2)之后还包括如下步骤：
3)过滤和/或干燥步骤2)所得固体，制得所述的(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A晶型。
在本发明中，所述干燥条件(如温度、压力、时间等)均没有特别限制。
在另一优选例中，所述干燥的温度为10-70℃，较佳地为20-80℃，更佳地为25-40℃。
在另一优选例中，所述干燥的压力为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，所述方法的产率为50％-99％，较佳地为75％-99％，更佳地为 85％-99％。
在本发明中，在所述第一溶液中，溶质(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-羧酸的浓度为0.1g/L-饱和浓度。
在另一优选例中，在所述第一溶液中，溶质(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-羧酸的浓度为0.1g/L-100g/L，较佳地为1g/L-870g/L，更佳地为10g/L-70g/L，最佳地为10g/L-50g/L。
在另一优选例中，在所述第一溶液中，溶质(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-羧酸的浓度为非饱和浓度。
典型地，所述析晶在0-50℃下进行。
在另一优选例中，所述析晶在0-40℃下进行，较佳地为20-30℃下进行；优选为室温。
在另一优选例中，所述析晶时间没有特别限制，优选地为0.05-72小时(或更长)，较佳地为0.1-48小时，更佳地为1-24小时，最佳地为2-12小时。
在另一优选例中，所述析晶在搅拌下进行。
药物组合物和应用
本发明提供了一种药物组合物，所述药物组合物包含所述的(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A晶型以及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。
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-羧酸晶体的A晶型或所述的晶体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A晶型或所述的晶体组合物或所述的药物组合物。
本发明的A晶型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A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。
与现有技术相比，本发明具有以下主要优点：
(1)使用本发明方法制备的A晶型具有更高的纯度；
(2)本发明A晶型具有更优的稳定性，尤其是热稳定性；
(3)本发明A晶型具有更低的吸湿性，当相对湿度RH小于50％时，所述A晶型的吸湿性小于0.3％；
(4)本发明A晶型在常规条件下不易降解；
(5)本发明A晶型的制备方法操作简单，容易控制，重现性好，适合工业化生产。
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℃。
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。
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。
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℃。
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-羧酸晶体的A晶型(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1mL乙醇中，加入12mL石油醚，室温搅拌下析晶，至不再有固体析出，析晶时间约为2小时。过滤，将所得固体物料置于真空干燥箱中，于25℃、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A晶体110mg。
结果
对实施例1所制得晶体的A晶型进行偏光、XRD、TGA、DSC、DVS、IR和Raman等测试。
图1为实施例1晶体的A晶型的偏光照片，从图1中可以看出A晶型为粉末状晶体。
图2为实施例1晶体的A晶型的XRD图，从图2中可以看出A晶型在
Figure PCTCN2016073386-appb-000033
Figure PCTCN2016073386-appb-000034
Figure PCTCN2016073386-appb-000035
处有吸收峰。
图3为实施例1晶体的A晶型的TG图，从图3中可以看出A晶型在210-400℃有77.65％的失重。
图4为实施例1晶体的A晶型的差示扫描量热分析(DSC)图，从图4中可以看出A晶型对应的DSC显示熔点为131.84℃。
图5为实施例1晶体的A晶型的吸湿性分析(DVS)图，从图5中可以看出A晶型略有引湿性，在常规储存湿度范围内，湿度变化幅度小，小于2.0％。在40％RH含水分0.26％，在65％RH吸收水分0.42％，在80％RH吸收水分0.57％。
图6为实施例1晶体的A晶型的红外光谱(IR)图，从图6中可以看出A晶型在3368、2940、2848、2222、1729、1672、1564、1529、1470、1454、1387、1298、1203、1105、1075、921、781、709cm-1处有特征吸收峰。
图7为实施例1晶体的A晶型的拉曼光谱(Raman)图，从图7中可以看出A晶型在3375.5、3300.3、3081.8、3074.7、2961.9、2839.7、2224.1、1711.9、1676.6、1596.8、1554.5、1521.6、1474.6、1373.5、1267.8、1209.1、1157.4、1039.9、917.7、812.0、755.6、633.4cm-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-羧酸晶体的A晶型(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1mL乙酸乙酯中，加入8mL石油醚，室温搅拌下析晶，至不再有固体析出，过滤，将所得固体物料置于真空干燥箱中，于25℃、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A晶体100mg。
所得产物的XRD结果基本同实施例1。
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-羧酸晶体的A晶型(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1mL乙酸乙酯中，加入10mL乙醚，室温搅拌下析晶，至不再有固体析出，过滤，将所得固体物料置于真空干燥箱中，于25℃、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A晶体80mg。
所得产物的XRD结果基本同实施例1。
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-羧酸晶体的A晶型(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1mL乙醇中，加入10mL乙醚，室温搅拌下析晶，至不再有固体析出，过滤，将所得固体物料置于真空干燥箱中，于25℃、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A晶体60mg。
所得产物的XRD结果基本同实施例1。
实施例5
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-羧酸晶体的A晶型(No.5)
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1mL丙酮中，加入10mL石油醚，室温搅拌下析晶，至不再有固体析出，过滤，将所得固体物料置于真空干燥箱中，于25℃、 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A晶体80mg。
所得产物的XRD结果基本同实施例1。
实施例6
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-羧酸晶体的A晶型(No.6)
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1mL二氯甲烷中，加入8mL石油醚，室温搅拌下析晶，至不再有固体析出，过滤，将所得固体物料置于真空干燥箱中，于25℃、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A晶体100mg。
所得产物的XRD结果基本同实施例1。
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(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A晶型，其特征在于，所述A晶型的XRD图谱包括用晶面距d表示的以下特征吸收峰：
    Figure PCTCN2016073386-appb-100001
    Figure PCTCN2016073386-appb-100002
    Figure PCTCN2016073386-appb-100003
  2. 如权利要求1所述的A晶型，其特征在于，所述A晶型的XRD图谱包括用晶面距d表示的以下特征吸收峰：
    Figure PCTCN2016073386-appb-100004
    Figure PCTCN2016073386-appb-100005
  3. 如权利要求1所述的A晶型，其特征在于，所述A晶型具有选自下组的一个或多个特征：
    1)所述A晶型的TG图在261±2℃存在特征吸收峰；
    2)所述A晶型的TG图在323±5℃存在特征吸收峰；
    3)所述A晶型在400℃的热失重为77-78wt％；
    4)所述A晶型的DSC图在135±5℃存在特征吸收峰；
    5)所述A晶型的吸湿性小于1％。
  4. 一种晶体组合物，其特征在于，所述晶体组合物包含权利要求1所述的A晶型晶体或由权利要求1所述的A晶型晶体制成。
  5. 一种权利要求1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A晶型的制备方法，其特征在于，所述方法包括如下步骤：
    1)提供第一溶液，所述第一溶液含有第一溶剂和溶于所述第一溶剂中的(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，其中，
    所述第一溶剂为良溶剂，选自下组：醇类、酮类、酯类、氯代烷烃、或其组合；
    2)添加第二溶剂至所述第一溶液中，析晶得到权利要求1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A晶型，其中，
    所述第二溶剂为不良溶剂，选自下组：水、醚类、烷烃类、四氢呋喃、1,4-二氧六环、或其组合。
  6. 如权利要求5所述的方法，其特征在于，在所述第一溶液中，溶质(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-羧酸的浓度为0.1g/L-饱和浓度。
  7. 如权利要求5所述的方法，其特征在于，所述析晶在0-50℃下进行。
  8. 一种药物组合物，其特征在于，所述药物组合物包含权利要求1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A晶型以及药学上可接受的赋形剂。
  9. 一种权利要求1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A晶型或权利要求4所述的晶体组合物或权利要求8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。
  10. 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，其特征在于，向患者给予治疗有效量的权利要求1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A晶型或权利要求4所述的晶体组合物或权利要求8所述的药物组合物。
PCT/CN2016/073386 2015-02-11 2016-02-03 一种化合物的a晶型及其制备方法 WO2016127898A1 (zh)

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