CN106674294A - Crystal form of glucopyranose derivative - Google Patents

Abstract

The invention relates to a crystal form of a glucopyranose derivative serving as a sodium-glucose co-transporter (SGLT) inhibitor, a preparation method thereof and a pharmaceutical application thereof, and also relates to a medicine compound containing the crystal form and the application thereof for preparing drugs for treating diabetes and/or diseases related to diabetes.

Description

The crystal form of glucopyranosyl derivatives

Technical field

The present invention relates to the crystal formation of glucopyranosyl derivatives and the pharmaceutical composition comprising crystal-form compound of the present invention, And they are used to prepare the purposes of the medicine as sodium dependent glucose transport protein (SGLT) inhibitor.

Background technology

Diabetes are a kind of common chronic diseases being characterized with hyperglycaemia, and the generation of diabetes is accompanied by peripheral tissues Insulin resistance, internal insulin secretion reduce and liver gluconeogenesis increase.When cannot be by diet and motion Method efficiently controlling during illness, needs are treated in addition using insulin or oral hypoglycemic.Current drop blood Sugared medicine includes biguanides, sulfonylurea, insulin sensitizer, meglitinide, alpha-glucosidase restrainer and DPP-IV suppression Preparation etc..However, at present these hypoglycemic agents all have shortcoming, biguanides can cause lactic acidosis, sulfonylurea to cause sternly The hypoglycemia of weight, meglitinide improper use can also cause hypoglycemia, insulin sensitizer to cause oedema, heart failure and body Increase again, alpha-glucosidase restrainer can cause belly flatulence and diarrhea, DPP-IV inhibitor to need and melbine joint Medication can be only achieved preferable hypoglycemic effect.Therefore, in the urgent need to developing safer and more effective novel blood sugar lowing medicine.

Research finds that GLUT is that a class is embedded on cell membrane the carrier protein for transporting glucose, Portugal Grape sugar must could be by the lipid bilayer structure of cell membrane by GLUT.GLUT is divided to two big Class a, class is sodium dependent glucose transport protein (sodium-dependent glucose transporters, SGLTs)； Another kind of is GLUT (glucose transporters, GLUTs).Two major families members of SGLTs are SGLT-1 and SGLT-2.SGLT-1 is mainly distributed in small intestine, kidney, heart and tracheae, be mainly expressed in intestinal brush border and In the kidney proximal tubule S3 stages farther out, heart and tracheae are expressed on a small quantity, with sodium-glucose 2:1 ratio transhipment glucose And galactolipin.And SGLT-2 is mainly distributed in kidney, in being mainly expressed in kidney proximal tubule S1 sections farther out, with sodium-Portugal Grape sugar 1:1 ratio transhipment glucose.In organism, SGLTs transports glucose with active mode against concentration gradient, while disappearing Energy consumption, and GLUTs transports glucose, its transport process not consumed energy in the way of easyization diffusion along concentration gradient.Research Show, plasma glucose is generally filtered in the glomerulus of kidney and has 90% glucose in renal tubule near-end S1 section quilts Into epithelial cell, 10% glucose is in tubular distal S3 sections by SGLT-1 active transports to epithelium for SGLT-2 active transports In cell, and it is transported in capillary network around by the GLUT of epithelial cell basilar memebrane side, completes renal tubule to glucose Reabsorption.Therefore, SGLTs is glycometabolic first outpost of the tax office of regulating cell, is also the promising target of energy effectively treatment diabetes. Research finds that the patient of SGLT-2 defects has substantial amounts of glucose in urine to discharge, and this is to reduce glucose by suppressing SGLT-2 activity Absorb and then treatment diabetes provide fact basis.So suppressing SGLTs transport proteins activity, renal tubule can be blocked to grape The reabsorption of sugar, increases glucose and drain in urine so that concentration of glucose normalization in blood plasma, and then control diabetes and The state of an illness of diabetic complication.Suppress SGLTs not interfere with normal glucose counter regulation mechanism, cause risk of hypoglycemia；Simultaneously Blood sugar is reduced by increasing the excretion of renal glucose sugar, the Body weight loss of obesity patient can be promoted.Study and also find, SGLTs inhibitor mechanism of action does not rely on the degree of pancreaticβ-cell dysfunction or insulin resistance, therefore, its effect Will not decline as the MSOF of beta cell or severe insulin are resisted.It can be used alone, it is also possible to and other Hypoglycemic agent therapeutic alliance.Therefore, SGLTs inhibitor is preferable novel blood sugar lowing medicine.

Additionally, research also finds that SGLTs inhibitor can be used for the treatment of diabetes-related complication.Such as retinopathy Insulin resistant, hyperinsulinemia, high fat of blood, obesity that change, neuropathy, ephrosis, glucose metabolism disorders are caused etc..Simultaneously SGLTs inhibitor also can be used in combination with existing medicine, such as sulfonamide, thiazolidinedione, melbine and insulin Deng, in the case where drug effect is not affected, dosage is reduced, so as to avoid or alleviate the generation of bad reaction, improve trouble Compliance of the person to treatment.At present, the SGLTs inhibitor class medicines for having listed have, canagliflozin and Dapagliflozin etc., main to use In treatment type ii diabetes and diabetic complication.

The application PCT/CN2014/087587 that present applicant was submitted on 09 26th, 2014 (WO2015043511) a class glucopyranosyl derivatives are described, and it is used as the application of SGLTs inhibitor, Jing tests Prove, the wherein compound of disclosed embodiment 1 (1R, 2S, 3S, 4R, 5S) -5- [the chloro- 3- of 4- [(4- ethoxyl phenenyls) methyl] benzene Base] -1- (1- ethoxys) -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- triols to the inhibitory action of SGLTs substantially, its knot Structure is as follows：

Therefore, using the whole bibliography as the present invention of its content.In further research process, the present patent application People prepares single (R)-type isomers, i.e. (1R, 2S, 3S, 4R, 5S) -5- [4- by Stereoselective synthesizing process Chloro- 3- [(4- ethoxyphenyls) methyl] phenyl] -1- [(1R) -1- ethoxys] -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- Triol, this compound is significantly better than its (S)-type isomers in the property of the aspects such as drug activity and (R, S)-diastereomer mixes Thing, (R)-type isomers that the synthetic method recorded according to the present invention is directly obtained is amorphous form.

Organic compound of many with pharmaceutically active can be crystallized with more than one three-dimensional crystalline structure.Also It is to say, compound can be crystallized with different crystal forms, this phenomenon (identical chemical constitution, different molecule rows Array structure) it is referred to as polytropism (polymorphism), the compound with this different crystal forms structure is referred to as many Crystal formation thing.The polymorph of specific organic drug compound, due to respective unique three-dimensional structure, and has different property Matter, such as dissolubility, hygroscopicity and stability.Although primary concern is that therapeutic efficiency for medical compounds, The solid-state form of compound develops no less important for it.Generally, medicament research and development person tries to find out the crystallization with desirable properties Form, for example gratifying solubility (including dissolution rate) of desirable properties, pharmacokinetics, storage stability, suction Moist, property prepared and repeatability, all of which can affect machinability, manufacture and/or the bioavilability of medicine.Cause This, finds with some in these required properties or various crystal forms it is that drug development institute is indispensable.Known nothing Amorphous Drug material can not well solve problem above.For example amorphous drug material is generally difficult to handle and prepares, carries For insecure solubility, and it is generally found the physics and unstable chemcial property of amorphous form.

Therefore, the R＆D personnel finds suitable crystalline forms in the development process of medicine, and many problems referred to above can To be resolved.In commercially available and pharmaceutically acceptable pharmaceutical composition preparation, medicine is provided in crystalline form It is very important.But, according only to molecular structure, generally unpredictable specific organic drug compound (compound itself or Salt form) crystallization behavior and result, unlikely predict crystal formation itself structure and property, need by it is substantial amounts of experiment visit Suo Caineng obtains beneficial result.The novel crystal forms or polymorph for exploring pharmaceutically acceptable compound are the globality for improving medical product Chance can be provided, while expanding available description of materials when formulation science man designs.

Therefore, the present invention is primarily directed to (1R, 2S, 3S, 4R, 5S) -5- [the chloro- 3- of 4- [(4- ethoxyphenyls) methyl] benzene Base] -1- [(1R) -1- ethoxys] -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- triols and its solvate polymorphic Studied.

The content of the invention

The present invention relates to (1R, 2S, 3S, 4R, 5S) -5- [the chloro- 3- of 4- [(4- ethoxyphenyls) methyl] phenyl] -1- [(1R) - 1- ethoxys] -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- triols, i.e. compound (I) and its alcoholate (II) crystalline substance Type.Three kinds of crystal formations prepared by the present invention can be by its characteristic X-ray powder diffraction (XRPD) collection of illustrative plates, DSC curve, Raman spectrum (Ramanspectrum) identified and brilliant with other with the means such as Fourier transform-infrared spectrum (FT-IR spectrum) Type is distinguished.By the property research to these crystal formations, it is found that they have preferable dissolution properties and excellent internal metabolism dynamic Mechanical property, being administered orally, it is good to absorb, and with higher exposed amount, the half-life is preferable, with preferable DEVELOPMENT PROSPECT.

On the one hand, on the basis of lot of experiments, the invention provides the crystal formation of the compound as shown in formula (I)：

It is crystal formation A, crystal formation B or its combination.

In some embodiments, crystal formation of the present invention, wherein, the X-ray powder diffraction pattern of crystal formation A includes 2 θ Angle be 4.36 ° ± 0.2 °, 12.97 ° ± 0.2 °, 18.12 ° ± 0.2 °, 18.86 ° ± 0.2 °, 20.24 ° ± 0.2 ° and 24.09 ° ± 0.2 ° of diffraction maximum.

In some embodiments, crystal formation of the present invention, wherein, the differential scanning calorimetric curve of crystal formation A is included 70.8 DEG C ± 3 DEG C of endothermic peak.

In some embodiments, crystal formation of the present invention, wherein, the Raman spectrogram of crystal formation A is included in 1610.51cm^-1±1cm^-1,801.70cm^-1±1cm^-1,725.87cm^-1±1cm^-1And 331.60cm^-1±1cm^-1The feature at place Absworption peak.

In some embodiments, crystal formation of the present invention, wherein, the Fourier transform-infrared spectrogram bag of crystal formation A It is contained in 3425.84cm^-1±5cm^-1,3317.08cm^-1±5cm^-1,2979.45cm^-1±5cm^-1,2881.54cm^-1±5cm^-1, 1581.67cm^-1±2cm^-1,1511.87cm^-1±2cm^-1,1299.92cm^-1±2cm^-1,1245.92cm^-1±2cm^-1, 1177.23cm^-1±2cm^-1,1086.79cm^-1±2cm^-1,1040.14cm^-1±2cm^-1,824.08cm^-1±2cm^-1, 806.54cm^-1±2cm^-1And 521.91cm^-1±2cm^-1The characteristic absorption peak at place.

In some embodiments, crystal formation of the present invention, wherein, the X-ray powder diffraction pattern of crystal formation B includes 2 θ Angle be 4.65 ° ± 0.2 °, 14.30 ° ± 0.2 °, 18.08 ° ± 0.2 °, 22.38 ° ± 0.2 °, 23.27 ° ± 0.2 °, 24.01 ° ± 0.2 ° and 28.07 ° ± 0.2 ° of diffraction maximum.

In some embodiments, crystal formation of the present invention, wherein, the differential scanning calorimetric curve of crystal formation B is included 98.1 DEG C ± 3 DEG C of endothermic peak.

In some embodiments, crystal formation of the present invention, wherein, the Raman spectrum of crystal formation B is included in 1610.60cm^-1±1cm^-1,800.26cm^-1±1cm^-1And 333.99cm^-1±1cm^-1The characteristic absorption peak at place.

In some embodiments, crystal formation of the present invention, wherein, the Fourier transform-infrared spectrogram bag of crystal formation B It is contained in 3331.11cm^-1±5cm^-1,2981.09cm^-1±5cm^-1,2930.07cm^-1±5cm^-1,2899.78cm^-1±5cm^-1, 2881.62cm^-1±5cm^-1,1612.08cm^-1±2cm^-1,1512.44cm^-1±2cm^-1,1247.61cm^-1±2cm^-1, 1177.78cm^-1±2cm^-1,1082.94cm^-1±2cm^-1,1037.45cm^-1±2cm^-1,1023.57cm^-1±2cm^-1, 801.45cm^-1±2cm^-1And 522.52cm^-1±2cm^-1The characteristic absorption peak at place.

In some embodiments, crystal formation of the present invention, wherein, the X-ray powder diffraction pattern of crystal formation A includes 2 θ Angle be 4.36 ° ± 0.2 °, 12.97 ° ± 0.2 °, 15.64 ° ± 0.2 °, 16.47 ° ± 0.2 °, 16.80 ° ± 0.2 °, 18.12 ° ± 0.2 °, 18.86 ° ± 0.2 °, 20.24 ° ± 0.2 °, 20.52 ° ± 0.2 °, 23.82 ° ± 0.2 °, 24.09 ° ± 0.2 ° and 29.24 ° ± 0.2 ° of diffraction maximum.

In some embodiments, crystal formation of the present invention, wherein, the X-ray powder diffraction pattern of crystal formation A includes 2 θ Angle be 4.36 ° ± 0.2 °, 10.34 ° ± 0.2 °, 11.86 ° ± 0.2 °, 12.97 ° ± 0.2 °, 15.05 ° ± 0.2 °, 15.64 ° ± 0.2°,16.47°±0.2°,16.80°±0.2°,18.12°±0.2°,18.86°±0.2°,19.36°±0.2°,20.24° ± 0.2 °, 20.52 ° ± 0.2 °, 21.22 ° ± 0.2 °, 21.41 ° ± 0.2 °, 21.69 ° ± 0.2 °, 23.82 ° ± 0.2 °, 24.09°±0.2°,25.16°±0.2°,25.50°±0.2°,26.93°±0.2°,27.24°±0.2°,28.46°± 0.2°,29.24°±0.2°,29.79°±0.2°,30.34°±0.2°,31.56°±0.2°,32.03°±0.2°,32.60° ±0.2°,33.96°±0.2°,34.37°±0.2°,34.89°±0.2°,35.73°±0.2°,36.68°±0.2°, 37.03 ° ± 0.2 °, 38.19 ° ± 0.2 ° and 38.59 ° ± 0.2 ° of diffraction maximum.

In some embodiments, crystal formation of the present invention, wherein, the differential scanning calorimetric curve of crystal formation A is included 70.8 DEG C ± 4 DEG C of endothermic peak.

In some embodiments, crystal formation of the present invention, wherein, the differential scanning calorimetric curve of crystal formation A is included 70.8 DEG C ± 5 DEG C of endothermic peak.

In some embodiments, crystal formation of the present invention, wherein, the X-ray powder diffraction pattern of crystal formation B includes 2 θ Angle be 4.65 ° ± 0.2 °, 9.14 ° ± 0.2 °, 14.30 ° ± 0.2 °, 16.23 ° ± 0.2 °, 18.08 ° ± 0.2 °, 22.38 ° ± 0.2 °, 23.27 ° ± 0.2 °, 24.01 ° ± 0.2 °, 27.25 ° ± 0.2 ° and 28.07 ° ± 0.2 ° of diffraction maximum.

In some embodiments, crystal formation of the present invention, wherein, the X-ray powder diffraction pattern of crystal formation B includes 2 θ Angle be 4.65 ° ± 0.2 °, 9.14 ° ± 0.2 °, 11.06 ° ± 0.2 °, 11.61 ° ± 0.2 °, 13.92 ° ± 0.2 °, 14.30 ° ± 0.2°,14.99°±0.2°,16.23°±0.2°,18.08°±0.2°,19.42°±0.2°,20.60°±0.2°,20.94° ±0.2°,21.19°±0.2°,21.65°±0.2°,22.38°±0.2°,23.27°±0.2°,24.01°±0.2°, 25.26°±0.2°,25.88°±0.2°,26.53°±0.2°,27.25°±0.2°,28.07°±0.2°,29.80°± 0.2°,30.19°±0.2°,31.34°±0.2°,32.20°±0.2°,32.85°±0.2°,33.35°±0.2°,34.09° ± 0.2 °, 35.95 ° ± 0.2 °, 36.70 ° ± 0.2 °, 37.63 ° ± 0.2 °, 38.67 ° ± 0.2 °, 39.37 ° ± 0.2 ° and 39.71 ° ± 0.2 ° of diffraction maximum.

In some embodiments, crystal formation of the present invention, wherein, the differential scanning calorimetric curve of crystal formation B is included 98.1 DEG C ± 4 DEG C of endothermic peak.

In some embodiments, crystal formation of the present invention, wherein, the differential scanning calorimetric curve of crystal formation B is included 98.1 DEG C ± 5 DEG C of endothermic peak.

In some embodiments, crystal formation of the present invention, wherein, the X-ray powder diffraction pattern of the crystal formation A with Fig. 1 is substantially the same.

In some embodiments, crystal formation of the present invention, wherein, the differential scanning calorimetric curve of the crystal formation A with Fig. 2 is substantially the same.

In some embodiments, crystal formation of the present invention, wherein, Raman spectrogram and Fig. 3 essence of the crystal formation A It is upper identical.

In some embodiments, crystal formation of the present invention, wherein, the Fourier transform-infrared spectrum of the crystal formation A Figure is substantially the same with Fig. 4.

In some embodiments, crystal formation of the present invention, wherein, the X-ray powder diffraction pattern of the crystal formation B with Fig. 5 is substantially the same.

In some embodiments, crystal formation of the present invention, wherein, the differential scanning calorimetric curve of the crystal formation B with Fig. 6 is substantially the same.

In some embodiments, crystal formation of the present invention, wherein, Raman spectrogram and Fig. 7 essence of the crystal formation B It is upper identical.

In some embodiments, crystal formation of the present invention, wherein, the Fourier transform-infrared spectrum of the crystal formation B Figure is substantially the same with Fig. 8.

On the other hand, on the basis of lot of experiments, present invention also offers the crystal formation of the compound shown in formula (II),

It is crystal formation D.

In some embodiments, the crystal formation of formula (II) compound of the present invention, wherein, the x-ray powder of crystal formation D Diffracting spectrum comprising 2 θ angles be 3.26 ° ± 0.2 °, 10.96 ° ± 0.2 °, 12.98 ° ± 0.2 °, 22.11 ° ± 0.2 °, 22.81 ° ± 0.2 ° and 26.44 ° ± 0.2 ° of diffraction maximum.

In some embodiments, the crystal formation of formula (II) compound of the present invention, wherein, the differential scanning of crystal formation D Calorimetric curve includes 90.6 DEG C ± 3 DEG C of endothermic peak.

In some embodiments, the crystal formation of formula (II) compound of the present invention, wherein, the Raman spectrum of crystal formation D Figure is included in 1615.26cm^-1±1cm^-1,1582.01cm^-1±1cm^-1,1454.43cm^-1±1cm^-1,1306.66cm^-1±1cm^-1,1050.55cm^-1±1cm^-1,991.32cm^-1±1cm^-1,879.86cm^-1±1cm^-1,812.30cm^-1±1cm^-1, 552.10cm^-1±1cm^-1And 362.77cm^-1±1cm^-1The characteristic absorption peak at place.

In some embodiments, the crystal formation of formula (II) compound of the present invention, wherein, the Fourier of crystal formation D becomes Change-infrared spectrogram is included in 3373.16cm^-1±5cm^-1,2978.28cm^-1±5cm^-1,2914.54cm^-1±5cm^-1, 2899.42cm^-1±5cm^-1,1616.95cm^-1±2cm^-1,1583.08cm^-1±2cm^-1,1512.66cm^-1±2cm^-1, 1242.36cm^-1±2cm^-1,1101.04cm^-1±2cm^-1,1050.42cm^-1±2cm^-1,1017.72cm^-1±2cm^-1, 1006.39cm^-1±2cm^-1,810.93cm^-1±2cm^-1,799.18cm^-1±2cm^-1And 739.74cm^-1±2cm^-1The feature at place Absworption peak.

In some embodiments, crystal formation of the present invention, wherein, X-ray powder diffraction (XRPD) the figure bag of crystal formation D Containing 2 θ angles be 3.26 ° ± 0.2 °, 10.96 ° ± 0.2 °, 12.98 ° ± 0.2 °, 17.00 ° ± 0.2 °, 17.69 ° ± 0.2 °, 18.28 ° ± 0.2 °, 20.01 ° ± 0.2 °, 22.11 ° ± 0.2 °, 22.46 ° ± 0.2 °, 22.81 ° ± 0.2 ° and 26.44 ° ± 0.2 ° of diffraction maximum.

In some embodiments, crystal formation of the present invention, wherein, X-ray powder diffraction (XRPD) the figure bag of crystal formation D It it is 3.26 ° ± 0.2 °, 9.74 ° ± 0.2 °, 10.96 ° ± 0.2 °, 11.32 ° ± 0.2 °, 11.56 ° ± 0.2 °, 12.55 ° containing 2 θ angles ±0.2°,12.98°±0.2°,14.39°±0.2°,14.96°±0.2°,16.52°±0.2°,17.00°±0.2°, 17.26°±0.2°,17.69°±0.2°,18.28°±0.2°,19.54°±0.2°,19.82°±0.2°,20.01°± 0.2°,20.22°±0.2°,20.74°±0.2°,22.11°±0.2°,22.46°±0.2°,22.81°±0.2°,23.29° ±0.2°,23.89°±0.2°,25.02°±0.2°,26.44°±0.2°,26.90°±0.2°,28.14°±0.2°, 28.85°±0.2°,30.19°±0.2°,31.61°±0.2°,32.59°±0.2°,33.37°±0.2°,34.24°± 0.2 °, 35.02 ° ± 0.2 °, 35.87 ° ± 0.2 ° and 38.38 ° ± 0.2 ° of diffraction maximum.

In some embodiments, crystal formation of the present invention, wherein, the differential scanning calorimetric curve of crystal formation D is included 90.6 DEG C ± 4 DEG C of endothermic peak.

In some embodiments, crystal formation of the present invention, wherein, the differential scanning calorimetric curve of crystal formation D is included 90.6 DEG C ± 5 DEG C of endothermic peak.

In some embodiments, crystal formation of the present invention, wherein, the X-ray powder diffraction pattern of the crystal formation D with Fig. 9 is substantially the same.

In some embodiments, crystal formation of the present invention, wherein, the differential scanning calorimetric curve of the crystal formation D with Figure 10 is substantially the same.

In some embodiments, crystal formation of the present invention, wherein, Raman spectrogram and Figure 11 realities of the crystal formation D It is identical in matter.

In some embodiments, crystal formation of the present invention, wherein, the Fourier transform-infrared spectrum of the crystal formation D Figure is substantially the same with Figure 12.

On the other hand, the present invention provides a kind of pharmaceutical composition, comprising crystal formation A of the present invention, crystal formation B, crystal formation D or Its combination and pharmaceutically acceptable auxiliary material.

In some embodiments, pharmaceutical composition of the present invention further includes additional therapeutic agent, wherein Antidiabetic medicine, antihyperglycemic medicine, anti-obesity medicine, anti-height of the additional therapeutic agent selected from non-SGLT-2 inhibitor Blood pressure medication, antiplatelet drug, Antiatherosclerosis medicine, fat-reducing medicament, anti-inflammation drugs or its combination.

In some embodiments, the antidiabetic medicine and antihyperglycemic of non-SGLT-2 inhibitor of the present invention Thing is separately selected from biguanides, sulfonylureas, glucosidase inhibitor, PPAR activator (peroxide Enzyme body proliferator activated receptor activator), α P2 inhibitor (adipocyte fatty acid binding-protein inhibitors), PPAR α/γ it is double Activator (the double activator of peroxisome proliferator-activated receptor alpha/γ), DPP IV (DPP-IV) inhibitor, lattice Row how class medicine, insulin, glucagon-like-peptide-1 inhibitor, PTP1B inhibitor (PTP 1B suppresses Agent), glycogen phosphorylase inhibitors, G-6-Pase inhibitor or its combination.

In some embodiments, selected from MTP inhibitor, (microsomal triglyceride is shifted fat-reducing medicament of the present invention Protein inhibitor), HMGCoA reductase inhibitors (HMG CoA reductase inhibitor), squalene synthetase suppression Preparation, shellfish butyric acid class blood lipid-lowering medicine, ACAT inhibitor (acetyl cholesterol acetyl transferase inhibitor), lipoxygenase suppress Agent, cholesterol absorption inhibitor, ileum sodium ion/bile acid cotransporter inhibitor, ldl receptor activity be adjusted up Thing (LDL Receptor Activity is adjusted up thing), nicotinic acid class blood lipid-lowering medicine, bile acid chelate or its combination.

In other embodiments, fat-reducing medicament of the present invention selected from Pravastatin, Simvastatin, Ah cutting down he Spit of fland, Fluvastatin, cerivastatin, Etard cut down statin, rosuvastatin or its combination.

On the other hand, the present invention relates to as described in the present invention crystal-form compound or its dynamic isomer or its combination are in system Purposes in standby medicine, wherein the medicine is used to suppress SGLT-2.

On the other hand, the present invention relates to as described in the present invention crystal-form compound or its dynamic isomer or its combination are in system Purposes in standby medicine, wherein the medicine is used for the level of increasing high density lipoprotein.

The present invention also provide it is a kind of using crystal-form compound of the present invention or its dynamic isomer or its combination or its Pharmaceutical composition, the purposes in medicine is prepared, wherein the medicine is used to preventing or treating following disease, mitigates following disease Symptom delays following advancing of disease or outbreak, wherein described disease is diabetes, diabetic retinopathy, glycosuria Aliphatic acid or glycerine level in characteristic of disease neuropathy, nephrosis, insulin resistance, hyperglycaemia, hyperinsulinemia, blood Rising, hyperlipidemia, obesity, hypertriglyceridemia, X syndromes, diabetic complication, atherosclerotic or height Blood pressure.

Content noted earlier only outlines certain aspects of the invention, but in terms of being not limited to these aspects and others Content will below make more specific complete description.

Detailed description of the invention

The present invention is on the basis of lot of experiments, there is provided formula (I) compound (1R, 2S, 3S, 4R, 5S) -5- [the chloro- 3- of 4- [(4- ethoxyphenyls) methyl] phenyl] -1- [(1R) -1- ethoxys] -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- triols And its three kinds of crystal formations of alcoholate (II), the preparation method of the crystal formation, the drug regimen comprising the crystal formation or its combination Thing and the crystal formation and its pharmaceutical composition are in application pharmaceutically.Specifically, all similar replacements and Change apparent to those skilled in the art, they are considered as being included in the invention.In the present invention, institute The moisture of certain content may be included in crystal formation A, B or D for stating, as long as the above-mentioned crystal formation containing a certain amount of moisture has the present invention Any feature of described crystal formation A, B or D, is considered as within the scope of the present invention.

Read it is described in detail below after, those of ordinary skill in the art can be more easily understood the feature of the disclosure and excellent Point.It should be understood that in understanding reason, above and the following present invention some features individually described in the context of embodiment Also can be combined to form single embodiment.Conversely, for succinct reason, in the sheet described in the context of single embodiment Invention different characteristic also may be combined to form their sub-portfolio.

Definition and general terms

Unless otherwise stated, the term used by the present invention in the specification and in the claims has following definitions.

Certain embodiments of the present invention are will now be described in more detail, the example is by the structural formula and chemical formula explanation enclosed.This Invention intention covers all of replacement, modification and equivalent technical solutions, and they are included in such as the present invention of claim definition In the range of.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method described herein and material Trample the present invention.The present invention is not limited to method described herein and material.The one of the document, patent and similar material for being combined Or many it is different from the application or conflicting in the case of it is (including but not limited to defined term, term application, described Technology, etc.), be defined by the application.

It will further be appreciated that some features of the present invention, are clearly visible, carry out in multiple independent embodiments Description, but it is also possible to provide in combination in single embodiment.Conversely, the various features of the present invention, for brevity, It is described in single embodiment, but it is also possible to individually or with arbitrarily suitable sub-portfolio provide.

Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood that identical implication.All patents according to the present invention and public publication are integrally incorporated by reference this It is bright.

Unless otherwise indicated, following definition should be obtained using used herein.For purposes of the present invention, chemical element with Periodic table of elements CAS versions, and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can join Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999 With " March's Advanced Organic Chemistry " by Michael B.Smith andJerry March, JohnWiley&Sons,NewYork:Description in 2007, entire contents are incorporated herein by.

Term " study subject " used in the present invention refers to animal.Typically described animal is mammal.It is tested right As for example also referring to primate (such as the mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, little Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described to receive Examination pair as if people.

Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some enforcements In scheme, " patient " refers to people.

Term " equivalent " number used in the present invention or its abbreviation " eq ", are according to the equivalent relation of chemical reaction, with every In step on the basis of base stock used (1 equivalent), the equivalent amount of required other raw material.

Term "comprising" used in the present invention is open language, i.e., including the content specified by the present invention, but not Exclude otherwise content.

Crystal formation is believed that is characterized by the graph data of chart " description " in the present invention.These data include, such as powder X-ray X ray diffraction collection of illustrative plates, Raman spectrum, Fourier transform-infrared spectrum, DSC curve and solid state NMR spectroscopy.Technical staff will manage Solution, the figure of this kind of data represents can little change (such as peak relative intensity and peak position), and reason is that such as instrument rings The factor changed with sample concentration and purity should be changed, this is known for technical staff.Even so, technical staff can Graph data and the graph data to the generation of unknown crystal formation relatively in this texts and pictures, and can confirm whether two block graphics data characterize Identical crystal formation.

" XRPD " refers to X-ray powder diffraction.

Term " amorphous " used in the present invention or " amorphous form " be intended to mean that discussed material, component or Product, the crystal shape or crystalline texture of lacking in individuality property are generally not crystal or institute when for example being determined by XRPD The material of discussion, component or product, such as be not birefringent, or x-ray powder when being watched using polarization microscope Diffraction pattern does not have spike.In certain embodiments, the sample of the amorphous form comprising material can be substantially free of other nothings Amorphous form and/or crystal form.

Term " polymorphous " used in the present invention or " polymorphism " are defined as identical chemical molecular There is the possibility of at least two different crystalline arrangements.

Term " polymorphic " used in the present invention, " polymorph (polymorphs) ", " crystal version (crystalmodification) ", " crystal formation (crystal form) ", " crystallization version (crystalline Modification) ", " polymorphic forms " and " crystal form (crystalline form) " are understood to be synonymous, The solid crystalline form of compound or compound is referred in the present invention, includes, but not limited to one pack system or multicomponent crystal, And/or polymorph, solvate, hydrate, inclusion compound, eutectic, salt, the solvate of salt, the hydrate of salt of compound.

Can be with technology for detection well-known to those skilled in the art, identification, classification and qualitative polymorph, these technology examples Such as, but not limited to,：Differential scanning calorimetry (DSC), thermogravimetry (TGA), x-ray powder diffraction (XRPD), monocrystalline X are penetrated Line diffraction approach, Vibrational Spectrometry, Solution calorimetry, solid state nmr (SSNMR), Fourier transform-infrared spectrum (FT- IRspectrum) method, Raman spectrum (Ramanspectrum) method, hot microscope carrier optical microscopy, scanning electron microscopy (SEM), electronics Crystallography and quantitative analysis, grain size analysis (PSA), surface region analysis, solubility and dissolution rate.Can be by crystal formation (Polymorphism) depict specific compound as and crystallized while maintaining identical chemical structural formula with different crystal version Ability.The polymorph of given material is chemistry equivalent, and it contains in the same manner the same atoms of bonding mutually, but it Crystal version it is different, this can affect one or more physical property, such as dissolution rate (dissolution Rate), fusing point, bulk density (bulk density), stability, flowing property etc..The figure of this kind of data is represented can be sent out The little change (such as peak relative intensity and peak position) of life, reason is such as instrument response change and sample concentration and purity change Factor, this is well known to the skilled person.Even so, those skilled in the art can compare in this texts and pictures Graph data and the graph data that unknown crystal formation is produced, and can confirm whether two block graphics data characterize identical crystal formation.

Unless otherwise stated, when the data (for example, XRPD, FT-IR, the drawing that spectrum are referred in text or is graphically occurred Graceful and H NMR spectroscopy) when, term " peak " refer to the peak that the discernible non-background noise of one of ordinary skill in the art causes or other Specific characteristic.Term " effective peak " refers to the middle size (such as height) at other peaks at least spectrum or data or is at least The peak of 1.5,2 or 2.5 times of the middle size at other peaks in spectrum or data.

As in X-ray powder diffraction (XRPD) well known in the art, for any crystal formation specified, obtain X- and penetrate Equipment therefor, humidity, temperature, the orientation of powder crystal and other parameters may cause and spread out during line powder diffraction (XRPD) figure Penetrate some variability of the outward appearance, intensity and position of Tu Zhongfeng.For example, with reference to The United States Pharmacopeia#23, National Formulary#18,1843-1844 page, 1995.In present case, ± 0.2 ° 2 The variability of θ peak positions take into account these possible changes, the clearly identification without hindering shown crystal formation.The discriminating of crystal formation can By based on arbitrarily unique difference peak (in terms of ° 2 θ units) or its combination, typically more significant peak.Therefore, in some realities In applying scheme, the present invention crystalline compounds be characterized by some peak positions XRPD figure, with accompanying drawing of the present invention The XRPD of middle offer schemes substantially the same feature.According to this test instrument situation, diffraction maximum position there may be ± 0.2 ° Error margin.For example, with provided herein is Fig. 1,5 or 9 " basically identical " X-ray powder diffraction figure can with accompanying drawing in XRPD figures are identical, or more likely it can be slightly different.Such XRPD figures unnecessary can be shown in diffraction pattern presented herein Each peak, and/or can show due to the condition difference that is related to when data are obtained the outward appearance at the caused peak, intensity or The slight change of displacement.Those skilled in the art are schemed by comparing their XRPD, and can determine the sample of crystalline compounds is It is no with from crystal formation identical crystal formation disclosed herein or different crystal formations.Similarly, those skilled in the art can determine to Whether the diffraction maximum position (being represented with ° 2 θ) for deriving from XRPD figures for going out is in the position roughly the same with numerical value presented herein. In the context of the present invention, 2 θ values in X-ray powder diffraction figure are to spend (°) as unit.

Equally, as means of differential scanning calorimetry (DSC) well known in the art, the melting peak height of DSC curve depends on sample Preparation and many relevant factors such as tester condition, and peak position is to experimental detail relative insensitivity.Therefore, at some In embodiment, the present invention crystalline compounds be characterized by characteristic peak positions DSC figure, with accompanying drawing of the present invention The DSC of middle offer schemes substantially the same property.According to this test instrument situation, melt temperature has ± 3 DEG C, ± 4 DEG C Or ± 5 DEG C of error margin.

As Raman spectrum well known in the art, the location and shape of the absworption peak of Raman spectrum depend on sample molecule Interact with light and the frequency of scattered light occurs.Therefore, in some embodiments, the feature of crystalline compounds of the invention exists In the Raman spectrogram with characteristic peak positions and shape, with the substantial phase of Raman spectrogram with offer in accompanying drawing of the present invention Same property.According to this test instrument situation, absworption peak presence ± 1cm^-1Error margin.

As Fourier transform-infrared spectrum well known in the art, the location and shape of the absworption peak of infrared spectrum take Certainly in sample molecule covalent key motion energy level transition.Therefore, in some embodiments, of the invention crystalline compounds Be characterized by the Fourier transform-infrared spectrogram of characteristic peak positions and shape, with accompanying drawing of the present invention in provide Substantially the same property of Fourier transform-infrared spectrogram.According to《Chinese Pharmacopoeia》(2010 editions) annex IV C- infrared spectroscopies Photometry, and this test instrument situation, absworption peak is in 3000cm^-1± the 5cm of presence nearby^-1Error margin, 1000cm^-1± the 2cm of presence nearby^-1Error margin.

X-ray powder diffraction figure, DSC curve figure, Raman spectrogram and Fourier transform-infrared spectrogram " substantial phase Refer to together " in X-ray powder diffraction figure, DSC curve figure, Raman spectrogram and Fourier transform-infrared spectrogram at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% peak shows Show in figure.

Term " combination " refers to pure with respect to its dynamic isomer containing its dynamic isomer, the i.e. crystal formation in a kind of crystal formation Degree at least 60%, or at least 70%, or at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, Or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or At least 99.9%；Or refer to can contain in a kind of crystal formation another or various crystal formations, the i.e. crystal formation with respect to another or it is many The purity at least 60% of crystal formation, or at least 70%, or at least 80%, or at least 85%, or at least 90%, or at least 93% are planted, Or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or extremely Few 99.8%, or at least 99.9%；Or refer in the crystal formation containing other crystal formations, described other crystal formations crystal formation cumulative volume or Percentage in gross weight is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

" relative intensity " refers to that the intensity at the last the first peak in all diffraction maximums of X-ray powder diffraction figure (XRPD) is When 100%, the ratio of the intensity at other peaks and the intensity at the last the first peak.

Whenever disclose one have N values it is digital when, it is any with N ± 0.01, N ± 0.02, N ± 0.03, N ± 0.05, N ± 0.07, N ± 0.08, N ± 0.1, N ± 0.15, N ± 0.2, N ± 1, N ± 1.5, N ± 2, N ± 3, N ± 4, N ± 5, N ± 6, N ± 7, N ± 8, N ± 9, N ± 10, the numeral of value can be specifically disclosed, wherein " ± " refers to adding deduct.Whenever disclosing a numerical value A lower limit RL in scope, and upper limit RU, when, any numerical value within the scope of the disclosed can be by clearly It is open.

(1R, 2S, 3S, 4R, 5S) -5- [the chloro- 3- of 4- [(4- ethoxyphenyls) methyl] phenyl] -1- of the present invention The novel crystal forms of [(1R) -1- ethoxys] -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- triols and its alcoholate are crystal formation A, crystal formation B or crystal formation D, they exist with essentially pure crystal habit.

Term " essentially pure " refers to chemical purity and crystal form purity, and more particularly, a kind of crystal formation is substantially not Purity at least 60% containing another or various crystal formations, i.e. crystal formation, or at least 70%, or at least 80%, or at least 85%, or At least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least Contain other crystal formations, described other crystalline substances in 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or crystal formation Percentage of the type in the cumulative volume or gross weight of crystal formation is less than 30%, or less than 20%, or less than 10%, or less than 5%, or Less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

The purity of the crystal of the present invention can be by, for example, known method X-ray powder diffraction, heat analysis etc. To determine.The crystal of the present invention or the purity of mixed crystal need not be 100%, and can be not less than 70%, preferably not Less than 80%, more preferably not less than 90%, more preferably not less than 95%, and most preferably not less than 98%.It is preferred that Should in the range of purity ensureing quality.

Term used herein " about " and " about " typically refer within ± the 10% of specified value or scope, suitably Ground within ± 5%, particularly within ± 1%.Or, for those of ordinary skills, term " about " and " big About " represent in the range of the acceptable standard error of mean value.

Term " solution " used in the present invention refers to one containing at least one solvent and at least one compound Mixture, the compound dissolves at least in part in the solvent.

Term " solvate " used in the present invention is meant on surface, in lattice or on the surface and in lattice In there is solvent, the solvent is, for example, that water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl are sub- Sulfone, 1,4- dioxane, ethanol, ethyl acetate, butanol, the tert-butyl alcohol, DMAC N,N' dimethyl acetamide, N,N-dimethylformamide, Formamide, formic acid, heptane, hexane, isopropanol, methyl alcohol, methyl ethyl ketone, l- N-methyl-2-2-pyrrolidone Ns, nitromethane, poly- second Glycol, propyl alcohol, 2- acetone, pyridine, tetrahydrofuran, toluene, dimethylbenzene, their mixture etc..One tool of solvate Style is hydrate, wherein solvent on the surface, in lattice or on the surface and in lattice is water.In material On surface, in lattice or on the surface and in lattice, hydrate can with or without except other of water it is molten Agent.

Unless otherwise stated, it is w/w (w/w) percentage through the percentage described in this specification.

Term " pharmaceutical composition " represent one or more compound described herein or its physiologically/pharmaceutically can be with The salt or pro-drug of acceptance and the mixture of other chemical constituents, other components for example physiologically/pharmaceutically can receive Carrier, excipient, diluent, assistant agent, medium, and anti-diabetic reagent, antihyperglycemic reagent, anti-obesity reagent, The additional therapeutic agents such as anti-hypertension reagent, antiplatelet reagent, antiatherosclerotic agents or lipid-lowering agents.Drug regimen The purpose of thing is to promote the administration of compound on organism body.

Term " X syndromes ", the also referred to as illness of metabolic syndrome, disease, its illness is specified in Johannsson et Al., J.Clin.Endocrinol.Metab., in 1997,82,727-734.

The as used in the present invention any disease of term " treatment " or illness, wherein some embodiment middle fingers improve disease Disease or illness (slowing down or prevent or mitigate the development of disease or its at least one clinical symptoms).In other embodiments In, " treatment " refers to slow and/or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another In some embodiments, " treatment " refers to that (for example stablizing perceptible symptom) physiologically from body (for example stablizes body Parameter) or above-mentioned two aspects regulation disease or illness.In other embodiments, " treatment " refer to prevention or postpone disease or disease Outbreak, generation or the deterioration of disease.

Pharmaceutical composition comprising crystal-form compound of the present invention or its combination

As described in the invention, pharmaceutically acceptable composition of the invention is further comprising pharmaceutically acceptable auxiliary Material, these auxiliary materials, such as the present invention is applied, including any solvent, solid excipient, diluent, adhesive, disintegration Agent, or other liquid excipients, dispersant, flavouring or suspending agent, surfactant, isotonic agent, thickener, emulsifying agent is prevented Rotten agent, solid binder or lubricant, etc. are suitable for distinctive target formulation.As described by documents below：In Remington:The Science and Practice ofPharmacy,21st edition,2005,ed.D.B.Troy, Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, it is comprehensive Close the content of document herein, show different auxiliary materials can be applicable to the preparation of pharmaceutically acceptable composition and they known to Preparation method.Except any conventional auxiliary material scope incompatible with the compound of the present invention, such as produced is any bad Biological effect or the interaction that produces in harmful manner with any other component of pharmaceutically acceptable composition, it Purposes be also the scope that considered of the present invention.

Can include, but is not limited to as the material of pharmaceutically acceptable auxiliary material, ion-exchanger；Aluminium；Aluminum stearate；Ovum Phosphatide；Haemocyanin, such as human albumin；Buffer substance, such as phosphate；Glycine；Sorbic acid；Potassium sorbate；Saturation plant The partial glyceride mixtures of aliphatic acid；Water；Salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, chlorine Change sodium, zinc salt；Colloidal silicon；Magnesium trisilicate；Polyvinylpyrrolidone；Polyacrylate；Wax；Polyethylene-polyoxypropylene-blocking gathers It is fit；Lanolin；Sugar, such as lactose, dextrose and saccharose；Starch such as cornstarch and potato starch；Cellulose is derivative with its Thing such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate；Gum powder；Malt；Gelatin；Talcum powder；Auxiliary material such as cocoa Beans fat and suppository wax；Oil such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soya-bean oil；Glycols chemical combination Thing, such as propane diols and polyethylene glycol；Esters such as ethyl oleate and ethyl laurate；Agar；Buffer such as magnesium hydroxide and Aluminium hydroxide；Alginic acid；Pyrogen-free water；Isotonic salt；Lin Ge (family name) solution；Ethanol；Phosphate buffer solution；It is nontoxic with other Suitable lubricant such as Sodium Laurylsulfate and magnesium stearate；Colouring agent；Releasing agent；Coating agents；Sweetener；Flavor enhancement；Spices； Preservative and antioxidant.

The crystal-form compound of the present invention or its combination or its pharmaceutical composition with only pharmaceutical agents or can combine one Being administered, wherein drug combination causes acceptable bad reaction for individual or multiple other additional treatment (pharmacy) agent, this for The treatment of diabetes, diabetic complication and other relevant diseases has special meaning, and these described diseases include, but It is not limited to, type i diabetes, type ii diabetes, diabetic retinopathy, diabetic neuropathy, nephrosis, pancreas Rising, hyperlipidemia, obesity, the height of aliphatic acid or glycerine level in island element resistance, hyperglycaemia, hyperinsulinemia, blood Triglyceride, X syndromes, diabetic complication, atherosclerotic, hypertension etc..It is used in the present invention " additional to control Treat agent " including antidiabetic medicine, antihyperglycemic medicine, anti-obesity medicine, the anti-high blood of known non-SGLT-2 inhibitor Pressing thing, antiplatelet drug, Antiatherosclerosis medicine, fat-reducing medicament or antiphlogistic, or its combination.

Wherein, the anti-diabetic reagent of non-SGLT-2 inhibitor of the present invention includes, but is not limited to biguanide drug Thing (such as insoral (phenformin), melbine (metformin)), sulfonylureas, (such as acetodexamide (acetohexamide), chlorpropamide (chlorpropamide), glibenclamide (glibenclamide, glibenclamide), lattice row Pyrazine (glipizide, Glipizide), gliclazide (gliclazide, Diamicron), Glimepiride (glimepiride), Glipentide (glipentide), gliquidone (gliquidone), tolazamide (tolazamide) and orinase (tolbutamide), meglitinide (meglitinide)), glinides (for example Repaglinide (repaglinide) and Nateglinide (nateglinide)), alpha-glucosaccharase hydrolase inhibitor (such as acarbose (acarbose)), α-grape Glycosidase inhibitor (such as esterlysis element, Camiglibose (camiglibose), emiglitate (emiglitate), Miglitol (miglitol), voglibose (voglibose), pradimicin (pradimicin) and husky glass rhzomorph (salbostatin)), PPAR activators (for example Ba Gelie ketone (balaglitazone), Ciglitazone (ciglitazone), Darglitazone (darglitazone), Englitazone (englitazone), Yi Shalie ketone (isaglitazone), Pioglitazone (pioglitazone), Rosiglitazone (rosiglitazone) and troglitazone (troglitazone)), PPAR α/γ bidifly Agent (such as CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB- living 219994), DPP-IV inhibitor (Xi Gelieting (sitagliptin), vildagliptin (vidagliptin), Egelieting (alogliptin), Li Gelieting (linagliptin) and BMS-477118 (saxagliptin)), glucagon-like-peptide-1 (GLP-1) activator (first -3 (exendin-3) of element of second and second -4 (exendin-4) of first element), protein tyrosine phosphatase -1B (PTP1B) inhibitor (curvature Kui Ming, Hai Tisuo extract and by Zhang, S. et al., modern medicines find, 12 (9/10), Compound disclosed in 373-381 (2007)), insulin, insulin intend like thing, glycogen phosphorglase inhibitor, VPAC2 acceptors Activator, activators of glucokinase, glycogen phosphorylase inhibitors or Robison ester enzyme inhibitor；α P2 inhibitor, second Acyl group-CoA carboxylases -2 (ACC-2) inhibitor, the inhibitor of phosphodiesterase (PDE) -10, diacylglycerol acyltransferase (DGAT) 1 or 2 inhibitor, glucose transporter 4 (GLUT4) conditioning agent and GFAT (GFAT) inhibitor.

Wherein, antihyperglycemic reagent of the present invention includes, but is not limited to biguanides (such as insoral (phenformin), melbine (metformin)), sulfonylureas (such as acetodexamide (acetohexamide), Chlorpropamide (chlorpropamide), glibenclamide (glibenclamide, glibenclamide), Glipizide (glipizide, pyrrole Sulphur ring urea), gliclazide (gliclazide, Diamicron), Glimepiride (glimepiride), Glipentide (glipentide), gliquidone (gliquidone), tolazamide (tolazamide) and orinase (tolbutamide), meglitinide (meglitinide)), glinides (for example Repaglinide (repaglinide) and Nateglinide (nateglinide)), alpha-glucosaccharase hydrolase inhibitor (such as acarbose (acarbose)), α-grape Glycosidase inhibitor (such as esterlysis element, Camiglibose (camiglibose), emiglitate (emiglitate), Miglitol (miglitol), voglibose (voglibose), pradimicin (pradimicin) and husky glass rhzomorph (salbostatin)), PPAR activators (for example Ba Gelie ketone (balaglitazone), Ciglitazone (ciglitazone), Darglitazone (darglitazone), Englitazone (englitazone), Yi Shalie ketone (isaglitazone), Pioglitazone (pioglitazone), Rosiglitazone (rosiglitazone) and troglitazone (troglitazone)), PPAR α/γ bidifly Agent (such as CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB- living 219994), DPP IV (DPP-IV) (such as Xi Gelieting (sitagliptin), vildagliptin (vidagliptin), Egelieting (alogliptin) and BMS-477118 (saxagliptin)), glucagon-like-peptide-1 (GLP-1) activator (second First first -4 (exendin-4) of element of -3 (exendin-3) of element and second), protein tyrosine phosphatase -1B (PTP1B) inhibitor it is (bent Du Kuiming, Hai Tisuo extract and by Zhang, S. et al., modern medicines find, 12 (9/10), 373-381 (2007) is disclosed Compound), insulin, insulin intend like thing, glycogen phosphorglase inhibitor, VPAC2 receptor stimulating agents, Glucokinase Activation Agent, glycogen phosphorylase inhibitors or Robison ester enzyme inhibitor；α P2 inhibitor, acetyl-CoA carboxylase -2 (ACC-2 inhibitor), the inhibitor of phosphodiesterase (PDE) -10, the inhibitor of diacylglycerol acyltransferase (DGAT) 1 or 2, Glucose transporter 4 (GLUT4) conditioning agent and GFAT (GFAT) inhibitor.

Wherein, lipid-lowering agents of the present invention include, but is not limited to MTP inhibitor, HMGCoA reductase inhibitors (HMG CoA reductase inhibitor), inhibitor for squalene synthetic enzyme, fibrates blood lipid-lowering medicine (shellfish butyric acid class Blood lipid-lowering medicine), ACAT inhibitor (acetyl cholesterol acetyl transferase inhibitor), lipoxygenase inhibitor, cholesterol absorption Inhibitor, ileum sodium ion/bile acid cotransporter inhibitor, be adjusted up thing, the bile acid of ldl receptor activity are chelated Thing or nicotinic acid class blood lipid-lowering medicine.Some of them embodiment is, described lipid-lowering agents selected from Pravastatin, Simvastatin, Atorvastatin, Fluvastatin, cerivastatin, Etard cut down statin or rosuvastatin.Wherein, described anti-obesity reagent choosing From CB-1 antagonists (such as Rimonabant (rimonabant), Tai Lunnaban (taranabant), Surinabant (surinabant), Alternan class (otenabant), SLV319 and AVE1625), intestines-selectivity MTP inhibitor (such as Lip river He sends (dirlotapide), rice his moral (mitratapide) bent and implitapide (implitapide)), CCKa activators, 5HT2c activators (such as lorcaserin (lorcaserin)), MCR4 activators, lipase inhibitor (such as ATL-962 (Cetilistat))、PYY_3-36, OPIOIDS antagonist (such as naltrexone (naltrexone)), oleoyl-oestrone, Buddhist nun difficult to understand Peptide (obinepitide), pramlintide (pramlintide), Te Suofenxin (tesofensine), leptine, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] (liraglutide), bromocriptine, orlistat (orlistat), Exenatide (exenatide), AOD-9604 and west Cloth Qu Ming (sibutramide).

Wherein, appropriate antiphlogistic of the present invention includes genital tract/urethral infection prevention and treatment medicine, such as acid Really climing (Vaccinium macrocarpon) and european cranberry derivative, for example european cranberry juice, european cranberry extraction liquid or european cranberry Flavonols.Additionally, other appropriate antiphlogistics also include, but is not limited to aspirin, non-steroidal anti-inflammatory drug, sugared cortex Steroids, SASP and epoxidase II select inhibitor etc..

The composition of the present invention can be administered orally, and drug administration by injection, local is administered, buccal administration, or by implantable Medicine box is administered.Term used herein " drug administration by injection " include it is subcutaneous, vein, intramuscular, IA, synovial membrane (chamber) Interior, it is intrasternal, in film, intraocular, in liver, in focus, and injection or the infusion techniques of encephalic.Preferred combination Thing is oral administration, to Intraperitoneal medication or intravenous injection.The present invention composition sterile injection system can be water or Oleaginous suspension.These suspension can according to known technology using suitable dispersant, wetting agent and suspending agent by matching somebody with somebody Side's manufacture.

The pharmaceutically acceptable composition of the present invention can be administered orally with any acceptable peroral dosage form, its In include, but is not limited to, capsule, tablet, water suspension or solution.Orally use with regard to tablet, carrier generally comprises breast Sugar and cornstarch.Lubricant, such as magnesium stearate, are all typically added.For capsule oral administration, suitable diluent bag Include lactose and dry cornstarch.When it is water suspension to be administered orally, its active ingredient is made up of emulsifying agent and suspending agent. If expecting these formulations, some sweeteners, flavor enhancement or colouring agent can also be added.

The liquid dosage form of oral administration is included, but is not limited to, pharmaceutically acceptable emulsion, microemulsion, solution, is suspended Liquid, syrup and elixir.In addition to the active compound, liquid dosage form can include known general inert diluent, for example, water Or other solvents, solubilizer and emulsifying agent, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, phenmethylol, Ergol, Propane diols, 1,3-BDO, dimethylformamide, grease (particularly cottonseed, peanut, corn, microorganism, olive, castor-oil plant and Sesame oil), glycerine, Tetrahydrofurfuryl Alcohol, polyethylene glycol, sorbitan alcohol fatty acid ester, and their mixture.Except lazy Property diluent outside, Orally administered composition can also include assistant agent such as wetting agent, emulsifying agent or suspending agent, sweetener, flavor enhancement And aromatic.

Injection, such as aseptic parenteral solution or oleaginous suspension can according to known technology using suitable dispersant, Wetting agent and suspending agent are prepared by pharmaceutical formulation.Aseptic injection can be nontoxic Jing parenterally acceptable diluents Or aseptic parenteral solution, suspension or emulsion made by solvent, for example, 1,3-BDO solution.Acceptable excipient and solvent Can be water, Lin Ge (family name) solution, U.S.P. and isotonic sodium chlorrde solution.In addition, aseptic nonvolatile oil is by convention As solvent or suspension media.With this end in view any gentle nonvolatile oil can include that the list or two Portugal's bases of synthesis is sweet Oily diester.In addition, aliphatic acid such as oleic acid can apply to the preparation of injection, as natural pharmaceutically acceptable grease, Such as olive oil or castor oil, particularly their polyoxyethylene deriv.These oil solutions or suspension can include long-chain alcohol Diluent or dispersant, such as carboxymethylcellulose calcium or similar dispersing agents, are generally used for the pharmaceutical preparation of pharmaceutically acceptable formulation Including emulsion and suspension.Other conventional surfactants, such as Tweens, spans and other emulsifying agents or biological effect The hardening agent of rate, is generally used for pharmaceutically acceptable solid, liquid, or other formulations, it is possible to be applied to drug target system The preparation of agent.

The sterilization method of injection is including but not limited to filtered as defended filter by bacterium, or with sterile solid combination The form of thing mixes bactericidal agent, and disinfectant or other sterile injectable mediums can be dissolved in or be scattered in using front bactericidal agent In.In order to extend the effect of the compound of the present invention, it usually needs slow down compound by hypodermic injection or intramuscular injection Absorb.So can realize solving the problems, such as crystal or AMAT poorly water-soluble using liquid suspension.The suction of compound Yield depends on its dissolution rate, successively depending on grain size and crystal shape.Furthermore it is possible to pass through compound assign in oils Dissolve or disperse the delay to complete compound injection administration to absorb in shape agent.

Injection drug release forms in vivo are such as many lactic acid-polyglycolic acids by biodegradable polymer Lactide forms what the microcapsule matrix of compound was completed.The controlled release ratio of compound depends on the ratio that compound forms polymer With the property of particular polymer.Other biodegradable polymers include poly- (positive esters) and poly- (acid anhydrides).Injection stores shape Formula can also be prepared by the embedded liposome compatible with bodily tissue of compound or microemulsion.

The solid dosage forms of oral administration includes capsule, tablet, pill, pulvis and granula.In these formulations, active ingredient Thing mixes with least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or calcium phosphate or filler or a) Filler such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) adhesive such as carboxymethylcellulose calcium, alginates are bright Glue, polyvinyl pyrrolidone, sucrose and Arabic gum, c) NMF such as glycerine, d) disintegrant such as agar, calcium carbonate, potato starch Or tapioca, alginic acid, some silicate and sodium carbonate, e) block agent solution such as paraffin, f) sorbefacient such as quaternary ammonium Compound, g) wetting agent such as hexadecanol and glycerin monostearate, h) absorbent such as white bole and bentonite, i) lubricant such as talcum Powder, calcium stearate, magnesium stearate, solid polyethylene glycol, Sodium Laurylsulfate, and their mixture.As for capsule, tablet and ball Agent, these formulations can include buffer.

The solid composite of similar type can be that filler riddles soft or hard capsule, and the auxiliary material for being used has breast Sugared and high molecular polyethylene glycol etc..Solid dosage forms photo agent, lozenge, capsule, pill and granula can pass through coating, shell adding As known coating method is prepared on enteric coating and other drugs preparation.They can optionally include opacifier, or Preferably, in certain part of enteron aisle, arbitrarily, the sole active agent in composition is discharged in the method for postponing.As being implanted into Composition can be comprising multimeric species and wax.

Reactive compound can form microcapsule formulations together with one or more excipient described in the invention.Solid Formulation photo agent, lozenge, capsule, pill and granula can be by coating or shell addings, such as enteric coating, controlled release coat and other public affairs The drug formulation process known.In these solid dosage forms, reactive compound can mix with least one inert diluent, such as sugarcane Sugar, lactose or starch.Such formulation can also include additive besides inert diluents as general application, such as Tableting lubricant and other compression aids such as magnesium stearate and microcrystalline cellulose.As for capsule, tablet and pill, these formulations can With comprising buffer.They can optionally include sedative, or preferably, certain in enteron aisle is a part of, with any delay Sole active agent in method release composition.Applicable implant compositions can be included, but is not limited to, polymer and Wax.

The crystal-form compound or its combination of the present invention preferably is prepared into dosage unit form to mitigate administration by pharmaceutical formulation The uniformity of amount and dosage.Term " dosage " unit type " obtains the physical dispersion of medicine needed for appropriate treatment referred to herein as patient Unit.It should be appreciated, however, that the daily total usage of the compound or composition of the present invention will be by the doctor in charge according to reliable doctor Learn scope to judge to determine.Specific effective dose level will be depending on many for any one special patient or organism Factor includes the seriousness of the illness and illness being treated, the activity of particular compound, concrete composition used, the year of patient The discharge rate of age, body weight, health status, sex and eating habit, administration time, method of administration and particular compound used, The duration for the treatment of, medicinal application is combined in drug combination or with specific compound, and some other pharmaceutical field Known factor.

The purposes of crystal-form compound of the present invention and pharmaceutical composition

The amount of crystal-form compound effectively can detectably suppress in the crystal-form compound or pharmaceutical composition of the present invention The activity of sodium dependent glucose transport protein (sodium-dependent glucose transporters, SGLTs), especially It is the activity of SGLT-2.SGLT-2 is responsible for D-Glucose of the reabsorption in the GF of kidney, suppresses glucose Reabsorption in the blood vessel advantageously reduces blood sugar concentration.Therefore, compound of the invention will be applied to diabetes and related disease The prevention of disease, the symptom for treating or improving these diseases.

The crystal-form compound of the present invention will be applied to, but be not limited to, using the crystal-form compound or medicine group of the present invention Diabetes mellitus and relevant disease are prevented patient's administration or treated to the effective dose of compound, or mitigates diabetes and related disease Disease symptoms, or delay development or outbreak or the level for increasing HDL of diabetes and relevant disease.So Disease include, but is not limited to diabetes, especially type ii diabetes, and insulin resistance, hyperglycaemia, hyperinsulinemia The rising of aliphatic acid or glycerine level, hyperlipidemia, such as hypertriglyceridemia in disease, blood, obesity, X syndromes, glycosuria Sick complication, such as diabetic retinopathy, diabetic neuropathy, nephrosis, atherosclerotic, high blood Pressure.

Additionally, crystal-form compound of the present invention or pharmaceutical composition are further adapted for preventing and treating the damage of diabetic keratopathy later stage, example As ephrosis, retinopathy, neuropathy and miocardial infarction, peripheral arterial closure disease, thrombosis, artery sclerosis, inflammation, Immunological diseases, autoimmune disease such as AIDS, asthma, osteoporosis, cancer, psoriasis, Alzheimer's disease, spirit Split disease and infectious diseases.

The crystal-form compound of the present invention applies also for veterinary treatment pet, introduces in addition to beneficial to human treatment The animal of kind and the animal on farm, including mammal, rodent etc..The example of other animal include horse, Dog and cat.Here, the compound of the present invention includes its pharmaceutically acceptable derivates.

The present invention crystal-form compound or pharmaceutically acceptable pharmaceutical composition " effective dose ", " effectively treatment amount " or " effective dose " refers to process or mitigates the effective dose that one or more present invention are previously mentioned the severity of illness.The crystalline substance of the present invention Type compound or pharmaceutically acceptable pharmaceutical composition are effective in comparatively wide dosage range.For example, take daily Dosage about in the range of 0.1mg-1000mg/ people, be divided into and once or being for several times administered.The method according to the invention, crystal formation chemical combination Thing and pharmaceutical composition can be any dosage and any method of administration being efficiently used for processing or mitigating the serious of disease Degree.Required accurate amount changes the situation according to patient, and this depends on race, age, the general condition of patient, sense The order of severity of dye, special factor, administering mode etc..The present invention compound or pharmaceutical composition can and one or more Other therapeutic agents administering drug combinations, as discussed in the present invention.

Description of the drawings

Fig. 1 be the present invention prepare (1R, 2S, 3S, 4R, 5S) -5- [the chloro- 3- of 4- [(4- ethoxyphenyls) methyl] phenyl] - The X-ray powder diffraction of 1- [(1R) -1- ethoxys] -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- triol crystal formation A (XRPD) collection of illustrative plates.

Fig. 2 be the present invention prepare (1R, 2S, 3S, 4R, 5S) -5- [the chloro- 3- of 4- [(4- ethoxyphenyls) methyl] phenyl] - The means of differential scanning calorimetry (DSC) of 1- [(1R) -1- ethoxys] -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- triol crystal formation A Curve.

Fig. 3 be the present invention prepare (1R, 2S, 3S, 4R, 5S) -5- [the chloro- 3- of 4- [(4- ethoxyphenyls) methyl] phenyl] - Raman spectrum (the Raman of 1- [(1R) -1- ethoxys] -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- triol crystal formation A Spectrum) figure.

Fig. 4 be the present invention prepare (1R, 2S, 3S, 4R, 5S) -5- [the chloro- 3- of 4- [(4- ethoxyphenyls) methyl] phenyl] - Fourier transform-the infrared light of 1- [(1R) -1- ethoxys] -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- triol crystal formation A Spectrum (FT-IR spectrum) figure.

Fig. 5 be the present invention prepare (1R, 2S, 3S, 4R, 5S) -5- [the chloro- 3- of 4- [(4- ethoxyphenyls) methyl] phenyl] - The X-ray powder diffraction of 1- [(1R) -1- ethoxys] -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- triol crystal formation B (XRPD) collection of illustrative plates.

Fig. 6 be the present invention prepare (1R, 2S, 3S, 4R, 5S) -5- [the chloro- 3- of 4- [(4- ethoxyphenyls) methyl] phenyl] - The means of differential scanning calorimetry (DSC) of 1- [(1R) -1- ethoxys] -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- triol crystal formation B Curve.

Fig. 7 be the present invention prepare (1R, 2S, 3S, 4R, 5S) -5- [the chloro- 3- of 4- [(4- ethoxyphenyls) methyl] phenyl] - Raman spectrum (the Raman of the crystal formation B of 1- [(1R) -1- ethoxys] -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- triols Spectrum) figure.

Fig. 8 be the present invention prepare (1R, 2S, 3S, 4R, 5S) -5- [the chloro- 3- of 4- [(4- ethoxyphenyls) methyl] phenyl] - The Fourier transform of the crystal formation B of 1- [(1R) -1- ethoxys] -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- triols-infrared Spectrum (FT-IR spectrum) figure.

Fig. 9 be the present invention prepare (1R, 2S, 3S, 4R, 5S) -5- [the chloro- 3- of 4- [(4- ethoxyphenyls) methyl] phenyl] - The X-ray of the crystal formation D of the alcoholate of 1- [(1R) -1- ethoxys] -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- triols Powder diffraction (XRPD) collection of illustrative plates.

Figure 10 be the present invention prepare (1R, 2S, 3S, 4R, 5S) -5- [the chloro- 3- of 4- [(4- ethoxyphenyls) methyl] phenyl] - The differential of the crystal formation D of the alcoholate of 1- [(1R) -1- ethoxys] -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- triols is swept Retouch calorimetric (DSC) curve.

Figure 11 be the present invention prepare (1R, 2S, 3S, 4R, 5S) -5- [the chloro- 3- of 4- [(4- ethoxyphenyls) methyl] phenyl] - The Raman light of the crystal formation D of the alcoholate of 1- [(1R) -1- ethoxys] -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- triols Spectrum (Raman spectrum) figure.

Figure 12 be the present invention prepare (1R, 2S, 3S, 4R, 5S) -5- [the chloro- 3- of 4- [(4- ethoxyphenyls) methyl] phenyl] - The Fourier of the crystal formation D of the alcoholate of 1- [(1R) -1- ethoxys] -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- triols Conversion-infrared spectrum (FT-IR spectrum) figure.

It is typically prepared and authentication method

The present invention is further illustrated below by the mode of embodiment, described enforcement is not therefore limited the present invention to Among example scope.

Those skilled in the art can use for reference present disclosure, be suitably modified experiment parameter realization.Specifically, All similar replacements and change are apparent to those skilled in the art, and they are considered as being included in the present invention Scope in.The method of the present invention is described by preferred embodiment, and related personnel substantially can be without departing from this Method described herein is modified in bright content, spirit and scope or suitably change is realized and using this with combining Bright technology.

It is typically prepared method

The structure of compound be by nuclear magnetic resonance (¹H-NMR、¹³C-NMR) determining.¹H-NMR、¹³C-NMR chemical potentials Move (δ) to be given with the unit of hundred a ten thousandths (ppm).¹H-NMR、¹³The measure of C-NMR is to use Bruker Ultrashield- 400 nuclear magnetic resonance spectrometers and the nuclear magnetic resonance spectrometers of Bruker Avance III HD 600, measure solvent is deuterochloroform (CDCl₃), deuterated methanol (CD₃) or deuterated DMSO-d OD₆.With TMS (0ppm) or chloroform (7.25ppm) as reference standard. When there is multiplet, by using following abbreviation：S (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet Ofdoublets, double doublet), dt (doublet oftriplets, double triplets), coupling constant J, unit is with hertz (Hz) Represent.

The measure of MS Agilen-6120Quadrupole LC/MS mass spectrographs.

Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 silica gel plates.

It is carrier that column chromatography generally uses the mesh~400 mesh silica gel of Qingdao Haiyang chemical industry 300.

The initiation material of the present invention is known, and can be commercially commercially available, and is bought from Shanghai Shao Yuan companies (ShanghaiAccela Company), An Naiji companies (Energy Company), lark prestige company (J＆K), Tianjin Ah method The companies such as Ai Sha companies (Alfa Company), can either adopt or synthesize according to methods known in the art.

Without specified otherwise in embodiment, reaction is carried out under nitrogen atmosphere；

Blanket of nitrogen refers to that reaction bulb connects the nitrogen balloon or steel kettle of an about 1L volume；

Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume or the stainless steel of an about 1L volume Autoclave；

Without specified otherwise in embodiment, solution refers to the aqueous solution；

Without specified otherwise in embodiment, reaction temperature is room temperature, and without specified otherwise, room temperature is 20 DEG C~30 DEG C；

Reaction temperature, baking temperature in embodiment is the temperature shown by monitoring instrument, it is allowed to have ± 3 DEG C~± 5 DEG C error.

Crystal type can be prepared by various methods, crystallized including but not limited to for example from suitable solvent mixture or weighed Crystallization, distillation, from it is another it is mutually solid state transformed, from supercritical fluid liquid crystalization and spraying, etc..For the crystallization of solvent mixture The crystallization of type or the technology of recrystallization are included but is not limited to, such as solvent evaporation, temperature, the compound of reduction solvent mixture And/or the supersaturation seeding (crystal seeding) of solvent mixture of its salt, solvent mixture freeze-drying and by prosperity And add in solvent mixture.Crystal type can be prepared with high yield crystallization technique, including polycrystal etc..

The sign of the crystal (including polymorphs body), preparation method and drug crystal forms of medicine is discussed at Solid-State Chemistry ofDrugs, S.R.Byrn, R.R.Pfeiffer and J.G.Stowell, the second edition, SSCI, WestLafayette,Indiana(1999).

In utilizing the crystallization technique of solvent wherein, solvent is typically based on one or more selecting factors, the factor bag Include but be not limited to the vapour pressure of the solubility, crystallization technique used and solvent of such as compound.Using the combination of solvent, example Such as, compound can be made solubilized to obtain solution in the first solvent, compound is molten in being subsequently adding anti-solvent to reduce solution Xie Du, and precipitating crystalline formation.Anti-solvent is the solvent that wherein compound has low solubility.

Crystal seed can be added into any crystalline mixture to promote crystallization.The growth of specific polymorphs body can be controlled with seeding, And/or the grain size distribution of control crystallized product.Therefore, the calculating of the amount of required crystal seed depend on available crystal seed size and The desired size of average product particle, such as " Programmed Cooling Batch Crystallizers ", J.W.Mullin And described in J.Nyvlt, Chemical Engineering Science, 1971,26,369-377.Generally require undersized crystalline substance Kind, with the crystal growth in effective control material.Sieved by big crystal, ground or micronizing, or by solution controlled micro crystallization, Undersized crystal seed can be produced.In crystal grinding or micronizing, it should be noted that avoid crystallinity from changing from desired crystal type (that is, becoming armorphous or other polymorphics).

The crystalline mixture of Jing coolings can be under vacuo filtered, separated solid product is (for example, cold with solvent is adapted to Recrystallization solvent) washing.After washing, product can be dried to obtain required crystal type under nitrogen purging.Product can be by being adapted to Spectrum or analytical technology analysis, including but not limited to for example, X-ray powder diffraction (XRPD) analysis, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform-infrared spectrum (FT-IR) analysis and Raman spectrum (Raman spectrum) Analysis etc..To ensure that the crystal type of compound has been formed.

The general authentication method of crystal formation

1st, X-ray powder diffraction (XRPD) analysis method

In the Dutch PANalytical of the Transflective sample stage for being equipped with the automation Background Samples framves of 3,*15 zero X-ray powder diffraction (XRPD) pattern is collected on Empyrean x-ray diffractometers.Radiation source used is (Cu, k α, K α 1 1.540598；Kα21.544426；The intensities of K α 2/K α 1：0.50), wherein voltage is set in 45KV, and current settings exist 40mA.The effective dimensions of X-ray constraint, is 10mm in the divergence of X-ray, i.e. sample.Mould is continuously scanned using θ-θ Formula, obtains 3 °~40 ° of effective 2 θ scopes.Take appropriate powdered samples at ambient conditions (about 18 DEG C~32 DEG C) in zero background At specimen holder circular groove, gently pressed with clean slide, obtain a smooth plane, and zero Background Samples frame is fixed. By sample with 0.0167 ° of scanning step, the sweep speed that 10s/ is walked produces traditional in the range of 3~40 ° of 2 θ ± 0.2 ° XRPD patterns.Data, HighScore Plus software data processings, DataViewer are collected using Data Collector softwares Software reads data.

2nd, differential scanning calorimetry (DSC) analysis method

Dsc measurement is in the TAInstruments with heat analysis controller^TMSealed disk assembly is used in model Q2000 module Carry out.Sample (about 1~5mg) is weighed to exactly in the special aluminium crucible with lid, precision recorded one of percentage milli Gram, and sample is transferred in instrument measures.During test, DSC furnace chambers are purged with 50mL/min with nitrogen.Arrive in room temperature Data are collected with the rate of heat addition of 10 DEG C/min between 300 DEG C.Drawn downwards with endothermic peak, data TA Instruments Thermal Solutions are analyzed and shown.

3rd, Raman spectrum (Roman spectrum) analysis method

Raman spectrum is tested using Thermo DXR type confocal lasers Raman spectrometer.Optical maser wavelength：780nm, laser energy Amount：24Mw, detection range：3500~50cm^-1, scanning times：20 times, resolution ratio：4.7~8.7cm^-1.Using MONIC softwares Carry out data process＆analysis.

4th, Fourier transform-infrared spectrum (FT-IR spectrum) analysis method

Infrared spectrum is tested using the Fourier transformation infrared spectrometers of Bruker TENSOR 27.Using pressing potassium bromide troche Method, takes appropriate testing sample with the KBr being dried by about 1:150 ratio is mixed, finely ground, compressing tablet, in 4000~400cm^-1Model Enclose and interior sample is detected.

5th, thermal weight loss (TGA) analysis method

Thermal weight loss is carried out using the TA Q500 modules with heat analysis controller.About 10mg samples are weighed to exactly In platinum sample disc, data are collected with the rate of heat addition of 10 DEG C/min between room temperature to 300 DEG C.During test, instrument nitrogen Gas purges TGA furnace chambers with 50mL/min.Data are collected using TA Instruments Thermal Solutions softwares to go forward side by side Row analysis.

The present invention is further illustrated by examples hereinbelow, and these embodiments should not be construed as scope disclosed by the invention It is limited to wherein described concrete steps.

For a further understanding of the present invention, with reference to embodiment, the present invention is described in detail.

Specific embodiment

Embodiment

Armorphous (1R, 2S, 3S, 4R, the 5S) -5- of embodiment 1 [the chloro- 3- of 4- [(4- ethoxyphenyls) methyl] phenyl] -1- The preparation of [(1R) -1- ethoxys] -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- triols (compound I)

The synthetic route of compound (I) as it appears from the above, wherein, compound [(1S, 2S, 3S, 4R, 5S) -2,3,4- tri- benzyloxies Base -5- [the chloro- 3- of 4- [(4- ethoxyl phenenyls) methyl] phenyl] -6,8- dioxy-bicyclos [3.2.1] octane -1- formaldehyde (I-l) Preparation method described in preparation method referenced patent WO2015043511, and related content therein is integrally incorporated into this In bright.

Step 1 (1R) -1- [benzyloxy -5- of (1R, 2S, 3S, 4R, 5S) -2,3,4- three [the chloro- 3- of 4- [(4- ethoxyphenyls) Methyl] phenyl] -6,8- dioxy-bicyclos [3.2.1] octane -1- bases] ethanol (I-m)

At room temperature, chiral ligand Cr-Salen (11.0g, 17.4mmol, 0.15eq) is added to [(1S, 2S, 3S, 4R, 5S) benzyloxy -5- of -2,3,4- three [the chloro- 3- of 4- [(4- ethoxyl phenenyls) methyl] phenyl] -6,8- dioxy-bicyclos [3.2.1] In toluene (600mL) solution of octane -1- formaldehyde (I-l) (82.0g, 116mmol, 1.0eq).Reactant liquor under nitrogen protection, After being stirred at room temperature 30 minutes, be cooled to -10 DEG C, be slowly added in 1 hour zinc methide hexane solution (150.8mL, 150.8mmol, 1.3eq, 1.0M), room temperature reaction 20 hours.At -10 DEG C, gone out reaction with 50mL water quenchings, water mutually uses acetic acid second Ester (100mL × 2) is extracted, and merges organic phase, is washed with water (500mL × 2) and saturated aqueous common salt (500mL × 2) successively, anhydrous Sodium sulphate is dried, and filters, reduced pressure concentration filtrate, obtains crude product for rufous grease, 115g.

115g rufous grease is beaten with petrol ether/ethyl acetate (v/v=4/1,100mL), 10 is stirred at room temperature little When, filter, filter cake is washed with petrol ether/ethyl acetate (v/v=30/1,40mL), filter cake is collected, vacuum drying obtains title Compound (I-m) (46.0g, yellow solid, ee:96.7%), yield：53.0%.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.48(dd,2H),7.41(dd,1H),7.37-7.32(m,2H), 7.32-7.24(m,8H),7.24-7.16(m,3H),7.05(d,2H),6.85(d,2H),6.75(d,2H),5.04(s,1H), 4.79(m,4H),4.26(d,1H),4.12(d,1H),4.00(dd,2H),3.96-3.84(m,5H),3.79(d,1H),3.73 (dd,2H),1.29(t,3H),1.15(d,3H)。

Step 2 (1R, 2S, 3S, 4R, 5S) -5- [the chloro- 3- of 4- [(4- ethoxyphenyls) methyl] phenyl] -1- [(1R) -1- hydroxyls Ethyl] -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- triols (I)

At room temperature, successively by 10% palladium/carbon (0.55g, 5.2mmol) and concentrated hydrochloric acid (17mL, 395mmol, 12M) addition (1R) -1- [benzyloxy -5- of (1R, 2S, 3S, 4R, 5S) -2,3,4- three [the chloro- 3- of 4- [(4- ethoxyphenyls) methyl] phenyl] -6, 8- dioxy-bicyclos [3.2.1] octane -1- bases] ethanol (I-m) (46.0g, 63.7mmol) methyl alcohol/tetrahydrofuran (v/v=10/ Isosorbide-5-Nitrae 40mL) in solution, hydrogenation 2 hours under room temperature.Palladium/carbon is filtered to remove, filtrate reduced in volume, the residue for obtaining is molten In 100mL ethyl acetate, adjusted to pH=7, then with saturated common salt water washing (100mL), nothing with saturated sodium bicarbonate solution Aqueous sodium persulfate is dried, and filters, reduced pressure concentration filtrate, and residue Jing silica gel column chromatographies purifying [100% ethyl acetate] obtain target Product (I) (22.0g, white solid, ee%:97.1%), yield：74.5%.

MS(ESI,pos.ion)m/z:451.2[M+H]⁺；

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.41(dd,2H),7.35-7.29(m,1H),7.11(d,2H), 6.84(d,2H),5.30(d,1H),5.01(d,1H),4.92(d,1H),4.64(d,1H),4.03-3.95(m,5H),3.85 (p,1H),3.78(d,1H),3.59-3.53(m,1H),3.44(dd,1H),3.38(m,1H),1.30(t,3H),1.18(d, 3H)。

Embodiment 2

1st, the preparation of crystal formation A

At room temperature, by (1R, 2S, 3S, 4R, 5S) -5- [the chloro- 3- of 4- [(4- ethoxyl phenenyls) methyl] phenyl] -1- [(1R) -1- ethoxys] -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- triols (I) (1.00g, 2.22mmol) is dissolved in methyl alcohol (2mL) in, stir while water (4mL) is added in solution, during dropwise addition, solution is gradually changed into white from achromaticity and clarification Color emulsion.After dripping, gained mixed system at room temperature, continues to stir 2 hours, suction filtration, and filter cake vacuum at 50 DEG C is done It is dry to constant weight (vacuum be -0.098Mpa), obtain white solid.This solid is placed in environment of the relative humidity higher than 60%, Obtain crystal A (white solid, 0.96g, yield 96%).

2nd, the identification of crystal formation A

(1) X-ray powder diffraction (XRPD) analysis

X-ray powder diffraction (XRPD) collection of illustrative plates of crystal formation A spreads out as shown in figure 1, its concrete analysis result is as shown in table 1 below Penetrate peak position and there may be ± 0.2 ° of error margin.

Table 1：The X-ray powder diffraction analysis result of crystal formation A

(2) differential scanning calorimetry (DSC) analysis

The differential scanning calorimetry experimental result of crystal formation A is as shown in Fig. 2 its differential scanning calorimetric curve includes 70.8 DEG C Endothermic peak, the error margin that there may be ± 3 DEG C~± 5 DEG C.

(3) Raman spectrum (Roman spectrum) analysis

The Raman spectrogram of crystal formation A is as shown in figure 3, it includes displacement is：1610.51cm^-1,1447.10cm^-1, 1299.25cm^-1,1177.71cm^-1,1037.56cm^-1,842.83cm^-1,821.89cm^-1,801.70cm^-1,725.87cm^-1, 691.04cm^-1,634.84cm^-1,573.61cm^-1, 379.32 and 331.60cm^-1Characteristic absorption peak, there may be ± 1cm^-1's Error margin.

(4) Fourier transform-infrared spectrum (FT-IR spectrum) analysis method

As shown in Figure 4, it includes wave number and is the Fourier transform-infrared spectrogram of crystal formation A：3563.71cm^-1, 3425.84cm^-1,3317.08cm^-1,3035.99cm^-1,2979.45cm^-1,2926.54cm^-1,2900.00cm^-1, 2881.54cm^-1,1611.36cm^-1,1581.67cm^-1,1511.87cm^-1,1476.77cm^-1,1443.38cm^-1, 1397.44cm^-1,1326.01cm^-1,1299.92cm^-1,1245.92cm^-1,1177.23cm^-1,1109.55cm^-1, 1086.79cm^-1,1040.14cm^-1,997.79cm^-1,975.50cm^-1,931.50cm^-1,908.67cm^-1,868.57cm^-1, 824.08cm^-1,806.54cm^-1,774.00cm^-1,699.29cm^-1,618.90cm^-1,573.39cm^-1,550.68cm^-1With 521.91cm^-1Characteristic absorption peak, error meets《Chinese Pharmacopoeia》Regulation, i.e. 3000cm^-1Nearby there may be ± 5cm^-1Error Tolerance limit, 1000cm^-1Nearby there may be ± 2cm^-1Error margin.

Embodiment 3

1st, the preparation of crystal formation B

At room temperature, by (1R, 2S, 3S, 4R, 5S) -5- [the chloro- 3- of 4- [(4- ethoxyl phenenyls) methyl] phenyl] -1- [(1R) -1- ethoxys] -6,8- dioxy-bicyclos [3.2.1] octane -2,3,4- triols (I) (1.00g, 2.22mmol) is dissolved in methyl alcohol (2mL) in, stir while water (4mL) is dropwise instilled in solution, during dropwise addition, solution is gradually become by achromaticity and clarification For white emulsion.After dripping, gained mixed system at room temperature, continues to stir 2 hours, and suction filtration, filter cake is true at 50 DEG C Sky is dried to constant weight (vacuum is -0.098Mpa), obtains white solid.This solid is put in environment of the relative humidity less than 40% Put, that is, obtain crystal B (white solid, 0.96g, yield 96%).

2nd, the identification of crystal formation B

(1) X-ray powder diffraction (XRPD) analysis

X-ray powder diffraction (XRPD) collection of illustrative plates of crystal formation B spreads out as shown in figure 5, its concrete analysis result is as shown in table 2 below Penetrate peak position and there may be ± 0.2 ° of error margin.

Table 2：The X-ray powder diffraction analysis result of crystal formation B

(2) differential scanning calorimetry (DSC) analysis

The differential scanning calorimetric curve of crystal formation B is as shown in fig. 6, its differential scanning calorimetric curve includes 98.1 DEG C of heat absorption Peak, the error margin that there may be ± 3 DEG C~± 5 DEG C.

(3) Raman spectrum (Roman spectrum) analysis

The Raman spectrum of crystal formation B is as shown in fig. 7, it includes displacement is：1610.60cm^-1,1446.96cm^-1, 1299.00cm^-1,1177.94cm^-1,1038.17cm^-1,842.21cm^-1,821.86cm^-1,800.26cm^-1,690.45cm^-1, 635.61cm^-1,574.24cm^-1,507.32cm^-1,381.19cm^-1And 333.99cm^-1Characteristic absorption peak, there may be ± 1cm^-1 Error margin.

(4) Fourier transform-infrared spectrum (FT-IR spectrum) analysis method

Fourier transform-the infrared spectrogram of crystal formation B is as shown in figure 8, it includes wave number is：3331.11cm^-1, 2981.09cm^-1,2930.07cm^-1,2899.78cm^-1,2881.62cm^-1,1891.33cm^-1,1678.05cm^-1, 1612.08cm^-1,1583.03cm^-1,1512.44cm^-1,1477.37cm^-1,1421.75cm^-1,1401.55cm^-1, 1346.97cm^-1,1329.50cm^-1,1299.98cm^-1,1247.61cm^-1,1217.38cm^-1,1177.78cm^-1, 1146.07cm^-1,1132.81cm^-1,1110.58cm^-1,1082.94cm^-1,1062.91cm^-1,1037.45cm^-1, 1023.57cm^-1,1015.03cm^-1,998.60cm^-1,979.29cm^-1,935.25cm^-1,918.88cm^-1,906.15cm^-1, 871.43cm^-1,843.72cm^-1,821.98cm^-1,812.00cm^-1,801.45cm^-1,775.19cm^-1,739.04cm^-1, 725.99cm^-1,706.18cm^-1,690.42cm^-1,619.40cm^-1,573.39cm^-1,553.62cm^-1,522.52cm^-1, 473.00cm^-1And 452.68cm^-1Characteristic absorption peak, error meets《Chinese Pharmacopoeia》Regulation, i.e. 3000cm^-1Nearby there may be ±5cm^-1Error margin, 1000cm^-1Nearby there may be ± 2cm^-1Error margin.

Embodiment 4

1st, the preparation of crystal formation D

To (1R, 2S, 3S, 4R, 5S) -5- [the chloro- 3- of 4- [(4- ethoxyl phenenyls) methyl] phenyl] -1- [(1R) -1- hydroxyls second Base] -6,8- dioxy-bicyclos [3.2.1] octane -2, absolute ethyl alcohol (4mL) is added in 3,4- triols (I) (1.00g, 2.22mmol), Gained mixed system is warming up to 80 DEG C and stirs to solid and is completely dissolved, and stops heating.Resulting solution is down to room temperature naturally, and after Continuous stirring 15 hours.Suction filtration, the filter cake of collection is dried under vacuum to constant weight (vacuum is -0.098Mpa) at 50 DEG C, obtains crystalline substance Body D (white solid, 0.85g, yield 77.2%).

2nd, the identification of crystal formation D

(1) X-ray powder diffraction (XRPD) analysis

X-ray powder diffraction (XRPD) spectrogram of crystal formation D spreads out as shown in figure 9, its concrete analysis result is as shown in table 3 below Penetrate peak position and there may be ± 0.2 ° of error margin.

Table 3：The X-ray powder diffraction analysis result of crystal formation D

(2) differential scanning calorimetry (DSC) analysis

As shown in Figure 10, its differential scanning calorimetric curve includes 90.6 DEG C of heat absorption to the differential scanning calorimetric curve of crystal formation D Peak, the error margin that there may be ± 3 DEG C~± 5 DEG C.

(3) Raman spectrum (Roman spectrum) analysis

As shown in figure 11, it includes displacement and is for the Raman spectrogram of crystal formation D：1615.26cm^-1,1582.01cm^-1, 1454.43cm^-1,1306.66cm^-1,1176.38cm^-1,1050.55cm^-1,991.32cm^-1,879.86cm^-1,845.54cm^-1, 822.92cm^-1,812.30cm^-1,684.79cm^-1,631.47cm^-1,577.30cm^-1,552.10cm^-1,501.08cm^-1, 362.77cm^-1And 335.72cm^-1Characteristic absorption peak, there is ± 1cm^-1Error margin.

(4) Fourier transform-infrared spectrum (FT-IR spectrum) analysis method

As shown in figure 12, it includes wave number and is for the Fourier transform-infrared spectrogram of crystal formation D：3373.16cm^-1, 3260.78cm^-1, 2978.28cm^-1, 2937.04cm^-1, 2914.54cm^-1, 2899.42cm^-1, 2740.39cm^-1, 2543.47cm^-1, 1616.95cm^-1, 1583.08cm^-1, 1512.66cm^-1, 1472.36cm^-1, 1455.67cm^-1, 1393.34cm^-1, 1371.53cm^-1, 1352.10cm^-1, 1328.60cm^-1, 1305.76cm^-1, 1288.77cm^-1, 1265.96cm^-1, 1242.36cm^-1, 1177.47cm^-1, 1132.85cm^-1, 1101.04cm^-1, 1076.98cm^-1, 1050.42cm^-1, 1017.72cm^-1, 1006.39cm^-1, 978.80cm^-1, 937.63cm^-1, 923.32cm^-1, 913.89cm^-1, 897.90cm^-1, 828.80cm^-1, 810.93cm^-1, 799.18cm^-1, 771.85cm^-1, 739.74cm^-1, 722.10cm^-1, 703.58cm^-1, 683.83cm^-1, 644.82cm^-1, 591.06cm^-1, 546.76cm^-1And 514.08cm^-1Characteristic absorption peak, by mistake Difference meets《Chinese Pharmacopoeia》Regulation, i.e. 3000cm^-1Nearby there may be ± 5cm^-1Error margin, 1000cm^-1Nearby there may be ± 2cm^-1Error margin.

Testing example

1st, dissolubility test

Test method：According to《Chinese Pharmacopoeia》(2010) test method of regulation, weighs test sample (this for being ground into fine powder Sample prepared by bright embodiment), at 25 DEG C ± 2 DEG C, in adding the solvent of certain capacity, every strength shaking 30 in 5 minutes Second, the dissolving situation observed in 30 minutes when such as without visually visible particles of solute or drop, that is, is considered as and is completely dissolved.

Dissolubility criterion is as in Table A：

Table A:

Record given the test agent dissolving situation, is specifically shown in table 4 below:

Table 4:The solubility test result of crystal formation A and crystal formation D

Result of the test shows：The crystal formation A and crystal formation D dissolubility in acetonitrile, methyl alcohol, DMA and DMSO is preferable.

2nd, the Pharmacokinetic Evaluation after oral quantitative the compounds of this invention

Test method：Capsule is filled into after given the test agent (sample prepared by the embodiment of the present invention) is mixed with pharmaceutical adjunct In, give male Beagle dogs with the dosage of 5mg/kg respectively.Upon administration 0.25,0.5,1,2,4,6,8 and 24 hours respectively Small saphenous vein or forelimb medial head cava vein blood blood sample (about 0.3mL) on the outside of collection hind leg, are placed in EDTAK₂Anticoagulant tube In, it is centrifuged 10 minutes under 3000 or 4000rpm, prepare plasma containing drug.Analyze tested with LC/MS/MS (API 4000QTRAP) Concentration of the sample in blood plasma, using the non-compartment model method of the softwares of WinNonlin 6.3 pharmacokinetic parameters are calculated, and draw bent during medicine Line.

The LC/MS/MS systems of analysis include the serial vacuum degassing furnace of Agilent 1200, binary syringe pump, orifice plate from Dynamic sampler, post insulating box, charged spray ionizes the triple level Four bar mass spectrographs of API 4000QTRAP in (ESI) source.Quantitative analysis Carry out under MRM patterns, each parameter is as shown in tableb：

Table B

Analysis uses μM post of Waters Xbridge-C18,2.1 × 30mm, 3.5, injects 5 μ L samples.Analysis condition：Stream The formic acid methanol solution (B) of dynamic aqueous formic acid (A) and 2mM ammonium formates+0.1% mutually for 2mM ammonium formates+0.1%.Flow velocity is 0.4mL/min.Eluent gradient is as shown in table C：

Table C

Time	The gradient of Mobile phase B
		0.0min	30%
1.0min	30%
		1.5min	95%
3.8min	95%
		3.9min	30%
5.0min	30%

Medicine of the given the test agent in Beagle dog bodies is as shown in table 5 below for token test result：

Table 5：Medicine after crystal formation oral administration provided in an embodiment of the present invention in Beagle dog bodies is for token test result

Result of the test shows：After oral administration, crystal formation A and crystal formation D absorbs good in Beagle dog bodies, with higher Exposed amount (AUC_last)；Wherein, the absorption of crystal formation D is better than crystal formation A, with higher exposed amount.

In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means to combine specific features, structure, material or spy that the embodiment or example are described Point is contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not Identical embodiment or example must be directed to.And, the specific features of description, structure, material or feature can be with office Combine in an appropriate manner in one or more embodiments or example.Additionally, in the case of not conflicting, the skill of this area Art personnel can be tied the feature of the different embodiments or example described in this specification and different embodiments or example Close and combine.

Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment is example Property, it is impossible to limitation of the present invention is interpreted as, one of ordinary skill in the art within the scope of the invention can be to above-mentioned Embodiment is changed, changes, replacing and modification.All publications or patent cited in the present invention are all using as the present invention's Bibliography.

Claims (14)

1. the crystal formation of the compound shown in formula (I)

It is crystal formation A, crystal formation B or its combination, wherein, the crystal formation A has at least one of following characteristics：

(1) its X-ray powder diffraction pattern includes 2 θ angles for 4.36 ° ± 0.2 °, 12.97 ° ± 0.2 °, 18.12 ° ± 0.2 °, 18.86 ° ± 0.2 °, 20.24 ° ± 0.2 ° and 24.09 ° ± 0.2 ° of diffraction maximum, or

(2) its differential scanning calorimetric curve includes 70.8 DEG C ± 3 DEG C of endothermic peak, or

(3) its Raman spectrogram is included in 1610.51cm^-1±1cm^-1,801.70cm^-1±1cm^-1,725.87cm^-1±1cm^-1With 331.60cm^-1±1cm^-1The characteristic absorption peak at place, or

(4) its Fourier transform-infrared spectrogram is included in 3425.84cm^-1±5cm^-1,3317.08cm^-1±5cm^-1, 2979.45cm^-1±5cm^-1,2881.54cm^-1±5cm^-1,1581.67cm^-1±2cm^-1,1511.87cm^-1±2cm^-1, 1299.92cm^-1±2cm^-1,1245.92cm^-1±2cm^-1,1177.23cm^-1±2cm^-1,1086.79cm^-1±2cm^-1, 1040.14cm^-1±2cm^-1,824.08cm^-1±2cm^-1,806.54cm^-1±2cm^-1And 521.91cm^-1±2cm^-1The feature at place Absworption peak；

Wherein, the crystal formation B has at least one of following characteristics:

(1) its X-ray powder diffraction pattern includes 2 θ angles for 4.65 ° ± 0.2 °, 14.30 ° ± 0.2 °, 18.08 ° ± 0.2 °, 22.38 ° ± 0.2 °, 23.27 ± 0.2 °, 24.01 ° ± 0.2 ° and 28.07 ° ± 0.2 ° of diffraction maximum, or

(2) its differential scanning calorimetric curve includes 98.1 DEG C ± 3 DEG C of endothermic peak, or

(3) its Raman spectrogram is included in 1610.60cm^-1±1cm^-1,800.26cm^-1±1cm^-1And 333.99cm^-1±1cm^-1 The characteristic absorption peak at place, or

(4) its Fourier transform-infrared spectrogram is included in 3331.11cm^-1±5cm^-1,2981.09cm^-1±5cm^-1, 2930.07cm^-1±5cm^-1,2899.78cm^-1±5cm^-1,2881.62cm^-1±5cm^-1,1612.08cm^-1±2cm^-1, 1512.44cm^-1±2cm^-1,1247.61cm^-1±2cm^-1,1177.78cm^-1±2cm^-1,1082.94cm^-1±2cm^-1, 1037.45cm^-1±2cm^-1,1023.57cm^-1±2cm^-1,801.45cm^-1±2cm^-1And 522.52cm^-1±2cm^-1The feature at place Absworption peak.

2. crystal formation according to claim 1, wherein, the X-ray powder diffraction pattern of the crystal formation A is comprising 2 θ angles 4.36°±0.2°,12.97°±0.2°,15.64°±0.2°,16.47°±0.2°,16.80°±0.2°,18.12°±0.2°, 18.86 ° ± 0.2 °, 20.24 ° ± 0.2 °, 20.52 ° ± 0.2 °, 23.82 ° ± 0.2 °, 24.09 ° ± 0.2 ° and 29.24 ° ± 0.2 ° of diffraction maximum.

3. crystal formation according to claim 1, wherein, the X-ray powder diffraction pattern of the crystal formation A is comprising 2 θ angles 4.36°±0.2°,10.34°±0.2°,11.86°±0.2°,12.97°±0.2°,15.05°±0.2°,15.64°±0.2°, 16.47°±0.2°,16.80°±0.2°,18.12°±0.2°,18.86°±0.2°,19.36°±0.2°,20.24°± 0.2°,20.52°±0.2°,21.22°±0.2°,21.41°±0.2°,21.69°±0.2°,23.82°±0.2°,24.09° ±0.2°,25.16°±0.2°,25.50°±0.2°,26.93°±0.2°,27.24°±0.2°,28.46°±0.2°, 29.24°±0.2°,29.79°±0.2°,30.34°±0.2°,31.56°±0.2°,32.03°±0.2°,32.60°± 0.2°,33.96°±0.2°,34.37°±0.2°,34.89°±0.2°,35.73°±0.2°,36.68°±0.2°,37.03° ± 0.2 °, 38.19 ° ± 0.2 ° and 38.59 ° ± 0.2 ° of diffraction maximum.

4. crystal formation according to claim 1, wherein, the X-ray powder diffraction pattern of the crystal formation B is comprising 2 θ angles 4.65°±0.2°,9.14°±0.2°,14.30°±0.2°,16.23°±0.2°,18.08°±0.2°,22.38°±0.2°, 23.27 ° ± 0.2 °, 24.01 ° ± 0.2 °, 27.25 ° ± 0.2 ° and 28.07 ° ± 0.2 ° of diffraction maximum.

5. crystal formation according to claim 1, wherein, the X-ray powder diffraction pattern of the crystal formation B is comprising 2 θ angles 4.65°±0.2°,9.14°±0.2°,11.06°±0.2°,11.61°±0.2°,13.92°±0.2°,14.30°±0.2°, 14.99°±0.2°,16.23°±0.2°,18.08°±0.2°,19.42°±0.2°,20.60°±0.2°,20.94°± 0.2°,21.19°±0.2°,21.65°±0.2°,22.38°±0.2°,23.27°±0.2°,24.01°±0.2°,25.26° ±0.2°,25.88°±0.2°,26.53°±0.2°,27.25°±0.2°,28.07°±0.2°,29.80°±0.2°, 30.19°±0.2°,31.34°±0.2°,32.20°±0.2°,32.85°±0.2°,33.35°±0.2°,34.09°± 0.2 °, 35.95 ° ± 0.2 °, 36.70 ° ± 0.2 °, 37.63 ° ± 0.2 °, 38.67 ° ± 0.2 °, 39.37 ° ± 0.2 ° and 39.71 ° ± 0.2 ° of diffraction maximum.

6. crystal formation according to claim 1, wherein, the crystal formation A has at least one of following characteristics：

(1) its X-ray powder diffraction pattern is substantially the same with Fig. 1, or

(2) its differential scanning calorimetric curve is substantially the same with Fig. 2, or

(3) its Raman spectrogram is substantially the same with Fig. 3, or

(4) its Fourier transform-infrared spectrogram is substantially the same with Fig. 4；

Wherein, the crystal formation B has at least one of following characteristics：

(1) its X-ray powder diffraction pattern is substantially the same with Fig. 5, or

(2) its differential scanning calorimetric curve is substantially the same with Fig. 6, or

(3) its Raman spectrogram is substantially the same with Fig. 7, or

(4) its Fourier transform-infrared spectrogram is substantially the same with Fig. 8.

7. the crystal formation of compound of the one kind as shown in formula (II)

It is crystal formation D, wherein, the crystal formation D has in following characteristics At least one：

(1) its X-ray powder diffraction pattern includes 2 θ angles for 3.26 ° ± 0.2 °, 10.96 ° ± 0.2 °, 12.98 ° ± 0.2 °, 22.11 ° ± 0.2 °, 22.81 ° ± 0.2 ° and 26.44 ° ± 0.2 ° of diffraction maximum, or

(2) its differential scanning calorimetric curve includes 90.6 DEG C ± 3 DEG C of endothermic peak, or

(3) its Raman spectrogram is included in 1615.26cm^-1±1cm^-1,1582.01cm^-1±1cm^-1,1454.43cm^-1±1cm^-1,1306.66cm^-1±1cm^-1,1050.55cm^-1±1cm^-1,991.32cm^-1±1cm^-1,879.86cm^-1±1cm^-1, 812.30cm^-1±1cm^-1,552.10cm^-1±1cm^-1And 362.77cm^-1±1cm^-1The characteristic absorption peak at place, or

(4) its Fourier transform-infrared spectrogram has in 3373.16cm^-1±5cm^-1,2978.28cm^-1±5cm^-1, 2914.54cm^-1±5cm^-1,2899.42cm^-1±5cm^-1,1616.95cm^-1±2cm^-1,1583.08cm^-1±2cm^-1, 1512.66cm^-1±2cm^-1,1242.36cm^-1±2cm^-1,1101.04cm^-1±2cm^-1,1050.42cm^-1±2cm^-1, 1017.72cm^-1±2cm^-1,1006.39cm^-1±2cm^-1,810.93cm^-1±2cm^-1,799.18cm^-1±2cm^-1With 739.74cm^-1±2cm^-1Characteristic absorption peak.

8. crystal formation according to claim 7, wherein, the X-ray powder diffraction pattern of the crystal formation D is comprising 2 θ angles 3.26°±0.2°,10.96°±0.2°,12.98°±0.2°,17.00°±0.2°,17.69°±0.2°,18.28°±0.2°, 20.01 ° ± 0.2 °, 22.11 ° ± 0.2 °, 22.46 ° ± 0.2 °, 22.81 ° ± 0.2 ° and 26.44 ° ± 0.2 ° of diffraction maximum.

9. crystal formation according to claim 7, wherein, the X-ray powder diffraction pattern of the crystal formation D is comprising 2 θ angles 3.26°±0.2°,9.74°±0.2°,10.96°±0.2°,11.32°±0.2°,11.56°±0.2°,12.55°±0.2°, 12.98°±0.2°,14.39°±0.2°,14.96°±0.2°,16.52°±0.2°,17.00°±0.2°,17.26°± 0.2°,17.69°±0.2°,18.28°±0.2°,19.54°±0.2°,19.82°±0.2°,20.01°±0.2°,20.22° ±0.2°,20.74°±0.2°,22.11°±0.2°,22.46°±0.2°,22.81°±0.2°,23.29°±0.2°, 23.89°±0.2°,25.02°±0.2°,26.44°±0.2°,26.90°±0.2°,28.14°±0.2°,28.85°± 0.2°,30.19°±0.2°,31.61°±0.2°,32.59°±0.2°,33.37°±0.2°,34.24°±0.2°,35.02° ± 0.2 °, 35.87 ° ± 0.2 ° and 38.38 ° ± 0.2 ° of diffraction maximum.

10. crystal formation according to claim 7, wherein, described crystal formation D has at least one of following characteristics：

(1) its X-ray powder diffraction pattern is substantially the same with Fig. 9, or

(2) its differential scanning calorimetric curve is substantially the same with Figure 10, or

(3) its Raman spectrogram is substantially the same with Figure 11, or

(4) its Fourier transform-infrared spectrogram is substantially the same with Figure 12.

A kind of 11. pharmaceutical compositions, comprising the crystal formation described in claim 1-10 any one or its combination, and pharmaceutically can connect The auxiliary material received.

12. pharmaceutical compositions according to claim 11, it further includes additional therapeutic agent, wherein the additional treatment Agent is selected from the antidiabetic medicine of non-SGLT-2 inhibitor, antihyperglycemic medicine, anti-obesity medicine, drug for hypertension, anti- Antiplatelet drug, Antiatherosclerosis medicine, fat-reducing medicament, anti-inflammation drugs or its combination.

13. pharmaceutical compositions according to claim 12, wherein, the antidiabetic medicine of the non-SGLT-2 inhibitor and Antihyperglycemic medicine is separately exciting selected from biguanides, sulfonylureas, glucosidase inhibitor, PPAR Agent, α P2 inhibitor, the double activator of PPAR α/γ, DPP IV (DPP-IV) inhibitor, glinides, insulin, Glucagon-like-peptide-1 inhibitor, PTP1B inhibitor, glycogen phosphorylase inhibitors, G-6-Pase inhibitor or Its combination, the fat-reducing medicament is selected from MTP inhibitor, HMGCoA reductase inhibitors, inhibitor for squalene synthetic enzyme, shellfish butyric acid Class blood lipid-lowering medicine, ACAT inhibitor, lipoxygenase inhibitor, cholesterol absorption inhibitor, ileum sodium ion/bile acid collaboration Transporter inhibitors, ldl receptor activity be adjusted up thing, nicotinic acid class blood lipid-lowering medicine, bile acid chelate or its combination； Or described fat-reducing medicament cuts down him selected from Pravastatin, Simvastatin, Atorvastatin, Fluvastatin, cerivastatin, Etard Spit of fland, rosuvastatin or its combination.

Described in crystal formation or its combination or claim 11-13 any one described in a kind of 14. claim 1-10 any one Purposes of the pharmaceutical composition in medicine is prepared, wherein, the medicine is used to suppress SGLT-2, or for increasing high density fat The level of albumen, or for preventing or treat disease, mitigating the disease symptomses or delaying the advancing of disease or outbreak, Wherein described disease be diabetes, diabetic retinopathy, diabetic neuropathy, nephrosis, insulin resistance, The rising of aliphatic acid or glycerine level, hyperlipidemia, obesity, hypertriglyceridaemia in hyperglycaemia, hyperinsulinemia, blood Disease, X syndromes, diabetic complication, atherosclerotic or hypertension.