CN104230907A - Method for preparing crystals and application of crystals - Google Patents

Method for preparing crystals and application of crystals Download PDF

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CN104230907A
CN104230907A CN201410386285.7A CN201410386285A CN104230907A CN 104230907 A CN104230907 A CN 104230907A CN 201410386285 A CN201410386285 A CN 201410386285A CN 104230907 A CN104230907 A CN 104230907A
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methyl
crystal form
glucopyranosyl
fluorophenyl
benzene
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CN104230907B (en
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王军
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SUZHOU JINRAN PHARMACEUTICAL TECHNOLOGY Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Abstract

The invention discloses novel crystal form III and crystal form IV of 1-(beta-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl, a preparation method of the crystal form III and the crystal form IV and a medicinal application of the crystal form III and the crystal form IV in treatment of diabetes mellitus. The crystal form III serving as an octanol compound has a more remarkable action effect on treatment of diabetes mellitus, and is prepared by carrying out supersaturated precipitation or re-crystallization in octanol or a solution containing octanol. The octanol serving as a gap junction blocker has an effect of reducing diabetic complications, such as a pharmacological action for resisting cardiomyocyte edema and hypertrophy and a neuroprotective effect, so that compared with other crystal forms, the crystal form III has a more remarkable action effect on diabetes mellitus treatment, especially prevention of cardiovascular complications of patients with early diabetes mellitus.

Description

Crystal preparation method and uses thereof
Technical field
The present invention relates to new crystal B of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene and its production and use.
Background technology
Diabetes are a kind of internal secretion-metabolic troubles, jointly indicate for it with hyperglycemia.Because the water and electrolyte metabolism of Regular Insulin is absolute or relative hyposecretion causes sugar, protein, fat and secondary is disorderly.It can relate to each system of whole body particularly eye, kidney, heart, blood vessel, neural chronic lesion, dysfunction, even brings out many mortality complication.Along with the aging of world population, diabetes have become a kind of common disease, frequently-occurring disease, are a kind of diseases of serious harm human health.Data shows, global diabetic subject by 2000 1.5 hundred million be increased to 2.8 hundred million, expecting the year two thousand thirty whole world will have nearly 500,000,000 people to suffer from diabetes.
Human body in normal state, regulate and control glucose metabolism balance be glucose transporter.Sodium glucose co-transporter 2 white (SGLT) is a kind of known glucose transporter.SGLT comprises SGLT1 and SGLT2, and wherein SGLT1 is expressed in small intestine and kidney proximal tubule compared with in the S3 sections of far-end, absorbs the sugar of about 10%; SGLT2 is mainly expressed in before kidney proximal tubule in SI sections, and the glucose reabsorption of more than 90% is responsible for by this SGLT2.Therefore suppress SGLT, particularly suppress SGLT2 that the heavily absorption of sugar and then can be suppressed, thus sugar is discharged through urine, reduce the concentration of sugar in blood.
Canagliflozin (Ka Gelie clean, 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene) is the oral antidiabetic drug that medicine that U.S. FDA has been ratified is used for the treatment of diabetes B.This medicine is the inhibitor of optionally sodium dependent glucose transporter (SGLT2).The clean molecular formula of Ka Gelie is C24H25FO5S, and its molecular weight is that the clean chemical structural formula of 444.52, Ka Gelie is as follows:
Generally speaking, in order to the operability that bulk drug and preparation are produced, the object of the stability that medicine is preserved and raising curative effect of medication, needs state medicine being made crystal.
The clean existing crystal formation of Ka Gelie has following several.In US 2008/0146515 A1 patent, disclose the clean semihydrate of Ka Gelie (called after crystal form A) structure as follows, the X-ray powder diffraction figure of this crystal formation comprises following 2 θ values (recording with Cu K α): 4.36 ± 0.2,13.54 ± 0.2,16.00 ± 0.2,19.32 ± 0.2 and 20.80 ± 0.2.Semihydrate XRPD schemes as shown in Figure 2, also reveal that the preparation method of this semihydrate crystal formation simultaneously.
In US 2009/0233874 A1 patent, also reveal that the another kind of crystal formation that Ka Gelie is clean, Fig. 3 show the XRPD figure of this crystal formation, the diffraction peak of XRPD figure is listed in the table below:
The clean five kinds of eutectic crystal formations of Ka Gelie are disclosed in WO2013064909 A2 patent, comprise Ka Gelie clean-L-PROLINE eutectic and Ka Gelie clean-eutectic of D-PROLINE-ethanolates, Ka Gelie is clean-L-Phe monohydrate eutectic crystal formation, Ka Gelie is clean-L-Phe eutectic crystal formation and Ka Gelie clean-D-PROLINE eutectic crystal formation.
Patent CN103641822A also discloses the clean semihydrate crystal formation of Ka Gelie, and compare according to the comparison of XRPD figure and diffraction peak data, crystal formation disclosed in patent CN103641822A is identical in fact with the crystal formation in US 2009/0233874 A1 patent.Patent CN103588762A and patent CN103554092A discloses clean 3 new crystal of Ka Gelie called after crystal form B respectively, C, D.Wherein crystal form B and C room temperature in Aquo System is slowly volatilized and is obtained, but the preparation method of slowly volatilization is difficult to use in industrial mass production crystal form B; In addition, the room temperature slowly condition of volatilizing is difficult to control, and affected by environment very large, product form is difficult to control, and is easy to obtain semihydrate crystal form A (US 2008/0146515A1 crystal formation) in Aquo System.As mentioned above, only propose 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the benzene crystal form B preparation condition that slowly volatilizees of room temperature in a solvent in CN103588762A, for the crystal form B of other types preparation method both without record also without enlightening.
Summary of the invention
Main purpose of the present invention is preparation method and the medicinal use thereof of the crystal form B providing 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene.
The preparation method of the crystal form B of 1-of the present invention (β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, the method comprises the steps:
A., the aqueous solution containing following molecular formula compound or the mixed solvent containing water are provided;
B. the crystal seed of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene crystal form B is added in the component obtained to step a;
C. create supersaturated condition and make above-claimed cpd crystallization, obtain suspension;
D. the suspension balance will obtained in step c;
E. suspension is carried out solid-liquid separation, obtain target product.
Produce oversaturated method including, but not limited to intensification falling temperature method.Namely utilize Canagliflozin in same system, the dissolubility difference under differing temps, create supersaturated condition and crystallize out.Intensification falling temperature method first by crystallizing system heat up, produce supersaturated solution, then by Temperature fall or program controlled rate of temperature fall cooling, separate out solid.Or at room temperature without intensification, directly can carry out cooling and obtain solid.
Produce oversaturated method also comprise but do not limit to anti-solvent additive process.Namely utilize the dissolubility difference of Canagliflozin in different solvents, create supersaturated condition and crystallize out.Anti-solvent additive process can by the anti-solvent of Canagliflozin (Canagliflozin solubleness in this solvent be very little), crystal seed can be added in anti-solvent and also can not add crystal seed, slow dropping or join fast be dissolved with Canagliflozin positive solvent in the middle of, and produce crystal separate out.Or the positive solvent being dissolved with Canagliflozin is slowly dripped or joins fast in anti-solvent system, can add in anti-solvent system and also can not add crystal seed, temperature can be reduced in anti-solvent system and also can not reduce temperature.Vapor infiltration method is anti-another mode of molten additive process, namely adding of anti-solvent is atmosphere by anti-solvent, be diffused under the environment of normal temperature, intensification, low temperature, containing in the positive solvent system of Canagliflozin, produce the process of supersaturation and crystallize out.
In addition, the method creating supersaturated condition also should comprise vapor phase grafting, and namely anti-solvent is with the form of gas, and at low temperature, normal temperature, under the condition of high temperature, penetrates in the solid of Canagliflozin, and this solid can be crystal formation or amorphous.After the molecule of the atmosphere Canagliflozin of infiltration, dissolve moieties, and form supersaturated solution, then separate out new crystal, and gradually by whole solid crystal or be transformed into another crystal formation.
In addition, under Elevated Temperature Conditions (higher than common room temperature) or also can create supersaturated condition lower than volatilised liq under common room temperature condition, volatilised liq also by higher or lower than common room temperature by reduce air pressure method volatilised liq (such as, but be not limited to decompression volatilization or rotary evaporation) create supersaturated condition crystallization.Can also reduce by the mode of distillation the object that solvent reaches crystallization, such as, but be not limited to lyophilize.
Concrete, the preparation method of the crystal form B of aforesaid 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, the JZPD capsule method of described 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene crystal form B comprises the steps:
A., mixture containing following molecular formula compound and water or nonelectrolyte mixed aqueous solution is provided;
B. poly-hydroxy compounds is added in the mixture obtained to step a;
C. create supersaturated condition and make above-claimed cpd crystallization, obtain suspension;
D. the suspension balance will obtained in Step d;
E. suspension is carried out solid-liquid separation, obtain target product.
Concrete, the preparation method of the crystal form B of aforesaid 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, the JZPD capsule method of described 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene crystal form B comprises the steps:
A., mixture containing following molecular formula compound and water or nonelectrolyte mixed aqueous solution is provided;
B. the mixture obtained in a step is heated to exist without solid;
C. by the system in b step, cooling part makes above-claimed cpd crystallization, obtains suspension;
D. the suspension balance will obtained in Step d;
E. suspension is carried out solid-liquid separation, obtain target product.
Concrete, the preparation method of the crystal form B of aforesaid 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, the described mixed solvent containing water comprises the mixture of the alcohols of C1-C8, the ketone of C3-C6, nitrile, amides, sulfone class, ethers, amine, ester class and above-mentioned organic solvent thereof.
Concrete, the preparation method of the crystal form B of aforesaid 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, the alcohols of described C1-C8 is: methyl alcohol, ethanol, propyl alcohol, propylene glycol, butanols, amylalcohol or octanol; The ketone of C3-C6 is: acetone, butanone, pentanone or Propiophenone; Nitrile is acetonitrile or butyronitrile; Amides is N,N-DIMETHYLACETAMIDE or dimethyl formamide; Sulfone class is dimethyl sulfoxide (DMSO); Ethers is ether or methyl ethyl ether; Amine is diethylamine, methylamine, ethamine or triethylamine quadrol.
Concrete, the preparation method of the crystal form B of aforesaid 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, the described content containing water in the mixed solvent of water is not less than 10% volume ratio.
Concrete, the preparation method of the crystal form B of aforesaid 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, the method for described creation supersaturated condition is intensification falling temperature method, anti-solvent additive process or vapor phase grafting.
Concrete, the preparation method of the crystal form B of aforesaid 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, described poly-hydroxy compounds is sugar alcohol.
Concrete, the preparation method of the crystal form B of aforesaid 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, described sugar alcohol is glucose, erythrose, threitol, arabitol, ribitol, N.F,USP MANNITOL, sorbyl alcohol, hexan-hexol, iditol, hydroxyl isomaltulose, maltose alcohol, Saccharum lactis, poly-poly-hydroxy sugar alcohol, or containing the biglycan of sugar unit, saccharan, glycopolymers molecule or cyclodextrin.
Medical composition, its crystal form B containing 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene is as effective constituent.
Crystal form B and one or more antidiabetics, antihyperglycemic agents and/or the other diseases therapeutic combination of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene use.
Concrete, aforesaid 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-the fluorophenyl)-2-thienyl methyl] crystal form B of benzene and the purposes of medical composition thereof: be used for the treatment of or delay diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing delay, insulin resistance, hyperglycemia, hyperinsulinemia, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, the complication of diabetes, atherosclerosis, hypertension or hyperuricemia.
Compared with prior art beneficial effect of the present invention is: the new preparation process of 1-of the present invention (β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene crystal form B may be used for the industrial production of crystal form B, and present method is also easy to carry out strict condition to be controlled, and reaches stably, repeatably produces crystal form B object.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction figure of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene crystal form B, the longitudinal axis represents peak intensity (cps), and transverse axis represents diffraction angle (2 θ [°]);
Fig. 2 is the X-ray powder diffraction figure of 1-in prior art (β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene semihydrate (crystal form A), the longitudinal axis represents peak intensity (cps), and transverse axis represents diffraction angle (2 θ [°]);
Fig. 3 is the X-ray powder diffraction figure of 1-in prior art (β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene crystal form II, the longitudinal axis represents peak intensity (cps), and transverse axis represents diffraction angle (2 θ [°]).
Embodiment
Below in conjunction with drawings and Examples, the specific embodiment of the present invention is described in further detail.Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
Prepare the crystal seed of crystal form B
The Canagliflozin semihydrate (crystal form A) of 50mg, is suspended in the water of 5mL, is then heated to 85 DEG C, add 20mg N.F,USP MANNITOL, stirs.With the rate of temperature fall of 10 degrees Celsius per hour, above-mentioned heated solution is cooled to 5 degrees Celsius.In temperature-fall period, obvious white solid is had to produce, these white solids of collecting by filtration.Use after seasoning 1h-NMR characterizes white solid, and nuclear magnetic data display white solid is only containing Canagliflozin and water.Nuclear magnetic data shows below: 1H NMR (d6-DMSO, 400 MHZ): 2.26 (3H, s), 3.13-3.28 (4H, m), 3.44 (1H, m), 3.69 (1H, m), 3.96 (1H, d, J=9.2HZ), 4.10, 4.15 (each 1H, d, J=16.0HZ), 4.44 (1H, t, J=5.6HZ), 4.73 (1H, d, J=6.0HZ), 4.92 (2H, d, J=4.8HZ), 6.80 (1H, d, J=3.6HZ), 7.11-7.16 (2H, m), 7.18-7.25 (3H, m), 7.28 (1H, d, J=3.6HZ), 7.59 (2H, dd, J=8.8, 5.4HZ).Carry out characterization test with XRPD to sample again, result display gained crystal formation is crystal form B.X-ray powder diffraction is done to the crystal formation in embodiment 1, operation and analytical procedure as follows:
In Cu K α radiation so that the Bruker D8 Discover x-ray powder diffraction instrument of GADDS (the general area diffraction detector system) CS of reflection mode operation to gather X-ray powder diffraction figure, tube voltage and the magnitude of current are set to 40kV and 40mA respectively, the 2 θ scope interscan sample times of 180 seconds of 3.0 ° to 40.0 °, for the peak position that 2 θ represent, use corundum standard product calibration diffractometer, normally implement all analyses under the room temperature of 20 DEG C-30 DEG C, use the GADDS of 4.1.14T version WNT software, gather and integration data.Use has 5.0.37 version JADE XRD diffractogram process software (Materials Data, Inc) and evaluates diffractogram.
The Bruker D8 Discover x-ray powder diffraction instrument of GADDS CS is implemented X-ray diffraction measure, usually sample is laid on monocrystalline silicon piece, sample powder is pressed gently by slide glass or equivalent, to guarantee that sample powder keeps smooth surface and suitable height, then the monocrystalline silicon piece being loaded with sample is put on the support of Bruker instrument, and uses above-described instrument parameter to gather x-ray diffractogram of powder.The measurement difference relevant to this kind of X-ray powder diffraction analytical results is produced: the error in (a) sample preparation thing (such as height of specimen) by comprising following many factors, (b) instrumental error, (c) calibration difference, (d) personal error (being included in the error occurred when measuring peak position), and the character of (e) material (such as preferred orientation error).Alignment error and sample height errors often cause the displacement of all peaks in equidirectional.When using flat support, the little difference of height of specimen will cause the Large travel range of XRPD peak position.The sample height difference of systematic study display 1mm can cause height to the peak shift of 2 θ of 1 °.These displacements can be identified from X-ray diffractogram, and can by compensate for described displacement (the system calibration factor being used for all peak positions value) or again calibration instrument eliminate described displacement.As mentioned above, make peak position consistent by application system calibration factor, recoverable is from the measuring error of different instrument.
The crystal form B of 1-of the present invention (β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, be at least 19.91 ± 0.2 in 2 θ values in its X-ray powder diffraction figure, 19.68 ± 0.2 and 6.33 ± 0.2 places have characteristic peak, can also comprise and be positioned at 9.46 ± 0.2, 24.78 ± 0.2, 24.19 ± 0.2, 12.37 ± 0.2, 15.31 ± 0.2, 22.9 ± 0.2, 12.62 ± 0.2, 28.85 ± 0.2, 15.52 ± 0.2, 15.88 ± 0.2, 26.86 ± 0.2, 27.14 ± 0.2, 21.27 ± 0.2, 19.00 ± 0.2, 17.48 ± 0.2, 16.79 ± 0.2, 29.73 ± 0.2, 30.01 ± 0.2, 22.49 ± 0.2, 18.24 ± 0.2, 34.08 ± 0.2, 33.66 ± 0.2, 37.46 ± 0.2, 37.23 ± 0.2, 13.71 ± 0.2, 21.81 ± 0.2, 15.03 ± 0.2, 27.42 ± 0.2, the characteristic peak at 18.03 ± 0.2 places, Fig. 1 shows the XRPD figure of this crystal formation, the diffraction peak of XRPD figure is listed in the table below.
Embodiment 2
Prepare crystal form B
The Canagliflozin semihydrate (crystal form A) of 156mg, be suspended in the water of 22mL, then 85 DEG C are heated to, with the speed of 10 DEG C/h, cool to 75 DEG C, add 10mg crystal form B crystal seed (preparing in embodiment 1), continue with the speed of 10 DEG C/h, cool to 5 DEG C, above operation all under agitation completes.Produce white solid after cooling, continue stirring and spend the night.Collecting by filtration white solid, and at room temperature vacuum-drying 1 hour.Dried solid is used 1h-NMR and XRPD analysis and characterization, result display gained crystal formation is crystal form B.
Embodiment 3
The Canagliflozin semihydrate (crystal form A) of 200mg, be suspended in (ethanol content 10% in the water/alcohol mixed solvent of 20mL, v/v), then be heated to 70 DEG C, with the speed of 10 DEG C/h, cool to 65 DEG C, add 10mg crystal form B crystal seed (implementing to prepare in 1), continue with the speed of 10 DEG C/h, cool to 5 DEG C, above operation all under agitation completes.Produce white solid after cooling, continue stirring and spend the night.Collecting by filtration white solid, and at room temperature vacuum-drying 1 hour.Dried solid is used 1h-NMR and XRPD analysis and characterization, result display gained crystal formation is crystal form B.
Embodiment 4
The Canagliflozin semihydrate (crystal form A) of 50mg, be suspended in (ethanol content 10%, v/v) in 3mL water, be then heated to 80 DEG C, with the speed of 10 DEG C/h, cool to 5 DEG C, above operation all under agitation completes.Produce white solid after cooling, continue stirring and spend the night.Collecting by filtration white solid, and at room temperature vacuum-drying 1 hour.Dried solid is used 1h-NMR and XRPD analysis and characterization, result display gained crystal formation is crystal form B.
Crystal form B and the medical composition thereof of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene prepared by the present invention may be used for following purposes: treatment, prevention or diabetes-alleviating (I type and type ii diabetes etc.), diabetic complication is (as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy), post prandial hyperglycemia, retardance wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, lipid acid blood level raises, the hemotoncus concentration of glycerine raises, hyperlipidemia, fat, increased TG, X syndrome, atherosclerosis or hypertension, the progress of hyperuricemia or morbidity.
The crystal form B of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene prepared by the present invention and pharmaceutically useful auxiliary material or carrier can oral or parenterai administrations, and use with other suitable pharmaceutical preparation form.Suitable solid dosage for oral administration comprises, such as tablet, granule, capsule, pulvis or solid dispersion etc., and the appropriate liquid formulation for oral administration comprises oral liquid, suspensoid, emulsion etc.Suitable preparation for parenterai administration comprises, such as suppository, injection, intravenous infusion agent, subcutaneous implant and suction preparation.1-of the present invention (β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene crystal form B has the activity relying on suction pressure inhibitor as sodium, and shows splendid blood sugar decreasing effect.
If desired, time, crystal formation of the present invention can use with one or more other antidiabetic, antihyperglycemic agents and/or other diseases therapeutic combination.The compounds of this invention and this other treatment agent can same dosage form or the oral dosage form separated or drug administration by injection.
The dosage of this therapeutical agent can be according to, such as age, body weight, illness symptom, route of administration, different from dosage form.People's dosage about, about 0.01 mg/day/kg body weight to 100 mg/day/kg body weight.
This medical composition can be applied in mammals, comprises the mankind, ape, dog, such as tablet, capsule, particle, or the dosage form of the injection of parenterai administration or intranasal administration or skin patch.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the prerequisite not departing from the technology of the present invention principle; can also make some improvement and modification, these improve and modification also should be considered as protection scope of the present invention.

Claims (12)

  1. The preparation method of the crystal form B of 1.1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, it is characterized in that, the method comprises the steps:
    A., mixture containing following molecular formula compound and water or nonelectrolyte mixed aqueous solution is provided;
    B. the crystal seed of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene crystal form B is added in the component obtained to step a;
    C. create supersaturated condition and make above-claimed cpd crystallization, obtain suspension;
    D. the suspension balance will obtained in step c;
    E. suspension is carried out solid-liquid separation, obtain target product.
  2. 2. the preparation method of the crystal form B of 1-according to claim 1 (β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, it is characterized in that, the JZPD capsule method of described 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene crystal form B comprises the steps:
    A., mixture containing following molecular formula compound and water or nonelectrolyte mixed aqueous solution is provided;
    B. poly-hydroxy compounds is added in the mixture obtained to step a;
    C. create supersaturated condition and make above-claimed cpd crystallization, obtain suspension;
    D. the suspension balance will obtained in Step d;
    E. suspension is carried out solid-liquid separation, obtain target product.
  3. 3. the preparation method of the crystal form B of 1-according to claim 1 (β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, it is characterized in that, the JZPD capsule method of described 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene crystal form B comprises the steps:
    A., mixture containing following molecular formula compound and water or nonelectrolyte mixed aqueous solution is provided;
    B. the mixture obtained in a step is heated to exist without solid;
    C. by the system in b step, cooling part makes above-claimed cpd crystallization, obtains suspension;
    D. the suspension balance will obtained in Step d;
    E. suspension is carried out solid-liquid separation, obtain target product.
  4. 4. the preparation method of the crystal form B of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-the fluorophenyl)-2-thienyl methyl] benzene according to any one of claim 1-3, it is characterized in that, the described mixed solvent containing water comprises the mixture of the alcohols of C1-C8, the ketone of C3-C6, nitrile, amides, sulfone class, ethers, amine, ester class and above-mentioned organic solvent thereof.
  5. 5. the preparation method of the crystal form B of 1-according to claim 4 (β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, it is characterized in that, the alcohols of described C1-C8 is: methyl alcohol, ethanol, propyl alcohol, propylene glycol, butanols, amylalcohol or octanol; The ketone of C3-C6 is: acetone, butanone, pentanone or Propiophenone; Nitrile is acetonitrile or butyronitrile; Amides is N,N-DIMETHYLACETAMIDE or dimethyl formamide; Sulfone class is dimethyl sulfoxide (DMSO); Ethers is ether or methyl ethyl ether; Amine is diethylamine, methylamine, ethamine or triethylamine quadrol.
  6. 6. the preparation method of the crystal form B of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-the fluorophenyl)-2-thienyl methyl] benzene according to claim 1-3, it is characterized in that, the described content containing water in the mixed solvent of water is not less than 10% volume ratio.
  7. 7. the preparation method of the crystal form B of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-the fluorophenyl)-2-thienyl methyl] benzene according to any one of claims 1 to 3, it is characterized in that, the method for described creation supersaturated condition is intensification falling temperature method, anti-solvent additive process or vapor phase grafting.
  8. 8. the preparation method of the crystal form B of 1-according to claim 2 (β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, it is characterized in that, described poly-hydroxy compounds is sugar alcohol.
  9. 9. the preparation method of the crystal form B of 1-according to claim 6 (β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, it is characterized in that, described sugar alcohol is glucose, erythrose, threitol, arabitol, ribitol, N.F,USP MANNITOL, sorbyl alcohol, hexan-hexol, iditol, hydroxyl isomaltulose, maltose alcohol, Saccharum lactis, poly-poly-hydroxy sugar alcohol, or containing the biglycan of sugar unit, saccharan, glycopolymers molecule or cyclodextrin.
  10. 10. medical composition, its crystal form B containing 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene is as effective constituent.
  11. Crystal form B and one or more antidiabetics, antihyperglycemic agents and/or the other diseases therapeutic combination of 11.1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene use.
  12. 12. 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] crystal form Bs of benzene as described in any one of claims 1 to 3 and the purposes of medical composition thereof: be used for the treatment of or delay diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing postpones, insulin resistance, hyperglycemia, hyperinsulinemia, hyperlipidemia, fat, hypertriglyceridemia, X syndrome, the complication of diabetes, atherosclerosis, hypertension or hyperuricemia.
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016041530A1 (en) * 2014-09-16 2016-03-24 Zentiva, K.S. Complexes of canagliflozin and cyclodextrins
WO2016191173A1 (en) * 2015-05-22 2016-12-01 Janssen Pharmaceutica Nv Anhydrous crystalline form of (1s)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-d-glucitol
WO2017084644A1 (en) 2015-11-20 2017-05-26 Zentiva, K.S. A crystalline form of canagliflozin and a method of its preparation
JP2018500368A (en) * 2014-12-25 2018-01-11 重慶医薬工業研究院有限責任公司 Canagliflozin crystal form I and process for producing the same
CN107693362A (en) * 2017-09-26 2018-02-16 侯马高知新生物科技有限公司 A kind of method for increasing mannitol particles granularity
WO2021185072A1 (en) * 2020-03-17 2021-09-23 广州再极医药科技有限公司 Crystal form of aromatic vinyl derivatives, and preparation method therefor and use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101801371A (en) * 2007-09-10 2010-08-11 詹森药业有限公司 The preparation method of the chemical compound of useful as inhibitors of sglt
CN103554092A (en) * 2013-11-11 2014-02-05 苏州晶云药物科技有限公司 New crystal form B of 1-(beta-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene and preparation method of new crystal form B
US20140128595A1 (en) * 2011-11-07 2014-05-08 Scinopharm Taiwan, Ltd. Process for the Preparation of ß-C-Aryl Glucosides

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101801371A (en) * 2007-09-10 2010-08-11 詹森药业有限公司 The preparation method of the chemical compound of useful as inhibitors of sglt
US20140128595A1 (en) * 2011-11-07 2014-05-08 Scinopharm Taiwan, Ltd. Process for the Preparation of ß-C-Aryl Glucosides
CN103554092A (en) * 2013-11-11 2014-02-05 苏州晶云药物科技有限公司 New crystal form B of 1-(beta-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene and preparation method of new crystal form B

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016041530A1 (en) * 2014-09-16 2016-03-24 Zentiva, K.S. Complexes of canagliflozin and cyclodextrins
JP2018500368A (en) * 2014-12-25 2018-01-11 重慶医薬工業研究院有限責任公司 Canagliflozin crystal form I and process for producing the same
CN108003149A (en) * 2014-12-25 2018-05-08 重庆医药工业研究院有限责任公司 A kind of canagliflozin crystal form I and preparation method thereof
WO2016191173A1 (en) * 2015-05-22 2016-12-01 Janssen Pharmaceutica Nv Anhydrous crystalline form of (1s)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-d-glucitol
WO2017084644A1 (en) 2015-11-20 2017-05-26 Zentiva, K.S. A crystalline form of canagliflozin and a method of its preparation
CN108349927A (en) * 2015-11-20 2018-07-31 赞蒂瓦有限合伙公司 The crystal form and preparation method of canagliflozin
US10457671B2 (en) 2015-11-20 2019-10-29 Zentiva K.S. Crystalline form of Canagliflozin and a method of its preparation
CN107693362A (en) * 2017-09-26 2018-02-16 侯马高知新生物科技有限公司 A kind of method for increasing mannitol particles granularity
WO2021185072A1 (en) * 2020-03-17 2021-09-23 广州再极医药科技有限公司 Crystal form of aromatic vinyl derivatives, and preparation method therefor and use thereof

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