CN103936726B - Crystal, preparation method and its usage - Google Patents

Crystal, preparation method and its usage Download PDF

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CN103936726B
CN103936726B CN201410155712.0A CN201410155712A CN103936726B CN 103936726 B CN103936726 B CN 103936726B CN 201410155712 A CN201410155712 A CN 201410155712A CN 103936726 B CN103936726 B CN 103936726B
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methyl
benzene
glucopyranosyl
fluorophenyl
anhydrate
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CN103936726A (en
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王军
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Wang Jun
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings

Abstract

The present invention discloses crystal form II I and the form IV of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, its X-ray powder diffraction figure is at least that 6.61 ± 0.2,3.92 ± 0.2 and 19.68 ± 0.2 places and 17.40 ± 0.2,15.35 ± 0.2 and 14.91 ± 0.2 places have characteristic peak in 2 θ values respectively, and its preparation method and pharmaceutical usage. Crystal form II I is that octanol compound has more significantly action effect in treating diabetes effect. Form IV is anhydrate, purity height, prepares anhydrate drying process simple, and in preparation technology, anhydrate relative hydropathic thing has clear superiority.

Description

Crystal, preparation method and its usage
Technical field
The present invention relates to novel crystal of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene and its production and use.
Background technology
Diabetes are one group of internal secretion-metabolic troubles, jointly indicate taking hyperglycemia as it. The water and electrolyte metabolism definitely or relatively secreting the not enough sugar, protein, fat and the secondary that cause because of Regular Insulin is disorderly. It can relate to each system of whole body particularly eye, kidney, heart, blood vessel, neural chronic lesion, dysfunction, even bring out many mortality complication. Along with the aging of world population, diabetes have become a kind of common disease, frequently-occurring disease, are the diseases of a kind of serious harm humans health. Data shows, whole world diabetic subject is increased to 2.8 hundred million by 1.5 hundred million in 2000, it is contemplated that nearly 500,000,000 people will be had to suffer from diabetes to the year two thousand thirty whole world.
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 and saves in section compared with the S3 of far-end, absorbs the sugar of about 10%; Before SGLT2 is mainly expressed in kidney proximal tubule, SI saves in section, 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 is clean, 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene) is the oral antidiabetic drug that the medicine that U.S. FDA has been ratified is used for the treatment of diabetes B. This medicine is optionally sodium dependent glucose transporter (SGLT2) inhibitor.The clean molecular formula of Ka Gelie is C24H25FO5S, and its molecular weight is 444.52. The clean chemical structural formula of 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 preserves and raising curative effect of medication, it is necessary to medicine is made the state of crystal.
The clean existing brilliant type of Ka Gelie has following several. Disclosing Ka Gelie clean semihydrate structure in US2008/0146515A1 patent as follows, the X-ray powder diffraction figure of this crystalline substance type comprises following 2 θ values (recording with CuK 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 3, also reveal that the preparation method of the brilliant type of this semihydrate simultaneously.
In US2009/0233874A1 patent, also reveal that another kind of brilliant type that Ka Gelie is clean, Fig. 4 show the XRPD figure of this crystalline substance type, the diffraction peak of XRPD figure arranges in following table:
WO2013064909A2 patent discloses the Ka Gelie brilliant type of clean five kinds of eutectics, comprise Ka Gelie clean-L-PROLINE eutectic and Ka Gelie clean-eutectic of D-PROLINE-ethanolates, Ka Gelie is clean-the brilliant type of L-Phe monohydrate eutectic, Ka Gelie is clean-the brilliant type of L-Phe eutectic and Ka Gelie clean-the brilliant type of D-PROLINE eutectic.
Patent CN103641822A also discloses the brilliant type of the clean semihydrate of Ka Gelie, compares according to the comparison of XRPD figure and diffraction peak data, and the disclosed brilliant type of patent CN103641822A is substantially identical with crystalline substance type in US2009/0233874A1 patent. Patent CN103588762A and patent CN103554092A discloses Ka Gelie clean 3 new crystal called after crystal form B respectively, C, D. Wherein crystal form B and C are hydrate or solvate, and volatilizing in Aquo System obtains, and preparation method is difficult to amplify. In aqueous solvent system, easily obtain semihydrate crystal form A (the brilliant type of US2008/0146515A1) in addition, crystal form B and C preparation are produced interference. Brilliant type D is that heating obtains from crystal C.
As mentioned above, only proposing the brilliant type of the semihydrate of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, hydrate and eutectic, whether the brilliant type for other types exists both without recording also without enlightening.
Summary of the invention
The main purpose of the present invention is to provide the new crystal of a kind of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene and its preparation method and pharmaceutical usage.
The crystal form II I of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-the fluorophenyl)-2-thienyl methyl] benzene of the present invention, its X-ray powder diffraction figure is at least 6.61 ± 0.2 in 2 θ values, 3.92 ± 0.2 and 19.68 ± 0.2 places have characteristic peak, can also comprise and be positioned at 21.35 ± 0.2, 10.46 ± 0.2, 18.72 ± 0.2, 20.00 ± 0.2, 9.60 ± 0.2, 4.90 ± 0.2, 17.14 ± 0.2, 11.62 ± 0.2, 14.41 ± 0.2, 17.50 ± 0.2, 6.13 ± 0.2, 21.89 ± 0.2, 19.35 ± 0.2, 9.86 ± 0.2, the characteristic peak at 29.23 ± 0.2 places.
The crystal form II I of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene is octanol solvate.
Wherein in the octanol solvate of the crystal form II I of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, the mol ratio of octanol and 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene is 0.5:1～3:1, crystal form II I is carried out magnetic resonance detection, result is: 1HNMR (d6-DMS0, 400MHz): δ 0.86 (1.5H, t, J=8.0Hz), 1.25 (5H, br), 1.36-1.43 (1H, m), 2.26 (3H, s), 3.13-3.28 (4H, m), 3.37 (1H, q, J=7.0Hz), 3.44 (1H, m), 3.69 (1H, m), 3.96 (1H, d, J=9.2Hz), 4.10, 4.15 (each1H, d, J=16.0Hz), 4.32 (0.5H, t, J=5.2Hz), 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=3.56Hz), 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), from above result, the mol ratio of octanol and 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene is the most stable when being 0.5:1.
The form IV of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-the fluorophenyl)-2-thienyl methyl] benzene of the present invention, its X-ray powder diffraction figure is at least 17.40 ± 0.2 in 2 θ values, 15.35 ± 0.2 and 14.91 ± 0.2 places have characteristic peak, can also comprise and be positioned at 31.72 ± 0.2, 30.03 ± 0.2, 28.04 ± 0.2, 24.41 ± 0.2, 23.47 ± 0.2, 22.43 ± 0.2, 20.57 ± 0.2, 18.32 ± 0.2, 16.18 ± 0.2, 7.42 ± 0.2, 10.26 ± 0.2, the characteristic peak at 13.23 ± 0.2 places, form IV is anhydrate, fusing point is at 120 degrees centigrade.
Medical composition comprises the crystal form II I of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene and form IV as effective constituent.
Prepare the method for 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene crystal form II I, octanol or containing the solution of octanol in supersaturation precipitation or recrystallization prepare crystal form II I, from 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-the fluorophenyl)-2-thienyl methyl] benzole soln of crude product, amorphous or other brilliant types, by adding anti-solvent or the method for intensification-cooling, precipitate out solid, then after solid-liquid separation, obtain crystal form II I.
The method of the form IV of preparation 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, wherein one method is taking the crystal form II I of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene as starting raw material, is sloughed by the octanol in crystal form II I and obtains described form IV.
Another kind of method of the form IV of preparation 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-the fluorophenyl)-2-thienyl methyl] benzole soln of supersaturation adds the crystal seed of form IV, prepares described form IV by precipitation or recrystallization.
The crystal form II I of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-the fluorophenyl)-2-thienyl methyl] benzene of the present invention or form IV and one or more antidiabetics, antihyperglycemic agents and/or other diseases therapeutical agent combinationally use.
1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the crystal form II I of benzene of the present invention or the purposes of form IV and 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 or hypertension, subtract heavily, hyperuricemia.
Compared with prior art the useful effect of the present invention is: crystal form II I is the octanol solvate of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, this solvate inherently can be regarded as a kind of pharmaceutical composition existed with crystalline forms, owing to octanol connects blocker itself as gap, there is the effect reducing diabetic complication, such as pharmacological action and the neuroprotective of anti-myocardial oedema hypertrophy, therefore other brilliant type of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene it is compared to, crystal form II I is in treating diabetes effect, the prevention of diabetic subject's cardiovascular complication has more significantly action effect especially in early days.
Form IV is the brilliant type of anhydrate of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, namely lattice does not comprise the brilliant type of other molecule except drug molecule, make the brilliant type of medicine purer, the quality of compound is reduced under identical metering, such as, current FDA ratifies the brilliant type of semihydrate of clinical upper 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, the metering used is 300mg, if replacing the brilliant type of semihydrate only to need 294mg with the brilliant type of anhydrate, thus reduce the content of main component in preparation to a certain extent, reduce the difficulty of formulation development. in addition, the hydrate crystal forms (brilliant type I and crystal form II) of anhydrous crystal forms invention relatively before is relative simple in preparation technology, because hydrate crystal forms is easy dehydration in drying process, need rehydrated step, to generate the equal good hydrate crystal forms of quality, or the dry residual removing organic solvent under certain humidity condition, these two kinds of modes all need strict process regulation, more complicated, then drying process is simple to prepare anhydrate, do not need the problem considering water content, therefore in preparation technology, anhydrate relative hydropathic thing has clear superiority.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction figure of 1-of the present invention (β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene crystal form II I, 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-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene form IV, 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 semihydrate (brilliant type I), the longitudinal axis represents peak intensity (cps), and transverse axis represents diffraction angle (2 θ [°]);
Fig. 4 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 [°]);
Fig. 5 is the DSC figure of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene anhydrate (form IV), the longitudinal axis represents hot-fluid (mW), upwards, transverse axis represents temperature (DEG C) to endotherm(ic)peak;
Fig. 6 is the TGA figure of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene anhydrate (form IV), the longitudinal axis represents quality change percentage ratio (%), and transverse axis represents temperature (DEG C);
Fig. 7 is the DVS figure of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene anhydrate (form IV), the longitudinal axis represents quality change percentage ratio (%), and transverse axis represents target relative humidity (%);
Fig. 8 is that 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene anhydrate (form IV) is before and after DVS test, X-ray powder diffraction compares figure, top is sample before test, bottom is the XRPD figure of sample after test, 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 are for illustration of the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
Taking about 10mg1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene adds in vial, 0.4mL n-Octanol is added by sample dissolution to clear under room temperature condition, then sample be placed under 5 DEG C of conditions hold over night (12h), precipitation obtains solid, suspension liquid is placed in and filters centrifuge tube, 4000rpm centrifuging 3 minutes, obtain solid XRPD and carry out brilliant type detection according to the method that this patent specifies, and with the molar ratio of 1H core Magnetic testi octanol and 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene. showing gained solid position by XRPD result is crystal form II I, and the mol ratio of octanol and 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene is 0.5:1. X-ray powder diffraction in this patent, operation and analytical procedure are as follows:
(1.54A) is radiated at CuK α, the BrukerD8DiscoverX ray powder diffractometer of GADDS (the general area diffraction detector system) CS operated in the mode of reflecting gathers 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 substance 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 JADEXRD diffractogram process software (MaterialsData, Inc) and evaluates diffractogram.
The BrukerD8DiscoverX ray powder diffractometer of GADDSCS 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 prepared product (such as height of specimen) by comprising following multiple factor, (b) instrumental error, (c) calibration difference, d () operator error (is included in the error occurred when measuring peak position), and the character of (e) material (such as preferred directed error). Alignment error often causes the displacement of all peaks in identical direction with sample height errors. 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 (system calibration factor is used for all peak positions value) or again calibration instrument eliminate described displacement. As mentioned above, it is necessary, make peak position consistent by application system calibration factor, the measuring error from different instrument can be corrected.
The crystal form II I of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene prepared by the present invention, its X-ray powder diffraction figure is 6.61 ± 0.2 in 2 θ values, 3.92 ± 0.2, 19.68 ± 0.2, 21.35 ± 0.2, 10.46 ± 0.2, 18.72 ± 0.2, 20.00 ± 0.2, 9.60 ± 0.2, 4.90 ± 0.2, 17.14 ± 0.2, 11.62 ± 0.2, 14.41 ± 0.2, 17.50 ± 0.2, 6.13 ± 0.2, 21.89 ± 0.2, 19.35 ± 0.2, 9.86 ± 0.2, 29.23 ± 0.2 places have characteristic peak, diffracting spectrum is as shown in Figure 1, the diffraction peak of the XRPD figure of crystal form II I arranges in following table:
Crystal form II I is octanol solvate, the mol ratio of octanol and 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, between 0.5:1～3:1, is generally mol ratio 0.5:1 when stability.The solvate of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene and octanol is carried out magnetic resonance detection, result is: 1HNMR (d6-DMS0, 400MHz): δ 0.86 (1.5H, t, J=8.0Hz), 1.25 (5H, br), 1.36-1.43 (1H, m), 2.26 (3H, s), 3.13-3.28 (4H, m), 3.37 (1H, q, J=7.0Hz), 3.44 (1H, m), 3.69 (1H, m), 3.96 (1H, d, J=9.2Hz), 4.10, 4.15 (each1H, d, J=16.0Hz), 4.32 (0.5H, t, J=5.2Hz), 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=3.56Hz), 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), from above result, the mol ratio of octanol and 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene is 0.5:1.
Embodiment 2
Taking about 10mg1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene adds in vial, the n-Octanol adding 0.5mL under room temperature condition is extremely clear by sample dissolution, then 3.05mL normal heptane is added gradually, crystallization solid, suspension liquid is placed in and filters centrifuge tube, 4000rpm centrifuging 3 minutes, obtains the XRPD method described in solid embodiment 1 and detects, and is crystal form II I.
Embodiment 3
Take about 10mg1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene to adding in vial, the n-Octanol adding 0.5mL under room temperature condition is extremely clear by sample dissolution, in negate solvent 3mL to 20mL vial, the 1.5mL vial that this compound n-Octanol solution is housed is put into 20mL vial, anti-solvent gas is allowed to diffuse in sample solution, suspension liquid is placed in and filters centrifuge tube, 4000rpm centrifuging 3 minutes, obtain the XRPD method described in solid embodiment 1 to detect, for crystal form II I. herein, anti-solvent can also with normal hexane, pentane, hexanaphthene, toluene, normal heptane etc.
Embodiment 4
Taking about 600mg1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene crystal form II I (for the preparation of arbitrary of the embodiment of the present invention 1～3) adds in vial, add 45mL normal heptane again, then after stirring 24 hours under sample is placed on 40 DEG C of conditions, filtration under diminished pressure obtains solid, wash with normal heptane again, it is placed in vacuum drying oven, during room temperature in vacuo 24 hour, obtain the XRPD method described in solid embodiment 1 to detect, it is form IV.
The form IV of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene prepared by the present invention, its X-ray powder diffraction figure is 17.40 ± 0.2 in 2 θ values, 15.35 ± 0.2, 14.91 ± 0.2, 31.72 ± 0.2, 30.03 ± 0.2, 28.04 ± 0.2, 24.41 ± 0.2, 23.47 ± 0.2, 22.43 ± 0.2, 20.57 ± 0.2, 18.32 ± 0.2, 16.18 ± 0.2, 7.42 ± 0.2, 10.26 ± 0.2, the characteristic peak at 13.23 ± 0.2 places, as shown in Figure 2, the diffraction peak of the XRPD figure of form IV arranges in following table:
Form IV in embodiment 4 doing poor gesture scanning amount heat (DSC) analyze, operation and analytical procedure are as follows:
Perkin-ElmerDSC carries out dsc (DSC).By the sample weighing of 1-3mg is entered aluminium dish, then use aluminium lid envelope lid. The sample prepared is put into instrument analyze. Instrument condition is, tests, and under nitrogen purge (25ml/min), with 10 DEG C/every minute, sample is heated to 180 DEG C from 50 DEG C. The data that instrument gathers process with DataAnalysis (version: 10.1.0.0412) software analysis.
NETZSCHTG instrument carries out thermogravimetric (TGA) analytical procedure. By the sample of 1-3mg is added Al2O3Crucible, puts into instrument and analyzes. Instrument condition is, tests, and under nitrogen purge (25ml/min), with 10 DEG C/every minute, sample is heated to 400 DEG C from 30 DEG C.
Dynamic vapor adsorption (DVS) is analyzed and is carried out on surface measurement system (SMS) DVSIntrinsic moisture absorption analyser. Described instrument is controlled by SMSAnalysisSuite software (DVS-IntrinsicControlvl.0.0.30). MicrosoftExcel2007 and DVSStandardAnalysisSuite is used data to be analyzed. Sample temperature is remained on 25 DEG C and Sample moisture obtains as follows: nitrogen wet gas current and nitrogen dry gas stream are mixed with the overall flow rate of 200ml/min. Relative humidity uses calibrated Rotronic probe (dynamicrange is 1-100% relative humidity (RH)) being positioned near sample to measure. Constantly by microbalance (accuracy is scholar 0.005mg), the example weight change as %RH function is monitored. Usually, carry out XRPD before analysis. Then at ambient conditions 3-10mg sample is placed in the stainless steel basket through claiming tare weight. Start under 40% relative humidity: (typical indoor conditions) load and unloading sample also last 2 cycles and make sample stand gradual DVS scheme, wherein use the parameter shown in following table. Calculate DVS thermoisopleth by these data and carry out final XRPD after analysis to check the change of solid-state form.
Form IV is in 120 degrees centigrade melting heat releases, and fusing point is 122.7 degrees Celsius (peak values), as shown in Figure 5. Form IV is before melting (before 120 degrees Celsius), and weight loss on heating is only 0.9%, proves that form IV is anhydrate, as shown in Figure 6. The water absorbability of form IV and the physical stability to humidity are adsorbed instrument (DVS) by dynamic water and are investigated. Under result is displayed in the relative humidity of 80%, the form IV moisture absorption of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene is 0.56%, illustrate that form IV only has slight water absorbability, it is beneficial to pharmacy exploitation. In addition, absorption and De contamination process be reversible, and adsorb and De contamination curve do not form back stagnant ring, as shown in Figure 7, even if illustrating when high humidity, it does not have generation hydrate. Before and after dynamic water adsorption test, form IV does not change, and as shown in Figure 8, also illustrates that form IV also has good physical stability under high humidity environment.
The crystal form II I of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene prepared by the present invention or form IV and medical composition thereof may be used for following purposes: treatment, prevention or diabetes-alleviating (I type and type ii diabetes etc.), diabetic complication is (such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy), postprandial hyperglycemia disease, retardance wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, in fat acidemia, concentration raises, the hemotoncus concentration of glycerine raises, hyperlipidemia, fat, increased TG, X syndrome, atherosclerosis or hypertensive progress or morbidity, hyperuricemia can also be used for the treatment of.
The crystal form II I of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene prepared by the present invention or form IV and pharmaceutically useful auxiliary material or carrier can oral or parenterai administration, 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-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] the benzene crystal form II I of the present invention has the activity relying on suction pressure inhibitor as sodium, and shows extremely good blood sugar decreasing effect.
If desired, time, the brilliant type of the present invention can combinationally use with one or more other antidiabetic, antihyperglycemic agents and/or other diseases therapeutical agent. 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, and such as age, body weight, ill symptom, route of administration are 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, with 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 is noted that for those skilled in the art, under the prerequisite not departing from the technology of the present invention principle; can also making some improvement and modification, these improve and modification also should be considered as protection scope of the present invention.

Claims (4)

  1. The brilliant type of the anhydrate of 1.1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, it is characterized in that, its X-ray powder diffraction figure is at least that 17.40 ± 0.2,15.35 ± 0.2,14.91 ± 0.2,20.57 ± 0.2,10.26 ± 0.2 and 22.43 ± 0.2 places have characteristic peak in 2 θ values.
  2. 2. medical composition, it contains crystal according to claim 1 as effective constituent.
  3. 3. prepare the method for the brilliant type of anhydrate of 1-according to claim 1 (β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, it is characterized in that, 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene octanol or containing octanol solution in supersaturation precipitation or recrystallization, obtain the brilliant type of octanol solvate of benzene, then the octanol in brilliant for the octanol solvate of benzene type is sloughed the brilliant type of the anhydrate obtaining described 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene.
  4. 4. prepare the method for the brilliant type of anhydrate of 1-according to claim 1 (β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, it is characterized in that, 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-the fluorophenyl)-2-thienyl methyl] benzole soln of supersaturation adds the crystal seed of the brilliant type of anhydrate of described 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, prepares described brilliant type by precipitation or recrystallization.
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CN103936726B (en) * 2014-04-18 2016-06-15 王军 Crystal, preparation method and its usage
CN104530024B (en) * 2015-02-04 2017-08-08 上海迪赛诺药业有限公司 Crystal formation of 1 (β D glycopyranosyls) 4 methyl 3 [5 (4 fluorophenyl) 2 thienyl methyls] benzene and preparation method thereof
JP2018087140A (en) * 2015-02-27 2018-06-07 田辺三菱製薬株式会社 NOVEL CRYSTAL OF 1-(β-D-GLUCOPYRANOSYL)-4-METHYL-3-[5-(4-FLUOROPHENYL)-2-THIENYLMETHYL]BENZENE
EP3298007B1 (en) * 2015-05-22 2020-07-22 Janssen Pharmaceutica NV Anhydrous crystalline form of (1s)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-d-glucitol
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