CN108239055A - A kind of THR1442 L-Aspartic acids eutectic, preparation method and pharmaceutical composition - Google Patents
A kind of THR1442 L-Aspartic acids eutectic, preparation method and pharmaceutical composition Download PDFInfo
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- CN108239055A CN108239055A CN201710674102.5A CN201710674102A CN108239055A CN 108239055 A CN108239055 A CN 108239055A CN 201710674102 A CN201710674102 A CN 201710674102A CN 108239055 A CN108239055 A CN 108239055A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention relates to SGLT2 inhibitor THR1442 (Bexagliflozin) and the eutectic of L aspartic acids, and with known bis- proline eutectic phase ratios of THR1442, THR1442L aspartic acids eutectic of the invention has one or more improved characteristics.Preparation method, its pharmaceutical composition the invention further relates to THR1442L aspartic acid eutectics and its method for treating the disease influenced or illness by SGLT or SGLT2 inhibition.
Description
Technical field
This application involves pharmaceutical chemistry crystallization technique fields.Specifically, this application involves THR1442 and L-Aspartic acid
Eutectic and its preparation method and application and include the pharmaceutical composition of the eutectic.
Background technology
THR1442 is a kind of sodium glucose co-transporter 2 white 2 (SGLT2) inhibitor, can reduce diabetic's blood
Blood sugar concentration and glycosylated hemoglobin in liquid lose weight.
THR1442 chemical names are (2S, 3R, 4R, 5S, 6R) -2- (the chloro- 3- of 4- (- (4- (2- ring propoxyl group ethyoxyl) benzyls
Base) phenyl -6- (methylol)-tetrahydrochysene -2H- pyrans -3,4,5 triols, English name bexagliflozin, molecular formula is
C24H29ClO7, molecular weight 464.94, CAS 1118567-05-7, chemical structural formula is as follows：
Disclosed in patent CN102933592B and CN102177147A THR1442 crystal form and secondly proline eutectic and
Preparation method and its pharmaceutical composition, the fusing point that patent CN102177147A discloses two proline eutectics are 150 DEG C.
The present inventor has found to be prepared into according to the information that prior art CN102933592B patents provide in the course of the research
The bis- proline eutectic solids of THR1442 arrived have hygroscopicity height, meet water into oil, the irregular defect of granule-morphology.
In view of the prior art remains deficiency, the THR1442 solid forms with more advantage performances need to be developed.
Invention content
The object of the present invention is to provide eutectic of THR1442 and L-Aspartic acid and its preparation method and application and packets
Pharmaceutical composition containing the THR1442 L-Aspartic acids eutectic.With known bis- proline eutectic phase ratios of THR1442, the present invention
New eutectic there are one or more improved characteristics, it is specific to improve performance for example, with higher crystallinity, preferable outer
See pattern, relatively low hygroscopicity, preferable bin stability, preferable mobility and advantageous processing and treatment characteristic etc..Especially
It is, solid forms of the invention have relatively low hygroscopicity, preferable bin stability, preferable granule-morphology, preferable
Mobility and advantageous processing and treatment characteristic.
Purpose according to the present invention, the present invention provide THR1442 L-Aspartic acid eutectics.
The THR1442 L-Aspartic acids eutectic is anhydride, and structural formula is as schemed shown in (I)：
It is radiated using Cu-K α, the X-ray powder diffraction that the THR1442 L-Aspartic acids eutectic is represented with 2 θ angles
Figure has following characteristics peak：6.1 ± 0.2 °, 12.1 ± 0.2 °, 16.8 ± 0.2 °, 17.7 ± 0.2 °, 23.7 ± 0.2 ° and 24.4
±0.2°。
It is highly preferred that the THR1442L- aspartic acids eutectic with the X-ray powder diffraction figure that 2 θ angles represent with
Lower position has characteristic peak：6.1±0.2°、11.9±0.2°、12.1±0.2°、16.8±0.2°、17.7±0.2°、21.7±
0.2 °, 22.5 ± 0.2 °, 23.7 ± 0.2 °, 24.4 ± 0.2 °, 25.5 ± 0.2 °, 29.7 ± 0.2 ° and 35.9 ± 0.2 °.
It is further preferred that the THR1442 L-Aspartic acid eutectics, X-ray powder diffraction collection is following
There is characteristic peak and its relative intensity at 2 θ of the angle of diffraction：
Without limitation, a representative instance of the THR1442 L-Aspartic acids eutectic has X- as shown in Figure 2
Ray powder diffraction (XRPD) collection of illustrative plates.
Without limitation, a representative instance of the THR1442 L-Aspartic acids eutectic has DSC as shown in Figure 5
Collection of illustrative plates, display fusing point are 94 DEG C.
The FTIR spectrum of the THR1442 L-Aspartic acids eutectic wave number for 1510 ± 2,1236 ± 2,
1089 ± 2,1210 ± 2,1054 ± 2,1036 ± 2,1011 ± 2,986 ± 2,967 ± 2 and 900 ± 2cm-1Place has characteristic peak.
Purpose according to the present invention, the present invention provide the preparation method of THR1442 L-Aspartic acid eutectics, and feature exists
In the preparation method uses any one in following methods：
(1) by THR1442 solids in C1-C3Solution is formed in alcohol, L-Aspartic acid solid is formed into solution in water, is mixed
Close L-Aspartic acid aqueous solution and THR1442 alcoholic solutions, stirring and crystallizing by the crystal separation of precipitation, dry, obtains described
THR1442 L-Aspartic acid eutectics；
Preferably, the C1-C3Alcohol is ethyl alcohol；
Preferably, the time of the stirring is 3~7 days；
Preferably, the molar ratio of THR1442 solids and L-Aspartic acid is 1 in the preparation method:1~1:2；
Preferably, the operation temperature of the preparation method is 10~40 DEG C, more preferably room temperature；
Preferably, the mass volume ratio of THR1442 solids and the alcohol is 100~500mg in the preparation method：1mL,
More preferably 200~500mg：1mL；
(2) by THR1442 solids in C1-C3Solution is formed in alcohol, L-Aspartic acid solid is formed into solution in water, is mixed
L-Aspartic acid aqueous solution and THR1442 alcoholic solutions are closed, volatilize crystallization, obtains the THR1442 L-Aspartic acid eutectics；
Preferably, the C1-C3Alcohol is ethyl alcohol；
Preferably, the molar ratio of THR1442 solids and L-Aspartic acid is 1 in the preparation method:1~1:2；
Preferably, the volatilization temperature is 20~60 DEG C, more preferably 20~40 DEG C；
Preferably, a concentration of THR1442 solids of the THR1442 solution in the alcohol solubility 0.1~0.7
Times, more preferably 0.1~0.5 times.
The THR1442 L-Aspartic acids eutectic has the advantages that：
1. by the result of comparative example 1 it is found that the eutectic of the present invention and known bis- proline eutectic phase ratios of THR1442, tool
There is lower hygroscopicity.
2. the present invention eutectic room temperature, relative humidity 10%~90% drier in place 4 months, appearance,
XRPD and fusing point are all constant.
3. the eutectic of the present invention and known bis- proline eutectic phase ratios of THR1442, have more regular shape under PLM
Looks, when being conducive to preparation and the mixing of auxiliary material.
4. by the result of comparative example 2 it is found that eutectic and the known bis- proline eutectic phase ratios of THR1442 of the present invention,
There can be the stability of longer time in water.
5. by the fusing point in DSC figures it is found that the eutectic melting point of the present invention is than known bis- proline eutectic melting points of THR1442
Low about 60 DEG C, illustrate exploitation of the eutectic more suitable for preparations such as hot-melt extrudeds of the present invention.
More than beneficial property illustrates the stability and mobility that the eutectic of the present invention has had, and can better ensure that drug
Active constituent itself and preparation formulation containing THR1442 avoid and reduce quality during drug manufacture and/or storage etc.,
Safety and stability problem, such as active component content is uneven, impurity etc., avoids special and expensive packaging.
In any preparation method of the THR1442 L-Aspartic acid eutectics of the present invention：
It is indicated except no special, " room temperature " refers to 10~30 DEG C of temperature.
The conventional method of this field may be used, such as agitating mode includes magnetic agitation, machinery stirs in " stirring "
It mixes, mixing speed is 50~1800 revs/min, preferably 300~900 revs/min.
The conventional method of this field, such as centrifugation or filtering may be used in " separation ".It is preferred that it is filtered under diminished pressure, usually
It is filtered at room temperature with being less than the pressure of atmospheric pressure, preferably pressure is less than 0.09MPa.
Ordinary skill in the art completion may be used in " drying ", such as air drying, forced air drying or decompression are done
It is dry；It can depressurize or normal pressure, preferably pressure are less than 0.09MPa.Dry instrument and method are unrestricted, can be draught cupboard, drum
Wind baking oven, spray dryer, fluidized bed drying or vacuum drying oven；It can be carried out in the case where depressurizing or not depressurizing, preferably pressure is small
In 0.09Mpa.
Starting material THR1442 can refer to 10 described side of embodiment 2- embodiments in patent document CN102933592B
Method is prepared, and can be also commercially available by commercially available, the document is incorporated by way of quoting its full text in the application.
Further, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes treatment and/or prevention is effective
One or more THR1442L- aspartic acids eutectics of the present invention of amount or the THR1442L- being prepared by the method for the present invention
Aspartic acid eutectic and at least one pharmaceutically acceptable carrier.
Excipient in described pharmaceutical composition, is well known to those skilled in the art, the choosing of type, usage, dosage
It selects and is also well known to those skilled in the art.Such as including carbohydrate, cellulose and its derivates, starch or modified starch, solid
Inorganic matter such as calcium phosphate, dicalcium phosphate, hydroxyapatite, calcium sulfate, calcium carbonate, semisolid such as lipid or paraffin, adhesive
Such as microcrystalline cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, glidant such as glue
State silica, light anhydrous silicic acid, avicel cellulose, talcum powder or magnesium stearate, disintegrant such as Sodium Carboxymethyl Starch are handed over and are gathered
Tie up ketone, cross-linked carboxymethyl cellulose, sodium carboxymethylcellulose, dried corn starch, lubricant such as stearic acid, magnesium stearate, tristearin
Acyl fumaric acid sodium, polyethylene glycol.
The administration route of the pharmaceutical composition include oral, vein be subcutaneously injected, be injected into tissue administration, cutaneous penetration,
Rectally, intranasal administration etc..The pharmaceutical composition can be prepared into certain dosage form, can be according to administration route or needs
Solid-state or liquid.Solid oral dosage form, such as including tablet, granule, powder, pill and capsule；Liquid oral dosage form, example
Such as include solution, syrup, suspension, dispersant and emulsion；Injectable formulation, such as including solution, dispersant and jelly
Dry agent.Formula may be adapted to the quick-release, sustained release or controlled release of active constituents of medicine.Can be conventional, dispersible, chewable
, Orally dissolving or rapid melting preparation.
Described pharmaceutical composition can use that well known to a person skilled in the art methods to prepare.Prepare pharmaceutical composition
When, the THR1442L- aspartic acids eutectic of the present invention is mixed with one or more pharmaceutically acceptable excipient, optionally
Ground and other crystal forms, amorphous article, the eutectic of pharmaceutical THR1442 mix, optionally with one or more other medicines
Object active constituent mixes.Solid pharmaceutical preparation can be prepared by the techniques such as directly mixing, pelletizing.
Further, the present invention provides one or more THR1442L- aspartic acids eutectics of the present invention or by the present invention
The THR1442L- aspartic acids eutectic that preparation method obtains is preparing for treating and/or prevent one or more illnesss or not
Purposes in the drug of good situation, the illness or undesirable condition are medically to need selection to sodium dependent glucose corotation
The inhibited compounds of body SGLT are transported, wherein the illness or undesirable condition include I types and type-2 diabetes mellitus, hyperglycemia
Disease, diabetic complication, insulin resistance, metabolic syndrome, hyperinsulinemia, hypertension, hyperuricemia, obesity,
Oedema, dyslipidemia, chronic heart failure, atherosclerosis and cancer.
Further, the present invention provides a kind for the treatment of and/or prevents one or more illnesss or the method for undesirable condition, institute
State method include give needs patient treatment and/or prevention effective dose the present invention THR1442 eutectics or combination or its
Pharmaceutical composition, the illness or undesirable condition are that selection is medically needed to select the body that cotransports to sodium dependent glucose
Compound inhibited SGLT, wherein the illness or undesirable condition include I types and type-2 diabetes mellitus, hyperglycemia,
Diabetic complication, insulin resistance, metabolic syndrome, hyperinsulinemia, hypertension, hyperuricemia, obesity, water
Swollen, dyslipidemia, chronic heart failure, atherosclerosis and cancer etc..The patient includes but not limited to lactation and moves
Object.
Description of the drawings
Fig. 1 is the known of the described method preparations of embodiment 1F in referenced patent document CN102933592B
The X-ray powder diffraction collection of bis- proline eutectics of THR1442.
Fig. 2 is the known of the described method preparations of embodiment 1F in referenced patent document CN102933592B
The PLM collection of illustrative plates of bis- proline eutectics of THR1442.
Fig. 3 is the known of the described method preparations of embodiment 1F in referenced patent document CN102933592B
The isothermal adsorption collection of illustrative plates of bis- proline eutectics of THR1442.
Fig. 4 is the X-ray powder diffraction figure of THR1442 L-Aspartic acid eutectics that the embodiment of the present invention 1 is prepared
Spectrum.
Fig. 5 is the DSC collection of illustrative plates of THR1442 L-Aspartic acid eutectics that the embodiment of the present invention 1 is prepared.
Fig. 6 is the IR collection of illustrative plates of THR1442 L-Aspartic acid eutectics that the embodiment of the present invention 1 is prepared.
Fig. 7 is the isothermal adsorption collection of illustrative plates of THR1442 L-Aspartic acid eutectics that the embodiment of the present invention 1 is prepared.
Fig. 8 is the PLM collection of illustrative plates of THR1442 L-Aspartic acid eutectics that the embodiment of the present invention 1 is prepared.
Specific embodiment
It will be helpful to further understand the present invention by following embodiments, but be not used in limitation present disclosure.
Detecting instrument and method：
X-ray powder diffraction (XRPD)：Instrument is Bruker D8Advance diffractometer.Sample is in room temperature
Lower test.Testing conditions are as follows, angular range：3~40 ° of 2 θ, step-length：0.02 ° of 2 θ, speed：0.2 second/step.
Polarization microscope (PLM) collection of illustrative plates is picked up from XP-500E polarization microscopes (the limited public affairs of the rectangular optical instrument in Shanghai
Department).Object lens multiple is 4 times, and eyepiece multiple is 10 times, and the pattern of observing samples is simultaneously taken pictures.
Differential thermal analysis data (DSC) are picked up from TA Instruments Q200MDSC.Detection method is：Take 1~10 milligram
Sample be positioned in aperture aluminium crucible, with the heating rate of 10 DEG C/min 40mL/min dry N2Protection under by sample from
Room temperature rises to 200~250 DEG C.
Thermogravimetric analysis data (TGA) is picked up from TA Instruments Q500TGA.Detection method is：Take 5~15mg's
Sample is positioned in platinum crucible, by the way of high resolution detection is segmented, with the heating rate of 10 DEG C/min in 40mL/min
Dry N2Protection under sample risen to 300 DEG C from room temperature.
Dynamic moisture content adsorption analysis data and isothermal adsorption analysis data are picked up from TA Instruments Q5000TGA.
Detection method：The sample of 1-10mg is usually taken to be positioned in platinum crucible, N is dried in 10mL/min2Protection under investigate sample
Relative humidity from 0% to 80% to the weight change in 0% change procedure, software processing is used to obtain isothermal adsorption collection of illustrative plates.
Infrared spectrum analysis (IR) data are picked up from Bruker Tensor 27, using ATR equipment, in 600-4000cm-1
In the range of, acquire infrared absorption spectrum.
Nucleus magnetic hydrogen spectrum data (1HNMR it) picks up from Bruker Avance II DMX 500MHz nuclear magnetic resonance chemical analysers.Claim
1~5mg samples are measured, is dissolved into nuclear-magnetism sample cell and is detected with about 0.5mL deuterated reagents.
It is indicated except no special, embodiment operates at room temperature, and solvent ratio is volume ratio.
Various reagents used in embodiment are commercially available purchase unless otherwise instructed.
Preparation example 1
It is prepared according to embodiment [0110-0123] described method in patent document CN102933592B
THR1442。
1HNMR (500MHz, Methanol-d4):δ 7.38-7.27 (m, 3H), 7.13 (d, J=8.3Hz, 2H), 6.85
(d, J=8.4Hz, 2H), 4.13-4.03 (m, 5H), 3.91-3.87 (m, 1H), 3.87-3.83 (m, 2H), 3.71 (dd, J=
11.9,5.0Hz, 1H), 3.50-3.40 (m, 4H), 3.30 (d, J=9.1Hz, 1H), 0.59 (d, J=3.4Hz, 2H), 0.53-
0.48 (m, 2H) is shown as known THR1442.
Preparation example 2
Bis- proline of THR1442 is prepared in the described methods of embodiment 1F in referenced patent document CN102933592B
Eutectic.
Its X-ray powder diffraction collection is as shown in Figure 1.
Its PLM collection of illustrative plates is as shown in Figure 2.
Its isothermal adsorption collection of illustrative plates is as shown in Figure 3.
Embodiment 1
1 gained THR1442 solid sample 40mg of preparation example are taken, 0.2mL ethyl alcohol is added in and forms dissolved clarification liquid, take 11.4mgL- days
Winter propylhomoserin adds in 4mL water and is ultrasonically formed dissolved clarification liquid, L-Aspartic acid aqueous solution is added in the ethanol solution of THR1442, is precipitated
White casse after stirring 5 days at room temperature, is filtered under diminished pressure, and 40 DEG C of solid is dried in vacuo 10 hours, obtains 47.3mg THR1442
L-Aspartic acid eutectic, yield 92%.
Its X-ray powder diffraction collection is as shown in Figure 4.
Its DSC collection of illustrative plates is as shown in Figure 5.
Its IR collection of illustrative plates is as shown in Figure 6.
Its isothermal adsorption collection of illustrative plates is as shown in Figure 7.
Its PLM collection of illustrative plates is as shown in Figure 8.
Its nucleus magnetic hydrogen spectrum data is：1HNMR (500MHz, DMSO-d6):δ 7.33-7.22 (m, 2H), 7.16 (dd, J=
8.2,2.1Hz, 1H), 7.02 (d, J=8.5Hz, 2H), 6.77 (d, J=8.6Hz, 2H), 4.88 (dd, J=5.0,1.8Hz,
2H), 4.76 (d, J=5.8Hz, 1H), 4.38 (t, J=5.8Hz, 1H), 3.98-3.85 (m, 5H), 3.68-3.59 (m, 3H),
3.36 (dt, J=11.9,6.0Hz, 2H), 3.21-3.00 (m, 5H), 1.16 (s, 1H), 0.40 (q, J=2.9Hz, 2H), 0.35
(dt, J=8.4,5.2Hz, 2H) is shown as the eutectic of THR1442 and L-Aspartic acid.
Embodiment 2
1 gained THR1442 solid sample 40mg of preparation example are taken, 0.4mL isopropanol dissolved clarifications is added in, takes 11.5mg L- asparagus ferns
Propylhomoserin adds in 4mL water and is ultrasonically formed dissolved clarification liquid, L-Aspartic acid aqueous solution is added in the aqueous isopropanol of THR1442, is precipitated
White casse after stirring 3 days at 10 DEG C, is filtered under diminished pressure, and 10 DEG C of solid is dried in vacuo 48 hours, obtains 44.0mg THR1442
L-Aspartic acid eutectic, yield 85%.
Embodiment 3
1 gained THR1442 solid sample 50mg of preparation example are taken, 0.1mL methanol dissolved clarifications is added in, takes 14.3mgL- asparagus fern ammonia
Acid adds in 4mL water Ultrasonic Heating and forms dissolved clarification liquid, L-Aspartic acid aqueous solution is added in the methanol solution of THR1442, is precipitated
White casse after stirring 7 days at 40 DEG C, is filtered under diminished pressure, and 40 DEG C of solid is dried in vacuo 24 hours, obtains 55.9mg THR1442
L-Aspartic acid eutectic, yield 87%.
Embodiment 4
1 gained THR1442 solid sample 50mg of preparation example are taken, 0.1mL ethyl alcohol dissolved clarifications is added in, takes 28.6mgL- asparagus fern ammonia
Acid adds in 5mL water Ultrasonic Heating and forms dissolved clarification liquid, L-Aspartic acid aqueous solution is added in the ethanol solution of THR1442, is precipitated
White casse after stirring 5 days at room temperature, is filtered under diminished pressure, and 40 DEG C of solid is dried in vacuo 24 hours, obtains 55.5mg THR1442
L-Aspartic acid eutectic, yield 86%.
Embodiment 5
1 gained THR1442 solid sample 46.5mg of preparation example are taken, 2.0mL methanol dissolved clarifications is added in, takes 13.3mgL- asparagus fern ammonia
Acid adds in 3mL water and is ultrasonically formed dissolved clarification liquid, L-Aspartic acid aqueous solution added in the methanol solution of THR1442, and gained is molten
Liquid places 10 DEG C of volatilizations, obtains 57.0mg THR1442 L-Aspartic acid eutectics, yield 95%.
Embodiment 6
1 gained THR1442 solid sample 46.5mg of preparation example are taken, 10.0mL ethyl alcohol dissolved clarifications is added in, takes 20mgL- asparagus fern ammonia
Acid adds in 4mL water and is ultrasonically formed dissolved clarification liquid, L-Aspartic acid aqueous solution added in the ethanol solution of THR1442, and gained is molten
Liquid places 60 DEG C of volatilizations, obtains 56.2mg THR1442 L-Aspartic acid eutectics, yield 94%.
Embodiment 7
1 gained THR1442 solid sample 46.5mg of preparation example are taken, 14mL isopropanol dissolved clarifications is added in, takes 26.6mgL- asparagus ferns
Propylhomoserin adds in 5mL water Ultrasonic Heating and forms dissolved clarification liquid, L-Aspartic acid aqueous solution added in the aqueous isopropanol of THR1442,
Acquired solution is placed into 40 DEG C of volatilizations, obtains 55.6mg THR1442 L-Aspartic acid eutectics, yield 93%.
There is the same or similar XRPD collection of illustrative plates, DSC to scheme for the sample that embodiment 2~7 is prepared and the sample of embodiment 1
Spectrum, TGA collection of illustrative plates, IR collection of illustrative plates illustrate that 2~7 sample of embodiment and the sample of embodiment 1 are identical cocrystalization compounds.
Embodiment 8
It can be may include by typical tablet prepared by Conventional compression technology：
Embodiment 9
The THR1442 of the present invention and eutectic 25.7mg, the grape of L-Aspartic acid are included for the exemplary capsule of oral administration
Sugared bonding agent 122.8mg and magnesium stearate 1.5mg.Mixture by 30 mesh is sieved and is filled into No. 2 gelatine capsules.
Comparative example 1
Take known THR1442 and two proline eutectics prepared by preparation example 1 and prepared by embodiment 1 THR1442L- days
Winter propylhomoserin eutectic solid carries out crystal form hygroscopicity contrast experiment, and concrete operations are as follows：2~5mg samples is taken to carry out DVS tables respectively
Sign, investigates hygroscopicity of its crystal form in 0-80% relative humidity conditions.
Table 1：1 comparative experimental data of comparative example counts
As shown in Table 1, the bis- proline eutectic phase ratios of THR1442 obtained with prior art preparation, it is of the invention
THR1442L- aspartic acids eutectic hygroscopicity under 0-80%RH environment is lower, can effectively avoid preparing and storage waited
In journey as the preparation caused by the foeign elements such as ambient moisture it is non-machinable the problems such as.It is accurate in prepared by unit formulation to be conducive to
Quantitative and the later stage transport and storage, are more suitable for the application of preparation.
Comparative example 2
Take bis- proline eutectics of known THR1442 prepared by preparation example 1 and THR1442L- asparagus ferns prepared by embodiment 1
Propylhomoserin eutectic solid carries out water stability contrast experiment, and concrete operations are as follows：At room temperature, 5mg samples is taken to be positioned over 5mL respectively
In vial, 0.5mL water, 100 revs/min of mixing speed, the deployment conditions of observation sample system are added at room temperature.
Table 2：2 comparative experimental data of comparative example counts
As shown in Table 2, the bis- proline eutectic phase ratios of THR1442 obtained with prior art preparation, THR1442 of the invention
Better dispersion can be formed in L-Aspartic acid eutectic water, the use due to water in production process can be avoided to cause
The situation that sample topography, crystal form change, it is ensured that formulation products have better homogeneity, stability.
Cited all patents, patent application publication, patent application and non-patent publications, pass through in this specification
Reference is incorporated by herein with it.
The above description is merely a specific embodiment, but protection scope of the present invention is not limited thereto, any
Those skilled in the art disclosed herein technical scope in, can without the variation that creative work is expected or
It replaces, should be covered by the protection scope of the present invention.Therefore, protection scope of the present invention should be limited with claims
Subject to fixed protection domain.
Claims (8)
1. the eutectic of THR1442 and L-Aspartic acid of a kind of structural formula as shown in figure (I),
It is characterized in that, the eutectic has following characteristics peak with the X-ray powder diffraction figure that 2 θ angles represent：6.1±
0.2 °, 12.1 ± 0.2 °, 16.8 ± 0.2 °, 17.7 ± 0.2 °, 23.7 ± 0.2 ° and 24.4 ± 0.2 °.
2. THR1442L- aspartic acids eutectic according to claim 1, which is characterized in that penetrated with the X- that 2 θ angles represent
Line powder diagram has following characteristics peak：6.1±0.2°、11.9±0.2°、12.1±0.2°、16.8±0.2°、17.7±
0.2 °, 21.7 ± 0.2 °, 22.5 ± 0.2 °, 23.7 ± 0.2 °, 24.4 ± 0.2 °, 25.5 ± 0.2 °, 29.7 ± 0.2 ° and 35.9
±0.2°。
3. THR1442L- aspartic acids eutectic according to claim 2, which is characterized in that penetrated with the X- that 2 θ angles represent
Line powder diagram has characteristic peak and its relative intensity in following position：
4. according to any one of claims 1 to 3 THR1442L- aspartic acids eutectic, which is characterized in that the eutectic
FTIR spectrum wave number for 1510 ± 2,1236 ± 2,1089 ± 2,1210 ± 2,1054 ± 2,1036 ± 2,1011 ±
2nd, 986 ± 2,967 ± 2 and 900 ± 2cm-1Place has characteristic peak.
5. THR1442 according to claims 1 to 4 and the preparation method of L-Aspartic acid eutectic, which is characterized in that described
Preparation method uses any one in following methods：
(1) by THR1442 solids in C1-C3Dissolved clarification liquid is formed in alcohol, L-Aspartic acid solid is formed into solution in water, is mixed
L-Aspartic acid aqueous solution and THR1442 alcoholic solutions, stirring and crystallizing by the crystal of precipitation separation, dry, obtain described
The eutectic of THR1442 and L-Aspartic acid；
Preferably, the C1-C3Alcohol is ethyl alcohol；
Preferably, the time of the stirring is 3~7 days；
Preferably, the molar ratio of THR1442 solids and L-Aspartic acid is 1 in the preparation method:1~1:2；
Preferably, the operation temperature of the preparation method is 10~40 DEG C, more preferably room temperature；
Preferably, the mass volume ratio of THR1442 solids and the alcohol is 100~500mg in the preparation method：1mL, it is more excellent
It is selected as 200~500mg：1mL；
(2) THR1442 solids are formed into solution in C1-C3 alcohol, L-Aspartic acid solid is formed into solution in water, mixes L-
Aspartic acid aqueous solution and THR1442 alcoholic solutions, volatilize crystallization, obtains the eutectic of the THR1442 and L-Aspartic acid；
Preferably, the C1-C3Alcohol is ethyl alcohol；
Preferably, the molar ratio of THR1442 solids and L-Aspartic acid is 1 in the preparation method:1~1:2；
Preferably, the volatilization temperature is 10~60 DEG C, more preferably 10~40 DEG C；
Preferably, a concentration of THR1442 solids of the THR1442 solution are 0.1~0.7 times of solubility in the alcohol, more
Preferably 0.1~0.5 times；
6. a kind of pharmaceutical composition, it includes treat and/or the one or more of prevention condition effective amount are selected from claim 1
THR1442L- aspartic acids eutectic and at least one pharmaceutically acceptable carrier described in any one of~5.
7. drug described in the eutectic or claim 6 of THR1442 according to any one of claims 1 to 5 and L-Aspartic acid
Purposes of the composition in the drug for treating and/or preventing one or more illnesss or undesirable condition is prepared, the illness
Or undesirable condition be selected from I types and type-2 diabetes mellitus, hyperglycemia, diabetic complication, insulin resistance, metabolic syndrome,
Hyperinsulinemia, hypertension, hyperuricemia, obesity, oedema, dyslipidemia, chronic heart failure, artery are athero-
Hardening and cancer etc..
8. a kind of treat and/or prevent one or more illnesss or the method for undesirable condition, the method includes giving needs
Patient treat and/or prevention condition effective amount it is one or more selected from according to any one of claims 1 to 5
The eutectic of THR1442 and L-Aspartic acid, the illness or undesirable condition are selected from type-1 diabetes mellitus, type-2 diabetes mellitus and hyperglycemia
Disease etc..
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| CN113336733A (en) * | 2021-05-31 | 2021-09-03 | 北京惠之衡生物科技有限公司 | Preparation method of L-proline co-crystal of SGLT-2 inhibitor |
| WO2022073151A1 (en) * | 2020-10-05 | 2022-04-14 | Theracos Sub, Llc | Pharmaceutical formulations |
| WO2024062421A1 (en) | 2022-09-22 | 2024-03-28 | Macfarlan Smith Limited | Bexagliflozin in monohydrate, dihydrate or amorphous forms |
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| CN113336733A (en) * | 2021-05-31 | 2021-09-03 | 北京惠之衡生物科技有限公司 | Preparation method of L-proline co-crystal of SGLT-2 inhibitor |
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| WO2024062421A1 (en) | 2022-09-22 | 2024-03-28 | Macfarlan Smith Limited | Bexagliflozin in monohydrate, dihydrate or amorphous forms |
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| CN108239055B (en) | 2023-07-18 |
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