CN105461650B - Solvate of Yi Zhong oxadiazole compounds and preparation method thereof - Google Patents
Solvate of Yi Zhong oxadiazole compounds and preparation method thereof Download PDFInfo
- Publication number
- CN105461650B CN105461650B CN201410464639.5A CN201410464639A CN105461650B CN 105461650 B CN105461650 B CN 105461650B CN 201410464639 A CN201410464639 A CN 201410464639A CN 105461650 B CN105461650 B CN 105461650B
- Authority
- CN
- China
- Prior art keywords
- fluorophenyls
- bases
- oxadiazole
- benzoic acid
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to 3, [the dimethylsulfoxide solvent compound of 5 (2 fluorophenyls) [1,2,4] oxadiazoles, 3 base] benzoic acid, its stability is good, purity is high, granule-morphology is good, is adapted to pharmaceutical preparation application.The invention further relates to the preparation method of the dimethylsulfoxide solvent compound, its pharmaceutical composition and its preparing the purposes in being used to treat the medicine of genetic disease.
Description
Technical field
The present invention relates to medicine crystal technical field.In particular to it is a kind of [1,2,4] oxadiazole compounds, especially
It is that [the dimethylsulfoxide solvent compound of 5- (2- fluorophenyls)-[1,2,4] oxadiazole -3- bases] benzoic acid, the invention further relates to institute by 3-
State the preparation method, its pharmaceutical composition and purposes of dimethylsulfoxide solvent compound.
Background technology
3- [5- (2- fluorophenyls)-[1,2,4] oxadiazole -3- bases] benzoic acid (English name ataluren, also known as
PCT124) be a kind of oral experimental drug for being developed by PTC Therapeutics Inc. of the U.S., it is intended to by the albumen of function of creation come
The rare property disease caused by nonsense mutation is corrected, Duchenne/Becker types myotrophy caused by for treating nonsense mutation is not
The genetic diseases such as good (DMD/BMD) and cystic fibrosis (cystic fibrosis, CF), are currently in the clinical III phases.Nonsense
Too early stop code mutation (premature stop codon mutations) is also named in mutation (nonsense mutations), makes
The process of cell synthetic protein stops too early, has finally synthesized truncated non-functional albumen.About 10~15%
DMD/BMD patient belongs to nonsense mutation.The Design Mechanism of ataluren is cell is ignored gene mutation in synthetic protein
Caused by too early stop code, complete protein synthesis overall process.
[molecular formula of 5- (2- fluorophenyls)-[1,2,4] oxadiazole -3- bases] benzoic acid is C to 3-15H9FN2O3, molecular weight is
284.25 chemical structural formula is as follows：
Patent document WO2004091502A2 and WO2008030570A1 disclose ataluren and preparation method thereof.
Patent document WO2008039431A2 discloses the A crystal forms of ataluren, B crystal form and preparation method thereof, is used in combination
XRPD, DSC, TGA, FTIR, DVS and13C-NMR characterizes it.For convenience, referred to as they are " in the present invention
The A crystal forms known " and " known B crystal form ".
The present inventor has carried out known A crystal forms and B crystal form to repeat experiment and nature examination, the results show：Known A
Crystal form and B crystal form are acicular crystal.The general mobility of acicular crystal is bad, and bulk density is low, it is difficult to filtering and dry, influence
The operability of preparation processing；In addition, acicular crystal need to could be used for the pharmaceutical preparation of solid dosage forms through crushing, and crush to crystalline substance
Type can form destruction, be unfavorable for the stability of crystal form and the storage stability of preparation.
In order to meet strict demand of the pharmaceutical preparation for active constituents of medicine, expand the raw material shape selected by formulation development
State, this area still need the novel crystal forms of exploitation ataluren.
The content of the invention
The object of the present invention is to provide the novel crystal forms of ataluren to solve the problems, such as that known crystal form exists.Meanwhile this hair
The bright preparation method for further relating to the novel crystal forms, its pharmaceutical composition and purposes.
Purpose according to the present invention, the present invention provide the dimethylsulfoxide solvent compound of ataluren (in the present invention referred to as
For " dimethylsulfoxide solvent compound "), it is ataluren and dimethyl sulfoxide (DMSO) with about 1:The compound that 1 molar ratio is formed, its structure
Formula is as follows：
Radiated using Cu-K α, the dimethylsulfoxide solvent compound is existed with the X-ray powder diffraction collection that 2 θ angles represent
Following position has characteristic peak：5.6 ± 0.2 °, 15.0 ± 0.2 °, 16.7 ± 0.2 °, 20.5 ± 0.2 °, 22.3 ± 0.2 ° and
27.0±0.2°。
In a currently preferred embodiment, X-ray that the dimethylsulfoxide solvent compound is represented with 2 θ angles
Powder diffraction spectrum has characteristic peak in following position：5.6±0.2°、15.0±0.2°、16.7±0.2°、20.5±0.2°、
22.3 ± 0.2 °, 24.1 ± 0.2 °, 25.0 ± 0.2 ° and 27.0 ± 0.2 °.
In the preferred embodiment of the present invention, the dimethylsulfoxide solvent compound is penetrated with the X- that 2 θ angles represent
Line powder diffraction spectrum has characteristic peak and its relative intensity in following position：
Without limitation, a representative instance of the dimethylsulfoxide solvent compound has X-ray powder as shown in Figure 3
Last diffraction pattern.
The FTIR spectrum of the dimethylsulfoxide solvent compound wave number for 1688,1620,1554,1466,1368,
1295th, 1252,1152,1004,959,823,746,720 and 667cm-1Place has characteristic peak.
Without limitation, a representative instance of the dimethylsulfoxide solvent compound is red with Fourier as shown in Figure 6
External spectrum (IR) figure.
Thermogravimetric analysis (TGA) collection of illustrative plates of the dimethylsulfoxide solvent compound is shown：The weightlessness 18.80% before 150 DEG C, about
Unification molecule ataluren combines a molecule dimethyl sulfoxide.
Compared with known A crystal forms and B crystal form, dimethylsulfoxide solvent compound of the invention has with least one following
Beneficial property：Stability is good, such as stability of crystal form, thermal stability, chemical stability, mechanical stability, bin stability etc.；
Dissolubility is good；Dissolution rate is fast；Crystallinity is high；It is not easy to moisture absorption；It is easy to purify and handles；Chemical purity is high；Low-residual solvent；
Particle shape looks are good；Suitable preparation machinability such as good fluidity, favourable powder viscosity, tight ness rating and rammability；Improve medicine
The bioavilability of thing；Extend preparation storage life；It is adapted to novel form application etc..Particularly dimethylsulfoxide solvent compound of the invention
With following beneficial property and application effect：
(1) dimethylsulfoxide solvent compound of the invention is bulk crystals, and granule-morphology is good, relative to the needle-shaped of known crystal form
Crystal, there is more preferable mobility, compressibility and machinability, is conducive to the stability of crystal form and the storage stability of preparation.
(2) dimethylsulfoxide solvent compound of the invention room temperature, 10%~90%RH of relative humidity drier in place 4
A month, crystal form was constant.Illustrate the excellent storage stability of dimethylsulfoxide solvent compound of the present invention, be suitable as the activity of pharmaceutical preparation
Component, can preferably resist medicine manufacture and/or storage etc. during the activity as caused by the factors such as environment temperature, humidity into
Divide the problems such as content is uneven, purity reduces, impurity increase, reduce the effect of thus bringing downside risk and security risk, and
Be conducive to the accurate quantitative analysis in medicine manufacture, improve preparation homogeneity, and facilitate the storage and transport in later stage.
(3) compared with known ataluren and its crystal form, dimethylsulfoxide solvent compound of the invention has the pure of higher
Degree, its HPLC purity are more than 99.0%.Active ingredient has high-purity, can reduce the undesirable toxicity effect that impurity may be brought
Should, it is more suitable for clinical drug application.
Purpose according to the present invention, the present invention provides the preparation method of the dimethylsulfoxide solvent compound, using following systems
Any one in Preparation Method：
(1) dimethyl sulfoxide solution of ataluren is mixed with anti-solvent, wherein the anti-solvent be selected from water, isopropyl ether,
Acetonitrile or its mixture, stirring and crystallizing, obtain the dimethylsulfoxide solvent compound.
Preferably, the anti-solvent is selected from water or acetonitrile.
Preferably, the volume of the anti-solvent is 1~4 times of dimethyl sulfoxide volume；More preferably 2~4 times.
Preferably, the temperature of the crystallization is 25~60 DEG C；More preferably 25~40 DEG C.
Preferably, when the time of the crystallization is 1~5 small；More preferably 1~3 it is small when.
Preferably, the concentration of the dimethyl sulfoxide solution is the dissolving in dimethyl sulfoxide of ataluren under recrystallization temperature
0.2~1 times of degree；More preferably 0.5~1 times.
The dimethyl sulfoxide solution of the ataluren and the hybrid mode of anti-solvent can be selected from：(i) to ataluren's
Anti-solvent is added in dimethyl sulfoxide solution, the dimethyl sulfoxide solution of ataluren is added in anti-solvent by (ii),
Preparation method (1) employs the crystallization mode of " anti-solvent recrystallization ", is that sample is dissolved in good solvent to be formed
Solution, then mixed with appropriate anti-solvent, using dissolubility difference of the sample in different solvents, separate out crystal.
(2) by ataluren in the in the mixed solvent or dimethyl sulfoxide of dimethyl sulfoxide and organic solvent and the mixed solvent of water
Middle formation suspension, wherein the organic solvent is selected from isopropyl ether, acetonitrile or its mixture, dimethyl sulfoxide and organic solvent or two
The volume ratio of first sulfoxide and water is 1:1~1:4, stirring and crystallizing, obtains the dimethylsulfoxide solvent compound.
Preferably, the organic solvent is acetonitrile.
Preferably, the in the mixed solvent dimethyl sulfoxide of the dimethyl sulfoxide and organic solvent and the volume ratio of organic solvent are
1:2~1:4, the in the mixed solvent dimethyl sulfoxide of the dimethyl sulfoxide and water and the volume ratio of water are 1:2~1:4.
Preferably, the temperature of the crystallization is 10~60 DEG C；More preferably 30~50 DEG C.
Preferably, the time of the crystallization is 1~5 day；More preferably 1~3 day.
Preferably, the dosage of ataluren is its dissolving in the in the mixed solvent under recrystallization temperature in the suspension
2~10 times of degree；More preferably 2~5 times.
Preparation method (2) employs the crystallization mode of " magma ", is (to have undissolved solid to deposit the supersaturated solution of sample
) stir in a solvent, obtain required crystal.
In the preparation method of above-mentioned dimethylsulfoxide solvent compound, starting material ataluren can be published
Ataluren compounds, its various crystal forms or amorphous article, such as include but not limited to according to patent document
2 method of WO2004091502A2 embodiments prepare ataluren, according to patent document WO2008039431A2 embodiments
5.1.1.1 A crystal forms or according to patent document WO2008039431A2 embodiments known to the ataluren that prepared by method
5.1.2.1 B crystal form known to the ataluren that prepared by method.
In the preparation method of above-mentioned dimethylsulfoxide solvent compound：
" stirring ", can use the conventional method of this area to complete, agitating mode such as magnetic agitation, mechanical agitation
It is 50~1800 revs/min Deng, mixing speed, is preferably 300~900 revs/min.
The dimethylsulfoxide solvent compound obtained according to the preparation method crystallization, can use the ordinary skill in the art into
One step is separated, washed and dried.The separation, such as filtering or centrifugation；Filtering be usually at ambient temperature with less than
The pressure of atmospheric pressure is filtered, and preferably pressure is less than 0.09MPa；The concrete operations of centrifugation are：Separated sample is intended to be placed in
In centrifuge tube, centrifuged with 6000 revs/min of speed, until solid is all sink to centrifugation bottom of the tube.It is excellent to wash solvent for use
Choosing is identical with solvent for use in crystal preparation method, and the dosage of cleaning solvent is solvent for use volume in crystal preparation method
0.3~1 times.The drying, such as air drying, forced air drying or be dried under reduced pressure, drying equipment is fume hood, convection oven or
Vacuum drying oven；It can be carried out in the case where depressurizing or not depressurizing, preferably pressure is less than 0.09Mpa；About 20~60 DEG C of drying temperature, preferably
For 20~40 DEG C；When drying time is 10~48 small, when being preferably 10~24 small.
In the present invention, " room temperature " refers to about 10~30 DEG C of temperature.
Dimethylsulfoxide solvent compound of the present invention, is pure, single, does not mix any other crystal form substantially.This
In invention, " not having substantially " refers to this crystal form and contains other crystal forms less than 20% (weight), especially when being used to refer to novel crystal forms
Refer to less than 10% (weight) other crystal forms, more refer to other crystal forms less than 5% (weight), more refer to less than 1% (weight) its
His crystal form.
In the present invention, " crystal " or " crystal form " refers to what is confirmed by shown X-ray diffractogram characterization.This area skill
Art personnel are it is understood that experimental error therein depends on condition, the preparation of sample and the purity of sample of instrument.Particularly,
Well known to those skilled in the art, X-ray diffractogram would generally be changed with the condition of instrument.In particular
It is that the relative intensity of X-ray diffractogram may also change with the change of experiment condition, so the order of peak intensity cannot be made
For unique or deciding factor.In addition, the experimental error of peak angle degree, usually 5% or less, the error of these angles also should
It is considered into, allows generally for ± 0.2 error.Further, since the influence of the empirical factor such as height of specimen, can cause peak angle
The overall offset of degree, allows generally for certain offset.Thus, it will be appreciated by persons skilled in the art that any have and this
The same or similar crystal form of characteristic peak of invention collection of illustrative plates belongs to scope of the invention.
Purpose according to the present invention, the present invention provide a kind of pharmaceutical composition, described pharmaceutical composition include treatment and/or
The ataluren dimethylsulfoxide solvent compounds of the invention of prevention effective dose, and at least one pharmaceutically acceptable carrier or
Auxiliary agent.Described pharmaceutical composition can also include ataluren or other crystal forms or amorphous article of its officinal salt.Optionally,
Described pharmaceutical composition includes one or more other active constituents of medicine, includes but not limited to cancer therapy drug and anti-inflammatory agent
Thing.
Appropriate pharmaceutical dosage form can be made in described pharmaceutical composition, pass through oral, parenteral, transdermal, mucous membrane, nose
Chamber, oral cavity or sublingual administration.Pharmaceutical dosage form can be tablet, caplet；Capsule, for example, soft elastic gelatin capsule；It is flat
Wafer；Dragee；Lozenge；Dispersant；Suppository；Ointment；Paste；Past；Powder；Dressings；Creme；Emplastrum；Solution；
Patch；(such as nasal spray or inhalant, dimethylsulfoxide solvent compound of the invention is kept aerosol preparations in aerosol preparations
For solid form.)；Gelling agent.Taken orally suitable for patient or the liquid dosage form of mucosa delivery, including supensoid agent (such as it is aqueous or
Water-free liquid suspension, oil-in-water emulsion or water-in-oil emulsion, dimethylsulfoxide solvent compound of the invention is kept in supensoid agent
For solid form.), solution and elixir.Suitable for the liquid dosage form of patient's parenteral, including intravenous drip preparations, muscle
Or subcutaneous injection agent；Or it is restructural with suitable for patient provide parenteral liquid dosage form sterilizing solid (such as
Crystal form or amorphous solid).
Acceptable carrier or auxiliary agent in described pharmaceutical composition Chinese pharmacology, are adapted in the case of being administered orally, including but
It is not limited to：Adhesive, for example, cornstarch, farina or other starch, gelatin, natural and synthesis natural gum for example I
Primary glue, mosanom, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivates are (for example, ethyl cellulose
Element, cellulose ethanoate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pre- glue
Change starch, HYDROXY PROPYL METHYLCELLULOSE microcrystalline cellulose and its mixture；Filler, such as talcum, calcium carbonate, microcrystalline cellulose
Element, dextrates, white bole, xylitol, silicic acid, D-sorbite, starch, pregelatinized starch and its mixture；Disintegrant,
Such as agar, alginic acid, calcium carbonate, microcrystalline cellulose, Ac-Di-Sol, crosslinked polyvinylpyrrolidone, poly- gram it is vertical
Woods potassium, sodium starch glycolate, potato or tapioca, pregelatinized starch, other starch, clay, other mosanoms, other fibres
Dimension element, natural gum and its mixture；Lubricant, such as calcium stearate, polyethylene glycol, other glycol, stearic acid, lauryl sulfate
Sodium, talcum, hydrogenated vegetable oil, zinc stearate, ethyl oleate, ethyl laurate, agar and its mixture；Glidant, for example, it is sliding
Mountain flour, cataloid etc.；Complex forming agents, such as the cyclodextrin and resin of various ranks；Rate of release controlling agent, example
Such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methylcellulose, methacrylic acid
Methyl esters, wax etc.；Other available pharmaceutically acceptable carriers or auxiliary agent include but not limited to film forming agent, plasticizer, colouring agent,
Flavor enhancement, viscosity modifier, preservative, antioxidant etc..In the case of being adapted to parenteral, water or non-aqueous sterile solution
Injection containing buffer, antioxidant, bacteriostatic agent and can make the pharmaceutical composition and the isotonic solute of blood, water or
Non-aqueous sterile suspensions can contain suspending agent and thickener.Aerosol preparations (such as nasal spray or inhalant) can contain
There are propellant, solvent, surfactant, stabilizer, flavor enhancement etc..Each carrier or auxiliary agent must be it is acceptable, can be with
Other compositions in formula are compatible and harmless for sufferer.
Described pharmaceutical composition can use that well known to a person skilled in the art method to prepare.Prepare pharmaceutical composition
When, dimethylsulfoxide solvent compound of the invention is mixed with one or more pharmaceutically acceptable carriers or auxiliary agent, optionally, with
One or more others active constituents of medicine mix.Solid dosage forms can be prepared by the technique such as mixing, pelletizing.Liquid
Formulation can be by dissolving, disperseing, the technique such as emulsifying and prepare.
Purpose according to the present invention, the dimethylsulfoxide solvent compound that the present invention provides the present invention are being prepared for treating, preventing
Or alleviate purposes in the medicine of one or more symptoms related with genetic disease or its clinical manifestation, the genetic disease bag
It is waxy to include rheumatoid arthritis, graft versus host disease, arthritis, multiple sclerosis, muscular dystrophy, infantile neuronal
Matter lipofuscinosis, Duchenne/Becker muscular dystrophy, Alzheimer's disease, Tay Sachs diseases, neurodegeneration
Property disease, Parkinson's disease, Niemann's disease, hemophilia, Feng's von Willebrand disease, asynergy-capillary dilation,
B- thalassemias, kidney stone, osteogenesis imperfecta, hepatic sclerosis, familial erythrocytosis, immune deficiency, nephrosis, capsule fiber
Change, familial hypercholesterolemia, retinitis pigmentosa, amyloidosis, atherosclerosis, giantism, nanism,
Hypothyroidism, hyperthyroidism, aging, obesity or Marfan syndrome.
Purpose according to the present invention, the present invention provide a kind for the treatment of, prevention or alleviate one kind or more related with genetic disease
The method of kind symptom or its clinical manifestation, the described method includes the patient for giving needs to treat, prevent or alleviate condition effective amount
Dimethylsulfoxide solvent compound of the invention or include the present invention dimethylsulfoxide solvent compound foregoing pharmaceutical composition, wherein
The genetic disease include rheumatoid arthritis, graft versus host disease, arthritis, multiple sclerosis, muscular dystrophy,
Infantile neuronal ceroid lipofuscinosis, Duchenne/Becker muscular dystrophy, Alzheimer's disease, Tay
Sachs diseases, neurodegenerative disease, Parkinson's disease, Niemann's disease, hemophilia, Feng's von Willebrand disease, mutual aid are lost
It is tune-telangiectasia, b- thalassemias, kidney stone, osteogenesis imperfecta, hepatic sclerosis, familial erythrocytosis, immune
Defect, nephrosis, cystic fibrosis, familial hypercholesterolemia, retinitis pigmentosa, amyloidosis, Atherosclerosis
Change, giantism, nanism, hypothyroidism, hyperthyroidism, aging, obesity or Marfan syndrome.Institute
It is mammal to state patient, the people for obtaining hereditary disease risk is preferably susceptible to suffer from or has, particularly by nonsense mutation screening test
Screen, determine people there are nonsense mutation.The dosage and times for spraying can according to the age of patient, weight and response without
Together.Usually, daily dose is given with single dose or decile dosage, recommended scope is between daily about 0.1 milligram~2000
In the range of milligram.Specifically, daily dose scope should be from about 5 milligrams~500 milligrams daily, more particularly in daily about 10 millis
Gram~200 milligrams between.When treating patient, depending on the Whole Response of the patient, treatment should be since low dosage, as single dose
Amount or separate doses, perhaps about 1 milligram~25 milligrams daily, and increase to up to about 200 milligrams~2000 millis if desired
Gram.
Brief description of the drawings
Fig. 1 is the XRPD figures of known A crystal forms prepared by preparation example 2.
Fig. 2 is the XRPD figures of known B crystal form prepared by preparation example 2.
Fig. 3 is that the XRPD of dimethylsulfoxide solvent compound of the present invention schemes.
Fig. 4 is that the DSC of dimethylsulfoxide solvent compound of the present invention schemes.
Fig. 5 is that the TGA of dimethylsulfoxide solvent compound of the present invention schemes.
Fig. 6 is that the IR of dimethylsulfoxide solvent compound of the present invention schemes.
Embodiment
For the present invention with further reference to following embodiments, preparation and the user of crystal form of the present invention is described in detail in the embodiment
Method.It will be apparent for a person skilled in the art that many changes for both material and method can not depart from the present invention
Implement in the case of scope.
Instrument and method used in gathered data：
X-ray powder diffraction (XPRD)：Used instrument is Bruker D8 Advance diffractometer,
Use K α X-ray of the copper target wavelength for 1.54nm, under the operating condition of 40kV and 40mA, θ -2 θ angular instruments, Mo monochromators,
Lynxeye detectors.Instrument is calibrated with diamond dust before use.Acquisition software is Diffrac Plus XRD Commander.
Sample is tested at ambient temperature, and the sample that needs are detected is placed on areflexia plate.Detailed testing conditions are as follows, angle model
Enclose：3~40 ° of 2 θ, step-length：0.02 ° of 2 θ, speed：0.2 second/step.
Differential thermal analysis (DSC)：Data are picked up from is in TA Instruments Q200 MDSC, instrument control software
Thermal Advantage, analysis software are Universal Analysis.1~10 milligram of sample is usually taken to be positioned over aluminium
In disk, N is dried in 40 ml/mins with 10 DEG C/min of programming rate2Protection under sample risen to 300 DEG C from room temperature.
Thermogravimetric analysis (TGA)：Data are picked up from TA Instruments Q500 TGA, and instrument control software is Thermal
Advantage, analysis software are Universal Analysis.5~15 milligrams of sample is usually taken to be positioned in platinum crucible,
By the way of high resolution detection is segmented, N is dried in 40 ml/mins with 10 DEG C/min of programming rate2Protection under by sample
Product rise to 300 DEG C from room temperature.
Hydrogen nuclear magnetic resonance spectrum analysis (1H-NMR) data are picked up from Bruker Ascend Tm 500.Swash usually using full range
Hair, spectrum width 30PPM, pulse, 30 ° of angle excitations, are scanned 16 times, digitized quadrature detection, temperature control 298K.
FTIR spectrum analysis (IR) data are picked up from BrukerTensor 27, instrument control software and data point
Analysis software is all OPUS, generally use ATR equipment, in 600~4000cm-1In the range of gather infrared absorption spectroscopy, sample and sky
The sweep time of white background is 16 seconds, instrumental resolution 4cm-1。
Efficient liquid phase chromatographic analysis (HPLC) data are picked up from Agilent 1100.Using C18 chromatographic columns,
250 millimeters × 4.6 millimeters, 35 DEG C of column temperature, 254 nanometers of wavelength, 0.85 ml/min of flow velocity, 20 microlitres of sample size,
Run time 30 minutes.Solvent is methanol, and mobile phase A is that 2.4 grams of dihydrogen sulfate sodium is diluted with water to 1000 milliliters, uses phosphorus again
Acid adjusts pH to 3.5, and Mobile phase B is methanol, and gradient is shown in Table 1.
1 HPLC gradient tables of table
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 45 | 55 |
| 3 | 45 | 55 |
| 5 | 15 | 85 |
| 7 | 15 | 85 |
| 20 | 45 | 55 |
| 25 | 45 | 55 |
Various reagents used are commercially available unless otherwise instructed in embodiment.
Temperature in embodiment is room temperature unless otherwise instructed.
In embodiment, the ratio of in the mixed solvent component is volume ratio unless otherwise instructed.
Ultrasound procedure in embodiment can promote sample to dissolve, and equipment is ultrasonic cleaner, is carried out under 40kHz power
5 minutes.
Preparation example 1(ataluren known to preparation)
Ataluren can be prepared according to the method that patent document WO2004091502A2 embodiments 2 describe.
Specifically preparation method is：
To 62.19 grams of potassium carbonate of addition in the 44.14g3- cyanobenzoic acids of 0.6 liter of DMF are dissolved in, 30 points are stirred at room temperature
Clock.Iodomethane 28 milliliters (450mmol) was added into the suspension with 20 minutes, it is small to stir the reaction mixture 4 at room temperature
When.The reaction mixture is poured into 1.2 liters of frozen water, stirs 30 minutes, filters out its precipitation.The white filter cake is dissolved in 70 milliliters
In methanol, the then reprecipitation in cold water.Obtain the 3- cyano-benzoic acid methyl esters that yield is 79%.
50 grams of 3- cyano-benzoic acid methyl esters are dissolved in 500 milliliters of ethanol, the 50% of 41 milliliters of addition is aqueous thereto
Azanol (620 mmol).100 DEG C stir the reaction mixture 1 it is small when, solvent is removed under reduced pressure.It is dissolved in the oiliness residue
In 100 milliliters of 20/80 ethanol/toluene, concentrate again.Obtain 61 grams of 3- (N- hydroxyls amidino groups (carbamimidoyl))-benzene
Methyl formate.
60 grams of 3- (N- hydroxyls amidino groups (carbamimidoyl))-methyl benzoate is dissolved in 200 milliliters of anhydrous tetrahydrochysene furan
In muttering, 75 milliliters of diisopropylethylamine (434 mmol) are then added thereto, were then added with 20 minutes into the mixture
48.1 milliliters of 2- Fluorobenzoyl chlorides (403mmol).Stir at room temperature the reaction mixture 1 it is small when.Precipitation is filtered out, is concentrated under reduced pressure
Filtrate.Residue is dissolved in 400 milliliters of ethyl acetate, then washed twice with 400 milliliters of moisture.Solvent, Yu Han is removed under reduced pressure
Have and required product is crystallized in the hexane of 60% ethyl acetate, generate 81 grams of 3- (N-2- Fluorobenzoyls amidino groups)-benzoic acid first
Ester.
44 grams of 3- (the N-2- fluorobenzene first being dissolved in 500 milliliters of toluene is heated at reflux with Dean-Stark devices at 130 DEG C
Acyl group amidino groups)-methyl benzoate 4 it is small when.Stirred at 5 DEG C the reaction mixture 18 it is small when.White precipitate is filtered out, concentrates filtrate,
Crystallized in toluene.Obtain 38 grams of 3- [5- (2- fluorophenyls)-[1,2,4] oxadiazole -3- bases]-methyl benzoate.
By 33 grams of 3-, [5- (2- fluorophenyls)-[1,2,4] oxadiazole -3- bases]-methyl benzoate is dissolved in 400 milliliters of tetrahydrochysene
In furans, the sodium hydrate aqueous solution of 100 milliliters of 1.5M is added thereto.It is small that the reaction mixture 2 is heated at reflux in 100 DEG C
When.Solvent is removed under reduced pressure, in 5 DEG C stir the aqueous solution 2 it is small when.Organic solvent is removed, the aqueous solution is diluted with 50 milliliters of water, connects
And be acidified to pH with hydrochloric acid as 1.White precipitate is filtered out, filter cake is washed with cold water, is then dried with freeze-dryer.Obtain
3.0 grams of 3- [5- (2- fluorophenyls)-[1,2,4] oxadiazole -3- bases] benzoic acid.1H-NMR(500MHz,d6-DMSO):8.31
(1H),8.18(2H),8.08(1H),7.88(2H),7.51(2H).Display：Preparation example 1 prepare sample with
Ataluren prepared by WO2004091502A2 embodiments 2 is consistent.
Preparation example 2(A crystal forms known to preparation)
Known A crystal forms can be prepared into according to the patent document WO2008039431A2 embodiments 5.1.1.1 methods described
Arrive.Specially：Ataluren prepared by 100 milligrams of preparation examples 1,60 DEG C of additions, 16.2 milliliters of isopropanol ultrasound dissolved clarifications, by this
Solution is filtered by 0.2 micron of filter, and filtrate is placed in the bottle of the foraminate aluminium foil covering of apparatus, 60 DEG C of evaporations.Separation
The solid of formation, obtains the A crystal forms of ataluren.
It is acicular crystal.
Its XRPD figure is shown in Fig. 1, and display is consistent with the A crystal forms of ataluren disclosed in patent document WO2008039431A2.
Preparation example 3(B crystal form known to preparation)
Known B crystal form can be prepared into according to the patent document WO2008039431A2 embodiments 5.1.2.1 methods described
Arrive.Specially：Ataluren prepared by 50 milligrams of preparation examples 1,25 DEG C of additions, 20 milliliters of acetone ultrasound dissolved clarifications, which is led to
0.2 micron of filter filtering is crossed, filtrate is placed in the bottle of the foraminate aluminium foil covering of apparatus, 50 DEG C of evaporations.What separation was formed
Solid, obtains the B crystal form of ataluren.
It is acicular crystal.
Its XRPD figure is shown in Fig. 2, and display is consistent with the B crystal form of ataluren disclosed in patent document WO2008039431A2.
Embodiment 1
Ataluren prepared by 1 gram of preparation example 1 is weighed, adds 20.0 milliliters of dimethyl sulfoxides, ultrasonic dissolved clarification (this ataluren
The concentration of solution be under recrystallization temperature ataluren 1 times of solubility in dimethyl sulfoxide), then toward adding 40.0 in dissolved clarification liquid
Milliliter water, when 25 DEG C of stirrings 1 are small, filtering, with 6.0 milliliters of water washings, when 40 DEG C of dryings 12 are small, obtains 1.1 grams of ataluren's
Dimethylsulfoxide solvent compound, yield 86.3%.
It is bulk crystals.
Its XRPD figure is shown in Fig. 3.
Its DSC figure is shown in Fig. 4.
Its TGA figure is shown in Fig. 5, display：The weightlessness 18.80% before 150 DEG C, about unifies molecule ataluren and combines a molecule
Dimethyl sulfoxide.
IR figures are shown in Fig. 6.
Embodiment 2
Known A crystal forms prepared by 800 milligrams of preparation examples 2 are weighed, add 20.0 milliliters of dimethyl sulfoxides, ultrasonic dissolved clarification (this
The concentration of ataluren solution be under recrystallization temperature ataluren 0.8 times of solubility in dimethyl sulfoxide), then by dissolved clarification liquid
Add into 60.0 milliliters of acetonitriles, when 30 DEG C of stirrings 2 are small, filtering, is washed with 8.0 milliliters of acetonitriles, when 35 DEG C of dryings 15 are small, obtained
The dimethylsulfoxide solvent compound of 912.4 milligrams of ataluren, yield 89.5%.
Embodiment 3
Known B crystal form prepared by 500 milligrams of preparation examples 3 is weighed, adds 20.0 milliliters of dimethyl sulfoxides, ultrasonic dissolved clarification (this
The concentration of ataluren solution be under recrystallization temperature ataluren 0.5 times of solubility in dimethyl sulfoxide), then by dissolved clarification liquid
Add into 80.0 milliliters of isopropyl ethers, when 40 DEG C of stirrings 3 are small, filtering, is washed, 20 DEG C of dryings 24 are small with 15.0 milliliters of isopropyl ethers
When, obtain the dimethylsulfoxide solvent compound of 546.4 milligrams of ataluren, yield 85.7%.
Embodiment 4
Known B crystal form prepared by 100 milligrams of preparation examples 3 is weighed, adds 10.0 milliliters of dimethyl sulfoxides, ultrasonic dissolved clarification (this
The concentration of ataluren solution be under recrystallization temperature ataluren 0.2 times of solubility in dimethyl sulfoxide), then by dissolved clarification liquid
Add into 10.0 milliliters of water, when 60 DEG C of stirrings 5 are small, filtering, is washed with 15.0 milliliters of isopropyl ethers, when 60 DEG C of dryings 48 are small, obtained
To the dimethylsulfoxide solvent compound of 91.3 milligrams of ataluren, yield 71.6%.
Embodiment 5
Ataluren prepared by 400 milligrams of preparation examples 1 is weighed, adds 20.0 milliliters of dimethyl sulfoxides：Water (1:4) formed and be suspended
Liquid (in this suspension the dosage of ataluren be recrystallization temperature under its in dimethyl sulfoxide：Water (1:4) 2 times of solubility in), will
This suspension stirs 1 day at 30 DEG C, filtering, with 6.0 milliliters of dimethyl sulfoxides：Water (1:4) wash, when 40 DEG C of dryings 12 are small, obtain
The dimethylsulfoxide solvent compound of 443.5 milligrams of ataluren, yield 87.0%.
Embodiment 6
Known A crystal forms prepared by 900 milligrams of preparation examples 2 are weighed, add 20.0 milliliters of dimethyl sulfoxides：Isopropyl ether (1:3)
Formed suspension (in this suspension the dosage of ataluren be recrystallization temperature under its in dimethyl sulfoxide：Isopropyl ether (1:3) dissolving in
3 times of degree), this suspension is stirred 2 days at 40 DEG C, filtering, with 8.0 milliliters of dimethyl sulfoxides：Isopropyl ether (1:3) wash, 20 DEG C
When drying 15 is small, the dimethylsulfoxide solvent compound of 960 milligrams of ataluren, yield 83.7% are obtained.
Embodiment 7
Known B crystal form prepared by 1 gram of preparation example 3 is weighed, adds 20.0 milliliters of dimethyl sulfoxides：Water (1:2) formed and be suspended
Liquid (in this suspension the dosage of ataluren be recrystallization temperature under its in dimethyl sulfoxide：Water (1:2) 5 times of solubility in), will
This suspension stirs 3 days at 50 DEG C, filtering, with 8.0 milliliters of dimethyl sulfoxides：Water (1:2) wash, when 60 DEG C of dryings 48 are small, obtain
The dimethylsulfoxide solvent compound of 1.05 grams of ataluren, yield 82.4%.
Embodiment 8
Ataluren prepared by 800 milligrams of preparation examples 1 is weighed, adds 2.0 milliliters of dimethyl sulfoxides：Acetonitrile (1:1) formed mixed
Suspension(In this suspension the dosage of ataluren be recrystallization temperature under its in dimethyl sulfoxide：Acetonitrile (1:1) the 10 of solubility in
Times, this suspension is stirred 5 days at 60 DEG C, filtering, with 10.0 milliliters of dimethyl sulfoxides：Acetonitrile (1:1) wash, 50 DEG C of dryings 48 are small
When, obtain the dimethylsulfoxide solvent compound of 760.3 milligrams of ataluren, yield 74.5%.
2~8 sample of embodiment with 1 sample of embodiment there is the same or similar XRPD figures, DSC figures, TGA figures and IR to scheme
(not shown), illustrates that 2~8 sample of embodiment and 1 sample of embodiment are identical crystal forms.
Embodiment 9
The dimethylsulfoxide solvent compound using the present invention is prepared as the capsule of active constituents of medicine, specification is every weight
500 milligrams, containing 200 milligrams of ataluren.Specific formula is shown in Table 2.
2 capsule agent prescription of table
The preparation process of the capsule (8400 scales) is as follows：
The dimethylsulfoxide solvent compound of pregelatinized corn starch and the present invention is set then to be inserted by 710 tm screens with baffle
Enter thing and load diffusion mixer, stir 15 minutes.Magnesium stearate is set to be added by 210 tm screens in diffusion mixer.Then
The mixture is encapsulated in the capsule of 0 ﹟ specifications with Dosator type capsule loaders, every capsule weighs 500 milligrams.
Embodiment 10
The dimethylsulfoxide solvent compound using the present invention is prepared as the tablet of active constituents of medicine, specification is every weight 250
Milligram, containing 100 milligrams of ataluren.Specific formula is shown in Table 3.
3 tablet formulation of table
The preparation process of the tablet (200,000 scales) is as follows：
Make 30 mesh sieves of dimethylsulfoxide solvent compound Tong Guo ﹟ of microcrystalline cellulose, Ac-Di-Sol and the present invention.
Make 20 mesh sieves of poloxamer F-68 surfactant Tong Guo ﹟.Poloxamer F-68 surfactants are added into three-dimensional mixer
With 0.5 kilogram of Ac-Di-Sol, mix about 5 minutes.The mixture is transferred to 3 cubic foot twin shell tumbles
In mixer, microcrystalline cellulose is added thereto, is mixed about 5 minutes, adds the dimethylsulfoxide solvent compound of the present invention, then is mixed
Close 25 minutes.Pass the mixture through and the roller compactor that hammer pulverizes device is connected with outlet, return again to described roll and mix
In device.Remaining Ac-Di-Sol and magnesium stearate are added in the rolling mixer, mixed about 3 minutes.With
Rotary pelleting machine suppresses final mixture, every 250 milligrams of weight.
Embodiment 11
Prepare the aerosol preparations using the dimethylsulfoxide solvent compound of the present invention as active constituents of medicine.Specific formula is shown in
Table 4.
4 aerosol preparations formula of table
The preparation process of the aerosol preparations (7400 bottles of scales) is as follows：In the sealing stainless steel equipped with high-shear mixer
In container, 0.1 kilogram of dimethylsulfoxide solvent compound and 12.6 kilograms of F-11 of the invention are mixed, mixes 20 points
Clock, prepares concentrate.Again by make the concentrate and products pot (temperature control at 21~27 DEG C, pressure control 2.4~
Propellant (the mixing of 27.5 kilograms of dicholorodifluoromethane and 11.7 kilograms of trichlorine tetrafluoro of counterweight in 4.0BAR)
Thing) it is mixed in the sealing container, prepare barreled suspension.It is designed with 17 milliliters of aerosol containers of metered amount valve, there is provided
Aerosol preparations of the invention 100 times inhalable.
Comparative example 1
The ataluren of the preparation of preparation example 1, the ataluren A crystal forms of the preparation of preparation example 2, preparation example 3 is taken to prepare
Dimethylsulfoxide solvent compound of the invention prepared by ataluren B crystal forms and embodiment 1, detects HPLC purity, as a result such as table 5
It is shown.
5 HPLC purity detecting results of table
The results show that the purity that the purity of ataluren is 95.6%, ataluren A crystal forms is 96.5%, ataluren
The purity of B crystal form is 96.8%, and ataluren dimethylsulfoxide solvent compounds prepared by the present invention, its purity are more than 99.0%,
Purity has raising by a relatively large margin, illustrates that dimethylsulfoxide solvent compound prepared by the present invention has preferable refining effect.
The general description of the above-mentioned invention to involved in the present invention and the description to its embodiment should not be understood
For be to the inventive technique scheme form limitation.Those skilled in the art disclose according to the present invention, can not disobey
On the premise of the involved invention inscape of the back of the body, to above-mentioned general description or/and embodiment (including embodiment)
In public technology feature increased, reduced or combined, formed and belong to other technical solutions of the invention.The present invention's
Protection domain should be determined by the scope of protection defined in the claims.
Claims (9)
1. the structural formula 3- as follows [dimethylsulfoxide solvents of 5- (2- fluorophenyls)-[1,2,4] oxadiazole -3- bases] benzoic acid
Compound,
It is characterized in that, radiated using Cu-K α, the X-ray powder diffraction that the dimethylsulfoxide solvent compound is represented with 2 θ angles
Collection of illustrative plates has characteristic peak in following position：5.6±0.2°、15.0±0.2°、16.7±0.2°、20.5±0.2°、22.3±
0.2 ° and 27.0 ± 0.2 °.
2. 3- [the dimethyl sulfoxides of 5- (2- fluorophenyls)-[1,2,4] oxadiazole -3- bases] benzoic acid according to claim 1
Solvate, it is characterised in that the dimethylsulfoxide solvent compound with the X-ray powder diffraction collection that 2 θ angles represent with
Lower position has characteristic peak：5.6±0.2°、15.0±0.2°、16.7±0.2°、20.5±0.2°、22.3±0.2°、24.1±
0.2 °, 25.0 ± 0.2 ° and 27.0 ± 0.2 °.
3. 3- [the dimethyl sulfoxides of 5- (2- fluorophenyls)-[1,2,4] oxadiazole -3- bases] benzoic acid according to claim 2
Solvate, it is characterised in that the dimethylsulfoxide solvent compound with the X-ray powder diffraction collection that 2 θ angles represent with
Lower position has characteristic peak and its relative intensity：
4. according to any one of claims 1 to 3 3- [5- (2- fluorophenyls)-[1,2,4] oxadiazole -3- bases] benzoic acid
Dimethylsulfoxide solvent compound, it is characterised in that the FTIR spectrum of the dimethylsulfoxide solvent compound wave number for 1688,
1620th, 1554,1466,1368,1295,1252,1152,1004,959,823,746,720 and 667cm-1Place has characteristic peak.
5. 3- [the two of 5- (2- fluorophenyls)-[1,2,4] oxadiazole -3- bases] benzoic acid according to any one of claims 1 to 4
The preparation method of first sulfoxide solvent compound, using any one in following preparation methods：
(1) by 3- [dimethyl sulfoxide solution of 5- (2- fluorophenyls)-[1,2,4] oxadiazole -3- bases] benzoic acid is mixed with anti-solvent,
Wherein described anti-solvent is selected from water, isopropyl ether, acetonitrile or its mixture, stirring and crystallizing, obtain the 3- [5- (2- fluorophenyls)-
The dimethylsulfoxide solvent compound of [1,2,4] oxadiazole -3- bases] benzoic acid；
(2) by 3- [mixing of 5- (2- fluorophenyls)-[the 1,2,4] oxadiazole -3- bases] benzoic acid in dimethyl sulfoxide and organic solvent
In solvent or the in the mixed solvent of dimethyl sulfoxide and water formed suspension, wherein the organic solvent be selected from isopropyl ether, acetonitrile or
Its mixture, dimethyl sulfoxide are 1 with organic solvent or the volume ratio of dimethyl sulfoxide and water:1~1:4, stirring and crystallizing, obtains described
3- [the dimethylsulfoxide solvent compounds of 5- (2- fluorophenyls)-[1,2,4] oxadiazole -3- bases] benzoic acid.
6. [dimethyl sulfoxide of 5- (2- fluorophenyls)-[1,2,4] oxadiazole -3- bases] benzoic acid is molten by 3- according to claim 5
The preparation method of agent compound, it is characterised in that
In preparation method (1)：
The volume of the anti-solvent is 1~4 times of dimethyl sulfoxide volume；
The temperature of the crystallization is 25~60 DEG C；
When the time of the crystallization is 1~5 small；
The concentration of the dimethyl sulfoxide solution is 3- [5- (2- fluorophenyls)-[1,2,4] oxadiazole -3- bases] benzene first under recrystallization temperature
0.2~1 times of solubility of the acid in dimethyl sulfoxide；
Or in preparation method (2)：
The temperature of the crystallization is 10~60 DEG C；
The time of the crystallization is 1~5 day；
3- in the suspension [dosage of 5- (2- fluorophenyls)-[1,2,4] oxadiazole -3- bases] benzoic acid be under recrystallization temperature its
At 2~10 times of the solubility of the in the mixed solvent.
7. a kind of pharmaceutical composition, it includes treatment and/or the 3- according to any one of claims 1 to 4 of prevention effective dose
[the dimethylsulfoxide solvent compound of 5- (2- fluorophenyls)-[1,2,4] oxadiazole -3- bases] benzoic acid or according to 5 or 6 institute of claim
State 3- made from preparation method [the dimethylsulfoxide solvent compound of 5- (2- fluorophenyls)-[1,2,4] oxadiazole -3- bases] benzoic acid,
And at least one pharmaceutically acceptable carrier or auxiliary agent.
8. pharmaceutical composition according to claim 7, it is characterised in that described pharmaceutical composition can pass through oral, stomach and intestine
Outside, transdermal, mucous membrane, nose, oral cavity or sublingual administration, the dosage form of pharmaceutical composition can be tablet, capsule, lozenge, powder,
Suppository, paste, paste, dressings, creme, solution, patch, aerosol preparations, gelling agent, supensoid agent, elixir restructural are
The sterilizing solid of liquid dosage form.
9. 3- [the two of 5- (2- fluorophenyls)-[1,2,4] oxadiazole -3- bases] benzoic acid according to any one of claims 1 to 4
3- [5- (2- fluorophenyls)-[1,2,4] Evil made from first sulfoxide solvent compound or preparation method according to claim 5 or 6
Diazole -3- bases] benzoic acid dimethylsulfoxide solvent compound prepare treatment, prevention or alleviate muscular dystrophy, Parkinson's disease,
Hemophilia, asynergy-capillary dilation, cystic fibrosis, the medicine of retinitis pigmentosa or Marfan syndrome
In purposes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410464639.5A CN105461650B (en) | 2014-09-12 | 2014-09-12 | Solvate of Yi Zhong oxadiazole compounds and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410464639.5A CN105461650B (en) | 2014-09-12 | 2014-09-12 | Solvate of Yi Zhong oxadiazole compounds and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105461650A CN105461650A (en) | 2016-04-06 |
| CN105461650B true CN105461650B (en) | 2018-04-13 |
Family
ID=55599867
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410464639.5A Active CN105461650B (en) | 2014-09-12 | 2014-09-12 | Solvate of Yi Zhong oxadiazole compounds and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105461650B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201808922A (en) * | 2016-06-20 | 2018-03-16 | 台灣神隆股份有限公司 | Process for preparing ataluren and its intermediates |
| CN111675672A (en) * | 2020-05-12 | 2020-09-18 | 石家庄市度智医药科技有限公司 | Method for preparing astallurens |
| CN113045510B (en) * | 2021-03-31 | 2022-05-27 | 北京大学生命科学华东产业研究院 | Preparation method of atralone |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1802360A (en) * | 2003-04-11 | 2006-07-12 | Ptc治疗公司 | 1,2,4-oxadiazole benzoic acid compounds |
| CN101535284A (en) * | 2006-09-08 | 2009-09-16 | Ptc医疗公司 | Processes for the preparation of 1,2,4-oxadiazole benzoic acids |
| CN101541770A (en) * | 2006-09-25 | 2009-09-23 | Ptc医疗公司 | Crystalline forms of 3-[5-(2-fhjorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid |
-
2014
- 2014-09-12 CN CN201410464639.5A patent/CN105461650B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1802360A (en) * | 2003-04-11 | 2006-07-12 | Ptc治疗公司 | 1,2,4-oxadiazole benzoic acid compounds |
| CN101535284A (en) * | 2006-09-08 | 2009-09-16 | Ptc医疗公司 | Processes for the preparation of 1,2,4-oxadiazole benzoic acids |
| CN101541770A (en) * | 2006-09-25 | 2009-09-23 | Ptc医疗公司 | Crystalline forms of 3-[5-(2-fhjorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105461650A (en) | 2016-04-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105121434B (en) | Canagliflozin monohydrate and its crystal formation, their preparation method and purposes | |
| WO2018108101A1 (en) | New crystal forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid and preparation method therefor | |
| CN105121409B (en) | Crystalline form of dolutegravir sodium salt and preparation method therefor | |
| CN112624985B (en) | Compound crystal, preparation method and application | |
| CN105188699B (en) | Solid form of enzalutamide, preparation method and use thereof | |
| CN105461650B (en) | Solvate of Yi Zhong oxadiazole compounds and preparation method thereof | |
| RU2248966C2 (en) | Ground form of (s)-2-ethoxy-3-[4-(2-{4-metanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid | |
| WO2015180060A1 (en) | Salt of diazacycloheptane compound and crystal form and amorphous substance thereof | |
| CN106458857A (en) | Crystalline free acid, hemicalcium salt and alfa-phenylethylamine salt of ahu-377 as well as preparation method therefor and application thereof | |
| WO2022122014A1 (en) | Crystal form of lanifibranor, preparation method therefor, and use thereof | |
| CN104918937A (en) | Crystalline forms of trametinib and solvate thereof, preparation method therefor, pharmaceutical composition comprising same and use thereof | |
| JP2022542159A (en) | Solid Form Relugolix | |
| CN101235013A (en) | Crystallized 1-(3-fluorophenyl)-5-methyl-2-(1H)pyridine and its preparation method composition and application | |
| CN106458886A (en) | Solid forms of a pharmaceutically active compound | |
| CN106581680B (en) | A pharmaceutical composition for reducing food influence on drug absorption | |
| CN105367492B (en) | His quinoline not crystal form of moral and preparation method thereof, its pharmaceutical composition and purposes | |
| CN105308043B (en) | Crystal formation of hepatitis C medicine and preparation method thereof, its pharmaceutical composition and purposes | |
| CN106928228A (en) | Ao Gelieting salt and its crystal formation, their preparation method and pharmaceutical composition | |
| CN115379830A (en) | Solid pharmaceutical preparation, method for the production thereof and use thereof | |
| CN105228986B (en) | A kind of lorcaserin eutectic and preparation method thereof, pharmaceutical composition and purposes | |
| TW201623294A (en) | Crystal forms of 1-{2-fluoro-4-[5-(4-isobutyl phenyl)-1,2,4-oxadiazole-3-yl]-benzyl}-3-azetidinecarboxylic acid | |
| CN105228988A (en) | Crystal of bent Ge Lieting hemisuccinic acid salt and preparation method thereof and pharmaceutical composition | |
| CN104995189B (en) | Crystal formation of hepatitis C medicine and preparation method thereof, its pharmaceutical composition and purposes | |
| CN110105417A (en) | A kind of pharmaceutical co-crystals body and preparation method and application | |
| CN104955816B (en) | Crystal formation that a kind of Ansai is bent and preparation method thereof, its pharmaceutical composition and purposes |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190822 Address after: 310018 Room 2B12, Building 452, No. 6 Street, Hangzhou Economic and Technological Development Zone, Zhejiang Province Patentee after: Hangzhou Ling Ye Pharmaceutical Technology Co., Ltd Address before: 310018 room 2B12, building 452, No. 6, Hangzhou Economic & Technological Development Zone, Hangzhou, Zhejiang, China Patentee before: HANGZHOU PUSHA PHARMACEUTICAL TECHNOLOGY CO., LTD. |