CN114671914A - Salt and crystal form of neurokinin-1 antagonist and preparation method thereof - Google Patents
Salt and crystal form of neurokinin-1 antagonist and preparation method thereof Download PDFInfo
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- CN114671914A CN114671914A CN202111594476.9A CN202111594476A CN114671914A CN 114671914 A CN114671914 A CN 114671914A CN 202111594476 A CN202111594476 A CN 202111594476A CN 114671914 A CN114671914 A CN 114671914A
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Abstract
The present disclosure relates to salts, crystalline forms, and methods of making neurokinin-1 antagonists. In particular, the present disclosure relates to sodium salts of compounds of formula II, a crystals of the sodium salt, and methods of preparation. The novel crystal form disclosed by the invention has good physicochemical properties and is more beneficial to clinical treatment.
Description
Technical Field
The disclosure relates to a salt and a crystal form of a neurokinin-1 antagonist and a preparation method thereof, in particular to a crystal form and a preparation method of a sodium salt and a sodium salt of a compound shown in a formula II.
Background
Tachykinins are peptide ligands of neurokinin receptors. Neurokinin receptors, such as NK1, NK2 and NK3, are involved in various biological processes. They are found in the nerve and circulatory system of mammals and in the surrounding tissues. Thus, modulation of such receptors has been investigated for potential treatment or prevention of various physiological disorders, conditions and diseases in mammals.
On the other hand, the hemolysis of the medicine is caused by the damage of a large number of red blood cells caused by immune factors after the medicine enters a human body, and the hemolysis phenomena of anemia, jaundice, soy sauce, urine and the like appear clinically. Drug-induced hemolytic anemia can be classified into three types, (1) drug-induced immunity, which results in antibody-mediated hemolytic reactions; (2) drugs act on red blood cells with genetic enzyme defects (e.g., G6PD defects); (3) hemolytic reaction of the drug to abnormal hemoglobin. The key to treating the disease is to stop using related drugs and control the occurrence of hemolysis to prevent the occurrence of complications.
PCT/CN2020/098460 provides a novel NK1 antagonist prodrug compound (formula II) which is effective in the treatment of various physiological disorders, conditions and diseases with minimal side effects, and which has good pharmaceutical activity.
The crystal structure of the active ingredient for medical use often affects the chemical stability of the medicine, and the difference of crystallization conditions and storage conditions may cause the change of the crystal structure of the compound and sometimes accompany the generation of other forms of crystal forms. Generally, amorphous drug products have no regular crystal structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, poor flowability and the like. Therefore, it is necessary to improve various properties of the compound shown in formula II, and intensive research is needed to find a new crystal form with high purity and good chemical stability.
Disclosure of Invention
The present disclosure provides a sodium salt of a compound represented by formula II and a crystal form a thereof, which have good stability and can be better applied to clinical applications.
The crystal form A of the sodium salt of the compound shown in the formula II has characteristic peaks at the 2 theta angles of 6.685, 7.751, 9.551, 10.312, 12.330, 13.674 and 14.221 in an X-ray powder diffraction pattern.
The A crystal form of the sodium salt of the compound shown in the formula II has characteristic peaks at positions with 2 theta angles of 6.685, 7.751, 9.551, 10.312, 12.330, 13.674, 14.221, 15.618, 17.016, 18.050, 21.007 and 21.807.
The A crystal form of the sodium salt of the compound shown in the formula II has characteristic peaks at positions with 2 theta angles of 6.685, 7.751, 9.551, 10.312, 12.330, 13.674, 14.221, 14.755, 15.618, 17.016, 18.050, 19.564, 21.007, 21.807, 22.770, 24.003, 27.826, 28.689, 30.744 and 31.648 in an X-ray powder diffraction pattern.
The crystal form A of the sodium salt of the compound shown in the formula II provided by the disclosure has an X-ray powder diffraction pattern shown in figure 2.
The present disclosure provides a crystalline form a of a sodium salt of a compound represented by formula II, wherein the range of error for the 2 θ angle is ± 0.2.
The present disclosure further provides a process for preparing form a of the sodium salt of the compound of formula II, comprising: dissolving the compound shown in the formula II and sodium hydroxide in an organic solvent, and crystallizing and precipitating, wherein the solvent is alcohol and water, and preferably isopropanol and water.
The crystal form obtained by the present disclosure is subjected to structure determination and crystal form research through X-ray powder diffraction pattern (XRPD) and Differential Scanning Calorimetry (DSC).
The crystallization method of the crystal form in the present disclosure is conventional, such as volatile crystallization, cooling crystallization or room temperature crystallization.
The starting materials used in the preparation method of the crystalline forms of the present disclosure may be any form of the compound represented by formula II, including but not limited to: amorphous, random crystalline, hydrate, solvate, and the like.
The present disclosure further provides a pharmaceutical composition comprising the form a of the sodium salt of the compound of formula II, and one or more pharmaceutically acceptable carriers or excipients.
A process for the preparation of a pharmaceutical composition comprising the step of admixing a sodium salt of a compound of formula II with one or more pharmaceutically acceptable carriers or excipients.
A preparation method of a pharmaceutical composition comprises the step of mixing the crystal form A of the sodium salt of the compound shown in the formula II with one or more pharmaceutically acceptable carriers or excipients.
The present disclosure further provides the use of a sodium salt of a compound of formula II as described above, or a crystalline form a of a sodium salt of a compound of formula II, or a composition prepared by the foregoing method, for the manufacture of a medicament for the treatment of a physiological disorder, condition or disease in a patient, wherein the physiological disorder, condition or disease is preferably a respiratory disease, cough, inflammatory disease, skin disorder, ophthalmic disorder, depression, anxiety, phobia, bipolar disorder, alcohol dependence, substance abuse having a significant effect on nerves, epilepsy, nociception, psychosis, schizophrenia, alzheimer's disease, dementia associated with AIDs, Towne's disease, stress-related disorder, obsessive/compulsive disorder, bulimia, anorexia nervosa, crazy feeding, mania, premenstrual syndrome, gastrointestinal dysfunction, atherosclerosis, fibrotic disorder, obesity, stress, depression, alcohol dependence, or a neurological disorder, Type II diabetes, headache, neuropathic pain, post-operative pain, chronic pain syndrome, bladder disorders, urogenital disorders or emesis or nausea.
In the description and claims of this application, unless otherwise indicated, the scientific and technical terms used herein have the meaning commonly understood by those of skill in the art. However, for a better understanding of the present disclosure, the following provides definitions and explanations of some of the relevant terms. In addition, where the definitions and explanations of terms provided herein are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.
The term "X-ray powder diffraction pattern or XRPD" as used in the present disclosure means that when X-rays are incident on an atomic plane having a d-lattice spacing of a crystal or a partial crystal sample at a grazing angle θ (complementary angle of incidence, also referred to as bragg angle) according to bragg formula 2d sin θ ═ n λ (where λ is the wavelength of the X-rays, n is any positive integer, and n is generally a first-order diffraction peak, and n is 1), the bragg equation is satisfied, and thus the set of X-ray powder diffraction patterns is obtained.
The "X-ray powder diffraction pattern or XRPD" described in this disclosure is a pattern obtained by using Cu-ka radiation in an X-ray powder diffractometer.
The differential scanning calorimetry or DSC in the present disclosure refers to measuring the temperature difference and the heat flow difference between a sample and a reference substance during the process of temperature rise or constant temperature of the sample, so as to characterize all the physical changes and chemical changes related to the thermal effect, and obtain the phase change information of the sample.
"thermogravimetric analysis or TGA" as used in this disclosure refers to the continuous measurement of the mass of a sample as a function of temperature or time at a programmed temperature.
The "2 theta or 2 theta angle" referred to in the present disclosure means the diffraction angle, theta is the bragg angle in degrees or degrees, and the error range of 2 theta is ± 0.3 or ± 0.2 or ± 0.1.
The term "interplanar spacing or interplanar spacing (d value)" as used in this disclosure means that the spatial lattice selects 3 non-parallel unit vectors a, b, c connecting two adjacent lattice points, which divide the lattice into juxtaposed parallelepiped units, called interplanar spacing. The space lattice is divided according to the determined connecting lines of the parallelepiped units to obtain a set of linear grids called space grids or lattices. The lattice and lattice are crystal junctions reflected by geometrical points and lines, respectivelyThe periodicity of the structure, different crystal planes, the interplanar spacing (i.e. the distance between two adjacent parallel crystal planes) of which is different; has a unit ofOr angstroms.
Drawings
FIG. 1 is an XRPD pattern for form A of the sodium salt of the compound of formula II;
FIG. 2 is a DSC of form A of the sodium salt of the compound of formula II;
FIG. 3 is a TGA profile of form A of the sodium salt of the compound of formula II;
Detailed Description
The present disclosure will be explained in more detail with reference to examples, which are only used for illustrating the technical solutions of the present disclosure and do not limit the spirit and scope of the present disclosure.
Test conditions of the apparatus used for the test:
1. differential Scanning Calorimeter (DSC)
The instrument model is as follows: mettler Toledo DSC 3+
And (3) purging gas: nitrogen, 50mL/min
The heating rate is as follows: 10.0 ℃/min
Temperature range: 25-250 deg.C
2. X-ray Powder diffractometer (X-ray Powder Diffraction, XRPD)
The instrument model is as follows: BRUKER D8 DISCOVER
Ray: monochromatic Cu-Kalpha radiation (Cu-Kalpha 1 wavelength ofCu-K alpha 2 wavelength ofThe Cu-Ka wavelength is taken as the weighted average of Ka 1 and Ka 2)
The scanning mode is as follows: θ/2 θ, scan range: 3-50 °
Voltage: 40KV, current: 40mA
3. Thermogravimetric Analyzer (TGA)
The instrument model is as follows: METTLER TOLEDO TGA 2
And (3) purging gas: nitrogen, 50mL/min
The heating rate is as follows: 10.0 ℃/min
Temperature range: 25-350 deg.C
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) 6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS).
MS was determined using a FINNIGAN LCQad (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC1200 DAD, Agilent HPLC1200VWD and Waters HPLC e2695-2489 HPLC.
Chiral HPLC assay using Agilent 1260DAD HPLC.
High Performance liquid preparation A preparative chromatograph was used from Waters 2767, Waters 2767-SQ Detector 2, Shimadzu LC-20AP and Gilson-281.
Chiral preparation a Shimadzu LC-20AP preparative chromatograph was used.
The CombiFlash rapid preparation instrument uses CombiFlash Rf200(TELEDYNE ISCO).
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Silica gel column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan ChemBiotech (Accela ChemBio Inc), Darril Chemicals, and the like.
In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.
The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.
The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: n-hexane/ethyl acetate system, B: the volume ratio of the solvent in the dichloromethane/methanol system is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.
Example 1: preparation of Compounds of formula II
The first step is as follows:
at N2Compound 1(2.43g,4.86mmol, 1eq) was dissolved in dichloromethane (36mL), diisopropylethylamine (5g, 38.76mmol, 8eq) was added, cooled to-30 deg.C, trimethylchlorosilane (1.36g, 12.52mmol, 2.6eq) was added and stirred at room temperature for 2 h. And then cooled to-25 ℃, a dichloromethane solution of chloromethyl chloroformate (0.77g, 6mmol, 1.23eq) is added dropwise, the temperature is controlled to-20 ℃ to-5 ℃, the mixture is stirred until the reaction is finished, the reaction solution is poured into ice water, liquid separation is carried out, dichloromethane is extracted, water and 1N hydrochloric acid solution are added, liquid separation is carried out, then the mixture is washed by saline solution, saturated sodium bicarbonate water solution and saline solution in sequence, anhydrous sodium sulfate is dried, filtered and concentrated, and 3.0g of yellow jelly is obtained, and the yield is 104%.
The second step:
in N2Compound 2(2.8g, 4.53mmol, 1eq), tetrabutylammonium iodide (1.68g, 4.55mmol, 1eq), di-tert-butyl phosphate potassium salt (5.63g, 22.67mmol, 5eq) and dioxane (84mL) were added to a 500mL three-necked flask with protection and heated to 55 deg.C and stirred for 4 h. The reaction solution was cooled, poured into ethyl acetate and water, separated, extracted with ethyl acetate, washed with an aqueous solution of sodium sulfite, then washed with water and brine in this order, dried over anhydrous sodium sulfate, filtered, and concentrated to give 3.73g of yellow foam with a yield of 107%.
The third step:
at N2Under protection, compound 3(6.65g, 8.67mmol, 1eq) was added to a 500mL single-neck flask and dissolved in dichloromethane (200mL), trifluoroacetic acid (9.89g, 86.7mmol, 10.0eq) was slowly added under ice water cooling, stirring was carried out until the reaction was complete, concentration was carried out to give 2.29g of an oil, which was purified by reverse phase silica gel column (C18) (solution A: 20mmol NH 18)4HCO3Aqueous solution, solution B: acetonitrile), adjusting the pH value to 1-2 by using 1M phosphoric acid, extracting by using dichloromethane, washing by using saturated saline, and using anhydrous sulfuric acidSodium drying, filtering and concentrating to obtain the target product 2.7 g.
1H-NMR(400MHz,CD3OD):δ(ppm)7.89(s,2H),7.86(s,1H),7.41-7.27(m,5H),5.66(d,J=12Hz,1H),5.50-5.47(m,1H),4.60(d,J=8Hz,1H),4.20-3.88(m,3H),2.51-2.10(m,5H),1.86-1.66(m,3H),1.44-1.31(m,4H).
Test example 1: solubility in water
1.1 preparation of reagents
Reagent: NaH2PO4·2H2O
1.2 preparation method
The formulation according to the 100ml specification is as follows:
pH 3.0: phosphate buffer solution: 100ml 20mmol/L NaH2PO4,0.1M H3PO4The pH was adjusted to 3.0.
pH 4.0: phosphate buffer solution: 100ml 20mmol/L NaH2PO4,0.1M H3PO4The pH was adjusted to 4.0.
pH 7.0: ultra-pure water
pH 9.0: phosphate buffer solution: 100ml 20mmol/L Na2HPO40.1M NaOH solution adjusted pH to 9.0
1.3 test methods
Accurately weighing a proper amount of the compound in the example 1, adding a small amount of the compound into the solution for multiple times, stirring the solution until the compound is dissolved, and measuring the content of the compound in the solution. The data are shown in Table 1.
TABLE 1
pH | Solubility in water | Saturated solubility |
7.4 | 26mg/ml | 19.8mg/ml |
9.0 | 28mg/ml | 21.4mg/ml |
Test example 2: haemolysis
Red Blood Cells (RBC) were randomly collected from the jugular vein or central auricular artery of a rabbit (EDTA whole blood) in 10ml, and placed in a glass bead Erlenmeyer flask and shaken for 10 minutes to remove fibrinogen, resulting in defibrinated blood. Adding about 10 times of sodium chloride injection, shaking, centrifuging at 1500 rpm for 10 min, removing supernatant, washing the precipitated red blood cells with sodium chloride injection for 3 times, and making the supernatant not red. The obtained red blood cells are prepared into 2% (v/v) suspension by sodium chloride injection for standby.
The compound of example 1 was dissolved in PBS (pH 7.4 or pH 5), filtered, and prepared to 0.4mg/ml, 0.8mg/ml, 1.2mg/ml, 1.6mg/ml and 2mg/ml for use.
An amount of the compound solution of example 1 was added to the hemoglobin supernatant for testing.
If the solution in the test tube is in clear red, no cells or a small amount of red blood cells remain at the bottom of the tube, which indicates that hemolysis occurs; if the erythrocytes sink completely, the supernatant is colorless and clear, indicating no hemolysis. If the solution has a brownish red or reddish brown flocculent precipitate, the solution is slightly inverted for 3 to 5 times and still does not disperse, which indicates that red blood cell coagulation possibly occurs; the cells should be further observed under a microscope, and the red blood cells can be seen to aggregate into aggregates. The compounds provided by the present disclosure employ this method for determining hemolysis.
And (4) conclusion: the compound of example 1 showed no haemolysis up to concentrations of 2 mg/ml.
Test example 3: hemolytic effect of Lazopitan emulsion
Lapidan emulsion (formulation: 4.4% polyethylene glycol-15 hydroxystearate, 1.1% medium chain triglyceride and 0.66% soybean oil) was prepared by the method described in CN102573475, and 0.18mg/ml, 0.09mg/ml, 0.045mg/ml, 0.023mg/ml, 0.011mg/ml, 0.056mg/ml and 0.028mg/ml were prepared in PBS for further use.
Hemolysis was determined by referring to the method in test example 2.
And (4) conclusion: hemolysis was present in all concentrations of the emulsion of Lapidan.
Test example 4: pharmacokinetic testing in cynomolgus monkeys
The drug concentrations in the plasma of cynomolgus monkeys were measured at different times after injection of the compound prepared in reference example 1 by the LC/MS/MS method using the cynomolgus monkeys as test animals. The pharmacokinetic behavior of the compound in cynomolgus monkeys was studied and evaluated for its pharmacokinetic profile.
Pharmaceutical formulation
A certain amount of the test compound was weighed and prepared into a solution with pH 4.0 using 20mmol/L sodium dihydrogen phosphate for use.
1.1 administration of drugs
Intravenous drip, the time of bolus injection is about 30min, the administration dosage is 3.54mg/kg, the administration concentration is 2mg/ml, and the administration volume is 5 ml/kg.
1.2 operating
Collecting blood via femoral vein for 5min, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h and 24h before administration and after administration, collecting each sample by 0.6mL, anticoagulating heparin sodium, and immediately placing on ice after collection. The blood sample is collected and placed in a marked centrifuge tube, and plasma is separated by centrifugation (the centrifugation condition is 2200g for centrifugation for 10min at 2-8 ℃).
The plasma samples were assayed for the amount of compound of example 1 and lapitan using LC/MS.
1.3 pharmacokinetic parameter results
TABLE 2
Note: in the examples, the pharmacokinetics parameters of the compounds in cynomolgus monkeys are a, and in the examples, the metabolism of the compounds into the pharmacokinetics parameters of Lapidan in cynomolgus monkeys is b.
And (4) conclusion: in the research of pharmacokinetics in a cynomolgus monkey, the compound is quickly converted into an active metabolite Lapidan in most of the cynomolgus monkeys, and has good pharmacokinetic properties.
EXAMPLE 2 preparation of the sodium salt form A of the Compound of formula II
About 100mg of the compound of formula II was weighed, 1mL of 90% isopropanol/water was added, and 42. mu.l of 4mol/L sodium hydroxide was added. Stirring and reacting at 25 ℃, centrifuging to obtain a solid, and then drying in vacuum to obtain a crystal form A of the sodium salt of the compound shown in the formula II, wherein the characteristic peak position is shown in Table 3:
Table 3: XRD characteristic peak position of crystal form A
Example 3 stability study
The sodium salt form a was left to stand at 4 ℃ for stability and had a purity of 99.18% (initial purity 99.25%) after 14 days. The result shows that the sodium salt A crystal form has good stability at the temperature of 4 ℃.
Claims (11)
2. a crystal form A of a sodium salt of a compound shown as a formula II has a characteristic peak in an X-ray powder diffraction pattern at 2 theta angles of 6.685, 7.751, 9.551, 10.312, 12.330, 13.674 and 14.221.
3. The crystal form A of the sodium salt of the compound shown in the formula II as claimed in claim 2, and has an X-ray powder diffraction pattern with characteristic peaks at 2 theta angles of 6.685, 7.751, 9.551, 10.312, 12.330, 13.674, 14.221, 15.618, 17.016, 18.050, 21.007 and 21.807.
4. The crystal form A of the sodium salt of the compound shown in the formula II as claimed in claim 3, and has an X-ray powder diffraction pattern with characteristic peaks at 2 theta angles of 6.685, 7.751, 9.551, 10.312, 12.330, 13.674, 14.221, 14.755, 15.618, 17.016, 18.050, 19.564, 21.007, 21.807, 22.770, 24.003, 27.826, 28.689, 30.744 and 31.648.
5. The crystalline form a of the sodium salt of the compound of formula II as defined in claim 2 having an X-ray powder diffraction pattern as shown in figure 2.
6. Form a of the sodium salt of a compound of formula II according to any one of claims 2-5, wherein the 2 Θ angle has a tolerance of ± 0.2.
7. A process for preparing the crystalline form a of the sodium salt of the compound of formula II as described in any one of claims 2-6, comprising: dissolving the compound shown in the formula II and sodium hydroxide in an organic solvent, and crystallizing and precipitating, wherein the solvent is alcohol and water, and preferably isopropanol and water.
8. A pharmaceutical composition comprising a sodium salt of a compound of formula II and one or more pharmaceutically acceptable carriers or excipients.
9. A process for the preparation of a pharmaceutical composition comprising the step of admixing a sodium salt of a compound of formula II with one or more pharmaceutically acceptable carriers or excipients.
10. The pharmaceutical composition of claim 8 or the process for preparing a pharmaceutical composition of claim 9, wherein the sodium salt of the compound of formula II is form a.
11. Use of a sodium salt of a compound of formula II according to claim 1, or a crystalline form a of a sodium salt of a compound of formula II according to any one of claims 2 to 6, or a composition according to claim 8, for the manufacture of a medicament for the treatment of a physiological disorder, condition or disease in a patient, preferably a respiratory disease, cough, inflammatory disease, skin disorder, ophthalmic disorder, depression, anxiety, phobia, bipolar disorder, alcohol dependence, substance abuse having a significant effect on nerves, epilepsy, nociception, psychosis, schizophrenia, alzheimer's disease, dementia associated with AIDs, Towne's disease, stress-related disorder, obsessive/compulsive disorder, bulia, anorexia nervosa, binge eating, mania, premenstrual syndrome, gastrointestinal dysfunction, mania, or a, Atherosclerosis, fibrotic disorders, obesity, type II diabetes, headache, neuropathic pain, post-motion pain, chronic pain syndrome, bladder disorders, genitourinary disorders or emesis or nausea.
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WO2023134723A1 (en) * | 2022-01-12 | 2023-07-20 | 江苏恒瑞医药股份有限公司 | Crystal form of neurokinin-1 antagonist prodrug compound |
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WO2023134723A1 (en) * | 2022-01-12 | 2023-07-20 | 江苏恒瑞医药股份有限公司 | Crystal form of neurokinin-1 antagonist prodrug compound |
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