WO2017198201A1 - Forme cristalline, sel et complexe de dérivé de dihydropyrimidine, et leurs utilisations en médecine - Google Patents

Forme cristalline, sel et complexe de dérivé de dihydropyrimidine, et leurs utilisations en médecine Download PDF

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WO2017198201A1
WO2017198201A1 PCT/CN2017/084976 CN2017084976W WO2017198201A1 WO 2017198201 A1 WO2017198201 A1 WO 2017198201A1 CN 2017084976 W CN2017084976 W CN 2017084976W WO 2017198201 A1 WO2017198201 A1 WO 2017198201A1
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crystalline form
salt
ray powder
powder diffraction
complex
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PCT/CN2017/084976
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Xinchang LIU
Qingyun REN
Yingjun Zhang
Siegfried Goldmann
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Sunshine Lake Pharma Co., Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

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  • the present invention belongs to the field of medicine. Specifically, it relates to a variety of solid forms of 3- ( (R) -4- ( ( (R) -6- (2-bromo-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) morpholin-2-yl) propanoic acid (I) or tautomer (Ia) thereof, such as complex, acid addition salt, crystalline form and pharmaceutically composition thereof. Further more, it relates to the uses of solid forms and pharmaceutically compositions thereof in the manufacture of a medicament, especially in the manufacture of a medicament for preventing, managing, treating or lessening hepatitis B virus (HBV) infection.
  • HBV hepatitis B virus
  • the hepatitis B virus belongs to the family of hepadnaviridae. It can cause acute and/or persistent or progressive chronic diseases. Many other clinical manifestations in the pathological morphology can be also caused by HBV—in particular chronic hepatitis, cirrhosis and hepatocellular carcinogenesis. Additionally, coinfection with hepatitis D virus may have adverse effects on the progress of the disease.
  • the conventional medicaments approved to be used for treating chronic hepatitis are interferon and lamivudine.
  • the interferon has just moderate activity but has an adverse side reaction.
  • lamivudine has good activity, its resistance develops rapidly during the treatment and relapse effects often appear after the treatment has stopped.
  • the IC 50 value of lamivudine (3-TC) is 300 nM (Science, 2003, 299, 893-896) .
  • HAP heteroaryl-substituted dihydropyrimidine
  • Patent applications WO 2014029193 and CN 201310373003.5 have disclosed a number of dihydropyrimidine compounds which have the effect of blocking replication of HBV virus, wherein the compounds of formula (II) and (IIa) have better activity,
  • Patent application WO 2015144093 have disclosed preparation methods of compound having formula (I) or (Ia) , and obtained optically pure stereoisomers.
  • the stereoisomer having Formula (I) or (Ia) have better activity than the racemic compound having formula (II) or (IIa) , as well as the pharmacokinetic parameters and the stability of liver microsome thereof also have significant differences compared to the racemic compound having formula (II) or (IIa) .
  • Different salts and solid forms of a pharmaceutically active ingredient may have different properties.
  • the change of properties of different salts and solid forms can provide improved formulations, such as easily synthesis or managing, improvement of dissolution rate or stability and shelf life.
  • the final dosage form can also be improved due to changes in properties caused by different salts or solid forms, for example if such changes can increase exposure, bioavailability or prolong half-life.
  • Different salts and solid forms of the pharmaceutically active ingredient can also produce polycrystalline or other crystalline forms, thereby providing more opportunities to assess the property changes of a solid active pharmaceutical ingredient.
  • the inventors have obtained the complex, a variety of salts and solid forms thereof of the compound of formula (I) or a tautomer (Ia) thereof through many experimental studies.
  • the preparation purity of the product has obviously improved, and the physical properties are more favorable for the formulation.
  • the preparations of crystalline forms of complexes and many salts of the compound of formula (I) or tautomer (Ia) thereof, properties of drug metabolism and the physicochemical properties thereof, and the like, have been researched, and it has been found that the crystal forms of complexes and salts also have good water solubility, stability and pharmacokinetic properties, and the like.
  • the present invention relates to citric acid complex, acid addition salt, free base crystalline form of 3- ( (R) -4- ( ( (R) -6- (2-bromo-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) morpholin-2-yl) propanoic acid (I) or tautomer (Ia) thereof, and pharmaceutically compositions thereof. Further more, it relates to the uses of complex, acid addition salt, crystalline forms thereof, and pharmaceutical composition thereof in the manufacture of a medicament, especially in the manufacture of a medicament for preventing, managing, treating or lessening HBV infection.
  • the citric acid complex disclosed herein has crystalline form I (A) exhibiting the following characteristic X-ray powder diffraction peaks expressed in degrees 2 ⁇ at 7.21 ⁇ 0.2°, 11.79 ⁇ 0.2°, 14.13 ⁇ 0.2°, 16.11 ⁇ 0.2°, 18.67 ⁇ 0.2° and 22.32 ⁇ 0.2°.
  • the citric acid complex disclosed herein has crystalline form I (A) exhibiting the following characteristic X-ray powder diffraction peaks expressed in degrees 2 ⁇ at 6.19 ⁇ 0.2°, 7.21 ⁇ 0.2°, 8.60 ⁇ 0.2°, 11.79 ⁇ 0.2°, 14.13 ⁇ 0.2°, 16.11 ⁇ 0.2°, 18.67 ⁇ 0.2°, 19.61 ⁇ 0.2°, 22.32 ⁇ 0.2° and 25.20 ⁇ 0.2°.
  • the citric acid complex disclosed herein has crystalline form I (A) , and wherein the crystalline form I (A) has a differential scanning calorimetry thermogram comprising an endothermic peak at 152.95 °C ⁇ 3 °C.
  • the citric acid complex disclosed herein has crystalline form I (A) having an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 1; and/or a differential scanning calorimetry thermogram substantially the same as shown in Figure 2.
  • XRPD X-ray powder diffraction
  • salt is a pharmaceutically acceptable acid addition salt.
  • the pharmaceutically acceptable acid addition salt disclosed herein is an inorganic acid salt or an organic acid salt
  • the inorganic acid salt is selected from at least one of the following salts: hydrochloride, sulfate, hydrosulfate, nitrate, hydrobromide, hydriodate, borate, carbonate, hydrocarbonate, sulphite, hydrosulphite, pyrosulfate, monohydric phosphate, dihydric phosphate, perchlorate, persulfate, hemisulphate, bisulphate, thiocyanate, phosphate, pyrophosphate or metaphosphate; and wherein the organic acid salt is selected from at least one of the following salts: citrate, mesylate, oxalate, tartrate, L-tartrate, formate, acetate, propionate, butyrate, benzoate, malonate, succinate, pyruvate, esilate, propanesulfonate, 4-nitro
  • the pharmaceutically acceptable acid addition salt disclosed herein is a mesylate having crystalline form I (B) , and wherein the crystalline form I (B) exhibits the following characteristic X-ray powder diffraction peaks expressed in degrees 2 ⁇ at 11.74 ⁇ 0.2°, 17.34 ⁇ 0.2°, 18.33 ⁇ 0.2°, 21.08 ⁇ 0.2°, 23.92 ⁇ 0.2° and 26.44 ⁇ 0.2°.
  • the pharmaceutically acceptable acid addition salt disclosed herein is a mesylate having crystalline form I (B) , and wherein the crystalline form I (B) exhibits the following characteristic X-ray powder diffraction peaks expressed in degrees 2 ⁇ at 9.03 ⁇ 0.2°, 11.74 ⁇ 0.2°, 14.11 ⁇ 0.2°, 15.98 ⁇ 0.2°, 17.34 ⁇ 0.2°, 18.33 ⁇ 0.2°, 19.80 ⁇ 0.2°, 21.08 ⁇ 0.2°, 23.92 ⁇ 0.2° and 26.44 ⁇ 0.2°.
  • the pharmaceutically acceptable acid addition salt disclosed herein is a mesylate having crystalline form I (B) , and wherein the crystalline form I (B) exhibits the following characteristic X-ray powder diffraction peaks expressed in degrees 2 ⁇ at 4.57 ⁇ 0.2°, 9.03 ⁇ 0.2°, 9.90 ⁇ 0.2°, 11.74 ⁇ 0.2°, 14.11 ⁇ 0.2°, 14.71 ⁇ 0.2°, 14.92 ⁇ 0.2°, 15.98 ⁇ 0.2°, 17.34 ⁇ 0.2°, 18.03 ⁇ 0.2°, 18.33 ⁇ 0.2°, 19.80 ⁇ 0.2°, 21.08 ⁇ 0.2°, 21.38 ⁇ 0.2°, 22.47 ⁇ 0.2°, 23.51 ⁇ 0.2°, 23.92 ⁇ 0.2°, 24.81 ⁇ 0.2°, 25.08 ⁇ 0.2°, 25.77 ⁇ 0.2°, 26.44 ⁇ 0.2°, 26.61 ⁇ 0.2°, 27.14 ⁇
  • the pharmaceutically acceptable acid addition salt disclosed herein is a mesylate having crystalline form I (B) , and wherein the crystalline form I (B) has a differential scanning calorimetry thermogram comprising an endothermic peak at 125.91 °C ⁇ 3 °C.
  • the pharmaceutically acceptable acid addition salt disclosed herein is a mesylate having crystalline form I (B) , and wherein the crystalline form I (B) has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 3.
  • XRPD X-ray powder diffraction
  • the pharmaceutically acceptable acid addition salt disclosed herein is a mesylate having crystalline form I (B) , and wherein the crystalline form I (B) has a differential scanning calorimetry thermogram substantially the same as shown in Figure 4.
  • the pharmaceutically acceptable acid addition salt disclosed herein is a mesylate having crystalline form II, and wherein the crystalline form II exhibits the following characteristic X-ray powder diffraction peaks expressed in degrees 2 ⁇ at 11.35 ⁇ 0.2°, 16.76 ⁇ 0.2°, 19.31 ⁇ 0.2°, 20.73 ⁇ 0.2°, 22.86 ⁇ 0.2° and 24.55 ⁇ 0.2°.
  • the pharmaceutically acceptable acid addition salt disclosed herein is a mesylate having crystalline form II, and wherein the crystalline form II exhibits the following characteristic X-ray powder diffraction peaks expressed in degrees 2 ⁇ at 8.31 ⁇ 0.2°, 10.32 ⁇ 0.2°, 11.35 ⁇ 0.2°, 16.76 ⁇ 0.2°, 18.83 ⁇ 0.2°, 19.31 ⁇ 0.2°, 20.54 ⁇ 0.2°, 20.73 ⁇ 0.2°, 22.86 ⁇ 0.2° and 24.55 ⁇ 0.2°.
  • the pharmaceutically acceptable acid addition salt disclosed herein is a mesylate having crystalline form II, and wherein the crystalline form II exhibits the following characteristic X-ray powder diffraction peaks expressed in degrees 2 ⁇ at 7.09 ⁇ 0.2°, 8.31 ⁇ 0.2°, 8.85 ⁇ 0.2°, 10.32 ⁇ 0.2°, 11.35 ⁇ 0.2°, 12.13 ⁇ 0.2°, 13.61 ⁇ 0.2°, 15.02 ⁇ 0.2°, 15.76 ⁇ 0.2°, 16.76 ⁇ 0.2°, 17.79 ⁇ 0.2°, 18.10 ⁇ 0.2°, 18.38 ⁇ 0.2°, 18.83 ⁇ 0.2°, 19.31 ⁇ 0.2°, 20.54 ⁇ 0.2°, 20.73 ⁇ 0.2°, 21.29 ⁇ 0.2°, 21.64 ⁇ 0.2°, 22.05 ⁇ 0.2°, 22.86 ⁇ 0.2°, 23.33 ⁇ 0.2°, 23.58 ⁇ 0.2°, 24.01 ⁇
  • the pharmaceutically acceptable acid addition salt disclosed herein is a mesylate having crystalline form II, and wherein the crystalline form II has a differential scanning calorimetry thermogram comprising an endothermic peak at 201.21 °C ⁇ 3 °C.
  • the pharmaceutically acceptable acid addition salt disclosed herein is a mesylate having crystalline form II, and wherein the crystalline form II has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 5.
  • XRPD X-ray powder diffraction
  • the pharmaceutically acceptable acid addition salt disclosed herein is a mesylate having crystalline form II, and wherein the crystalline form II a differential scanning calorimetry thermogram substantially the same as shown in Figure 6.
  • the pharmaceutically acceptable acid addition salt disclosed herein is a mesylate having crystalline form III, and wherein the crystalline form III exhibits the following characteristic X-ray powder diffraction peaks expressed in degrees 2 ⁇ at 9.01 ⁇ 0.2°, 18.03 ⁇ 0.2°, 21.06 ⁇ 0.2°, 22.58 ⁇ 0.2°, 25.08 ⁇ 0.2° and 27.16 ⁇ 0.2°.
  • the pharmaceutically acceptable acid addition salt disclosed herein is a mesylate having crystalline form III, and wherein the crystalline form III exhibits the following characteristic X-ray powder diffraction peaks expressed in degrees 2 ⁇ at 4.54 ⁇ 0.2°, 9.01 ⁇ 0.2°, 17.32 ⁇ 0.2°, 18.03 ⁇ 0.2°, 21.06 ⁇ 0.2°, 22.58 ⁇ 0.2°, 25.08 ⁇ 0.2°, 26.54 ⁇ 0.2°, 27.16 ⁇ 0.2° and 31.79 ⁇ 0.2°.
  • the pharmaceutically acceptable acid addition salt disclosed herein is a mesylate having crystalline form III, and wherein the crystalline form III exhibits the following characteristic X-ray powder diffraction peaks expressed in degrees 2 ⁇ at 4.54 ⁇ 0.2°, 9.01 ⁇ 0.2°, 11.69 ⁇ 0.2°, 13.52 ⁇ 0.2°, 14.08 ⁇ 0.2°, 14.88 ⁇ 0.2°, 15.91 ⁇ 0.2°, 17.32 ⁇ 0.2°, 18.03 ⁇ 0.2°, 19.68 ⁇ 0.2°, 21.06 ⁇ 0.2°, 22.36 ⁇ 0.2°, 22.58 ⁇ 0.2°, 23.45 ⁇ 0.2°, 23.91 ⁇ 0.2°, 25.08 ⁇ 0.2°, 25.68 ⁇ 0.2°, 26.54 ⁇ 0.2°, 27.16 ⁇ 0.2°, 28.74 ⁇ 0.2°, 29.00 ⁇ 0.2°, 31.11 ⁇ 0.2°, 31.79 ⁇ 0.2°, 32
  • the pharmaceutically acceptable acid addition salt disclosed herein is a mesylate having crystalline form III, and wherein the crystalline form III has a differential scanning calorimetry thermogram comprising an endothermic peak at 137.79 °C ⁇ 3 °C.
  • the pharmaceutically acceptable acid addition salt disclosed herein is a mesylate having crystalline form III, and wherein the crystalline form III has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 7.
  • XRPD X-ray powder diffraction
  • the pharmaceutically acceptable acid addition salt disclosed herein is a mesylate having crystalline form III, and wherein the crystalline form III has a differential scanning calorimetry thermogram substantially the same as shown in Figure 8.
  • crystalline form is crystalline form A exhibiting the following characteristic X-ray powder diffraction peaks expressed in degrees 2 ⁇ at 9.12 ⁇ 0.2°, 12.08 ⁇ 0.2°, 15.95 ⁇ 0.2°, 18.54 ⁇ 0.2°, 23.30 ⁇ 0.2° and 26.31 ⁇ 0.2°.
  • the crystalline form A disclosed herein exhibits the following characteristic X-ray powder diffraction peaks expressed in degrees 2 ⁇ at 9.12 ⁇ 0.2°, 12.08 ⁇ 0.2°, 14.02 ⁇ 0.2°, 15.95 ⁇ 0.2°, 17.19 ⁇ 0.2°, 18.54 ⁇ 0.2°, 19.81 ⁇ 0.2°, 22.12 ⁇ 0.2°, 23.30 ⁇ 0.2° and 26.31 ⁇ 0.2°.
  • the crystalline form A disclosed herein exhibits the following characteristic X-ray powder diffraction peaks expressed in degrees 2 ⁇ at 6.01 ⁇ 0.2°, 9.12 ⁇ 0.2°, 10.39 ⁇ 0.2°, 11.16 ⁇ 0.2°, 11.49 ⁇ 0.2°, 12.08 ⁇ 0.2°, 14.02 ⁇ 0.2°, 14.38 ⁇ 0.2°, 14.85 ⁇ 0.2°, 15.33 ⁇ 0.2°, 15.95 ⁇ 0.2°, 17.19 ⁇ 0.2°, 18.54 ⁇ 0.2°, 19.51 ⁇ 0.2°, 19.81 ⁇ 0.2°, 20.52 ⁇ 0.2°, 20.96 ⁇ 0.2°, 21.57 ⁇ 0.2°, 22.12 ⁇ 0.2°, 22.46 ⁇ 0.2°, 22.97 ⁇ 0.2°, 23.30 ⁇ 0.2°, 23.79 ⁇ 0.2°, 24.51 ⁇ 0.2°, 24.81 ⁇ 0.2°, 25.11 ⁇ 0.2°, 26
  • the crystalline form A disclosed herein has a differential scanning calorimetry thermogram comprising an endothermic peak at 100.37 °C ⁇ 3 °C.
  • the crystalline form A disclosed herein has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in Figure 9.
  • XRPD X-ray powder diffraction
  • the crystalline form A disclosed herein has a differential scanning calorimetry thermogram substantially the same as shown in Figure 10.
  • the complex, the salt, the crystalline form, or the pharmaceutical composition disclosed herein, wherein the virus disease is hepatitis B infection or a disease caused by hepatitis B infection.
  • the above-mentioned crystalline form having a certain amount of water or other solvent has any of the characteristics of the crystalline form of the compound represented by formula (I) or (Ia) , the citric acid complex and the acid addition salt thereof according to the present invention, it is intended to be included within the scope of the present invention.
  • the measurement of DSC thermogram could have some experimental error, for example the measurements of peak position and peak value in DSC thermogram could be different because of different instruments and different samples. Therefore, the numerical value of peak position and peak value of endothermic peak in DSC thermogram is not absolute.
  • the error margin in the melting peaks is ⁇ 1 °C, ⁇ 2 °C, ⁇ 3 °C, ⁇ 4 °C or ⁇ 5 °C. In some embodiments, the error margin in the melting peaks is ⁇ 3 °C.
  • DSC Differential scanning calorimetry
  • HBV disease is a hepatic disease caused by hepatitis B virus infection or hepatitis B infection, including acute hepatitis, chronic hepatitis, cirrhosis and hepatocellular carcinoma.
  • the symptoms of acute hepatitis B virus infection may be asymptomatic or manifested as acute hepatitis symptoms.
  • a patient with chronic virus infection suffers an active disease, which can progress to cirrhosis and liver cancer.
  • Figure 2 provides a differential scanning calorimetry (DSC) thermogram of citric acid complex having crystaline form I (A) .
  • Figure 8 provides a differential scanning calorimetry (DSC) thermogram of mesylate having crystalline form III.
  • Figure 9 provides an X-ray powder diffraction (XRPD) pattern of crystaline form A of the invention.
  • a cooled crystallization mixture may be filtered under vacuum, and the isolated solids may be washed with a suitable solvent, such as cold recrystallization solvent, and dried under a nitrogen purge to afford the desired crystalline form.
  • the isolated solids may be analyzed by a suitable spectroscopic or analytical technique, including but not limited to, differential scanning calorimetry (DSC) , X-Ray powder diffraction (XRPD) , thermogravimetric analysis (TGA) , to assure formation of the preferred crystalline form of the product.
  • the resulting crystalline form is typically produced in an amount of greater than about 70 weight percent isolated yield, preferably greater than 90 weight percent isolated yield, based on the weight of the compound originally employed in the crystallization procedure.
  • the product may be co-milled or passed through a mesh screen to delump, if necessary.
  • Thermo gravimetric Analysis was recorded on a TA Q500 instrument with a thermoanalysis controller. The data was collected and analyzed by TA Instruments Thermal Solutions software. About 10 mg sample was weighed accurately in platinum sample pans, then heated from ambient temperature to 300 °C using a linear heating device at a scan rate of 10 °C/minute for sample analysis. During the period of sample analysis, TGA furnace chamber was purged by dry nitrogen.
  • MS data were also determined on an Agilent 6320 series LC-MS spectrometer equipped with G1312A binary pumps, a G1316A TCC (Temperature Control of Column, maintained at 30 °C) , a G1329A autosampler and a G1315B DAD detector were used in the analysis.
  • An ESI source was used on the LC-MS spectrometer.
  • Table 1 The gradient condition of the mobile phase in Low-resolution mass spectrum analysis
  • the compound of formula (I) can be prepared refer to the method described in Patent WO 2015144093, or other reasonable synthetic methods,
  • the residual liquid was rinsed with acetone (50 mL) , then the resulting mixture was heated to 50 °C and stirred for 1.5 hours maintaining at this temperature.
  • the reaction mixture was cooled naturally to room temperature and continued to stir for 24 hours, then there was a solid precipitated out.
  • the mixture was filtered and the filter cake was washed with ethyl acetate (250 mL) .
  • the filter cake was collected and dried in the air for 1 hour, then dried in vacuum for 3 hours at room temperature, and then dried at 70 °C in vacuum for 12 hours. Heating was stopped, and the filter cake was continued to dry in vacuum until the temperature was cooled to room temperature to give the title compound as an off-white solid (47.22 g, yield 81.05%) .
  • the error margin in 2 ⁇ of the characteristic peaks was ⁇ 0.2°.
  • Crystalline form I (A) was identified by using TA Q2000 differential scanning calorimetry (DSC) with a scan rate of 10 °C/minute, and the DSC curve was shown in Figure 2, comprising an endothermic peak at 152.95 °C. The error margin of the endothermic peaks was ⁇ 3 °C.
  • reaction mixture was stirred for 12 hours at room temperature, then there was a solid precipitated out.
  • the mixture was filtered, and the filter cake was washed with ethyl acetate (50 mL) .
  • the filter cake was collected and dried in vacuum for 6 hours at room temperature to give the title compound as a yellow solid (8 g, yield 68.64%) .
  • Table 4 The XRPD data of mesylate having crystaline form I (B) .
  • the error margin in 2 ⁇ of the diffraction peaks was ⁇ 0.2°.
  • Crystalline form I (B) was identified by using TA Q2000 differential scanning calorimetry (DSC) with a scan rate of 10 °C/minute, and the DSC curve was shown in Figure 4, comprising an endothermic peak at 125.91 °C. The error margin of the endothermic peaks was ⁇ 3 °C.
  • the error margin in 2 ⁇ of the diffraction peaks was ⁇ 0.2°.
  • Crystalline form II was identified by using TA Q2000 differential scanning calorimetry (DSC) with a scan rate of 10 °C/minute, and the DSC curve was shown in Figure 6, comprising an endothermic peak at 201.21°C. The error margin of the endothermic peaks was ⁇ 3 °C.
  • the error margin in 2 ⁇ of the diffraction peaks was ⁇ 0.2°.
  • crystalline form I (A) (0.3 g) prepared from example 1 and acetone (2.5 mL) .
  • the mixture was heated to 55 °C, then water (3.5 mL) was added.
  • the resulting mixture was stirred for 30 minutes and dissolved completely, then the mixture was cooled slowly to room temperature. There was a solid precipitated out and the mixture was continued to stir for 8 hours.
  • the mixture was filtered, and the filter cake was rinsed with water (3 mL) . Then the filter cake was dried in vacuum for 8 hours at 40 °C to give the title compound as a light yellow solid (0.2 g, yield 64%) .
  • the error margin in 2 ⁇ of the diffraction peaks was ⁇ 0.2°.
  • Crystalline form A was identified by using TA Q2000 differential scanning calorimetry (DSC) with a scan rate of 10 °C/minute, and the DSC curve was shown in Figure 10, comprising an endothermic peak at 100.37 °C. The error margin of the endothermic peaks was ⁇ 3 °C.
  • High temperature test an appropriate amount of test sample was put in a weighing bottle in the form of a thin layer of ⁇ 5 mm under a temperature of 60 °C or 40 °C for 10 days. Appearance, impurity and purity of the samples were detected respectively at the 5 th and 10 th day by sampling. If the test sample has changed significantly occurred at 60 °C, then the test sample needs to be retested in the same manner at 40 °C. If the sample has no significant change occurred at 60 °C, it is not necessary to do the experiment under the condition of 40 °C.
  • High humidity test an appropriate amount of test sample was put in a weighing bottle in the form of a thin layer of ⁇ 5 mm under the conditions of 25 °C and RH 90% ⁇ 5%for 10 days. Appearance, impurity, purity and weight of the samples were detected respectively at the 5 th and 10 th day by sampling to evaluate the moisture absorption performance of the samples. If the moisture-absorption weight of the test sample gains more than 5%, then the test sample needs to be retested under the conditions of 25 °C and RH 75% ⁇ 5%. If the moisture-absorption weight of the test sample gains less than 5%, and other results meet the requirements, it is not necessary to do the experiment any more.
  • the weighing bottle should be presaturated for one day by putting it into the humidistat (or a dryer containing a saturated solution of potassium nitrate) before high humidity test, then the test sample and weighing bottle were weighed together, and the weigh was recorded. )
  • Illumination test an appropriate amount of test sample was put in a flat weighing bottle in the form of a thin layer of ⁇ 5 mm, and the sample in the flat weighting bottle without sealing was placed in light box (with UV) under the condition of illumination of 4500 ⁇ 500lx, UV ⁇ 0.7 w/m 2 for 10 days. Appearance, impurity and purity of the samples were detected respectively at the 5 th and 10 th day by sampling. Results were as shown in table 8 and table 9.
  • test compounds were administered intragastrically at a dosage of 2.5 mg/kg, 5 mg/kg or 10 mg/kg.
  • Blood samples of foreleg-vein were taken at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after the administration, and collected in anticoagulation tube with EDTA-K 2 .
  • the test compounds were extracted from plasma samples by liquid-liquid extraction. Then quantitative analysis was performed on a triple-quadrupole tandem mass spectrometer using multiple reaction monitoring (MRM) .
  • Pharmacokinetic parameters were calculated using a noncompartmental method by WinNonLin 6.1 software. Results were as shown in table 10:
  • test results showed that, the test compound prepared from example of the invention had good pharmacokinetic properties in test animals, specifically for the higher exposure level and longer half-life, which were shown that the compounds prepared from examples 1-4 had better absorption, longer half-life, and the administration interval can be appropriately prolonged, the number of times of administration can be reduced.
  • a dry glass weighing bottle (the outer diameter was 50 mm and height was 15 mm) with a plug was placed in a suitable thermostatic drier at 25 °C ⁇ 1 °C (saturated solution of ammonium chloride or ammonium sulfate were placed on the bottom, and the relative humidity was 90% ⁇ 2%) on the day before the experiment, and weighed precisely (m 1 ) .
  • the appropriate amount of the sample was plated into the weighing bottle, wherein the thickness of the sample typically was about 1 mm, and the sample was weighed precisely (m 2 ) .
  • the weighing bottle was open and placed with the plug in the above constant temperature and humidity condition for 24 hours.
  • the weighing bottle was capped with plug, and then weighed precisely (m 3 ) , and the weight gain percentage was calculated (%) .
  • Hygroscopicity characteristics the percentage (%) of hygroscopic weight gain.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des sels de dérivé de dihydropyrimidine et leurs utilisations en médecine. Spécifiquement, elle concerne un complexe d'acide citrique, un sel d'addition d'acide 3-((R)-4-(((R)-6-(2-bromo-4-fluorophényl)-5-(éthoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)méthyl)morpholin-2-yl) propanoïque ou un tautomère de celui-ci, ou une forme cristalline de celui-ci, et des compositions pharmaceutiques de celui-ci.
PCT/CN2017/084976 2016-05-19 2017-05-18 Forme cristalline, sel et complexe de dérivé de dihydropyrimidine, et leurs utilisations en médecine WO2017198201A1 (fr)

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WO2020255015A1 (fr) * 2019-06-18 2020-12-24 Janssen Sciences Ireland Unlimited Company Combinaison de vaccins contre le virus de l'hépatite b (vhb) et de dérivés de dihydropyrimidine en tant que modulateurs d'assemblage de capside
EP3766880A4 (fr) * 2018-05-16 2021-08-11 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Forme solide d'un composé de dihydropyrimidine, son procédé de préparation et son utilisation

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CN111632196A (zh) * 2020-06-01 2020-09-08 内蒙古自治区中医药研究所 一种去α-半乳糖基抗原脱细胞基质的制备方法

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WO2014029193A1 (fr) * 2012-08-24 2014-02-27 Sunshine Lake Pharma Co., Ltd. Composés de dihydropyrimidine et leur application dans des produits pharmaceutiques
WO2014048355A1 (fr) * 2012-09-27 2014-04-03 Sunshine Lake Pharma Co., Ltd. Formes cristallines de dérivés de dihydropyrimidine
WO2015144093A1 (fr) * 2014-03-28 2015-10-01 Sunshine Lake Pharma Co., Ltd. Composés dihydropyrimidine et leur application dans des produits pharmaceutiques
WO2016012470A1 (fr) * 2014-07-25 2016-01-28 F. Hoffmann-La Roche Ag Nouvelles formes amorphes et cristallines de l'acide (3s)-4-[[(4r)-4-(2-chloro-4-fluorophényl)-5-méthoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]méthyl]morpholine-3-carboxilique

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WO2014029193A1 (fr) * 2012-08-24 2014-02-27 Sunshine Lake Pharma Co., Ltd. Composés de dihydropyrimidine et leur application dans des produits pharmaceutiques
WO2014048355A1 (fr) * 2012-09-27 2014-04-03 Sunshine Lake Pharma Co., Ltd. Formes cristallines de dérivés de dihydropyrimidine
WO2015144093A1 (fr) * 2014-03-28 2015-10-01 Sunshine Lake Pharma Co., Ltd. Composés dihydropyrimidine et leur application dans des produits pharmaceutiques
WO2016012470A1 (fr) * 2014-07-25 2016-01-28 F. Hoffmann-La Roche Ag Nouvelles formes amorphes et cristallines de l'acide (3s)-4-[[(4r)-4-(2-chloro-4-fluorophényl)-5-méthoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]méthyl]morpholine-3-carboxilique

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3766880A4 (fr) * 2018-05-16 2021-08-11 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Forme solide d'un composé de dihydropyrimidine, son procédé de préparation et son utilisation
JP2021523880A (ja) * 2018-05-16 2021-09-09 シチュアン ケルン−バイオテック バイオファーマシューティカル カンパニー リミテッド ジヒドロピリミジン化合物の固体形態及びその調製方法及びその使用
US11434235B2 (en) 2018-05-16 2022-09-06 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Solid form of dihydropyrimidine compound and preparation method therefor and use thereof
WO2020255015A1 (fr) * 2019-06-18 2020-12-24 Janssen Sciences Ireland Unlimited Company Combinaison de vaccins contre le virus de l'hépatite b (vhb) et de dérivés de dihydropyrimidine en tant que modulateurs d'assemblage de capside

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