WO2015074281A1 - Sel de rigosertib, forme cristalline de celui-ci, et procédé de préparation et application associés - Google Patents

Sel de rigosertib, forme cristalline de celui-ci, et procédé de préparation et application associés Download PDF

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Publication number
WO2015074281A1
WO2015074281A1 PCT/CN2013/087793 CN2013087793W WO2015074281A1 WO 2015074281 A1 WO2015074281 A1 WO 2015074281A1 CN 2013087793 W CN2013087793 W CN 2013087793W WO 2015074281 A1 WO2015074281 A1 WO 2015074281A1
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Prior art keywords
salt
ringer
crystal form
diethylamine
ringeride
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PCT/CN2013/087793
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English (en)
Chinese (zh)
Inventor
胡晨阳
盛晓霞
盛晓红
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杭州普晒医药科技有限公司
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Application filed by 杭州普晒医药科技有限公司 filed Critical 杭州普晒医药科技有限公司
Priority to PCT/CN2013/087793 priority Critical patent/WO2015074281A1/fr
Priority to CN201380066027.4A priority patent/CN104884128B/zh
Publication of WO2015074281A1 publication Critical patent/WO2015074281A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C211/03—Monoamines
    • C07C211/05—Mono-, di- or tri-ethylamine

Definitions

  • Ligesite salt and its crystal form their preparation method and use
  • This application relates to the field of medicinal chemical crystallization technology. Specifically, it relates to a salt of the antitumor drug ligastide and a crystal form thereof, and to a method for preparing the salt and a crystal form thereof, a pharmaceutical composition thereof and use thereof. Background technique
  • the chemical name of the small molecule antitumor compound developed by Onconova Therapeutics is (E)-2,4,6-trimethoxyoxystyryl-3-(carboxyamido)-4-pyrene Oxybenzyl sulfone, also known as (E)-2-(5-((2,4,6-trimethoxyoxystyrenesulfonyl)indolyl)-2-nonyloxyanilino)acetic acid.
  • the English name is Rigosertib, the alias is ON01910. Its chemical structure is as follows:
  • Riggside is a multi-kinase inhibitor that targets the mitotic and PLK kinase pathways.
  • the drug has cell death activity and can act on 94 different tumor cell lines; it also inhibits some multi-drug resistant tumor cell lines and promotes the activity of chemotherapeutic agents in drug-resistant tumors.
  • Current clinical trials use forceazide sodium salt, indications include myelodysplastic syndrome (MDS), leukemia, lymphoma, ovarian cancer, pancreatic cancer, lung cancer, advanced liver cancer, head and neck cancer, cervical cancer, esophageal cancer.
  • MDS myelodysplastic syndrome
  • lung cancer advanced liver cancer, head and neck cancer
  • cervical cancer esophageal cancer.
  • the administration of ligastatin sodium salt includes intravenous injection and oral administration.
  • Patent documents WO2006074149 and WO2006104668 disclose Ligthatin compounds and synthetic methods thereof, the latter also providing a method for synthesizing the sodium salt thereof;
  • Patent Document WO2008088803 describes a method for purifying Ringer Sodium salt, and simultaneously discloses the force grid game Dipotassium salt;
  • Patent Document WO2008027049 discloses the melting point of ligastide, and discloses a method for synthesizing the sodium salt thereof; however, none of the above documents mentions the specific physical form, thermal analysis and other characterization data of the Ringer's salt. .
  • MV Ramana Reddy et al. J. Med. Chem. 2011, 54, 6254-6276 on Ringerdine sodium salt A description of the melting point and photosensitivity is carried out.
  • the Ringer Sodium salt prepared according to WO2006104668 has no crystalline state and is amorphous; from the isothermal adsorption curve, it is very easy to absorb moisture, and the weight change is 21.5% at 20% ⁇ 80% relative humidity.
  • the salt is easily oxidized and placed in a desiccator containing urea hydrogen peroxide for 5 days, and the purity is reduced by 34.58%. From the light stability experiment, the illumination is unstable, and the illumination condition is After 5 days of 45001x ⁇ 5001x illumination, the purity was reduced by 11.98%.
  • This application provides new Ringer's salt and its crystalline form, including Ringer's diethylamine salt, Riggsedrine calcium salt, and the crystalline forms of these salts.
  • Ringer's diethylamine salt and its crystal form, Ringer's 4 bow salt and its crystal form of the present application have one or more superior properties compared to the known Ringer Sodium salt.
  • favorable crystallinity, preferred crystal form, low hygroscopicity, good stability, good fluidity and good processability are examples of the Ringer Sodium salt.
  • One of the contents of the present application is to provide a Ringeride diethylamine salt and its crystal form A, Form B, Form C and a process for the preparation thereof.
  • the Ringeride diethylamine salt is a compound formed by a combination of Riggside and diethylamine in a molar ratio of 1:1, and has the structural formula shown below:
  • the preparation method of the Ringeride diethylamine salt adopts any one of the following methods:
  • the soluble solvent is selected from the group consisting of an alcohol or a ketone, preferably a d-C 3 alcohol or a C 3 -C 4 ketone, wherein the C-C 3 alcohol may be decyl alcohol, ethanol, n-propanol or iso
  • the propanol, C 3 -C 4 ketone may be acetone or butanone; in an embodiment of the invention, the soluble solvent is more preferably ethanol or acetone.
  • the molar ratio of the ligastide free acid to diethylamine is 1:1 to 1:10, preferably 1 : 2 ⁇ 1 : 5.
  • the preparation temperature is room temperature
  • the stirring time of the slurry is 10 to 24 hours, preferably 10 to 16 hours.
  • the concentration of the ligastide free acid in the soluble solvent is 10 to 50 mg/mL, and preferably the concentration of the ligastide free acid in the alcohol solvent is 10 to 25 mg/mL, preferably The concentration of the freezer acid in the ketone solvent is 16-50 mg/mL.
  • the "concentration to dryness” can be carried out by conventional operations in the art, such as evaporation, distillation, volatilization, lyophilization, etc., preferably under reduced pressure, at a pressure of less than 0.09 MPa.
  • the standing temperature is room temperature
  • the standing time is 1 to 3 days, preferably 1 to 2 days.
  • the preparation method is carried out, for example, in a large container containing diethylamine, and a small container containing ligastide free acid is placed, the small container is open, and the large container is sealed.
  • the Ringeride diethylamine salts obtained according to the above two preparation methods are all oily.
  • the Ringeride diethylamine salt described in the present application is a Ringeride diethylamine salt crystal form B (hereinafter referred to as "diethylamine salt crystal form B”), the diethylamine salt crystal
  • diethylamine salt crystal form B a Ringeride diethylamine salt crystal form B
  • the X-ray powder diffraction pattern of the type B represented by the diffraction angle 2 ⁇ has the following characteristic peaks: 4.4 ⁇ 0.2°, 10.2 ⁇ 0.2°, 11.7 ⁇ 0.2°, 13.0 ⁇ 0.2°,
  • the X-ray powder diffraction pattern of the diethylamine salt crystal form B represented by the diffraction angle 2 ⁇ has the following characteristic peaks: 4.4 ⁇ 0.2°, 10.2 ⁇ 0.2°, 11.7 ⁇ 0.2°, 12.7 ⁇ 0.2°, 13.0 ⁇ 0.2°, 13.9 ⁇ 0.2°,
  • the X-ray powder diffraction pattern of the diethylamine salt crystal form represented by the diffraction angle 2 ⁇ has the following characteristic peaks and their relative intensities:
  • a typical example of the crystalline form of the diethylamine salt has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the diethylamine salt crystal form ⁇ 's polarized light microscopy (PLM) pattern is shown as fine crystalline particles.
  • thermogravimetric analysis (TGA) pattern of the diethylamine salt crystal form B is shown in Fig. 10.
  • the differential thermal analysis (DSC) pattern of the diethylamine salt crystal form B showed a broad endothermic peak at 20 to 90 ° C, followed by a broad endothermic peak between 90 and 140 ° C.
  • the isothermal adsorption curve of the diethylamine salt form B showed a weight change of about 3.4% in the range of 20% to 80% relative humidity.
  • the Ringer's diethylamine salt crystal form B of the present application has the following beneficial effects as compared with the amorphous forceer sodium salt:
  • the diethylamine salt crystal form B has good chemical stability and crystal form stability:
  • the oxidation stability experiment it is placed in a desiccator containing urea hydrogen peroxide for 5 days, purity The reduction was only 8.95% (amorphous Ringer's salt was 34.58%) and the crystal form remained unchanged.
  • the illumination condition was 45001x ⁇ 5001x illumination for 5 days, the purity was reduced by only 3.19% (the amorphous force of the Saide salt was 11.98%) and the crystal form remained unchanged.
  • both of the above 2) and 3) indicate that the diethylamine salt form B of the present invention is better able to resist uneven content caused by external factors such as environmental moisture, light, oxygen, etc. during pharmaceutical preparation and/or storage. As well as problems such as reduced purity, it is more conducive to accurate quantification and post-transportation and storage in the preparation of unit preparations. And reduce the risk of decreased efficacy caused by unstable active substance content and increased impurity content.
  • the preparation method of the Ringeride diethylamine salt crystal form B comprises the following steps:
  • the Ringeride diethylamine salt obtained according to the preparation method of the aforementioned Ringeride diethylamine salt is at a relative humidity of 75 Placed in an environment of % ⁇ 85% to obtain the crystal form B of Ringer's diethylamine salt.
  • the standing temperature is room temperature
  • the standing time is 2 to 3 days, preferably 2 days.
  • the relative humidity is preferably 85%.
  • the Ringeride diethylamine salt described in the present application is a crystal form A of Ringeride diethylamine salt (hereinafter referred to as "diethylamine salt crystal form A”), the diethylamine salt crystal
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ of the type A has the following characteristic peaks: 4 ⁇ 3 ⁇ 0 ⁇ 2°, 11 ⁇ 2 ⁇ 0 ⁇ 2°, 16 ⁇ 2 ⁇ 0 ⁇ 2°, 17 ⁇ 0 ⁇ 0 ⁇ 2°, 20.3 ⁇ 0.2° and 22.5 ⁇ 0.2°.
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ of the diethylamine salt crystal form has the following characteristic peaks: 4 ⁇ 3 ⁇ 0 ⁇ 2°, 11 ⁇ 2 ⁇ 0 ⁇ 2°, 11 ⁇ 5 ⁇ 0 ⁇ 2°, 12 ⁇ 1 ⁇ 0 ⁇ 2°, 13 ⁇ 5 ⁇ 0 ⁇ 2°, 14 ⁇ 2 ⁇ 0 ⁇ 2°, 16 ⁇ 0 ⁇ 0 ⁇ 2°, 16 ⁇ 2 ⁇ 0 ⁇ 2° , 17 ⁇ 0 ⁇ 0 ⁇ 2°, 19 ⁇ 9 ⁇ 0 ⁇ 2°, 20 ⁇ 3 ⁇ 0 ⁇ 2° and 22 ⁇ 5 ⁇ 0 ⁇ 2°.
  • the X-ray powder diffraction pattern of the diethylamine salt crystal form represented by the diffraction angle 2? has the following characteristic peaks and their relative intensities:
  • a typical example of the diethylamine salt crystal form A has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the polarized light microscopy (PLM) pattern of the diethylamine salt crystal form A is shown as irregular bulk crystals.
  • thermogravimetric analysis (TGA) of the diethylamine salt form A shows a weight loss of about 1.1% before 90 °C.
  • DSC differential thermal analysis
  • the isothermal adsorption curve of the diethylamine salt crystal form A showed a weight change of about 2.5% in the range of 20% to 80% relative humidity.
  • the crystal form A of Ringer's diethylamine salt of the present application has the following beneficial effects as compared with the amorphous forceer sodium salt:
  • the above 2) shows that the diethylamine salt crystal form A of the present invention can better cope with problems such as uneven content and reduced purity caused by external factors such as environmental moisture during the preparation and/or storage of the pharmaceutical preparation, and the like. It facilitates accurate quantification and post-transportation and storage in the preparation of unit preparations, and reduces the risk of deteriorating efficacy caused by unstable active substance content and increased impurity content.
  • the preparation method of the Ringerdidiamine salt crystal form A comprises the following steps:
  • the Riggsedil diethylamine salt obtained according to the preparation method of the aforementioned Ringeride diethylamine salt is at a relative humidity of 92 Placed in an environment of % ⁇ 97%, obtain the crystal form A of Ringer's diethylamine salt.
  • the standing temperature is room temperature
  • the standing time is 1 to 4 days, preferably 1 to 2 days.
  • the relative humidity is preferably 92%.
  • the Ringeride diethylamine salt described in the present application is a crystalline form of Ringer's diethylamine salt C (hereinafter referred to as "diethylamine salt crystal form C”), the diethylamine salt crystal
  • the X-ray powder diffraction pattern of the type C represented by the diffraction angle 2 ⁇ has the following characteristic peaks: 7.1 ⁇ 0.2 °, 11.3 ⁇ 0.2 °, 12.5 ⁇ 0.2 °, 17.7 ⁇ 0.2 °, 18.7 ⁇ 0.2 °, and 20.0 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the diethylamine salt crystal form C represented by the diffraction angle 2 ⁇ has the following characteristic peaks: 7.1 ⁇ 0.2°, 9.4 ⁇ 0.2°, 11.3 ⁇ 0.2°, 11.7 ⁇ 0.2°, 12.5 ⁇ 0.2°, 17.2 ⁇ 0.2°, 17.7 ⁇ 0.2°, 18.7 ⁇ 0.2°, 20.0 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.1 ⁇ 0.2° and 24.1 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the diethylamine salt crystal form C represented by the diffraction angle 2 ⁇ has the following characteristic peaks and their relative intensities: 2 ⁇ Relative strength%
  • a typical example of the diethylamine salt crystal form C has the structure shown in FIG.
  • XRPD X-ray powder diffraction
  • the polarized light microscopy (PLM) pattern of the diethylamine salt crystal form C is shown as an irregular fine crystal.
  • thermogravimetric analysis (TGA) pattern of the diethylamine salt crystal form C showed a weight loss of about 0.8% before 75 °C.
  • the differential thermal analysis (DSC) pattern of the diethylamine salt crystal form C shows a broad endothermic peak at 90 to 130 °C.
  • the isothermal adsorption curve of the diethylamine salt crystal form C showed a weight change of about 9.9% in the range of 20% to 80% relative humidity.
  • the Ringer's diethylamine salt crystal form C of the present application has the following beneficial effects as compared with the amorphous force gemide sodium salt:
  • the diethylamine salt crystal form C has a relatively low hygroscopicity.
  • the above 2) shows that the diethylamine salt crystal form C of the present invention can better cope with problems such as uneven content and reduced purity caused by external factors such as environmental moisture during pharmaceutical preparation and/or storage. It is more conducive to accurate quantification and post-transportation and storage in the preparation of unit preparations, and reduces the risk of decreased efficacy caused by unstable active substance content and increased impurity content.
  • the preparation method of the Ringerdidiamine salt crystal form C comprises the following steps: adding an organic solvent to the Ringeride diethylamine salt obtained according to the preparation method of the aforementioned Ringeride diethylamine salt The crystallizing is stirred, wherein the organic solvent is selected from the group consisting of an ester, a ketone or a mixture thereof to obtain the crystal form c of the Ringeride diethylamine salt.
  • the organic solvent is c 4 ⁇ c 5 ester or c 3 ⁇ c 4 ketone, wherein the c 4 ⁇ c 5 ester may be ethyl acetate, propyl acetate, isopropyl acetate or ethyl propionate.
  • the C c 4 ketone may be acetone or methyl ethyl ketone; the organic solvent is more preferably ethyl acetate or acetone.
  • the crystallization temperature is room temperature
  • the crystallization time is 0.5 to 16 hours, preferably 0.5 to 8 hours.
  • the mass to volume ratio of the Ringeride diethylamine salt to the organic solvent is 20 mg to 80 mg: 1 mL, preferably 50 mg to 80 mg: 1 mL.
  • the second content of the present application is to provide Ringer's 4 bow salt and its crystal form A, crystal form B and their preparation.
  • the Ringer's 4 Bow Salt is a compound formed by Ringeride and calcium ions in a molar ratio of 2:1, and its structural formula is as follows
  • the preparation method of the Ringer's 4 bow salt comprises the following steps: forming a solution of ligastide free acid in a soluble solvent, adding calcium hydroxide to form a slurry and stirring, separating the solid, washing with water, drying, and obtaining Lige Sai 4 bow salt.
  • the molar ratio of the freezer acid to the calcium hydroxide is from 1:0.5 to 1:2, preferably from 1:1 to 1:1.5.
  • the soluble solvent is selected from the group consisting of a ketone or an alcohol, preferably a C 3 -C 4 ketone or a d-C 3 alcohol, the c 3 -c 4 ketone may be acetone, butanone, and the C-C 3 alcohol may be hydrazine.
  • the temperature of the slurry is room temperature, and the stirring time of the slurry is 10 to 24 hours, preferably Choose 10 to 16 hours.
  • the concentration of the Ringer's free acid in the soluble solvent is 10 to 50 mg/mL, and preferably the concentration of the preferablystatin free acid in the ketone solvent is 10 to 50 mg/mL, more preferably 10 ⁇ 20 mg/mL;
  • the concentration of the ligastide free acid in the alcohol solvent is 10-20 mg/mL.
  • the Ringer's 4 bow salt described in the present application is a Ringer's 4 bow salt crystal form A (hereinafter referred to as "calcium salt crystal form A”), and the 4 bow salt crystal form A is at a diffraction angle.
  • the X-ray powder diffraction pattern indicated by 2 ⁇ has the following characteristic peaks: 4 ⁇ 5 ⁇ 0 ⁇ 2°, 8 ⁇ 6 ⁇ 0 ⁇ 2°, 10 ⁇ 3 ⁇ 0 ⁇ 2°, 13 ⁇ 5 ⁇ 0 ⁇ 2°, 20 ⁇ 2 ⁇ 0 ⁇ 2° and 20 ⁇ 4 ⁇ 0 ⁇ 2°.
  • the X-ray powder diffraction pattern represented by the diffraction angle of 2 ⁇ has the following characteristic peaks: 4.5 ⁇ 0.2°, 8.6 ⁇ 0.2°, 9.0 ⁇ 0.2°, 10.3 ⁇ 0.2°, 13.2 ⁇ 0.2°, 13.5 ⁇ 0.2°, 14.1 ⁇ 0.2°, 17 ⁇ 3 ⁇ 0 ⁇ 2°, 18 ⁇ 7 ⁇ 0 ⁇ 2°, 20 ⁇ 2 ⁇ 0 ⁇ 2°, 20 ⁇ 4 ⁇ 0 ⁇ 2° and 24 ⁇ 0 ⁇ 0 ⁇ 2°.
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ of the 4 ⁇ salt crystal form has the following characteristic peaks and their relative intensities:
  • a typical example of the 4-butter salt crystal form has an X-ray powder diffraction (XRPD) pattern as shown in Fig. 18.
  • XRPD X-ray powder diffraction
  • PLM polarized light microscopy
  • thermogravimetric analysis (TGA) pattern of the calcium salt form A showed a weight loss of about 4.7% before 150 °C.
  • the differential thermal analysis (DSC) pattern of calcium salt crystal form A shows a broad endothermic peak at 130-170 °C.
  • the isothermal adsorption curve of the calcium salt crystal form A shows that the weight change in the range of 20% to 80% relative humidity is about 0.5%.
  • the Ringer's 4 Bow Salt Crystal Form A of the present application has the following beneficial effects compared with the amorphous Ringerdine sodium salt:
  • the calcium salt form A has a low hygroscopicity.
  • the above 2) shows that the calcium salt crystal form A of the present invention can better cope with problems such as uneven content and purity reduction caused by external factors such as environmental moisture in the process of pharmaceutical preparation and/or storage, and is more advantageous for the unit. Accurate quantification and later transport and storage in the preparation of the formulation, and reduce the risk of a decrease in efficacy due to unstable active substance content and increased levels of impurities.
  • the preparation method of the Ringer's 4 bow salt crystal form A comprises the following steps: stirring the Riggsetti 4 bow salt obtained according to the aforementioned method for preparing the Ringer's 4 bow salt in water to obtain Lige Saide 4 bow salt crystal form A.
  • the mass to volume ratio of the Ringer's calcium salt to water is 5 mg to 10 mg: 1 mL, preferably 5 mg to 8 mg: lrtLL.
  • the stirring temperature is room temperature
  • the stirring time is 24 to 72 hours, preferably 24 to 36 hours.
  • the Ringer's 4 bow salt of the present application is a Ringer's 4 bow salt crystal form B (hereinafter referred to as "calcium salt crystal form B")
  • the 4 bow salt crystal form B is at a diffraction angle.
  • the X-ray powder diffraction pattern represented by 2 ⁇ has the following characteristic peaks: 10 ⁇ 2 ⁇ 0 ⁇ 2°, 13 ⁇ 3 ⁇ 0 ⁇ 2°, 18 ⁇ 2 ⁇ 0 ⁇ 2°, 18 ⁇ 8 ⁇ 0 ⁇ 2°, 19 ⁇ 8 ⁇ 0 ⁇ 2° and 20 ⁇ 6 ⁇ 0 ⁇ 2°.
  • the X-ray powder diffraction pattern represented by the diffraction angle of 2 ⁇ has the following characteristic peaks: 8 ⁇ 4 ⁇ 0 ⁇ 2°, 10 ⁇ 2 ⁇ 0 ⁇ 2°, 11 ⁇ 5 ⁇ 0 ⁇ 2°, 13 ⁇ 3 ⁇ 0 ⁇ 2°, 14 ⁇ 4 ⁇ 0 ⁇ 2°, 14 ⁇ 8 ⁇ 0 ⁇ 2°, 18 ⁇ 2 ⁇ 0 ⁇ 2°, 18 ⁇ 8 ⁇ 0 ⁇ 2°, 19 ⁇ 8 ⁇ 0 ⁇ 2°, 20 ⁇ 6 ⁇ 0 ⁇ 2°, 23 ⁇ 2 ⁇ 0 ⁇ 2° and 25 ⁇ 3 ⁇ 0 ⁇ 2°.
  • the calcium salt crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ having the following characteristic peaks and their relative intensities:
  • a typical example of the 4-butter salt crystal form has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • thermogravimetric analysis (TGA) pattern of strontium showed a weight loss of approximately 1.0% before 150 °C.
  • the differential thermal analysis (DSC) pattern of the calcium salt crystal form B shows a broad endothermic peak (melting peak) at 170 to 220 °C.
  • the isothermal adsorption curve of the calcium salt form B shows a weight change of about 0.4% in the range of 20% to 80% relative humidity.
  • the Ringer's 4 Bow Salt Form B of the present application has the following beneficial effects as compared with the amorphous Ringerdine sodium salt:
  • the preparation method of the Ringer's 4 bow salt crystal form B comprises the following steps: taking the Agathridin 4 ⁇ salt crystal form A, dissolving with dimethyl sulfoxide, adding water to crystallize, obtaining Lige Sai 4 bow salt crystal form B.
  • the volume ratio of the dimercaptosulfoxide to water is from 1:5 to 1:10, preferably from 1:5 to 1:8.
  • the strength of the Ringer's calcium salt crystal form A in the dimercapto sulfoxide is 40 to 60 mg/mL, preferably 40 to 50 mg/mLo.
  • the crystallization temperature is room temperature
  • the crystallization time is 5 to 24 hours, preferably 5 to 16 hours.
  • "crystalline" means confirmed by the X-ray powder diffraction pattern representation. It is well known to those skilled in the art that the experimental error therein depends on instrument conditions, sample preparation, and sample purity. The map will usually change with the instrument conditions. The relative intensity of the peaks may vary with experimental conditions, so the order of peak intensities should not be the sole or decisive factor; the experimental error of the peak angle should also be taken into account, usually allowing soil 0.2. The error of the experimental factors such as the height of the sample causes an overall shift in the peak angle, which usually allows a certain offset.
  • any crystal form having the same or similar characteristic peaks as the present application X-ray powder diffraction pattern is within the scope of the present application.
  • the "single crystal form” means a single crystal form detected by X-ray powder diffraction.
  • the crystalline form of Ringer's salt as described herein is pure, single, and substantially free of any other crystalline or amorphous state.
  • substantially free when used to refer to a new crystalline form means that the other crystalline form or amorphous form contained in the new crystalline form is less than 20% by weight, more preferably less than 10% by weight, especially Refers to less than 5% by weight, especially less than 1% by weight.
  • room temperature as used herein means 10 to 30 °C.
  • stirring is usually carried out unless otherwise specified.
  • the stirring may be carried out by a conventional method in the art, for example, the stirring method includes magnetic stirring, mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the "separation" described in the present application can be carried out by a conventional method in the art, such as filtration, centrifugation or the like.
  • the specific operation of the filtration is as follows: The sample to be separated is placed on a filter paper, and filtered under reduced pressure.
  • the specific operation of centrifugation is as follows: The sample to be separated is placed in a centrifuge tube, and then rotated at a high speed until the solid is completely sunk to the bottom of the centrifuge tube, and the centrifugation rate is, for example, 6000 rpm.
  • the "drying" described in the present application can be carried out by conventional methods in the art, such as blast drying and decompression. Drying, etc.
  • the drying temperature is 30 to 50 ° C, preferably 30 to 40 ° C; and the drying time is 5 to 24 hours, preferably 5 to 16 hours.
  • the pressure under reduced pressure was 0.09 MPa.
  • the drying equipment is equipped with a fume hood, a forced air oven or a vacuum oven.
  • “Overnight” as used in this application refers to the time that the operation steps span the night, during which time the experimental phenomenon is not actively observed.
  • the overnight time is 8 to 22 hours, preferably 10 to 18 hours, more preferably 16 hours.
  • the starting material of the present application Ringer's free acid
  • the comparative substance Ringeride sodium salt of the present application can be obtained by referring to the production method of Example 5 of the patent document WO2006104668.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more pharmaceutically active ingredients selected from the group consisting of the Ringer's salt of the present application and its crystalline form or The Ringeride salt and its crystalline form prepared by the preparation method of the present application, and at least one pharmaceutically acceptable carrier.
  • the Ringer's salt and its crystal form of the present application include Ringeride diethylamine salt and its crystal form A, crystal form B and crystal form C, Lige Sai 4 bow salt and its crystal form A, crystal form B.
  • the pharmaceutical composition may also comprise other pharmaceutically acceptable salts, crystal forms or amorphous forms of ligastide.
  • the pharmaceutical composition may also comprise one or more additional pharmaceutically active ingredients.
  • Pharmaceutically acceptable carriers in the pharmaceutical compositions include, but are not limited to, diluents such as starch, modified starch, lactose, powdered cellulose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, tricalcium phosphate, mannose Alcohol, sorbitol, sugar, etc.; binders such as acacia, guar, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, copolyvidone, etc.; a disintegrating agent, such as starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silica, etc.; a lubricant such as stearin Acid, magnesium stearate, stearic acid, sodium benzoate, sodium acetate, etc.; glidants, such as colloidal silica; complex forming agents, such as various grades of cyclo
  • compositions include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, antioxidants, and the like.
  • commonly used carriers include lactose and corn starch, and lubricants such as magnesium stearate may also be added;
  • useful carriers/diluents include lactose, high and low molecular weight poly Ethylene glycol and dry corn starch; in the case of gelatin capsules, powder carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like; when administered orally as a suspension,
  • the active ingredient is mixed with emulsifying and suspending agents; if desired, certain sweetening and/or flavoring and/or coloring agents may be added. Every carrier must be acceptable It is compatible with the other ingredients in the formula and is harmless to the patient.
  • the pharmaceutical composition may be in a solid or liquid form, such as a solid oral dosage form, including tablets, granules, powders, pills, powders, and capsules; liquid oral dosage forms including solutions, syrups, suspensions, dispersions And emulsions; injectable preparations, including solutions, dispersions and lyophilizates.
  • the formulation may be adapted for rapid release, delayed release or modified release of the active ingredient. It may be a conventional, dispersible, chewable, orally dissolved or rapidly melted formulation.
  • Routes of administration include oral administration, feeding through the stomach, feeding through the duodenum, intravenous, intra-arterial, intramuscular, subcutaneous, intraosseous, intradermal, intravaginal, intrarectal, intraperitoneal, transdermal, intranasal , eye drops, ear drops, etc.
  • the pharmaceutical composition can be prepared using methods well known to those skilled in the art.
  • the Ringer's salt of the present invention or a crystalline form thereof is mixed with one or more pharmaceutically acceptable carriers, optionally, with one or more other pharmaceutically active ingredients.
  • the solid preparation can be produced by a process such as direct mixing, granulation, or the like.
  • the present application provides the Ringer's salt of the present application and its crystal form or the Ringer's salt obtained by the preparation method of the present application and its crystal form in the preparation of a medicament for treating and/or preventing solid tumor diseases.
  • the salt of Ringeride and its crystal form of the present application include ligastide diethylamine salt and its crystal form A, crystal form B and crystal form C, Lige Saidi 4 bow salt and Form A, Form B, preferably the solid tumor disease is a solid tumor disease susceptible to treatment with a nucleotide analog chemotherapeutic agent.
  • the solid tumor diseases include, but are not limited to, malignant blood diseases such as leukemia, myelodysplastic syndrome, lymphoma, pancreatic cancer, liver cancer, breast cancer, cervical cancer, ovarian cancer, lung cancer, gastric cancer, bladder cancer, prostate cancer, colorectal Cancer, kidney cancer, esophageal cancer, biliary tract cancer, basal cell carcinoma, head and neck cancer, melanoma or glioma.
  • malignant blood diseases such as leukemia, myelodysplastic syndrome, lymphoma, pancreatic cancer, liver cancer, breast cancer, cervical cancer, ovarian cancer, lung cancer, gastric cancer, bladder cancer, prostate cancer, colorectal Cancer, kidney cancer, esophageal cancer, biliary tract cancer, basal cell carcinoma, head and neck cancer, melanoma or glioma.
  • the nucleotide analog chemotherapeutic agent including cladribine, clofarabine, f udarabine, mercaptopurine, pentostatin, Shu guanine (thioguanine), capecitabine (capecitabine), cytosine arabinoside (cytarabine), decitabine (decitabine), fluorouracil density ⁇ 1 3 ⁇ 4 (fluorouracil), floxuridine (floxuridine), Rocha Sapacitabine and gemcitabine.
  • These compounds are structurally similar, typically by disrupting cell division or inhibiting the growth of relatively fast dividing cells, at least by interfering with DNA replication, thereby inhibiting tumor cell proliferation.
  • the solid tumor disease susceptible to treatment with a nucleotide analog chemotherapeutic agent can be understood as a patient who initially receives a nucleotide analog chemotherapeutic agent for treating a solid tumor disease and then develops into a nucleoside analog chemotherapeutic agent. It is resistant or has developed resistance.
  • Solid tumor diseases affected by therapeutic treatment include, but are not limited to, hematological malignancies such as leukemia, myelodysplastic syndrome, lymphoma, pancreatic cancer, liver cancer, breast cancer, cervical cancer, ovarian cancer, lung cancer, stomach cancer, bladder cancer, prostate Cancer, colorectal cancer, kidney cancer, esophageal cancer, biliary tract cancer, basal cell carcinoma, head and neck cancer, melanoma or glioma.
  • hematological malignancies such as leukemia, myelodysplastic syndrome, lymphoma, pancreatic cancer, liver cancer, breast cancer, cervical cancer, ovarian cancer, lung cancer, stomach cancer, bladder cancer, prostate Cancer, colorectal cancer, kidney cancer, esophageal cancer, biliary tract cancer, basal cell carcinoma, head and neck cancer, melanoma or glioma.
  • the application provides a method of treating and/or preventing a solid tumor disease, the method comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of one or more of the Ringer's salt of the present application and a crystalline form thereof or a pharmaceutical composition thereof, wherein the Ringer's salt of the present application and its crystalline form include Ringer's diethylamine salt and its crystalline form A, crystalline form B and crystalline form C, Ligge Di 4 bow salt and its crystal form A, crystal form B, preferably the solid tumor disease is a solid tumor disease susceptible to treatment with a nucleotide analog chemotherapeutic agent, the patient refers to a mammal including a human .
  • the method comprises administering to a patient who is initially treated with a nucleotide analog chemotherapeutic agent to develop drug resistance,
  • Fig. 1 is a nuclear magnetic resonance spectrum of the Ringer's diethylamine salt of the present invention.
  • Figure 2 is an X-ray powder diffraction pattern of the crystalline form A of Ringer's diethylamine salt of the present invention.
  • Figure 3 is a PLM diagram of the crystalline form A of Ringeride diethylamine salt of the present invention.
  • Figure 4 is a DSC chart of Form A of Ringer's diethylamine salt of the present invention.
  • Figure 5 is a TGA diagram of Form A of Ringer's diethylamine salt of the present invention.
  • Fig. 6 is a graph showing the isothermal adsorption curve of the crystal form A of the Ringer's diethylamine salt of the present invention.
  • Figure 7 is an X-ray powder diffraction pattern of the crystalline form B of the Ringer's diethylamine salt of the present invention.
  • Figure 8 is a PLM diagram of Form B of Ringer's diethylamine salt of the present invention.
  • Figure 9 is a DSC chart of the crystalline form B of the Ringer's diethylamine salt of the present invention.
  • Figure 10 is a TGA diagram of Form B of Ringer's diethylamine salt of the present invention.
  • Fig. 11 is a graph showing the isothermal adsorption curve of the crystal form B of the Ringer's diethylamine salt of the present invention.
  • Figure 12 is an X-ray powder diffraction pattern of the crystalline form C of Ringeride diethylamine salt of the present invention.
  • Figure 13 is a PLM diagram of Form A of Ringer's diethylamine salt of the present invention.
  • Figure 14 is a DSC chart of the crystalline form C of the Ringer's diethylamine salt of the present invention.
  • Figure 15 is a TGA diagram of the crystal form C of the Ringer's diethylamine salt of the present invention.
  • Figure 16 is a graph showing the isothermal adsorption curve of the crystalline form C of the Ringer's diethylamine salt of the present invention.
  • Figure 17 is a nuclear magnetic resonance spectrum of the Ringer's 4 bow salt of the present invention.
  • Figure 18 is an X-ray powder diffraction pattern of the Ringer's 4 Bow Salt Form A of the present invention.
  • Figure 19 is a PLM diagram of the Ringer's 4 Bow Salt Crystal Form A of the present invention.
  • Figure 20 is a DSC chart of the Ringer's 4 Bow Salt Crystal Form A of the present invention.
  • Figure 21 is a TGA diagram of the Ringer's 4 Bow Salt Form A of the present invention.
  • Figure 22 is a graph showing the isothermal adsorption curve of Ringer's 4 Bow Salt Crystal Form A of the present invention.
  • Figure 23 is an X-ray powder diffraction pattern of Ringer's 4 Bow Salt Form B of the present invention.
  • Figure 24 is a PLM diagram of the Ringer's 4 Bow Salt Form B of the present invention.
  • Figure 25 is a DSC chart of the Ringer's 4 Bow Salt Crystal Form B of the present invention.
  • Figure 26 is a TGA map of Ringer's 4 Bow Salt Form B of the present invention.
  • Figure 27 is an isotherm adsorption diagram of the Ringer's 4 Bow Salt Form B of the present invention.
  • Figure 28 is an X-ray powder diffraction pattern of Comparative Example 1 amorphous Ringer Sodium salt.
  • Figure 29 is a graph showing the isothermal adsorption curve of the amorphous 1 Ringer Sodium salt of Comparative Example 1.
  • DETAILED DESCRIPTION OF THE INVENTION The present invention will be further understood by the following examples, but is not intended to limit the scope of the invention.
  • the X-ray powder diffraction (XRPD) instrument is a Bruker D8 Advance diffractometer with a Ka X-ray with a copper target wavelength of 1.54 nm under operating conditions of 40 kV and 40 mA, a ⁇ -2 ⁇ goniometer, a Mo monochromator Lynxeye detector. .
  • the instrument was tested with diamonds before use.
  • the acquisition software is Diffrac Plus XRPD Commander, and the analysis software is MDI Jade 5.0.
  • the sample is tested at room temperature and the sample to be tested is placed on a non-reflecting plate.
  • the detailed detection conditions are as follows, angle range: 3-40 ° 2 ⁇ , step size: 0.02 ° 2 ⁇ , speed: 0.2 sec / step. Samples were not ground prior to testing unless otherwise stated.
  • Polarized light microscopy (PLM) spectra were taken from a ⁇ -500 ⁇ polarized light microscope (Shanghai Changfang Optical Instrument Co., Ltd.). Take a small amount of powder sample on the glass slide, add a small amount of mineral oil to better disperse the powder sample, cover the cover glass, and then place the sample on the stage of the ⁇ -500 ⁇ polarized light microscope, select the appropriate magnification Multiply observe the morphology of the sample and take a picture.
  • the differential thermal analysis data was taken from the TA Instruments Q200 MDSC, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis.
  • thermogravimetric analysis data was taken from the TA Instruments Q500 TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis.
  • the sample of 5-15 mg was usually placed in a platinum crucible, using a segmented high-resolution detection method at 10°.
  • the temperature rise rate of C/min was increased from room temperature to 300 °C under the protection of 40 mL/min dry N 2 , while the TA software recorded the change in weight of the sample during the temperature increase.
  • Dynamic moisture adsorption analysis data and isothermal adsorption analysis data were taken from the TA Instruments Q5000 TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis.
  • a sample of l-10 mg is usually placed in a platinum crucible, and the TA software records the change in weight of the sample during a change in relative humidity from 0% to 80% to 0%. Depending on the sample, different adsorption and desorption steps are also applied to the sample.
  • Nuclear magnetic resonance spectroscopy data were taken from a Bruker Avance II DMX 400 MHZ NMR spectrometer. A sample of l-5 mg was weighed and dissolved in 0.5 mL of deuterated chloroform (CDC1 3 ) to prepare a solution of 2 mg/mL - 1 Omg/mL.
  • High performance liquid chromatography (HPLC) analysis data was taken from Agilent 1260 and ChemStation was B.04. The corresponding parameters are as follows: column 5micron C18 4.6x250mm, column temperature 35 °C, flow rate 1.Oml/min, mobile phase 80% acetonitrile and 20% water, wavelength 254nm, injection volume 20 ⁇ 1 and run time 15 minutes.
  • the Riggside free acid was synthesized by the preparation method of Example 1 of the patent document WO2006104668.
  • the specific operations are as follows:
  • the Rigastron sodium salt is prepared by the preparation method of Example 5 of the patent document WO2006104668.
  • the specific operations are as follows:
  • the isotherm adsorption curve is shown in Figure 29, which shows that it is highly hygroscopic, with a weight change of 21.5% at 20% to 80% relative humidity.
  • Fig. 1 The nuclear magnetic resonance spectrum of Fig. 1 was confirmed to be Ringer's diethylamine salt, and the Ringer's free base and diethylamine were salted in a 1:1 molar ratio.
  • Ringer's free acid was placed in a sealed container filled with diethylamine gas, and after 2 days, oily Ringeride diethylamine salt was obtained.
  • Ringer's free acid was placed in a sealed container filled with diethylamine gas, and after 3 days, an oily Ringeride diethylamine salt was obtained.
  • the samples prepared in Examples 2 to 11 had the same or similar nuclear magnetic hydrogen spectroscopy and HPLC detection results (not shown) as the samples of Example 1, indicating that the samples of Examples 2 to 11 were the same as those of Example 1.
  • the X-ray powder diffraction pattern of the diethylamine salt crystal form A is shown in Fig. 2.
  • the PLM spectrum of the diethylamine salt crystal form A is shown in Fig. 3 and is shown as an irregular bulk crystal.
  • the isothermal adsorption curve of the diethylamine salt crystal form A is shown in Fig. 6, showing a weight change of about 2.5% in the range of 20% to 80% relative humidity.
  • the samples prepared in Examples 13 to 14 have the same or similar X-rays as the sample of Example 12.
  • a powder diffraction pattern, a DSC pattern, and a TGA pattern indicate that the samples of Examples 13 to 14 were the same as the samples of Example 12.
  • the X-ray powder diffraction pattern of the diethylamine salt crystal form B is shown in Fig. 7.
  • the PLM spectrum of the diethylamine salt crystal form B is shown in Figure 8, which is shown as fine crystalline particles.
  • the isothermal adsorption curve of the diethylamine salt form B is shown in Fig. 11, showing a weight change of about 3.4% in the range of 20% to 80% relative humidity.
  • Ringer's diethylamine salt crystal form B has a good crystalline state and morphology, and has low hygroscopicity compared with the known Lith spinach salt.
  • Example 16 had the same or similar X-ray powder diffraction pattern, DSC pattern and TGA pattern (not shown) as the Example 15 sample, indicating that the sample of Example 16 was the same as the sample of Example 15.
  • the X-ray powder diffraction pattern of the diethylamine salt crystal form C is shown in Fig. 12.
  • the PLM spectrum of the diethylamine salt crystal form C is shown in Fig. 13, and it is shown as an irregular fine crystal.
  • the isothermal adsorption curve of the diethylamine salt crystal form C is shown in Fig. 16, showing a weight change of about 9.9% in the range of 20% to 80% relative humidity.
  • the above test results show that:
  • the Ringer's diethylamine salt crystal form C has a good crystal state and morphology, and has low hygroscopicity compared with the known Ringerdine salt.
  • the samples prepared in Examples 18 to 20 had the same or similar X-ray powder diffraction patterns, DSC patterns and TGA patterns (not shown) as the samples of Examples 17, indicating that the samples of Examples 18 to 20 were identical to the samples of Example 17. Substance.
  • Example 28 The samples prepared in Examples 22 to 27 had the same or similar nuclear magnetic hydrogen spectra and HPLC results (not shown) as the samples of Example 21, indicating that the samples of Examples 22 to 27 were the same as the samples of Example 21.
  • Example 28
  • Ringeride 4 ⁇ salt prepared by the present invention was placed in 60 mL of water, stirred for 36 hours, filtered, and dried under vacuum at 40 ° C overnight to obtain 242.5 mg of white Ringer's 4 bow salt crystal form A, The yield was 80.8%.
  • the X-ray powder diffraction pattern of the calcium salt crystal form A is shown in Fig. 18.
  • the PLM spectrum of the calcium salt crystal form A is shown in Figure 19 and is shown as a very fine irregular crystal.
  • the isothermal adsorption curve of the calcium salt crystal form A is shown in Fig. 22, showing a weight change of about 0.5% in the range of 20% to 80% relative humidity.
  • Ringer's 4 bow salt crystal form A has good crystal morphology and morphology, and has low hygroscopicity.
  • Ringer's 4 bow salt prepared in the present invention was placed in 15 mL of water, stirred for 24 hours, filtered, and dried under vacuum at 40 ° C overnight to obtain 93.6 mg of white Ringer's 4 bow salt crystal form A. The yield was 78.0%.
  • Ringer's 4 bow salt prepared according to the present invention was placed in 12 mL of water, stirred for 72 hours, filtered, and dried under vacuum at 40 ° C overnight to obtain 88.7 mg of white Ringer's 4 bow salt crystal form A, The yield was 73.9%.
  • the samples prepared in Examples 29 to 30 had the same or similar X-ray powder diffraction patterns, DSC patterns, and TGA patterns (not shown) as the samples of Examples 28, indicating that the samples of Examples 29 to 30 were the same as the samples of Example 28. Substance.
  • Ringer's 4 Bow Salt Form A prepared by the present invention was dissolved in 10.4 mL of dimethyl sulfoxide, and 84.0 mL of water was added thereto with stirring, and stirred for 16 hours to precipitate a white solid, and filtered, 40°. C was vacuum dried overnight to obtain 382.3 mg of white licylide 4 salt crystal form B, yield 73.5%.
  • the X-ray powder diffraction pattern of the calcium salt crystal form B is shown in Fig. 23.
  • the PLM spectrum of the calcium salt form B is shown in Figure 24 and is shown as a very fine irregular crystal.
  • the DSC spectrum of the calcium salt crystal form B is shown in Fig. 25, which shows a broad endothermic peak (melting peak) at 170 to 220 °C.
  • the TGA spectrum of the calcium salt form B is shown in Figure 26, showing a weight loss of about 1.0% before 150 °C.
  • the isothermal adsorption curve of the calcium salt form B is shown in Fig. 27, showing a weight change of about 0.4% in the range of 20% to 80% relative humidity.
  • Lige Saidi 4 bow salt crystal form B has a crystalline state and has good physical properties such as low moisture absorption and high decomposition temperature.
  • the samples prepared in Examples 32 to 33 had the same or similar X-ray powder diffraction patterns, DSC patterns and TGA patterns (not shown) as the samples of Examples 31, indicating that the samples of Examples 32 to 33 were identical to the samples of Example 31. Substance.
  • the amorphous Ringer Sodium salt prepared in Comparative Example 1, the Ringeride diethylamine salt crystal form B prepared by the present invention, and the Ringer's 4 Bow Salt Crystal Form B were subjected to light and oxidation for 0 days, 1 Day and 5 days stability experiments.
  • the illumination conditions were 45001 x ⁇ 5001 x illuminance and the oxidation conditions were a dryer equipped with urea hydrogen peroxide. The results are shown in Table 1.
  • the Ringer's 4 Bow Salt Form B and the Ringer's Diethylamine Salt Form B of the present invention are significantly more stable to oxidation and light than the known Ringer Sodium salt.
  • Ringeride diethylamine salt Tablets of the present application of Ringeride diethylamine salt are prepared, and the formulation is shown in Table 2.
  • Ringer's diethylamine salt may be in the form of crystal form A, form B or form C.
  • the above Ringer's 4 bow salt can be either Form A or Form B.
  • the above-mentioned Ringer's diethylamine salt may be in the form of crystal form A, form B or form C.
  • the foregoing is only a specific embodiment of the present application, but the scope of protection of the present application is not limited thereto, and any person skilled in the art can change without thinking of creative work within the technical scope disclosed by the present application. Replacement should be covered by the scope of this application. All patent documents and non-patent publications cited in the present specification are hereby incorporated by reference in their entirety.

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Abstract

La présente invention concerne un sel de rigosertib et une forme cristalline de celui-ci. Comparé au sel de rigosertib existant, le sel de rigosertib et sa forme cristalline dans la présente invention présentent des avantages relativement à la cristallinité, au faciès cristallin, à l'hygroscopie, et à la stabilité. En outre, la présente application concerne également un procédé de préparation du sel de rigosertib et de sa forme cristalline, de compositions pharmaceutiques, et de leurs applications dans la préparation de médicaments pour le traitement d'une maladie liée à une tumeur solide.
PCT/CN2013/087793 2013-11-25 2013-11-25 Sel de rigosertib, forme cristalline de celui-ci, et procédé de préparation et application associés WO2015074281A1 (fr)

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CN201380066027.4A CN104884128B (zh) 2013-11-25 2013-11-25 力格赛狄盐及其晶型、它们的制备方法和用途

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020086789A1 (fr) 2018-10-26 2020-04-30 Teva Pharmaceuticals International Gmbh Nouveaux polymorphes cristallins de sodium de rigosertib
WO2023056067A1 (fr) * 2021-09-30 2023-04-06 Onconova Therapeutics, Inc. Méthodes et compositions pour le traitement du cancer

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Publication number Priority date Publication date Assignee Title
WO2008027049A1 (fr) * 2006-08-30 2008-03-06 Temple University - Of The Commonwealth System Of Higher Education Composition et procédés permettant de traiter le syndrome myélodysplasique et la leucémie aiguë myéloïde
CN101432264A (zh) * 2006-03-22 2009-05-13 奥克萨根有限公司 具有crth2拮抗剂活性的盐

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WO2006104668A2 (fr) * 2005-03-11 2006-10-05 Temple University - Of The Commonwealth System Of Higher Education Compositions et procedes de traitement de maladies profilerantes
KR20090114398A (ko) * 2007-01-16 2009-11-03 온코노바 테라퓨틱스, 인코포레이티드 (ｅ)-2,6-다이알콕시스티릴 4-치환된 벤질설폰의 비경구 투여용 제형

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Publication number Priority date Publication date Assignee Title
CN101432264A (zh) * 2006-03-22 2009-05-13 奥克萨根有限公司 具有crth2拮抗剂活性的盐
WO2008027049A1 (fr) * 2006-08-30 2008-03-06 Temple University - Of The Commonwealth System Of Higher Education Composition et procédés permettant de traiter le syndrome myélodysplasique et la leucémie aiguë myéloïde

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020086789A1 (fr) 2018-10-26 2020-04-30 Teva Pharmaceuticals International Gmbh Nouveaux polymorphes cristallins de sodium de rigosertib
WO2023056067A1 (fr) * 2021-09-30 2023-04-06 Onconova Therapeutics, Inc. Méthodes et compositions pour le traitement du cancer

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