CN116120301A - Mesylate crystal form of compound, pharmaceutical composition and application - Google Patents
Mesylate crystal form of compound, pharmaceutical composition and application Download PDFInfo
- Publication number
- CN116120301A CN116120301A CN202211413921.1A CN202211413921A CN116120301A CN 116120301 A CN116120301 A CN 116120301A CN 202211413921 A CN202211413921 A CN 202211413921A CN 116120301 A CN116120301 A CN 116120301A
- Authority
- CN
- China
- Prior art keywords
- mesylate
- compound
- formula
- xrpd
- crystal form
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to a mesylate crystal form, a pharmaceutical composition and application of a compound, in particular to different crystal forms of mesylate of 1- (3-cyano-5-methylthiophene-2-yl) -N- (6-methoxy-1H-benzo [ d ] imidazole-2-yl) -2, 5-dimethyl-1H-pyrrole-3-carboxamide, a pharmaceutical composition containing the crystal forms and application thereof.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to different crystal forms of mesylate of 1- (3-cyano-5-methylthiophene-2-yl) -N- (6-methoxy-1H-benzo [ d ] imidazol-2-yl) -2, 5-dimethyl-1H-pyrrole-3-carboxamide (hereinafter referred to as a compound of formula (1)), pharmaceutical compositions comprising the crystal forms and medical uses thereof.
Background
DHX33 belongs to the family of RNA helicase proteins containing the DEAD/H cassette. Wherein DEAD/H represents the abbreviation Asp-Glu-Ala-Asp/His of an amino acid, which sequence, along with a number of other conserved amino acid sequences, is present in the protein sequence of an RNA helicase family member, is highly involved in nucleic acid substrate binding and ATP hydrolysis. Although these family members share these same sequences, each RNA helicase has its own specific and unique biological functions. The molecular weight of the human DHX33 protein is 72kDa, and the human DHX33 protein has the function of unwinding nucleic acid, and utilizes bioenergy released by ATP hydrolysis to drive and change the conformation of RNA and protein complexes, thereby participating in the metabolic activities of various RNAs, in particular a series of biological processes from RNA transcription, shearing, editing, translation, degradation and the like. The function of DHX33 is not limited to modification of RNA molecules, but studies have shown that DHX33 protein is involved in DNA metabolism in addition to unwinding RNA duplex. In particular, DHX33 protein can break the double-stranded structure of DNA and play an important role in gene expression.
The research shows that DHX33 influences the methylation state of DNA by being combined with gene promoters related to various cancers, so that the genome level regulates and controls the expression of various cancer genes and signal paths related to tumor development, and plays a vital role in various cell activities such as cell growth, proliferation, migration, apoptosis, metabolism and the like. In addition, DHX33 was found to be able to sense invasion of foreign double stranded RNA molecules and play an important role in the innate immunity of the cell. DHX33 is highly expressed as a very important cell growth regulatory gene in various cancers such as lung cancer, lymphoma, glioblastoma, breast cancer, colon cancer, liver cancer, etc. The development and progression of a variety of cancers is dependent on the high expression of DHX33 protein. The genetic knockout of DHX33 can obviously inhibit the occurrence and development of RAS oncogene-driven lung cancer; in vivo and in vitro experiments prove that after the DHX33 protein is inhibited, the occurrence and development of various cancers such as breast cancer, colon cancer, glioma, lymphoma and the like are obviously inhibited. Since the protein function of DHX33 depends on its helicase activity, the deletion mutant of DHX33 does not have the function of DHX33 protein, and thus cannot replace the function of the protein encoded by the wild-type DHX33 gene.
Applicants have discovered a variety of compounds that inhibit the RNA helicase activity of DHX33 (e.g., 1- (3-cyano-5-methylthiophene-2-yl) -N- (6-methoxy-1H-benzo [ d ] imidazol-2-yl) -2, 5-dimethyl-1H-pyrrole-3-carboxamide) and have demonstrated that these compounds significantly inhibit the growth and proliferation of cancer cells in vitro and in vivo.
Disclosure of Invention
The present invention aims to provide different crystal forms of 1- (3-cyano-5-methylthiophene-2-yl) -N- (6-methoxy-1H-benzo [ d ] imidazol-2-yl) -2, 5-dimethyl-1H-pyrrole-3-carboxamide (hereinafter referred to as "compound of formula (1)) mesylate, pharmaceutical compositions comprising the crystal forms and uses thereof.
The structural formula of the compound of formula (1) is as follows:
in a first aspect, the present invention provides a mesylate salt form B of a compound of formula (1), having an X-ray powder diffraction (XRPD) pattern having characteristic diffraction peaks at the following 2Θ angles: 8.88.+ -. 0.2 °, 14.85.+ -. 0.2 °, and 15.35.+ -. 0.2 °.
In some embodiments, the X-ray powder diffraction pattern of mesylate form B of the compound of formula (1) also has characteristic diffraction peaks at one or more of the following 2θ angles: 21.33±0.2°, 21.57±0.2° and 21.99±0.2°.
In some embodiments, the X-ray powder diffraction pattern of mesylate form B of the compound of formula (1) also has characteristic diffraction peaks at one or more of the following 2θ angles: 7.66±0.2°, 18.84±0.2° and 23.13±0.2°.
The invention also provides a preparation method of the mesylate crystal form B of the compound shown in the formula (1), which comprises the following steps: adding an organic solvent into the free crystal form A of the compound of the formula (1), then adding methanesulfonic acid, stirring for about 2-5 days at room temperature, collecting solid, and then drying to obtain the methanesulfonate crystal form B; the organic solvent is selected from isopropanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran or dichloromethane.
In some embodiments, in the above preparation method, drying is performed under vacuum at 40-95 ℃ for about 8-16 hours.
In a second aspect, the present invention provides a mesylate salt form C of a compound of formula (1), having an X-ray powder diffraction (XRPD) pattern having characteristic diffraction peaks at the following 2Θ angles: 8.07 + 0.2 deg. and 15.17 + 0.2 deg..
In some embodiments, the X-ray powder diffraction pattern of mesylate form C of the compound of formula (1) also has characteristic diffraction peaks at one or more of the following 2θ angles: 12.64±0.2°, 23.51 ±0.2° and 24.47±0.2°.
In some embodiments, the X-ray powder diffraction pattern of mesylate form C of the compound of formula (1) also has characteristic diffraction peaks at one or more of the following 2θ angles: 7.17±0.2°, 8.63±0.2° and 17.34±0.2°.
The invention also provides a preparation method of the mesylate crystal form C of the compound of the formula (1), which comprises any one of the following methods:
(I) Adding water or a mixed solvent of water/organic solvent into the mesylate crystal form B of the compound shown in the formula (1), stirring at room temperature for about 2-5 days to obtain the mesylate crystal form C, wherein the organic solvent is selected from ethanol or 1, 4-dioxane, and the volume ratio of water to the organic solvent in the mixed solvent is 1:1.
(II) adding a mixed solvent of water/organic solvent to the mesylate salt crystal form B of the compound of the formula (1), and stirring at 4-8 ℃ for about 2-5 days to obtain the mesylate salt crystal form C, wherein the organic solvent is selected from methanol, n-propanol, acetonitrile or acetone, and the volume ratio of water to the organic solvent in the mixed solvent is 1:1-3:1.
(III) adding a mixed solvent of water/organic solvent to the mesylate salt crystal form B of the compound of the formula (1), and stirring at 50 ℃ for about 2-5 days to obtain the mesylate salt crystal form C, wherein the organic solvent is selected from isopropanol or tetrahydrofuran, and the volume ratio of water to the organic solvent in the mixed solvent is 1:1.
In a third aspect, the present invention provides a mesylate salt form F of a compound of formula (1), having an X-ray powder diffraction (XRPD) pattern having characteristic diffraction peaks at the following 2Θ angles: 9.60.+ -. 0.2 °, 18.39.+ -. 0.2 ° and 19.48.+ -. 0.2 °.
In some embodiments, the X-ray powder diffraction pattern of mesylate form F of the compound of formula (1) also has characteristic diffraction peaks at one or more of the following 2θ angles: 27.94 + -0.2 deg., 28.27 + -0.2 deg., and 28.73 + -0.2 deg..
In some embodiments, the X-ray powder diffraction pattern of mesylate form F of the compound of formula (1) also has characteristic diffraction peaks at one or more of the following 2θ angles: 5.88.+ -. 0.2 °, 12.47.+ -. 0.2 ° and 37.34.+ -. 0.2 °.
The invention also provides a preparation method of the mesylate crystal form F of the compound shown in the formula (1), which comprises the following steps: adding a mixed solvent of water and methanol into a mesylate crystal form B of a compound of the formula (1), dissolving, filtering, and stirring the filtrate at 5 ℃ for about 2-24 hours to obtain the mesylate crystal form F, wherein the volume ratio of water to methanol in the mixed solvent is 1:3 to 1:5.
in some embodiments, in the above preparation method, the solubilization is performed by raising the temperature to 50 ℃, sonication, long-term stirring, or vortexing conditions.
In some embodiments, in the above preparation method, the volume ratio of water and methanol in the mixed solvent is 1:3.
in some embodiments, in the above preparation method, the volume ratio of water and methanol in the mixed solvent is 1:5.
In a fourth aspect, the invention provides a pharmaceutical composition comprising at least one of the above crystalline forms, and one or more pharmaceutically acceptable carriers.
In a fifth aspect, the present invention provides the use of the above crystalline form or the above pharmaceutical composition for the manufacture of a medicament for the prevention and/or treatment of a disease or condition mediated at least in part by DHX 33.
In a sixth aspect, the present invention provides a method for preventing and/or treating a disease or disorder mediated at least in part by DHX33, comprising the steps of: administering a prophylactically and/or therapeutically effective amount of the above crystalline form or the above pharmaceutical composition to a subject in need thereof; preferably, the disease is selected from the group consisting of DHX33 mediated cancer, viral infection and inflammation.
The present invention is not limited to the specific embodiments described herein; it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
Definition of terms
Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. If there is a conflict, the present application provides definitions. When an amount, concentration, or other value or parameter is expressed as a range, a preferred range, or an upper preferable range value, and a lower preferable range value, this is to be understood as equivalent to any range specifically disclosed by combining any pair of upper range values or preferred range values with any lower range value or preferred range value, regardless of whether the range is specifically disclosed. Unless otherwise indicated, the numerical ranges set forth herein are intended to include the endpoints of the ranges and all integers and fractions (fractions) within the range.
The term "about" when used in conjunction with a numerical variable generally means that the numerical value of the variable and all values of the variable are within experimental error (e.g., within a confidence interval of 95% for the average) or within + -10% of the specified numerical value, or more.
The expression "comprising" or similar expressions "including", "containing" and "having" etc. synonymously therewith are open ended and do not exclude additional unrecited elements, steps or components. The expression "consisting of …" excludes any element, step or ingredient not specified. The expression "consisting essentially of …" means that the scope is limited to the specified elements, steps, or components, plus any elements, steps, or components that are optionally present that do not materially affect the basic and novel characteristics of the claimed subject matter. It should be understood that the expression "comprising" encompasses the expressions "consisting essentially of …" and "consisting of …".
The term "X-ray powder diffraction pattern (XRPD pattern)" refers to an experimentally observed diffraction pattern or parameter, data or value derived therefrom. XRPD patterns are typically characterized by peak position (abscissa) and/or peak intensity (ordinate).
The term "diffraction angle" or "2θ" refers to the peak position in degrees (°) based on the settings in the X-ray diffraction experiment, and is typically the unit of abscissa in the diffraction pattern. If the incident beam is diffracted by reflection when it makes an angle θ with a certain lattice plane, the experimental setup requires recording the reflected beam at an angle 2θ. It should be understood that reference herein to a particular 2θ value for a particular crystalline form is intended to refer to the 2θ value (in degrees) measured using the X-ray diffraction experimental conditions described herein.
In the powder X-ray diffraction spectrum, the position of the peak or the relative intensity of the peak may be different depending on factors such as a measurement instrument, a measurement method, and conditions. For any particular crystal form, there may be an error in the position of the peak, and the error in the measurement of the 2 theta value may be + -0.2 deg.. Therefore, this error should be taken into account when determining each crystal form, and also falls within the scope of the present application.
For the same crystal form, the endothermic peak occurrence position of DSC may be different depending on the measurement instrument, measurement method/condition and the like. For any particular crystal form, there may be an error in the position of the endothermic peak, which may be + -5deg.C, which may be + -3deg.C. Therefore, this error should be taken into account when determining each crystal form, and also falls within the scope of the present application.
For the same crystal form, the location of occurrence of the weight loss temperature of the TGA may vary due to factors such as the measuring instrument, the measuring method/conditions, etc. For any particular crystal form, there may be an error in the position of the weight loss temperature, which may be ±5 ℃, and may be ±3 ℃. Therefore, this error should be taken into account when determining each crystal form, and also falls within the scope of the present application.
It will be appreciated that different types of equipment or with different test conditions may give slightly different XRPD patterns and characteristic peaks or different DSC patterns and characteristic peaks. The specific values provided cannot be used as absolute values.
The term "room temperature" refers to 20 ℃ + -5 ℃.
The term "preventing" refers to the prophylactic administration to reduce the likelihood of, or delay the onset of, a disease or condition.
The term "treatment" is intended to reduce or eliminate the disease state or condition for which it is intended. It is also to be understood that the treatment of the disease state or condition includes not only complete treatment, but also less than complete treatment, but achieves some biologically or medically relevant result.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or crystal forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. By "pharmaceutically acceptable carrier" is meant an inert substance administered with the active ingredient that facilitates administration of the active ingredient, including but not limited to any glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring enhancers, surfactants, wetting agents, dispersing agents, disintegrants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers that are acceptable for use in humans or animals (e.g., livestock) as permitted by the national food and drug administration.
The above pharmaceutical composition may act systematically and/or locally. For this purpose, they may be administered by a suitable route, for example by parenteral, topical, intravenous, oral, subcutaneous, intra-arterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular route or as an inhalant.
The above route of administration may be accomplished by suitable dosage forms. Dosage forms useful in the present invention include, but are not limited to: tablets, capsules, troches, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like.
When administered orally, the above pharmaceutical compositions may be formulated into any orally acceptable dosage form, including, but not limited to, tablets, capsules, aqueous solutions, aqueous suspensions, and the like.
The term "disease or disorder mediated at least in part by DHX 33" refers to a disease in which the pathogenesis includes at least a portion of DHX 33-related factors, such as cancer, viral infection, inflammation, and the like.
The term "effective amount" refers to a dose capable of eliciting a biological or medical response from a cell, tissue, organ or organism (e.g., an individual) and sufficient to achieve a desired prophylactic and/or therapeutic effect.
The therapeutically effective amount of the crystalline forms described herein is from about 0.0001 to 20mg/Kg body weight/day, for example from 0.001 to 10mg/Kg body weight/day.
The frequency of dosage of the crystalline forms described herein is determined by the needs of the individual patient, for example, 1 or 2 times per day, or more times per day. The administration may be intermittent, for example, wherein the patient receives daily doses of the crystalline form over a period of several days, followed by a period of several days or more, the patient does not receive daily doses of the crystalline form.
Drawings
Fig. 1: x-ray powder diffraction (XRPD) pattern of free crystalline form a of compound of formula (1).
Fig. 2: thermogravimetric analysis (TGA) profile of the free form of crystalline form a of the compound of formula (1).
Fig. 3: differential Scanning Calorimetric (DSC) profile of the free crystalline form a of the compound of formula (1).
Fig. 4: free form A of the compound of formula (1) 1 H NMR chart.
Fig. 5: x-ray powder diffraction (XRPD) pattern of mesylate form a of compound of formula (1).
Fig. 6: thermogravimetric analysis (TGA) profile of mesylate form a of compound of formula (1).
Fig. 7: differential Scanning Calorimetric (DSC) profile of mesylate form a of compound of formula (1).
Fig. 8: x-ray powder diffraction (XRPD) pattern of mesylate form B of compound of formula (1).
Fig. 9: thermogravimetric analysis (TGA) profile of mesylate form B of compound of formula (1).
Fig. 10: differential Scanning Calorimetry (DSC) profile of mesylate form B of compound of formula (1).
Fig. 11: mesylate salt form B of the compound of formula (1) 1 H NMR chart.
Fig. 12: x-ray powder diffraction (XRPD) pattern of mesylate form C of compound of formula (1).
Fig. 13: XRPD contrast pattern before and after warming of mesylate form C of compound of formula (1).
Fig. 14: x-ray powder diffraction (XRPD) pattern of mesylate form L of compound of formula (1).
Fig. 15: XRPD contrast pattern of mesylate form L of compound of formula (1) before and after standing at room temperature.
Fig. 16: thermogravimetric analysis (TGA) profile of mesylate form C of compound of formula (1).
Fig. 17: differential Scanning Calorimetry (DSC) profile of mesylate form C of compound of formula (1).
Fig. 18: x-ray powder diffraction (XRPD) pattern of mesylate form D of compound of formula (1).
Fig. 19: XRPD contrast pattern before and after drying of mesylate form D of compound of formula (1) at 40 ℃.
Fig. 20: x-ray powder diffraction (XRPD) pattern of mesylate form D1 of compound of formula (1).
Fig. 21: XRPD contrast pattern of mesylate form D1 of compound of formula (1) before and after warming.
Fig. 22: thermogravimetric analysis (TGA) profile of mesylate form D1 of compound of formula (1).
Fig. 23: differential Scanning Calorimetric (DSC) profile of mesylate form D1 of compound of formula (1).
Fig. 24: x-ray powder diffraction (XRPD) pattern of mesylate form E of compound of formula (1).
Fig. 25: XRPD contrast pattern of mesylate form E of compound of formula (1) before and after warming.
Fig. 26: thermogravimetric analysis (TGA) profile of mesylate form E of compound of formula (1).
Fig. 27: differential Scanning Calorimetry (DSC) profile of mesylate form E of compound of formula (1).
Fig. 28: mesylate salt form E of the compound of formula (1) 1 H NMR chart.
Fig. 29: x-ray powder diffraction (XRPD) pattern of mesylate form J of compound of formula (1).
Fig. 30: XRPD contrast pattern of mesylate form J of compound of formula (1) stirred in acetone.
Fig. 31: x-ray powder diffraction (XRPD) pattern of mesylate form F of compound of formula (1).
Fig. 32: XRPD contrast pattern of mesylate form F of compound of formula (1) before and after warming.
Fig. 33: thermogravimetric analysis (TGA) profile of mesylate form F of compound of formula (1).
Fig. 34: differential Scanning Calorimetry (DSC) profile of mesylate form F of compound of formula (1).
Fig. 35: x-ray powder diffraction (XRPD) pattern of mesylate form G of compound of formula (1).
Fig. 36: XRPD contrast pattern of mesylate form G of compound of formula (1) before and after drying.
Fig. 37: x-ray powder diffraction (XRPD) pattern of mesylate form G1 of compound of formula (1).
Fig. 38: XRPD contrast pattern of mesylate form G1 of compound of formula (1) before and after warming.
Fig. 39: x-ray powder diffraction (XRPD) pattern of mesylate form K of compound of formula (1).
Fig. 40: XRPD contrast pattern of mesylate form K of compound of formula (1) stirred in acetone.
Fig. 41: thermogravimetric analysis (TGA) profile of mesylate form G1 of compound of formula (1).
Fig. 42: differential Scanning Calorimetry (DSC) profile of mesylate form G1 of compound of formula (1).
Fig. 43: x-ray powder diffraction (XRPD) pattern of mesylate form H of compound of formula (1).
Fig. 44: XRPD contrast pattern before and after warming of mesylate form H of compound of formula (1).
Fig. 45: thermogravimetric analysis (TGA) profile of mesylate form H of compound of formula (1).
Fig. 46: differential Scanning Calorimetry (DSC) profile of mesylate form H of compound of formula (1).
Fig. 47: mesylate form H of the compound of formula (1) 1 H NMR chart.
Fig. 48: x-ray powder diffraction (XRPD) pattern of mesylate form I of compound of formula (1).
Fig. 49: XRPD contrast pattern of mesylate form I of compound of formula (1) before and after warming.
Fig. 50: thermogravimetric analysis (TGA) profile of mesylate form I of compound of formula (1).
Fig. 51: differential Scanning Calorimetric (DSC) profile of mesylate form I of compound of formula (1).
Fig. 52: mesylate salt of the compound of formula (1) form I 1 H NMR chart.
Fig. 53: XRPD overlay of mesylate form a, mesylate form B and mesylate form D1 of the compound of formula (1).
Fig. 54: XRPD overlay of mesylate form C, mesylate form F and mesylate form G1 of the compound of formula (1).
Fig. 55: XRPD pattern of mesylate form E, mesylate form H and mesylate form I of the compound of formula (1).
Fig. 56: XRPD overlay of mesylate form D, mesylate form G, mesylate form J, mesylate form K and mesylate form L of the compound of formula (1).
Fig. 57: XRPD contrast profile of mesylate form a and mesylate form B suspension competition of compound of formula (1).
Fig. 58: XRPD contrast pattern of mesylate form B and mesylate form D1 suspension competition of compound of formula (1).
Fig. 59: water activity tests (aw-0/0.248) for mesylate form B, mesylate form C, mesylate form G1 and mesylate form L of the compound of formula (1).
Fig. 60: water activity tests (aw-0.4/0.61/0.847/1.0) for mesylate form B, mesylate form C, mesylate form G1 and mesylate form L of the compound of formula (1).
Fig. 61: XRPD contrast patterns of the free form of compound of formula (1) a before and after stability testing.
Fig. 62: XRPD contrast patterns of mesylate form B of compound of formula (1) before and after stability testing.
Fig. 63: XRPD contrast patterns of mesylate form C of compound of formula (1) before and after stability testing.
Fig. 64: XRPD contrast pattern of mesylate form F of compound of formula (1) before and after stability testing.
Fig. 65: DVS test chart of mesylate form B of compound of formula (1).
Fig. 66: XRPD contrast pattern of mesylate form B of compound of formula (1) before and after DVS testing.
Fig. 67: DVS test chart of mesylate form C of compound of formula (1).
Fig. 68: XRPD contrast pattern of mesylate form C of compound of formula (1) before and after DVS test.
Fig. 69: DVS test plot of mesylate form F of compound of formula (1).
Fig. 70: XRPD contrast pattern of mesylate form F of compound of formula (1) before and after DVS test.
Detailed Description
Intermediate compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present application.
The chemical reactions of the embodiments of the present application are accomplished in a suitable solvent that is suitable for the chemical changes of the present application and the reagents and materials needed. In order to obtain the compounds of the present application, modifications or choices of synthesis steps or reaction schemes based on the existing embodiments are sometimes required by those skilled in the art.
The present application will be specifically described by examples, which are not meant to be limiting in any way.
X-ray powder diffraction (XRPD)
XRPD test parameters
Thermogravimetric analysis (TGA) and differential scanning calorimeter analysis (DSC)
TGA and DSC test parameters
1 Nuclear magnetic hydrogen spectrum (H NMR)
1 H NMR test parameters
Ion Chromatography (IC)
IC test parameters
High Performance Liquid Chromatography (HPLC)
HPLC test parameters
Dynamic moisture adsorption analysis (DVS)
DVS test parameters
Example 1: free crystalline form A of compound (1- (3-cyano-5-methylthiophene-2-yl) -N- (6-methoxy-1H-benzo [ d ] imidazol-2-yl) -2, 5-dimethyl-1H-pyrrole-3-carboxamide) of formula (I) and process for its preparation
(1) Preparation method of compound 3 (2-acetyl-4-ethyl valeronate)
Compound 1 (ethyl acetoacetate) (5 g,38.42mmol,1.0 eq) was dissolved in triethylamine (75 mL) and compound 2 (chloroacetone) (3.5 g,38.42mmol,1.0 eq) was added. The reaction was allowed to react at 110℃for 2 hours under nitrogen protection. After concentration, the residue was dissolved in water (100 mL) and then extracted twice with dichloromethane (50 mL each). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate=100/1 to 50/1 to 20/1) to obtain compound 3 (ethyl 2-acetyl-4-valerate) as a colorless oil (1.3 g, yield: 18.3%). MS (ESI) m/z 187[ M+H ] + ]。TLC：PE/EA(2/1)；R f (compound 1) =0.6; r is R f (compound 3) =0.4.
(2) Preparation method of compound 5 (1- (3-cyano-5-methylthiophene-2-yl) -2, 5-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester)
Compound 3 (ethyl 2-acetyl-4-pentanoate) (1 g,7.23mmol,1.0 eq) was dissolved in toluene (20 mL) and compound 4 (2-amino-3-cyano-5-methylthiophene) (1.6 g,8.68mmol,1.2 eq) and p-toluenesulfonic acid (249 mg,1.45mmol,0.2 eq) were added. The reaction was stirred at 110℃for 16 hours. The solid was filtered and concentrated. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate=50/1 to 30/1) to give compound 5 (1- (3-cyano-5-methylthiophene-2-yl) -2, 5-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester) (860 mg, yield: 41%) as a yellow oil. MS (ESI) m/z 289[ M+H ] + ]. TLC: petroleum ether/ethyl acetate (10/1); r is R f (compound 3) =0.2; r is R f (compound 5) =0.4.
(3) Process for the preparation of the free crystalline form A of a compound of formula (I)
To compound 5 (1- (3-cyano-5-methylthiophene-2-yl) -2, 5-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester) (50 mg,0.306mmol,1.0 eq) and compound 7 (5-methoxy-1H-benzoimidazol-2-amine) (88 mg,0.306mmol,1.0 eq) dissolved in 1mL of toluene was added trimethylaluminum (0.15 mL,0.306mmol,1.0eq,2m dissolved in toluene). The reaction was stirred at 100℃for 16 hours. The mixture was cooled to room temperature, quenched with methanol (10 mL) and then pH adjusted to 3 with 3M hydrochloric acid. The mixture was diluted with water (30 mL) and extracted three times with 20mL each time with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to preparative high pressure liquid phase Prep-HPLC (acetonitrile/water (0.1% formic acid) to obtain the free form of crystalline form a (5 mg, yield: 4%) of the compound of formula (I). MS (ESI) m/z 406[ M+H ] + ]。 1 H NMR(400MHz,DMSO-d 6 ):δ12.04(s,1H),11.20(s,1H),7.32(s,1H),7.29(s,1H),6.98(s,1H),6.89(s,1H),6.69(d,J＝7.2Hz,1H),3.73(s,3H),2.47(s,3H)，2.38(s,3H)，2.04(s,3H)。
Form a in the free form has an XRPD pattern substantially as shown in figure 1.
XRPD patterns of free form a have characteristic diffraction peaks at the following 2θ angles, as shown in table 1-1:
TABLE 1-1
As shown in fig. 2, the thermogravimetric analysis (TGA) profile of the free form a loses about 1.02% weight when heated to about 200 ℃.
As shown in fig. 3, the differential scanning calorimeter analysis (DSC) curve for form a in the free form has an endothermic peak at about 163 ℃.
Example 2: mesylate crystal forms of compound of formula (I) and preparation method thereof
Preparation method of mesylate crystal form A of compound of formula (I)
About 20mg of the free form A was weighed into a 3mL glass vial, 1.2 equivalents (5.78 mg) of methanesulfonic acid (methanesulfonic acid mass content: 99%) was added, 0.5mL of acetone was added, the sample was ultrasonically accelerated to dissolve, after stirring at room temperature for about 2 days, the solid was obtained by centrifugation, and the solid was dried under vacuum at 25℃for 4 hours. And (3) separating and testing the XRPD to obtain the mesylate crystal form A. The method replaces acetone with isopropanol or acetonitrile, and can also prepare the mesylate crystal form A.
Mesylate salt form a has an XRPD pattern substantially as shown in figure 5.
The XRPD pattern of mesylate form a had characteristic diffraction peaks at the following 2θ angles, as shown in table 2-1:
TABLE 2-1
As shown in fig. 6, the thermogravimetric analysis (TGA) curve of mesylate form a lost about 0.34% when heated to about 150 ℃. The mesylate salt form a is anhydrous.
As shown in fig. 7, the Differential Scanning Calorimetric (DSC) curve for mesylate form a has an endothermic peak at about 246 ℃, an exothermic peak at about 251 ℃, and an endothermic peak at about 267 ℃.
Preparation method of mesylate crystal form B of compound of formula (I)
3500.77mg of the free base form A was weighed into a 250mL single-necked flask, 70mL of acetone was added, and the flask was left to stir at room temperature. Under stirring, 10mL of acetone solution containing 673uL of methanesulfonic acid is slowly added into the single-mouth bottle, a small bottle filled with acid is further rinsed by 2mL of acetone, the rinse is added into the single-mouth bottle again, the system is changed from suspension to clear, solid is separated out after stirring for about 2 hours, after stirring for 3 days, filtration is carried out, and a filter cake is placed at 40 ℃ for vacuum drying for about 16 hours, thus 3865.63mg of methanesulfonate crystal form B is obtained.
Mesylate salt form B has an XRPD pattern substantially as shown in figure 8.
The XRPD pattern of mesylate form B had characteristic diffraction peaks at the following 2θ angles, as shown in table 2-2:
TABLE 2-2
As shown in fig. 9, the thermogravimetric analysis (TGA) curve of mesylate form B lost about 0.25% weight when heated to about 150 ℃. The mesylate salt form B is anhydrous.
As shown in fig. 10, the differential scanning calorimetric analysis (DSC) curve for mesylate form B has an endothermic peak at about 273 ℃.
The molar ratio of the compound of formula (I) to methanesulfonic acid in methanesulfonate salt form B is about 1:1.
Coarse solubility of mesylate form B of compound of formula (I) at room temperature
About 2.0mg of the starting sample was weighed into a 3.0mL vial, and 50. Mu.L (100. Mu.L, 200. Mu.L, 400. Mu.L, 1000. Mu.L, 2000. Mu.L) of the corresponding solvent-dissolved sample (spiral, ultrasound-assisted sample dissolution) was added until the sample was dissolved or the volume reached 2000. Mu.L and stopped. V1 is the sample volume of the previous step of the lysis, V2 is the sample volume of the lysis, and S is the rough solubility (N/A indicates not measured).
Preparation method of mesylate crystal form C of compound of formula (I)
About 200mg of mesylate form B was weighed into a 20mL vial and 5mL of water was added to sonicate. The suspension was stirred at room temperature for 3 days. And (3) separating and testing the XRPD to obtain the mesylate crystal form C.
Mesylate salt form C has an XRPD pattern substantially as shown in figure 12.
XRPD patterns of mesylate form C had characteristic diffraction peaks at the following 2θ angles, as shown in tables 2-3:
tables 2 to 3
As shown in fig. 16, the thermogravimetric analysis (TGA) curve of mesylate form C lost about 6.82% weight when heated to about 120 ℃. Mesylate salt form C is a hydrate form wherein the number ratio of mesylate salt of the compound of formula (1) to water molecules is about 1:2.
As shown in fig. 17, the Differential Scanning Calorimetric (DSC) curve for mesylate form C has an endothermic peak at about 90 ℃, an exothermic peak at about 188 ℃, an endothermic peak at about 230 ℃, an exothermic peak at about 235 ℃, a minute endothermic peak at about 252 ℃, and an endothermic peak at about 272 ℃.
As shown in fig. 13, mesylate form C was air dried at 40 ℃ for about 16 hours with form unchanged; heating to 155 ℃, and desolventizing and crystallizing to obtain a mesylate crystal form L; and (3) heating to 205 ℃ to convert the crystal into the mesylate crystal form A.
Preparation method of mesylate crystal form L of compound of formula (I)
Mesylate form C was warmed to 155 ℃. And (3) separating and testing the XRPD to obtain the mesylate crystal form L.
Mesylate salt form L has an XRPD pattern substantially as shown in figure 14.
XRPD patterns of mesylate form L had characteristic diffraction peaks at the following 2θ angles, as shown in tables 2-4:
tables 2 to 4
Mesylate form L is a metastable form. As shown in fig. 15, the methanesulfonate crystal form L was left at room temperature for 2 hours in a closed state, and the diffraction peak of the methanesulfonate crystal form C appeared, and the methanesulfonate crystal form C was mostly converted into methanesulfonate crystal form C after continuing to stand at room temperature for 3 days in a closed state.
Preparation method of mesylate crystal form D of compound of formula (I)
About 100mg of mesylate form B was weighed into a 20mL vial, 15mL ethanol was added, sonicated at 50℃and filtered into a 20mL vial, and stirred at 5℃for 3 days. And (3) separating and testing the XRPD to obtain the mesylate crystal form D.
Mesylate salt form D has an XRPD pattern substantially as shown in figure 18.
XRPD patterns of mesylate form D had characteristic diffraction peaks at the following 2θ angles, as shown in tables 2-5:
tables 2 to 5
Mesylate form D is a metastable form. As shown in fig. 19, the mesylate form D was air dried at 40 ℃ for about 16 hours to convert to mesylate form D1.
Preparation method of mesylate crystal form D1 of compound of formula (I)
Methanesulfonate salt form D was air-dried at 40 ℃ for about 16 hours. And (3) separating and testing the XRPD to obtain the mesylate crystal form D1.
Mesylate salt form D1 has an XRPD pattern substantially as shown in figure 20.
The XRPD pattern of mesylate form D1 had characteristic diffraction peaks at the following 2θ angles, as shown in tables 2-6:
tables 2 to 6
As shown in fig. 22, the thermogravimetric analysis (TGA) profile of mesylate form D1 lost about 0.10% weight when warmed to about 150 ℃. Mesylate form D1 is the anhydrate.
As shown in fig. 23, the Differential Scanning Calorimetric (DSC) curve for mesylate form D1 has a slight exothermic peak at about 204 ℃, an endothermic peak at about 250 ℃, an exothermic peak at about 254 ℃, and an endothermic peak at about 271 ℃.
As shown in fig. 21, the mesylate salt form D1 was transcrystalline to a mixed crystal of mesylate salt form K and mesylate salt form J by heating to 225 ℃.
Preparation method of mesylate crystal form E of compound of formula (I)
About 100mg of mesylate form B was weighed into a 20mL vial, 15mL of 1, 4-dioxane was added, sonicated at 50 ℃, filtered into a 20mL vial, and stirred at room temperature for 3 days. And (3) separating and testing the XRPD to obtain the mesylate crystal form E.
Mesylate salt form E has an XRPD pattern substantially as shown in figure 24.
XRPD patterns of mesylate form E had characteristic diffraction peaks at the following 2θ angles, as shown in tables 2-7:
tables 2 to 7
As shown in fig. 26, the thermogravimetric analysis (TGA) curve of mesylate form E lost about 13.58% weight when heated to about 190 ℃. Mesylate salt form E is a 1, 4-dioxane solvate form, wherein the molar ratio of mesylate salt to 1, 4-dioxane is about 1:1, the arrow in FIG. 28 shows the 1, 4-dioxane solvent peak.
As shown in fig. 27, the Differential Scanning Calorimetric (DSC) curve for mesylate form E has an endothermic peak at about 130 ℃, an exothermic peak at about 231 ℃, and an endothermic peak at about 273 ℃.
As shown in fig. 25, mesylate form E was desolvated by heating to 190 ℃ to give mesylate form J.
Preparation method of mesylate crystal form J of compound of formula (I)
Mesylate form E was warmed to 190 ℃. And (3) separating and testing the XRPD to obtain the mesylate crystal form J.
Mesylate form J has an XRPD pattern substantially as shown in figure 29.
The XRPD pattern of mesylate form J has characteristic diffraction peaks at the following 2θ angles, as shown in tables 2-8:
tables 2 to 8
Mesylate form J is a metastable form. As shown in fig. 30, methanesulfonate form J was converted to methanesulfonate form B by stirring in acetone at room temperature for 1 day.
Preparation method of mesylate crystal form F of compound of formula (I)
Method 1: about 20mg of methanesulfonate salt form B was weighed into a 3mL vial, 0.6mL of a mixed solvent of water/methanol (v: v 1:3) was added, the solution was sonicated at 50℃and filtered into a 20mL vial, and stirred at 5℃for 1 day. And (3) separating and testing the XRPD to obtain the mesylate crystal form F.
Method 2: about 100mg of methanesulfonate salt form B was weighed into a 20mL vial, 4mL of a water/methanol (v: v 1:5) mixed solvent was added, the solution was sonicated at 50℃and filtered into a 20mL vial, and stirred at 5℃for 2 hours. And (3) separating and testing the XRPD to obtain the mesylate crystal form F.
Mesylate form F has an XRPD pattern substantially as shown in figure 31.
XRPD patterns of mesylate form F had characteristic diffraction peaks at the following 2θ angles, as shown in tables 2-9:
Tables 2 to 9
As shown in fig. 33, the thermogravimetric analysis (TGA) curve of mesylate form F lost about 3.17% weight when heated to about 120 ℃. Mesylate salt form F is a hydrate form wherein the number ratio of mesylate salt to water molecules is about 1:1.
as shown in fig. 34, the Differential Scanning Calorimetric (DSC) curve for mesylate form F had a continuous endothermic peak before about 170 ℃, an exothermic peak at about 188 ℃, an endothermic peak at about 248 ℃, an endothermic peak at about 252 ℃, and an endothermic peak at about 268 ℃.
As shown in fig. 32, mesylate form F was air dried at 40 ℃ for about 16 hours with the form unchanged; heating to 155 ℃ for dehydration, cooling to room temperature, and keeping the crystal form unchanged; and (3) raising the temperature to 215 ℃ to convert the crystals into mixed crystals of the mesylate crystal form J and the mesylate crystal form K.
Preparation method of mesylate crystal form G of compound of formula (I)
About 20mg of methanesulfonate salt form B was weighed into a 3mL vial, 2mL of a mixed solvent of methanol/methyl tert-butyl ether (v: v3: 1) was added, and the solution was sonicated at 50℃and then filtered into a 3mL vial, followed by stirring at 5℃for 1 day. And (3) separating and testing the XRPD to obtain the mesylate crystal form G.
Mesylate salt form G has an XRPD pattern substantially as shown in figure 35.
The XRPD pattern of mesylate form G had characteristic diffraction peaks at the following 2θ angles, as shown in tables 2-10:
tables 2 to 10
Mesylate form G is a metastable form. As shown in fig. 36, mesylate form G was dried at room temperature and converted to mesylate form G1.
Preparation method of mesylate crystal form G1 of compound of formula (I)
About 100mg of methanesulfonate salt form B was weighed into a 20mL vial, 7mL of a mixed solvent of methanol/isopropyl acetate (v: v3: 1) was added, ultrasonic dissolution was promoted at 50℃and then filtered into a 3mL vial, stirred at 5℃for 1 day and then filtered, and the filter cake was dried at 40℃for about 16 hours. And (3) separating and testing the XRPD to obtain the mesylate crystal form G1.
Mesylate salt form G1 has an XRPD pattern substantially as shown in figure 37.
The XRPD pattern of mesylate form G1 had characteristic diffraction peaks at the following 2θ angles, as shown in tables 2-11:
tables 2 to 11
As shown in fig. 41, the thermogravimetric analysis (TGA) profile of the mesylate salt form G1 of the compound of formula (1) loses about 3.73% weight when heated to about 120 ℃. Mesylate salt form G1 is a hydrate form wherein the number ratio of mesylate salt to water molecules is about 1:1.
as shown in fig. 42, the Differential Scanning Calorimetric (DSC) curve of the mesylate salt form G1 of the compound of formula (1) has a continuous endothermic peak before about 120 ℃, an endothermic peak at about 152 ℃, an exothermic peak at about 179 ℃, an endothermic peak at about 250 ℃, an exothermic peak at about 254 ℃, and an endothermic peak at about 273 ℃.
As shown in fig. 38, mesylate form G1 was dehydrated by heating to 130 ℃ and then cooled to room temperature, leaving the form unchanged; the temperature is raised to 190 ℃ to be converted into mesylate crystal form K.
Preparation method of mesylate crystal form K of compound of formula (I)
Mesylate form G1 was warmed to 190 ℃. And (3) separating and testing the XRPD to obtain the mesylate crystal form K.
Mesylate form K has an XRPD pattern substantially as shown in figure 39.
XRPD patterns of mesylate form K had characteristic diffraction peaks at the following 2θ angles, as shown in tables 2-12:
tables 2 to 12
Mesylate form K is a metastable form. As shown in fig. 40, mesylate form K was converted to mesylate form B upon stirring in acetone for 1 day at room temperature.
Preparation method of mesylate crystal form H of compound of formula (I)
About 200mg of methanesulfonate salt form B was weighed into a 20mL vial, 5mL of a mixed solvent of N-methylpyrrolidone/isopropyl acetate (v: v 1: 5) was added, and the solution was sonicated to dissolve, and stirred at 5℃for 3 days. And (3) separating and testing the XRPD to obtain the mesylate crystal form H.
Mesylate form H has an XRPD pattern substantially as shown in figure 43.
The XRPD pattern of mesylate form H had characteristic diffraction peaks at the following 2θ angles, as shown in tables 2-13:
tables 2 to 13
As shown in fig. 45, the thermogravimetric analysis (TGA) curve of the mesylate form H of the compound of formula (1) loses about 16.15% weight when heated to about 155 ℃. Mesylate salt form H is an N-methylpyrrolidone solvate form, wherein the ratio of the number of molecules of mesylate salt to N-methylpyrrolidone is about 1:1, FIG. 47 shows the N-methylpyrrolidone solvent peak by an arrow.
As shown in fig. 46, the differential scanning calorimetric analysis (DSC) curve of the mesylate form H of the compound of formula (1) has an endothermic peak at about 143 ℃, an endothermic peak at about 156 ℃, and an endothermic peak at about 272 ℃.
As shown in fig. 44, mesylate form H was desolvated to form B by heating to 200 ℃.
Preparation method of mesylate crystal form I of compound of formula (I)
About 200mg of methanesulfonate salt form B was weighed into a 20mL vial, 5mL of N, N-dimethylformamide/isopropyl ether (v: v 1:5) was added, and the solution was sonicated to dissolve, and suspended and stirred at 5℃for 3 days. And (3) separating and testing the XRPD to obtain the mesylate crystal form I.
Mesylate salt form I has an XRPD pattern substantially as shown in figure 48.
The XRPD pattern of mesylate form I has characteristic diffraction peaks at the following 2θ angles, as shown in tables 2-14:
tables 2 to 14
As shown in fig. 50, the thermogravimetric analysis (TGA) curve of the mesylate salt form I of the compound of formula (1) loses about 11.89% weight when heated to about 180 ℃. Mesylate salt form I is an N, N-dimethylformamide solvate form, wherein the molar ratio of mesylate salt to N, N-dimethylformamide is about 1:1, arrows in fig. 52 indicate N, N-dimethylformamide solvent peaks.
As shown in fig. 51, the differential scanning calorimetric analysis (DSC) curve of the mesylate salt form I of the compound of formula (1) has an endothermic peak at about 143 ℃, an endothermic peak at about 147 ℃, and an endothermic peak at about 272 ℃.
As shown in fig. 49, the mesylate form I was desolvated to form B by heating to 200 ℃.
Example 3: suspension competition test
To confirm the interconversion relationship between mesylate form A/B/D1, suspension competition experiments were performed at room temperature and 50℃in acetone and ethyl acetate systems, respectively. Firstly preparing saturated solution of an initial sample of mesylate crystal form B at corresponding temperature and solvent, 1) mixing the mesylate crystal form A and the mesylate crystal form B with equal weight, adding the mixture into the filtered saturated solution to form suspension, and respectively suspending and stirring for 3 days at the temperature of 50 ℃; 2) And mixing the mesylate crystal form B and the mesylate crystal form D1 with equal weight, adding the mixture into the filtered saturated solution to form suspension, and respectively suspending and stirring for 3 days at the temperature of 50 ℃.
The results are shown in FIG. 57, FIG. 58 and Table 3-1, where both the physical mixture of mesylate form A/B and the physical mixture of mesylate form B/D1 were converted to mesylate form B, indicating that mesylate form B has higher thermodynamic stability than mesylate form A/D1 over the range of room temperature to 50 ℃.
TABLE 3-1
Example 4: water activity studies
The water activity was studied to confirm the interconversion relationship between mesylate form B/C/G1/L. A saturated solution of the starting sample mesylate form B at room temperature and the corresponding solvent was first prepared, and then a solid mixture of mesylate form B, mesylate form C, mesylate form G1 and mesylate form L was added. The results show that the mesylate anhydrate form B is more stable in a system without water at room temperature; in the humidity interval with water activity Aw <0.4, the mesylate hydrate form F is relatively stable; in the humidity range with the water activity Aw more than or equal to 0.4, the mesylate hydrate crystal form C is relatively stable. The results are shown in FIG. 59, FIG. 60 and Table 4-1.
TABLE 4-1
Example 5: 24 hour equilibrium solubility experiment in Water
The free base form a and mesylate form B were tested for 24 hours equilibrium solubility. The method comprises the following specific steps: 10mg of the free base form A and the methanesulfonate form B were weighed separately into 1mL of water to prepare suspensions, magnetically stirred at 37.+ -. 2 ℃ and sampled after 24 hours, the obtained solids were used for XRPD testing, and the supernatant was filtered through a 0.22 μm PTFE filter membrane and subjected to solubility testing. As a result, the solubility of the mesylate salt form B was about 13.2. Mu.g/mL, which was improved over the free base form A, as shown in Table 5-1.
TABLE 5-1
| Solid form | Equilibrium solubility in water at 37 ℃ (μg/mL) |
| Free base form A | 1.92 |
| Mesylate salt form B | 13.2 |
Example 6: one week stability test
After taking the free base form a and mesylate form B/C/F samples and standing for one week at 25 ℃/60% rh (long term) and 40 ℃/75% rh (accelerated), respectively, HPLC purity and form change were tested. The results are shown in Table 6-1, and after the mesylate crystal form B/C/F is placed for one week under two test conditions, the HPLC purity and the crystal form are not obviously changed, and the chemical stability and the crystal form stability are good. XRPD contrast patterns of the stability samples before and after placement are shown in fig. 61-64.
TABLE 6-1
Example 7: moisture permeability test
The stability risk of the samples at 25 ℃ with humidity was evaluated, the mesylate form B/C/F was subjected to DVS testing, and the solid samples after testing were collected for XRPD testing. The results are summarized in Table 7-1.
Under the condition of 0-80% RH, the water absorption of the mesylate crystal form B is less than 0.2%, and the sample has no hygroscopicity.
The mesylate crystal form C absorbs water at about 0.363% of 50-80% RH, dehydrates about 0.510% of 80-20% RH, starts to change obviously at 20% RH, dehydrates suddenly down at 20-0% RH, then starts to absorb water rapidly in the environment of 0-40% RH, absorbs water at about 0.801% of 40-80% RH, and is stable in the environment of more than or equal to 40% RH.
Mesylate form F absorbed about 0.073% water at 60-80% rh, about 0.2212% dehydrated at 80-20% rh, about 0.3599% dehydrated at 20-0% rh, then absorbed about 0.3936% water at 0-20% rh, about 0.2038% water at 20-80% rh, with no significant water absorption and dehydration during the entire humidity cycle, indicating that mesylate form F has some stability in the 0-80% rh humidity environment (stability over 6 hours of each humidity stage).
After DVS testing, no significant changes were made to the mesylate form B/C/F sample form (differences in XRPD were mainly due to preferential orientation and crystallinity). DVS and XRPD test results are shown in fig. 65-70.
TABLE 7-1
Example 8: polymorphism screening experiments for the mesylate salt of Compound of formula (1)
Slurry conversion at 4-8deg.C
About 20mg of each mesylate form B was weighed into a 3mL vial, 0.5mL of the solvents listed in Table 8-1 were added, and the resulting suspension was magnetically stirred at 5℃for about 3 days, after which the solids were collected by centrifugation and XRPD testing was performed. The test results are shown in Table 8-1.
TABLE 8-1
| Solvent v | Solid crystal forms |
| Tetrahydrofuran (THF) | Mesylate salt form B |
| Water/methanol, 1:1 | Methanesulfonate salt form C |
| Water/acetone, 1:1 | Methanesulfonate salt form C |
| N-heptane/ethanol, 1:1 | Mesylate salt form B |
| Diethyl ether/1, 4-dioxane, 1:1 | Mesylate salt form B |
| Dimethyl sulfoxide/ethyl acetate, 1:5 | Mesylate salt form B |
| Dichloromethane/n-propanol, 1:2 | Mesylate salt form B |
Room temperature slurry conversion
About 20mg of each mesylate form B was weighed into a 3mL vial, 0.5mL of the solvents listed in table 8-2 were added, and the resulting suspension was magnetically stirred at room temperature for about 3 days, after which the solids were collected by centrifugation and XRPD testing. The test results are shown in Table 8-2.
TABLE 8-2
* : the sample was directly transcrystalline to methanesulfonate form B in acetone and ethyl acetate at room temperature and was not studied further.
Slurry conversion at high temperature 50 DEG C
About 20mg of each mesylate form B was weighed into a 3mL vial, 0.5mL of the solvents listed in Table 8-3 were added, and the resulting suspension was magnetically stirred at 50℃for about 3 days, after which the solids were collected by centrifugation and XRPD testing was performed. The test results are shown in tables 8-3.
TABLE 8-3
| Solvent v | Solid crystal forms |
| Acetic acid ethyl ester | Mesylate salt form B |
| Toluene (toluene) | Mesylate salt form B |
| Water/isopropanol, 1:1 | Methanesulfonate salt form C |
| Water/tetrahydrofuran, 1:1 | Methanesulfonate salt form C |
| Ethanol/methyl isobutyl ketone 1:1 | Mesylate salt form B |
| Ethyl acetate/n-butanol 1:1 | Mesylate salt form B |
| N-propanol/isopropyl ether, 1:1 | Mesylate salt form B |
| N-heptane/acetonitrile, 1:1 | Mesylate salt form B |
| Cyclohexane/isopropyl acetate 1:1 | Mesylate |
| 1, 4-Dioxa-hexacyclic/isopropyl alcohol 1:1 | Mesylate salt form B |
Cooling crystallization
About 20mg of each mesylate form B was weighed into a 3mL vial, a volume of the corresponding solvent in table 8-4 was added, sonicated at 50 ℃, and filtered to another 3mL vial using a 0.45 μm PTFE filter. The clear filtrate was placed under stirring at 5 ℃, if solids precipitated, the solids were collected by centrifugation and XRPD testing was performed. If no solid is precipitated, the mixture is transferred to 50 ℃ for volatilization. The test results are shown in tables 8-4.
Tables 8 to 4
Temperature rise and fall due to cycle
20mg of each mesylate form B was weighed into a 3mL vial, 0.5mL of the solvent dissolution samples listed in tables 8-5 (vortex, ultrasound-assisted sample dissolution) were added, and the dissolution was recorded. Adding a stirrer, and circularly heating and cooling on a magnetic stirrer. The test results are shown in tables 8-5.
Tables 8 to 5
| Solvent(s) | Solid crystal forms |
| Water/methanol/acetone 1:1:1 | Methanesulfonate salt form C |
| Water/tetrahydrofuran/isopropanol 1:1:1 | Methanesulfonate salt form C |
| Ethanol/acetone/n-heptane, 1:1:1 | Mesylate salt form B |
| Methanol/acetonitrile/ethyl acetate, 1:1:1 | Mesylate salt form B |
| Methyl tert-butyl ether/isopropyl acetate/n-butanol, 1:1:1 | Mesylate salt form B |
| Dimethyl sulfoxide/ethyl acetate/toluene，1:2:2 | Mesylate salt form B |
| N, N-dimethylformamide/methyl tert-butyl ether/acetone 1:2:2 | Mesylate salt form B |
| Isopropanol/acetonitrile/2-methyltetrahydrofuran 1:1:1 | Mesylate salt form B |
| Isopropyl ether/ethyl acetate/n-propanol, 1:1:1 | Mesylate salt form B |
Claims (9)
1. A mesylate salt crystalline form of a compound of formula (1), wherein the compound of formula (1) has the formula:
2. the crystalline form of claim 1, which is mesylate form B, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ angles: 8.88±0.2°, 14.85±0.2° and 15.35±0.2°;
preferably, its X-ray powder diffraction pattern also has characteristic diffraction peaks at one or more of the following 2θ angles: 21.33±0.2°, 21.57±0.2° and 21.99±0.2°;
preferably, its X-ray powder diffraction pattern also has characteristic diffraction peaks at one or more of the following 2θ angles: 7.66±0.2°, 18.84±0.2° and 23.13±0.2°;
preferably, mesylate salt form B has an XRPD pattern substantially as shown in figure 8.
3. The crystalline form of claim 1, which is mesylate form C, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ angles: 8.07 + -0.2 DEG and 15.17 + -0.2 DEG;
preferably, its X-ray powder diffraction pattern also has characteristic diffraction peaks at one or more of the following 2θ angles: 12.64±0.2°, 23.51 ±0.2° and 24.47±0.2°;
preferably, its X-ray powder diffraction pattern also has characteristic diffraction peaks at one or more of the following 2θ angles: 7.17±0.2°, 8.63±0.2° and 17.34±0.2°;
preferably, mesylate form C has an XRPD pattern substantially as shown in figure 12.
4. The crystalline form of claim 1, which is mesylate form F, having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ angles: 9.60±0.2°, 18.39±0.2° and 19.48±0.2°;
preferably, its X-ray powder diffraction pattern also has characteristic diffraction peaks at one or more of the following 2θ angles: 27.94±0.2°, 28.27±0.2° and 28.73±0.2°;
preferably, its X-ray powder diffraction pattern also has characteristic diffraction peaks at one or more of the following 2θ angles: 5.88±0.2°, 12.47±0.2° and 37.34±0.2°;
preferably, mesylate form F has an XRPD pattern substantially as shown in figure 31.
5. A pharmaceutical composition comprising the crystalline form of any one of claims 1-4, and one or more pharmaceutically acceptable carriers.
6. Use of the crystalline form according to any one of claims 1-4 or the pharmaceutical composition according to claim 5 in the manufacture of a medicament for the prevention and/or treatment of a disease or disorder mediated at least in part by DHX 33; preferably, the disease is selected from the group consisting of DHX33 mediated cancer, viral infection and inflammation.
7. A process for the preparation of mesylate form B of a compound of formula (1), comprising: adding an organic solvent into the free crystal form A of the compound of the formula (1), then adding methanesulfonic acid, stirring for 2-5 days at room temperature, collecting solid, and then drying to obtain the methanesulfonate crystal form B; the organic solvent is selected from isopropanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran or dichloromethane.
8. A process for the preparation of mesylate form C of a compound of formula (1), comprising any one of the following processes:
(I) Adding water or a mixed solvent of water/organic solvent into the mesylate crystal form B of the compound shown in the formula (1), and stirring for 2-5 days at room temperature to obtain the mesylate crystal form C, wherein the organic solvent is selected from ethanol or 1, 4-dioxane, and the volume ratio of water to the organic solvent in the mixed solvent is 1:1;
(II) adding a mixed solvent of water/organic solvent into the mesylate salt crystal form B of the compound of the formula (1), and stirring for 2-5 days at the temperature of 4-8 ℃ to obtain the mesylate salt crystal form C, wherein the organic solvent is selected from methanol, n-propanol, acetonitrile or acetone, and the volume ratio of water to the organic solvent in the mixed solvent is 1:1-3:1;
(III) adding a mixed solvent of water/organic solvent into the mesylate crystal form B of the compound of the formula (1), stirring for 2-5 days at 50 ℃ to obtain the mesylate crystal form C, wherein the organic solvent is selected from isopropanol or tetrahydrofuran, and the volume ratio of water to the organic solvent in the mixed solvent is 1:1.
9. A process for the preparation of mesylate form F of a compound of formula (1), comprising: adding a mixed solvent of water and methanol into a mesylate crystal form B of a compound of the formula (1), dissolving, filtering, and stirring the filtrate at 5 ℃ for 2-24 hours to obtain a mesylate crystal form F, wherein the volume ratio of water to methanol in the mixed solvent is 1:3 to 1:5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211413921.1A CN116120301A (en) | 2022-11-11 | 2022-11-11 | Mesylate crystal form of compound, pharmaceutical composition and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211413921.1A CN116120301A (en) | 2022-11-11 | 2022-11-11 | Mesylate crystal form of compound, pharmaceutical composition and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116120301A true CN116120301A (en) | 2023-05-16 |
Family
ID=86298082
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211413921.1A Pending CN116120301A (en) | 2022-11-11 | 2022-11-11 | Mesylate crystal form of compound, pharmaceutical composition and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116120301A (en) |
-
2022
- 2022-11-11 CN CN202211413921.1A patent/CN116120301A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2021190467A1 (en) | Spiro ring-containing quinazoline compound | |
| CN112961120B (en) | Naphthyl urea compound, preparation method and application thereof | |
| CN112745335A (en) | Tri-heterocyclic compound and application thereof | |
| CN116390728A (en) | Quinazoline derivative, preparation method and application thereof | |
| CN108884099B (en) | Crystal form of free base of imidazo isoindole derivative and preparation method thereof | |
| CN107286220B (en) | 1,2, 4-triazole coupled dihydromyricetin derivative and preparation method and application thereof | |
| CN115043826B (en) | Sinomenine furazan derivatives, and preparation method and application thereof | |
| CN116120301A (en) | Mesylate crystal form of compound, pharmaceutical composition and application | |
| CN115697988B (en) | 3, 4-Dihydro isoquinoline compound and application thereof | |
| AU2022350240A1 (en) | Crystal form of macrocyclic compound, and preparation method therefor and use thereof | |
| CN112209884B (en) | 1-H benzimidazole derivative, preparation method and application thereof | |
| CN110194741B (en) | 4-benzoyl piperazine-3-nitro-1, 8-naphthalimide derivative and preparation method and application thereof | |
| EP3819296B1 (en) | Method for producing diarylpyridine derivatives | |
| WO2013170738A1 (en) | Agomelatine acid radical composite, and preparation method and application thereof | |
| CN113045554A (en) | Fexotinib crystal form and preparation method thereof | |
| CN116003394A (en) | Hydrochloride crystal form of amide compound, pharmaceutical composition and application | |
| CN115710257A (en) | Sulfate crystal form of amide compound, pharmaceutical composition and application | |
| CN112125910A (en) | Alvatinib crystal form and preparation method thereof | |
| WO2017215521A1 (en) | Plx3397 hydrochloride crystal form, preparation method therefor and use thereof | |
| CN112830919B (en) | Benzopiperidine derivatives as pharmaceutical agents and process for preparing them | |
| CN108623601A (en) | The eutectic and preparation method thereof of Temozolomide and baicalein | |
| TWI824626B (en) | Crystal forms of RIPK1 inhibitors and their acid salts and crystal forms of their acid salts | |
| EP3753942B1 (en) | Crystal form of 3,4-dihydrothieno[3,2-d]pyrimidine compound and preparation method therefor | |
| WO2023160663A1 (en) | Polymorph of jak tyrosine kinase inhibitor and preparation method therefor | |
| WO2021043200A1 (en) | Method for preparing quinazoline derivative and crystallization thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |