WO2022247772A1 - Formes cristallines de composé hétérocyclique contenant de l'oxygène, leur procédé de préparation et leur application - Google Patents

Formes cristallines de composé hétérocyclique contenant de l'oxygène, leur procédé de préparation et leur application Download PDF

Info

Publication number
WO2022247772A1
WO2022247772A1 PCT/CN2022/094390 CN2022094390W WO2022247772A1 WO 2022247772 A1 WO2022247772 A1 WO 2022247772A1 CN 2022094390 W CN2022094390 W CN 2022094390W WO 2022247772 A1 WO2022247772 A1 WO 2022247772A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
crystal form
compound
cancer
compound represented
Prior art date
Application number
PCT/CN2022/094390
Other languages
English (en)
Chinese (zh)
Inventor
许祖盛
楼杨通
唐佑海
Original Assignee
上海璎黎药业有限公司
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 上海璎黎药业有限公司 filed Critical 上海璎黎药业有限公司
Publication of WO2022247772A1 publication Critical patent/WO2022247772A1/fr

Links

Images

Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • 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

Definitions

  • the invention belongs to the field of medicine, and in particular relates to a crystal form of an oxygen-containing heterocyclic compound, a preparation method and an application thereof.
  • Ras Ras (Rat sarcoma viral oncogene, mouse sarcoma virus oncogene), was first discovered in rat sarcoma.
  • Mammalian ras gene family has three members, which are H-ras, K-ras, and N-ras, and the fourth exon of K-ras has two variants, A and B.
  • Ras genes are widely found in various eukaryotic organisms such as mammals, fruit flies, fungi, nematodes and yeasts, with varying degrees of expression in different tissues, among which H-Ras is mainly expressed in skin and skeletal muscle, and K-Ras is mainly expressed in skin and skeletal muscle.
  • N-Ras is highly expressed in the testis.
  • Ras protein regulates signal transduction by combining with GTP/GDP, and then regulates life processes such as cell proliferation, differentiation, aging and apoptosis.
  • Ras mutation is closely related to the occurrence and development of tumors.
  • the Ras gene is mutated in more than 30 percent of human tumors and is considered one of the most potent drivers of cancer.
  • Ras proto-oncogene mutations are mainly carried out through point mutations. More than 150 different Ras point mutations have been found, among which the mutations of glycine 12 and 13 and glutamine 61 are the most common.
  • a kind of oxygen-containing heterocyclic compound, its structure is as shown in formula (I) (hereinafter referred to as the compound represented by formula (I)), which can be used to treat and/or prevent various diseases mediated by Ras.
  • the compound was independently designed and synthesized by the present inventors.
  • OJ column (20*250mm, 10 ⁇ m; brand Daicel) was prepared by chiral resolution to obtain a solid form, which was determined to be amorphous by XRPD.
  • Studies have found that when the compound represented by formula (I) exists in the form of an amorphous solid, it has the following defects: high moisture absorption; poor stability, especially under high temperature and light. The purity of the compound decreases significantly.
  • the technical problem to be solved by the present invention is the defect that the solid form of the oxygen-containing heterocyclic compound is single, the hygroscopicity is high, and the stability is poor in the prior art.
  • a crystal form of the oxygen-containing heterocyclic compound and its preparation method are provided. and applications. These crystal forms have simple preparation methods, are suitable for industrial production, are not easy to absorb moisture, have good stability, and are beneficial to the preparation of preparations and the long-term storage of medicines.
  • the present invention solves the above-mentioned technical problems through the following technical solutions.
  • One aspect of the present invention provides a crystal form A of the compound represented by formula (I), its X-ray powder diffraction pattern represented by 2 ⁇ angle, at 4.8 ⁇ 0.2°, 12.4 ⁇ 0.2°, 15.6 ⁇ 0.2° and 23.3 ⁇ 0.2 ° have characteristic peaks, and the X-ray powder diffraction pattern is measured using the K ⁇ spectral line of the Cu target;
  • the crystal form A of the compound represented by formula (I), its X-ray powder diffraction pattern represented by 2 ⁇ angle can be at 4.8 ⁇ 0.2°, 9.1 ⁇ 0.2°, 9.7 ⁇ 0.2 °, 12.4 ⁇ 0.2°, 15.6 ⁇ 0.2°, 19.8 ⁇ 0.2°, 20.4 ⁇ 0.2°, 21.1 ⁇ 0.2°, 23.3 ⁇ 0.2°, 24.7 ⁇ 0.2° and 26.3 ⁇ 0.2° have characteristic peaks.
  • the crystal form A of the compound represented by formula (I) has an X-ray powder diffraction pattern represented by 2 ⁇ angles at 4.8 ⁇ 0.2°, 9.1 ⁇ 0.2°, 9.7 ⁇ 0.2° , 12.4 ⁇ 0.2°, 14.5 ⁇ 0.2°, 15.6 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.2 ⁇ 0.2°, 17.5 ⁇ 0.2°, 19.8 ⁇ 0.2°, 20.4 ⁇ 0.2°, 21.1 ⁇ 0.2°, 21.4 ⁇ 0.2° , 22.1 ⁇ 0.2°, 22.4 ⁇ 0.2°, 23.3 ⁇ 0.2°, 24.7 ⁇ 0.2°, 26.3 ⁇ 0.2°, 27.6 ⁇ 0.2° and 27.9 ⁇ 0.2° have characteristic peaks.
  • the crystal form A of the compound represented by formula (I), its X-ray powder diffraction pattern represented by 2 ⁇ angle, its diffraction peak and peak area percentage can also be as follows:
  • the X-ray powder diffraction pattern represented by the 2 ⁇ angle of the crystal form A of the compound represented by formula (I) may also be substantially as shown in FIG. 3 .
  • the differential scanning calorimetry (DSC) of the crystal form A of the compound represented by formula (I) may also have an endothermic peak at 167.7-171.0°C.
  • the differential scanning calorimetry (DSC) of the crystal form A of the compound represented by formula (I) may also be substantially as shown in FIG. 4 .
  • thermogravimetric analysis (TGA) of the crystal form A of the compound represented by formula (I) may also be substantially as shown in FIG. 5 .
  • the Form A has substantially no weight loss before heating to the decomposition temperature, which shows that the Form A is an anhydrate.
  • the increased weight of the crystalline form A compared to the initial weight can also be within 0 A weight gain of about 0.30% over the %-95% relative humidity range. It appears that the Form A is substantially non-hygroscopic.
  • the dynamic moisture sorption diagram (DVS) of the crystal form A of the compound represented by formula (I) can also be substantially as shown in FIG. 6 .
  • Form A of the compound represented by formula (I) is substantially pure.
  • the weight content of the crystal form A is at least 99%, at least 95%, or lower to 90%.
  • the weight content of the crystal form A is at least 80%, or at least 70%, or lower to 60%.
  • the weight content of the crystal form A reaches at least 50%.
  • Another aspect of the present invention provides a method for preparing the crystal form A of the compound represented by formula (I), which is method 1, method 2 or method 3:
  • Method 1 at 40°C to 80°C, cool the hot saturated solution formed by the compound represented by formula (I) and the solvent to room temperature, and crystallize; wherein, the solvent is selected from ethanol, ethyl acetate , one or more of methyl isobutyl ketone, acetonitrile and methyl tert-butyl ether;
  • Method 2 at 40°C to 80°C, mix the solution formed by the compound represented by formula (I) and solvent A with solvent B, and crystallize; wherein, the solvent A is ethanol, isopropanol, One or more of acetone, ethyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran and 1,4-dioxane, and the solvent B is selected from methyl tert-butyl ether, n-heptane and water one or more of
  • Method 3 Place an excess of the compound shown in formula (I) in a solvent to form a suspension. After the suspension is balanced, separate the solid-liquid phase and dry it; wherein, the solvent is selected from ethanol, methyl One or more of isobutyl ketone, methyl tert-butyl ether, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane.
  • the solvent is selected from ethanol, methyl One or more of isobutyl ketone, methyl tert-butyl ether, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane.
  • the compound represented by formula (I) in the method 1, method 2 or method 3, can be a compound represented by formula (I) in any solid form, for example, an amorphous Morphology A compound represented by formula (I) in the form of a solid.
  • the amount of the solvent used can be the conventional amount used in this type of operation in the field, as long as a saturated solution is formed.
  • the volume-to-mass ratio of the solvent to the compound shown in formula (I) is 10.0 ⁇ 30.0 mL/g, eg, 16.7 mL/g.
  • the crystallization can be carried out by cooling at a rate of 5-30° C./hour.
  • the hot saturated solution is filtered.
  • the filtration treatment method can be a conventional filtration method for such operations in the art, preferably thermal filtration.
  • the operation of solid-liquid separation and drying may also be included after the crystallization.
  • the solid-liquid separation can be filtering.
  • the drying may be drying under reduced pressure, for example, drying under reduced pressure at 40°C.
  • the volume-to-mass ratio of the solvent A to the compound represented by formula (I) is 8.0-11.0 mL/g, for example, 9.5 mL/g.
  • Said 40°C-80°C may be 70-75°C or 45-50°C.
  • the volume ratio of solvent A to solvent B is (0.2-5):1, for example, (0.38-1.9):1.
  • the timing of the mixing is not particularly limited, the solution formed by the compound shown in formula (I) and solvent A can be mixed with solvent B, or the solution formed by the compound shown in formula (I) and solvent A can be mixed Cool until a solid precipitates out and then mix with solvent B.
  • the mixing method can be dropwise, for example, add solvent B dropwise to the solution formed by the compound represented by formula (I) and solvent A.
  • solvent A when solvent B is n-heptane, solvent A is ethanol and/or ethyl acetate; when solvent B is methyl tert-butyl ether, solvent A is selected from One or more of ethanol, isopropanol and 2-methyltetrahydrofuran.
  • the solvent is selected from ethanol and/or methyl isobutyl ketone, for example, methyl isobutyl ketone.
  • the amount of the solvent does not need to be limited, it can be conventional in the art, as long as it forms a suspension with the compound shown in formula (I), for example, when the solvent is methyl isobutyl When a base ketone is used, its volume-to-mass ratio to the compound shown in formula (I) is 0.2 g/mL.
  • the suspension equilibrium temperature can be conventional, as long as it is not higher than the boiling point of the solvent system, it can be 30°C to 60°C, for example, 50°C.
  • the suspension equilibration time may depend on the scale of the reaction, generally within 2 hours to 14 days; for example, in a laboratory test, at room temperature, 2- It can be completed in about 24 hours; after amplification, the reaction time is extended, such as 24 hours to 14 days, preferably 7 days to 14 days, such as 7 days or 14 days.
  • One aspect of the present invention provides a crystal form B of the compound represented by formula (I), its X-ray powder diffraction pattern represented by 2 ⁇ angle, at 5.0 ⁇ 0.2°, 9.8 ⁇ 0.2°, 14.7 ⁇ 0.2° , 19.6 ⁇ 0.2°, 24.6 ⁇ 0.2° and 31.0 ⁇ 0.2° have characteristic peaks, and the X-ray powder diffraction pattern is measured using the K ⁇ line of the Cu target;
  • the crystal form B of the compound represented by formula (I), its X-ray powder diffraction pattern represented by 2 ⁇ angle, its diffraction peak and peak area percentage can also be as follows:
  • the X-ray powder diffraction pattern represented by the 2 ⁇ angle of the crystal form B of the compound represented by formula (I) may also be substantially as shown in FIG. 7 .
  • the differential scanning calorimetry (DSC) of the crystal form B of the compound represented by formula (I) may also have an endothermic peak at 132.0-142.5°C.
  • the differential scanning calorimetry (DSC) of the crystal form B of the compound represented by formula (I) may also be substantially as shown in FIG. 8 .
  • thermogravimetric analysis (TGA) of the crystal form B of the compound represented by formula (I) may also be substantially as shown in FIG. 9 .
  • the Form B has substantially no weight loss before heating to the decomposition temperature, which shows that the Form B is an anhydrate.
  • the weight of the crystalline form B increased compared to the initial weight can also be within 0 A weight gain of about 0.95% over the %-95% relative humidity range.
  • the Form B was shown to be substantially non-hygroscopic.
  • the dynamic moisture sorption diagram (DVS) of the crystalline form A of the compound represented by formula (I) may also be substantially as shown in FIG. 10 .
  • Form B of the compound represented by formula (I) is substantially pure.
  • the weight content of the crystal form B is at least 99%, at least 95%, or lower to 90%.
  • the weight content of the crystal form B is at least 80%, or at least 70%, or lower to 60%.
  • the weight content of the crystal form B reaches at least 50%.
  • Another aspect of the present invention provides a method for preparing crystal form B of the compound shown in formula (I), which is method A or method B:
  • Method A at 50-70°C, form a hot saturated solution of the compound represented by formula (I) with methanol, and evaporate the solvent at room temperature for crystallization;
  • Method B The compound represented by formula (I) is formed into a suspension with a solvent, and after the suspension is balanced, the solid-liquid phase is separated and dried; the solvent is methanol or "a mixture of methanol and water".
  • the compound represented by formula (I) in the method A or method B, can be a compound represented by formula (I) in any solid form, for example, in the form of an amorphous solid The compound shown in formula (I).
  • the hot saturated solution is filtered.
  • the filtration treatment method can be a conventional filtration method for such operations in the art, preferably thermal filtration.
  • drying may also be included after the crystallization. Described drying is drying under reduced pressure.
  • the volume ratio of methanol and water may be (5-95):5, such as 5:5 or 95:5.
  • the suspension equilibrium temperature can be conventional, as long as it is not higher than the boiling point of the solvent system, it can be 10°C to 40°C, for example, room temperature.
  • the suspension equilibration time depends on the scale of the reaction, generally within 2 days to 14 days; for example, in a laboratory test, at room temperature, 2 days It can be completed in about 10 minutes; after amplification, the reaction time is extended, such as 2 days to 14 days, preferably 7 days to 14 days, such as 7 days or 14 days.
  • the suspension in the method B, can be heated while the heating temperature should not be higher than the boiling point of the solvent system, such as about 40°C, about 50°C.
  • the heating can promote the transformation of the solid in the suspension into the crystal form B of the compound represented by formula (I).
  • Another aspect of the present invention also provides a crystal form C of the compound solvate shown in formula (I), the structure of the crystal form C is as follows:
  • the space group is P1
  • the crystal structure data of the crystal form C collected by X-ray single crystal diffraction are shown in Table 4 below:
  • Another aspect of the present invention also provides a pharmaceutical composition, which comprises the above-mentioned crystal form A of the compound shown in formula (I), the above-mentioned crystal form B of the compound shown in formula (I) and the above-mentioned formula ( I) one or more of the crystal forms C of the solvates of the compounds shown, and pharmaceutically acceptable auxiliary materials.
  • the crystal form A of the compound shown in formula (I), the crystal form B of the compound shown in formula (I) and the crystal form C of the solvate of the compound shown in formula (I) may also be used in combination with one or more other active ingredients; when used in combination, the active ingredients may be separate compositions for simultaneous administration in therapy by the same or different routes of administration or They are administered separately at different times, or they can also be administered together in the same pharmaceutical composition.
  • the administration method of the pharmaceutical composition is not particularly limited, and preparations in various dosage forms can be selected for administration according to the patient's age, gender, and other conditions and symptoms; for example, tablets, pills, solutions, suspensions, Emulsions, granules or capsules are administered orally; injections can be administered alone, or mixed with delivery fluids for injection (such as glucose solution and amino acid solution) for intravenous injection; suppositories are administered to the rectum.
  • delivery fluids for injection such as glucose solution and amino acid solution
  • Another aspect of the present invention also provides the use of the compound represented by formula (I) or the above pharmaceutical composition in the preparation of medicines for treating and/or preventing diseases mediated by Ras.
  • the compound represented by formula (I) is crystal form A of the compound represented by formula (I), crystal form B of the compound represented by formula (I) above, or the compound represented by formula (I) above.
  • the Ras is, for example, a G12C mutation of one or more of K-Ras, H-Ras and N-Ras, and another example is a G12C mutation of K-Ras.
  • the Ras-mediated disease is, for example, cancer.
  • cancers as colon cancer, appendix cancer, pancreatic cancer, MYH-associated polyposis, blood cancer, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer Cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophagus cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma.
  • Another aspect of the present invention also provides the application of the above-mentioned compound represented by formula (I) or the above-mentioned pharmaceutical composition in the preparation of Ras inhibitors.
  • the compound represented by formula (I) is crystal form A of the compound represented by formula (I), crystal form B of the compound represented by formula (I) above, or the compound represented by formula (I) above.
  • the Ras is, for example, a G12C mutation of one or more of K-Ras, H-Ras and N-Ras, and another example is a G12C mutation of K-Ras.
  • the Ras inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample to provide comparison, or prepared according to conventional methods in the art A kit that provides rapid detection of Ras inhibitory effects.
  • Another aspect of the present invention also provides the application of the above-mentioned compound represented by formula (I) or the above-mentioned pharmaceutical composition in the preparation of medicaments for treating and/or preventing cancer.
  • the compound represented by formula (I) is crystal form A of the compound represented by formula (I), crystal form B of the compound represented by formula (I) above, or the compound represented by formula (I) above.
  • the cancer is, for example, colon cancer, appendix cancer, pancreatic cancer, MYH-associated polyposis, blood cancer, breast cancer, endometrial cancer, gallbladder cancer, bile duct cancer, prostate cancer, lung cancer, brain cancer , ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophagus cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia and melanoma one or more.
  • Amorphous or “amorphous form” as used in the present invention means that the solid form of the compound represented by formula (I) is a non-crystalline form.
  • Crystal form used in the present invention can be used interchangeably in the present invention, specifically referring to the crystal form A of the compound shown in formula (I), the above-mentioned Crystal form B of the compound represented by formula (I) or crystal form C of the solvate of the compound represented by formula (I).
  • the crystal form of the present invention can be identified by one or several solid-state analysis methods. Such as X-ray powder diffraction, single crystal X-ray diffraction, infrared absorption spectrum, differential scanning calorimetry, thermogravimetric curve, etc. Those skilled in the art know that the peak intensity and/or peak situation of X-ray powder diffraction may vary due to different experimental conditions. At the same time, due to the different accuracy of the instrument, the measured 2 ⁇ value will have an error of about ⁇ 0.2°. The relative intensity value of the peak is more dependent on certain properties of the measured sample than the position of the peak, such as the size of the crystal and the degree of purity, so the measured peak intensity may have a deviation of about ⁇ 20%.
  • “Anhydrous” used in the present invention means that the sample contains no more than 1.0% (weight percent) or no more than 0.5% (weight percent) of water as determined by TGA.
  • “About” used in the present invention is used for a certain parameter, such as quantity, angle, temperature, time, etc., and means to deviate from the specified value by at most ⁇ 10%, preferably within ⁇ 5%, and most preferably within ⁇ 2%; however, when measuring the onset temperature and peak temperature of a thermal event in a differential scanning calorimetry (DSC) diagram, the term “about” means The onset or peak temperature can typically be within ⁇ 3°C.
  • DSC differential scanning calorimetry
  • substantially pure when used to describe a polymorphic form of a compound as represented by formula (I), means that the solid form of the compound contains this polymorphic form and substantially does not contain Other polymorphs of said compounds.
  • Typical substantially pure polymorphs contain less than 50%, preferably less than 40%, preferably less than 30%, preferably less than 20%, preferably less than 10%, preferably less than 5% by weight of other polymorphs. %, preferably less than 1%.
  • the polymorphic form of the compound shown in formula (I) when used to describe the polymorphic form of the compound shown in formula (I), it means that when using the dynamic moisture adsorption (DVS) technique to determine the polymorphism shown in formula (I), the polymorphic form of the compound has an increased mass of less than 2%, preferably less than 1%, compared to the initial mass in the range of 0-95% relative humidity.
  • DVD dynamic moisture adsorption
  • the "heated saturated liquid” refers to heating a solute in one or several solvents to form a supersaturated solution, wherein the solute is in excess.
  • the heating temperature is usually about 5-30°C below the boiling point of the solvent, for example, the heating temperature can be 40°C, 50°C, 60°C, 70°C, 75°C, 80°C.
  • the "hot filtration” used refers to filtering the hot saturated liquid through a pinhole filter, wherein the filter membrane material is preferably polyvinylidene fluoride (PVDF) or nylon, and the filter membrane pore size is preferably is 0.45 microns.
  • PVDF polyvinylidene fluoride
  • the "hot clarified solution” used refers to the complete dissolution of the solute in one or several solvents by heating, wherein the solvent is in excess.
  • the heating temperature is usually about 5-30°C below the boiling point of the solvent, for example, the heating temperature can be 40°C, 50°C, 60°C, 70°C, 75°C, 80°C.
  • the "suspension” used refers to forming a supersaturated solution of a solute in one or several solvents, wherein the solute is in significant excess, such as the suspension prepared in a suspension equilibrium experiment.
  • the "suspension equilibrium" used can be completed by conventional methods in the art, for example, by rotating the prepared suspension vial 360°, or by stirring the prepared suspension way.
  • the temperature of said suspension equilibrium usually refers to room temperature unless otherwise specified.
  • the "room temperature” refers to 10-30°C.
  • the operation of "solid-liquid phase separation” can be accomplished by conventional methods in the art, such as filtration and centrifugation.
  • the filtration unless otherwise specified, refers to suction filtration under reduced pressure.
  • the specific operation of the centrifugation is: place the pre-separated sample in a centrifuge, the centrifugation speed is usually 3000-15000 rpm, preferably 6000-12000 rpm.
  • the solid obtained through the "separation” can be further washed, and the solvent used for washing is preferably the same as that used in the crystal preparation method, and the amount of the washing solvent is generally 0.1-1 times the volume of the solvent used in the crystal preparation method.
  • the "drying" can be accomplished by conventional methods in the art, such as drying under normal pressure, drying under reduced pressure, preferably drying under reduced pressure.
  • the vacuum degree of the vacuum drying may be -0.09MPa; the temperature of the vacuum drying may be 30-80°C, preferably 40-70°C, such as 40°C, 50°C.
  • the drying time is generally 1 hour to overnight, that is, 1-24 hours, such as 2 hours, 16 hours.
  • the "stirring" can be accomplished by conventional methods in the field, such as magnetic stirring, mechanical stirring, and the stirring speed is 50-1200 rpm, preferably 200-500 rpm.
  • the used "volatile” refers to covering the mouth of the vial filled with the solution filtered by the filter membrane with aluminum foil and piercing a small hole, and then slowly volatilizing the solvent in a laboratory environment, for example, the bottle containing The mouth of the vial with the solution filtered by the filter membrane is covered with aluminum foil and a small hole is pierced, and the solvent is slowly evaporated in the fume hood.
  • treating refers to ameliorating a disease or disorder (i.e. arresting the disease or reducing the manifestations, extent or severity of its clinical symptoms); alternatively, improving at least one physical parameter, which may not be perceived by the subject; or slowing down Disease progression.
  • prevention means a reduction in the risk of acquiring or developing a disease or disorder (i.e. resulting in the absence of at least one of the clinical symptoms of the disease in subjects who may have been exposed to an agent causing the disease or susceptible to the disease before onset of the disease) .
  • pharmaceutically acceptable excipients refers to the excipients and additives used in the production of medicines and formulation of prescriptions, and refers to all substances contained in pharmaceutical preparations except active ingredients. See Pharmacopoeia of the People's Republic of China (2020 edition) four, or, Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).
  • the reagents and raw materials used in the present invention are all commercially available.
  • the crystal form of the compound represented by formula (I) provided by the present invention has one or more improved properties, especially in the properties of good purity, improved stability to high temperature and light, and improved high humidity conditions Hygroscopicity, not easy to crystallization, can better resist the problems of the purity of active ingredients and the growth of impurities caused by environmental temperature, humidity, light and other factors in the process of drug production, storage, transportation, etc., and reduce the resulting The risk of curative effect decline and safety risk; and the ability to better resist the risk of changes in the bioavailability of the drug due to the transformation of the solid form of the active ingredient during long-term storage of the drug preparation, and is suitable as an active ingredient for drug formulation development.
  • the preparation method provided by the invention is simple and easy to operate, and is suitable for industrial production.
  • Fig. 1 is an X-ray powder diffraction (XRPD) pattern of an amorphous form of the compound represented by formula (I).
  • Fig. 2 is the unimolecular three-dimensional structure ellipsoid diagram of the crystal form C of the compound solvate shown in formula (I).
  • Fig. 3 is the XRPD spectrum of the crystal form A of the compound represented by formula (I).
  • Fig. 4 is a differential scanning calorimetry (DSC) diagram of the crystal form A of the compound represented by formula (I).
  • Fig. 5 is a thermogravimetric analysis (TGA) diagram of the crystal form A of the compound represented by formula (I).
  • Fig. 6 is a dynamic moisture adsorption (DVS) diagram of the crystal form A of the compound represented by formula (I); wherein 1 is the hygroscopic curve, and 2 is the dehydration curve.
  • DVS dynamic moisture adsorption
  • Fig. 7 is the XRPD spectrum of the crystal form B of the compound represented by formula (I).
  • Fig. 8 is a DSC chart of the crystal form B of the compound represented by formula (I).
  • Fig. 9 is a TGA diagram of the crystal form B of the compound represented by formula (I).
  • Figure 10 is the DVS diagram of the crystal form B of the compound represented by formula (I); wherein 1 is the hygroscopic curve, and 2 is the dehydration curve.
  • Figure 11 is a DVS diagram of the amorphous form of the compound represented by formula (I); wherein 1 is the hygroscopic curve, and 2 is the dehydration curve.
  • Fig. 12 is a graph showing the body weight changes of mice in the subcutaneous xenograft tumor model of lung cancer cell NCI-H358.
  • Fig. 13 is a diagram showing the change of tumor volume in mice in the subcutaneous xenograft tumor model of lung cancer cell NCI-H358.
  • Fig. 14 is a graph showing the body weight changes of mice in the pancreatic cancer cell MIA PaCa-2 subcutaneous xenograft tumor model.
  • Fig. 15 is a graph showing the changes in tumor volume in mice in the pancreatic cancer cell MIA PaCa-2 subcutaneous xenograft tumor model.
  • Fig. 16 is a graph showing changes in body weight of mice in the subcutaneous xenograft tumor model of human-derived colon cancer cell SW837.
  • Fig. 17 is a diagram showing the change of mouse tumor volume in the subcutaneous xenograft tumor model of human colon cancer cell SW837.
  • solvents involved in the following examples are analytically pure or chromatographically pure, and when the solvents are mixed solvents, unless otherwise specified, all are volume ratios.
  • Bruker's D8Advance X-ray powder diffractometer is used for detection, and the K ⁇ line of the Cu target is used
  • the voltage is 40 kV
  • the current is 40 mA
  • the divergence slit is 1.0mm
  • the solar slit is 0.4°
  • the scanning mode is continuous scanning
  • the scanning angle range is 3°-45°
  • the step size is 0.02°
  • the scanning speed is 8 °/min
  • the DSC25 differential scanning calorimeter of TA Instruments was used for detection, the atmosphere was nitrogen, the heating rate was 10°C/min, and the temperature rising range was 25-300°C.
  • thermogravimetric analyzer of TA Instruments was used for detection, the atmosphere was nitrogen, and the temperature was heated to 350° C. at a heating rate of 10° C./min.
  • the Advantage 1.0 dynamic moisture adsorption instrument of SMS company is used for detection, the temperature is 25°C, the relative humidity range is 0%-95%, and the humidity change step is 5% relative humidity.
  • the value of the mass change rate dm/dt is less than 0.002%
  • the balance is considered to be balanced, when the mass change rate is less than 0.01%/min within 5 minutes, it is the balance standard in the detection process, and the longest balance time is 2 hours.
  • compound 1-c (88mg, 0.139mmol) was dissolved in toluene (10mL), then the reaction solution was cooled to 0°C, N-methylprolinol (29 ⁇ L, 0.243mmol) was added successively, t- BuONa (27 mg, 0.278 mmol). After the addition was complete, the reaction mixture was stirred in an ice-water bath under nitrogen for 0.5 hours, quenched with water (20 mL), and extracted with ethyl acetate (30 mL*2).
  • the chiral resolution of compound 1 to obtain the compound shown in formula (I) is the difficulty.
  • the two isomers of compound 1 were inseparable on the TLC plate and could not be separated by TLC means; even in HPLC, the two isomers of compound 1 were separated Degree is also very poor, can't realize separation by preparative HPLC;
  • the newly prepared compound 1 (260mg, 0.43mmol) was subjected to chiral resolution under the conditions shown in Table 2 below.
  • Compound 1-1 (76 mg, 29% yield) was obtained as a white solid;
  • Compound 1-2 (67 mg, 26% yield) was obtained as a white solid.
  • the compound 1-2 is the compound represented by the formula (I).
  • the unimolecular three-dimensional structure ellipsoid diagram of the crystal form C is shown in FIG. 2 .
  • Embodiment 2 Preparation of crystal form A of the compound shown in formula (I)
  • Gained powder sample is the crystalline form A of the compound shown in formula (I), and its X-ray powder diffraction pattern is as shown in Figure 3, and it is expressed in X with 2 ⁇ angle, d spacing, peak height percentage and peak area percentage.
  • the 2 ⁇ angle, d spacing, peak height percentage and peak area percentage of the main diffraction peaks are shown in Table 5 below, where the characteristic peaks (2 ⁇ 0.2°) are 4.839°, 9.141°, 9.694°, 12.433 °, 14.451°, 15.644°, 16.545°, 17.249°, 17.456°, 19.801°, 20.406°, 21.098°, 21.399°, 22.134°, 22.407°, 23.302°, 24.685°, 26.257°, 27.554°, and 27.9
  • thermogravimetric analysis diagram is shown in Figure 5. It can be seen from Figure 5 that the crystal form A loses 0.122% of its weight when heated to 220°C.
  • Embodiment 3 Preparation of crystal form A of the compound shown in formula (I)
  • Embodiment 4 Preparation of crystal form A of the compound shown in formula (I)
  • Embodiment 5 Preparation of crystal form A of the compound shown in formula (I)
  • Embodiment 6 Preparation of crystal form B of the compound shown in formula (I)
  • Gained powder sample is the crystalline form B of the compound shown in formula (I), and its X-ray powder diffraction pattern is as shown in Figure 7, and it is expressed in X with 2 ⁇ angle, d distance, peak height percentage and peak area percentage.
  • the 2 ⁇ angle, d spacing, peak height percentage and peak area percentage of the main diffraction peaks are shown in Table 6 below, where the characteristic peaks (2 ⁇ 0.2°) are 4.958°, 9.838°, 14.718°, 19.631 °, 24.582°, and 31.047°.
  • thermogravimetric analysis diagram is shown in Figure 9. It can be seen from Figure 9 that the crystal form B loses 0.207% of its weight when heated to 220°C.
  • Fig. 10 Its dynamic moisture adsorption diagram is shown in Fig. 10.
  • the DVS test shows that when the relative humidity changes from 0% to 95%, the mass percentage of the hygroscopic weight gain of the crystal form B is 0.9504%.
  • Embodiment 7 Preparation of crystal form B of the compound shown in formula (I)
  • the single solvent includes ethanol, n-propanol, isopropanol, n-butanol, acetone, 2-butanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, isopropyl ether, methyl tert-butyl base ether, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, dichloromethane, toluene, 1,4-dioxane, water, n-heptane, n-hexane, cyclohexane and cyclopentane;
  • the mixed solvent includes The volume ratios of ethanol and water are 15:85, 65:35 and 95:5 respectively, and the volume ratios of isopropanol and water are 35:65, 80:20 and 95:5 respectively.
  • the single solvent or mixed solvent includes methanol, methanol and water with a volume ratio of 50:50, 75:25 or 95:5, respectively. , methanol and acetonitrile, methanol and acetone, methanol and ethyl acetate, methanol and isopropyl acetate, methanol and isopropyl ether, methanol and methyl tert-butyl ether, methanol and dichloromethane in a volume ratio of 50:50 .
  • Crystal form A and crystal form B samples of the compound shown in formula (I) of equal weight respectively in the same vial add 1mL of solvent to the vial, and ultrasonically disperse to form a suspension.
  • the solvent includes ethanol, Acetone, ethyl acetate, and acetonitrile. After the suspension was covered and sealed, it was suspended and equilibrated at room temperature for 7 days. Centrifuge, discard the supernatant, and measure the XRPD after drying the solid at 40°C under reduced pressure.
  • Agilent ZORBAX SB-Phenyl column (3.5 ⁇ m, 4.6 ⁇ 150mm) was used for reverse-phase HPLC analysis, and the mobile phase components were (A) water containing 0.1% perchloric acid and (B) acetonitrile. The elution gradient was mobile phase B increased from 25% to 95% in 12 minutes, maintained at 95% for 3 minutes, and then equilibrated the system at 25% for 5 minutes.
  • the flow rate was 1.0 mL/min
  • the injection volume was 2 ⁇ L
  • the column temperature was 25° C.
  • the detection wavelength was 228 nm.
  • the test article was prepared in methanol to a final concentration of 0.5 mg/mL.
  • the crystal forms of the crystal form A, crystal form B and amorphous form did not change, and the chemical purity of the crystal form A and the crystal form B only decreased by 0.4%-0.5%; The chemical purity of the amorphous form decreased by 3.4%, and the total impurities increased by 3.34%.
  • the crystalline form A and crystalline form B of the present invention significantly improve the stability of the compound represented by formula (I) to high temperature and light.
  • the crystal form A and the crystal form B of the present invention significantly improve the hygroscopic performance of the compound represented by formula (I), which is more favorable for the storage of the drug.
  • CTG method was used to detect the proliferation inhibition experiments of the compounds on NCI-H358, MIA PaCa-2, A549 and A375 cell lines.
  • NCI-H358 is human non-small cell lung cancer cells with KRas G12C mutation
  • MIA PaCa-2 is human pancreatic cancer cells with KRasG12C mutation
  • A549 is human non-small cell lung cancer cells with KRas G12V mutation
  • A375 is wild-type malignant melanoma cells.
  • the inhibitory effect of the compound on different mutations was evaluated by detecting the inhibitory activity of the compound on the proliferation of four cell lines.
  • Table 11 The compound shown in formula (I) and diastereoisomer are to H358 cell, MIA PaCa-2 cell, A549 cell and the proliferation inhibitory activity of A375 cell
  • the experimental index is to investigate whether tumor growth can be inhibited, delayed or cured. Tumor diameters were measured twice a week with vernier calipers.
  • T/C% T RTV /C RTV ⁇ 100% (T RTV : RTV of the treatment group; C RTV : RTV of the solvent control group).
  • RTV relative tumor volume
  • V 1 is the tumor volume measured during cage administration (ie Day 1)
  • V T is the tumor volume measured on day T.
  • T/C (%) reflects the curative effect, according to the guiding principle of T/C% ⁇ 40% of the anti-tumor drug of the Drug Evaluation Center, it is considered that the test substance is effective.
  • the experiment was divided into solvent control group, such as 25mg/kg group, 50mg/kg group and 100mg/kg group of the compound represented by formula (I), administered orally orally for 21 days, once a day.
  • solvent control group such as 25mg/kg group, 50mg/kg group and 100mg/kg group of the compound represented by formula (I)
  • the mice in each group showed good tolerance without obvious abnormalities. See Figure 12 for the change in body weight of the mice.
  • Figure 13 shows the change in tumor volume in mice. Statistical analysis is carried out to each treatment group and solvent control group tumor volume, as shown in the compound 50mg/kg group and 100mg/kg group shown in formula (I) from the 5th day of administration to the end of administration, there is a very significant difference .
  • the T/C value of the 50mg/kg group and the 100mg/kg group was 66.58% (TGI %: 42.39%), 36.10% (TGI%: 81.00%) and 13.36% (TGI%: 109.91%).
  • the experiment was divided into solvent control group, such as 15mg/kg group, 30mg/kg group and 100mg/kg group of the compound represented by formula (I), administered orally orally for 21 days, once a day.
  • solvent control group such as 15mg/kg group, 30mg/kg group and 100mg/kg group of the compound represented by formula (I)
  • the mice in each group showed good tolerance without obvious abnormalities.
  • Figure 14 shows the change in body weight of the mice.
  • Figure 15 shows the change in tumor volume in mice. Statistical analysis is carried out to each treatment group and solvent control group tumor volume, as the compound 15mg/kg group shown in formula (I), 30mg/kg group and 100mg/kg group, from the 5th day that administration begins to administration end shows There is a very significant difference.
  • the T/C value of the 30mg/kg group and the 100mg/kg group were respectively 36.91% (TGI%: 75.39%), 13.55% (TGI%: 103.21%) and 0.56% (TGI%: 118.78%).
  • the 15mg/kg group, 30mg/kg group and 100mg/kg group of the compound represented by formula (I) showed good anticancer activity.
  • the experiment was divided into a solvent control group, such as the 100 mg/kg group of the compound represented by formula (I), which was administered orally or gavaged for 28 days, once a day. During the administration period, the mice in each group showed good tolerance without obvious abnormalities.
  • Figure 16 shows the change in body weight of the mice.
  • Figure 17 shows the change in tumor volume in mice. Statistical analysis was carried out on the tumor volume of the treatment group and the solvent control group, as shown in the 100 mg/kg group of the compound represented by formula (I), there was a very significant difference from the 4th day of administration to the end of administration.
  • the T/C value and TGI% value of the 100 mg/kg compound represented by formula (I) were 6.48% and 106.4% respectively.
  • the 100 mg/kg group of the compound represented by the formula (I) showed good anticancer activity.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des formes cristallines d'un composé hétérocyclique contenant de l'oxygène, un procédé de préparation associé et une application associée. Les formes cristallines comprennent une forme cristalline A d'un composé représenté par la formule (I), une forme cristalline B du composé représenté par la formule (I), et une forme cristalline C d'un solvate du composé représenté par la formule (I). Le procédé de préparation de la forme cristalline est simple, et approprié pour la production industrielle, et les formes cristallines n'absorbent pas facilement l'humidité, ont une bonne stabilité, et sont bénéfiques pour la production de préparations et pour le stockage à long terme de médicaments.
PCT/CN2022/094390 2021-05-24 2022-05-23 Formes cristallines de composé hétérocyclique contenant de l'oxygène, leur procédé de préparation et leur application WO2022247772A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110567540.8 2021-05-24
CN202110567540 2021-05-24

Publications (1)

Publication Number Publication Date
WO2022247772A1 true WO2022247772A1 (fr) 2022-12-01

Family

ID=84115516

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/094390 WO2022247772A1 (fr) 2021-05-24 2022-05-23 Formes cristallines de composé hétérocyclique contenant de l'oxygène, leur procédé de préparation et leur application

Country Status (2)

Country Link
CN (1) CN115385923A (fr)
WO (1) WO2022247772A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112390788A (zh) * 2019-08-13 2021-02-23 苏州闻天医药科技有限公司 一种用于抑制krasg12c突变蛋白的化合物及其制备方法和用途
WO2021109737A1 (fr) * 2019-12-02 2021-06-10 上海璎黎药业有限公司 Composé hétérocyclique contenant de l'oxygène, son procédé de préparation et son utilisation
CN112979664A (zh) * 2019-12-02 2021-06-18 上海璎黎药业有限公司 一种含氧杂环化合物、其制备方法及应用
WO2021248090A1 (fr) * 2020-06-05 2021-12-09 Sparcbio Llc Composés hétérocycliques et leurs procédés d'utilisation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112390788A (zh) * 2019-08-13 2021-02-23 苏州闻天医药科技有限公司 一种用于抑制krasg12c突变蛋白的化合物及其制备方法和用途
WO2021109737A1 (fr) * 2019-12-02 2021-06-10 上海璎黎药业有限公司 Composé hétérocyclique contenant de l'oxygène, son procédé de préparation et son utilisation
CN112979664A (zh) * 2019-12-02 2021-06-18 上海璎黎药业有限公司 一种含氧杂环化合物、其制备方法及应用
WO2021248090A1 (fr) * 2020-06-05 2021-12-09 Sparcbio Llc Composés hétérocycliques et leurs procédés d'utilisation

Also Published As

Publication number Publication date
CN115385923A (zh) 2022-11-25

Similar Documents

Publication Publication Date Title
JP7383652B2 (ja) Ｂ－ｒａｆキナーゼのマレイン酸塩、結晶形、調整方法、及びその使用
CN109970745B (zh) 取代的吡咯并三嗪类化合物及其药物组合物及其用途
JP7379680B2 (ja) テルフェニル化合物の新規な塩
BR112018003634B1 (pt) Forma cristalina de sesqui-hidrato de um inibidor parp, método de preparação da dita forma cristalina e composição farmacêutica compreendendo a dita forma
CN105980389B (zh) 一种jak激酶抑制剂的硫酸氢盐的结晶形式及其制备方法
EP3191475B1 (fr) Formes cristallines du 6-((6,7-diméthoxyquinazolin-4-yl)oxy)-n,2-diméthylbenzofuran-3-carboxamide
EP3812386A1 (fr) Forme cristalline d'un composé inhibiteur de l'activité cdk4/6 et son utilisation
US9453011B2 (en) Crystal form of dabrafenib mesylate and preparation method thereof
KR102466958B1 (ko) 단백질 키나제 활성을 억제하는 화합물의 결정 형태 및 이의 응용
WO2023193563A1 (fr) Forme cristalline d'un composé thiénopyridine, son procédé de préparation et composition pharmaceutique associée
WO2023093861A1 (fr) Mono-p-toluènesulfonate d'inhibiteur de kinase axl et forme cristalline de celui-ci
WO2022247772A1 (fr) Formes cristallines de composé hétérocyclique contenant de l'oxygène, leur procédé de préparation et leur application
CN113444073A (zh) 吗啉基喹唑啉类化合物的晶型ⅲ、其制备方法及应用
WO2022237892A1 (fr) Sel d'addition d'acide d'un inhibiteur de rock, et forme cristalline, composition et utilisation pharmaceutique associée
TW202206435A (zh) Ｊａｋ抑制劑化合物及其用途
JP2022517396A (ja) Ｅｇｆｒ阻害剤の塩、結晶形及びその製造方法
US10544129B2 (en) Crystalline forms of AP26113, and preparation method thereof
WO2018099451A1 (fr) Forme cristalline d'un composé
WO2023116895A1 (fr) Polymorphe d'inhibiteur de kras, son procédé de préparation et son utilisation
WO2024051771A1 (fr) Forme cristalline d'un composé hétérocyclique à cinq chaînons et à six chaînons, son procédé de préparation et son utilisation
WO2021073494A1 (fr) Sels d'un composé et leurs formes cristallines
CN110117272B (zh) 细胞周期蛋白依赖性激酶抑制剂的盐及其晶型
WO2023207944A1 (fr) Forme cristalline d'un inhibiteur de fgfr4 et son utilisation
US20240174669A1 (en) Crystalline forms of a parp1 inhibitor
WO2023230968A1 (fr) Inhibiteur de shp2, forme cristalline de celui-ci, procédé de préparation correspondant et utilisation associée

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22810497

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22810497

Country of ref document: EP

Kind code of ref document: A1