WO2018086608A1 - 一种GnRH受体拮抗剂的结晶形式及其制备方法 - Google Patents

一种GnRH受体拮抗剂的结晶形式及其制备方法 Download PDF

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WO2018086608A1
WO2018086608A1 PCT/CN2017/110685 CN2017110685W WO2018086608A1 WO 2018086608 A1 WO2018086608 A1 WO 2018086608A1 CN 2017110685 W CN2017110685 W CN 2017110685W WO 2018086608 A1 WO2018086608 A1 WO 2018086608A1
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solvent
formula
compound
alcohol
crystalline form
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PCT/CN2017/110685
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English (en)
French (fr)
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张全良
贾君磊
边林
高晓晖
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江苏恒瑞医药股份有限公司
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Priority to BR112019009455A priority Critical patent/BR112019009455A2/pt
Application filed by 江苏恒瑞医药股份有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to KR1020197015658A priority patent/KR102516017B1/ko
Priority to DK17869463.4T priority patent/DK3539545T3/da
Priority to JP2019525785A priority patent/JP2019535712A/ja
Priority to CN201780017902.8A priority patent/CN108778282B/zh
Priority to EP17869463.4A priority patent/EP3539545B1/en
Priority to AU2017357332A priority patent/AU2017357332B2/en
Priority to CA3040026A priority patent/CA3040026A1/en
Priority to US16/348,932 priority patent/US10787451B2/en
Priority to ES17869463T priority patent/ES2887018T3/es
Priority to PL17869463T priority patent/PL3539545T3/pl
Publication of WO2018086608A1 publication Critical patent/WO2018086608A1/zh
Priority to HRP20211379TT priority patent/HRP20211379T1/hr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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 present invention relates to 1-(4-(7-(2,6-difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazin-3-yl)- Form I of 4,6-dicarbonyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)phenyl)-3-methoxyurea And a method of preparation, its use in a pharmaceutical composition, and the use of the crystalline form I, composition for the preparation of a medicament for treating and/or preventing a GnRH receptor antagonist.
  • Endometriosis is a common estrogen-dependent gynecological disease that often occurs during the reproductive years of women, and its mechanism of action remains unclear.
  • endometriosis is mainly diagnosed by laparoscopic surgery and treated by surgery, or by taking birth control pills, GnRH receptor agonists or progesterone to reduce estrogen levels in the body.
  • Gonadotropin-releasing hormone also known as luteinizing hormone-releasing hormone (LHRH)
  • LHRH luteinizing hormone-releasing hormone
  • the secretion and release of gonadotropins such as luteinizing hormone (LH) and follicle stimulating hormone (FSH) regulate the normal development of the ovary and corpus luteum and play an important role in the hypothalamic-pituitary-gonadal axis.
  • the GnRH receptor exerts its regulation by coupling with the G protein that activates the second messenger system of phosphatidylinositol calcium, while LH regulates the production of sex steroids, which regulate male spermatogenesis and female follicular development.
  • LH and FSH are released into the circulation and bind to receptors on specific cells of the ovary or testis to stimulate steroid production.
  • diseases such as endometriosis, uterine fibroids and prostate cancer are exacerbated, and GnRH receptor agonists and antagonists of long-acting peptides need to be administered for therapeutic control.
  • Peptide compounds have many problems to be solved including oral absorption, dosage form, dosage volume, drug stability, sustained action, and metabolic stability.
  • the main reason why small molecule GnRH receptor antagonist therapy is superior to existing peptide-based therapy is that small molecule GnRH receptor antagonist can be directly administered orally, which is convenient and quick.
  • GnRH receptor agonist-mediated indirect inhibition of tumor mechanism is a long-term action on the hypothalamic-pituitary-gonadal axis, resulting in decreased pituitary gonadotropin (FSH, LH), thereby reducing the secretion of sex hormones and indirectly inhibiting the growth of tumor cells.
  • GnRH receptor antagonists directly inhibit the release of pituitary gonadotropins, thereby inhibiting the growth of tumor cells.
  • a series of small molecule GnRH receptor antagonist patents are currently disclosed including WO2006096785, WO2010026993, WO2011076687, WO2012175514, and the like.
  • Small molecule GnRH receptor antagonists have good application prospects in the pharmaceutical industry.
  • the applicant provides a novel high-efficiency and low-toxic GnRH receptor antagonist in the patent application WO2015062391A1 (publication date 2015.05.07). It has excellent effects and effects and can effectively treat diseases of the endocrine and reproductive system. Its chemical name is 1-(4-(7-(2,6-difluorobenzyl)-3-((dimethylamino)methyl)).
  • the crystal structure as a pharmaceutically active ingredient often affects the chemical stability of the drug.
  • the difference in the crystal form, preparation method and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by the formation of other forms of crystals. type.
  • amorphous drug products have no regular crystal structure and often have other defects, such as poor product stability, difficulty in filtration, agglomeration, and poor fluidity. These differences often lead to difficulties in production amplification.
  • the stability of the existing crystal form needs to be improved. Therefore, it is necessary to improve various aspects of the compound. We need to study in depth to find new crystal forms with high purity and good chemical stability.
  • the technical problem to be solved by the present invention is to provide a 1-(4-(7-(2,6-difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxy group) Pyridazin-3-yl)-4,6-dicarbonyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)phenyl)-3-
  • a crystal form of methoxyurea (as shown in formula (I)), which has good stability, and the crystallization solvent used is low in toxicity and low in residue, and can be better applied in clinical practice.
  • the present invention provides a crystalline form I of the compound of the formula (I), characterized in that an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ angle is obtained using Cu-K ⁇ radiation, the I crystal form being 5.56, There are characteristic peaks at 9.15, 9.79, 11.08, 19.59, 20.25, and 22.16, where the error range of each characteristic peak 2 ⁇ is ⁇ 0.2.
  • the present invention provides a crystalline form I of the compound of the formula (I), characterized in that X-ray powder diffraction represented by a diffraction angle 2 ⁇ angle is obtained using Cu-K ⁇ radiation.
  • the I crystal forms have characteristic peaks at 5.56, 9.15, 9.79, 10.29, 11.08, 14.21, 16.61, 19.59, 20.25, 22.16, and 25.69, wherein the error range of each characteristic peak 2 ⁇ is ⁇ 0.2.
  • the present invention provides a crystalline form I of the compound of the formula (I), characterized in that X-ray powder diffraction represented by a diffraction angle 2 ⁇ angle is obtained using Cu-K ⁇ radiation.
  • the map has a crystal form of 5.22, 5.56, 9.15, 9.79, 10.29, 11.08, 13.38, 13.81, 14.21, 14.89, 16.61, 17.19, 18.47, 19.59, 20.25, 22.16, 23.32, 24.67, 25.69, 26.72, 28.73, There are characteristic peaks at 29.38, 31.78, 34.02 and 36.95, where the error range of each characteristic peak 2 ⁇ is ⁇ 0.2.
  • the present invention provides a crystalline form I of the compound of the formula (I), characterized in that the melting endothermic peak of the DSC is from 160 ° C to 175 ° C, preferably 165 ° C. 170 ° C, more preferably 168.17 ° C.
  • the invention further provides a process for the preparation of the crystalline form I of the compound of formula (I), the process comprising:
  • Method 1 the compound of the formula (I) is dissolved in an organic solvent, crystallized, filtered and washed, and dried to obtain a target I crystal form, the organic solvent being selected from the group consisting of alcohols and ketones.
  • a mixed solvent of an ester, an ether, an ether and an alcohol, or a mixed solvent of a ketone and water the alcohol solvent is selected from the group consisting of methanol, ethanol or isopropanol
  • the ketone solvent is selected from acetone
  • the ester solvent is selected from the group consisting of ethyl acetate.
  • the ester, the ether solvent is selected from tetrahydrofuran
  • the mixed solvent of the ether and the alcohol is selected from tetrahydrofuran/ethanol or tetrahydrofuran/isopropanol
  • the mixed solvent of the ketone and water is selected from acetone/water
  • Method 2 the compound of the formula (I) is placed in a solvent, beaten, filtered and washed, and dried to obtain a target crystal form I, which is selected from the group consisting of alcohols, ketones, esters, a mixed solvent of an ether, an ether and an alcohol, or a mixed solvent of a ketone and water, the alcohol solvent is selected from methanol, ethanol or isopropanol, the ketone solvent is selected from acetone, and the ester solvent is selected from ethyl acetate and ether.
  • a target crystal form I which is selected from the group consisting of alcohols, ketones, esters, a mixed solvent of an ether, an ether and an alcohol, or a mixed solvent of a ketone and water
  • the alcohol solvent is selected from methanol, ethanol or isopropanol
  • the ketone solvent is selected from acetone
  • the ester solvent is selected from ethyl acetate and ether.
  • the solvent is selected from tetrahydrofuran
  • the mixed solvent of the ether and the alcohol is selected from tetrahydrofuran/ethanol or tetrahydrofuran/isopropanol
  • the mixed solvent of the ketone and water is selected from acetone/water
  • the ratio of the mixed solvent of the ketone to water is from 0.1:1 to 1:0.1.
  • acetone/water 1:1
  • the beating temperature is selected from room temperature to solvent boiling point
  • the room temperature is preferably 15 to 30 ° C, more preferably 25 ° C.
  • the invention further relates to a pharmaceutical composition of Form I of the compound of formula (I), characterized in that it comprises one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the invention further relates to the use of a pharmaceutical composition of Form I or Form I of a compound of formula (I) for the manufacture of a medicament for the treatment and/or prevention of a disease associated with a GnRH receptor antagonist, said disease being selected from the group consisting of Endocrine reproductive system diseases.
  • the obtained formula (I) was obtained by X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC).
  • XRPD X-ray powder diffraction pattern
  • DSC differential scanning calorimetry
  • the crystal form of the compound I represented by the formula (I) prepared according to the method of the present invention does not contain or contains only a low content of residual solvent, and meets the limit requirement of the residual solvent of the pharmaceutical product according to the national pharmacopoeia, so that the crystal of the present invention can be compared. It is used as a pharmaceutical active ingredient.
  • the method of recrystallization is not particularly limited and can be carried out by a usual recrystallization operation method.
  • the compound represented by the starting material (I) can be slowly cooled and crystallized by heating in an organic solvent, and after completion of crystallization, it can be dried by filtration to obtain a desired crystal.
  • the method for crystallization of the present invention includes room temperature crystallization, cooling crystallization, and the like.
  • the starting material used in the method for preparing a crystal form of the present invention may be any compound of the formula (I), and the specific forms include, but are not limited to, amorphous, arbitrary crystal forms and the like.
  • the "beating" as used in the present invention refers to a method in which the solubility of a substance in a solvent is poor, but the solubility of the impurity in a solvent is good, and the beating and purifying can remove the color, change the crystal form or remove a small amount of impurities.
  • C 1-6 alkyl group of the present invention means a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl.
  • n-butyl isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3 -methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, and the like.
  • the "hydroxy group” in the present invention means a group such as -OH.
  • the "ketone solvent” as used in the present invention means a compound in which a carbonyl group (-C(O)-) is bonded to two hydrocarbon groups, and the ketone can be classified into an aliphatic ketone, an alicyclic ketone, an aromatic ketone according to a hydrocarbon group in the molecule.
  • Saturated ketones and unsaturated ketones specific examples include, but are not limited to, acetone, methyl butanone or methyl isobutyl ketone.
  • ester solvent means a combination of a lower organic acid having 1 to 4 carbon atoms and a lower alcohol having 1 to 6 carbon atoms, and specific examples include, but are not limited to, acetic acid. Ethyl ester, isopropyl acetate or butyl acetate.
  • ether solvent as used in the present invention means a chain compound or a cyclic compound having an ether bond -O- and having 1 to 10 carbon atoms, and specific examples include, but are not limited to, propylene glycol methyl ether, tetrahydrofuran or , 4-dioxane.
  • the "alcohol solvent” as used in the present invention means a group derived from one or more "hydroxyl groups” substituted with one or more hydrogen atoms on the "C 1-6 alkyl group", said "hydroxyl group” and “C” 1-6 alkyl” is as defined above, and specific examples include, but are not limited to, methanol, ethanol, propanol or 2-propanol.
  • the “mixed solvent” as used in the present invention refers to a solvent in which one or more different kinds of organic solvents are mixed in a certain ratio, or a solvent in which an organic solvent and water are mixed in a certain ratio, and the ratio is a volume ratio.
  • the volume ratio is selected from 0.1:1 to 1:0.1, preferably 1:1 or 5:1; the mixed solvent is preferably a mixed solvent of an alcohol and an ether, a mixed solvent of an alcohol solvent and water, or a ketone solvent.
  • a mixed solvent of water is selected from 0.1:1 to 1:0.1, preferably 1:1 or 5:1; the mixed solvent is preferably a mixed solvent of an alcohol and an ether, a mixed solvent of an alcohol solvent and water, or a ketone solvent.
  • the "differential scanning calorimetry or DSC” as used in the present invention refers to measuring the temperature difference and heat flow difference between a sample and a reference during temperature rise or constant temperature of the sample to characterize all physical changes and chemistry related to thermal effects. Change to get the phase change information of the sample.
  • the "2 ⁇ or 2 ⁇ angle" as used in the present invention means a diffraction angle, ⁇ is a Bragg angle, and the unit is ° or degree, and the error range of 2 ⁇ is ⁇ 0.1 to ⁇ 0.5, preferably ⁇ 0.1 to ⁇ 0.3, more preferably ⁇ 0.2.
  • the "plane spacing or interplanar spacing (d value)" means that the spatial lattice selects three unit vectors a, b, c which are not parallel to each other and adjacent two lattice points, and they point the points.
  • the parallelepiped unit which is divided into juxtapositions, is called the interplanar spacing.
  • the spatial lattice is divided according to the determined parallelepiped unit lines, and a set of linear grids is obtained, which is called a space lattice or a lattice.
  • the lattice and the lattice reflect the periodicity of the crystal structure by geometric points and lines, respectively, and the interplanar spacing (ie, the distance between two adjacent parallel crystal planes) is different; Or ang.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form I of a compound of formula (I), and optionally one or more pharmaceutically acceptable carriers and/or diluents.
  • the pharmaceutical composition can be formulated into any of the pharmaceutically acceptable dosage forms.
  • the crystalline form I or the pharmaceutical preparation of the present invention can be formulated into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injection and concentrated injections). Solution), suppository, inhalant or spray.
  • the pharmaceutical composition of the present invention can also be administered to a patient or subject in need of such treatment by any suitable mode of administration, such as oral, parenteral, rectal, pulmonary or topical administration.
  • the pharmaceutical composition can be formulated into an oral preparation, such as an oral solid preparation such as a tablet, a capsule, a pill, a granule, or the like; or an oral liquid preparation such as an oral solution or an oral mixture. Suspension, syrup, and the like.
  • the pharmaceutical preparation may further contain a suitable filler, binder, disintegrant, lubricant, and the like.
  • the pharmaceutical preparation When used for parenteral administration, the pharmaceutical preparation can be prepared as an injection, including an injection, a sterile powder for injection, and a concentrated solution for injection.
  • the pharmaceutical composition When formulated as an injection, the pharmaceutical composition can be produced by a conventional method in the existing pharmaceutical field.
  • an additional agent may be added to the pharmaceutical preparation, and a suitable additional agent may be added depending on the nature of the drug.
  • the pharmaceutical preparation When used for rectal administration, The pharmaceutical preparation can be prepared as a suppository or the like.
  • the pharmaceutical preparation can be formulated as an inhalant or a spray.
  • the crystalline form I of the invention is present in a pharmaceutical composition or medicament in a therapeutically and/or prophylactically effective amount.
  • Form I of the invention is presented in a pharmaceutical composition or medicament in unit dosage form.
  • the crystalline form I of the compounds of formula (I) according to the invention can be used for the preparation of a medicament for the treatment and/or prophylaxis of diseases associated with GnRH receptor antagonists. Accordingly, the present application also relates to the use of the crystalline form I of the compound of the formula (I) of the present invention for the preparation of a medicament for the treatment and/or prevention of a disease associated with a GnRH receptor antagonist in a subject. Furthermore, the present application relates to a method of inhibiting a disease associated with a GnRH receptor antagonist comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a compound of the formula (I) of the present invention. A crystalline form, or a pharmaceutical composition of the invention.
  • the disease is a disease associated with a GnRH receptor antagonist selected from the group consisting of: an endocrine reproductive system disorder.
  • the crystalline form I of the compound of the formula (I) of the present invention does not contain or contains only a relatively low residual solvent, and meets the requirements of the national pharmacopoeia for the residual solvent of the pharmaceutical product, so that the crystal of the present invention can be better.
  • the ground is used as a pharmaceutically active ingredient.
  • the crystal form of the compound of the formula (I) prepared by the invention has high purity, and the crystal form has no change under the conditions of illumination, high temperature and high humidity, and the crystal form stability is not detected by XRPD. Good; small change in HPLC purity and high chemical stability; the crystal form of the compound of the formula (I) obtained by the technical solution of the present invention can meet the medicinal requirements for production transportation and storage, and the production process is stable, reproducible and controllable, and can be adapted. In industrial production.
  • Figure 1 is an XRPD pattern of the crystalline form of Compound I of formula (I).
  • Figure 2 is a DSC pattern of the compound I form of the formula (I).
  • Figure 3 is an XRPD pattern of the crystalline form of Compound A shown in Formula (I).
  • Figure 4 is a crystalline form DSC pattern of Compound A shown in Formula (I).
  • Figure 5 is an XRPD pattern of the crystalline form of Compound B of formula (I).
  • Figure 6 is a DSC pattern of the compound B of the formula (I).
  • Figure 7 is an XRPD pattern of the crystalline form of Compound C of formula (I).
  • Figure 8 is a DSC pattern of the compound C of the formula (I).
  • Figure 9 is an XRPD pattern of the crystalline form of Compound D of formula (I).
  • Figure 10 is a DSC pattern of the compound D of the formula (I).
  • the crude compound (300 mg, 0.49 mmol) (prepared according to the method of Example 11 of WO2015062391A1) was added to a reaction flask, and acetone (6 mL) was added thereto, and the mixture was stirred at room temperature overnight, filtered, and dried in vacuo.
  • the XRPD pattern of the crystal sample is shown in Fig. 1.
  • the DSC spectrum is shown in Fig. 2.
  • the melting endothermic peak of DSC is around 168.17 °C, and the initial melting temperature is 154.23 °C.
  • the characteristic peak positions are shown in the following table:
  • the crude compound of the formula (I) (500 mg, 0.82 mmol) (prepared according to the method of Example 11 of WO2015062391A1) was added to a reaction flask, methanol (50 mL) was added thereto, and the mixture was heated to reflux, and the solid was dissolved, the heating was stopped, and the mixture was stirred. Crystal, suction filtration, vacuum drying to give a solid 350 mg. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form I.
  • the crude compound of the formula (I) (500 mg, 0.82 mmol) (prepared according to the method of Example 11 of WO2015062391A1) was added to a reaction flask, and ethanol (125 mL) was added thereto, and the mixture was heated to reflux. The solid was dissolved, the heating was stopped, and the crystal was stirred. Filtration and vacuum drying gave 406 mg of a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form I.
  • the crude compound of the formula (I) (500 mg, 0.82 mmol) (prepared according to the method of Example 11 of WO2015062391A1) was added to a reaction flask, and isopropanol (10 mL) was added thereto, stirred at room temperature overnight, suction filtered, and dried in vacuo to give a solid. 445mg.
  • the XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form I.
  • the compound of the formula (I) (300 mg, 0.49 mmol) (prepared according to the method of Example 11 of WO2015062391A1) was added to a reaction flask, and ethyl acetate (9 mL) was added thereto, and the mixture was stirred at room temperature overnight, suction filtered and dried in vacuo. 224 mg.
  • the XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form I.
  • the compound of the formula (I) (300 mg, 0.49 mmol) (prepared according to the method of Example 11 of WO2015062391A1) was added to a reaction flask, and methanol (6 mL) was added thereto, and the mixture was stirred overnight at room temperature, filtered, and dried in vacuo to give 239 mg.
  • the XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form I.
  • the compound of the formula (I) (300 mg, 0.49 mmol) (prepared according to the method of Example 11 of WO2015062391A1) was added to a reaction flask, and ethanol (6 mL) was added thereto, and the mixture was stirred at room temperature overnight.
  • the XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form I.
  • the obtained crystal form of A was added to a reaction flask, and ethanol (4 mL) was added thereto, and the mixture was stirred at room temperature overnight, filtered, and dried in vacuo.
  • the XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form I.
  • the obtained crystal form of B was added to a reaction flask, and ethanol (4 mL) was added thereto, and the mixture was stirred at room temperature overnight, filtered, and dried in vacuo.
  • the XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form I.
  • the obtained crystal form of C was added to a reaction flask, and ethanol (10 mL) was added thereto, and the mixture was stirred at room temperature overnight, suction filtered, and dried in vacuo to give a solid (78 mg).
  • the XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form I.
  • the obtained crystal form of D was added to a reaction flask, and ethanol (10 mL) was added thereto, and the mixture was stirred at room temperature overnight, filtered, and dried in vacuo.
  • the XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form I.
  • Example 2 The sample of the I crystalline product obtained in Example 1 and the sample of the crystalline product of the A, B, C, and D obtained in Examples 12, 13, 14, and 15 were placed in an open position, and the light was irradiated (4,500 Lux) and heated (40). The stability of the sample under the conditions of °C, 60 °C) and high humidity (RH75%, RH90%), the sampling time was 5 days and 10 days, and the purity of HPLC was shown in Table 2.
  • the HPLC purity data of the compound I form of formula (I) decreased less than the crystal forms of A, B, C and D, and the crystal forms were not changed by XRPD. It is shown that the crystal form of the present invention is significantly better than the crystal forms of A, B, C, and D.

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Abstract

本发明提供了一种GnRH受体拮抗剂的结晶形式及其制备方法。具体地，本发明提供了1-(4-(7-(2,6-二氟苄基)-3-((二甲氨基)甲基)-5-(6-甲氧基哒嗪-3-基)-4,6-二羰基-4,5,6,7-四氢-2 H-吡唑并[3,4- d]嘧啶-2-基)苯基)-3-甲氧基脲(式I化合物)的I晶型及制备方法，其在药物组合物的应用以及该I晶型和组合物在制备治疗具有GnRH受体拮抗剂有关疾病中的用途。

Description

一种GnRH受体拮抗剂的结晶形式及其制备方法 技术领域
本发明涉及1-(4-(7-(2,6-二氟苄基)-3-((二甲氨基)甲基)-5-(6-甲氧基哒嗪-3-基)-4,6-二羰基-4,5,6,7-四氢-2H-吡唑并[3,4-d]嘧啶-2-基)苯基)-3-甲氧基脲的I晶型及制备方法，其在药物组合物中的应用以及该I晶型、组合物在制备治疗和/或预防具有GnRH受体拮抗剂有关疾病中的用途。
背景技术
子宫内膜异位症是一种常见的雌激素依赖的妇科疾病，常发生于女性生育年龄期间，其作用机制尚不清楚。目前，子宫内膜异位症主要通过腹腔镜手术诊断，并通过外科手术进行治疗，或者服用避孕药、GnRH受体激动剂或孕激素减少体内雌激素水平来进行控制。
促性腺激素释放激素(GnRH)也称黄体生成素释放激素(LHRH)，是内分泌生殖系统中的中枢调节因素。促性腺激素如黄体生成素(LH)和卵泡刺激素(FSH)的分泌和释放，调节卵巢和黄体的正常发育，在下丘脑-垂体-性腺轴发挥重要作用。GnRH受体通过与能够激活磷脂酰肌醇钙第二信使体系的G蛋白偶联发挥其调节作用，而LH则调节性类固醇的产生，FSH调节男性精子发生及女性卵泡的发育。
LH和FSH被释放到循环中，并与卵巢或睾丸的特异性细胞上受体相结合，刺激类固醇的生成。性类固醇存在情况下，疾病例如子宫内膜异位症、子宫肌瘤和前列腺癌等病情加重，需给予长效肽类的GnRH受体激动剂和拮抗剂进行治疗控制。
肽类化合物存在许多待解决的包括口服吸收性、剂型、剂量体积、药物稳定性、持续作用及代谢稳定性等问题。而小分子GnRH受体拮抗剂治疗优于现存的肽基治疗法的主要原因在于小分子GnRH受体拮抗剂可以直接进行口服给药，方便快捷。
GnRH受体激动剂介导的间接抑制肿瘤机制是通过长期作用于下丘脑-垂体-性腺轴，导致垂体促性腺激素(FSH,LH)降低，从而减少性激素的分泌而间接抑制肿瘤细胞的生长。而GnRH受体拮抗剂则直接抑制垂体促性腺激素的释放，进而抑制肿瘤细胞的生长。
目前公开了一系列的小分子GnRH受体拮抗剂专利包括WO2006096785、WO2010026993、WO2011076687、WO2012175514等。小分子GnRH受体拮抗剂作为药物在医药行业具有良好的应用前景，本申请人在专利申请WO2015062391A1(公开日2015.05.07)中提供了一种结构新型的高效低毒的的GnRH受体拮抗剂，具有优异的效果和作用，能够有效治疗内分泌生殖系统疾病，其化学名为1-(4-(7-(2,6-二氟苄基)-3-((二甲氨基)甲基)-5-(6-甲氧基哒嗪-3-基)-4,6- 二羰基-4,5,6,7-四氢-2H-吡唑并[3,4-d]嘧啶-2-基)苯基)-3-甲氧基脲，结构如下所示
Figure PCTCN2017110685-appb-000001
作为药用活性成分的晶型结构往往影响到该药物的化学稳定性，结晶形式、制备方法及储存条件的不同有可能导致化合物的晶型结构的变化，有时还会伴随着产生其他形态的晶型。一般来说，无定形的药物产品没有规则的晶体结构，往往具有其它缺陷，比如产物稳定性较差，过滤较难，易结块，流动性差等，这些差异往往导致生产放大时的困难。而现有晶型的稳定性有待提高。因此，改善化合物的各方面性质是很有必要的，我们需要深入研究找到晶型纯度较高并且具备良好化学稳定性的新晶型。
发明内容
本发明要解决的技术问题是提供一种1-(4-(7-(2,6-二氟苄基)-3-((二甲氨基)甲基)-5-(6-甲氧基哒嗪-3-基)-4,6-二羰基-4,5,6,7-四氢-2H-吡唑并[3,4-d]嘧啶-2-基)苯基)-3-甲氧基脲(如式(I)所示)的I晶型，该晶型具备良好的稳定性，并且所用结晶溶剂低毒低残留，可更好地应用于临床。
本发明的技术方案如下：
本发明提供一种式(I)所示化合物的I晶型，其特征在于：使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，所述I晶型在5.56、9.15、9.79、11.08、19.59、20.25和22.16处有特征峰，其中，每个特征峰2θ的误差范围为±0.2，
Figure PCTCN2017110685-appb-000002
在本发明的一个优选实施方案中，本发明提供一种式(I)所示化合物的I晶型，其特征在于：使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射 图谱，所述I晶型在5.56、9.15、9.79、10.29、11.08、14.21、16.61、19.59、20.25、22.16和25.69处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。
在本发明的一个优选实施方案中，本发明提供一种式(I)所示化合物的I晶型，其特征在于：使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，所述I晶型在5.22，5.56，9.15，9.79，10.29，11.08，13.38，13.81，14.21，14.89，16.61，17.19，18.47，19.59，20.25，22.16，23.32，24.67，25.69，26.72，28.73，29.38，31.78，34.02和36.95处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。
在本发明的一个优选实施例方案中，本发明提供一种式(I)所示化合物的I晶型，其特征在于：DSC的熔融吸热峰值为160℃～175℃，优选为165℃～170℃，更优选为168.17℃。
在本发明的一个优选实施方案中，本发明进一步提供一种制备式(I)所示化合物的I晶型的方法，所述方法包括：
(1)方法一，将式(I)所示化合物溶解于有机溶剂中，析晶，过滤结晶并洗涤，干燥后即可得到目标I晶型，所述有机溶剂选自醇类、酮类、酯类、醚类、醚类与醇类的混合溶剂或酮类与水的混合溶剂，醇类溶剂选自甲醇、乙醇或异丙醇，酮类溶剂选自丙酮，酯类溶剂选自乙酸乙酯，醚类溶剂选自四氢呋喃，醚类与醇类的混合溶剂选自四氢呋喃/乙醇或四氢呋喃/异丙醇，酮类与水的混合溶剂选自丙酮/水，所述醇类溶剂与醚类的混合溶剂的比例为0.1:1～1:0.1，优选四氢呋喃/乙醇＝1:1，四氢呋喃/异丙醇＝1:1，所述酮类与水的混合溶剂的比例为0.1:1～1:0.1，优选丙酮/水＝5:1；
(2)方法二，将式(I)所示化合物置于溶剂中，进行打浆，过滤结晶并洗涤，干燥后得到目标晶型I，所述有机溶剂选自醇类、酮类、酯类、醚类、醚类与醇类的混合溶剂或酮类与水的混合溶剂，醇类溶剂选自甲醇、乙醇或异丙醇，酮类溶剂选自丙酮，酯类溶剂选自乙酸乙酯，醚类溶剂选自四氢呋喃，醚类与醇类的混合溶剂选自四氢呋喃/乙醇或四氢呋喃/异丙醇，酮类与水的混合溶剂选自丙酮/水，所述醇类溶剂与醚类的混合溶剂的比例为0.1:1～1:0.1，优选四氢呋喃/乙醇＝1:1，四氢呋喃/异丙醇＝1:1，所述酮类与水的混合溶剂的比例为0.1:1～1:0.1，优选丙酮/水＝1:1，所述打浆温度选自室温～溶剂沸点温度，所述室温优选15～30℃，更优选25℃。
本发明进一步涉及式(I)所示化合物的I晶型的药物组合物，其特征在于包含一种或多种药学上可接受的载体、稀释剂或赋形剂。
本发明进一步涉及式(I)所示化合物的I晶型或I晶型的药物组合物在制备治疗和/或预防与GnRH受体拮抗剂有关的疾病的药物中的用途，所述疾病选自内分泌生殖系统疾病。
通过X-射线粉末衍射图谱(XRPD)、差示扫描量热分析(DSC)对所得到式(I)所 示化合物的I晶型进行结构测定、晶型研究，同时对所得结晶的溶剂残留进行了检测。
按照本发明的方法制备的式(I)所示化合物I晶型不含有或仅含有较低含量的残留溶剂，符合国家药典规定的有关医药产品残留溶剂的限量要求，因而本发明的结晶可以较好地作为医药活性成分使用。
重结晶的方法没有特别限定，可以用通常的重结晶操作方法进行。例如，可以用原料式(I)所示化合物在有机溶剂加热溶解后慢慢冷却析晶，结晶完成后，经过滤干燥，即可得到所需要的结晶。
本发明析晶的方法有室温析晶、冷却析晶等。
本发明晶型制备方法中所用的起始原料可以是任意形式的式(I)所示化合物，具体形式包括但不限于：无定形、任意晶型等。
发明详述
在本申请的说明书和权利要求书中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。然而，为了更好地理解本发明，下面提供了部分相关术语的定义和解释。另外，当本申请所提供的术语的定义和解释与本领域技术人员所通常理解的含义不一致时，以本申请所提供的术语的定义和解释为准。
本发明所述的“打浆”是指利用物质在溶剂中溶解性差，但杂质在溶剂中溶解性好的特性进行纯化的方法，打浆提纯可以去色、改变晶型或去除少量杂质。
本发明所述“C1-6烷基”表示直链或支链的含有1-6个碳原子的烷基，具体实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。
本发明所述“羟基”是指-OH等基团。
本发明所述的“酮类溶剂”是指羰基(-C(O)-)与两个烃基相连的化合物，根据分子中烃基的不同，酮可分为脂肪酮、脂环酮、芳香酮、饱和酮和不饱和酮，具体实例包括但不限于：丙酮、甲基丁酮或甲基异丁酮。
本发明所述的“酯类溶剂”是指含碳原子数为1至4个的低级有机酸与含碳原子数为1至6个的低级醇的结合物，具体实例包括但不限于：乙酸乙酯、乙酸异丙酯或乙酸丁酯。
本发明所述的“醚类溶剂”是指含有醚键-O-且碳原子数为1至10个的链状化合物或环状化合物，具体实例包括但不限于：丙二醇甲醚、四氢呋喃或1,4-二氧六环。
本发明所述的“醇类溶剂”是指一个或多个“羟基”取代“C1-6烷基”上的一个或多 个氢原子所衍生的基团，所述“羟基”和“C1-6烷基”如前文所定义，具体实例包括但不限于：甲醇、乙醇、丙醇或2-丙醇。
本发明所述的“混合溶剂”是指一种或多种不同种类的有机溶剂按照一定比例混合而成的溶剂，或有机溶剂与水按照一定比例混合而成的溶剂，所述比例为体积比，体积比选自0.1:1～1:0.1，优选为1:1或5:1；所述混合溶剂优选为醇类与醚类的混合溶剂醇类溶剂与水的混合溶剂或酮类溶剂与水的混合溶剂。
本发明所述的“X-射线粉末衍射图谱或XRPD”是指根据布拉格公式2d sinθ＝nλ(式中，λ为X射线的波长，
Figure PCTCN2017110685-appb-000003
衍射的级数n为任何正整数，一般取一级衍射峰，n＝1)，当X射线以掠角θ(入射角的余角，又称为布拉格角)入射到晶体或部分晶体样品的某一具有d点阵平面间距的原子面上时，就能满足布拉格方程，从而测得了这组X射线粉末衍射图。
本发明所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
本发明所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度，2θ的误差范围为±0.1～±0.5，优选±0.1～±0.3，更优选±0.2。
本发明所述的“晶面间距或晶面间距(d值)”是指空间点阵选择3个不相平行的连结相邻两个点阵点的单位矢量a，b，c，它们将点阵划分成并置的平行六面体单位，称为晶面间距。空间点阵按照确定的平行六面体单位连线划分，获得一套直线网格，称为空间格子或晶格。点阵和晶格是分别用几何的点和线反映晶体结构的周期性，不同的晶面，其面间距(即相邻的两个平行晶面之间的距离)各不相同；单位为
Figure PCTCN2017110685-appb-000004
或埃。
本发明还涉及，包括式(I)所示的化合物的I晶型，以及任选的一种或多种药用载体和/或稀释剂的药物组合物。所述药物组合物可以制成药学上可接受的任一剂型。例如，本发明的I晶型或药物制剂可以配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。
此外，本发明的所述药物组合物还可以以任何合适的给药方式，例如口服、肠胃外、直肠、经肺或局部给药等方式施用于需要这种治疗的患者或受试者。当用于口服给药时，所述药物组合物可制成口服制剂，例如口服固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；或，口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。当制成口服制剂时，所述药物制剂还可包含适宜的填充剂、粘合剂、崩解剂、润滑剂等。当用于肠胃外给药时，所述药物制剂可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。当制成注射剂时，所述药物组合物可采用现有制药领域中的常规方法来进行生产。当配制注射剂时，所述药物制剂中可以不加入附加剂，也可根据药物的性质加入适宜的附加剂。当用于直肠给药时，所 述药物制剂可制成栓剂等。用于经肺给药时，所述药物制剂可制成吸入剂或喷雾剂等。在某些优选的实施方案中，本发明的I晶型以治疗和/或预防有效量存在于药物组合物或药物中。在某些优选的实施方案中，本发明的I晶型以单位剂量的形式存在于药物组合物或药物中。
本发明式(I)化合物的I晶型可用于制备治疗和/或预防具有GnRH受体拮抗剂有关的疾病中的用途。因此，本申请还涉及，本发明式(I)化合物的I晶型用于制备药物的用途，所述药物用于治疗和/或预防受试者中由GnRH受体拮抗剂有关的疾病。此外，本申请还涉及，一种抑制由GnRH受体拮抗剂有关的疾病的方法，其包括给有此需要的受试者施用治疗和/或预防有效量的本发明式(I)化合物的I晶型，或者本发明的药物组合物。
在某些优选的实施方案中，所述疾病为由GnRH受体拮抗剂有关的疾病，选自：内分泌生殖系统疾病。
发明的有益效果
与现有技术相比，本发明的技术方案具有以下优点：
(1)本发明式(I)所示化合物的I晶型不含有或仅含有较低含量的残留溶剂，符合国家药典规定的有关医药产品残留溶剂的限量要求，因而本发明的结晶可以较好地作为医药活性成分使用。
(2)经研究表明，本发明制备的式(I)所示化合物的I晶型纯度较高，在光照、高温、高湿的条件下晶型经XRPD检测均未发生改变、晶型稳定性良好；HPLC纯度变化小、化学稳定性高；本发明技术方案得到的式(I)所示化合物的I晶型能够满足生产运输储存的药用要求，生产工艺稳定、可重复可控，能够适应于工业化生产。
附图说明
图1为式(I)所示化合物I晶型的XRPD图谱。
图2为式(I)所示化合物I晶型DSC图谱。
图3为式(I)所示化合物A晶型的XRPD图谱。
图4为式(I)所示化合物A晶型DSC图谱。
图5为式(I)所示化合物B晶型的XRPD图谱。
图6为式(I)所示化合物B晶型DSC图谱。
图7为式(I)所示化合物C晶型的XRPD图谱。
图8为式(I)所示化合物C晶型DSC图谱。
图9为式(I)所示化合物D晶型的XRPD图谱。
图10为式(I)所示化合物D晶型DSC图谱。
具体实施方式
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非限定本发明的实质和范围。
实验所用仪器的测试条件：
1、差示扫描量热仪(Differential Scanning Calorimeter,DSC)
仪器型号：Mettler Toledo DSC 1STARe System
吹扫气：氮气
升温速率：10.0℃/min
温度范围：40-300℃
2、X-射线粉末衍射谱(X-ray Powder Diffraction,XRPD)
仪器型号：Bruker D8Focus X-射线粉末衍射仪
射线：单色Cu-Kα射线(λ＝1.5406)
扫描方式：θ/2θ，扫描范围：2-40o
电压：40kV，电流：40mA
实施例1
将1-(4-(7-(2,6-二氟苄基)-3-((二甲氨基)甲基)-5-(6-甲氧基哒嗪-3-基)-4,6-二羰基-4,5,6,7-四氢-2H-吡唑并[3,4-d]嘧啶-2-基)苯基)-3-甲氧基脲(300mg，0.49mmol)(按WO2015062391A1的实施例11的方法制备)粗品加入反应瓶中，加入丙酮/水(5mL，V:V＝5:1)混合溶剂，加热至回流，固体全部溶解，停止加热，冷却析晶，抽滤，真空干燥后得到固体212mg。该结晶样品经XRPD检测衍射角2θ在5.19(17.02)，5.48(16.10)，9.08(9.73)，9.73(9.08)，10.24(8.63)，11.01(8.03)，13.80(6.41)，14.13(6.26)，14.82(5.97)，15.35(5.77)，16.56(5.35)，18.31(4.84)，18.65(4.75)，19.50(4.55)，20.18(4.40)，22.07(4.03)，23.26(3.82)，24.59(3.62)，25.61(3.48)，26.66(3.34)，28.69(3.11)，29.30(3.05)，33.96(2.64)和36.91(2.43)处有特征峰，将此晶型定义为I晶型。
实施例2
将式(I)所示化合物(300mg，0.49mmol)(按WO2015062391A1的实施例11的方法制备)粗品加入反应瓶中，加入丙酮(6mL)，室温搅拌过夜，抽滤，真空干燥得固体221mg。该结晶样品的XRPD图谱见图1，其DSC谱图见图2，DSC的熔融吸热峰值在168.17℃附近，起始熔化温度为154.23℃，其特征峰位置如下表所示：
表1、I晶型特征峰
Figure PCTCN2017110685-appb-000005
Figure PCTCN2017110685-appb-000006
实施例3
将式(I)所示化合物(500mg，0.82mmol)(按WO2015062391A1的实施例11的方法制备)粗品加入到反应瓶中，加入甲醇(50mL)，加热至回流，固体溶解后停止加热，搅拌析晶，抽滤，真空干燥得固体350mg。该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为I晶型。
实施例4
将式(I)所示化合物(500mg，0.82mmol)(按WO2015062391A1的实施例11的方法制备)粗品加入反应瓶中，加入乙醇(125mL)，加热至回流，固体溶解后停止加热，搅拌析晶，抽滤，真空干燥得固体406mg。该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为I晶型。
实施例5
将式(I)所示化合物(500mg，0.82mmol)(按WO2015062391A1的实施例11的方法制备)粗品加入反应瓶中，加入异丙醇(10mL)，室温搅拌过夜，抽滤，真空干燥得固体445mg。该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为I晶型。
实施例6
将式(I)所示化合物(500mg，0.82mmol)(按WO2015062391A1的实施例11的方法制备)粗品加入反应瓶中，加入丙酮(25mL)，加热至回流，固体溶解后停止加热，搅拌析晶，抽滤，真空干燥得固体251mg。该结晶样品的XRPD图谱和DSC图谱 经研究比对，确定产物为I晶型。
实施例7
将式(I)所示化合物(300mg，0.49mmol)(按WO2015062391A1的实施例11的方法制备)粗品加入反应瓶中，加入乙酸乙酯(9mL)，室温搅拌过夜，抽滤，真空干燥得固体224mg。该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为I晶型。
实施例8
将式(I)所示化合物(300mg，0.49mmol)(按WO2015062391A1的实施例11的方法制备)粗品加入反应瓶中，加入四氢呋喃/乙醇(8mL，V:V＝1:1)，加热至回流，固体溶解后停止加热，搅拌析晶，抽滤，真空干燥得固体197mg。该结晶样品XRPD图谱和DSC图谱经研究比对，确定产物为I晶型。
实施例9
将式(I)所示化合物(300mg，0.49mmol)(按WO2015062391A1的实施例11的方法制备)粗品加入反应瓶中，加入四氢呋喃/异丙醇(12mL，V:V＝1:1)，加热至回流，固体溶解后停止加热，搅拌析晶，抽滤，真空干燥得固体182mg。该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为I晶型。
实施例10
将式(I)所示化合物(300mg，0.49mmol)(按WO2015062391A1的实施例11的方法制备)粗品加入反应瓶中，加入甲醇(6mL)，室温搅拌过夜，抽滤，真空干燥得固体239mg。该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为I晶型。
实施例11
将式(I)所示化合物(300mg，0.49mmol)(按WO2015062391A1的实施例11的方法制备)粗品加入反应瓶中，加入乙醇(6mL)，室温搅拌过夜，抽滤，真空干燥得固体231mg。该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为I晶型。
实施例12
将1-(4-(7-(2,6-二氟苄基)-3-((二甲氨基)甲基)-5-(6-甲氧基哒嗪-3-基)-4,6-二羰基-4,5,6,7-四氢-2H-吡唑并[3,4-d]嘧啶-2-基)苯基)-3-甲氧基脲(500mg，0.82mmol)(按实施例1制备)加入反应瓶中，加入纯化水(10mL)，室温打浆5小时，抽滤，干燥得固体369mg，经XRPD和DSC检测确定该晶型为A晶型；
将所得到的A晶型加入反应瓶中，加入乙醇(4mL)，室温搅拌过夜，抽滤，真空干燥得固体89mg。该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为I晶型。
实施例13
将1-(4-(7-(2,6-二氟苄基)-3-((二甲氨基)甲基)-5-(6-甲氧基哒嗪-3-基)-4,6-二羰基-4,5,6,7-四氢-2H-吡唑并[3,4-d]嘧啶-2-基)苯基)-3-甲氧基脲(300mg，0.49mmol)(按实施例1制备)加入反应瓶中，加入乙腈(9mL)，加热至回流，固体全部溶清， 停止加热，冷却析晶，抽滤，干燥得固体243mg，经XRPD和DSC检测确定该晶型为B晶型；
将所得到的B晶型加入反应瓶中，加入乙醇(4mL)，室温搅拌过夜，抽滤，真空干燥得固体80mg。该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为I晶型。
实施例14
将1-(4-(7-(2,6-二氟苄基)-3-((二甲氨基)甲基)-5-(6-甲氧基哒嗪-3-基)-4,6-二羰基-4,5,6,7-四氢-2H-吡唑并[3,4-d]嘧啶-2-基)苯基)-3-甲氧基脲(300mg，0.49mmol)(按实施例1制备)加入反应瓶中，加入1,4-二氧六环(15mL)，加热至回流，固体全部溶清，停止加热，冷却析晶，抽滤，干燥得固体205mg，经XRPD和DSC检测确定该晶型为C晶型；
将所得到的C晶型加入反应瓶中，加入乙醇(10mL)，室温搅拌过夜，抽滤，真空干燥得固体78mg，产率为78.0％。该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为I晶型。
实施例15
将1-(4-(7-(2,6-二氟苄基)-3-((二甲氨基)甲基)-5-(6-甲氧基哒嗪-3-基)-4,6-二羰基-4,5,6,7-四氢-2H-吡唑并[3,4-d]嘧啶-2-基)苯基)-3-甲氧基脲(300mg，0.49mmol)(按实施例1制备)加入反应瓶中，加入四氢呋喃/水(15mL，V:V＝1:1)，加热至回流，固体全部溶清，停止加热，冷却析晶，抽滤，干燥得固体205mg，经XRPD和DSC检测确定该晶型为D晶型；
将所得到的D晶型加入反应瓶中，加入乙醇(10mL)，室温搅拌过夜，抽滤，真空干燥得固体78mg。该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为I晶型。
实施例16
将实施例1所得的I晶型产物样品和实施例12、13、14、15所得的A、B、C、D晶型产物样品敞口平摊放置，考察在光照(4500Lux)、加热(40℃，60℃)、高湿(RH75％，RH90％)条件下样品的稳定性，考察取样时间为5天和10天，HPLC检测纯度结果见表2。
试验结果：
表2、本发明式(I)所示化合物I晶型与A、B、C、D晶型稳定性比较
Figure PCTCN2017110685-appb-000007
Figure PCTCN2017110685-appb-000008
试验结论
由表2的稳定性考察结果显示：
在光照、高湿、高温敞口放置条件下，式(I)所示化合物I晶型的HPLC纯度数据降低幅度均小于A、B、C、D晶型，经XRPD检测晶型均未发生改变，说明本发明的I晶型稳定性显著优于A、B、C、D晶型。
实施例17
将实施例1方法所得的式(I)所示化合物I晶型样品进行研磨、加热及压片处理，样品的晶型稳定性，XRPD和DSC检测结果见表3。
试验结果：
表3、式(I)所示化合物I晶型特殊稳定性研究
Figure PCTCN2017110685-appb-000009
试验结论：
由表3的稳定性试验数据显示在研磨、加热及压片处理过程中，晶型均未发生改变，说明本发明的I晶型的稳定性高。

Claims (7)

  1. 式(I)所示化合物的I晶型，其特征在于：使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，所述I晶型在5.56、9.15、9.79、11.08、19.59、20.25和22.16处有特征峰，其中，每个特征峰2θ的误差范围为±0.2，
    Figure PCTCN2017110685-appb-100001
  2. 根据权利要求1所述的I晶型，其特征在于，所述I晶型在5.56、9.15、9.79、10.29、11.08、14.21、16.61、19.59、20.25、22.16和25.69处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。
  3. 根据权利要求2所述的I晶型，其特征在于，所述I晶型在5.22，5.56，9.15，9.79，10.29，11.08，13.38，13.81，14.21，14.89，16.61，17.19，18.47，19.59，20.25，22.16，23.32，24.67，25.69，26.72，28.73，29.38，31.78，34.02和36.95处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。
  4. 一种制备如权利要求1-3中任一项所述的式(I)所示化合物的I晶型的方法，其特征在于，所述方法包括：
    1)方法一，将式(I)所示化合物溶解于有机溶剂中，析晶，过滤结晶并洗涤，干燥后即可得到目标I晶型，所述有机溶剂选自醇类、酮类、酯类、醚类、醚类与醇类的混合溶剂或酮类与水的混合溶剂，醇类溶剂选自甲醇、乙醇或异丙醇，酮类溶剂优选丙酮，酯类溶剂优选乙酸乙酯，醚类溶剂优选四氢呋喃，醚类与醇类的混合溶剂优选四氢呋喃/乙醇或四氢呋喃/异丙醇，酮类与水的混合溶剂优选丙酮/水；
    2)方法二，将式(I)所示化合物置于溶剂中，进行打浆，过滤结晶并洗涤，干燥后得到目标晶型I，所述有机溶剂选自醇类、酮类、酯类、醚类、醚类与醇类的混合溶剂或酮类与水的混合溶剂，醇类溶剂选自甲醇、乙醇或异丙醇，酮类溶剂优选丙酮，酯类溶剂优选乙酸乙酯，醚类溶剂优选四氢呋喃，醚类与醇类的混合溶剂优选四氢呋喃/乙醇或四氢呋喃/异丙醇，酮类与水的混合溶剂优选丙酮/水。
  5. 一种如权利要求1-3中任一项所述的I晶型，其特征在于：DSC的熔融吸热峰值为160℃～175℃，优选为165℃～170℃，更优选为168.17℃。
  6. 含有权利要求1-3中任一项所述I晶型的药物组合物，其特征在于包含一种或多种药学上可接受的载体、稀释剂或赋形剂。
  7. 含有权利要求1-3任一项所述式(I)所示化合物的I晶型、权利要求6所述I晶型的药物组合物在制备治疗和/或预防与GnRH受体拮抗剂有关的疾病的药物中的用途，所述疾病选自内分泌生殖系统疾病。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022206968A1 (zh) * 2021-04-02 2022-10-06 江苏恒瑞医药股份有限公司 一种GnRH受体拮抗剂的结晶形式及其制备方法
WO2023030293A1 (zh) * 2021-08-30 2023-03-09 江苏恒瑞医药股份有限公司 一种GnRH受体拮抗剂的结晶工艺

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2020265969A1 (en) * 2019-04-30 2021-12-16 Beijing Tide Pharmaceutical Co., Ltd. Solid form of diaminopyrimidine compound or hydrate thereof, preparation method therefor, and application thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006096785A1 (en) 2005-03-07 2006-09-14 Wyeth Quinoxaline dihydrohalide dihydrates and synthetic methods therefor
WO2010026993A1 (ja) 2008-09-03 2010-03-11 武田薬品工業株式会社 製剤における吸収性改善方法および吸収性が改善された製剤
WO2011076687A1 (en) 2009-12-22 2011-06-30 Bayer Schering Pharma Aktiengesellschaft Pyridinone derivatives and pharmaceutical compositions thereof
WO2012175514A1 (en) 2011-06-21 2012-12-27 Bayer Intellectual Property Gmbh Pyridinone derivatives and pharmaceutical compositions thereof
WO2015062391A1 (zh) 2013-10-30 2015-05-07 上海恒瑞医药有限公司 吡唑并嘧啶酮类或吡咯并三嗪酮类衍生物、其制备方法及其在医药上的应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109053766B (zh) * 2012-09-28 2021-06-22 武田药品工业株式会社 噻吩并嘧啶衍生物的制备方法
CN104788435A (zh) * 2014-01-16 2015-07-22 江苏恒瑞医药股份有限公司 一种蛋白酪氨酸激酶抑制剂的二苯磺酸盐的i型结晶

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006096785A1 (en) 2005-03-07 2006-09-14 Wyeth Quinoxaline dihydrohalide dihydrates and synthetic methods therefor
WO2010026993A1 (ja) 2008-09-03 2010-03-11 武田薬品工業株式会社 製剤における吸収性改善方法および吸収性が改善された製剤
WO2011076687A1 (en) 2009-12-22 2011-06-30 Bayer Schering Pharma Aktiengesellschaft Pyridinone derivatives and pharmaceutical compositions thereof
WO2012175514A1 (en) 2011-06-21 2012-12-27 Bayer Intellectual Property Gmbh Pyridinone derivatives and pharmaceutical compositions thereof
WO2015062391A1 (zh) 2013-10-30 2015-05-07 上海恒瑞医药有限公司 吡唑并嘧啶酮类或吡咯并三嗪酮类衍生物、其制备方法及其在医药上的应用
CN104884457A (zh) * 2013-10-30 2015-09-02 上海恒瑞医药有限公司 吡唑并嘧啶酮类或吡咯并三嗪酮类衍生物、其制备方法及其在医药上的应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3539545A4

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022206968A1 (zh) * 2021-04-02 2022-10-06 江苏恒瑞医药股份有限公司 一种GnRH受体拮抗剂的结晶形式及其制备方法
WO2023030293A1 (zh) * 2021-08-30 2023-03-09 江苏恒瑞医药股份有限公司 一种GnRH受体拮抗剂的结晶工艺

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