WO2018072742A1 - 一种咪唑并异吲哚类衍生物的游离碱的结晶形式及其制备方法 - Google Patents

一种咪唑并异吲哚类衍生物的游离碱的结晶形式及其制备方法 Download PDF

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WO2018072742A1
WO2018072742A1 PCT/CN2017/107017 CN2017107017W WO2018072742A1 WO 2018072742 A1 WO2018072742 A1 WO 2018072742A1 CN 2017107017 W CN2017107017 W CN 2017107017W WO 2018072742 A1 WO2018072742 A1 WO 2018072742A1
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crystal form
cancer
compound
solvent
formula
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PCT/CN2017/107017
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French (fr)
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曹笑立
尤凌峰
肖昌琴
杜振兴
王立坤
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN201780017401.XA priority Critical patent/CN108884099B/zh
Publication of WO2018072742A1 publication Critical patent/WO2018072742A1/zh

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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

Definitions

  • the present invention relates to (S)-2-(4-(4-(4-(4-(4-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)benzene Crystalline forms of A, B, C, D, E, F of -1H-pyrazol-1-yl)ethanol, and methods for their preparation, their use in pharmaceutical compositions, and the A, B, C, D, Use of the E, F crystalline form, a pharmaceutical composition thereof, for the treatment of a disease having a pathological feature of an IDO-mediated tryptophan metabolism pathway.
  • Tumor biotherapy is a new treatment for cancer prevention and treatment using modern biotechnology and related products. Because of its safety, effectiveness, and low adverse reactions, it has become the fourth mode of tumor treatment after surgery, radiotherapy and chemotherapy.
  • the host's natural defense mechanisms such as inhibition of IDO-mediated tumor immune escape mechanisms) or the naturally occurring highly targeted substances to achieve anti-tumor effects.
  • Indoleamine-pyrrole-2,3-dioxygenase is a heme-containing monomeric protein consisting of 403 amino acid residues, including two folds.
  • the alpha-helical domain, the large domain contains a catalytic pocket, and the substrate can be hydrophobic with the IDO in the catalytic pocket.
  • IDO is an enzyme that catalyzes the conversion of tryptophan to formyl kynurenine. It is widely distributed in tissues other than the liver of humans and other mammals (rabbits, mice) and is the only restriction outside the liver that catalyzes the catabolism of tryptophan.
  • Fast enzyme which is an essential amino acid for cells to maintain activation and proliferation, is also an indispensable component of protein.
  • IDO interferon
  • IL interleukin
  • tumor necrosis factor tumor necrosis factor
  • IDO interferon
  • IL interleukin
  • tumor necrosis factor tumor necrosis factor
  • other cytokines they can activate IDO under certain conditions.
  • IDO In the cell cycle of T-cells, there is a regulation point that is very sensitive to tryptophan levels.
  • IDO depletes local tryptophan, causing T-cells to arrest in the middle of G1 phase, thereby inhibiting the proliferation of T cells;
  • IDO catalyzes the main product produced by the metabolism of tryptophan.
  • Canine urea is induced by oxygen free radicals to induce changes in intracellular oxidants and antioxidants to induce T-cell apoptosis, which is an intrinsic immunosuppressive mechanism present in the body.
  • IDO is highly expressed in leukemia cells, which inhibits the proliferation of local T cells, inhibits T-cell-mediated immune responses, and blocks T-cell activation signal transduction, thereby mediating tumor cell escape from the immune system. attack.
  • Most human tumors have been found to constitutively express IDO. Therefore, IDO is a potential target for cancer immunotherapy.
  • Inhibitors of the disclosed selective inhibitors of IDO include WO2012142237, WO2004094409, WO2006122150, WO2007075598, WO2010005958 and WO2014066834, and the like.
  • the IDO inhibitor has a good application prospect as a drug in the pharmaceutical industry.
  • the applicant has provided a novel high-efficiency and low-toxic selective IDO in the patent application PCT/CN2016/079054 (WO2016169421A1, publication date 2016-10-27).
  • the inhibitor compound has excellent effects and effects, especially excellent pharmacogen absorption activity, and its chemical name is (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5] , 1-a]isoindole-5-yl)piperidine -1-yl)phenyl)-1H-pyrazol-1-yl)ethanol, the structure is as follows
  • 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, fine crystallization, difficult filtration, easy agglomeration, poor fluidity, etc. These differences often lead to production. Difficulties in zooming in.
  • the stability of existing crystal forms needs to be improved. Therefore, it is necessary to improve the various properties 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 free base of the imidazoisoindole derivative (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5,1] a, B, C, D, E, F crystal forms of -a]isoindole-5-yl)piperidin-1-yl)phenyl)-1H-pyrazol-1-yl)ethanol
  • Good crystal form stability and chemical 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 A 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 at 6.3, 7.7, 9.0, 10.4, 11.0, 12.2, 14.8, 15.2, 16.3, 16.7, 17.3, 17.9, 18.4, 19.5, 19.7, 20.9, 21.2, 21.5, 21.7, 22.1, 24.3, 25.6 and 28.9 have characteristic peaks, the error range of 2 ⁇ Is ⁇ 0.2,
  • the present invention provides a crystalline form A of the compound of the formula (I), characterized in that the crystalline form A is at 6.3, 7.4, 8.99, 10.4, 11.0, 12.2, 14.8, 15.2, 16.3, 16.7, 17.3, 17.9, 18.1, 19.2, 19.7, 20.1, 20.9, 21.2, 21.5, 21.7, 22.1, 22.8, 24.3, 24.6, 25.6, 26.4, 27.3, 28.9, 30.1, 31.5, 32.2, There are characteristic peaks at 32.5, 34.6, 36.1, 37.3, and 39.0, and the error range of the 2 ⁇ is ⁇ 0.2.
  • the present invention provides a method for preparing a crystalline form of Compound A represented by Formula (I), which comprises:
  • the compound of the formula (I) is added to an organic solvent, beaten, filtered and washed, and after drying, the target A crystal form is obtained, the organic solvent is selected from an alcohol solvent, preferably methanol; the beating temperature is selected from 30 ° C.
  • the solvent boiling point temperature is preferably 50 °C.
  • the present invention provides a crystalline form B of a compound of the formula (I), characterized in that an X-ray powder represented by a diffraction angle 2 ⁇ angle is obtained using Cu-K ⁇ radiation. Diffraction pattern having characteristics at 6.2, 7.6, 8.7, 10.0 11.1, 12.1, 14.6, 16.0, 16.5, 17.9, 18.2, 19.2, 19.9, 21.121.5, 22.3, 24.3, 25.3, 26.4, 27.3, 28.9 and 31.7 Peak, the 2 ⁇ error range is ⁇ 0.2,
  • the invention provides a crystalline form B of a compound of formula (I), characterized in that said crystalline form B is at 6.2, 6.7, 7.6, 8.7, 10., 11.1 There are characteristic peaks at 12.1, 14.6, 16.0, 16.5, 17.9, 18.2, 19.2, 19.9, 21.1, 21.5, 22.3, 24.3, 25.3, 26.4, 27.3, 28.9 and 31.7, and the error range of the 2 ⁇ is ⁇ 0.2.
  • the present invention provides a method for preparing a crystalline form of Compound B represented by Formula (I), which comprises:
  • Method 1 the compound of the formula (I) is dissolved in a solvent, crystallized, filtered, and dried to obtain a target B crystal form,
  • the solvent is selected from a halogenated hydrocarbon solvent, preferably dichloromethane;
  • the compound represented by the formula (I) is added to an organic solvent, beaten, filtered and washed, and after drying, the target B crystal form is obtained, and the organic solvent is selected from the group consisting of:
  • a mixed solvent of a nitrile, an ester, a halogenated hydrocarbon, an ether, an alcohol, a nitroalkane, an alcohol and a water the nitrile solvent being selected from the group consisting of acetonitrile, and the ester solvent is selected from the group consisting of ethyl acetate.
  • the halogenated hydrocarbon solvent is selected from the group consisting of dichloromethane, the ether solvent is selected from tetrahydrofuran, the alcohol solvent is selected from n-propanol, and the nitroalkane solvent is selected from the group consisting of nitromethane, the alcohol
  • the mixed solvent with water is selected from a mixed solvent of isopropyl alcohol and water, preferably 5% water - 95% isopropanol; the beating temperature is selected from room temperature to solvent boiling point temperature, preferably 50 ° C, and the room temperature is preferably 15-25 °C, more preferably 25 °C.
  • the present invention provides a crystalline form C of a compound of the formula (I), characterized in that an X-ray powder represented by a diffraction angle 2 ⁇ angle is obtained using Cu-K ⁇ radiation. Diffraction pattern at 6.0, 6.3, 7.6, 8.4, 8.7, 9.0, 10.1, 10.7, 12.1, 12.5, 15.2, 16.3, 17.9, 18.4, 18.8, 19.4, 19.9, 20.5, 21.3, 22.1, 22.6, 23.4, 24.2 There are characteristic peaks at 25.6, 26.4, 27.3 and 28.3, and the error range of the 2 ⁇ is ⁇ 0.2.
  • the invention provides a crystalline form C of a compound of formula (I), characterized in that said C crystal form is at 4.1, 6.0, 6.3, 6.5, 7.6, 8.4, 8.7), 9.0, 10.1, 10.7, 12.1, 12.5, 14.2, 15.2, 16.3, 17.9, 18.4, 18.8, 19.4, 19.9, 20.5, 21.3, 22.1, 22.6, 23.4, 24.2, 25.6, 26.4, 27.0, 27.3, 28.3 There are characteristic peaks at 28.8, 30.0 and 31.6, and the error range of the 2 ⁇ is ⁇ 0.2.
  • the present invention provides a method for preparing a crystalline form of Compound C represented by Formula (I), which comprises:
  • the compound of the formula (I) is added to an organic solvent, beaten, filtered and washed, and after drying, the target C crystal form is obtained, the organic solvent is a ketone solvent, and the ketone solvent is selected from acetone;
  • the beating temperature is selected from room temperature to solvent boiling point temperature, preferably 50 ° C, and the room temperature is preferably 15-25 ° C, more preferably 25 ° C.
  • the present invention provides a crystalline form of D of the compound of the formula (I), characterized in that an X-ray powder represented by a diffraction angle 2 ⁇ angle is obtained using Cu-K ⁇ radiation. a diffraction pattern having characteristic peaks at 15.1, 16.6, 17.6, 18.2, 19.5, 20.1, 20.4, 21.6, 21.9, 22.1, 24.6, 26.7, 27.6, and 29.2, the error range of the 2 ⁇ being ⁇ 0.2,
  • the invention provides a crystalline form of the compound of formula (I), wherein the crystalline form of D is at 15.1, 16.6, 17.6, 18.2, 19.5, 20.1, There are characteristic peaks at 20.4, 21.6, 21.9, 22.1, 24.6, 26.7, 27.6, 29.2, 30.4 and 31.9, and the error range of the 2 ⁇ is ⁇ 0.2.
  • the present invention provides a method for preparing a crystalline form of Compound D represented by Formula (I), which comprises:
  • the compound of the formula (I) is added to an organic solvent, beaten, filtered and washed, and dried to obtain a crystalline form of the target D, the organic solvent being selected from an aromatic hydrocarbon solvent, preferably cumene or two. Toluene; the beating temperature is selected from the range of 30 ° C to the boiling point of the solvent, preferably 50 ° C.
  • the present invention provides an E crystal form of the compound of the formula (I), characterized in that X-ray powder represented by a diffraction angle 2 ⁇ angle is obtained using Cu-K ⁇ radiation. a diffraction pattern having characteristic peaks at 18.2, 18.7, 19.2, 20.1, 21.7, 22.8, 24.6, 26.7, 27.7, and 29.2, the error range of the 2 ⁇ being ⁇ 0.2,
  • the present invention provides a process for the preparation of the crystalline form of the compound E represented by the formula (I), which comprises:
  • the compound of the formula (I) is added to an organic solvent, beaten, filtered and washed, and after drying, the target crystal form E is obtained, and the organic solvent is selected from an alcohol solvent, preferably ethanol; From 30 ° C to the boiling point of the solvent, preferably 50 ° C.
  • the present invention provides an F crystal form of a compound of the formula (I), characterized in that an X-ray powder represented by a diffraction angle 2 ⁇ angle is obtained using Cu-K ⁇ radiation. a diffraction pattern having characteristic peaks at 18.7, 19.5, 20.2, 21.5, 22.0, 22.6, 24.4, 25.6, 26.6, 27.6, 29.2, and 32.0, the error range of the 2 ⁇ being ⁇ 0.2,
  • the present invention provides a process for the preparation of the crystalline form of the compound F represented by the formula (I), which comprises:
  • the compound of the formula (I) is added to an organic solvent, beaten, filtered and washed, and dried to obtain a target F crystal form, the organic solvent being selected from an alcohol solvent, preferably 2-propanol;
  • the temperature is selected from the range of 30 ° C to the boiling point of the solvent, preferably 50 ° C.
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a crystal form of the compound represented by the formula (I), a B crystal form, a C crystal form, a D crystal form, an E crystal form, an F crystal form, and a pharmaceutically acceptable form.
  • the present invention further relates to a pharmaceutical composition of Form A, Form B, Form C, Form D, Form E and Form F of the compound of Formula (I), characterized in that the pharmaceutical composition is further Including one or more second therapeutically active agents selected from the group consisting of anti-inflammatory agents, matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, antibiotics A cancer agent, an antiviral agent, a growth factor modulator, an immunomodulator or an anti-vascular hyperproliferative compound.
  • second therapeutically active agents selected from the group consisting of anti-inflammatory agents, matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, antibiotics A cancer agent, an antiviral agent, a growth factor modulator, an immunomodulator or an anti-vascular hyperproliferative compound.
  • the present invention further relates to a process for the preparation of the above pharmaceutical composition, which comprises the A crystal form, the B crystal form, the C crystal form, the D crystal form, and the E crystal form of the compound represented by the formula (I). And a step of mixing the Form C with a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention further relates to the A crystal form, the B crystal form, the C crystal form, the D crystal form, the E crystal form, the F crystal form or the A, B, C, D, E, F crystal forms of the compound of the formula (I).
  • a pharmaceutical composition for the treatment of a disease having a pathological feature of an IDO-mediated tryptophan metabolism pathway selected from the group consisting of cancer, Alzheimer's disease, autoimmune disease, depression, anxiety, cataract , psychological disorders and AIDS the cancer is selected from breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer , bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck cancer, leukemia, lymphoma , myeloma
  • a of the compound of the formula (I) obtained by X-ray powder diffraction pattern (XRPD), differential scanning calorimetry (DSC), thermogravimetric analyzer (TGA) or dynamic water adsorption meter (DVS), Structural determination, crystal form studies, etc. of B, C, D, E, and F crystal forms.
  • the method for crystallization of the present invention comprises room temperature crystallization, cooling crystallization, crystallization of a volatile solvent, seed crystal induced crystallization, etc., and the cooling temperature is selected from the group consisting of 40 ° C or lower, preferably -10 ° C to 40 ° C. It can also be stirred during the crystallization process.
  • 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.
  • halogenated as used in the present invention means substituted by "halogen atom", and "halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like.
  • hydroxy group, cyano group, nitro group, etc. as used in the present invention means a group such as -OH, -CN, -NO 2 or the like.
  • 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.
  • 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, acetic acid Isopropyl ester 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, n-propanol or 2-propanol.
  • aromatic hydrocarbon solvent refers to a conjugated system having a closed ring in a molecule, and a general term for a carbon ring compound and a derivative thereof having a ⁇ electron number in accordance with the Huckel rule, and specific examples include but are not limited to: Propyl benzene or xylene.
  • halogenated hydrocarbon solvent as used in the present invention means a group derived by substituting one or more "halogen atoms” for one or more hydrogen atoms on a "C 1-6 alkyl group", said "halogen atom” And “C 1-6 alkyl” are as defined above, and specific examples include, but are not limited to, methyl chloride, dichloromethane, chloroform or carbon tetrachloride.
  • nitrile solvent as used in the present invention means a group derived from one or more hydrogen atoms on one or more "cyano" substituted “C 1-6 alkyl", said “cyano” and “C 1-6 alkyl” is as defined above, and specific examples include, but are not limited to, acetonitrile or propionitrile.
  • the “nitroalkane solvent” as used in the present invention means a group derived from one or more hydrogen atoms of one or more "nitro” substituted “C 1-6 alkyl", said "nitro group” And “C 1-6 alkyl” are as defined above, and specific examples include, but are not limited to, nitromethane.
  • the “mixed solvent” as used in the present invention means a solvent obtained by mixing one or more different kinds of organic solvents in a certain ratio, or a solvent obtained by mixing an organic solvent and water in a certain ratio, and the certain ratio is 0.05. 1 to 1:0.05, preferably 19:1; the mixed solvent is preferably a mixed solvent of an alcohol solvent and water; the mixed solvent of the alcohol solvent and water is preferably a mixed solvent of isopropyl alcohol and water.
  • the alcohol solvent is as defined above.
  • 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, and ⁇ is a Bragg angle in units of ° or degree.
  • 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 to obtain a set of linear grids called spatial lattices or lattices.
  • 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 of A, B, C, D, E, F 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 A, B, C, D, E, F crystal form or pharmaceutical preparation of the present invention can be formulated into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections) , sterile powder for injection and concentrated solution for injection), 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, can be formulated into a suppository or the like.
  • the pharmaceutical preparation For pulmonary administration, the pharmaceutical preparation can be formulated as an inhalant or a spray.
  • the crystalline forms A, B, C, D, E, F of the invention are present in a pharmaceutical composition or medicament in a therapeutically and/or prophylactically effective amount. In certain preferred embodiments, the crystalline forms A, B, C, D, E, F of the invention are present in a pharmaceutical composition or medicament in unit dosage form.
  • the crystalline forms A, B, C, D, E, F of the compounds of formula (I) of the invention may be administered alone or in combination with one or more second therapeutic agents.
  • the pharmaceutical composition further comprises one or more second therapeutic agents.
  • the second therapeutic agent is selected from the group consisting of an anti-inflammatory agent, a matrix metalloproteinase inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressive agent, an anticancer agent, and an anti-disease A toxicant, a growth factor modulator, an immunomodulator or an anti-vascular hyperproliferative compound.
  • the components to be combined may be administered simultaneously or sequentially.
  • the second therapeutic agent can be administered prior to, concurrently with, or after administration of the A, B, C, D, E, F crystalline forms of the invention or stereoisomers thereof.
  • the ingredients to be combined may also be administered in combination in the form of the same formulation or in separate separate formulations.
  • the crystalline forms A, B, C, D, E, F of the compounds of formula (I) of the invention are useful in the preparation of a medicament for the treatment and/or prevention of IDO-mediated tryptophan metabolism. Accordingly, the present application also relates to the use of the crystalline forms A, B, C, D, E, F of the compounds of formula (I) of the invention for the preparation of a medicament for use in the treatment and/or prevention of a subject IDO-mediated diseases associated with tryptophan metabolism.
  • the present application relates to a method of inhibiting a disease associated with tryptophan metabolism mediated by IDO, comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of the formula (I) of the present invention A crystalline form of the compound A, B, C, D, E, F, or a pharmaceutical composition of the invention.
  • the disease is a disease associated with tryptophan metabolism mediated by IDO, selected from the group consisting of: cancer, Alzheimer's disease, autoimmune disease, depression, anxiety, cataract, Psychological disorder or AIDS;
  • the cancer is selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, Bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck cancer, leukemia, lymphoma, Myeloma or non-small cell lung cancer.
  • the crystalline form of the compound A, B, C, D, E, F of the formula (I) of the present invention does not contain or contains only a low content of residual solvent, and meets the limits of the residual solvent of the pharmaceutical product according to the national pharmacopoeia. It is required that the crystal of the present invention can be preferably used as a pharmaceutically active ingredient.
  • the crystals of A, B, C, D, E, and F of the compound of formula (I) of the present invention have high purity, and the crystal forms are not changed under the conditions of illumination, high temperature and high humidity.
  • the crystal form has good stability; the HPLC purity change is small, and the chemical stability is high; the compound A, B, C, D, E, F crystal form of the formula (I) obtained by the technical scheme of the invention can satisfy the production and transportation of the medicine.
  • the production process is stable, repeatable and controllable, and can be adapted to industrial production.
  • Figure 1 is an XRPD pattern of the crystalline form of Compound A shown in Formula (I);
  • Figure 2 is an XRPD pattern of the crystalline form of Compound B of Formula (I);
  • Figure 3 is an XRPD pattern of the crystalline form of Compound C of Formula (I);
  • Figure 4 is an XRPD pattern of the crystalline form of Compound D of formula (I);
  • Figure 5 is an XRPD pattern of the crystal form of Compound E shown in Formula (I);
  • Figure 6 is an XRPD pattern of the crystalline form of Compound F of Formula (I);
  • Figure 7 is a DSC pattern of the crystalline form of Compound A shown in Formula (I);
  • Figure 8 is a DSC spectrum of the compound B crystal form of the formula (I);
  • Figure 9 is a DSC pattern of the crystalline form of Compound C of formula (I);
  • Figure 10 is a DSC spectrum of the compound D crystal form of the formula (I);
  • Figure 11 is a DSC chart of the crystalline form of Compound E of formula (I);
  • Figure 12 is a DSC pattern of the crystalline form of Compound F of formula (I);
  • Figure 13 is a first cycle diagram of DVS of the compound B crystal form of the formula (I);
  • Figure 14 is a second cycle diagram of DVS of the compound B crystal form of the formula (I);
  • Figure 15 is an XRPD pattern of Form B of Day 0;
  • Figure 16 is an XRPD pattern of the B crystal form after being placed at 40 ° C and a relative humidity of RH 75% for 15 days;
  • Figure 17 is an XRPD pattern of Form C of Day 0;
  • Fig. 18 is an XRPD pattern of the C crystal form after being allowed to stand at 40 ° C and a relative humidity of RH 75% for 15 days.
  • Lithium diisopropylamide (32.5 mL, 65.0 mmol) was added to tetrahydrofuran (50 mL), and pre-prepared 1-bromo-3-fluorobenzene 1a (8.75 g, 50.0 mmol, 25 mL) in tetrahydrofuran was added dropwise at -78 °C. Stir at -78 ° C for 1 hour. Further, a pre-formed solution of tert-butyl 4-formylpiperidine-1-carboxylate 1b (8.75 g, 50.0 mmol, 25 mL) in THF was added dropwise at -78 ° C, and stirred at -78 ° C for one hour. After completion of the reaction, the reaction was quenched with EtOAc (EtOAc) (EtOAc) 1c (16.3 g, yellow syrup solid, yield 84.0%).
  • EtOAc EtOAc
  • the imidazole (12.5 g, 184.3 mmol) was dissolved in N,N-dimethylformamide (50 mL), sodium hydride (7.40 g, 184.3 mmol) was added portionwise, and the mixture was stirred at room temperature for 1 hour, and the pre-formed compound 1d was added dropwise. (10.0 g, 18.43 mmol, 20 mL) of N,N-dimethylformamide was stirred at 100 ° C for 12 hours.
  • Tris(dibenzylideneacetone)dipalladium (2.92 g, 3.19 mmol) was added, and the reaction mixture was heated to 110 ° C, and the reaction was stirred for 2 hours. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was evaporated to dryness crystals crystals. 6.38 g, gray oil, yield: 29%).
  • the compound 40b (9 g, 17.1 mmol) was dissolved in methanol (100 mL), and concentrated hydrochloric acid (12M, 5.7 mL) was added, and the reaction mixture was warmed to 45 ° C, and the reaction was stirred for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, and then the mixture was stirred and evaporated, and the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with eluent system (dichloromethane and methanol) Compound 40c (5.2 g, yellow solid, yield: 65%).
  • the B crystal form sample obtained in an ethyl acetate solvent at 50 ° C was subjected to XRPD to detect diffraction angles 2 ⁇ at 6.27, 7.61, 8.67, 9.88, 10.20, 11.01, 11.40, 11.93, 12.44, 14.49, 15.40, 16.31, 16.88, 17.61, There are characteristic peaks at 18.35, 18.78, 19.19, 19.71, 20.77, 21.40, 22.38, 24.26, 25.39, 26.09, 27.36, 28.84 and 31.73.
  • the B crystal form sample obtained in a tetrahydrofuran solvent at 50 ° C was subjected to XRPD to detect diffraction angles 2 ⁇ at 6.27, 7.62, 8.68, 9.88, 10.18, 11.18, 11.95, 12.15, 14.46, 15.16, 16.34, 17.58, 18.33, 18.75, 19.13, There are characteristic peaks at 19.83, 20.78, 21.42, 22.33, 24.25, 25.14, 26.51, 27.38, 28.86 and 31.66.
  • the crystal sample was subjected to XRPD to detect diffraction angles 2 ⁇ at 6.27, 7.60, 8.67, 9.88, 10.20, 11.01, 11.40, 11.92, 12.45, 14.49, 15.40, 16.31, 16.88, 17.61, 18.35, 18.78, 19.19, 19.71, 20.77, 21.40, There are characteristic peaks at 22.38, 25.40, 26.10, 27.38, 28.85 and 31.72, and the product is determined to be Form B.
  • the C crystal form sample obtained in an acetone solvent at 25 ° C was subjected to XRPD to detect diffraction angles 2 ⁇ at 5.99, 6.24, 7.53, 8.30, 8.95, 9.94, 10.64, 12.00, 12.42, 15.92, 16.56, 17.81, 18.17, 18.71, 19.30, There are characteristic peaks at 19.76, 20.48, 21.26, 21.54, 22.04, 22.47, 24.17, 25.00, 26.29, 26.61, 27.32, 28.74 and 31.47.
  • the B crystal form and the C crystal form sample were placed in an open position, and the stability of the sample under the condition of 40 ° C and relative humidity RH 75% was examined, and the sampling time was 15 days.
  • Figure 15 of the accompanying drawings is an XRPD pattern of Form B of 0 crystal
  • Figure 16 is an XRPD pattern of the B crystal form after being placed at 40 ° C and a relative humidity of 75% for 15 days;
  • Figure 17 of the accompanying drawings is an XRPD pattern of a C crystal form for 0 days;
  • FIG. 18 is an XRPD pattern of the C crystal form after being placed at 40 ° C and a relative humidity of 75% for 15 days.

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Abstract

本发明涉及一种咪唑并异吲哚类衍生物的游离碱的结晶形式及其制备方法。具体而言，本发明涉及式(I)所示化合物的A,B,C,D,E,F晶型，化学名称为(S)-2-(4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-1H-吡唑-1-基)乙醇。本发明还涉及用于制备A,B,C,D,E,F晶型的制备方法，其在药物组合物的应用以及A,B,C,D,E,F晶型和药物组合物在制备治疗具有IDO介导的色氨酸代谢途径病理学特征的疾病中的用途，本发明所得到式(I)化合物的A,B,C,D,E,F晶型具备良好的稳定性，并且所用结晶溶剂低毒低残留，可更好地用于临床治疗。

Description

一种咪唑并异吲哚类衍生物的游离碱的结晶形式及其制备方法 技术领域
本发明涉及(S)-2-(4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-1H-吡唑-1-基)乙醇的A,B,C,D,E,F晶型及其制备方法，其在药物组合物的应用，以及该A,B,C,D,E,F晶型、其药物组合物在制备治疗具有IDO介导的色氨酸代谢途径病理学特征的疾病中的用途。
背景技术
肿瘤生物治疗是应用现代生物技术及其相关产品进行肿瘤防治的新疗法，因其安全、有效、不良反应低等特点，成为继手术、放疗、化疗之后肿瘤治疗的第四种模式，其通过调动宿主的天然防御机制(比如抑制IDO介导的肿瘤免疫逃逸机制)或给予天然产生的靶向性很强的物质来获得抗肿瘤的效应。
吲哚胺-吡咯-2,3-双加氧酶(Indoleamine-pyrrole-2,3-dioxygenase，IDO)是一种含铁血红素单体蛋白，由403个氨基酸残基组成，包括两个折叠的α-螺旋结构域，大结构域包含催化口袋，底物可在催化口袋内与IDO发生疏水等作用。IDO是催化色氨酸转化为甲酰犬尿氨酸的酶，广泛分布在人和其他哺乳动物(兔、鼠)除肝脏以外的组织中，是肝脏以外唯一可催化色氨酸分解代谢的限速酶，而色氨酸是细胞维持活化和增殖所必需的氨基酸，也是构成蛋白质不可缺少的重要成分。IDO与干扰素(interferon，IFN)、白细胞介素(interleukin，IL)、肿瘤坏死因子等多种细胞因子关系密切，它们在一定条件下可激活IDO。而T-细胞的细胞周期中存在一个对色氨酸水平非常敏感的调节点，一方面，IDO使局部色氨酸耗竭，致使T-细胞停滞于G1期中期，从而抑制了T细胞的增殖；另一方面，IDO催化色氨酸代谢产生的主要产物犬尿素由氧自由基介导引起细胞内氧化剂和抗氧化剂改变而诱导T-细胞凋亡，这是存在于机体的固有的免疫抑制机制。目前大量研究表明IDO在白血病细胞中较高表达，使局部T细胞增殖受抑，抑制T-细胞介导的免疫反应，使T-细胞活化信号转导受阻，从而介导肿瘤细胞逃逸免疫系统的攻击。已经发现大多数人类肿瘤组成性地表达IDO。因此，IDO是一个具潜力的癌症免疫治疗的靶标。
公开的选择性抑制IDO的抑制剂专利申请包括WO2012142237、WO2004094409、WO2006122150、WO2007075598、WO2010005958和WO2014066834等。
IDO抑制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PCT/CN2016/079054(WO2016169421A1，公开日2016-10-27)提供了一种结构新型的高效低毒的选择性IDO抑制剂化合物，具有优异的效果和作用，特别是优异的药代吸收活性，其化学名为(S)-2-(4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶 -1-基)苯基)-1H-吡唑-1-基)乙醇，结构如下所示
Figure PCTCN2017107017-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型结构，往往具有其它缺陷，比如产物稳定性较差，析晶较细，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。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的新晶型。
发明内容
本发明要解决的技术问题是提供一种咪唑并异吲哚类衍生物的游离碱(S)-2-(4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-1H-吡唑-1-基)乙醇的A,B,C,D,E,F晶型，该结晶具备良好的晶型稳定性和化学稳定性，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A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，其在6.3,7.7,9.0,10.4,11.0,12.2,14.8,15.2,16.3,16.7,17.3,17.9,18.4,19.5,19.7,20.9,21.2,21.5,21.7,22.1,24.3,25.6和28.9处有特征峰，所述2θ的误差范围为±0.2，
Figure PCTCN2017107017-appb-000002
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A晶型，其特征在于：所述A晶型在6.3,7.4,8.99,10.4,11.0,12.2,14.8,15.2,16.3,16.7,17.3,17.9,18.1,19.2,19.7,20.1,20.9,21.2,21.5,21.7,22.1,22.8,24.3,24.6,25.6,26.4,27.3,28.9,30.1,31.5,32.2,32.5,34.6,36.1,37.3和39.0处有特征峰，所述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A晶型的制备方法，其包括：
将式(I)所示化合物加入有机溶剂中，进行打浆，过滤结晶并洗涤，干燥后即可得到目标A晶型，所述有机溶剂选自醇类溶剂，优选甲醇；打浆温度选自30℃～溶剂沸点温度，优选50℃。
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B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，其在6.2,7.6,8.7,10.0 11.1,12.1,14.6,16.0,16.5,17.9,18.2,19.2,19.9,21.121.5,22.3,24.3,25.3,26.4,27.3,28.9和31.7处有特征峰，所述2θ的误差范围为±0.2，
Figure PCTCN2017107017-appb-000003
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B晶型，其特征在于：所述B晶型在6.2,6.7,7.6,8.7,10.,11.1,12.1,14.6,16.0,16.5,17.9,18.2,19.2,19.9,21.1,21.5,22.3,24.3,25.3,26.4,27.3,28.9和31.7处有特征峰，所述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B晶型的制备方法，其包括：
方法一，将式(I)所示化合物溶解于溶剂中，析晶，过滤、干燥后即可得到目标B晶型，所述溶剂选自卤代烃类溶剂，优选二氯甲烷；
方法二，将式(I)所示化合物加入有机溶剂中，进行打浆，过滤结晶并洗涤，干燥后即可得到目标B晶型，所述有机溶剂选自：
腈类、酯类、卤代烃类、醚类、醇类、硝基烷烃类、醇类与水的混合溶剂，所述腈类溶剂选自乙腈，所述酯类溶剂选自乙酸乙酯，所述卤代烃类溶剂选自二氯甲烷，所述醚类溶剂选自四氢呋喃，所述醇类溶剂选自正丙醇，所述硝基烷烃类溶剂选自硝基甲烷，所述醇类与水的混合溶剂选自异丙醇与水的混合溶剂，优选5％水-95％异丙醇；所述打浆温度选自室温～溶剂沸点温度，优选50℃，所述室温优选15-25℃，更优选25℃。
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C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，其在6.0,6.3,7.6,8.4,8.7,9.0,10.1,10.7,12.1,12.5,15.2,16.3,17.9,18.4,18.8,19.4,19.9,20.5,21.3,22.1,22.6,23.4,24.2,25.6,26.4,27.3和28.3处有特征峰，所述2θ的误差范围为±0.2，
Figure PCTCN2017107017-appb-000004
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C晶型，其特征在于：所述C晶型在4.1,6.0,6.3,6.5,7.6,8.4,8.7),9.0,10.1,10.7,12.1,12.5,14.2,15.2,16.3,17.9,18.4,18.8,19.4,19.9,20.5,21.3,22.1,22.6,23.4,24.2,25.6,26.4,27.0,27.3,28.3,28.8,30.0和31.6处有特征峰，所述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C晶型的制备方法，其包括：
将式(I)所示化合物加入有机溶剂中，进行打浆，过滤结晶并洗涤，干燥后即可得到目标C晶型，所述有机溶剂为酮类溶剂，所述酮类溶剂选自丙酮；所述打浆温度选自室温～溶剂沸点温度，优选50℃，所述室温优选15-25℃，更优选25℃。
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D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，其在15.1,16.6,17.6,18.2,19.5,20.1,20.4,21.6,21.9,22.1,24.6,26.7,27.6和29.2处有特征峰，所述2θ的误差范围为±0.2，
Figure PCTCN2017107017-appb-000005
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D晶型，其特征在于：所述D晶型在15.1,16.6,17.6,18.2,19.5,20.1,20.4,21.6,21.9,22.1,24.6,26.7,27.6,29.2,30.4和31.9处有特征峰，所述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D晶型的制备方法，其包括：
将式(I)所示化合物置加入有机溶剂中，进行打浆，过滤结晶并洗涤，干燥后即可得到目标D晶型，所述有机溶剂选自芳香烃类溶剂，优选异丙基苯或二甲苯；所述打浆温度选自30℃～溶剂沸点温度，优选50℃。
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E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，其在18.2,18.7,19.2,20.1,21.7,22.8,24.6,26.7,27.7和29.2处有特征峰，所述2θ的误差范围为±0.2，
Figure PCTCN2017107017-appb-000006
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E晶型的制备方法，其包括：
将式(I)所示化合物加入有机溶剂中，进行打浆，过滤结晶并洗涤，干燥后即可得到目标的E晶型，所述有机溶剂选自醇类溶剂，优选乙醇；所述打浆温度选自30℃～溶剂沸点温度，优选50℃。
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F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，其在18.7,19.5,20.2,21.5,22.0,22.6,24.4,25.6,26.6,27.6,29.2和32.0处有特征峰，所述2θ的误差范围为±0.2，
Figure PCTCN2017107017-appb-000007
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F晶型的制备方法，其包括：
将式(I)所示化合物加入有机溶剂中，进行打浆，过滤结晶并洗涤，干燥后即可得到目标F晶型，所述有机溶剂选自醇类溶剂，优选2-丙醇；所述打浆温度选自30℃～溶剂沸点温度，优选50℃。
本发明进一步涉及一种药物组合物，所述药物组合物由式(I)所示化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型与药学上可接受的载体、稀释剂或赋形剂组成。
本发明进一步涉及式(I)所示化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型的药物组合物，其特征在于，所述药物组合物还包含一种或多种第二治疗活性剂，所述的第二治疗活性剂选自：抗炎剂、基质金属蛋白酶抑制剂、脂氧合酶抑制剂、细胞因子拮抗剂、免疫抑制剂、抗癌剂、抗病毒剂、生长因子调节剂、免疫调节剂或抗血管过度增殖化合物。
本发明进一步涉及一种制备上述药物组合物的方法，其特征在于，所述方法包括由式(I)所示化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型与药学上可接受的载体、稀释剂或赋形剂混合的步骤。
本发明进一步涉及式(I)所示化合物的A晶型、B晶型、C晶型、D晶型、E晶型、F晶型或A,B,C,D,E,F晶型的药物组合物在制备治疗具有IDO介导的色氨酸代谢途径病理学特征的疾病中的用途，所述疾病选自癌症、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍和艾滋病，所述癌症选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤或非小细胞肺癌。
通过X-射线粉末衍射图谱(XRPD)、差示扫描量热分析(DSC)、热重分析仪(TGA)或动态水吸附仪(DVS)等对所得到式(I)所示化合物的A,B,C,D,E,F晶型进行结构测定、晶型研究等。
本发明析晶的方法有室温析晶、冷却析晶、挥发溶剂析晶、加入晶种诱导析晶等，所述冷却的温度选自40℃以下，优选-10℃至40℃，所述析晶过程中还可以搅拌。
发明详述
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。
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“卤代”是指被“卤素原子”取代，“卤素原子”是指氟原子、氯原子、溴原子、碘原子等。
本发明所述“羟基、氰基、硝基等”是指-OH、-CN、-NO2等基团。
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、正丙醇或2-丙醇。
本发明所述的“芳香烃类溶剂”是指分子中具有闭合环状的共轭体系，п电子数符合休克尔规则的碳环化合物及其衍生物的总称，具体实例包括但不限于：异丙基苯或二甲苯。
本发明所述的“卤代烃类溶剂”是指一个或多个“卤素原子”取代“C1-6烷基”上的一个或多个氢原子所衍生的基团，所述“卤素原子”和“C1-6烷基”如前文所定义，具体实例包括但不限于：氯甲烷、二氯甲烷、氯仿或四氯化碳。
本发明所述的“腈类溶剂”是指一个或多个“氰基”取代“C1-6烷基”上的一个或多个氢原子所衍生的基团，所述“氰基”和“C1-6烷基”如前文所定义，具体实例包括但不限于：乙腈或丙腈。
本发明所述的“硝基烷烃类溶剂”是指一个或多个“硝基”取代“C1-6烷基”上的一个或多个氢原子所衍生的基团，所述“硝基”和“C1-6烷基”如前文所定义，具体实例包括但不限于：硝基甲烷。
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，所述一定比例为0.05:1～1:0.05，优选为19:1；所述混合溶剂优选为醇类溶剂与水的混合溶剂；所述醇类溶剂与水的混合溶剂优选为异丙醇与水的混合溶剂，所述醇类溶剂如上文所定义。
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 PCTCN2017107017-appb-000008
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。
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 PCTCN2017107017-appb-000009
或埃。
本发明还涉及，包括式(I)所示的化合物的A,B,C,D,E,F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A,B,C,D,E,F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A,B,C,D,E,F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A,B,C,D,E,F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A,B,C,D,E,F晶型可以单独给药，或者与一种或多种第二治疗剂联合使用。因此，在某些优选的实施方案中，所述的药物组合物还含有一种或多种第二治疗剂。在某些优选的实施方案中，所述第二治疗剂选自：抗炎剂、基质金属蛋白酶抑制剂、脂氧合酶抑制剂、细胞因子拮抗剂、免疫抑制剂、抗癌剂、抗病毒剂、生长因子调节剂、免疫调节剂或抗血管过度增殖化合物。
待组合的各成分(例如，本发明的A,B,C,D,E,F晶型与第二治疗剂)可同时给药或依次顺序地分开用药。例如，可以在施用本发明A,B,C,D,E,F晶型或其立体异构体之前、同时或之后，施用第二治疗剂。此外，待组合的各成分还可以以同一制剂形式或以分开的不同制剂的形式联合给药。
本发明式(I)化合物的A,B,C,D,E,F晶型可用于制备治疗和/或预防由IDO介导的色氨酸代谢的疾病中的用途。因此，本申请还涉及，本发明式(I)化合物的A,B,C,D,E,F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IDO介导的色氨酸代谢相关的疾病。此外，本申请还涉及，一种抑制由IDO介导的色氨酸代谢相关的疾病的方法，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A,B,C,D,E,F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IDO介导的色氨酸代谢有关的疾病，选自：癌症、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍或艾滋病；所述癌症选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤或非小细胞肺癌。
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)本发明的式(I)所示化合物A,B,C,D,E,F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，本发明式(I)所示化合物的A,B,C,D,E,F晶型纯度较高，在光照、高温、高湿的条件下晶型均未发生改变、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A,B,C,D,E,F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A晶型的XRPD图谱；
图2为式(I)所示化合物B晶型的XRPD图谱；
图3为式(I)所示化合物C晶型的XRPD图谱；
图4为式(I)所示化合物D晶型的XRPD图谱；
图5为式(I)所示化合物E晶型的XRPD图谱；
图6为式(I)所示化合物F晶型的XRPD图谱；
图7为式(I)所示化合物A晶型的DSC图谱；
图8为式(I)所示化合物B晶型的DSC图谱；
图9为式(I)所示化合物C晶型的DSC图谱；
图10为式(I)所示化合物D晶型的DSC图谱；
图11为式(I)所示化合物E晶型的DSC图谱；
图12为式(I)所示化合物F晶型的DSC图谱；
图13为式(I)所示化合物B晶型的DVS第一次循环图谱；
图14为式(I)所示化合物B晶型的DVS第二次循环图谱；
图15为B晶型0天的XRPD图；
图16为B晶型在40℃、相对湿度RH75％条件下放置15天后的XRPD图；
图17为C晶型0天的XRPD图；
图18为C晶型在40℃、相对湿度RH75％条件下放置15天后的XRPD图。
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 3+STARe System
吹扫气：氮气
升温速率：10.0℃/min
温度范围：20-250
2、X-射线粉末衍射谱(X-ray Powder Diffraction,XRPD)
(1)仪器型号：Bruker D8Discover A25X-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：10-48°
电压：40KV，电流：40mA
(2)仪器型号：Rigaku UltimalV X-射线粉末衍射仪
射线：单色Cu-Kα射线(λ＝1.5418)
扫描方式：θ/2θ，扫描范围：3-45°
电压：40KV，电流：40mA
3、动态水吸附仪(Dynamic Vapour Sorption,DVS)
仪器型号：DVS advantage
温度：25℃
溶剂：水
湿度变化：0-95-0-95-0％RH,dm/dt＝0.002
对比例、(S)-2-(4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-1H-吡唑-1-基)乙醇(式(I)所示化合物的制备，可参考专利申请PCT/CN2016/079054(WO2016169421A1(公开日2016-10-27))中的实施例40、41中的制备方法)的制备
Figure PCTCN2017107017-appb-000010
(1)6-氟-5-(哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚二三氟乙酸盐(化合物1g)(参见专利申请PCT/CN2016/079054(WO2016169421A1(公开日2016-10-27))中的实施例1中的制备方法)
Figure PCTCN2017107017-appb-000011
第一步
4-((2-溴-6-氟苯)(羟基)甲基)哌啶-1-甲酸叔丁酯1c
将二异丙基氨基锂(32.5mL，65.0mmol)加入四氢呋喃(50mL)中，于-78℃滴加预制的1-溴-3-氟苯1a(8.75g，50.0mmol，25mL)的四氢呋喃溶液，于-78℃搅拌1小时。再于-78℃滴加预制的4-甲酰基哌啶-1-甲酸叔丁酯1b(8.75g，50.0mmol，25mL)的四氢呋喃溶液，于-78℃搅拌1小时。反应结束后，于-78℃滴加甲醇(25mL)淬灭反应，将反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系(正己烷和乙酸乙酯)纯化所得残留物，得到化合物1c(16.3g，黄色糖浆固体，产率84.0％)。
MS m/z(LC-MS):332.0[M-56]
第二步
4-((2-溴-6-氟苯基)(对甲苯磺酰基氧基)甲基)哌啶-1-甲酸叔丁酯1d
将化合物1c(15g，38.63mmol)溶于四氢呋喃(350mL)中，分批加入氢化钠(3.09g，77.26mmol)，搅拌至无气体放出。滴加预制的对甲苯磺酰氯(8.10g，42.49mmol，250mL)的四氢呋喃溶液，于室温下搅拌30分钟，回流搅拌4小时，于70℃搅拌48小时。反应结束后，冷却至0℃，滴加水(50mL)淬灭反应，加入饱和氯化钠溶液(50mL)，分液，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(正己烷和乙酸乙酯)纯化所得残留物，得到化合物1d(6.6g，淡黄色粘稠固体，产率：31.80％)。
MS m/z(LC-MS):314.0/316.0[M-56-TsO]
第三步
4-((2-溴-6-氟苯)(1H-咪唑-1-基)甲基)哌啶-1-甲酸叔丁酯1e
将咪唑(12.5g，184.3mmol)溶于N,N-二甲基甲酰胺(50mL)中，分批加入氢化钠(7.40g，184.3mmol)，于室温搅拌1小时，滴加预制的化合物1d(10.0g，18.43mmol，20mL)的N,N-二甲基甲酰胺溶液，于100℃搅拌12小时。反应结束后，加入乙酸乙酯(300mL)，用饱和氯化钠溶液洗涤(150mL×3)，有机相用无水硫酸钠干 燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(二氯甲烷和甲醇)纯化所得残留物，得到化合物1e(1.90g，棕色粘稠固体，产率：23.5％)。
MS m/z(LC-MS):438.1/440.1[M+1]
第四步
4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-甲酸叔丁酯1f
将化合物1e(1.90g，4.33mmol)，N,N-二环己基甲基胺(1.35g，6.93mmol)，三苯基磷(908mg，3.46mmol)加入N,N-二甲基甲酰胺溶液(10mL)中，氩气氛下，加入醋酸钯(390mg，1.74mmol)，于100℃搅拌4.5小时。反应结束后，将反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系(正己烷和乙酸乙酯)纯化所得残留物，得到化合物1f(1.30g，黄色粘稠固体，产率：83.8％)。
MS m/z(LC-MS):358.1[M+1]
第五步
6-氟-5-(哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚二三氟乙酸盐1g
将化合物1f(1.30g，3.64mmol)溶于二氯甲烷(5mL)中，滴加三氟乙酸(5mL)，于室温下搅拌1小时。反应结束后，将反应液减压浓缩，得到粗品化合物1g(1.77g，棕色粘稠固体)，产品不经纯化直接进行下一步反应。
MS m/z(LC-MS):258.3[M+1]
(2)4-(4-溴苯基)-1-(2-((四氢-2H-吡喃-2-基)氧基)乙基)-1H-吡唑(化合物40a)(参见CN104755477A(公开日2015.07.01)说明书第44页中的制备方法)
Figure PCTCN2017107017-appb-000012
(3)(S)-2-(4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯基)-1H-吡唑-1-基)乙醇(化合物41，PCT/CN2016/079054(WO2016169421A1(公开日2016-10-27)实施例40、41中的制备方法)
Figure PCTCN2017107017-appb-000013
第一步
将4-(4-溴苯基)-1-(2-((四氢-2H-吡喃-2-基)氧基)乙基)-1H-吡唑40a(14.8g，42mmol)，6-氟-5-(哌啶-4-基)-5H-咪唑并[5,1-a]异吲哚17a(13.9g，42mmol)加入N,N-二甲基甲酰胺(300mL)中，加入四氟硼酸三叔丁基膦(1.863g，64.5mmol)和磷酸钾(35g，168mmol)，氩气置换三次。加入三(二亚苄基丙酮)二钯(2.92g，3.19mmol)，氩气置换一次，反应液升温至110℃，搅拌反应2小时。反应结束后，将反应液过滤，滤液减压浓缩除去N,N-二甲基甲酰胺，用硅胶柱色谱法以洗脱剂体系(二氯甲烷和甲醇)纯化所得残留物，得到化合物40b(6.38g，灰色油状物，产率：29％)。
第二步
将化合物40b(9g，17.1mmol)溶于甲醇(100mL)中，加入浓盐酸(12M，5.7mL)，反应液升至45℃，搅拌反应1小时。反应结束后，将反应液冷却至室温，加入饱和碳酸钠调反应液pH为8，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(二氯甲烷和甲醇)纯化所得残留物，得到化合物40c(5.2g，黄色固体，产率：65％)。
第三步
将化合物40c(1.4g,3.16mmol)进行手性制备(分离条件：手性制备柱Superchiral S-AS(Chiralway),2cm I.D.×25cm Length,5μm；流动相：CO2/MeOH/DEA＝60/40/0.05(v/v/v)，流速：50mL/min)，收集其相应组分，减压浓缩，得到化合物40(630mg，黄色固体)和化合物41(652mg，黄色固体)，其中化合物41经XRPD测定为晶型，该晶型在4.1,6.0,6.3,6.5,7.6,8.4,8.7),9.0,10.1,10.7,12.1,12.5,14.2,15.2,16.3,17.9,18.4,18.8,19.4,19.9,20.5,21.3,22.1,22.6,23.4,24.2,25.6,26.4,27.0,27.3,28.3,28.8,30.0和31.6处有特征峰，该晶型为C晶型。
实施例1
将50mg式(I)所示化合物粗品加入到反应瓶中，加入甲醇(50-100μL)，恒温50℃搅拌5天，过滤，真空干燥，得到白色至淡黄色粉末。该结晶样品的XRPD图谱见图1，其DSC图谱见图7，吸热峰值在217.9℃附近，起始熔化温度为216.8℃，将此晶型定义为A晶型，其特征峰位置如下表1所示：
表1、A晶型特征峰
Figure PCTCN2017107017-appb-000014
Figure PCTCN2017107017-appb-000015
实施例2
将50mg式(I)所示化合物粗品加入到反应瓶中，加入乙腈(50-100μL)，恒温25℃搅拌5天，过滤，而后25℃真空干燥，得到白色至淡黄色粉末。该结晶样品的XRPD见图2，其DSC谱图见图8，吸热峰值在210.5℃附近，起始熔化温度为210.3℃，将此晶型定义为B晶型，由图13和图14的DVS图谱可以判断该B晶型不含结晶水，其特征峰位置如下表2所示：
表2、B晶型特征峰
Figure PCTCN2017107017-appb-000016
Figure PCTCN2017107017-appb-000017
在50℃的乙酸乙酯溶剂中得到的B晶型样品经XRPD检测衍射角2θ在6.27,7.61,8.67,9.88,10.20,11.01,11.40,11.93,12.44,14.49,15.40,16.31,16.88,17.61,18.35,18.78,19.19,19.71,20.77,21.40,22.38,24.26,25.39,26.09,27.36,28.84和31.73处有特征峰。
在50℃的四氢呋喃溶剂中得到的B晶型样品经XRPD检测衍射角2θ在6.27,7.62,8.68,9.88,10.18,11.18,11.95,12.15,14.46,15.16,16.34,17.58,18.33,18.75,19.13,19.83,20.78,21.42,22.33,24.25,25.14,26.51,27.38,28.86和31.66处有特征峰。
实施例3
将50mg式(I)所示化合物粗品加入到反应瓶中，加入丙酮(1.5mL)，升温至80℃，保温10分钟后，再降至20℃，过滤，干燥得固体。该结晶样品经XRPD检测衍射角2θ在6.27,7.60,8.67,9.88,10.20,11.01,11.40,11.92,12.45,14.49,15.40,16.31,16.88,17.61,18.35,18.78,19.19,19.71,20.77,21.40,22.38,25.40,26.10,27.38,28.85和31.72处有特征峰，确定产物为B晶型。
实施例4
将50mg式(I)所示化合物粗品加入到反应瓶中，加入丙酮(50-100μL)，恒温25℃搅拌5天，过滤，而后25℃真空干燥，得到白色至淡黄色粉末，该结晶样品的XRPD见图3，其DSC谱图见图9，吸热峰值在210.1℃附近，起始熔化温度为209.5℃，将此晶型定义为C晶型，其特征峰位置如下表3所示：
表3、C晶型特征峰
Figure PCTCN2017107017-appb-000018
Figure PCTCN2017107017-appb-000019
在25℃的丙酮溶剂中得到的C晶型样品经XRPD检测衍射角2θ在5.99,6.24,7.53,8.30,8.95,9.94,10.64,12.00,12.42,15.92,16.56,17.81,18.17,18.71,19.30,19.76,20.48,21.26,21.54,22.04,22.47,24.17,25.00,26.29,26.61,27.32,28.74和31.47处有特征峰。
实施例5
将50mg式(I)所示化合物粗品加入到反应瓶中，加入异丙基苯(50-100μL)，恒温50℃搅拌5天，过滤，真空干燥，得到白色至淡黄色粉末。该结晶样品的XRPD见图4，其DSC图谱见图10，吸热峰值在212.9℃附近，起始熔化温度为211.1℃，将此晶型定义为D晶型，其特征峰位置如下表4所示：
表4、D晶型特征峰
Figure PCTCN2017107017-appb-000020
实施例6
将50mg式(I)所示化合物粗品加入到反应瓶中，加入乙醇(50-100μL)，恒温50℃搅拌5天，过滤，真空干燥，得到白色至淡黄色粉末。该固体样品的XRPD见图5，其DSC图谱见图11，吸热峰值在211.5℃附近，起始熔化温度为210.2℃，将此晶型定义为E晶型，其特征峰位置如下表5所示：
表5、E晶型特征峰
Figure PCTCN2017107017-appb-000021
实施例7
将50mg式(I)所示化合物粗品加入到反应瓶中，加入2-丙醇(50-100μL)，恒温50℃搅拌5天，过滤，真空干燥，得到白色至淡黄色粉末。该固体样品的XRPD见图6，其DSC图谱见图12，吸热峰值在208.6℃附近，起始熔化温度为206.9℃，将此晶型定义为F晶型，其特征峰位置如下表6所示：
表6、F晶型特征峰
Figure PCTCN2017107017-appb-000022
实验方案
以下提供本发明的结晶形产物的示例性试验方案，以显示本发明结晶形产物的有利活性或有益技术效果。但是应当理解，下述试验方案仅仅是对本发明内容的示例，而不是对本发明范围的限制。本领域技术人员在本说明书的教导下，能够对本发明的技术方案进行适当的修改或改变，而不背离本发明的精神和范围。
实验例1、B晶型与C晶型的稳定性考察
将B晶型和C晶型样品敞口平摊放置，考察40℃、相对湿度RH75％条件下样品的稳定性，考察取样时间为15天。
实验结果：
说明书附图图15为B晶型0天的XRPD图；
说明书附图图16为B晶型在40℃，相对湿度75％条件下放置15天后的XRPD图；
说明书附图图17为C晶型0天的XRPD图；
说明书附图图18为C晶型在40℃，相对湿度75％条件下放置15天后的XRPD图。
实验结论：
由说明书附图图15、图16、图17、图18的稳定性考察结果表明式(I)所示化合物的B晶型在40℃、相对湿度RH75％放置的条件下，XRPD峰型基本未发生变化，晶型稳定；C晶型在40℃、相对湿度RH75％放置的条件下，XRPD峰型发生了改变，部分峰型特征消失，结晶度降低；由此可见，在40℃RH75％放置的条件下B晶型的物理稳定性优于C晶型。

Claims (20)

  1. 一种式(I)所示化合物的A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，其在6.3,7.7,9.0,10.4,11.0,12.2,14.8,15.2,16.3,16.7,17.3,17.9,18.4,19.5,19.7,20.9,21.2,21.5,21.7,22.1,24.3,25.6和28.9处有特征峰，所述2θ的误差范围为±0.2，
    Figure PCTCN2017107017-appb-100001
  2. 如权利要求1所述的A晶型，其特征在于：所述A晶型在6.3,7.4,8.99,10.4,11.0,12.2,14.8,15.2,16.3,16.7,17.3,17.9,18.1,19.2,19.7,20.1,20.9,21.2,21.5,21.7,22.1,22.8,24.3,24.6,25.6,26.4,27.3,28.9,30.1,31.5,32.2,32.5,34.6,36.1,37.3和39.0处有特征峰，所述2θ的误差范围为±0.2。
  3. 权利要求1-2任一项所述的A晶型的制备方法，其特征在于，所述方法为：
    将式(I)所示化合物加入有机溶剂中，进行打浆，过滤结晶并洗涤，干燥后即可得到目标A晶型，所述有机溶剂选自醇类溶剂，优选甲醇。
  4. 一种式(I)所示化合物的B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，其在6.2,7.6,8.7,10.0 11.1,12.1,14.6,16.0,16.5,17.9,18.2,19.2,19.9,21.1 21.5,22.3,24.3,25.3,26.4,27.3,28.9和31.7处有特征峰，所述2θ的误差范围为±0.2，
    Figure PCTCN2017107017-appb-100002
  5. 如权利要求4所述的B晶型，其特征在于：所述B晶型在6.2,6.7,7.6,8.7,10.,11.1,12.1,14.6,16.0,16.5,17.9,18.2,19.2,19.9,21.1,21.5,22.3,24.3,25.3,26.4,27.3,28.9和31.7处有特征峰，所述2θ的误差范围为±0.2。
  6. 权利要求4-5任一项所述的B晶型的制备方法，其选自：
    方法一，将式(I)所示化合物溶解于溶剂中，析晶，过滤，干燥后即可得到目标B晶型，所述溶剂选自卤代烃类溶剂，优选二氯甲烷；
    方法二，将式(I)所示化合物加入有机溶剂中，进行打浆，过滤结晶并洗涤，干燥后即可得到目标B晶型，所述有机溶剂选自：
    腈类、酯类、卤代烃类、醚类、醇类、硝基烷烃类或醇类与水的混合溶剂，所述腈类溶剂选自乙腈，所述酯类溶剂选自乙酸乙酯，所述卤代烃类溶剂选自二氯甲烷，所述醚类溶剂选自四氢呋喃，所述醇类溶剂选自正丙醇，所述硝基烷烃类溶剂选自硝基甲烷，所述醇类与水的混合溶剂选自异丙醇与水的混合溶剂。
  7. 一种式(I)所示化合物的C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，其在6.0,6.3,7.6,8.4,8.7,9.0,10.1,10.7,12.1,12.5,15.2,16.3,17.9,18.4,18.8,19.4,19.9,20.5,21.3,22.1,22.6,23.4,24.2,25.6,26.4,27.3和28.3处有特征峰，所述2θ的误差范围为±0.2，
    Figure PCTCN2017107017-appb-100003
  8. 如权利要求7所述的C晶型，其特征在于：所述C晶型在4.1,6.0,6.3,6.5,7.6,8.4,8.7),9.0,10.1,10.7,12.1,12.5,14.2,15.2,16.3,17.9,18.4,18.8,19.4,19.9,20.5,21.3,22.1,22.6,23.4,24.2,25.6,26.4,27.0,27.3,28.3,28.8,30.0和31.6处有特征峰，所述2θ的误差范围为±0.2。
  9. 权利要求7-8任一项所述的C晶型的制备方法，其特征在于，所述方法为：
    将式(I)所示化合物加入有机溶剂中，进行打浆，过滤结晶并洗涤，干燥后即可得到目标C晶型，所述有机溶剂为酮类溶剂，优选丙酮。
  10. 一种式(I)所示化合物的D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，其在15.1,16.6,17.6,18.2,19.5,20.1,20.4,21.6,21.9,22.1,24.6,26.7,27.6和29.2处有特征峰，所述2θ的误差范围为±0.2，
    Figure PCTCN2017107017-appb-100004
  11. 如权利要求10所述的D晶型，其特征在于：所述D晶型在15.1,16.6,17.6,18.2,19.5,20.1,20.4,21.6,21.9,22.1,24.6,26.7,27.6,29.2,30.4和31.9所述的D晶型特征峰，所述2θ的误差范围为±0.2。
  12. 权利要求10-11任一项所述的D晶型的制备方法，其特征在于，所述方法为：
    将式(I)所示化合物加入有机溶剂中，进行打浆，过滤结晶并洗涤，干燥后即可得到目标D晶型，所述有机溶剂选自芳香烃类溶剂，优选异丙基苯或二甲苯。
  13. 一种式(I)所示化合物的E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，其在18.2,18.7,19.2,20.1,21.7,22.8,24.6,26.7,27.7和29.2处有特征峰，所述2θ的误差范围为±0.2，
    Figure PCTCN2017107017-appb-100005
  14. 权利要求13所述的E晶型的制备方法，其特征在于，所述方法为：
    将式(I)所示化合物加入有机溶剂中，进行打浆，过滤结晶并洗涤，干燥后即可得到目标的E晶型，所述有机溶剂选自醇类溶剂，优选乙醇。
  15. 一种式(I)所示化合物的F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，其在18.7,19.5,20.2,21.5,22.0,22.6,24.4,25.6,26.6,27.6,29.2和32.0处有特征峰，所述2θ的误差范围为±0.2，
    Figure PCTCN2017107017-appb-100006
  16. 权利要求15所述的F晶型的制备方法，其特征在于，所述方法为：
    将式(I)所示化合物加入有机溶剂中，进行打浆，过滤结晶并洗涤，干燥后即可得到目标F晶型，所述有机溶剂选自醇类溶剂，优选2-丙醇。
  17. 一种药物组合物，所述药物组合物由权利要求1-2中任一项所述的A晶型、权利要求4-5中任一项所述的B晶型、权利要求7-8中任一项所述的C晶型、权利要求10-11中任一项所述的D晶型、权利要求13所述的E晶型、权利要求15所述的F晶型与药学上可接受的载体、稀释剂或赋形剂组成。
  18. 如权利要求17所述的药物组合物，其特征在于，所述药物组合物还包含一种或多种第二治疗活性剂，所述的第二治疗活性剂选自：抗炎剂、基质金属蛋白酶抑制剂、脂氧合酶抑制剂、细胞因子拮抗剂、免疫抑制剂、抗癌剂、抗病毒剂、生长因子调节剂、免疫调节剂或抗血管过度增殖化合物。
  19. 一种制备如权利要求17、18所述药物组合物的方法，其特征在于，所述方法包括由权利要求1-2中任一项所述的A晶型、权利要求4-5中任一项所述的B晶型、权利要求7-8中任一项所述的C晶型、权利要求10-11中任一项所述的D晶型、权利要求13所述的E晶型、权利要求15所述的F晶型与药学上可接受的载体、稀释剂或赋形剂混合的步骤。
  20. 如权利要求1-2中任一项所述的A晶型、权利要求4-5中任一项所述的B晶型、权利要求7-8中任一项所述的C晶型、权利要求10-11中任一项所述的D晶型、权利要求13所述的E晶型、权利要求15所述的F晶型、权利要求17-18中任一项所述的药物组合物在制备治疗具有IDO介导的色氨酸代谢途径病理学特征的疾病中的用途，所述疾病选自癌症、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍和艾滋病，所述癌症选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤或非小细胞肺癌。
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