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WO2019001551A1 - Forme cristalline de base libre de dérivé d'imidazo-isoindole et son procédé de préparation - Google Patents

Forme cristalline de base libre de dérivé d'imidazo-isoindole et son procédé de préparation Download PDF

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Publication number
WO2019001551A1
WO2019001551A1 PCT/CN2018/093533 CN2018093533W WO2019001551A1 WO 2019001551 A1 WO2019001551 A1 WO 2019001551A1 CN 2018093533 W CN2018093533 W CN 2018093533W WO 2019001551 A1 WO2019001551 A1 WO 2019001551A1
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Prior art keywords
solvent
cancer
group
compound
angle
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PCT/CN2018/093533
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English (en)
Chinese (zh)
Inventor
曹笑立
尤凌峰
肖昌琴
杜振兴
王立坤
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
Original Assignee
Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Priority to CN201880004410.XA priority Critical patent/CN109983018A/zh
Publication of WO2019001551A1 publication Critical patent/WO2019001551A1/fr
Anticipated expiration legal-status Critical
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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-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)benzene
  • 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.
  • Patent application WO2016169421A1 discloses a novel high-efficiency and low-toxic selective IDO inhibitor compound with excellent effects and effects. In particular, it has excellent pharmacogen absorption activity and its chemical name is (S)-2-(4-(4-(4-(4-(6-fluoro-5H-imidazo[5,1-a]isoindole-5-)
  • the base)piperidin-1-yl)phenyl)-1H-pyrazol-1-yl)ethanol has the structure shown below:
  • 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 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 crystal form of -a]isoindole-5-yl)piperidin-1-yl)phenyl)-1H-pyrazol-1-yl)ethanol, which has good crystal form stability and chemical stability Sex, and the crystallization solvent used is low in toxicity and low in residue, and can be better applied to the clinic.
  • the present invention provides a G crystal form 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, and the diffraction angle 2 ⁇ angle is 6.3. There are characteristic peaks at 7.2, 10.4, 11.0, 12.1, 14.6, 16.4, 18.0, 19.2, 19.8, 22.5, 24.2, 26.4 and 28.9, wherein the error range of the 2 ⁇ angle of each characteristic peak is ⁇ 0.2.
  • the present invention provides a G crystal form of a 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 spectrum has diffraction angles 2 ⁇ of 6.32, 7.24, 8.92, 10.41, 11.03, 12.08, 14.56, 15.13, 16.42, 17.24, 18.00, 19.15, 19.79, 21.21, 21.73, 22.53, 24.18, 26.41, 27.11, 28.90 and 30.16.
  • the present invention provides a G crystal form of a 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 spectrum has a diffraction angle 2 ⁇ angle of 6.32, 7.24, 8.92, 10.41, 11.03, 12.08, 14.56, 15.13, 16.42, 17.24, 18.00, 19.15, 19.79, 21.21, 21.73, 22.53, 24.18, 26.41, 27.11, 28.90, 30.16,
  • the invention provides a crystalline form of G of the compound of formula (I), characterized by a melting point of from 210 ° C to 220 ° C, preferably from 212.1 ° C to 213.5 ° C, more preferably 213.24 ° C.
  • the invention further provides a process for the preparation of the G crystalline form of the compound of formula (I), the process being selected from the group consisting of:
  • Method 1 the compound of the formula (I) is dissolved in an appropriate amount of a solvent, volatilized, crystallized and washed, and dried to obtain a target G crystal form selected from ester solvents and ethers.
  • a solvent, a nitrile, an alcohol solvent the ester solvent is selected from ethyl acetate or isopropyl acetate
  • the ether solvent is selected from the group consisting of tetrahydrofuran, propylene glycol methyl ether or 1,4-dioxane, the nitrile
  • the solvent is selected from the group consisting of acetonitrile
  • the alcohol solvent is selected from the group consisting of isopropanol, ethanol or methanol;
  • Method 2 by dissolving the compound of the formula (I) in an appropriate amount of a good solvent, adding an anti-solvent, performing crystallization, filtering and crystallization, washing, and drying to obtain a target G crystal form, the good solvent It is selected from a halogenated hydrocarbon or ether solvent, the halogenated hydrocarbon solvent is selected from dichloromethane, the ether solvent is selected from tetrahydrofuran or 1,4-dioxane, and the anti-solvent is selected from aliphatic hydrocarbons.
  • a good solvent It is selected from a halogenated hydrocarbon or ether solvent
  • the halogenated hydrocarbon solvent is selected from dichloromethane
  • the ether solvent is selected from tetrahydrofuran or 1,4-dioxane
  • the anti-solvent is selected from aliphatic hydrocarbons.
  • the aliphatic hydrocarbon solvent is selected from n-heptane; or the good solvent is selected from an ether solvent or an alcohol solvent, the ether solvent is selected from the group consisting of propylene glycol methyl ether, and the alcohol solvent is selected from the group consisting of ethanol, 2-propanol or methanol, the anti-solvent is selected from pure water;
  • Method 3 the compound of the formula (I) is placed in an appropriate amount of a solvent, beaten, filtered and washed, and dried to obtain a target crystal form G, the organic solvent being selected from the group consisting of:
  • an ether solvent selected from the group consisting of propylene glycol methyl ether, tetrahydrofuran or 1,4-dioxane the alicyclic hydrocarbon solvent is selected from cyclohexane
  • the aliphatic hydrocarbon solvent is selected from n-heptane.
  • the aromatic hydrocarbon solvent is selected from cumene or xylene
  • the alcohol solvent is selected from the group consisting of ethanol, 2-propanol or methanol
  • the halogenated hydrocarbon solvent is selected from dichloromethane
  • the mixed solvent is selected from the group consisting of dichloromethane. a mixed solvent of an alcohol and an ether, a mixed solvent of two different alcohol solvents, or a mixed solvent of an alcohol solvent and water, and the ratio of the mixed solvent of the alcohol solvent to the ether is from 0.1:1 to 1:0.1.
  • the beating temperature is selected from room temperature to solvent boiling point temperature, and may also be 5 0 ° C, the room temperature is selected from 15-25 ° C, and can also be 25 ° C.
  • the invention further relates to a pharmaceutical composition of Form G 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 a G crystalline form pharmaceutical composition of a compound of formula (I), characterized in that it comprises one or more second therapeutically active agents selected from the group consisting of: an anti-inflammatory agent, a matrix Metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, anticancer agents, antiviral agents, growth factor modulators, immunomodulators or anti-vascular hyperproliferative compounds.
  • an anti-inflammatory agent a matrix Metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, anticancer agents, antiviral agents, growth factor modulators, immunomodulators or anti-vascular hyperproliferative compounds.
  • the invention further relates to the use of a pharmaceutical composition of Form G or Form G of the compound of formula (I) for the preparation of a medicament for the treatment of a pathological feature having an IDO-mediated tryptophan metabolism pathway 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, skin, oral, prostate, bone, kidney, ovarian, bladder, liver, fallopian tube, ovarian, peritoneal, stage IV melanoma, glioma, glioblastoma , hepatocellular carcinoma, mastoid renal tumor, head and neck tumor, leukemia, lymphoma, myeloma or non-small cell lung cancer.
  • a pharmaceutical composition of Form G or Form G of the compound of formula (I) for the preparation of a medicament for the treatment of a pathological feature
  • the G crystal form of the compound of the formula (I) obtained by X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC) was subjected to structural measurement, crystal form study, and solvent residue of the obtained crystal was carried out. The test.
  • the preparation method of the crystal form in the present invention includes crystallization, crystallization, a positive and negative solvent (good solvent-antisolvent) or beating.
  • the method for crystallization of the present invention includes room temperature crystallization, cooling crystallization, crystallization of a volatile solvent, seed crystal induced crystallization, etc., and the cooling temperature is selected from 40 ° C or lower, and may also be -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.
  • 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.
  • hydroxy group, cyano group or the like as used in the present invention means a group such as -OH or -CN.
  • 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.
  • aliphatic hydrocarbon solvent refers to a carbon having a basic property of an aliphatic compound and having carbon atoms in the molecule which are connected to each other in a chain, and the carbon atoms are 1-10.
  • Hydrogen compounds such as saturated aliphatic hydrocarbons include alkane solvents, specific examples including, but not limited to, n-butane, n-pentane, n-hexane or n-heptane.
  • alicyclic hydrocarbon solvent refers to a hydrocarbon compound having a cyclic carbon skeleton and having similar properties to aliphatic hydrocarbons and having a number of ring atoms of 1-8, and specific examples include, but are not limited to, rings. Pentane or cyclohexane.
  • 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.
  • aromatic hydrocarbon solvent refers to a conjugated system having a closed ring in a molecule, a carbocyclic compound having a ⁇ electron number conforming to the Huckel rule and containing 6-8 ring carbon atoms, and a derivative thereof.
  • General examples include, but are not limited to, cumene 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 “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 0.1. 1 to 1:0.1, preferably 1:1;
  • the mixed solvent is preferably a mixed solvent of an alcohol and an ether, a mixed solvent of two different alcohol solvents, or a mixed solvent of an alcohol solvent and water;
  • the mixed solvent of the ether and the ether is preferably a mixed solvent of methanol and methyl tert-butyl ether, and the mixed solvent of the two different alcohol solvents is preferably a mixed solvent of methanol and isopropyl alcohol, and the alcohol solvent and water
  • the mixed solvent is preferably a mixed solvent of methanol and water.
  • the "good solvent” as used in the present invention means a solvent having a strong solubility to a molecule (or a solute) and a small interaction with a molecule (or a solute).
  • anti-solvent means that the solubility to a molecule (or a solute) is low, poor or insoluble.
  • the solubility of the crystal to be crystallized in the solvent is lowered. Since the anti-solvent combines well with it, the solubility of the molecule (or solute) is lowered, so that the molecule (or solute) is precipitated to form a solid phase. The solid is then filtered from the liquid phase, and the two solvents are separated to obtain the desired crystal.
  • the good solvent and the anti-solvent system are preferably a system in which a halogenated hydrocarbon, an ether solvent and an aliphatic hydrocarbon solvent are combined, or an ether solvent, an alcohol solvent and water, and a system 2;
  • the solvent is selected from a halogenated hydrocarbon or ether solvent, the halogenated hydrocarbon solvent is selected from the group consisting of dichloromethane, the ether solvent is selected from tetrahydrofuran or 1,4-dioxane, and the anti-solvent is selected from the group consisting of fat.
  • the aliphatic hydrocarbon solvent is selected from n-heptane;
  • the good solvent in the system 2 is selected from an ether solvent or an alcohol solvent, and the ether solvent is selected from the group consisting of propylene glycol methyl ether, and the alcohol solvent is selected.
  • the anti-solvent is selected from pure water;
  • the “differential scanning calorimetry or DSC” described in the present invention refers to measuring the temperature difference and the heat flow difference between the sample and the reference during the temperature rise or constant temperature of the sample to characterize all physical changes and chemistry related to the thermal effect. 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 G crystalline form 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 G crystalline form or 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, 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 G crystalline form of the invention is present in a pharmaceutical composition or medicament in a therapeutically and/or prophylactically effective amount.
  • the G crystalline form of the invention is present in a pharmaceutical composition or medicament in unit dosage form.
  • the G crystalline form of the compound 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 sequentially.
  • the second therapeutic agent can be administered prior to, concurrently with, or after administration of the G crystalline form of the invention or a stereoisomer 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 form of G of the compounds of formula (I) of the present invention can be used for 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 G crystalline form of the compound of the formula (I) of the present invention for the preparation of a medicament for the treatment and/or prevention of IDO-mediated tryptophan metabolism in a subject. disease. Further, 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 Form G of the compound, 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 G crystal form of the anhydrous compound represented by the formula (I) 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, and thus the crystal of the present invention can be It is preferably used as a pharmaceutically active ingredient.
  • the G crystal form of the compound of the formula (I) prepared by the invention has high purity, and the crystal form is unchanged under the conditions of illumination, high temperature and high humidity, and the crystal form stability is good; HPLC The purity change is small and the chemical stability is high; the G crystal form of the anhydrous compound represented by the formula (I) obtained by the technical scheme of the present invention can meet the pharmaceutical requirements for production transportation and storage, and the production process is stable, reproducible and controllable, and can be adapted to Industrial production.
  • Figure 1 is an X-ray powder diffraction pattern of the crystalline form of Compound G of formula (I).
  • Figure 2 is a DSC chart of the crystalline form of Compound G of formula (I).
  • Figure 3 is a first cycle map of DVS of the compound G crystal form of the formula (I).
  • Figure 4 is a second cycle view of DVS of the compound G crystal form of the formula (I).
  • Figure 5 is an X-ray powder diffraction pattern of the compound B crystal form of the formula (I).
  • Figure 6 is a DSC chart of the crystalline form of Compound B of formula (I).
  • Figure 7 is an XRPD pattern of the G crystal form for 0 days.
  • Fig. 8 is an XRPD pattern of the G crystal form after being allowed to stand at 40 ° C and a relative humidity of RH 75% for 15 days.
  • Figure 9 is an XRPD pattern of Form C for 0 days.
  • Figure 10 is an XRPD pattern of Form C after 15 days of standing at 40 ° C and relative humidity RH 75%.
  • 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
  • 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 DSC spectrum is shown in Figure 2. There is a sharp melting endothermic peak near 213.24 ° C. This crystal form is defined as G crystal form, passing DVS ( Figures 3 and 4).
  • the G crystal form of the anhydrous compound represented by the formula (I) is determined by the detection, and the characteristic peak positions thereof are as follows:
  • the crystal sample was subjected to XRPD to detect diffraction angles 2 ⁇ at 6.31, 7.30, 8.96, 10.32, 10.95, 12.15, 14.70, 15.15, 16.42, 17.20, 17.82, 19.10, 19.79, 21.18, 21.66, 22.53, 24.22, 26.51, 27.24, 28.83, There are characteristic peaks near 29.10, 31.44, 32.07, 37.06 and 40.41, and the product is determined to be a G crystal form.
  • the crystal sample was subjected to XRPD to detect diffraction angles 2 ⁇ at 6.30, 7.27, 8.92), 10.26, 10.92, 12.10, 14.67, 15.10, 16.40, 17.14, 17.80, 19.06, 19.66, 21.18, 21.54, 22.84, 24.21, 26.27, 27.21, 28.85. There are characteristic peaks near 29.98, 31.40, 32.12 and 39.97, and the product is determined to be a G crystal form.
  • the crystal sample was subjected to XRPD to detect diffraction angles 2 ⁇ at 6.38, 7.34, 8.97, 10.31, 10.97, 12.17, 14.75, 15.16, 16.23, 17.15, 17.83, 19.14, 19.68, 21.46), 21.62, 22.53, 24.25, 26.32, 27.28, 28.83. There are characteristic peaks near 30.05, 31.48, 32.16 and 40.02, and the product is determined to be a G crystal form.
  • the solid sample was subjected to XRPD to detect diffraction angles 2 ⁇ at 6.02, 6.31, 7.55, 8.85, 9.80, 11.14, 12.16, 14.57, 16.02, 16.60, 17.92, 18.33, 19.15, 19.79, 21.34, 21.62, 22.36, 24.28, 25.53, 26.41, There are characteristic peaks near 27.39, 28.90 and 31.61, and the product is determined to be Form B.
  • Example 2 The G crystal form obtained in Example 2 and the sample of the B crystal form product prepared in the patent application WO2016169421A1 (publication date 2016.10.27) were placed in an open position, and the stability of the sample under illumination (4500 Lux) was examined. .
  • the sampling time was 5 days and 10 days, and the HPLC and XPRD results are shown in Table 1.
  • the G crystal form was placed in an open state with a solid prepared by the method of Examples 40 and 41 in the patent application WO2016169421A1 (publication date 2016.10.27) (the solid was determined to be C crystal form by XRPD detection), and 40 ° C was observed. Stability under humidity RH 75%. The sampling time was 15 days, and the XRPD test results are shown in the attached drawings.
  • Figure 7 is an XRPD diagram of the G crystal type 0 day
  • Figure 8 is an XRPD pattern of G crystal form placed at 40 ° C and relative humidity RH 75% for 15 days;
  • Figure 9 of the accompanying drawings is an XRPD pattern of a C crystal type 0 day
  • FIG. 10 is an XRPD pattern of a C crystal form placed at 40 ° C and a relative humidity of RH 75% for 15 days.

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Abstract

L'invention concerne une forme cristalline G d'une base libre d'un dérivé d'imidazo-isoindole et son procédé de préparation. La structure chimique du composé est représentée dans la formule (I), et son nom chimique est représenté par la formule (I) (S)-2-(4- (4- (4- (6-fluoro -5 H-imidazo [5,1-a] isoindole-5-yl) pipéridine-1-yl) phényl) -1 H-pyrazol-1-yl) éthanol. L'invention concerne l'application de la forme cristalline G du composé dans une composition pharmaceutique et l'utilisation pharmaceutique de la forme cristalline G et de la composition dans la préparation d'un médicament pour le traitement de maladies avec des caractéristiques pathologiques de la voie métabolique du tryptophane médiée par IDO (indoléamine-pyrrole -2,3-dioxygénase). La forme cristalline G du composé présente une bonne stabilité, et le solvant de cristallisation qui est utilisé présente une faible toxicité et un faible résidu et peut être utilisé de manière satisfaisante dans un traitement clinique.
PCT/CN2018/093533 2017-06-30 2018-06-29 Forme cristalline de base libre de dérivé d'imidazo-isoindole et son procédé de préparation Ceased WO2019001551A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016169421A1 (fr) * 2015-04-21 2016-10-27 江苏恒瑞医药股份有限公司 Dérivé imidazo isoindole, méthode de préparation correspondante et utilisation médicale correspondante
WO2018072742A1 (fr) * 2016-10-21 2018-04-26 江苏恒瑞医药股份有限公司 Forme cristalline de base libre de dérivé d'imidazo-isoindole et son procédé de préparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016169421A1 (fr) * 2015-04-21 2016-10-27 江苏恒瑞医药股份有限公司 Dérivé imidazo isoindole, méthode de préparation correspondante et utilisation médicale correspondante
WO2018072742A1 (fr) * 2016-10-21 2018-04-26 江苏恒瑞医药股份有限公司 Forme cristalline de base libre de dérivé d'imidazo-isoindole et son procédé de préparation

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