WO2020140960A1 - Forme cristalline pour dérivé d'indole-formamide et procédé de préparation de la forme cristalline - Google Patents

Forme cristalline pour dérivé d'indole-formamide et procédé de préparation de la forme cristalline Download PDF

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WO2020140960A1
WO2020140960A1 PCT/CN2020/070188 CN2020070188W WO2020140960A1 WO 2020140960 A1 WO2020140960 A1 WO 2020140960A1 CN 2020070188 W CN2020070188 W CN 2020070188W WO 2020140960 A1 WO2020140960 A1 WO 2020140960A1
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formula
compound represented
crystal form
ray powder
powder diffraction
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PCT/CN2020/070188
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English (en)
Chinese (zh)
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赵苗苗
陈杰
尤凌峰
杜振兴
王捷
贺峰
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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 CN202080007450.7A priority Critical patent/CN113227048B/zh
Publication of WO2020140960A1 publication Critical patent/WO2020140960A1/fr

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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the invention relates to a crystal form of indolecarboxamide derivatives and a preparation method thereof, and belongs to the field of pharmaceuticals.
  • Retinoid-related orphan receptors are members of the nuclear receptor family and are a class of ligand-dependent transcription factors that can regulate various physiological and biochemical processes, including reproductive development, Metabolism, immune system regulation, etc. (Mech Dev. 1998 Jan, 70 (1-2:147-53; EMBO J. 1998 Jul 15, 17(14):3867-77).
  • the ROR family includes three types ROR ⁇ , ROR ⁇ and ROR ⁇ ( Curr Drugs Targets Inflamm Allergy. 2004Dec, 3(4):395-412), where ROR ⁇ can be expressed in many tissues, including thymus, liver, kidney, fat and skeletal muscle (Immunity.1998Dec,9(6):797 -806.).
  • ROR ⁇ 1 ROR ⁇ 1
  • ROR ⁇ t ROR ⁇ 2
  • ROR ⁇ t can regulate the survival of T cells during the differentiation of immune cells, and can activate and promote the differentiation of CD4+ and CD8+ cells into helper T cells 17 (Th17) and cytotoxic T cells (Tc17)
  • Th17 and Tc17 cells are a type of effector cells, which promote the inflammatory response and enhance the availability by secreting interleukin 17 (IL-17) and other inflammatory factors (such as IL-21) Immune response and autoimmune response.
  • IL-17 interleukin 17
  • IL-21 interleukin-21
  • Th17 can also recruit cytotoxic CD8+ T cells and natural killer cells into the tumor microenvironment, thereby killing the tumor cells and achieving the purpose of anti-tumor (Blood.2009Aug6,114(6):1141-9; ClinCancerRes.2008Jun 1,14(11):3254-61). Therefore, activating ROR ⁇ t may become a new anti-tumor therapy.
  • ROR ⁇ t agonists such as the small molecule drug LYC-55716 developed by Lycera Corp.
  • LYC-54143 can regulate the differentiation of Th17 and Tc17 cells through traditional pathways, promote the expression of IL-17 and other cytokines, and increase T cell activity.
  • activated ROR ⁇ t can regulate the expression of various genes in the immune system, inhibit the expression of PD-1, which reduces the immune suppression and improves the anticancer activity (Oncoimmunology.2016Nov4,5(12):e1254854; ACS Chem Biol.
  • PCT/CN2018/094610 (application date 2018.07.05) provides a ROR agonist represented by formula (I), and its crystal structure is not described in the text.
  • the crystalline structure as a medicinal active ingredient often affects the chemical stability of the drug. Different crystallization conditions and storage conditions may lead to changes in the crystalline structure of the compound, sometimes accompanied by the production of other forms of crystalline form. Therefore, it is necessary to thoroughly study the crystal form of the compound of formula (I) and related preparation methods to improve various aspects of the compound of formula (I).
  • the object of the present invention is to provide a new crystal form of the compound represented by formula (I).
  • the new crystal form has good stability and can be better used in clinic.
  • the present invention provides a crystal form I of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is 8.99, 9.715, 10.594, 12.560, 13.530, 15.141, 16.238, 17.109, 21.725, at 2 ⁇ There are characteristic peaks at 24.633 and 25.156.
  • the present invention provides a crystal form I of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is 8.99, 9.715, 10.594, 12.560, 12.904 at a 2 ⁇ angle , 13.530, 15.141, 16.238, 17.109, 17.903, 18.974, 19.658, 21.725, 23.258, 24.633, 25.156 have characteristic peaks.
  • the present invention provides a crystal form I of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is shown in FIG. 3.
  • any crystalline form or amorphous formula (I) compound in an appropriate amount of solvent, heating and dissolving, cooling and crystallizing, and filtering, the solvent is selected from n-propanol, isopropanol, ethanol, tert-butyl Alcohol, water-ethanol mixture; or
  • the present invention provides a crystal form II of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has 2 ⁇ angles of 14.080, 15.259, 16.285, 17.047, 18.577, 20.356, 21.932, 25.507 Characteristic peaks.
  • the invention provides a crystal form II of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern at 2 ⁇ angles is 14.080, 15.259, 16.285, 17.047, 18.577, There are characteristic peaks at 20.356, 21.932, 22.571, 25.507, 28.465, 29.360, 32.104, 35.644.
  • the present invention provides a crystal form II of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is shown in FIG. 8.
  • the present invention provides a crystal form III of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is 6.203, 6.962, 9.163, 12.298, 13.774, 14.679, 15.353, 16.094, 18.702 at 2 ⁇ angle , There is a characteristic peak at 20.234.
  • the present invention provides a III crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is 2.203, 6.962, 9.163, 12.298, 13.774 at a 2 ⁇ angle , 14.679, 15.353, 16.094, 16.835, 18.702, 20.234, 23.163, 24.921, 27.936 have characteristic peaks.
  • the present invention provides a crystal form III of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is shown in FIG. 9.
  • a method for preparing compound III crystal form of formula (I) includes:
  • the present invention provides an IV crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has 2 ⁇ angles at 7.229, 9.160, 11.423, 13.782, 14.524, 17.060, 17.832, 21.628 Characteristic peaks.
  • the present invention provides an IV crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern at 2 ⁇ angles is 7.229, 9.160, 11.423, 13.782, 14.524 , 17.060, 17.832, 21.628, 22.575, 23.028, 26.495 have characteristic peaks.
  • the present invention provides an IV crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is shown in FIG. 10.
  • the present invention provides a crystal form V of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2 ⁇ angles of 14.920, 15.298, 19.136, 24.132, 25.319, 26.396, and 28.897 .
  • the present invention provides a crystal form V of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is 2.472, 9.857, 14.920, 15.298, 19.136 at a 2 ⁇ angle , 22.108, 24.132, 25.319, 26.396, 27.729, 28.897 have characteristic peaks.
  • the present invention provides a crystal form V of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is shown in FIG. 11.
  • the solvent is selected from methanol-water, isopropanol-water, Ethanol-water, cyclohexane, n-heptane, water.
  • the present invention provides a VI crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2 ⁇ angles of 6.151, 7.533, 8.447, 11.454, 12.429, 16.156, 18.166 .
  • the present invention provides a VI crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is 2.151, 7.533, 8.447, 11.454, 12.429 at a 2 ⁇ angle , 13.904, 14.313, 16.156, 18.166, 19.341, 22.001, 23.064, 24.933 have characteristic peaks.
  • the present invention provides a VI crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is shown in FIG. 14.
  • a method for preparing the crystal form VI of the compound represented by formula (I) includes the steps of mixing the compound of formula III of the formula (I) in crystal form III with an appropriate amount of solvent at room temperature and filtering, the solvent selected from 4-methyl Yl-2-pentanone.
  • the present invention provides a VII crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern at 2 ⁇ angles is 6.744, 8.415, 10.545, 11.581, 15.199, 16.585, 17.340, 18.482, 20.099 There are characteristic peaks.
  • the present invention provides a VII crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern at 2 ⁇ angles is 6.744, 8.415, 10.545, 11.581, 15.199 , 16.585, 17.340, 18.482, 20.099, 22.837, 23.409, 25.515, 26.657 have characteristic peaks.
  • the present invention provides a VII crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is shown in FIG. 15.
  • a method for preparing the crystal form VII of the compound represented by the formula (I) includes the steps of mixing the compound represented by the crystalline form III (I) with a suitable amount of solvent at room temperature and filtering, the solvent selected from dioxane and tetrahydrofuran .
  • the present invention provides a VIII crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2 ⁇ angles of 6.917, 11.614, 13.018, 14.992, 16.616, and 17.613.
  • the present invention provides a VIII crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern at 2 ⁇ angles is 6.917, 11.614, 13.018, 14.992, 16.616, There are characteristic peaks at 17.613, 20.641, 24.178, 24.712, 26.541 and 27.317.
  • the present invention provides a VIII crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is shown in FIG. 16.
  • the invention provides a method for preparing the VIII crystal form of the compound represented by formula (I), which comprises the steps of mixing the crystalline form V of the compound represented by formula (I) in an appropriate amount of o-xylene and then pulping and filtering at room temperature.
  • the present invention provides a IX crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2 ⁇ angles of 8.016, 12.372, 13.896, 16.197, 18.037, and 22.022.
  • the present invention provides a IX crystal form of the compound represented by formula (I), characterized in that: its X-ray powder diffraction pattern at a 2 ⁇ angle of 7.556, 8.016, 11.409, 12.372, 13.896, There are characteristic peaks at 14.392, 16.197, 18.037, 22.022 and 24.851.
  • the present invention provides a IX crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is shown in FIG. 17.
  • the invention provides a method for preparing the IX crystal form of the compound represented by formula (I), which includes the steps of mixing the crystalline form V of the compound represented by formula (I) in an appropriate amount of isoamyl alcohol at room temperature, and filtering.
  • the present invention provides an X crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2 ⁇ angles of 5.954, 7.945, 9.279, 13.358, 15.065, 19.900, 21.920 .
  • the present invention provides an X crystalline form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern at 2 ⁇ angles is 5.954, 6.801, 7.945, 9.279, 12.419, There are characteristic peaks at 13.358, 15.065, 15.807, 19.900, 21.920 and 24.863.
  • the present invention provides an X crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is shown in FIG. 18.
  • the invention provides a method for preparing the crystal form X of the compound represented by formula (I), which comprises dissolving the compound V of formula (I) in an appropriate amount of dichloromethane at room temperature, adding paraxylene to crystallize, and filtering A step of.
  • the present invention provides a XI crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2 ⁇ angles of 5.119, 7.451, 12.115, 15.253, 16.303, and 18.857.
  • the present invention provides a XI crystal form of the compound represented by formula (I), characterized in that: its X-ray powder diffraction pattern at 2 ⁇ angles is 5.119, 6.603, 7.451, 12.115, 15.253, There are characteristic peaks at 16.303, 17.797, 18.857, 20.001, 24.623 and 25.259.
  • the present invention provides a XI crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is shown in FIG. 19.
  • the invention provides a method for preparing the XI crystal form of the compound represented by formula (I), which comprises dissolving the compound V crystal form represented by formula (I) in an appropriate amount of tetrahydrofuran at room temperature, and adding methyl tert-butyl ether to crystallize , Filtering steps.
  • the present invention provides an XII crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is 2.929, 7.069, 13.448, 15.504, 16.354, 17.926, 18.814, 22.574, 25.320 at 2 ⁇ angles There are characteristic peaks.
  • the present invention provides an XII crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is shown in FIG. 20.
  • the invention provides a method for preparing the crystal form XII of the compound represented by formula (I), which comprises the steps of mixing the crystal form V of the compound represented by formula (I) with an appropriate amount of isopropyl ether at room temperature and filtering.
  • the present invention provides an XIII crystal form of a compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is 6.201, 10.0451, 12.119, 14.042, 15.779, 18.045, 19.231, 21.982, 25.665 at 2 ⁇ angles There are characteristic peaks.
  • the present invention provides an XIII crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is shown in FIG. 21.
  • the invention provides a method for preparing crystal form XIII of the compound represented by formula (I), which comprises dissolving compound V of formula (I) in an appropriate amount of dichloromethane to dissolve at room temperature and adding methyl tert-butyl ether Crystallization and filtration steps.
  • the present invention provides a XIV crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has 2 ⁇ angles of 9.879, 14.723, 15.315, 16.500, 19.137, 24.137, 25.334, 26.387 Characteristic peaks.
  • the present invention provides a XIV crystal form of the compound represented by formula (I), characterized in that its X-ray powder diffraction pattern is shown in FIG. 22.
  • dissolved at room temperature or “heated solvent” refers to a state where the compound is completely dissolved
  • “beating” refers to a state where the compound is not completely dissolved
  • the method for preparing the crystal form of the compound represented by formula (I) according to the present invention optionally includes a drying step.
  • the present invention also relates to the crystal form I, II, III, IV, V, VI, VII, VII, VIII, and IX of the compound represented by formula (I)
  • the pharmaceutical composition further contains an anti-PD-1 antibody, preferably an anti-mouse PD-1 antibody.
  • the pharmaceutical composition can be made into any pharmaceutically acceptable dosage form.
  • the pharmaceutical preparations of IX crystal form, X crystal form, XI crystal form, XII crystal form, XIII crystal form, XIV crystal form can be formulated into tablets, capsules, pills, granules, solutions, suspensions, syrups, Injection (including injection, sterile powder for injection and concentrated solution for injection), suppository, inhalation or spray.
  • the pharmaceutical composition of the present invention can also be administered to patients or subjects in need of such treatment in any suitable way of administration, such as oral, parenteral, rectal, pulmonary or local administration.
  • oral administration the pharmaceutical composition can be made into oral preparations, such as oral solid preparations, such as tablets, capsules, pills, granules, etc.; or, oral liquid preparations, such as oral solutions, oral mixtures Suspension, syrup, etc.
  • oral preparations such as oral solid preparations, such as tablets, capsules, pills, granules, etc.
  • oral liquid preparations such as oral solutions, oral mixtures Suspension, syrup, etc.
  • the pharmaceutical preparation may also contain suitable fillers, binders, disintegrating agents, lubricants and the like.
  • parenteral administration the pharmaceutical preparation can be made into injections, including injections, sterile powders for injection and concentrated solutions for injection.
  • the pharmaceutical composition When prepared as an injection, the pharmaceutical composition can be produced using conventional methods in the existing pharmaceutical field. When preparing an injection, no additional agent may be added to the pharmaceutical preparation, or an appropriate additional agent may be added according to the nature of the drug. When used for rectal administration, the pharmaceutical preparation can be made into suppositories and the like. When used for pulmonary administration, the pharmaceutical preparation can be made into an inhalant or spray.
  • the present invention further relates to the crystal form I, II, III, IV, V, VI, VII, VII, VIII, and IX of the compound represented by formula (I) Form X, Form X, Form XI, Form XII, Form XIII, Form XIV or Form I, Form II, Form III, Form IV, Form V
  • the present invention further relates to the crystal form I, II, III, IV, V, VI, VII, VII, VIII, and IX of the compound represented by formula (I) Form X, Form XI, Form XII, Form XIII, Form XIV as ROR agonists or contain compounds of formula (I) Form I, Form II, Form III, Form IV
  • the compositions of the V crystal form, the VI crystal form, the VII crystal form, the VII crystal form, the VIII crystal form, the IX crystal form, the X crystal form, the XI crystal form, the XII crystal form, the XIII crystal form, the XIV crystal form are used in the preparation Use in medicine to prevent and/or treat tumors or cancer.
  • the present invention further relates to the crystal form I, II, III, IV, V, VI, VII, VII, VIII, and IX of the compound represented by formula (I) Use of Form X, Form X, Form XI, Form XII, Form XIII, Form XIV in combination with anti-PD-1 antibodies in the preparation of a medicament for the prevention and/or treatment of tumors or cancer.
  • the present invention further relates to the crystal form I, II, III, IV, V, VI, VII, VII, VIII, and IX of the compound represented by formula (I) Use of a composition of Form X, Form X, Form XI, Form XII, Form XIII, Form XIV and an anti-PD-1 antibody in the preparation of a medicament for preventing and/or treating tumor or cancer.
  • the compound of formula (I) of the present invention has crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V, crystal form VI, crystal form VII, crystal form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV are present in the pharmaceutical composition or medicine in therapeutically and/or prophylactically effective amounts.
  • the crystalline form of the compound represented by formula (I) of the present invention is present in the pharmaceutical composition or drug in unit dosage form.
  • the present invention provides a composition comprising any crystal form of the compound represented by formula (I), any crystal form of the compound represented by formula (I) or a mixture thereof provided by the present invention, and at least one pharmaceutically acceptable carrier, The step of mixing diluent or excipient.
  • the present invention further relates to a method of preparing a pharmaceutical composition, which comprises mixing a crystalline form selected from the compound represented by formula (I) of the present invention with at least one pharmaceutically acceptable carrier, diluent or excipient.
  • any crystalline or amorphous compound represented by formula (I) is mixed with an appropriate amount of solvent, and then heated Decrease the temperature or cool the crystal.
  • the "heating” in the preparation method provided by the present invention means that the heating temperature does not exceed the boiling temperature corresponding to the solvent used; the "temperature reduction” and “cooling” in the preparation method provided in the present invention refer to the internal temperature of the system Any temperature lower than the heating temperature, the temperature can be a point value or a range value, the “cooling” and “cooling” process can be program or non-program, in addition, the process of cooling or cooling is as in the art It is well known to the skilled person that agitation is optional.
  • the crystal form of the obtained compound represented by formula (I) was subjected to structure measurement and crystal form study by X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC).
  • XRPD X-ray powder diffraction pattern
  • DSC differential scanning calorimetry
  • the “X-ray powder diffraction pattern or XRPD” described in the present invention is a pattern obtained by using Cu-K ⁇ radiation in an X-ray powder diffractometer.
  • the “differential scanning calorimetry or DSC” described in the present invention refers to the measurement of the temperature difference and heat flow difference between the sample and the reference substance during the sample heating or constant temperature process 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" in the present invention refers to the diffraction angle, ⁇ is the 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, and more preferably ⁇ 0.2.
  • crystal plane spacing or crystal plane spacing (d value) in the present invention means that the spatial lattice selects three non-parallel unit vectors a, b, and c that connect two adjacent lattice points, which point
  • the array is divided into juxtaposed parallelepiped units, called interplanar spacing.
  • the spatial lattice is divided according to the determined parallel hexahedral unit connection to obtain a set of straight grids, called spatial lattices or lattices.
  • the lattice and lattice reflect the periodicity of the crystal structure with geometric dots and lines, respectively. Different crystal planes have different surface spacing (ie, the distance between two adjacent parallel crystal planes); the unit is Or Egypt.
  • the compounds of formula (I) prepared in the present invention are of the crystal form I, II, III, IV, V, VI, VII, VII, VIII Types IX, X, X, XI, XII, XIII, and XIV have good stability and high purity, and can meet the pharmaceutical requirements for production, transportation and storage.
  • the production process is stable and Repeatable and controllable, able to adapt to industrial production.
  • Figure 2 Shows the effect of compound of formula (I) alone or in combination with anti-mouse-PD-1 antibody on MC38 colorectal tumor growth in C57BL/6 mice;
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the measurement of NMR was performed by Bruker AVANCE-400 nuclear magnetic instrument.
  • the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four.
  • Methylsilane (TMS) Methylsilane
  • the MS was measured with a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • HPLC was determined using Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm chromatographic column) and Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6mm chromatographic column).
  • XRPD is X-ray powder diffraction detection: the measurement is carried out using a BRUKER D8 X-ray diffractometer, the specific collection information: Cu anode (40kV, 40mA), Cu-K ⁇ 1 ray K ⁇ 2 rays K ⁇ rays Scanning range (2q range): 3 ⁇ 64°, scanning step length 0.02, slit width (collimator) 1.0mm.
  • the scanning steps are 3 steps, the scanning range of each step is 19°, the starting degree is 10°, the ending degree is 48°, and the length of each step is 45s.
  • DSC differential scanning calorimetry: the measurement adopts METTLER TOLEDO DSC 3+ differential scanning calorimeter, the heating rate is 10°C/min, the specific temperature range refers to the corresponding map (mostly 25-300 or 25-350°C), nitrogen purge The speed is 50mL/min.
  • TGA thermogravimetric analysis: the detection adopts METTLER TOLEDO TGA type 2 thermogravimetric analyzer, the heating rate is 10°C/min, the specific temperature range refers to the corresponding map (mostly 25-300°C), and the nitrogen purge speed is 20mL/min.
  • DVS dynamic moisture adsorption: the detection adopts SMS DVS Advantage, at 25 °C, the humidity change is 50%-95%-0%-95%-50%, the step is 10% (the last step is 50%) (specific range of humidity Based on the corresponding map, most of the methods listed here), the judgment standard is dm/dt is not greater than 0.02%.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the reaction progress was monitored by thin layer chromatography (TLC), the developing agent used in the reaction, the eluent system of column chromatography used for purifying the compound, and the developing agent system of thin layer chromatography include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system.
  • A Dichloromethane/methanol system
  • B n-hexane/ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound. It can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • reaction liquid was cooled, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1c (13 g, yield: 88.47%).
  • the prepared compound represented by formula (I) is characterized by XRPD as amorphous, and the XRPD pattern is shown in FIG. 1.
  • Test Example 1 Determination of the activity of the compound of the present invention on ROR ⁇ in vitro
  • TR-FRET ROR ⁇ co-activation system (Life Technologies)
  • the LanthaScreen TR-FRET (Time Resolved Fluorescence Energy Resonance Transfer) ROR ⁇ co-activation system was used to screen the compounds of the invention for the modulation of ROR ⁇ activity.
  • the negative control well was 5 ⁇ L complete buffer D, without ROR ⁇ LBD. Complete buffer D was used to prepare a mixture of anti-GST antibody (4X) (Life Technologies) containing 0.6 ⁇ M fluorescein-D22 (4X) and 8 nM terbium (Tb), and 5 ⁇ L of the mixture was added to a 384-well plate. The total reaction system is 20 ⁇ L. The 384-well plate was gently mixed on a shaker and incubated at room temperature in the dark for 2-4 hours.
  • Tecan Infinite M1000 detecting fluorescence readings by GraphPad Prism 6.0 software emission logarithmic curve plotted compound concentration ratio of wavelength 520nm / 495nm was calculated 50 / IC 50 value of the test compound EC.
  • the in vitro activity of the compound represented by formula (I) against ROR ⁇ was determined by the above test, and the measured EC 50 value was 15 (nM), and the Emax (%) was 107%, indicating the in vitro activity of compound represented by formula (I) against ROR ⁇ . It has obvious stimulating effect.
  • Test Example 2 Determination of the activity of the compound of the present invention on IL-17A enzyme-linked immunoassay
  • PBMC Human peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • the cell culture plate was placed in a 5% carbon dioxide 37°C incubator and incubated for 3 days. After 3 days of drug treatment, the cell culture supernatant was collected and the suspension was removed by centrifugation. Then IL-17A ELISA kit was used to quantify IL-17A in the supernatant. GraphPad Prism 6.0 was used to calculate the EC 50 value of the test compound.
  • the IL-17A enzyme-linked immunoassay quantitative analysis of the compound represented by formula (I) was determined by the above test, and the measured EC 50 value was 85 (nM), and the Emax (%) was 93%.
  • the compound represented by formula (I) It can obviously regulate the activity of IL-17A ELISA quantitative analysis.
  • Test Example 3 Mouse pharmacokinetic test of the compound of the present invention
  • mice Using mice as test animals, the drug concentration in the plasma at different times after intragastric administration of the compound of formula (I) was measured by LC/MS/MS method. The pharmacokinetic behavior of the compound of the present invention in mice was studied to evaluate its pharmacokinetic characteristics.
  • mice Nine C57 mice are group 1, female, purchased from Shanghai Jie Sijie Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2013-0006.
  • mice were given by intragastric administration after fasting overnight.
  • the dosage was 2.0 mg/kg and the volume was 0.2 ml/10 g.
  • mice were given the compound of formula (I) by intragastric administration. Before and after the administration, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours were collected with 0.1ml blood (3 mice per time point). Animals), placed in a heparinized test tube, centrifuged at 3500 rpm for 10 minutes to separate plasma, and stored at -20°C.
  • Determination of the content of the test compound in the plasma of mice after intragastric administration of different concentrations of drugs take 25 ⁇ l of mouse plasma at each moment after administration, add 80 ⁇ l (100 ng/mL) of internal standard solution camptothecin, 200 ⁇ l of acetonitrile Spin to mix for 5 minutes, centrifuge for 10 minutes (3600 rpm), and take 1 ⁇ l of the supernatant of the plasma sample for LC/MS/MS analysis.
  • the compound of the present invention has good pharmacokinetic absorption and has pharmacokinetic advantages.
  • Test Example 4 The efficacy of ROR ⁇ agonist in the mouse model of colorectal tumor of isotype MC38
  • the MC38 mouse model was used to evaluate the inhibitory effect of the compound represented by formula (I) on the growth of MC38 tumors.
  • mice The experimental female C57BL/6 mice were purchased from Charles River Lab (USA), 20-25 grams at the time of purchase, and 7-9 weeks old. 10 animals/cage rearing, constant temperature 23 ⁇ 1°C, humidity 50-60%, free to eat and water. All in accordance with the laboratory animal care and use committee (IACUC approved guidelines) for care and use. After the animals were purchased, the experiment was started after 7 days of adaptive feeding.
  • IACUC approved guidelines laboratory animal care and use committee
  • Anti-mouse PD-1 (CD279) antibody was purchased from BioXcell (clone RMP1-14; catalog number BP0146);
  • IgG2a isotype control antibody was purchased from BioXcell (clone 2A3; catalog number BE0089).
  • mice After the adaptive breeding of mice, group them as follows:
  • Dosing regimen IgG2a isotype control antibody loading body control group 8
  • Intraperitoneal injection Q3dx4 Compound of formula (I) 8 oral BIDx21 Anti-mouse PD-1 antibody plus compound of formula (I) 8
  • Q3dx4 represents administration every three days, giving a total of four times, fixed on the 5th, 8th, 11th and 14th day;
  • BIDx21 represents administration twice a day for 21 consecutive days
  • the experiment used female C57BL/6 mice (20-25 grams, 7-9 weeks old). Evaluation of the growth of isotype MC38 colorectal tumors (Synta Pharmaceuticals) in inbred line C57BL/6 mice to evaluate the compound of formula (I) alone or the compound of formula (I) and anti-mouse-PD-1 Antitumor activity in vivo of antibody co-administration.
  • Five hundred thousand (5 ⁇ 10 5 ) MC38 cells were implanted subcutaneously on the right abdomen of each mouse. After 5 days, when the tumor had grown to 40-80 mm 3 , the mice were randomly divided into groups and administered with formula (I) every day. The compound (30 mg/kg) was given twice, and it was continuously administered for 21 days.
  • Antibody PD-1 (CD279) was injected intraperitoneally (ip) in mice bearing MC38 tumors on days 5, 8, 11, and 14 in the treatment experiment of antibody alone or in combination with the compound of formula (I) ) Antibody (BioXcell) (5 mg/kg).
  • the control group is the carrier CMC-Na agent formula and IgG2a isotype control antibody.
  • tumor volume (mm 3 ) l ⁇ w ⁇ h ⁇ 0.5236, where 1 is the length of the tumor, w is the width of the tumor, and h is the height of the tumor , In millimeters.
  • TGI As shown in FIG. 2, when 30 mg/kg of the compound represented by formula (I) is administered alone, the TGI is 40%. When the anti-mouse PD-1 (CD279) antibody (5 mg/kg) was injected alone, the TGI was 51%. When co-administered with anti-mouse PD-1 monoclonal antibody (5 mg/kg), the compound of formula (I) (30 mg/kg) showed a synergistic effect (TGI was 63%.
  • TGA spectrum is shown in Figure 5, with a weight loss of 1.026% from 40°C to 140°C.
  • the DSC spectrum of Form II shows the endothermic peaks at 111.42°C, 126.73°C and 160.57°C;
  • the TGA spectrum of Form II shows a weight loss of 0.82% from 45°C to 120°C.
  • the DSC spectrum of Form III shows that the endothermic peak value is 120.24°C, 165.14°C;
  • the TGA spectrum of Form III shows a weight loss of 0.85% from 40°C to 130°C.
  • the crystalline form III (150 mg, 245.48 ⁇ mol) of the compound represented by formula (I) was added to nitromethane (1.0 mL), and the slurry was stirred at room temperature for 72 hours, filtered, and the filter cake was collected and dried in vacuum to obtain the compound of formula (I)
  • the compound is solid (65mg, yield: 43.33%), which is defined as crystal form IV by X-ray powder diffraction.
  • the XRPD spectrum is shown in Figure 10, and the characteristic peak positions are shown in Table 6 below:
  • the DSC spectrum of Form IV shows that the endothermic peak value is 119.92°C;
  • the TGA spectrum of Form IV shows a weight loss of 1.75% from 40°C to 130°C.
  • the compound represented by formula (I) (300 mg, 490.96 umol) was added to methanol (3.0 mL), heated to reflux to dissolve, slowly cooled to room temperature, stirred at room temperature for 3 hours, filtered, the filter cake was collected, and vacuum dried to obtain
  • the compound solid represented by formula (I) (212 mg, yield: 70.67%) was detected by X-ray powder diffraction, and the product was defined as crystal form V.
  • the XRPD spectrum is shown in FIG. 11 and the characteristic peak positions are shown in Table 7 below :
  • the TGA spectrum is shown in Figure 13, with a weight loss of 2.83% from 45°C to 120°C.
  • the DSC spectrum of Form VI shows that the endothermic peaks are 102.03°C and 122.64°C;
  • the TGA spectrum of Form VI shows a weight loss of 4.28% at 40°C-90°C and a weight loss of 5.70% at 90°C-115°C.
  • the DSC spectrum of Form VII shows that the endothermic peak value is 107.35°C;
  • the TGA spectrum of Form VII shows a weight loss of 9.09% at 40°C-110°C and a weight loss of 3.77% at 110°C-245°C.
  • Form I (10mg, 16 ⁇ mol), Form II (10mg, 16 ⁇ mol), Form III (10mg, 16 ⁇ mol), Form IV (10mg, 16 ⁇ mol) were added to 0.1mL isopropanol All of them are suspensions. After mixing, the mixture was stirred at room temperature for 72 hours. The filter cake was collected and dried in vacuo to obtain the product (15.7 mg, yield: 39.25%). The product was Form I by X-ray powder diffraction.
  • Form I (10 mg, 16 ⁇ mol), Form II (10 mg, 16 ⁇ mol), Form III (10 mg, 16 ⁇ mol), and Form IV (10 mg, 16 ⁇ mol) were added to 0.1 mL of ethanol, Both were suspensions. After mixing, the mixture was stirred at room temperature for 72 hours. The filter cake was collected and dried in vacuo to obtain the product (24.8 mg, yield: 62.0%). The product was Form I by X-ray powder diffraction.
  • Form I (10mg, 16 ⁇ mol), Form II (10mg, 16 ⁇ mol), Form III (10mg, 16 ⁇ mol), Form IV (10mg, 16 ⁇ mol) were added to 0.1mL isopropyl ether All of them are suspensions. After mixing, the mixture was stirred at room temperature for 72 hours. The filter cake was collected and dried in vacuo to obtain the title product (21.8 mg, yield: 54.5%). The product was Form I by X-ray powder diffraction. .
  • Form I The compound represented by formula (I) Form I (5mg, 8 ⁇ mol), Form II ((5mg, 8 ⁇ mol), Form III (5mg, 8 ⁇ mol), Form V (5mg, 8 ⁇ mol), Form VI (5mg , 8 ⁇ mol), Form VII (5mg, 8 ⁇ mol) was added to 1mL of methyl tert-butyl ether, suspended, stirred at room temperature for 72 hours, the filter cake was collected and dried in vacuo to give the title product (10.9mg, yield: 36.33% ), detected by X-ray powder diffraction, the product is Form I.
  • Crystal form VIII DSC spectrum shows that the endothermic peak value is 109.72°C and the exothermic peak value is 122.15°C;
  • the crystalline form VIII TGA spectrum shows that the weight loss at 25°C-80°C is 1.27%, the weight loss at 80°C-110°C is 8.70%, and the weight loss at 110°C-250°C is 5.53%.
  • the TGA spectrum of Form IX shows a weight loss of 1.40% at 25°C-80°C and a weight loss of 5.57% at 80°C-120°C.
  • the DSC spectrum of Form X shows that the endothermic peak value is 87.31°C and the exothermic peak value is 109.48°C;
  • the TGA spectrum of Form X shows that the weight loss at 25°C-65°C is 0.76%, the weight loss at 80°C-110°C is 5.15%, and the weight loss at 110°C-270°C is 9.97%.
  • the DSC spectrum of Form XI shows that the first endothermic peak is 96.72°C, the second endothermic peak is 101.39°C, and the exothermic peak is 139.08°C;
  • the TGA spectrum of Form XI shows a weight loss of 3.23% at 25°C-80°C, a weight loss of 5.15% at 80°C-110°C, and a weight loss of 8.62% at 80°C-240°C.
  • the compound represented by formula (I) (50 mg, Form V) was added with 1 ml of isopropyl ether, and the mixture was stirred and beaten at room temperature. After stirring for 72 h, it was centrifuged to dry the precipitated solid in a 100 mb vacuum drying oven at 50° C. for two hours. Take it out, and detect it by X-ray powder diffraction. The product is defined as crystal form XII.
  • the XRPD spectrum is shown in Figure 20.
  • the characteristic peak positions are shown in Table 14 below:
  • the DSC spectrum of crystal form XII shows that the endothermic peak value is 110.77°C;
  • the TGA spectrum of Form XIII shows a weight loss of 1.48% at 25°C-80°C and a weight loss of 1.19% at 80°C-110°C.
  • Example 21 the experiment of the influencing factors of crystal form I of the present invention
  • Example 22 the long-term accelerated stability experiment of the crystalline form I of the present invention
  • the compound of formula (I) crystalline form I (Example 2) has been subjected to long-term (25°C, 60%RH) and accelerated (40°C, 75%RH) stability investigations for 3 months. .
  • Example 23 the experiment of influencing factors of the crystalline form V of the present invention
  • the analysis method of related substances in the sample is the peak area normalization method.
  • the compound V of formula (I) was subjected to long-term (25°C, 60%RH) and accelerated (40°C, 75%RH) stability inspection for 3 months, and the planned inspection time was 6 months.
  • the analysis method of related substances in the sample is the peak area normalization method.

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Abstract

La présente invention concerne une forme cristalline pour un dérivé d'indole-formamide et un procédé de préparation de la forme cristalline. Une nouvelle forme cristalline d'un composé représenté par la formule (I) a une bonne stabilité, et peut être mieux utilisée dans un traitement clinique.
PCT/CN2020/070188 2019-01-04 2020-01-03 Forme cristalline pour dérivé d'indole-formamide et procédé de préparation de la forme cristalline WO2020140960A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017024018A1 (fr) * 2015-08-05 2017-02-09 Vitae Pharmaceuticals, Inc. Modulateurs de ror-gamma
WO2017157332A1 (fr) * 2016-03-18 2017-09-21 江苏恒瑞医药股份有限公司 Dérivé amide aromatique, procédé de préparation de ce dernier, et applications pharmaceutiques de ce dernier
WO2019007382A1 (fr) * 2017-07-06 2019-01-10 江苏恒瑞医药股份有限公司 Dérivé d'indole-formamide, son procédé de préparation et son utilisation en médecine
WO2019052440A1 (fr) * 2017-09-12 2019-03-21 江苏恒瑞医药股份有限公司 Dérivé d'indole-formamide substitué par un atome de deutérium, son procédé de préparation et ses applications médicales

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017024018A1 (fr) * 2015-08-05 2017-02-09 Vitae Pharmaceuticals, Inc. Modulateurs de ror-gamma
WO2017157332A1 (fr) * 2016-03-18 2017-09-21 江苏恒瑞医药股份有限公司 Dérivé amide aromatique, procédé de préparation de ce dernier, et applications pharmaceutiques de ce dernier
WO2019007382A1 (fr) * 2017-07-06 2019-01-10 江苏恒瑞医药股份有限公司 Dérivé d'indole-formamide, son procédé de préparation et son utilisation en médecine
WO2019052440A1 (fr) * 2017-09-12 2019-03-21 江苏恒瑞医药股份有限公司 Dérivé d'indole-formamide substitué par un atome de deutérium, son procédé de préparation et ses applications médicales

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