WO2020140960A1 - 吲哚甲酰胺类衍生物的晶型及其制备方法 - Google Patents

吲哚甲酰胺类衍生物的晶型及其制备方法 Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound represented
crystal form
ray powder
powder diffraction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2020/070188
Other languages
English (en)
French (fr)
Inventor
赵苗苗
陈杰
尤凌峰
杜振兴
王捷
贺峰
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
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jiangsu Hengrui Medicine Co Ltd, Shanghai Hengrui Pharmaceutical Co Ltd filed Critical Jiangsu Hengrui Medicine Co Ltd
Priority to CN202080007450.7A priority Critical patent/CN113227048B/zh
Publication of WO2020140960A1 publication Critical patent/WO2020140960A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—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.

Landscapes

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

Abstract

涉及吲哚甲酰胺类衍生物的晶型及其制备方法。式(I)所示化合物的新晶型具备良好的稳定性，可更好地用于临床治疗。

Description

吲哚甲酰胺类衍生物的晶型及其制备方法
本申请要求申请日为2019年1月4日的中国专利申请CN201910006064.5的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种吲哚甲酰胺类衍生物的晶型及其制备方法，属于制药领域。
背景技术
维甲酸相关孤儿核受体(Retinoid-related orphan receptors,ROR)是核受体家族的成员之一，也是一类配体依赖的转录因子，它能够调控多种生理和生化过程，包括生殖发育、新陈代谢、免疫系统调节等(Mech Dev.1998Jan,70(1-2:147-53；EMBO J.1998Jul 15,17(14):3867-77)。ROR家族包括三种类型RORα、RORβ和RORγ(Curr Drug Targets Inflamm Allergy.2004Dec,3(4):395-412),其中RORγ可以在许多组织中表达，包括胸腺、肝脏、肾脏、脂肪和骨骼肌等(Immunity.1998Dec,9(6):797-806.)。
RORγ有两种亚型：RORγ1和RORγt(RORγ2)，其中RORγ1在许多组织中表达，如：胸腺、肌肉、肾脏和肝脏中表达，而RORγt则只在免疫细胞内表达(Eur J Immunol.1999Dec,29(12):4072-80)。已有文献报道，RORγt能够调节在免疫细胞分化的过程中T细胞的存活，并能激活和促进CD4+、CD8+的细胞分化成辅助T细胞17(Th17)和细胞毒性T细胞(Tc17)(J Immunol.2014 Mar 15,192(6):2564-75)，其中TH17和Tc17细胞是一类效应细胞，通过分泌白介素17(IL-17)和其他炎症因子(如IL-21)促进炎症反应、增强获得性免疫反应和自身免疫应答。此外，现有研究证明，通过将Th17和Tc17细胞移植到荷瘤小鼠中，可以明显抑制移植瘤的生长(J Immunol.2010 Apr 15,184(8):4215-27)。Th17还可以招募细胞毒性CD8+T细胞和自然杀伤细胞进入肿瘤微环境，从而杀死肿瘤细胞，达到抗肿瘤的目的(Blood.2009 Aug 6,114(6):1141-9；Clin Cancer Res.2008 Jun 1,14(11):3254-61)。因此，激活RORγt，有可能成为新的抗肿瘤疗法。
目前，已有医药公司开发出RORγt的激动剂，比如Lycera Corp.公司开发的小分子药物LYC-55716。临床前研究表明，其类似物LYC-54143可通过两条不同的通路抑制肿瘤生长，表现出优越的抗癌活性。首先，LYC-54143激活RORγt后可通过传统途径调节Th17和Tc17细胞的分化，促进IL-17等其他细胞因子的表达，提高T细胞活性。另外，激活的RORγt可以调节免疫系统中的多种基因表达，抑制细胞检查受体PD-1的表达，从而降低免疫抑 制，提高抗癌活性(Oncoimmunology.2016 Nov 4,5(12):e1254854；ACS Chem Biol.2016 Apr 15,11(4):1012-8)。虽然LYC-55716目前已经进入临床II期，但是有关该靶点激动剂的药物仍然非常少，并且无上市药物出现，已公开的专利有如WO2015171558、WO2008152260、WO2007068580、WO2007068579、WO2005056516、WO2005056510、WO2005066116、WO00228810，仍需要继续开发更高效的新的RORγt激动剂，以期为患者提供新的有效的抗癌药物。
PCT/CN2018/094610(申请日2018.07.05)中提供了一种式(I)所示的ROR激动剂，文本中对于其晶型结构未做描述，
Figure PCTCN2020070188-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，结晶条件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。因此，深入研究式(I)化合物的晶型及相关制备方法，改善式(I)所示化合物的各方面性质是很有必要的。
发明内容
本发明的目的在于提供一种式(I)所示化合物的新晶型，新晶型具备良好的稳定性，可更好地应用于临床。
本发明提供一种式(I)所示化合物的I晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为8.999、9.715、10.594、12.560、13.530、15.141、16.238、17.109、21.725、24.633、25.156处有特征峰。
Figure PCTCN2020070188-appb-000002
在一个优选的实施方案中，本发明提供了一种式(I)所示化合物的I晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为8.999、9.715、10.594、12.560、12.904、13.530、15.141、16.238、17.109、17.903、18.974、19.658、21.725、23.258、24.633、25.156处有特征峰。
在一个优选的实施方案中，本发明提供一种式(I)所示化合物的I晶型，其特征在于：其X-射线粉末衍射图谱如图3所示。
一种制备式(I)所示化合物I晶型的方法，包括
1)将任意晶型或者无定型式(I)所示化合物混于适量的溶剂中加热溶解，冷却析晶，过滤的步骤，所述溶剂选自正丙醇、异丙醇、乙醇、叔丁醇、水-乙醇混合物；或
2)将含有I晶型的式(I)所示化合物混于适量的溶剂中室温打浆，过滤的步骤，所述溶剂选自乙醇、异丙醇、异丙醚、甲基叔丁基醚。
本发明提供了一种式(I)所示化合物的II晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为14.080、15.259、16.285、17.047、18.577、20.356、21.932、25.507处有特征峰。
在一个优选的实施方案中，发明提供了一种式(I)所示化合物的II晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为14.080、15.259、16.285、17.047、18.577、20.356、21.932、22.571、25.507、28.465、29.360、32.104、35.644处有特征峰。
在一个优选的实施方案中，本发明提供一种式(I)所示化合物的II晶型，其特征在于：其X-射线粉末衍射图谱如图8所示。
一种制备式(I)所示化合物II晶型的方法，包括
1)将式(I)所示化合物任意晶型或无定型混于适量的丙酮中，加热溶解，冷却析晶，过滤的步骤；或
2)将式(I)所示化合物任意晶型或无定型混于适量的丙酮中，室温溶解，加入选自异丙醚、正庚烷、甲基叔丁基醚、环己烷任意一种的反溶剂，析晶，过滤的步骤。
本发明提供了一种式(I)所示化合物的III晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为6.203、6.962、9.163、12.298、13.774、14.679、15.353、16.094、18.702、20.234处有特征峰。
在一个优选的实施方案中，本发明提供了一种式(I)所示化合物的III晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为6.203、6.962、9.163、12.298、13.774、14.679、15.353、16.094、16.835、18.702、20.234、23.163、24.921、27.936处有特征峰。
在一个优选的实施方案中，本发明提供一种式(I)所示化合物的III晶型，其特征在于：其X-射线粉末衍射图谱如图9所示。
一种制备式(I)所示化合物III晶型的方法，包括：
1)将式(I)所示化合物任意晶型或无定型混于适量的乙腈中，加热溶解，冷却析晶，过滤的步骤；或
2)将式(I)所示化合物任意晶型或无定型混于适量的乙腈中，室温溶解，加水析晶、过滤的步骤。
本发明提供了一种式(I)所示化合物的IV晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为7.229、9.160、11.423、13.782、14.524、17.060、17.832、21.628处有特征峰。
在一个优选的实施方案中，本发明提供了一种式(I)所示化合物的IV晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为7.229、9.160、11.423、13.782、14.524、17.060、17.832、21.628、22.575、23.028、26.495处有特征峰。
在一个优选的实施方案中，本发明提供一种式(I)所示化合物的IV晶型，其特征在于：其X-射线粉末衍射图谱如图10所示。
一种制备式(I)所示化合物IV晶型的方法，包括
1)将式(I)所示化合物的III晶型混于硝基甲烷中室温打浆，过滤；
2)将式(I)所示化合物的V晶型混于二氯乙烷中室温打浆，过滤，或
3)将式(I)所示化合物任意晶型或无定型混于适量的二氯甲烷中室温溶解，加入正庚烷析晶，过滤的步骤。
本发明提供了一种式(I)所示化合物的V晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为14.920、15.298、19.136、24.132、25.319、26.396、28.897处有特征峰。
在一个优选的实施方案中，本发明提供了一种式(I)所示化合物的V晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为5.472、9.857、14.920、15.298、19.136、22.108、24.132、25.319、26.396、27.729、28.897处有特征峰。
在一个优选的实施方案中，本发明提供一种式(I)所示化合物的V晶型，其特征在于：其X-射线粉末衍射图谱如图11所示。
一种制备式(I)所示化合物V晶型的方法，包含
1)式(I)所示化合物任意晶型或无定型混于适量的甲醇中，加热溶解，冷却析晶，过滤的步骤；或
2)将不含I晶型的式(I)所示化合物的晶型或无定型混于适量的溶剂中室温打浆，过滤的步骤，所述溶剂选自甲醇-水、异丙醇-水、乙醇-水、环己烷、正庚烷、水。
本发明提供了一种式(I)所示化合物的VI晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为6.151、7.533、8.447、11.454、12.429、16.156、18.166处有特征峰。
在一个优选的实施方案中，本发明提供了一种式(I)所示化合物的VI晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为6.151、7.533、8.447、11.454、12.429、13.904、 14.313、16.156、18.166、19.341、22.001、23.064、24.933处有特征峰。
在一个优选的实施方案中，本发明提供一种式(I)所示化合物的VI晶型，其特征在于：其X-射线粉末衍射图谱如图14所示。
一种制备式(I)所示化合物VI晶型的方法，包括将III晶型的式(I)所示化合物混于适量的溶剂中室温打浆，过滤的步骤，所述溶剂选自4-甲基-2-戊酮。
本发明提供了一种式(I)所示化合物的VII晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为6.744、8.415、10.545、11.581、15.199、16.585、17.340、18.482、20.099处有特征峰。
在一个优选的实施方案中，本发明提供了一种式(I)所示化合物的VII晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为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处有特征峰。
在一个优选的实施方案中，本发明提供一种式(I)所示化合物的VII晶型，其特征在于：其X-射线粉末衍射图谱如图15所示。
一种制备式(I)所示化合物VII晶型的方法，包括将III晶形式(I)所示化合物混合适量的溶剂中室温打浆、过滤的步骤，所述溶剂选自二氧六环、四氢呋喃。
本发明提供了一种式(I)所示化合物的VIII晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为6.917、11.614、13.018、14.992、16.616、17.613处有特征峰。
在一个优选的实施方案中本发明提供了一种式(I)所示化合物的VIII晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为6.917、11.614、13.018、14.992、16.616、17.613、20.641、24.178、24.712、26.541、27.317处有特征峰。
在一个优选的实施方案中，本发明提供一种式(I)所示化合物的VIII晶型，其特征在于：其X-射线粉末衍射图谱如图16所示。
本发明提供一种制备式(I)所示化合物的VIII晶型的方法，包括将式(I)所示化合物V晶型混于适量的邻二甲苯中室温打浆、过滤的步骤。
本发明提供了一种式(I)所示化合物的IX晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为8.016、12.372、13.896、16.197、18.037、22.022处有特征峰。
在一个优选的实施方案中本发明提供了一种式(I)所示化合物的IX晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为7.556、8.016、11.409、12.372、13.896、14.392、16.197、18.037、22.022、24.851处有特征峰。
在一个优选的实施方案中，本发明提供一种式(I)所示化合物的IX晶型，其特征在于：其X-射线粉末衍射图谱如图17所示。
本发明提供一种制备式(I)所示化合物的IX晶型的方法，包括将式(I)所示化合物V晶型混于适量的异戊醇中室温打浆、过滤的步骤。
本发明提供了一种式(I)所示化合物的X晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为5.954、7.945、9.279、13.358、15.065、19.900、21.920处有特征峰。
在一个优选的实施方案中本发明提供了一种式(I)所示化合物的X晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为5.954、6.801、7.945、9.279、12.419、13.358、15.065、15.807、19.900、21.920、24.863处有特征峰。
在一个优选的实施方案中，本发明提供一种式(I)所示化合物的X晶型，其特征在于：其X-射线粉末衍射图谱如图18所示。
本发明提供一种制备式(I)所示化合物的X晶型的方法，包括将式(I)所示化合物V晶型混于适量二氯甲烷中室温溶解，加对二甲苯析晶，过滤的步骤。
本发明提供了一种式(I)所示化合物的XI晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为5.119、7.451、12.115、15.253、16.303、18.857处有特征峰。
在一个优选的实施方案中本发明提供了一种式(I)所示化合物的XI晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为5.119、6.603、7.451、12.115、15.253、16.303、17.797、18.857、20.001、24.623、25.259处有特征峰。
在一个优选的实施方案中，本发明提供一种式(I)所示化合物的XI晶型，其特征在于：其X-射线粉末衍射图谱如图19所示。
本发明提供一种制备式(I)所示化合物的XI晶型的方法，包括将式(I)所示化合物V晶型混于适量的四氢呋喃中室温溶解，加甲基叔丁基醚析晶、过滤的步骤。
本发明提供了一种式(I)所示化合物的XII晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为4.829、7.069、13.448、15.504、16.354、17.926、18.814、22.574、25.320处有特征峰。
在一个优选的实施方案中，本发明提供一种式(I)所示化合物的XII晶型，其特征在于：其X-射线粉末衍射图谱如图20所示。
本发明提供一种制备式(I)所示化合物的XII晶型的方法，包括将式(I)所示化合物V晶型混于适量的异丙醚室温打浆，过滤的步骤。
本发明提供了一种式(I)所示化合物的XIII晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为6.201、10.0451、12.119、14.042、15.779、18.045、19.231、21.982、25.665处有特征峰。
在一个优选的实施方案中，本发明提供一种式(I)所示化合物的XIII晶型，其特征在 于：其X-射线粉末衍射图谱如图21所示。
本发明提供一种制备式(I)所示化合物的XIII晶型的方法，包括将式(I)所示化合物V晶型混于适量的二氯甲烷中室温溶解、加甲基叔丁基醚析晶、过滤的步骤。
本发明提供了一种式(I)所示化合物的XIV晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为9.879、14.723、15.315、16.500、19.137、24.137、25.334、26.387处有特征峰。
在一个优选的实施方案中，本发明提供一种式(I)所示化合物的XIV晶型，其特征在于：其X-射线粉末衍射图谱如图22所示。
本发明中所述的“室温溶解”或“加热溶剂”指化合物全溶的状态，所述“打浆”指化合物非全溶状态。
本发明所述的制备式(I)所示化合物的晶型的方法，任选包含干燥的步骤。
本发明还涉及包括式(I)所示化合物I晶型、II晶型、III晶型、IV晶型、V晶型、VI晶型、VII晶型、VII晶型、VIII晶型、IX晶型、X晶型、XI晶型、XII晶型、XIII晶型、XIV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。在本发明一个实施方案中，所述药物组合物进一步含有抗PD-1抗体，优选抗鼠PD-1抗体。所述药物组合物可以制成药学上可接受的任一剂型。例如，含本发明的式(I)所示化合物的I晶型、II晶型、III晶型、IV晶型、V晶型、VI晶型、VII晶型、VII晶型、VIII晶型、IX晶型、X晶型、XI晶型、XII晶型、XIII晶型、XIV晶型的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。
本发明进一步涉及式(I)所示化合物的I晶型、II晶型、III晶型、IV晶型、V晶型、 VI晶型、VII晶型、VII晶型、VIII晶型、IX晶型、X晶型、XI晶型、XII晶型、XIII晶型、XIV晶型或含有式(I)所示化合物I晶型、II晶型、III晶型、IV晶型、V晶型、VI晶型、VII晶型、VII晶型、VIII晶型、IX晶型、X晶型、XI晶型、XII晶型、XIII晶型、XIV晶型的组合物在制备ROR激动剂中的用途。
本发明进一步涉及式(I)所示化合物的I晶型、II晶型、III晶型、IV晶型、V晶型、VI晶型、VII晶型、VII晶型、VIII晶型、IX晶型、X晶型、XI晶型、XII晶型、XIII晶型、XIV晶型作为ROR激动剂或含有式(I)所示化合物I晶型、II晶型、III晶型、IV晶型、V晶型、VI晶型、VII晶型、VII晶型、VIII晶型、IX晶型、X晶型、XI晶型、XII晶型、XIII晶型、XIV晶型的组合物在制备用于预防和/或治疗肿瘤或癌症的药物中的用途。
本发明进一步涉及式(I)所示化合物的I晶型、II晶型、III晶型、IV晶型、V晶型、VI晶型、VII晶型、VII晶型、VIII晶型、IX晶型、X晶型、XI晶型、XII晶型、XIII晶型、XIV晶型联合抗PD-1抗体在制备用于预防和/或治疗肿瘤或癌症的药物中的用途。
本发明进一步涉及包含式(I)所示化合物I晶型、II晶型、III晶型、IV晶型、V晶型、VI晶型、VII晶型、VII晶型、VIII晶型、IX晶型、X晶型、XI晶型、XII晶型、XIII晶型、XIV晶型与抗PD-1抗体的组合物在制备用于预防和/或治疗肿瘤或癌症的药物中的用途。
在某些实施方案中，本发明的式(I)所示化合物的I晶型、II晶型、III晶型、IV晶型、V晶型、VI晶型、VII晶型、VII晶型、VIII晶型、IX晶型、X晶型、XI晶型、XII晶型、XIII晶型、XIV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，本发明的式(I)所示化合物的晶型以单位剂量的形式存在于药物组合物或药物中。
本发明提供一种包含式(I)所示化合物的任意晶型的组合物，由本发明提供的式(I)所示化合物的任意晶型或其混合物与至少一种药学上可接受的载体、稀释剂或赋形剂混合的步骤。
本发明进一步涉及一种制备药物组合物的方法，包括使选自本发明的式(I)所示化合物的晶型与至少一种药学上可接受的载体、稀释剂或赋形剂混合。
在一种实施方案中，本发明提供的式(I)所示化合物的晶型的制备方法中，任意晶形或无定型的式(I)所示化合物混合于适量的溶剂的操作，先加热后降温或者冷却析晶。
本发明提供的制备方法中所述的“加热”是指加热温度不超过使用溶剂对应的沸点温度；本发明中提供的制备方法中所述的“降温”、“冷却”是指体系的内部温度降至低于加热 温度的任意温度，该温度可以是点值或者区间值，所述的“降温”、“冷却”过程可以是程序式或非程序式，另外降温或冷却的过程中如本领域技术人员公知任选有搅拌的操作。
通过X-射线粉末衍射图谱(XRPD)、差示扫描量热分析(DSC)对所得到式(I)所示化合物的晶型进行结构测定、晶型研究。
发明详述
在本申请的说明书和权利要求书中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。然而，为了更好地理解本发明，下面提供了部分相关术语的定义和解释。另外，当本申请所提供的术语的定义和解释与本领域技术人员所通常理解的含义不一致时，以本申请所提供的术语的定义和解释为准。
本发明所述的“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 PCTCN2020070188-appb-000003
衍射的级数n为任何正整数，一般取一级衍射峰，n＝1)，当X射线以掠射角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“X-射线粉末衍射图谱或XRPD”是通过在X-射线粉末衍射仪中使用Cu-Kα辐射得到的图谱。
本发明所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
本发明所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度，2θ的误差范围为±0.1～±0.5，优选±0.1～±0.3，更优选±0.2。
本发明所述的“晶面间距或晶面间距(d值)”是指空间点阵选择3个不相平行的连结相邻两个点阵点的单位矢量a，b，c，它们将点阵划分成并置的平行六面体单位，称为晶面间距。空间点阵按照确定的平行六面体单位连线划分，获得一套直线网格，称为空间格子或晶格。点阵和晶格是分别用几何的点和线反映晶体结构的周期性，不同的晶面，其面间距(即相邻的两个平行晶面之间的距离)各不相同；单位为
Figure PCTCN2020070188-appb-000004
或埃。
经研究表明，本发明制备的式(I)所示化合物的I晶型、II晶型、III晶型、IV晶型、V晶型、VI晶型、VII晶型、VII晶型、VIII晶型、IX晶型、X晶型、XI晶型、XII晶型、XIII晶型、XIV晶型晶型稳定性良好、纯度较高，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.式(I)所示化合物无定型XRPD图谱；
图2.显示式(I)所示化合物单独施用或者与抗鼠-PD-1抗体联合用药在C57BL/6小鼠中对MC38结肠直肠肿瘤生长的影响；
图3.式(I)所示化合物I晶型XRPD图谱；
图4.式(I)所示化合物I晶型DSC图谱；
图5.式(I)所示化合物I晶型TGA图谱；
图6.式(I)所示化合物I晶型DVS图谱；
图7.式(I)所示化合物I晶型DVS测试前后XRPD图谱；
图8.式(I)所示化合物II晶型XRPD图谱；
图9.式(I)所示化合物III晶型XRPD图谱；
图10.式(I)所示化合物IV晶型XRPD图谱；
图11.式(I)所示化合物V晶型XRPD图谱；
图12.式(I)所示化合物V晶型DSC图谱；
图13.式(I)所示化合物V晶型TGA图谱；
图14.式(I)所示化合物VI晶型XRPD图谱；
图15.式(I)所示化合物VII晶型XRPD图谱；
图16.式(I)所示化合物VIII晶型XRPD图谱；
图17.式(I)所示化合物IX晶型XRPD图谱；
图18.式(I)所示化合物X晶型XRPD图谱；
图19.式(I)所示化合物XI晶型XRPD图谱；
图20.式(I)所示化合物XII晶型XRPD图谱；
图21.式(I)所示化合物XIII晶型XRPD图谱；
图22.式(I)所示化合物XIV晶型XRPD图谱。
具体实施方式
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非限定本发明的实质和范围。
实验所用仪器的测试条件：
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6 (ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Thermo，型号：Finnigan LCQ advantage MAX)。
HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
XRPD为X射线粉末衍射检测：测定使用BRUKER D8型X射线衍射仪进行，具体采集信息：Cu阳极(40kV，40mA)，Cu-Kα1射线
Figure PCTCN2020070188-appb-000005
Kα2射线
Figure PCTCN2020070188-appb-000006
Kβ射线
Figure PCTCN2020070188-appb-000007
扫描范围(2q范围)：3～64°、扫描步长0.02、狭缝宽度(准直器)1.0mm。采用分步扫描法，扫描步数为3步，每步扫描范围19°，起始度数10°，终止度数48°，每步时长45s。
DSC为差示扫描量热：测定采用METTLER TOLEDO DSC 3+示差扫描量热仪，升温速率10℃/min，温度具体范围参照相应图谱(多为25-300或25-350℃)，氮气吹扫速度50mL/min。
TGA为热重分析：检测采用METTLER TOLEDO TGA 2型热重分析仪，升温速率10℃/min，温度具体范围参照相应图谱(多为25-300℃)，氮气吹扫速度20mL/min。
DVS为动态水分吸附：检测采用SMS DVS Advantage，在25℃，湿度变化为50％-95％-0％-95％-50％，步进为10％(最后一步为50％)(湿度具体范围以相应图谱为准，此处所列为大多使用方法)，判断标准为dm/dt不大于0.02％。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1、式(I)所示化合物的制备
实施例1
2-(4-氯-2-(三氟甲基)苄基)-N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-1-(2-氟代乙基)-1H-吲哚-5-甲酰胺
Figure PCTCN2020070188-appb-000008
第一步
2-(4-氯-2-(三氟甲基)苄基)-1H-吲哚-5-甲酸甲酯1c
将1H-吲哚-5-甲酸甲酯1b(7g，39.96mmol)，1-(溴甲基)-4-氯-2-(三氟甲基)苯1a(13.11g，47.95mmol)溶于200mL N,N-二甲基乙酰胺中，加入双(乙腈)二氯化钯(II)(2.07g，7.99mmol)，双环[2.2.1]-2-庚烯(3.76g，39.96mmol)和碳酸钠(8.47g，79.92mmol)，氩气氛下，加热至80℃搅拌反应17小时。冷却反应液，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题化合物1c(13g，产率：88.47％)。
MS m/z(ESI):368.1[M+1]。
第二步
2-(4-氯-2-(三氟甲基)苄基)-1-(2-氟代乙基)-1H-吲哚-5-甲酸甲酯1d
将化合物1c(0.3g,815.77μmol)，1-溴-2-氟乙烷(310.7mg,2.45mmol)溶于10mL N,N-二甲基甲酰胺，加入碳酸铯(797.38mg,2.45mmol)，微波条件下100℃反应1小时。冷却反应，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标 题化合物1d(0.25g，产率：74.06％)。
MS m/z(ESI):414.1[M+1]。
第三步
2-(4-氯-2-(三氟甲基)苄基)-1-(2-氟代乙基)-1H-吲哚-5-甲酸1e
将化合物1d(0.25g，604.17μmol)溶于20mL甲醇中，加入1.5mL 4N的氢氧化钠溶液，回流搅拌反应1小时。反应液冷却至室温，滴加入1M盐酸调节pH为3～4，加入水和乙酸乙酯各20mL，乙酸乙酯萃取(20mL×2)，合并有机相，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A纯化所得残余物，得到标题化合物1e(0.24g，产率：99.4％)。
MS m/z(ESI):400.1[M+1]。
第四步
2-(4-氯-2-(三氟甲基)苄基)-N-(1-(4-(乙磺酰基)苯基)-2-羟乙基)-1-(2-氟代乙基)-1H-吲哚-5-甲酰胺1g
将化合物1e(10mg，25.01μmol)溶于2mL N,N-二甲基甲酰胺中，加入2-氨基-2-(4-乙磺酰基苯基)乙醇1f(8.67mg，37.83μmol,采用专利申请“WO2016061160”公开的方法制备而得)和N,N-二异丙基乙胺(6.47mg，50.03μmol)，再加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(11.77mg，50.03μmol)，室温搅拌反应2小时。减压浓缩反应液，用高效液相色谱法纯化所得残余物，制得化合物1g(7.9mg，51.7％)。
MS m/z(ESI):611.5[M+1]。
1H NMR(400MHz,CDCl 3)δ8.13(s,1H),7.93-7.90(m,2H),7.77-7.75(m,2H),7.64-7.62(m,2H),7.47-7.45(m,1H),7.37-7.35(m,1H),7.16-7.14(m,1H),7.13-7.11(m,1H),6.33(s,1H)，5.40-5.38(m,1H),4.70-4.68(m,1H)，4.57-4.56(m,1H)，4.37-4.35(m,1H),4.35(s,2H),4.30-4.31(m,1H),4.11-4.06(m,2H),3.16-3.11(m,2H),1.33-1.29(m,3H)。
第五步
将化合物1g(120mg，0.197mmol)进行手性制备(分离条件：Superchiral S-AD(Chiralway),2cm I.D.×25cm Length,5um；流动相：二氧化碳/乙醇/二乙胺＝60/40/0.05(v/v/v)，流速：50g/min)，收集其相应组分，减压浓缩，得到式(I)所示化合物(52mg)。MS m/z(ESI):611.0[M+1]。
手性HPLC分析:保留时间11.747分钟，手性纯度：100％(色谱柱：Lux Amylose-1(AD)4.6×150mm 5um(带保护柱)；流动相：正己烷/乙醇(0.1％二乙胺)＝60/40(v/v))。
1H NMR(400MHz,CDCl 3)δ8.12(s,1H),7.93-7.91(m,2H),7.76-7.74(m,2H),7.65-7.63 (m,2H),7.47-7.45(m,1H),7.37-7.35(m,1H),7.15-7.11(m,2H),6.33(s,1H)，5.39-5.38(m,1H),4.70-4.69(m,1H)，4.59-4.56(m,1H)，4.37-4.36(m,1H),4.35(s,2H),4.31-4.30(m,1H),4.11-4.06(m,2H),3.17-3.11(m,2H),2.33(brs,1H),1.34-1.30(m,3H)。
制备得到的式(I)所示化合物经XRPD表征为无定型，XRPD图谱如图1。
生物学评价
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。
测试例1、本发明化合物对RORγ体外活性的测定
一、实验材料及仪器
1.
Figure PCTCN2020070188-appb-000009
TR-FRET RORγ共激活体系(Life Technologies)
2.RORγLBD(AB Vector)
3.DMSO(SigmaAldrich)
4.酶标仪(Tecan)
二、实验步骤
采用LanthaScreen TR-FRET(时间分辨荧光能量共振转移)RORγ共激活体系筛选本发明的化合物对RORγ活性的调节。
首先配制完整缓冲液D(complete TR-FRET Coregulator)(Life Technologies)包含终浓度5mM DTT。DMSO终浓度为2％。将待测化合物在含有2％DMSO的完整缓冲液D中连续稀释为2x终浓度，最高的剂量为60μM。10μl/孔加入384孔板的试验孔(PerkinElmer)。每个检测化合物在相同浓度下设置2个平行对照孔。准备4X RORγLBD(AB Vector)。使用完整缓冲液D稀释RORγLBD浓度为1ng/μL。5μl/孔加入384孔测定板的试验孔。阴性对照孔为5μL完整缓冲液D，无RORγLBD。使用完全缓冲液D配制含有0.6μM荧光素-D22(4X)和8nM铽(Tb)标记的抗GST抗体(4X)(Life Technologies)混合液，将5μL混合液加入到384孔板中。总反应体系为20μL。在振荡器上轻轻混匀该384孔板并在室温下避光孵育2-4小时。
使用Tecan Infinite M1000检测荧光读数,通过GraphPad Prism 6.0软件绘制发射波长520nm/495nm的比值与化合物浓度的对数曲线，计算待测化合物的EC 50/IC 50值。
式(I)所示化合物对RORγ体外活性通过以上的试验进行测定，测得的EC 50值为15(nM),Emax(％)为107％，说明式(I)所示化合物对RORγ体外活性具有明显的激动作用。
测试例2、本发明化合物对IL-17A酶联免疫定量分析活性测定
一、实验材料及仪器
1.人外周血单核细胞(PBMC)(Zenbio)
2.淋巴细胞培养基(Zenbio)
3.TexMACS(Miltenyi Biotec)
4.人Cytostim(Miltenyi Biotec)
5.人IL-17酶联免疫试剂盒(R&D系统)
6.CO 2培养箱(Fisher Scientific)
7.离心机(Fisher Scientific)
8.96孔细胞培养板(Fisher Scientific)
9.酶标仪(Tecan)
二、实验步骤
将冻存的人外周血单核细胞(PBMC)在预热的淋巴细胞培养基中快速复苏，离心1000rpm，10min，除去细胞培养上清，将细胞轻轻悬浮于TexMACS培养基中，计数细胞。在细胞悬液中按比例加入T细胞激活试剂cytostim(10μl/ml)，然后以1×10 5外周血单核细胞/孔的密度将细胞种植于96孔细胞培养板中。使用TexMACS培养基梯度稀释待测化合物，分别加入各实验孔中，每组2-3个平行孔。准备只含细胞不含cytostim的阴性对照孔，以得到背景读数。将细胞培养板放置于5％二氧化碳37℃培养箱孵育3天。药物处理3天后收取细胞培养上清液，离心去除悬浮物。然后使用IL-17A酶联免疫试剂盒定量上清液中IL-17A。使用GraphPad Prism 6.0计算待测化合物的EC 50值。
式(I)所示化合物对IL-17A酶联免疫定量分析通过以上的试验进行测定，测得的EC 50值为85(nM)，Emax(％)为93％，式(I)所示化合物对IL-17A酶联免疫定量分析活性具有明显的调节作用。
药代动力学评价
测试例3、本发明化合物的小鼠药代动力学测试
1、摘要
以小鼠为受试动物，应用LC/MS/MS法测定了小鼠灌胃给予式(I)所示化合物后不同时刻血浆中的药物浓度。研究本发明化合物在小鼠体内的药代动力学行为，评价其药动学特征。
2、试验方案
2.1.试验药品
式(I)所示化合物。
2.2.试验动物
C57小鼠9只为1组，雌性，购自上海杰思捷实验动物有限公司，动物生产许可证号：SCXK(沪)2013-0006。
2.3.药物配制
称取一定量药物，加5％体积的DMSO、5％体积的吐温80和90％生理盐水配置成0.1mg/ml无色澄清透明液体。
2.4.给药
C57小鼠禁食过夜后灌胃给药，给药剂量均为2.0mg/kg，给药体积均为0.2ml/10g。
3、操作
小鼠灌胃给药式(I)所示化合物，于给药前及给药后0.25，0.5，1.0，2.0，4.0，6.0，8.0，11.0，24.0小时采血0.1ml(每个时间点3只动物)，置于肝素化试管中，3500转/分钟离心10分钟分离血浆，于-20℃保存。
测定不同浓度的药物灌胃给药后小鼠血浆中的待测化合物含量：取给药后各时刻的小鼠血浆25μl，加入内标溶液喜树碱80μl(100ng/mL)，乙腈200μl，涡旋混合5分钟，离心10分钟(3600转/分钟)，血浆样品取上清液1μl进行LC/MS/MS分析。
4、药代动力学参数结果
本发明化合物的药代动力学参数如下表1：
表1.小鼠药代实验结果
Figure PCTCN2020070188-appb-000010
结论：本发明化合物的药代吸收较好，具有药代动力学优势。
药效学评价
测试例4、RORγ激动剂在同种型MC38结肠直肠肿瘤小鼠模型的药效
1.实验目的
用MC38小鼠模型来评估式(I)所示化合物对MC38肿瘤生长的抑制作用。
2.实验方法和实验材料
2.1.实验动物和饲养条件
实验用雌性C57BL/6小鼠，购自Charles River Lab(美国)，购入时20-25克，7-9周龄。10只/笼饲养，温度23±1℃恒温，湿度50～60％，自由进食进水。一切按照实验动物护理和使用委员会(IACUC批准指南)进行护理和使用。动物购进后，进行7天适应性饲养后开始实验。
2.2.实验药品
式(I)所示化合物；
抗鼠PD-1(CD279)抗体购自BioXcell(克隆RMP1-14；目录编号BP0146)；
IgG2a同型对照抗体购自BioXcell(克隆2A3；目录编号BE0089)。
2.3.实验设计和实验方法
2.3.1.动物分组：
小鼠适应性饲养后，分组如下表2：
表2.小鼠给药实验方案
分组 n 给药方式 给药方案
IgG2a同型对照抗体加载体对照组 8 腹腔注射/口服 Q3dx4/BIDx21
抗鼠PD-1抗体 8 腹腔注射 Q3dx4
式(I)所示化合物 8 口服 BIDx21
抗鼠PD-1抗体加式(I)所示化合物 8 腹腔注射/口服 Q3dx4/BIDx21
注：1.Q3dx4代表每隔三天给药，总共给四次，固定在第5，8，11，14天给药；
2.BIDx21代表每天给药2次，连续给药21天；
2.3.2.实验方法：
实验使用雌性C57BL/6小鼠(20-25克，7-9周龄)。通过检测同种型MC38结肠直肠肿瘤(Synta Pharmaceuticals)在自交系C57BL/6小鼠的生长情况评估单独施用式(I)所示化合物或式(I)所示化合物与抗鼠-PD-1抗体联合施用的体内抗肿瘤活性。将五十万(5×10  5)MC38细胞植入每只小鼠的右侧腹部皮下，待5天后当肿瘤生长至40-80mm 3后，将小鼠随机分组，每天施用式(I)所示化合物(30mg/kg)2次，连续给药21天。在抗体单用或与式(I)所示化合物联合施用治疗实验中，固定在第5、8、11、14天分别对携 带MC38肿瘤的小鼠腹腔(i.p.)注射抗鼠PD-1(CD279)抗体(BioXcell)(5mg/kg)。对照组是载体CMC-Na药剂配方与IgG2a同型对照抗体。
2.4.数据表达：
用卡尺在三个维度中测量肿瘤体积，然后根据下式计算：肿瘤体积(mm 3)＝l×w×h×0.5236，其中，1表示肿瘤长度，w表示肿瘤的宽度，h表示肿瘤的高度，单位为毫米。肿瘤生长抑制率TGI％＝100x(TV 对照-TV 肿瘤)/(TV 对照-TV 初始)，其中TV 对照＝对照组的肿瘤体积；TV 肿瘤＝治疗组的肿瘤体积；TV 初始＝5天时起始肿瘤体积。
3.结果和讨论：
如图2所示，单独施用30mg/kg式(I)所示化合物时，TGI为40％。单独注射抗鼠PD-1(CD279)抗体(5mg/kg)时，TGI为51％。当与抗鼠PD-1单克隆抗体(5mg/kg)联合施用时，式(I)所示化合物(30mg/kg)表现出协同效应(TGI为63％。这些数据表明了在同基因的MC38结肠直肠肿瘤模型中，单独施用式(I)所示化合物表现出抑瘤活性，同时式(I)所示化合物与PD-1抗体联合施用表现出协同作用，这也表明式(I)所示化合物具有与RORγ激活(而非抑制)一致的生物活性，为提高免疫治疗的疗效开辟了新途径。
式(I)所示化合物晶型制备
实施例2、晶型I的制备
将式(I)所示化合物(1.2g，1.9638mmol)加入到乙醇(18mL)中，加热至回流溶清，缓慢降温至室温，室温搅拌3小时，过滤，滤液，收集滤饼，真空干燥，得到式(I)所示化合物固体(0.98g，收率：81.67％)。经X-射线粉末衍射检测，将该产物定义为晶型I，XRPD谱图如图3，其特征峰位置如下表3所示：
表3.I晶型特征峰
Figure PCTCN2020070188-appb-000011
Figure PCTCN2020070188-appb-000012
DSC谱图如图4，吸热峰峰值141.36℃；
TGA谱图如图5，40℃-140℃失重1.026％。
DVS检测显示在10％RH-80％RH之间，随着湿度增加，质量增加约为3.302％，小于15％但不小于2％，根据《中华人民共和国药典》2015年版药物引湿性试验指导原则，该样品有引湿性。在正常存储条件下(25℃，60％RH)吸收增重约为1.339％，在加速条件下(70％RH)吸湿增重约2.004％，在极端条件下(即90％RH)，吸湿增重约为3.019％，在0％-95％的湿度变化过程中，该样品的解吸附过程与吸附过程基本重合(见图6)。DVS检测后复测晶型，晶型未转变(见图7)。
实施例3、晶型II的制备
将式(I)所示化合物(300mg，490.96μmol)，加入丙酮(2.0mL)，加热至回流溶解，缓慢降温至室温，室温搅拌3小时，过滤，收集滤饼，真空干燥，得到式(I)所示化合物固体(159mg，产率：53.0％)，经X-射线粉末衍射检测，将该产物定义为晶型II，XRPD谱图如图8，其特征峰位置如下表4所示：
表4.II晶型特征峰
Figure PCTCN2020070188-appb-000013
Figure PCTCN2020070188-appb-000014
晶型II的DSC谱图显示吸热峰峰值111.42℃、126.73℃、160.57℃；
晶型II的TGA谱图显示45℃-120℃失重0.82％。
实施例4、晶型III的制备
将式(I)所示化合物(300mg，490.96μmol)，加入到乙腈(3.6mL)中，加热至回流溶清，缓慢降温至室温，室温搅拌3小时，过滤，收集滤饼，真空干燥得到式(I)所示化合物固体(201mg，产率：67.0％)，经X-射线粉末衍射检测，将该产物定义为晶型III，XRPD谱图如图9，特征峰位置如下表5所示：
表5.III晶型特征峰
Figure PCTCN2020070188-appb-000015
Figure PCTCN2020070188-appb-000016
晶型III的DSC谱图显示吸热峰峰值为120.24℃、165.14℃；
晶型III的TGA谱图显示40℃-130℃失重0.85％。
实施例5、晶型IV的制备
将式(I)所示化合物晶型III(150mg,245.48μmol)，加入到硝基甲烷中(1.0mL)，室温打浆搅拌72小时，过滤，收集滤饼，真空干燥，得到式(I)所示化合物固体(65mg，产率：43.33％)，经X-射线粉末衍射检测，将该产物定义为晶型IV，XRPD谱图如图10，特征 峰位置如下表6所示：
表6.IV晶型特征峰
Figure PCTCN2020070188-appb-000017
晶型IV的DSC谱图显示吸热峰峰值为119.92℃；
晶型IV的TGA谱图显示40℃-130℃失重1.75％。
实施例6、晶型V的制备
将式(I)所示化合物(300mg，490.96umol)，加入到甲醇中(3.0mL)，加热至回流溶清，缓慢降温至室温，室温搅拌3小时，过滤，收集滤饼，真空干燥，得到式(I)所示化合物固体(212mg，产率：70.67％)，经X-射线粉末衍射检测，将该产物定义为晶型V，XRPD谱图如图11，特征峰位置如下表7所示：
表7.V晶型特征峰
Figure PCTCN2020070188-appb-000018
Figure PCTCN2020070188-appb-000019
Figure PCTCN2020070188-appb-000020
DSC谱图如图12，吸热峰峰值为119.21℃；
TGA谱图如图13，45℃-120℃失重2.83％。
实施例7、晶型V的制备
式(I)所示化合物(100mg，V晶型)，加入1ml 10％水-异丙醇，室温打浆，离心，将沉淀固形物于60℃、100mb真空干燥箱内干燥两个小时后取出，经X-射线粉末衍射检测，显示为V晶型。
实施例8、晶型VI的制备
将式(I)所示化合物晶型III(50mg，82μmol)加入1.0mL 4-甲基-2-戊酮中，室温打浆72小时，过滤，收集滤饼，真空干燥，得到式(I)所示化合物固体(28.0mg，产率：56.0％)，经X-射线粉末衍射检测，将该产物定义为晶型VI，XRPD谱图如图14，特征峰位置如下表8所示：
表8.VI晶型特征峰
Figure PCTCN2020070188-appb-000021
Figure PCTCN2020070188-appb-000022
晶型VI的DSC谱图显示吸热峰峰值为102.03℃、122.64℃；
晶型VI的TGA谱图显示40℃-90℃失重4.28％，90℃-115℃失重5.70％。
实施例9、晶型VII的制备
将式(I)所示化合物晶型III(50mg，82μmol)加入1.0mL二氧六环中，室温打浆72小时，过滤，收集滤饼，真空干燥，得到式(I)所示化合物固体(31.0mg，产率：62.0％)，经X-射线粉末衍射检测，将该产物定义为晶型VII，XRPD谱图如图15，特征峰位置如下表9所示：
表9.VII晶型特征峰
Figure PCTCN2020070188-appb-000023
Figure PCTCN2020070188-appb-000024
晶型VII的DSC谱图显示吸热峰峰值为107.35℃；
晶型VII的TGA谱图显示40℃-110℃失重9.09％，110℃-245℃失重3.77％。
实施例10、晶型I的制备
将式(I)所示化合物晶型I(10mg，16μmol)、晶型II(10mg，16μmol)、晶型III(10mg，16μmol)、晶型IV(10mg，16μmol)分别加入0.1mL异丙醇中，均为混悬液，混合后室温搅拌72小时，收集滤饼，真空干燥，得到产物(15.7mg，产率：39.25％)，经X-射线粉末衍射检测，该产物为晶型I。
实施例11、晶型I的制备
将式(I)所示化合物晶型I(10mg，16μmol)、晶型II(10mg，16μmol)、晶型III(10mg，16μmol)、晶型IV(10mg，16μmol)分别加入0.1mL乙醇中，均为混悬液，混合后室温搅拌72小时，收集滤饼，真空干燥，得到产物(24.8mg，产率：62.0％)，经X-射线粉末衍射检测，该产物为晶型I。
实施例12、晶型I的制备
将式(I)所示化合物晶型I(10mg，16μmol)、晶型II(10mg，16μmol)、晶型III(10mg，16μmol)、晶型IV(10mg，16μmol)分别加入0.1mL异丙醚中，均为混悬液，混合后室 温搅拌72小时，收集滤饼，真空干燥，得到标题产物(21.8mg，产率：54.5％)，经X-射线粉末衍射检测，该产物为晶型I。
实施例13、晶型I的制备
将式(I)所示化合物晶型I(5mg，8μmol)、晶型II((5mg，8μmol)、晶型III(5mg，8μmol)、晶型V(5mg，8μmol)、晶型VI(5mg，8μmol)、晶型VII(5mg，8μmol)加入到1mL甲基叔丁基醚中，混悬，室温搅拌72小时，收集滤饼，真空干燥，得到标题产物(10.9mg，产率：36.33％)，经X-射线粉末衍射检测，该产物为晶型I。
实施例14、晶型VIII的制备
将式(I)所示化合物(10mg，V晶型)，加入1ml邻二甲苯，室温搅拌打浆，搅拌72h后，离心，将沉淀固形物于50℃、100mb真空干燥箱内干燥两个小时后取出，得到产物，经X-射线粉末衍射检测，将该产物定义为晶型VIII，XRPD谱图如图16，特征峰位置如下表10所示：
表10.VIII晶型特征峰
Figure PCTCN2020070188-appb-000025
Figure PCTCN2020070188-appb-000026
晶型VIII DSC谱图显示吸热峰峰值为109.72℃，放热峰峰值为122.15℃；
晶型VIII TGA谱图显示25℃-80℃失重1.27％，80℃-110℃失重8.70％，110℃-250℃失重5.53％。
实施例15、晶型IX的制备
式(I)所示化合物(10mg，V晶型)，加入1ml异戊醇，室温搅拌打浆，搅拌72h后，离心，将沉淀固形物于50℃、100mb真空干燥箱内干燥两个小时后取出，得到产物，经X-射线粉末衍射检测，将该产物定义为晶型IX，XRPD谱图如图17，特征峰位置如下表11所示：
表11.IX晶型特征峰
Figure PCTCN2020070188-appb-000027
Figure PCTCN2020070188-appb-000028
晶型IX的DSC谱图显示吸热峰峰值为99.73℃；
晶型IX的TGA谱图显示25℃-80℃失重1.40％，80℃-120℃失重5.57％。
实施例16、晶型X的制备
式(I)所示化合物(50mg，V晶型)，加入1ml二氯甲烷，室温搅拌溶解，依次加入1ml、2ml的对二甲苯，搅拌72个小时后，离心，将沉淀固形物于50℃、100mb真空干燥箱内干燥两个小时后取出，经X-射线粉末衍射检测，将该产物定义为晶型X，XRPD谱图如图18，特征峰位置如下表12所示：
表12.X晶型特征峰
Figure PCTCN2020070188-appb-000029
晶型X的DSC谱图显示吸热峰峰值为87.31℃，放热峰峰值为109.48℃；
晶型X的TGA谱图显示25℃-65℃失重0.76％，80℃-110℃失重5.15％，110℃-270℃失重9.97％。
实施例17、晶型XI的制备
式(I)所示化合物(50mg，V晶型)，加入1ml四氢呋喃，室温搅拌溶解，依次加入1ml、1ml、2ml的甲基叔丁基醚，搅拌72个小时后，离心，将沉淀固形物于50℃、100mb真空干燥箱内干燥两个小时后取出，经X-射线粉末衍射检测，将该产物定义为晶型XI，XRPD谱图如图19，特征峰位置如下表13所示：
表13.XI晶型特征峰
Figure PCTCN2020070188-appb-000030
晶型XI的DSC谱图显示，第一个吸热峰峰值为96.72℃，第二个吸热峰峰值为101.39℃，放热峰峰值为139.08℃；
晶型XI的TGA谱图显示25℃-80℃失重3.23％，80℃-110℃失重5.15％，80℃-240℃失重8.62％。
实施例18、晶型XII的制备
将式(I)所示化合物(50mg，V晶型)，加入1ml异丙醚，室温搅拌打浆，搅拌72h后，离心，将沉淀固形物于50℃、100mb真空干燥箱内干燥两个小时后取出，经X-射线 粉末衍射检测，将该产物定义为晶型XII，XRPD谱图如图20，特征峰位置如下表14所示：
表14.XII晶型特征峰
Figure PCTCN2020070188-appb-000031
晶型XII的DSC谱图显示，吸热峰峰值为110.77℃；
晶型XII的TGA谱图显示，25℃-110℃失重3.32％。
实施例19、晶型XIII的制备
式(I)所示化合物(50mg，V晶型)加入1ml二氯甲烷室温溶解，依次加入1ml、1ml、2ml甲基叔丁基醚，搅拌72个小时后，离心，将沉淀固形物于50℃、100mb真空干燥箱内干燥两个小时后取出，经X-射线粉末衍射检测，将该产物定义为晶型XIII，XRPD谱图如图21，特征峰位置如下表15所示：
表15.XIII晶型特征峰
Figure PCTCN2020070188-appb-000032
Figure PCTCN2020070188-appb-000033
晶型XIII的DSC谱图显示吸热峰峰值为110.98℃；
晶型XIII的TGA谱图显示25℃-80℃失重1.48％，80℃-110℃失重1.19％。
实施例20、晶型XIV的制备
将式(I)所示化合物(100mg，V晶型)，加入2ml异丙醚，室温搅拌打浆，搅拌72h后，离心，将沉淀固形物于50℃、100mb真空干燥箱内干燥两个小时后取出，经X-射线粉末衍射检测，将该产物定义为晶型XIV，XRPD谱图如图22，特征峰位置如下表16所示：
表16.XIV晶型特征峰
Figure PCTCN2020070188-appb-000034
Figure PCTCN2020070188-appb-000035
实施例21、本发明晶型I影响因素实验
将式(I)化合物晶型I(实施例2)样品敞口平摊放置，考察在加热(40℃、60℃)、光照(4500Lux)、高湿(RH 75％、RH 90％)条件下样品的稳定性，取样考察期为30天。
实验结果：
表17.式(I)化合物晶型I影响因素实验结果
Figure PCTCN2020070188-appb-000036
实验结论：
由表17影响因素实验结果表明：在光照、高温40℃、高温60℃、高湿75％、高湿90％条件下，放置30天，晶型I的物理化学稳定性较好。
实施例22、本发明晶型I长期加速稳定性实验
式(I)化合物晶型I(实施例2)进行3个月的长期(25℃、60％RH)、加速(40℃、75％RH)稳定性考察，已进行两个月，继续进行中。
实验结果:
表18.式(I)化合物晶型I长期加速稳定性实验结果：
Figure PCTCN2020070188-appb-000037
由表18的长期加速稳定性实验结果显示：晶型I长期(25℃、60％RH)、加速(40℃、75％RH)稳定性条件下放置3个月的化学稳定性好。
实施例23、本发明晶型V影响因素实验
将式(I)化合物晶型V样品敞口平摊放置，考察在加热(40℃、60℃)、光照、高湿(RH75％、RH 90％)条件下样品的稳定性，取样考察期为30天。
样品有关物质分析方法为峰面积归一化法。
表19.式(I)化合物晶型V影响因素实验结果
Figure PCTCN2020070188-appb-000038
Figure PCTCN2020070188-appb-000039
由表19的影响因素实验结果显示：晶型V在光照、高温、高湿情况杂质含量略有增长，化合物纯度下降约1-2％。
实施例24、本发明晶型V长期加速稳定性实验
式(I)化合物晶型V进行3个月的长期(25℃、60％RH)、加速(40℃、75％RH)稳定性考察,拟定考察时间为6个月。
样品有关物质分析方法为峰面积归一化法。
表20.式(I)化合物晶型V长期加速稳定性实验结果：
Figure PCTCN2020070188-appb-000040
由表20的长期及加速稳定性实验结果显示：晶型V长期(25℃、60％RH)、加速(40℃、75％RH)稳定性条件下放置3个月，化学稳定性良好。同时，经XRPD检测，未发生晶型转变。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (27)

  1. 一种式(I)所示化合物的I晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为8.999、9.715、10.594、12.560、13.530、15.141、16.238、17.109、21.725、24.633、25.156处有特征峰，
    Figure PCTCN2020070188-appb-100001
  2. 根据权利要求1所述的式(I)所示化合物的I晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为8.999、9.715、10.594、12.560、13.530、15.141、16.238、17.109、17.903、18.974、19.658、21.725、23.258、24.633、25.156处有特征峰。
  3. 根据权利要求2所述的式(I)所示化合物的I晶型，其特征在于：其X-射线粉末衍射图谱如图3所示。
  4. 一种式(I)所示化合物的II晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为14.080、15.259、16.285、17.047、18.577、20.356、21.932、25.507处有特征峰，
    Figure PCTCN2020070188-appb-100002
  5. 一种式(I)所示化合物的III晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为6.203、6.962、9.163、12.298、13.774、14.679、15.353、16.094、18.702、20.234处有特征峰，
    Figure PCTCN2020070188-appb-100003
  6. 一种式(I)所示化合物的IV晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为7.229、9.160、11.423、13.782、14.524、17.060、17.832、21.628处有特征峰，
    Figure PCTCN2020070188-appb-100004
  7. 一种式(I)所示化合物的V晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为14.920、15.298、19.136、24.132、25.319、26.396、28.897处有特征峰，
    Figure PCTCN2020070188-appb-100005
  8. 根据权利要求7所述的式(I)所示化合物的V晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为5.472、9.857、14.920、15.298、19.136、22.108、24.132、25.319、26.396、27.729、28.897处有特征峰。
  9. 根据权利要求8所述的式(I)所示化合物的V晶型，其特征在于：其X-射线粉末衍射图谱如图11所述。
  10. 一种式(I)所示化合物的VI晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为6.151、7.533、8.447、11.454、12.429、16.156、18.166处有特征峰，
    Figure PCTCN2020070188-appb-100006
  11. 一种式(I)所示化合物的VII晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为6.744、8.415、10.545、11.581、15.199、16.585、17.340、18.482、20.099处有特征峰，
    Figure PCTCN2020070188-appb-100007
  12. 一种式(I)所示化合物的VIII晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为6.917、11.614、13.018、14.992、16.616、17.613处有特征峰，
    Figure PCTCN2020070188-appb-100008
  13. 一种式(I)所示化合物的IX晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为8.016、12.372、13.896、16.197、18.037、22.022处有特征峰，
    Figure PCTCN2020070188-appb-100009
  14. 一种式(I)所示化合物的X晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为5.954、7.945、9.279、13.358、15.065、19.900、21.920处有特征峰，
    Figure PCTCN2020070188-appb-100010
  15. 一种式(I)所示化合物的XI晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为5.119、7.451、12.115、15.253、16.303、18.857处有特征峰，
    Figure PCTCN2020070188-appb-100011
  16. 一种式(I)所示化合物的XII晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为4.829、7.069、13.448、15.504、16.354、17.926、18.814、22.574、25.320处有特征峰，
    Figure PCTCN2020070188-appb-100012
  17. 一种式(I)所示化合物的XIII晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为6.201、10.0451、12.119、14.042、15.779、18.045、19.231、21.982、25.665处有特征 峰，
    Figure PCTCN2020070188-appb-100013
  18. 一种式(I)所示化合物的XIV晶型，其特征在于：其X-射线粉末衍射图谱在2θ角为9.879、14.723、15.315、16.500、19.137、24.137、25.334、26.387处有特征峰，
    Figure PCTCN2020070188-appb-100014
  19. 根据权利要求1-18任一项所述的晶型，其特征在于所述2θ角度的误差范围为±0.2。
  20. 一种制备权利要求1-3任一项所述的式(I)所示化合物的I晶型的方法，其特征在于，其包括：
    1)将任意晶型或者无定型式(I)所示化合物混于适量的溶剂中加热溶解，冷却析晶，过滤的步骤，所述溶剂选自正丙醇、异丙醇、乙醇、叔丁醇、水-乙醇混合物；或
    2)将含有I晶型的式(I)所示化合物混于适量的溶剂中室温打浆，过滤的步骤，所述溶剂选自乙醇、异丙醇、异丙醚、甲基叔丁基醚。
  21. 一种制备权利要求7-9任一项所述的(I)所示化合物的V晶型的方法，其特征在于，其包括：
    1)式(I)所示化合物任意晶型或无定型混于适量的甲醇中，加热溶解，冷却析晶，过滤的步骤；或
    2)将不含I晶型的式(I)所示化合物的晶型或无定型混于适量的溶剂中室温打浆，过滤的步骤，所述溶剂选自甲醇-水、异丙醇-水、乙醇-水、环己烷、正庚烷、水。
  22. 药物组合物，其包含权利要求1-19任一项所述的式(I)所示化合物的I晶型、II晶型、III晶型、IV晶型、V晶型、VI晶型、VII晶型、VIII晶型、IX晶型、X晶型、XI晶型、XII晶型、XIII晶型、XIV晶型中的一种或多种，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  23. 根据权利要求22所述的组合物，其特征在于，其由选自权利要求1-19任一项所述的式(I)所示化合物的晶型或其混合物与至少一种药学上可接受的载体、稀释剂或赋形 剂混合制得。
  24. 根据权利要求22所述的组合物进一步含有抗PD-1抗体。
  25. 根据权利要求1-19任一项所述的式(I)所示化合物的晶型或权利要求20所述的组合物在制备ROR激动剂中的用途。
  26. 根据权利要求1-19任一项所述的式(I)所示化合物的晶型作为ROR激动剂或权利要求22、23任一项所述的组合物在制备用于预防和/或治疗肿瘤或癌症的药物中的用途。
  27. 根据权利要求1-19任一项所述的式(I)所示化合物的晶型与抗PD-1抗体联合在制备用于预防和/或治疗肿瘤或癌症的药物中的用途。
PCT/CN2020/070188 2019-01-04 2020-01-03 吲哚甲酰胺类衍生物的晶型及其制备方法 Ceased WO2020140960A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202080007450.7A CN113227048B (zh) 2019-01-04 2020-01-03 吲哚甲酰胺类衍生物的晶型及其制备方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910006064.5 2019-01-04
CN201910006064 2019-01-04

Publications (1)

Publication Number Publication Date
WO2020140960A1 true WO2020140960A1 (zh) 2020-07-09

Family

ID=71407272

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/070188 Ceased WO2020140960A1 (zh) 2019-01-04 2020-01-03 吲哚甲酰胺类衍生物的晶型及其制备方法

Country Status (3)

Country Link
CN (1) CN113227048B (zh)
TW (1) TW202043197A (zh)
WO (1) WO2020140960A1 (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017024018A1 (en) * 2015-08-05 2017-02-09 Vitae Pharmaceuticals, Inc. Modulators of ror-gamma
WO2017157332A1 (zh) * 2016-03-18 2017-09-21 江苏恒瑞医药股份有限公司 芳香酰胺类衍生物、其制备方法及其在医药上的应用
WO2019007382A1 (zh) * 2017-07-06 2019-01-10 江苏恒瑞医药股份有限公司 吲哚甲酰胺类衍生物、其制备方法及其在医药上的应用
WO2019052440A1 (zh) * 2017-09-12 2019-03-21 江苏恒瑞医药股份有限公司 氘原子取代的吲哚甲酰胺类衍生物、其制备方法及其在医药上的应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017024018A1 (en) * 2015-08-05 2017-02-09 Vitae Pharmaceuticals, Inc. Modulators of ror-gamma
WO2017157332A1 (zh) * 2016-03-18 2017-09-21 江苏恒瑞医药股份有限公司 芳香酰胺类衍生物、其制备方法及其在医药上的应用
WO2019007382A1 (zh) * 2017-07-06 2019-01-10 江苏恒瑞医药股份有限公司 吲哚甲酰胺类衍生物、其制备方法及其在医药上的应用
WO2019052440A1 (zh) * 2017-09-12 2019-03-21 江苏恒瑞医药股份有限公司 氘原子取代的吲哚甲酰胺类衍生物、其制备方法及其在医药上的应用

Also Published As

Publication number Publication date
CN113227048A (zh) 2021-08-06
CN113227048B (zh) 2022-04-12
TW202043197A (zh) 2020-12-01

Similar Documents

Publication Publication Date Title
BR112020021650A2 (pt) sal de sódio de n-((1,2,3,5,6,7-hexahidro-s-indacen-4-il)-1-isopropil-1-pirazol-3-sulfonamida
CN114206878B (zh) 乌帕替尼的晶型及其制备方法和用途
CN104136437A (zh) N-(5s,6s,9r)-4-(2-氧代-2,3-二氢-1h-咪唑并[4,5-b]吡啶-1-基)哌啶-1-羧酸5-氨基-6-(2,3-二氟苯基)-6,7,8,9-四氢-5h-环庚三烯并[b]吡啶-9-基酯半硫酸盐
TWI613182B (zh) 雙環化合物
WO2017190682A1 (zh) 他发米帝司葡甲胺盐的晶型e及其制备方法和用途
CN106810582B (zh) 吡喃葡萄糖基衍生物的复合物、制备方法和应用
US10808005B2 (en) Ligand for orphan nuclear receptor Nur77 and uses thereof
WO2021148043A1 (zh) 硝基苯醚类化合物、其制备方法和药物组合物与用途
US10538482B2 (en) Adamantane and memantine derivatives as peripheral NMDA receptor antagonists
JP2022524111A (ja) Ｒａｒ活性化のための合成レチノイド
WO2020011257A1 (zh) 一种稠合三环γ-氨基酸衍生物的组合物及其制备
MX2015003151A (es) Compuestos cristalinos.
KR20180085814A (ko) 치환된 5,6-디히드로-6-페닐벤조[f]이소퀴놀린-2-아민의 제조 방법
US10011584B2 (en) Polymorphic form of [5-fluoro-3-({2-[(4-fluorobenzene) sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid
US20170121306A1 (en) Polymorphic form of [5-fluoro-3-(methyl)-2-methylindol-1-yl]-acetic acid
WO2020140960A1 (zh) 吲哚甲酰胺类衍生物的晶型及其制备方法
TW201010988A (en) 5-(4-methanesulfonyl-phenyl)-thiazole derivatives for the treatment of acute and chronic inflammatory diseases
US11584750B2 (en) Crystalline forms of (S)-4-amino-6-((1-(3-chloro-6-phenylimidazo[1,2-b]pyridazine-7-yl)ethyl)amino)pyrimidine-5-carbonitrile as inhibitors of phosphatidylinositol-3-kinase
CN115667241A (zh) TrkA抑制剂
CN113439083A (zh) 二芳基硫代乙内酰脲化合物结晶
WO2024017299A1 (zh) 一种桥杂环取代的苯酸衍生物或其盐的结晶及其制备方法
TW201922690A (zh) 環－amp反應元素結合蛋白的抑制劑
CN113365980B (zh) 氘原子取代的吲哚甲酰胺类衍生物的晶型及其制备方法
CN116615418A (zh) 一种吲唑类衍生物的药学上可接受的盐、结晶形式及其制备方法
CN113227069B (zh) 一种化合物的晶型、其组合物及使用方法

Legal Events

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

Ref document number: 20736090

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20736090

Country of ref document: EP

Kind code of ref document: A1