[go: up one dir, main page]

WO2024153219A1 - 一种三氮唑类化合物的可药用盐、晶型及其制备方法 - Google Patents

一种三氮唑类化合物的可药用盐、晶型及其制备方法 Download PDF

Info

Publication number
WO2024153219A1
WO2024153219A1 PCT/CN2024/073211 CN2024073211W WO2024153219A1 WO 2024153219 A1 WO2024153219 A1 WO 2024153219A1 CN 2024073211 W CN2024073211 W CN 2024073211W WO 2024153219 A1 WO2024153219 A1 WO 2024153219A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
pharmaceutically acceptable
crystalline form
diseases
Prior art date
Application number
PCT/CN2024/073211
Other languages
English (en)
French (fr)
Inventor
贾丽娜
王洁
杨俊然
杜振兴
王捷
Original Assignee
江苏恒瑞医药股份有限公司
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 江苏恒瑞医药股份有限公司 filed Critical 江苏恒瑞医药股份有限公司
Publication of WO2024153219A1 publication Critical patent/WO2024153219A1/zh

Links

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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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 present invention belongs to the pharmaceutical field and relates to a pharmaceutically acceptable salt of a triazole compound, a crystal form and a preparation method thereof.
  • Lysophospholipid membranes derive bioactive lipid mediators, of which the most important in medicine is lysophosphatidic acid (LPA). Lysophospholipids affect basic cellular functions including proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions affect many biological processes, including but not limited to neurogenesis, angiogenesis, wound healing, fibrosis, immunity, and carcinogenesis.
  • LPA lysophosphatidic acid
  • LPA is not a single molecular entity, but a group of endogenous structural variants of fatty acids with different lengths and saturations.
  • the structural backbone of LPA is derived from glycerol-based phospholipids, such as phosphatidylcholine (PC) or phosphatidic acid (PA).
  • Lysophosphatidic acid (LPA) is a lysophospholipid that acts in an autocrine and paracrine manner through a specific G-protein coupled receptor (GPCR) group. LPA binds to its cognate GPCR (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6), activating intracellular signal transduction pathways to produce various biological responses.
  • Antagonists of LPA receptors are found to be used to treat diseases, disorders or conditions in which LPA plays a role.
  • PCT/CN2022/106706 discloses a novel class of triazole derivatives, wherein the chemical name as shown in Formula I is (1S, 3aS, 5S, 6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydropentalene-1-carboxylic acid, which is used as an LPA1 inhibitor.
  • the present disclosure introduces the entire text of PCT/CN2022/106706.
  • the crystal structure as a pharmaceutically active ingredient often affects the chemical and physical stability of the drug.
  • the difference in crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, and sometimes it is accompanied by the generation of other morphological crystals.
  • amorphous drug products do not have a regular crystal structure and often have other defects, such as poor product stability, difficult filtration, easy agglomeration, poor fluidity, etc.
  • the present disclosure provides a crystalline form A of a compound of formula I, (1S, 3aS, 5S, 6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydropentalene-1-carboxylic acid.
  • the A crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.534, 10.223, 14.364, 17.269, 18.495 and 19.553.
  • the A crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.534, 10.223, 14.364, 15.816, 16.678, 17.269, 18.495 and 19.553.
  • the A crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.534, 10.223, 14.364, 15.816, 16.678, 17.269, 18.495, 19.553, 21.043, 21.342, 23.647 and 25.965.
  • the X-ray powder diffraction pattern expressed in terms of diffraction angle 2 ⁇ is as shown in FIG. 2 .
  • the present disclosure provides a method for preparing crystal form A of a compound of formula I, comprising: dissolving the compound of formula I in propylene glycol methyl ether, adding n-heptane, and stirring to crystallize.
  • the preparation method of the A crystal form of the compound of formula I comprises: dissolving the compound of formula I in a solvent (1), adding a solvent (2), and then adding a solvent (3), stirring and crystallizing; wherein the solvent (1) is selected from at least one solvent selected from propylene glycol methyl ether, 1,4-dioxane, 10% water/acetone, N,N-dimethylformamide, N,N-dimethylacetamide, 50% methanol/chloroform, and 67% tetrahydrofuran/ethanol; the solvent (2) is selected from methyl tert-butyl ether; and the solvent (3) is selected from n-heptane.
  • the solvent (1) is selected from at least one solvent selected from propylene glycol methyl ether, 1,4-dioxane, 10% water/acetone, N,N-dimethylformamide, N,N-dimethylacetamide, 50% methanol/chloroform, and 67% tetrahydrofuran/ethanol
  • the method for preparing the crystal form A of the compound of formula I comprises: dissolving the compound of formula I in acetone and stirring for crystallization.
  • the present disclosure provides a crystalline form B of a compound of formula I, a compound of (1S, 3aS, 5S, 6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydropentalene-1-carboxylic acid.
  • the B crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.437, 10.381, 14.955 and 17.513.
  • the B crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.437, 10.381, 14.717, 14.955, 17.513, 21.395, 22.607 and 23.221.
  • the B crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.437, 10.381, 14.717, 14.955, 17.513, 18.466, 21.395, 21.692, 22.607, 23.221 and 25.972.
  • the X-ray powder diffraction pattern of the B crystal form represented by the diffraction angle 2 ⁇ is shown in Figure 3.
  • the present disclosure provides a method for preparing the B crystal form of the compound of formula I, comprising: dissolving the compound of formula I in a solvent (A), adding a solvent (B), and then adding a solvent (C), and stirring for crystallization; wherein the solvent (A) is selected from at least one of tetrahydrofuran, dichloromethane, 10% water/isopropanol, and chloroform; the solvent (B) is selected from methyl tert-butyl ether; and the solvent (C) is selected from n-heptane.
  • the solvent (A) is selected from at least one of tetrahydrofuran, dichloromethane, 10% water/isopropanol, and chloroform
  • the solvent (B) is selected from methyl tert-butyl ether
  • the solvent (C) is selected from n-heptane.
  • the preparation method of Form B of the compound of Formula I comprises: dissolving the compound of Formula I in water, methanol, ethanol, isopropanol, n-propanol, ethyl acetate, acetonitrile, isopropyl acetate, methyl tert-butyl ether, 2-butanone, methyl isobutyl ketone, n-heptane, isopropyl ether, isoamyl alcohol, 10% water/methanol, 7% water/ethanol, 50% methanol/water, 50% ethyl acetate/ethanol, 50% ethyl acetate/n-heptane, cyclohexane, n-hexane, toluene, and stirring for crystallization.
  • the present disclosure provides a C crystalline form of a compound of formula I, a compound of (1S, 3aS, 5S, 6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydropentalene-1-carboxylic acid.
  • the C crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.702, 10.643, 17.229, 18.213, 18.666 and 20.900.
  • the C crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.702, 10.074, 10.643, 11.463, 17.229, 18.213, 18.666, 20.900, 22.422 and 23.968.
  • the C crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.702, 10.074, 10.643, 11.463, 16.738, 17.229, 18.213, 18.666, 20.900, 22.057, 22.422, 23.397 and 23.968.
  • the X-ray powder diffraction pattern of the C crystal form represented by the diffraction angle 2 ⁇ is shown in Figure 4.
  • the present disclosure also provides a pharmaceutically acceptable salt of a compound shown in Formula I (1S, 3aS, 5S, 6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydropentalene-1-carboxylic acid, wherein the pharmaceutically acceptable salt is selected from a sodium salt or an ethanolamine salt.
  • the chemical ratio of compound Formula I (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydropentalene-1-carboxylic acid and sodium ion is 1:1.
  • the present disclosure also provides a method for preparing a pharmaceutically acceptable salt of a compound of formula I (1S, 3aS, 5S, 6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydropentalene-1-carboxylic acid, comprising:
  • the invention further comprises the step of reacting the compound of formula I with a base, wherein the base is selected from sodium hydroxide or ethanolamine.
  • the solvent used for salt formation in the present invention is selected from but not limited to one or more solvents of acetonitrile, ethanol/ethyl acetate, methanol/acetonitrile, 2-butanone, isopropanol, isopropyl acetate, n-propanol, n-heptane, acetone, tetrahydrofuran, ethanol, methanol, 1,4-dioxane, dichloromethane/methanol, water/isopropanol, tetrahydrofuran/ethanol.
  • the method for preparing the aforementioned pharmaceutically acceptable salt further comprises the steps of crystallization, filtering, washing or drying.
  • the present disclosure also provides a compound of formula I, (1S, 3aS, 5S, 6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydropentalene-1-carboxylic acid sodium salt
  • Form I having an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 2 ⁇ , with characteristic peaks at 6.446, 8.350, 8.847, 9.335, 12.845, 16.901 and 17.874.
  • the sodium salt form I has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 6.446, 8.350, 8.847, 9.335, 9.807, 12.845, 13.328, 13.739, 15.728, 16.901 and 17.874.
  • the sodium salt form I has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 4.741, 6.446, 8.350, 8.847, 9.335, 9.807, 12.845, 13.328, 13.739, 15.728, 16.901, 17.874, 19.059 and 19.805.
  • the sodium salt form I has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 4.741, 6.446, 8.350, 8.847, 9.335, 9.807, 12.845, 13.328, 13.739, 15.728, 16.901, 17.874, 19.059, 19.805, 21.490, 23.607, 25.460 and 25.773.
  • the sodium salt form I has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG5 .
  • the present disclosure provides a method for preparing a sodium salt of a compound of formula I in crystal form I, comprising: dissolving the compound of formula I in 50% ethanol/ethyl acetate, 50% methanol/acetonitrile or tetrahydrofuran, adding sodium hydroxide solution, and then adding methyl tert-butyl ether, stirring and crystallizing.
  • the present disclosure provides a method for preparing a sodium salt of a compound of formula I in crystal form I, comprising: dissolving the compound of formula I in 2-butanone or acetonitrile, adding a sodium hydroxide ethanol solution, and stirring to crystallize.
  • the present disclosure also provides a compound of formula I (1S, 3aS, 5S, 6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydropentalene-1-carboxylic acid sodium salt II crystalline form, an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ , having characteristic peaks at 6.771, 13.464, 14.419 and 15.593.
  • the sodium salt II crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 6.771, 13.464, 13.970, 14.419, 15.593, 18.044 and 19.952.
  • the sodium salt II crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG6 .
  • the present disclosure provides a method for preparing a sodium salt II crystal form of a compound of formula I, comprising: dissolving the compound of formula I in isopropanol or 1,4-dioxane, adding sodium hydroxide ethanol solution, and stirring to crystallize.
  • the present disclosure provides a method for preparing a sodium salt II crystal form of a compound of formula I, comprising: dissolving the sodium salt I crystal form of the compound of formula I in isopropanol or isopropyl acetate, and stirring to crystallize.
  • the present disclosure provides a method for preparing a sodium salt II crystal form of a compound of formula I, comprising: dissolving the sodium salt I crystal form of the compound of formula I in ethanol or n-propanol, adding n-heptane, and stirring to crystallize.
  • the present disclosure also provides a compound of formula I (1S, 3aS, 5S, 6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydropentalene-1-carboxylic acid sodium salt III crystalline form, an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ , having characteristic peaks at 6.605, 18.597, 20.094, and 26.882.
  • the sodium salt III form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.639, 6.605, 10.311, 13.323, 18.597, 20.094, and 26.882.
  • the sodium salt III crystal form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 7 .
  • the present disclosure provides a method for preparing the sodium salt III crystal form of the compound of formula I, comprising: dissolving the sodium salt I crystal form of the compound of formula I in 1,4-dioxane, and stirring to crystallize.
  • the present disclosure also provides a compound of formula I (1S, 3aS, 5S, 6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydropentalene-1-carboxylic acid sodium salt IV crystalline form, an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 2 ⁇ , having characteristic peaks at 7.078, 14.227, 15.004, 18.812, and 20.081.
  • the sodium salt IV form has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.078, 7.078, 10.670, 13.231, 14.227, 15.004, 18.812, 20.081, and 24.018.
  • the X-ray powder diffraction pattern of the sodium salt IV form expressed in terms of a diffraction angle of 2 ⁇ is shown in FIG8 .
  • the present disclosure provides a method for preparing the sodium salt IV crystal form of the compound of formula I, comprising: heating the sodium salt I crystal form of the compound of formula I to 180° C. or above.
  • the present disclosure also provides a crystalline form I of the compound of formula I (1S, 3aS, 5S, 6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydropentalene-1-carboxylic acid ethanolamine salt, which has an X-ray powder diffraction pattern expressed in terms of a diffraction angle of 2 ⁇ , and has characteristic peaks at 5.343, 9.612, 10.751, 16.737, and 19.178.
  • the ethanolamine salt form I has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.343, 9.612, 10.751, 12.023, 14.613, 16.737, 17.886, 19.178, 20.434, and 21.788.
  • the X-ray powder diffraction pattern of the ethanolamine salt form I expressed in terms of a diffraction angle of 2 ⁇ is shown in FIG. 10 .
  • the present disclosure provides a method for preparing the ethanolamine salt of the compound of formula I in crystal form I, comprising: dissolving the compound of formula I in tetrahydrofuran, adding ethanolamine ethanol solution, and adding methyl tert-butyl ether and stirring to crystallize.
  • the compound of formula I disclosed in the present invention is a crystalline form of (1S, 3aS, 5S, 6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydropentalene-1-carboxylic acid, wherein the error range of the 2 ⁇ angle is ⁇ 0.2.
  • the method for preparing the crystalline form described in the present disclosure further comprises the steps of crystallization, filtering, washing or drying.
  • the present disclosure also provides a pharmaceutical composition, which includes the aforementioned compound Formula I compound (1S, 3aS, 5S, 6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydropentalene-1-carboxylic acid crystal form A, crystal form B, crystal form C, amorphous form, sodium salt, sodium salt I crystal form, sodium salt II crystal form, sodium salt III crystal form, sodium salt IV crystal form, sodium salt amorphous form, ethanolamine salt, ethanolamine salt I crystal form, and optionally selected from pharmaceutically acceptable excipients.
  • Formula I compound (1S, 3aS, 5S, 6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-tri
  • the present disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing the aforementioned compound of formula I (1S, 3aS, 5S, 6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydropentalene-1-carboxylic acid in form A, form B, form C, amorphous form, sodium salt, sodium salt I form, sodium salt II form, sodium salt III form, sodium salt IV form, sodium salt amorphous form, ethanolamine salt or ethanolamine salt I form with a pharmaceutically acceptable excipient.
  • the present disclosure also provides the aforementioned compound formula I compound (1S, 3aS, 5S, 6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydropentalene-1-carboxylic acid in form A, form B, form C, amorphous, sodium salt, sodium salt I form, sodium salt II form, sodium salt III form, sodium salt IV form, sodium salt amorphous, Use of the ethanolamine salt, ethanolamine salt I crystal form, or the aforementioned pharmaceutical composition as an LPA1 inhibitor.
  • the present disclosure also provides the use of the aforementioned compound formula I compound (1S, 3aS, 5S, 6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydropentalene-1-carboxylic acid in form A, form B, form C, amorphous form, sodium salt, sodium salt I form, sodium salt II form, sodium salt III form, sodium salt IV form, sodium salt amorphous form, ethanolamine salt, ethanolamine salt I form, or the aforementioned pharmaceutical composition for preventing and/or treating organ fibrotic degenerative diseases, respiratory diseases, kidney diseases, liver diseases, inflammatory diseases, nervous system diseases, cardiovascular and cerebrovascular diseases, gastrointestinal diseases, pain, urinary system diseases, eye diseases, metabolic diseases, cancer, and transplant organ rejection.
  • organ fibrotic degenerative diseases respiratory diseases, kidney diseases, liver
  • the present disclosure also provides the use of the aforementioned compound of formula I (1S, 3aS, 5S, 6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydropentalene-1-carboxylic acid in crystal form A, crystal form B, crystal form C, amorphous form, sodium salt, sodium salt I crystal form, sodium salt II crystal form, sodium salt III crystal form, sodium salt IV crystal form, sodium salt amorphous form, ethanolamine salt, ethanolamine salt I crystal form, or the aforementioned pharmaceutical composition in the preparation of drugs for preventing and/or treating organ fibrotic and degenerative diseases, respiratory diseases, kidney diseases, liver diseases, inflammatory diseases, nervous system diseases, cardiovascular and cerebrovascular diseases, gastrointestinal diseases, pain, urinary system diseases, eye diseases, metabolic diseases, cancer, and transplant organ rejection.
  • the "2 ⁇ or 2 ⁇ angle" mentioned in the present disclosure refers to the diffraction angle, ⁇ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2 ⁇ is ⁇ 0.20 (including the case where the number exceeding 1 decimal place is rounded off), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14 , 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.
  • crystallization or “crystallization” described in the present disclosure includes but is not limited to stirring crystallization, slurry crystallization, cooling crystallization and volatile crystallization.
  • the "differential scanning calorimetry or DSC” described in the present disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining a constant temperature of the sample to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.
  • the drying temperature in the present disclosure is generally 25°C-100°C, preferably 40°C-70°C, and the drying can be carried out under normal pressure or reduced pressure.
  • compositions include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent or emulsifier approved by the U.S. Food and Drug Administration for use by humans or livestock animals.
  • FIG1 is an XRPD spectrum of the amorphous form of the compound of formula I.
  • FIG. 2 is an XRPD spectrum of Form A of Compound I.
  • FIG3 is an XRPD spectrum of Form B of Compound I.
  • FIG. 4 is an XRPD spectrum of Form C of Compound I.
  • FIG5 is an XRPD spectrum of the sodium salt Form I of the compound of Formula I.
  • FIG6 is an XRPD spectrum of the sodium salt of the compound of formula I, Form II.
  • FIG. 7 is an XRPD spectrum of the sodium salt of the compound of formula I, Form III.
  • FIG8 is an XRPD spectrum of the sodium salt of the compound of formula I, Form IV.
  • FIG. 9 is an XRPD spectrum of the amorphous sodium salt of the compound of formula I.
  • FIG. 10 is an XRPD spectrum of the ethanolamine salt of the compound of formula I, Form I.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • ⁇ NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm).
  • NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • MS was determined using an Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS instrument (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), Waters ACQuity UPLC-QD/SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector/Waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q 15 Exactive).
  • HPLC HPLC was determined using an Agilent 1260DAD high pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6 mm column) and a Thermo U3000 high pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6 mm column).
  • XRPD is X-ray powder diffraction detection: the measurement is carried out using a BRUKER D8 X-ray diffractometer, specific collection information: Cu anode (40kV, 40mA), ray: monochromatic Cu-Ka ray Scanning mode: ⁇ /2 ⁇ , scanning range: 3-48°.
  • DSC differential scanning calorimetry: METTLER TOLEDO DSC 3+ differential scanning calorimeter is used for determination, heating rate is 10°C/min, specific temperature range refers to the corresponding spectrum (mostly 25°C-300°C), nitrogen purge rate is 50mL/min.
  • TGA thermogravimetric analysis: METTLER TOLEDO TGA 2 thermogravimetric analyzer is used for detection, heating rate is 10°C/min, specific temperature range refers to the corresponding spectrum (mostly 30°C-400°C), nitrogen purge rate is 50mL/min.
  • DVS dynamic moisture adsorption: Surface Measurement Systems instrinsic is used, humidity starts from 50%, the humidity range is 0%-95%, the step is 10%, and the judgment standard is that the mass change of each gradient dM/dT ⁇ 0.002%, TMAX 360min, and two cycles.
  • the known starting materials disclosed in the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals and other companies.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include: 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, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.
  • TLC thin layer chromatography
  • Example 1 Preparation of Compound I (Compound 1-P1, refer to the preparation method of Example 3 in application No. PCT/CN2022/106706)
  • the raw material cis-tetrahydropentalene-2,5(1H,3H)-dione 1a (24 g, 173.7 mmol) was dissolved in ethanol (500 mL), cooled to 0°C, sodium borohydride (1.47 g, 43.4 mmol) was added, and the mixture was stirred at 0°C for 2 hours.
  • the reaction solution was quenched with acetic acid (10 mL), concentrated, and the residue was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate) to obtain the title product 1b (9 g, yield 37.0%).
  • Step 3 5-((tert-Butyldiphenylsilyl)oxy)-2-oxooctahydropentalene-1-carboxylic acid methyl ester (1d)
  • Step 4 5-((tert-Butyldiphenylsilyl)oxy)-2-hydroxyoctahydropentalene-1-carboxylic acid methyl ester (1e)
  • Step 5 Methyl 5-((tert-butyldiphenylsilyl)oxy)-2-((methylsulfonyl)oxy)octahydropentalene-1-carboxylate (1f)
  • Step 6 5-((tert-Butyldiphenylsilyl)oxy)-3,3a,4,5,6,6a-hexahydropentalene-1-carboxylic acid methyl ester (1 g)
  • Step 10 5-((2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)octahydropentalene-1-carboxylic acid methyl ester (11)
  • Step 11 Methyl 5-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydropentalene-1-carboxylate (1m)
  • Step 12 5-((6-(5-(Hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydropentalene-1-carboxylic acid (1n)
  • Step 13 (1S,3aS,5S,6aR)-5-((6-(5-(((4-(methoxymethyl)pyrimidin-2-yl)oxy)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)octahydropentalene-1-carboxylic acid (1)
  • Compound 1-P1 has a shorter retention time: MS m/z (ESI): 495.2 [M+H] + ; Chiral SFC analysis: retention time 2.717 minutes, chiral purity 100% (chromatographic column: Chiralpak AS-3, 0.46 cm ID*100 mm, 3 um; mobile phase: A is CO 2 , B is ethanol (0.05% diethylamine).
  • Compound 1-P2 has a longer retention time: MS m/z (ESI): 495.2 [M+H] + ; Chiral SFC analysis: retention time 3.031 minutes, chiral purity 97.4% (chromatographic column: Chiralpak AS-3, 0.46 cmI.D.*100 mm, 3 um; mobile phase: A is CO 2 , B is ethanol (0.05% diethylamine).
  • the compound 1-P1 product was detected to be amorphous by X-ray powder diffraction, and the XRPD spectrum is shown in Figure 1
  • the antagonist properties of the compounds of the present disclosure which are inhibitors of intracellular calcium elevation induced by activation of hLPAR1 (human lysophosphatidic acid receptor 1) expressed in CHO-K1 cells (Chinese hamster ovary cells K1, HDB), were determined using the FLIPR (Fluorescence Imaging Plate Reader) method.
  • 2.2. 50x Red dye (a red dye used to shield the background signal in cells).
  • the preparation method is: weigh 4g of tartrazine and 10.2g of acid red and dissolve them in 100mL of H2O .
  • Fluo-8 staining mixture 4 mL reaction buffer, 32 ⁇ L fluo-8, 320 ⁇ L 50x Red dye, 40 ⁇ L probenecid.
  • LPA Dissolve in DPBS (containing 0.1% fatty acid-free BSA) to prepare a stock solution with a concentration of 0.8 ⁇ M, divide into aliquots and store at -20°C.
  • test compounds were dissolved in DMSO to prepare a 10mM stock solution and stored at -20°C. During the experiment, the compound was first diluted with DMSO in a gradient manner (starting concentration was 50 ⁇ M, 3-fold dilution, 10 points) to prepare a 200-fold compound solution. Then, the compound solution was diluted with reaction buffer to a 5-fold compound solution and transferred to a 384-well plate (Cat. No. 6008590) using Bravo.
  • CHO-K1/LPA1R cells were cultured with cell culture medium (F-12+10% FBS+400 ⁇ g/ml hygromycin B).
  • the XRPD spectrum is shown in Figure 2, and the characteristic peak positions are shown in Table 2.
  • the TGA spectrum shows that the weight loss is 1.55% before 100°C.
  • the DSC spectrum shows that the endothermic peak is at 183.35°C.
  • the DVS test results show that under normal storage conditions (i.e. 25°C, 60% RH), the sample has a moisture absorption weight gain of about 0.17%; under accelerated test conditions (i.e. 70% RH), the moisture absorption weight gain is about 0.20%; under extreme conditions (90% RH), the moisture absorption weight gain is about 0.37%. After the DVS test, the crystal form was retested and the crystal form did not change.
  • the XRPD spectrum is shown in Figure 3, and the characteristic peak positions are shown in Table 5.
  • the TGA spectrum shows that the weight loss is 1.66% before 100°C.
  • the DSC spectrum shows that the endothermic peaks are at 163.19°C and 182.43°C, and the exothermic peak is at 164.04°C.
  • the DVS test results show that under normal storage conditions (i.e. 25°C, 60% RH), the sample has a moisture absorption weight gain of about 0.25%; under accelerated test conditions (i.e. 70% RH), the moisture absorption weight gain is about 0.31%; under extreme conditions (90% RH), the moisture absorption weight gain is about 0.64%. After the DVS test, the crystal form was retested and the crystal form did not change.
  • the XRPD spectrum is shown in Figure 4 and the characteristic peak positions are shown in Table 7.
  • the TGA spectrum shows that the weight loss is 4.34% before 110°C and 8.22% from 110°C to 195°C.
  • the DSC spectrum shows that the endothermic peaks are at 106.12°C and 177.29°C.
  • the XRPD spectrum is shown in Figure 5 and the characteristic peak positions are shown in Table 9.
  • the sodium ion content is 4.85% as detected by ion chromatography.
  • the TGA spectrum shows that the weight loss is 7.36% at 30°C-110°C.
  • the DSC spectrum shows that the endothermic peaks are 90.11°C, 122.09°C and 210.70°C, and the exothermic peak is 145.47°C.
  • DVS testing showed that under normal storage conditions (i.e. 25°C, 60% RH), the sample had a moisture absorption weight gain of approximately 6.31%; under accelerated experimental conditions (i.e. 70% RH), the moisture absorption weight gain was approximately 7.08%; and under extreme conditions (90% RH), the moisture absorption weight gain was approximately 42.38%.
  • the XRPD spectrum is shown in Figure 6 and the characteristic peak positions are shown in Table 10.
  • the sodium ion content is 4.75% as detected by ion chromatography.
  • the TGA spectrum shows that the weight loss is 2.18% at 30°C-120°C.
  • the DSC spectrum shows that the endothermic peaks are 179.08°C and 223.40°C.
  • DVS testing showed that under normal storage conditions (i.e. 25°C, 60% RH), the sample's moisture absorption and weight gain were approximately 6.35%; under accelerated experimental conditions (i.e. 70% RH), the moisture absorption and weight gain were approximately 22.41%; and under extreme conditions (90% RH), the moisture absorption and weight gain were approximately 56.98%.
  • the XRPD spectrum is shown in Figure 10, and the characteristic peak positions are shown in Table 13.
  • the TGA spectrum shows that the weight loss is 13.57% at 30°C-190°C.
  • the DSC spectrum shows that the endothermic peaks are 59.63°C and 148.77°C.
  • the free crystal form A and crystal form B of the compound described in formula I were opened and spread out, and the stability of the samples was investigated under light (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH 75%, RH 93%) conditions.
  • the sampling period was 1 month.
  • the sodium salt form I and sodium salt form II of the compound represented by formula I were laid out in an open manner, and the stability of the samples was investigated under light (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH 75%) conditions. The sampling period was 1 month.
  • the sodium salt I crystal form and the sodium salt II crystal form of the compound represented by formula I were placed under 25°C/60%RH and 40°C/75%RH conditions to investigate their stability:

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Urology & Nephrology (AREA)
  • Diabetes (AREA)
  • Neurosurgery (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Pulmonology (AREA)
  • Neurology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

本公开涉及一种三氮唑类化合物的可药用盐、晶型及其制备方法。具体而言，本公开提供式I化合物(1S，3aS，5S，6aR)-5-((6-(5-(((4-(甲氧基甲基)嘧啶-2-基)氧基)甲基)-1-甲基-1H-1，2，3-三唑-4-基)-2-甲基吡啶-3-基)氧)八氢并环戊二烯-1-羧酸的可药用盐、晶型及其制备方法，相应盐具备良好的稳定性，可更好地用于临床治疗。

Description

一种三氮唑类化合物的可药用盐、晶型及其制备方法
本申请要求申请日为2023/1/19的中国专利申请2023100662824的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开属于制药领域，涉及一种三氮唑类化合物的可药用盐、晶型及其制备方法。
背景技术
血磷脂系膜衍生生物活性脂质介体，其中在医学上最重要的为溶血磷脂酸(LPA)。溶血磷脂影响包括增殖、分化、存活、迁移、黏附、侵袭及形态发生的基本细胞功能。这些功能影响许多生物进程，其包括但不限于神经发生、血管发生、伤口愈合、纤维化、免疫及致癌作用。
LPA是非单一分子实体，而是一组具有不同长度及饱和度的脂肪酸的内源结构变异体。LPA的结构主链是衍生自基于甘油的磷脂，诸如磷脂酰胆碱(PC)或磷脂酸(PA)。溶血磷脂酸(LPA)为经特异性G-蛋白偶联受体(GPCR)组以自分泌及旁分泌方式起作用的溶血磷脂。LPA结合至其同源GPCR(LPA1、LPA2、LPA3、LPA4、LPA5、LPA6)，活化细胞内信号传导途径以产生各种生物反应。发现LPA受体的拮抗剂用于治疗LPA起作用的疾病、障碍或病症。
PCT/CN2022/106706公开了一类新型的三氮唑类衍生物，其中如式I所示的化学名为(1S，3aS，5S，6aR)-5-((6-(5-(((4-(甲氧基甲基)嘧啶-2-基)氧基)甲基)-1-甲基-1H-1，2，3-三唑-4-基)-2-甲基吡啶-3-基)氧)八氢并环戊二烯-1-羧酸，展示了其作为LPA1抑制剂的应用。本公开将PCT/CN2022/106706全文引入。
作为药用活性成分的晶型结构往往影响到该药物的化学和物理稳定性，结晶条件及储存条件的不同有可能导致化合物的晶体结构的变化，有时还会伴随着产生其他形态的晶型。一般来说，无定形的药物产品没有规则的晶体结构，往往具有其它缺陷，比如产物稳定性较差，过滤较难，易结块，流动性差等。因此，研究式I所示的化学名为(1S，3aS，5S，6aR)-5-((6-(5-(((4-(甲氧基甲基)嘧啶-2-基)氧基)甲基)-1-甲基-1H-1，2，3-三唑-4-基)-2-甲基吡啶-3-基)氧)八氢并环戊二烯-1-羧酸的可药用盐、晶型，对开发适合工业生产且生物活性良好的药物具有重要意义。
发明内容
本公开一方面提供化合物式I化合物(1S，3aS，5S，6aR)-5-((6-(5-(((4-(甲氧基甲基)嘧啶-2-基)氧基)甲基)-1-甲基-1H-1，2，3-三唑-4-基)-2-甲基吡啶-3-基)氧)八氢并环戊二烯-1-羧酸的A晶型。
在一些实施方案中，所述A晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.534、10.223、14.364、17.269、18.495和19.553处有特征峰。
在另一些实施方案中，所述A晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.534、10.223、14.364、15.816、16.678、17.269、18.495和19.553处有特征峰。
在另一些实施方案中，所述A晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.534、10.223、14.364、15.816、16.678、17.269、18.495、19.553、21.043、21.342、23.647和25.965处有特征峰。
最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图2所示。
另一方面，本公开提供一种式I化合物的A晶型的制备方法，包括：将式I化合物溶于丙二醇甲醚，再加入正庚烷，搅拌析晶。
在另一些实施方案中，式I化合物的A晶型的制备方法，包括：将式I化合物溶于溶剂(1)，加入溶剂(2)，再加入溶剂(3)，搅拌析晶；其中溶剂(1)选自丙二醇甲醚、1，4-二氧六环、10％水/丙酮、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、50％甲醇/氯仿、67％四氢呋喃/乙醇中的至少一种溶剂；溶剂(2)选自甲基叔丁基醚；溶剂(3)选自正庚烷。
在另一些实施方案中，式I化合物的A晶型的制备方法，包括：将式I化合物溶于丙酮，搅拌析晶。
另一方面，本公开提供化合物式I化合物(1S，3aS，5S，6aR)-5-((6-(5-(((4-(甲氧基甲基)嘧啶-2-基)氧基)甲基)-1-甲基-1H-1，2，3-三唑-4-基)-2-甲基吡啶-3-基)氧)八氢并环戊二烯-1-羧酸的B晶型。
在一些实施方案中，所述B晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.437、10.381、14.955和17.513处有特征峰。
在另一些实施方案中，所述B晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.437、10.381、14.717、14.955、17.513、21.395、22.607和23.221处有特征峰。
在另一些实施方案中，所述B晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.437、10.381、14.717、14.955、17.513、18.466、21.395、21.692、22.607、23.221和25.972处有特征峰。
在另一些实施方案中，所述B晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图3所示。
另一方面，本公开提供一种式I化合物的B晶型的制备方法，包括：将式I化合物溶于溶剂(A)，加入溶剂(B)，再加入溶剂(C)，搅拌析晶；其中溶剂(A)选自四氢呋喃、二氯甲烷、10％水/异丙醇、三氯甲烷中的至少一种溶剂；溶剂(B)选自甲基叔丁基醚；溶剂(C)选自正庚烷。
在另一些实施方案中，式I化合物的B晶型的制备方法，包括：将式I化合物溶于水、甲醇、乙醇、异丙醇、正丙醇、乙酸乙酯、乙腈、乙酸异丙酯、甲基叔丁基醚、2-丁酮、甲基异丁基酮、正庚烷、异丙醚、异戊醇、10％水/甲醇、7％水/乙醇、50％甲醇/水、50％乙酸乙酯/乙醇、50％乙酸乙酯/正庚烷、环己烷、正己烷、甲苯，搅拌析晶。
另一方面，本公开提供化合物式I化合物(1S，3aS，5S，6aR)-5-((6-(5-(((4-(甲氧基甲基)嘧啶-2-基)氧基)甲基)-1-甲基-1H-1，2，3-三唑-4-基)-2-甲基吡啶-3-基)氧)八氢并环戊二烯-1-羧酸的C晶型。
在一些实施方案中，所述C晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.702、10.643、17.229、18.213、18.666和20.900处有特征峰。
在另一些实施方案中，所述C晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.702、10.074、10.643、11.463、17.229、18.213、18.666、20.900、22.422和23.968处有特征峰。
在另一些实施方案中，所述C晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.702、10.074、10.643、11.463、16.738、17.229、18.213、18.666、20.900、22.057、22.422、23.397和23.968处有特征峰。
在另一些实施方案中，所述C晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图4所示。
另一方面，本公开还提供一种式I所示化合物(1S，3aS，5S，6aR)-5-((6-(5-(((4-(甲氧基甲基)嘧啶-2-基)氧基)甲基)-1-甲基-1H-1，2，3-三唑-4-基)-2-甲基吡啶-3-基)氧)八氢并环戊二烯-1-羧酸的可药用盐，所述可药用盐选自钠盐或乙醇胺盐。
在可选实施方案中，化合物式I化合(1S，3aS，5S，6aR)-5-((6-(5-(((4-(甲氧基甲基)嘧啶-2-基)氧基)甲基)-1-甲基-1H-1，2，3-三唑-4-基)-2-甲基吡啶-3-基)氧)八氢并环戊二烯-1-羧酸与钠离子的化学配比为1∶1。
本公开还提供一种式I化合物(1S，3aS，5S，6aR)-5-((6-(5-(((4-(甲氧基甲基)嘧啶-2-基)氧基)甲基)-1-甲基-1H-1，2，3-三唑-4-基)-2-甲基吡啶-3-基)氧)八氢并环戊二烯-1-羧酸的可药用盐的制备方法，包 括式I化合物与碱反应的步骤，所述的碱选自氢氧化钠或乙醇胺。
本公开成盐所用溶剂选自但不限于乙腈、乙醇/乙酸乙酯、甲醇/乙腈、2-丁酮、异丙醇、乙酸异丙酯、正丙醇、正庚烷、丙酮、四氢呋喃、乙醇、甲醇、1，4-二氧六环、二氯甲烷/甲醇、水/异丙醇、四氢呋喃/乙醇一种或多种溶剂。
进一步地，在可选实施方案中，制备前述可药用盐的方法还包括析晶，过滤、洗涤或干燥等步骤。
另一方面，本公开还提供式I化合物(1S，3aS，5S，6aR)-5-((6-(5-(((4-(甲氧基甲基)嘧啶-2-基)氧基)甲基)-1-甲基-1H-1，2，3-三唑-4-基)-2-甲基吡啶-3-基)氧)八氢并环戊二烯-1-羧酸钠盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.446、8.350、8.847、9.335、12.845、16.901和17.874处有特征峰。
在另一些实施方案中，钠盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.446、8.350、8.847、9.335、9.807、12.845、13.328、13.739、15.728、16.901和17.874处有特征峰。
在另一些实施方案中，钠盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.741、6.446、8.350、8.847、9.335、9.807、12.845、13.328、13.739、15.728、16.901、17.874、19.059和19.805处有特征峰。
在另一些实施方案中，钠盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在4.741、6.446、8.350、8.847、9.335、9.807、12.845、13.328、13.739、15.728、16.901、17.874、19.059、19.805、21.490、23.607、25.460和25.773处有特征峰。
在另一些实施方案中，钠盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图5所示。
另一方面，本公开提供一种式I化合物的钠盐I晶型的制备方法，包括：将式I化合物溶于50％乙醇/乙酸乙酯、50％甲醇/乙腈或四氢呋喃，加入氢氧化钠溶液，再加入甲基叔丁基醚，搅拌析晶。
另一方面，本公开提供一种式I化合物的钠盐I晶型的制备方法，包括：将式I化合物溶于2-丁酮或乙腈，加入氢氧化钠乙醇溶液，搅拌析晶。
另一方面，本公开还提供式I化合物(1S，3aS，5S，6aR)-5-((6-(5-(((4-(甲氧基甲基)嘧啶-2-基)氧基)甲基)-1-甲基-1H-1，2，3-三唑-4-基)-2-甲基吡啶-3-基)氧)八氢并环戊二烯-1-羧酸钠盐II晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.771、13.464、14.419和15.593处有特征峰。
在另一些实施方案中，钠盐II晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.771、13.464、13.970、14.419、15.593、18.044和19.952处有特征峰。
在另一些实施方案中，钠盐II晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图6所示。
另一方面，本公开提供一种式I化合物的钠盐II晶型的制备方法，包括：将式I化合物溶于异丙醇或1，4-二氧六环，加入氢氧化钠乙醇溶液，搅拌析晶。
另一方面，本公开提供一种式I化合物的钠盐II晶型的制备方法，包括：将式I化合物的钠盐I晶型溶于异丙醇或乙酸异丙酯，搅拌析晶。
另一方面，本公开提供一种式I化合物的钠盐II晶型的制备方法，包括：将式I化合物的钠盐I晶型溶于乙醇或正丙醇，再加入正庚烷，搅拌析晶。
另一方面，本公开还提供式I化合物(1S，3aS，5S，6aR)-5-((6-(5-(((4-(甲氧基甲基)嘧啶-2-基)氧基)甲基)-1-甲基-1H-1，2，3-三唑-4-基)-2-甲基吡啶-3-基)氧)八氢并环戊二烯-1-羧酸钠盐III晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.605、18.597、20.094、26.882处有特征峰。
在另一些实施方案中，钠盐III晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.639、6.605、10.311、13.323、18.597、20.094、26.882处有特征峰。
在另一些实施方案中，钠盐III晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图7所示。
另一方面，本公开提供一种式I化合物的钠盐III晶型的制备方法，包括：将式I化合物的钠盐I晶型溶于1，4-二氧六环，搅拌析晶。
另一方面，本公开还提供式I化合物(1S，3aS，5S，6aR)-5-((6-(5-(((4-(甲氧基甲基)嘧啶-2-基)氧基)甲基)-1-甲基-1H-1，2，3-三唑-4-基)-2-甲基吡啶-3-基)氧)八氢并环戊二烯-1-羧酸钠盐IV晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.078、14.227、15.004、18.812、20.081处有特征峰。
在另一些实施方案中，钠盐IV晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.078、7.078、10.670、13.231、14.227、15.004、18.812、20.081、24.018处有特征峰。
在另一些实施方案中，钠盐IV晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图8所示。
另一方面，本公开提供一种式I化合物的钠盐IV晶型的制备方法，包括：将式I化合物的钠盐I晶型加热至180℃及以上。
另一方面，本公开还提供式I化合物(1S，3aS，5S，6aR)-5-((6-(5-(((4-(甲氧基甲基)嘧啶-2-基)氧基)甲基)-1-甲基-1H-1，2，3-三唑-4-基)-2-甲基吡啶-3-基)氧)八氢并环戊二烯-1-羧酸乙醇胺盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.343、9.612、10.751、16.737、19.178处有特征峰。
在另一些实施方案中，乙醇胺盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在5.343、9.612、10.751、12.023、14.613、16.737、17.886、19.178、20.434、21.788处有特征峰。
在另一些实施方案中，乙醇胺盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图10所示。
另一方面，本公开提供一种式I化合物的乙醇胺盐I晶型的制备方法，包括：将式I化合物溶于四氢呋喃，加入乙醇胺乙醇溶液，加入甲基叔丁基醚搅拌析晶。
进一步地，本公开化合物式I化合物(1S，3aS，5S，6aR)-5-((6-(5-(((4-(甲氧基甲基)嘧啶-2-基)氧基)甲基)-1-甲基-1H-1，2，3-三唑-4-基)-2-甲基吡啶-3-基)氧)八氢并环戊二烯-1-羧酸晶型，其中，所述2θ角度的误差范围为±0.2。
在某些实施方案中，本公开所述的晶型的制备方法还包括析晶、过滤、洗涤或干燥步骤。
另一方面，本公开还提供一种药物组合物，其包括含前述化合物式I化合物(1S，3aS，5S，6aR)-5-((6-(5-(((4-(甲氧基甲基)嘧啶-2-基)氧基)甲基)-1-甲基-1H-1，2，3-三唑-4-基)-2-甲基吡啶-3-基)氧)八氢并环戊二烯-1-羧酸的A晶型，B晶型、C晶型、无定形、钠盐、钠盐I晶型、钠盐II晶型、钠盐III晶型、钠盐IV晶型、钠盐无定形、乙醇胺盐、乙醇胺盐I晶型，和任选自药学上可接受的赋形剂。
本公开还提供了一种药物组合物的制备方法，包括将前述化合物式I化合物(1S，3aS，5S，6aR)-5-((6-(5-(((4-(甲氧基甲基)嘧啶-2-基)氧基)甲基)-1-甲基-1H-1，2，3-三唑-4-基)-2-甲基吡啶-3-基)氧)八氢并环戊二烯-1-羧酸的A晶型、B晶型、C晶型、无定形、钠盐、钠盐I晶型、钠盐II晶型、钠盐III晶型、钠盐IV晶型、钠盐无定形、乙醇胺盐或乙醇胺盐I晶型与药学上可接受的赋形剂混合的步骤。
本公开还提供了前述化合物式I化合物(1S，3aS，5S，6aR)-5-((6-(5-(((4-(甲氧基甲基)嘧啶-2-基)氧基)甲基)-1-甲基-1H-1，2，3-三唑-4-基)-2-甲基吡啶-3-基)氧)八氢并环戊二烯-1-羧酸的A晶型、B晶型、C晶型、无定形、钠盐、钠盐I晶型、钠盐II晶型、钠盐III晶型、钠盐IV晶型、钠盐无定形、 乙醇胺盐、乙醇胺盐I晶型、或者前述药物组合物作为LPA1抑制剂中的用途。
本公开还提供了前述化合物式I化合物(1S，3aS，5S，6aR)-5-((6-(5-(((4-(甲氧基甲基)嘧啶-2-基)氧基)甲基)-1-甲基-1H-1，2，3-三唑-4-基)-2-甲基吡啶-3-基)氧)八氢并环戊二烯-1-羧酸的A晶型、B晶型、C晶型、无定形、钠盐、钠盐I晶型、钠盐II晶型、钠盐III晶型、钠盐IV晶型、钠盐无定形、乙醇胺盐、乙醇胺盐I晶型、或者前述药物组合物用于预防和/或治疗器官纤维化变性疾病、呼吸系统疾病、肾脏疾病、肝脏疾病、炎性疾病、神经系统疾病、心脑血管疾病、胃肠道疾病、疼痛、泌尿系统疾病、眼病、代谢疾病、癌症、移植器官排斥的用途。
本公开还提供了前述化合物式I化合物(1S，3aS，5S，6aR)-5-((6-(5-(((4-(甲氧基甲基)嘧啶-2-基)氧基)甲基)-1-甲基-1H-1，2，3-三唑-4-基)-2-甲基吡啶-3-基)氧)八氢并环戊二烯-1-羧酸的A晶型、B晶型、C晶型、无定形、钠盐、钠盐I晶型、钠盐II晶型、钠盐III晶型、钠盐IV晶型、钠盐无定形、乙醇胺盐、乙醇胺盐I晶型、或者前述药物组合物在制备用于预防和/或治疗器官纤维化变性疾病、呼吸系统疾病、肾脏疾病、肝脏疾病、炎性疾病、神经系统疾病、心脑血管疾病、胃肠道疾病、疼痛、泌尿系统疾病、眼病、代谢疾病、癌症、移植器官排斥的药物中的用途。
本公开所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度；每个特征峰2θ的误差范围为±0.20(包括超过1位小数的数字经过四舍五入后的情况)，具体为-0.20、-0.19、-0.18、-0.17、-0.16、-0.15、-0.14、-0.13、-0.12、-0.11、-0.10、-0.09、-0.08、-0.07、-0.06、-0.05、-0.04、-0.03、-0.02、-0.01、0.00、0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.10、0.11、0.12、0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.20。
本公开中化合物与酸分子的化学配比测定存在一定程度的误差，一般而言，正负10％均属于合理误差范围内。随其所用之处的上下文而有一定程度的误差变化，该误差变化不超过正负10％，可以为正负9％、正负8％、正负7％、正负6％、正负5％、正负4％、正负3％、正负2％或正负1％，优选正负5％”。本公开“约”所表示的数值在前述合理误差范围内。
本公开所述的“结晶析出”或“析晶”包括但不限于搅拌结晶、打浆结晶、冷却结晶和挥发结晶。
本公开中所述的“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。
本公开中所述干燥温度一般为25℃-100℃，优选40℃-70℃，可以常压干燥，也可以减压干燥。
本公开中所述的“药学上可接受的赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂或乳化剂。
附图说明
图1为式I化合物无定形XRPD谱图。
图2为式I化合物A晶型XRPD谱图。
图3为式I化合物B晶型XRPD谱图。
图4为式I化合物C晶型XRPD谱图。
图5为式I化合物钠盐I晶型XRPD谱图。
图6为式I化合物钠盐II晶型XRPD谱图。
图7为式I化合物钠盐III晶型XRPD谱图。
图8为式I化合物钠盐IV晶型XRPD谱图。
图9为式I化合物钠盐无定形XRPD谱图。
图10为式I化合物乙醇胺盐I晶型XRPD谱图。
具体实施方式
通过以下实施例和实验例进一步详细说明本公开。这些实施例和实验例仅用于说明性目的，并不用于限制本公开的范围。
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-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)。waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q 15 Exactive)。HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Thermo U3000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)，射线：单色Cu-Ka射线扫描方式：θ/2θ，扫描范围：3-48°。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℃)，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30℃-400℃)，氮气吹扫速度50mL/min。DVS为动态水分吸附：采用Surface Measurement Systems instrinsic，湿度从50％起，考察湿度范围为0％-95％，步进为10％，判断标准为每个梯度质量变化dM/dT≤0.002％，TMAX 360min，循环两圈。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学30科技(Accela ChemBio Inc)、达瑞化学品等公司。
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：制备化合物I(化合物1-P1，参照申请号为PCT/CN2022/106706的申请中实施例3的制备方法)

步骤1：5-羟基六氢并环戊二烯-2(1H)-酮(1b)
将原料顺式-四氢并环戊二烯-2，5(1H，3H)-二酮1a(24g，173.7mmol)溶于乙醇(500mL)，冷却至0℃，加入硼氢化钠(1.47g，43.4mmol)，0℃搅拌反应2小时。将反应液用乙酸(10mL)淬灭，浓缩，残余物经硅胶快速柱层析(石油醚/乙酸乙酯)纯化得到标题产物1b(9g，收率37.0％)。1H NMR：(400MHz，CDCl3)δ4.55-4.37(m，1H)，2.90-2.75(m，2H)，2.64-2.48(m，2H)，2.36-2.14(m，4H)，1.65-1.49(m，3H)。
步骤2：5-((叔丁基二苯基硅基)氧基)六氢并环戊二烯-2(1H)-酮(1c)
将1b(15g，107.0mmol)溶于二氯甲烷(150mL)，加入咪唑(21.8g，321.0mmol)，将混合溶液冷却至0℃后，加入叔丁基二苯基氯硅烷(30.5mL，117.7mmol)，0℃搅拌反应1小时。将反应液用1M盐酸溶液洗涤(150mL×3)，饱和食盐水(300mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，残余物经硅胶快速柱层析(石油醚/乙酸乙酯)得到标题产物1c(41g，粗品)，未进一步提纯，直接用于下步反应。
步骤3：5-((叔丁基二苯基硅基)氧)-2-氧代八氢并环戊二烯-1-羧酸甲酯(1d)
将1c(41g，108.3mmol)四氢呋喃溶液(500mL)冷却至0℃，加入60％氢化钠(17.3g，433.2mmol)后，加入碳酸二甲酯(19.5g，216.6mmol)，升温至60℃，搅拌反应3小时。加入水(150mL)淬灭反应。乙酸乙酯萃取(100mL×3)，合并有机相，饱和食盐水(300mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，残余物经硅胶快速柱层析(石油醚/乙酸乙酯)得到标题产物1d(25g，收率52.9％)。MS(ESI)：m/z＝459.1[M+Na]+。
步骤4：5-((叔丁基二苯基硅基)氧)-2-羟基八氢并环戊二烯-1-羧酸甲酯(1e)
将1d(32g，73.3mmol)溶于四氢呋喃(350mL)，冷却至0℃，加入硼氢化钠(2.48g，73.3mmol)，0℃搅拌反应3小时。用0.5M盐酸溶液(30mL)淬灭反应，乙酸乙酯萃取(30mL×3)，合并有机相，饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，残余物经硅胶快速柱层析(石油醚/乙酸乙酯)得到标题产物1e(9g，收率28.0％)。MS(ESI)：m/z＝461.2[M+Na]+。
步骤5：5-((叔丁基二苯基硅基)氧)-2-((甲磺酰基)氧)八氢并环戊二烯-1-羧酸甲酯(1f)
将1e(9g，20.5mmol)溶于二氯甲烷(20mL)，加入三乙胺(5.19g，51.3mmol)，冷却至0℃，加入甲磺酸酐(5.36g，30.8mmol)后，将反应液恢复至室温，搅拌反应3小时。反应液用水洗涤(25mL×2)，饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，残余物经硅胶快速柱层析(石油醚/乙酸乙酯)得到标题产物1f(9g，收率84.9％)。MS(ESI)：m/z＝539.1[M+Na]+。
步骤6：5-((叔丁基二苯基硅基)氧)-3，3a，4，5，6，6a-六氢并环戊二烯-1-羧酸甲酯(1g)
将1f(9g，17.4mmol)溶于甲苯(100mL)，加入1，8-二氮杂二环[5.4.0]十一碳-7-烯(5.3g，34.8mmol)，升温至90℃，搅拌反应2小时。将反应液浓缩，残余物经硅胶快速柱层析(石油醚/乙酸乙酯)得到标题产物1g(6.5g，收率88.7％)。MS(ESI)：m/z＝443.2[M+Na]+。
步骤7：5-((叔丁基二苯基硅基)氧)八氢并环戊二烯-1-羧酸甲酯(1h)
将1g(6.5g，15.5mmol)溶于甲醇(65mL)，氮气氛下，加入10％Pd/C(600mg)后，用氢气置换数次后，反应液在氢气氛围(15psi)、室温下搅拌反应3小时。将反应液过滤，滤液浓缩，得到标题产物1h粗品(6.5g)，直接进行下一步反应。MS(ESI)：m/z＝445.2[M+Na]+。
步骤8：5-羟基八氢并环戊二烯-1-羧酸甲酯(1i)
将1h(6.3g，14.9mmol)溶于四氢呋喃(60mL)，加入1M四丁基氟化铵四氢呋喃溶液(16.4mL，16.4mmol)，室温反应3小时。向反应液中加入水(30mL)，乙酸乙酯萃取(20mL×3)，合并有机相，饱和食盐水(60mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，残余物经硅胶快速柱层析(石油醚/乙酸乙酯)得到标题产物1i(2.1g，收率76.5％)。1H NMR(400MHz，CDCl3)δ4.03(tt，J＝9.8，6.1Hz，1H)，3.65(s，3H)，2.75-2.61(m，2H)，2.50-2.38(m，1H)，2.26-2.15(m，1H)，2.02-1.88(m，2H)，1.83-1.74(m，2H)，1.66-1.49(m，2H)，1.22-1.07(m，2H)。
步骤9：2-甲基-6-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1，2，3-三氮唑-4-基)吡啶-3-醇(1k)
将3-溴-2-甲基-6-(1-甲基-5-((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1，2，3-三唑-4-基)吡啶1j(2.5g，6.81mmol，采用专利申请WO2017223016A1中说明书实施例1公开的方法制备而得)、二(二亚苄基丙酮)钯(391mg，0.68mmol)、2-二-叔丁膦基-2′，4′，6′-三异丙基联苯(578mg，1.36mmol)和氢氧化钾(1.15g，20.44mmol)溶于1，4-二氧六环(50mL)和水(10mL)，氮气氛下，100℃反应2小时。1M盐酸溶液调pH至6-7，加入水(10mL)，乙酸乙酯萃取(50mL×2)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得粗品，经硅基快速柱层析(乙酸乙酯/石油醚)纯化得到标题产物1k(1.9g，收率92％)。MS(ESI)m/z＝305.6[M+H]+。
步骤10：5-((2-甲基-6-(1-甲基-5-(((四氢-2H-吡喃-2-基)氧基)甲基)-1H-1，2，3-三氮唑-4-基)吡啶-3-基)氧基)八氢并环戊二烯-1-羧酸甲酯(11)
将1k(1g，3.29mmol)、三苯基膦(2.59g，9.86mmol)和1i(605mg，3.29mmol)溶于四氢呋喃(50mL)，加热至50℃，缓慢滴加溶于四氢呋喃(10mL)的偶氮二甲酸二叔丁酯(2.25g，9.86mmol)的溶液，50℃搅拌反应2小时。减压浓缩得到粗产品，粗品经过反相C18柱(乙腈/水)纯化得到标题产物1l(1.2g，收率77％)。MS(ESI)m/z＝471.8[M+H]+。
步骤11：5-((6-(5-(羟甲基)-1-甲基-1H-1，2，3-三氮唑-4-基)-2-甲基吡啶-3-基)氧基)八氢并环戊二烯-1-羧酸甲酯(1m)
将1l(1.2g，2.55mmol)溶于甲醇(30mL)，加入对甲苯磺酸水合物(194mg，1.02mmol)，将反应液加热至70℃，氮气氛下反应2小时。冷却，减压浓缩，得到标题产物粗品1m(900mg)，直接用于下步反应。MS(ESI)m/z＝387.7[M+H]+。
步骤12：5-((6-(5-(羟甲基)-1-甲基-1H-1，2，3-三氮唑-4-基)-2-甲基吡啶-3-基)氧基)八氢并环戊二烯-1-羧酸(1n)
将1m(900mg，2.33mmol)溶于四氢呋喃(10mL)、甲醇(10mL)和水(10mL)，然后加入氢氧化锂(536mg，23.29mmol)，室温反应3小时。1M盐酸溶液调pH至5-6，加入水(10mL)，乙酸乙酯萃取(30mL×2)，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到标题产物1n(800mg，收率82％)。MS(ESI)m/z＝373.6[M+H]+。
步骤13：(1S，3aS，5S，6aR)-5-((6-(5-(((4-(甲氧甲基)嘧啶-2-基)氧基)甲基)-1-甲基-1H-1，2，3-三唑-4-基)-2-甲基吡啶-3-基)氧基)八氢并环戊二烯-1-羧酸(1)
将1n(350mg，0.94mmol)溶于N，N-二甲基乙酰胺(20mL)，冰浴下加入60％氢化钠(180mg，7.52mmol)，反应30分钟，加入2-氯-4-(甲氧基甲基)嘧啶(179mg，1.13mmol)，室温下反应30分钟。加水(10mL)稀释，1M盐酸调节pH值至4～5，乙酸乙酯萃取(20mL×2)。合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到粗品，粗品经反相快速柱层析(乙腈/水)纯化后冻干，得到化合物1(200mg，收率43％)。MS(ESI)m/z＝495.5[M+H]+
将化合物1进行SFC手性制备(分离条件：SFC手性制备柱DAICEL CHIRALPAK AS(250mm*30mm，10um)；流动相：A为CO2，B为乙醇(0.1％氨水))，收集其相应组分，减压浓缩，得到化合物1-P1和1-P2。
化合物1-P1为保留时间较短者：MS m/z(ESI)：495.2[M+H]+；手性SFC分析：保留时间2.717分钟，手性纯度100％(色谱柱：Chiralpak AS-3，0.46cm I.D.*100mm，3um；流动相：A为CO2，B为乙醇(0.05％二乙胺)。1H NMR(400MHz，CDCl3)δ8.50(d，J＝5.0Hz，1H)，7.90(d，J＝8.5Hz，1H)，7.13(d，J＝6.6Hz，2H)，6.16-6.01(m，2H)，4.86(s，1H)，4.36(s，2H)，4.18(s，3H)，3.45(s，3H)，3.15-2.98(m，1H)，2.91-2.77(m，2H)，2.34(s，3H)，2.30-2.21(m，1H)，2.09-2.00(m，1H)，1.87-1.77(m，2H)，1.75-1.64(m，1H)，1.57-1.40(m，3H).
化合物1-P2为保留时间较长者：MS m/z(ESI)：495.2[M+H]+；手性SFC分析：保留时间3.031分钟，手性纯度97.4％(色谱柱：Chiralpak AS-3，0.46cmI.D.*100mm，3um；流动相：A为CO2，B为乙醇(0.05％二乙胺)。1H NMR(400MHz，CDCl3)δ8.50(d，J＝5.0Hz，1H)，7.91(d，J＝8.5Hz，1H)，7.16-7.10(m，2H)，6.17-6.01(m，2H)，4.87(s，1H)，4.36(s，2H)，4.18(s，3H)，3.45(s，3H)，3.14-3.00(m，1H)，2.91-2.78(m，2H)，2.35(s，3H)，2.31-2.21(m，1H)，2.11-2.02(m，1H)，1.89-1.78(m，2H)，1.75-1.63(m，1H)，1.58-1.39(m，3H).
化合物1-P1产物经X-射线粉末衍射检测为无定形，XRPD谱图如图1所示
实施例2：化合物的拮抗剂特性测试
对本公开中化合物的拮抗剂特性利用FLIPR(荧光成像读板仪)法进行测定，所述化合物是CHO-K1细胞(中国仓鼠卵巢细胞K1，HDB)中所表达的hLPAR1(人溶血磷脂酸受体1)激活所诱导的细胞内钙升高的抑制剂。
1、实验试剂及仪器耗材

2、试剂准备
2.1、反应缓冲液：HBSS+20mM HEPES+0.1％无脂肪酸BSA+0.001％F-127
2.2、50x Red dye：(一种红色染料，用于屏蔽细胞中的背景信号)，配制方法为：称取4g酒石黄和10.2g酸性红溶于100mL H2O。
2.3、Fluo-8染色混合液：4mL反应缓冲液，32μL fluo-8，320μL 50x Red dye，40μL丙磺舒。
3、化合物准备
3.1、LPA：溶解于DPBS(含有0.1％无脂肪酸BSA)，配成浓度为0.8μM的母液，分装并保存于-20℃。
3.2、待测化合物配制：待测化合物溶于DMSO，配成浓度为10mM的母液，保存于-20℃。实验时化合物先用DMSO梯度稀释(起始浓度为50μM，3倍稀释，10个点)，配成200倍浓度的化合物溶液。再用反应缓冲液稀释成5倍浓度的化合物溶液，用Bravo转移到384孔板(货号#6008590)中。
4、实验步骤
4.1、用细胞培养基(F-12+10％FBS+400μg/ml潮霉素B)培养CHO-K1/LPA1R细胞。
4.2、细胞汇合度达到80％，使用0.25％胰酶消化。
4.3、待细胞形态变圆，用培养基F-12(10％FBS)终止消化，细胞计数。然后用F-12(10％FBS)稀释成密度为6.7×105细胞/ml的细胞悬液。
4.4、使用Multidrop自动分液器将细胞添加到384孔黑色细胞培养板中，每孔30μL细胞悬液，于37℃、5％CO2培养箱中培养20-24小时。将培养基换成无血清的F-12培养基，饥饿24小时。
4.5、测试LPA的剂量实验。用反应缓冲液配制6x LPA溶液梯度稀释(起始浓度为60μM，3倍稀释，10个点)，弃掉384孔黑色细胞培养板中的培养基，换成反应缓冲液。加入10μL 5％DMSO的反应缓冲液，再加入10μL Fluo-8染色混合液，37℃、5％CO2培养箱中避光孵育0.5小时。
4.6、FLIPR设置相应程序添加6x LPA梯度溶液，读数。收集2分钟的数据。
4.7、根据LPA的数值得到其反应曲线，计算出EC80时LPA的浓度。配制6x LPA溶液于384孔板(货号#6008590)中，并在相应的位置加入HPE和ZPE。HPE(百分之百的效应)为60μM LPA，ZPE(百分之零的效应)为反应缓冲液。
4.8、化合物测试。弃掉384孔黑色细胞培养板中的培养基，换成反应缓冲液。Bravo转移10μL  5X化合物溶液，随后立即加入10μL Fluo-8染色混合液，37℃、5％CO2培养箱中避光孵育0.5小时。
4.9、FLIPR设置相应程序添加6x LPA溶液，读数。收集2分钟的数据。
4.10、最后对输出的荧光计数进行分析计算化合物的IC50。
5、实验结果
表1本公开化合物对LPAR1受体所获得的IC50

结论：结果显示上述化合物具有优异的LPAR1抑制活性，其作为LPAR1拮抗剂可应用于LPAR1
靶点相关疾病的治疗。
实施例3：式I化合物A晶型的制备
称取式I所示化合物约300mg，溶于7ml丙二醇甲醚中，加入21ml正庚烷，反应液搅拌1天，固体抽滤、干燥，得到式I化合物A晶型。
经X-射线粉末衍射检测，XRPD谱图如图2所示，其特征峰位置如表2所示。TGA谱图显示，在100℃前失重1.55％。DSC图谱显示，吸热峰峰值在183.35℃。
DVS检测结果显示在正常存储条件下(即25℃、60％RH)，该样品吸湿增重约为0.17％；在加速实验条件(即70％RH)，吸湿增重约为0.20％；在极端条件下(90％RH)，吸湿增重约为0.37％。DVS检测后复测晶型，晶型未转变。
表2

实施例4：式I化合物A晶型的制备
称取式(I)所示化合物约5mg，溶于溶剂A中溶清，加入溶剂B，再加入溶剂C，搅拌3天，析出固体离心、干燥，得到式(I)化合物A晶型。
表3式I化合物A晶型的制备
实施例5：式I化合物B晶型的制备
称取式(I)所示化合物约5mg，溶于0.1ml四氢呋喃中(溶剂A)溶清，加入0.2ml甲基叔丁基醚(溶剂B)，再加入0.2ml正庚烷(溶剂C)，搅拌1天，析出固体离心、干燥，得到式I化合物B晶型。
表4式I化合物B晶型的制备
经X-射线粉末衍射检测，XRPD谱图如图3所示，其特征峰位置如表5所示。TGA谱图显示，在100℃前失重1.66％。DSC图谱显示，吸热峰峰值在163.19℃和182.43℃，放热峰峰值在164.04℃。
DVS检测结果显示在正常存储条件下(即25℃、60％RH)，该样品吸湿增重约为0.25％；在加速实验条件(即70％RH)，吸湿增重约为0.31％；在极端条件下(90％RH)，吸湿增重约为0.64％。DVS检测后复测晶型，晶型未转变。
表5
实施例6：式I化合物B晶型的制备
称取式(I)所示化合物约5mg，溶于0.25ml水(溶剂A)中，反应液搅拌1天，固体离心、干燥，得到式I化合物B晶型。
表6式I化合物B晶型的制备

实施例7：式I化合物C晶型的制备
称取式(I)所示化合物约10mg，加入0.2ml 50％甲醇/乙腈或0.2ml四氢呋喃，加入乙醇胺的乙醇溶液(2mol/L，10μL)，反应液中加入0.4ml甲基叔丁基醚，搅拌2天，再加入0.8ml甲基叔丁基醚，50℃-5℃升降温(升降温速率为45℃/h)搅拌1天，在25℃搅拌2天，离心、干燥，得到式I化合物C晶型。
经X-射线粉末衍射检测，XRPD谱图如图4所示，其特征峰位置如表7所示。TGA谱图显示，在110℃前失重4.34％，110℃-195℃失重8.22％。DSC图谱显示，吸热峰峰值在106.12℃和177.29℃。
表7

实施例8：式I化合物钠盐I晶型的制备
称取式(I)所示化合物约10mg，加入0.2ml 50％乙醇/乙酸乙酯溶解(溶剂A)，加入氢氧化钠溶液(2mol/L，10.5μL)，加入0.8ml甲基叔丁基醚，反应液搅拌2天，离心、干燥，得到式I化合物钠盐I晶型。
表8式I化合物钠盐I晶型的制备
经X-射线粉末衍射检测，XRPD谱图如图5，其特征峰位置如表9所示。经离子色谱检测，钠离子的含量为4.85％。TGA谱图显示，30℃-110℃失重7.36％。DSC谱图显示，吸热峰峰值90.11℃、122.09℃和210.70℃，放热峰峰值在145.47℃。
DVS检测显示在正常存储条件下(即25℃、60％RH)，该样品吸湿增重约为6.31％；在加速实验条件(即70％RH)，吸湿增重约为7.08％；在极端条件下(90％RH)，吸湿增重约为42.38％。
表9

实施例9：式I化合物钠盐I晶型的制备
称取式(I)所示化合物约10mg，加入0.2ml 2-丁酮或0.2ml乙腈，加入氢氧化钠乙醇溶液(1mol/L，21μL)，反应液搅拌1天，离心、干燥，得到式I化合物钠盐I晶型。
实施例10：式I化合物钠盐II晶型的制备
称取式(I)所示化合物约10mg，加入0.2ml异丙醇或0.2ml 1，4-二氧六环，加入氢氧化钠乙醇溶液(1mol/L，21μL)，反应液搅拌1天，离心、干燥，得到式I化合物钠盐II晶型。
经X-射线粉末衍射检测，XRPD谱图如图6，其特征峰位置如表10所示。经离子色谱检测，钠离子的含量为4.75％。TGA谱图显示，30℃-120℃失重2.18％。DSC谱图显示，吸热峰峰值179.08℃和223.40℃。
DVS检测显示在正常存储条件下(即25℃、60％RH)，该样品吸湿增重约为6.35％；在加速实验条件(即70％RH)，吸湿增重约为22.41％；在极端条件下(90％RH)，吸湿增重约为56.98％。
表10

实施例11：式I化合物钠盐II晶型的制备
称取式(I)所示化合物钠盐I晶型约5mg，加入0.2ml异丙醇或0.2ml乙酸异丙酯，反应液搅拌2天，离心、干燥，得到式I化合物钠盐II晶型。
实施例12：式I化合物钠盐II晶型的制备
称取式(I)所示化合物钠盐I晶型约5mg，溶于0.2ml乙醇或0.2ml正丙醇，加入1ml正庚烷，反应液搅拌5天，离心、干燥，得到式I化合物钠盐II晶型。
实施例13：式I化合物钠盐III晶型的制备
称取式(I)所示化合物钠盐I晶型约5mg，加入0.2ml 1，4-二氧六环，反应液搅拌2天，离心、干燥，得到式I化合物钠盐III晶型。
经X-射线粉末衍射检测，XRPD谱图如图7，其特征峰位置如表11所示。
表11

实施例14：式I化合物钠盐IV晶型的制备
称取式(I)所示化合物钠盐I晶型约2mg，加热至180℃，得到式I化合物钠盐IV晶型。经X-射线粉末衍射检测，XRPD谱图如图8，其特征峰位置如表12所示。
表12
实施例15：式I化合物钠盐无定形的制备
称取式(I)所示化合物钠盐I晶型约2mg，加热至130℃，得到标题产物。经X-射线粉末衍射检测，该产物为钠盐无定形，XRPD谱图如图9。
实施例16：式I化合物乙醇胺盐I晶型的制备
称取式(I)所示化合物约30mg，加入0.6ml四氢呋喃，加入乙醇胺乙醇溶液(2mol/L，31.5μl)，加入3.6ml甲基叔丁基醚，反应液50℃-5℃升降温循环(升降温速度为45℃/h)搅拌3天，离心、干燥，得到式I化合物乙醇胺盐I晶型。
经X-射线粉末衍射检测，XRPD谱图如图10，其特征峰位置如表13所示。TGA谱图显示，30℃-190℃失重13.57％。DSC谱图显示，吸热峰峰值59.63℃和148.77℃。
表13
实施例17、影响因素稳定性研究：
将式I所述化合物游离态A晶型、B晶型敞口平摊放置，分别考察在光照(4500Lux)、高温(40℃、60℃)、高湿(RH 75％、RH 93％)条件下样品的稳定性，取样考察期为1个月。
表14影响因素

结论：式I所示化合物游离态A晶型和游离态B晶型放置1个月物理和化学稳定性良好。
将式I所示化合物钠盐I晶型、钠盐II晶型敞口平摊放置，分别考察在光照(4500Lux)、高温(40℃、60℃)、高湿(RH 75％)条件下样品的稳定性，取样考察期为1个月。
表15影响因素

结论：钠盐I晶型放置1个月物理和化学稳定性良好；钠盐II晶型除高湿外，物理和化学稳定
性良好。
实施例18、长期/加速稳定性：
将式I所示化合物游离态A晶型、游离态B晶型，分别放置25℃/60％RH和40℃/75％RH条件考察其稳定性：
表16长期加速


结论：游离态A晶型、游离态B晶型在长期加速条件下放置6个月，物理和化学稳定性良好。
将式I所示化合物钠盐I晶型、钠盐II晶型，分别放置25℃/60％RH和40℃/75％RH条件考察其稳定性：
表17长期加速

结论：钠盐I晶型和II晶型在长期加速条件下放置3个月，物理和化学稳定性良好。

Claims (12)

  1. 一种式I所示化合物的A晶型，
    以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.534、10.223、14.364、17.269、18.495和19.553处有特征峰，优选在7.534、10.223、14.364、15.816、16.678、17.269、18.495和19.553处有特征峰，更优选在7.534、10.223、14.364、15.816、16.678、17.269、18.495、19.553、21.043、21.342、23.647和25.965处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图2所示。
  2. 一种式I所示化合物的B晶型，
    以衍射角2θ角度表示的X-射线粉末衍射图谱，在7.437、10.381、14.955和17.513处有特征峰，优选在7.437、10.381、14.717、14.955、17.513、21.395、22.607和23.221处有特征峰，更优选在7.437、10.381、14.717、14.955、17.513、18.466、21.395、21.692、22.607、23.221和25.972处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图3所示。
  3. 一种式I所示化合物的可药用盐，所述可药用盐选自钠盐或乙醇胺盐，
  4. 根据权利要求3所述的可药用盐，其特征在于，所述式I所示化合物与碱离子的化学配比为1∶1或1∶2，优选化学配比为1∶1。
  5. 一种I所示化合物的可药用盐的制备方法，包括I所示化合物与碱反应的步骤，所述的碱选自氢氧化钠或乙醇胺，
  6. 一种式I所示化合物的钠盐I晶型，
    以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.446、8.350、8.847、9.335、12.845、16.901和17.874处有特征峰，优选在6.446、8.350、8.847、9.335、9.807、12.845、13.328、13.739、15.728、16.901和17.874处有特征峰，更优选在4.741、6.446、8.350、8.847、9.335、9.807、12.845、13.328、13.739、15.728、16.901、17.874、19.059和19.805处有特征峰，更优选在4.741、6.446、8.350、8.847、9.335、9.807、12.845、13.328、13.739、15.728、16.901、17.874、19.059、19.805、21.490、23.607、25.460和25.773处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图5所示。
  7. 一种式I所示化合物的钠盐II晶型，
    以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.771、13.464、13.970、14.419、15.593、18.044和19.952处有特征峰，优选在6.771、11.446、13.464、13.970、14.419、15.593、18.044、19.952和24.260处有特征峰，更优选在6.771、8.505、11.446、13.464、13.970、14.419、15.593、18.044、19.952、20.313、22.868、24.260和32.304处有特征峰，最优选以衍射角2θ角度表示的X-射线粉末衍射图谱如图6所示。
  8. 一种式I所示化合物的晶型或式I所示化合物可药用盐的晶型，其中，2θ角度的误差范围为±0.2，
  9. 一种药物组合物，其包含如下组分：
    i)权利要求1或2中任一项所述的式I所示化合物的晶型，或者权利要求3或4中任一项所述的式I所示化合物的可药用盐，或者权利要求6或7所述的晶型；和
    ii)一种或多种药学上可接受的赋形剂。
  10. 一种制备药物组合物的方法，包括下述步骤：将权利要求1或2中任一项所述的式I所示化合物的晶型，或者权利要求3或4中任一项所述的式I所示化合物的可药用盐，或者权利要求6或7所述的晶型与药学上可接受的赋形剂混合的步骤。
  11. 权利要求1或2中任一项所述的式I所示化合物的晶型，或者权利要求3或4中任一项所述的式I所示化合物的可药用盐，或者权利要求6或7所述的晶型，或者根据权利要求9所述的组合物在制备LPA1抑制剂中的用途。
  12. 权利要求1或2中任一项所述的式I所示化合物的晶型，或者权利要求3或4中任一项所述的式I所示化合物的可药用盐，或者权利要求6或7所述的晶型，或者根据权利要求9所述的组合物在制备用于治疗和/或预防器官纤维化变性疾病、呼吸系统疾病、肾脏疾病、肝脏疾病、炎性疾病、神经系统疾病、心脑血管疾病、胃肠道疾病、疼痛、泌尿系统疾病、眼病、代谢疾病、癌症、移植器官排斥患者的药物中的用途。
PCT/CN2024/073211 2023-01-19 2024-01-19 一种三氮唑类化合物的可药用盐、晶型及其制备方法 WO2024153219A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202310066282.4 2023-01-19
CN202310066282 2023-01-19

Publications (1)

Publication Number Publication Date
WO2024153219A1 true WO2024153219A1 (zh) 2024-07-25

Family

ID=91955332

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/073211 WO2024153219A1 (zh) 2023-01-19 2024-01-19 一种三氮唑类化合物的可药用盐、晶型及其制备方法

Country Status (2)

Country Link
TW (1) TW202432092A (zh)
WO (1) WO2024153219A1 (zh)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103596566A (zh) * 2010-12-07 2014-02-19 阿米拉制药公司 多环lpa1拮抗剂及其使用
CN109963843A (zh) * 2016-06-21 2019-07-02 百时美施贵宝公司 作为lpa拮抗剂的氨甲酰基氧甲基三唑环己基酸
WO2020060915A1 (en) * 2018-09-18 2020-03-26 Bristol-Myers Squibb Company Cyclopentyl acids as lpa antagonists
WO2020257135A1 (en) * 2019-06-18 2020-12-24 Bristol-Myers Squibb Company Triazole carboxylic acids as lpa antagonists
WO2023001177A1 (zh) * 2021-07-20 2023-01-26 上海拓界生物医药科技有限公司 一种lpa1小分子拮抗剂

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103596566A (zh) * 2010-12-07 2014-02-19 阿米拉制药公司 多环lpa1拮抗剂及其使用
CN109963843A (zh) * 2016-06-21 2019-07-02 百时美施贵宝公司 作为lpa拮抗剂的氨甲酰基氧甲基三唑环己基酸
WO2020060915A1 (en) * 2018-09-18 2020-03-26 Bristol-Myers Squibb Company Cyclopentyl acids as lpa antagonists
WO2020257135A1 (en) * 2019-06-18 2020-12-24 Bristol-Myers Squibb Company Triazole carboxylic acids as lpa antagonists
WO2023001177A1 (zh) * 2021-07-20 2023-01-26 上海拓界生物医药科技有限公司 一种lpa1小分子拮抗剂

Also Published As

Publication number Publication date
TW202432092A (zh) 2024-08-16

Similar Documents

Publication Publication Date Title
US20120101277A1 (en) Crystalline form of posaconazole
KR20140138941A (ko) 상피 성장 인자 수용체 키나제 억제제의 염
JP2023017840A (ja) Ｍｋ２阻害剤の形態および組成物
CZ201629A3 (cs) Krystalické modifikace solí (3R)-3-cyklopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propannitrilu a způsoby jejich přípravy
WO2023001177A1 (zh) 一种lpa1小分子拮抗剂
ES2960702T3 (es) Formas cristalinas C y E del compuesto de pirazin-2(1H)-ona y método de preparación de las mismas
WO2024153219A1 (zh) 一种三氮唑类化合物的可药用盐、晶型及其制备方法
JP2021505625A (ja) Ｆｇｆｒ及びｖｅｇｆｒ阻害剤としての化合物の塩形態、結晶形およびその製造方法
US20220281853A1 (en) Crystal form d of pyrazine-2(1h)-ketone compound and preparation method therefor
CN110437156B (zh) 丹皮酚二氢嘧啶酮类衍生物及其制备方法和应用
TW202024087A (zh) 四氫哌喃基胺基－吡咯并嘧啶酮化合物的固體形式
WO2023124824A1 (zh) 一种glp-1激动剂的盐及其晶型和在医药上的应用
JP2024547113A (ja) Ｇｌｐ－１受容体作動薬の薬学的に許容される塩、結晶形及びその調製方法
TW202328115A (zh) Glp-1受體激動劑的結晶形式及其製備方法
EP3893872B1 (en) Organophosphorus-substituted compounds as c-met inhibitors and therapeutic uses thereof
CN116528859A (zh) 含二并环类衍生物抑制剂自由碱的晶型及其制备方法和应用
EP3747871A1 (en) Crystal form of urate transporter 1 inhibitor and preparation method and use thereof
WO2024109871A1 (zh) 一种含氮杂环类化合物的可药用盐、晶型及制备方法
EP3960742A1 (en) Crystals of alkynyl-containing compound, salt and solvate thereof, preparation method, and applications
WO2024217545A1 (zh) 一种含氮四环化合物的结晶形式及其制备方法
TWI826013B (zh) 咪唑啉酮衍生物的晶型
EP3950694B1 (en) Salt form and crystal form of a2a receptor antagonist and preparation method therefor
WO2023078411A1 (zh) 氮杂螺环化合物
WO2022262841A1 (zh) 一种螺环化合物的盐型、晶型及其制备方法
WO2019019851A1 (zh) 钠离子通道抑制剂及其药学上可接受的盐和多晶型物及其应用

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: 24744389

Country of ref document: EP

Kind code of ref document: A1