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WO2024140868A1 - Forme cristalline d'un composé tricyclique et son utilisation - Google Patents

Forme cristalline d'un composé tricyclique et son utilisation Download PDF

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Publication number
WO2024140868A1
WO2024140868A1 PCT/CN2023/142570 CN2023142570W WO2024140868A1 WO 2024140868 A1 WO2024140868 A1 WO 2024140868A1 CN 2023142570 W CN2023142570 W CN 2023142570W WO 2024140868 A1 WO2024140868 A1 WO 2024140868A1
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crystalline form
disease
present
ray powder
powder diffraction
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Chinese (zh)
Inventor
单岳峰
陈亮
杨新业
王晓军
张英俊
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Sunshine Lake Pharma Co Ltd
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Sunshine Lake Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • FXR can be activated by bile acids, the end product of cholesterol metabolism (Makishima et al. Science (1999), 284:1362-1365; Parks et al. Science (1999), 284:1365-1368; Wang et al. MoI. Cell. (1999), 3:543-553), and bile acids serve to inhibit the catabolism of cholesterol (Urizar et al., (2000) J. Biol. Chem. 275:39313-393170).
  • FXR is a key regulator of cholesterol homeostasis, triglyceride synthesis and lipogenesis (Crawley, Expert Opinion Ther. Patents (2010), 20:1047-1057). In addition to being a target for the treatment of dyslipidemia, obesity, vitamin D-related diseases, intestinal diseases, drug-induced side effects and hepatitis (Crawley, Expert Opinion Ther.
  • FXR can also be used as a therapeutic target for hepatobiliary diseases, chronic hepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cholestasis, liver fibrosis, cirrhosis, hepatitis B, metabolic diseases, lipid metabolism diseases, carbohydrate metabolism diseases, cardiovascular metabolic diseases, atherosclerosis, type 2 diabetes and diabetic complications (Frank G. Schaap et al., Journal of Medicinal Chemistry (2005), 48:5383-5402).
  • Patent applications WO 2016127924A1 and CN 105884758A disclose tricyclic compounds that can be used as FXR activity regulators, as well as preparation methods and applications thereof, wherein Example 3 is specifically disclosed, namely, compound 2-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy-10,11-dihydrobenzo[6,7]oxazo[3,2-b]pyridine-7-carboxylic acid (compound shown in formula (I)).
  • the present invention provides a crystalline form of a compound represented by formula (I). Specifically, the crystalline form of a compound represented by formula (I) provided by the present invention can significantly improve the stability and pharmacokinetic properties of the compound, thereby having better drugability.
  • the present invention relates to a crystalline form of a compound represented by formula (I), and a pharmaceutical composition comprising the crystalline form, and also relates to their use in preparing a drug for preventing, treating or alleviating a disease mediated by FXR in a patient.
  • the present invention provides a crystalline form of a compound represented by formula (I);
  • the crystalline form of the compound represented by formula (I) of the present invention is crystalline form II, characterized in that the X-ray powder diffraction pattern of the crystalline form II comprises the following diffraction peaks at 2 ⁇ angles: 16.97° ⁇ 0.2°, 17.18° ⁇ 0.2°, 21.31° ⁇ 0.2°, 25.29° ⁇ 0.2°, 26.36° ⁇ 0.2°.
  • the crystalline form of the compound represented by formula (I) of the present invention is crystalline form II, characterized in that the X-ray powder diffraction pattern of the crystalline form II comprises the following diffraction peaks at 2 ⁇ angles: 11.36° ⁇ 0.2°, 13.45° ⁇ 0.2°, 16.97° ⁇ 0.2°, 17.18° ⁇ 0.2°, 20.77° ⁇ 0.2°, 21.08° ⁇ 0.2°, 21.31° ⁇ 0.2°, 23.56° ⁇ 0.2°, 24.31° ⁇ 0.2°, 24.52° ⁇ 0.2°, 25.29° ⁇ 0.2°, 26.36° ⁇ 0.2°, 26.67° ⁇ 0.2°.
  • the crystalline form of the compound represented by formula (I) of the present invention is crystalline form II, characterized in that the crystalline form II has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
  • the crystalline form of the compound represented by formula (I) of the present invention is crystalline form II, characterized in that the differential scanning calorimetry diagram of the crystalline form II comprises endothermic peaks at 125.84°C ⁇ 3°C and 198.41°C ⁇ 3°C.
  • the crystalline form of the compound represented by formula (I) of the present invention is crystalline form II, characterized in that the crystalline form II has a differential scanning calorimetry diagram substantially as shown in FIG. 2 .
  • the crystalline form of the compound represented by formula (I) of the present invention is crystalline form II, characterized in that the crystalline form II loses weight by 7.233% in the range of 70°C-160°C, with an error tolerance of ⁇ 0.1%.
  • the crystalline form of the compound represented by formula (I) of the present invention is crystalline form II, characterized in that the crystalline form II has a thermogravimetric analysis diagram substantially as shown in FIG. 3 .
  • the crystalline form of the compound represented by formula (I) described in the present invention is crystalline form III, characterized in that the X-ray powder diffraction pattern of the crystalline form III comprises the following diffraction peaks at 2 ⁇ angles: 17.17° ⁇ 0.2°, 20.92° ⁇ 0.2°, 24.38° ⁇ 0.2°, 25.19° ⁇ 0.2°, 26.21° ⁇ 0.2°.
  • the crystalline form of the compound represented by formula (I) described in the present invention is crystalline form III, characterized in that the X-ray powder diffraction pattern of the crystalline form III comprises the following diffraction peaks at 2 ⁇ angles: 9.59° ⁇ 0.2°, 17.17° ⁇ 0.2°, 20.92° ⁇ 0.2°, 21.12° ⁇ 0.2°, 23.51° ⁇ 0.2°, 24.38° ⁇ 0.2°, 24.67° ⁇ 0.2°, 25.19° ⁇ 0.2°, 25.98° ⁇ 0.2°, 26.21° ⁇ 0.2°, 26.83° ⁇ 0.2°, 28.59° ⁇ 0.2°, 28.92° ⁇ 0.2°.
  • the crystalline form of the compound represented by formula (I) of the present invention is crystalline form III, characterized in that the X-ray powder diffraction pattern of the crystalline form III comprises the following diffraction peaks at 2 ⁇ angles: 5.70° ⁇ 0.2°, 9.01° ⁇ 0.2°, 9.59° ⁇ 0.2°, 10.95° ⁇ 0.2°, 11.43° ⁇ 0.2°, 11.95° ⁇ 0.2°, 12.15° ⁇ 0.2°, 13.55° ⁇ 0.2°, 14.18° ⁇ 0.2°, 14.82° ⁇ 0.2°, 15.
  • the crystalline form of the compound represented by formula (I) of the present invention is crystalline form III, characterized in that the crystalline form III has an X-ray powder diffraction pattern substantially as shown in FIG. 4 .
  • the crystalline form of the compound represented by formula (I) of the present invention is crystalline form III, characterized in that the differential scanning calorimetry diagram of the crystalline form III comprises endothermic peaks at 104.93°C ⁇ 3°C and 199.52°C ⁇ 3°C.
  • the crystalline form of the compound represented by formula (I) of the present invention is crystalline form III, characterized in that the crystalline form III has a differential scanning calorimetry diagram substantially as shown in FIG. 5 .
  • the crystalline form of the compound represented by formula (I) of the present invention is crystalline form III, characterized in that the crystalline form III loses weight by 4.383% in the range of 70°C-160°C, with an error tolerance of ⁇ 0.1%.
  • the crystalline form of the compound represented by formula (I) of the present invention is crystalline form III, characterized in that the crystalline form III has a thermogravimetric analysis diagram substantially as shown in FIG. 6 .
  • the crystalline form of the compound represented by formula (I) of the present invention is crystalline form VII, characterized in that the X-ray powder diffraction pattern of the crystalline form VII comprises the following diffraction peaks at 2 ⁇ angles: 13.92° ⁇ 0.2°, 14.93° ⁇ 0.2°, 19.48° ⁇ 0.2°, 23.23° ⁇ 0.2°, 23.55° ⁇ 0.2°.
  • the crystalline form of the compound represented by formula (I) of the present invention is crystalline form VII, characterized in that the X-ray powder diffraction pattern of the crystalline form VII comprises the following diffraction peaks at 2 ⁇ angles: 8.88° ⁇ 0.2°, 10.57° ⁇ 0.2°, 10.90° ⁇ 0.2°, 11.87° ⁇ 0.2°, 12.91° ⁇ 0.2°, 13.92° ⁇ 0.2°, 14.93° ⁇ 0.2°, 16.00° ⁇ 0.2°, 16.35° ⁇ 0.2°, 17.10° ⁇ 0.2°, 17.97° ⁇ 0.2°, 18.57° ⁇ 0.2°, 18.86° ⁇ 0.2°, 19.48° ⁇ 0.2°, 20.60 ° ⁇ 0.2°,21.08° ⁇ 0.2°,21.72° ⁇ 0.2°,22.19° ⁇ 0.2°,22.66° ⁇ 0.2°,23.23° ⁇ 0.2°,23.55° ⁇ 0.2°,24.06° ⁇ 0.2°,25.04° ⁇ 0.2°,25.69° ⁇ 0.2°,26.42° ⁇ 0.2°,26.75° ⁇
  • the crystalline form of the compound represented by formula (I) of the present invention is crystalline form VII, characterized in that the crystalline form VII has an X-ray powder diffraction pattern substantially as shown in Figure 7.
  • the crystalline form of the compound represented by formula (I) of the present invention is crystalline form VII, characterized in that the differential scanning calorimetry diagram of the crystalline form VII comprises endothermic peaks at 177.53°C ⁇ 3°C and 199.42°C ⁇ 3°C and an exothermic peak at 179.32°C ⁇ 3°C.
  • the crystalline form of the compound represented by formula (I) of the present invention is crystalline form VII, characterized in that the crystalline form VII has a differential scanning calorimetry diagram substantially as shown in Figure 8.
  • the crystalline form of the compound represented by formula (I) of the present invention is crystalline form VII, characterized in that the crystalline form VII loses weight by 0.3968% in the range of 70°C-160°C, with an error tolerance of ⁇ 0.1%.
  • the crystalline form of the compound represented by formula (I) of the present invention is crystalline form VII, characterized in that the crystalline form VII has a thermogravimetric analysis diagram substantially as shown in FIG. 9 .
  • the crystalline form of the compound represented by formula (I) described in the present invention is crystalline form VIII, characterized in that the X-ray powder diffraction pattern of the crystalline form VIII comprises the following diffraction peaks at 2 ⁇ angles: 17.24° ⁇ 0.2°, 20.92° ⁇ 0.2°, 24.33° ⁇ 0.2°, 25.19° ⁇ 0.2°, 26.31° ⁇ 0.2°.
  • the crystalline form of the compound represented by formula (I) described in the present invention is crystalline form VIII, characterized in that the X-ray powder diffraction pattern of the crystalline form VIII comprises the following diffraction peaks at 2 ⁇ angles: 9.60° ⁇ 0.2°, 12.12° ⁇ 0.2°, 17.24° ⁇ 0.2°, 20.92° ⁇ 0.2°, 23.65° ⁇ 0.2°, 24.33° ⁇ 0.2°, 24.60° ⁇ 0.2°, 25.19° ⁇ 0.2°, 26.31° ⁇ 0.2°, 27.55° ⁇ 0.2°, 28.51° ⁇ 0.2°, 29.01° ⁇ 0.2°.
  • the crystalline form of the compound represented by formula (I) of the present invention is crystalline form VIII, characterized in that the X-ray powder diffraction pattern of the crystalline form VIII comprises the following diffraction peaks at 2 ⁇ angles: 5.70° ⁇ 0.2°, 9.60° ⁇ 0.2°, 11.34° ⁇ 0.2°, 11.82° ⁇ 0.2°, 12.12° ⁇ 0.2°, 12.71° ⁇ 0.2°, 13.35° ⁇ 0.2°, 14.75° ⁇ 0.2°, 14.89° ⁇ 0.2°, 16.48° ⁇ 0.2°, 17.24° ⁇ 0.2°, 17.75° ⁇ 0.2° ,18.08° ⁇ 0.2°,19.00° ⁇ 0.2°,19.24° ⁇ 0.2°,19.98° ⁇ 0.2°,20.92° ⁇ 0.2°,21.25° ⁇ 0.2°,21.87° ⁇ 0.2°,22.73° ⁇ 0.2°,23.65° ⁇ 0.2°,24.33° ⁇ 0.2°,24.60° ⁇ 0.2°,25.19° ⁇ 0.2°,25.58° ⁇ 0.2°,26.31°
  • the crystalline form of the compound represented by formula (I) described in the present invention is crystalline form IX, characterized in that the X-ray powder diffraction pattern of the crystalline form IX comprises the following diffraction peaks at 2 ⁇ angles: 15.92° ⁇ 0.2°, 21.17° ⁇ 0.2°, 21.82° ⁇ 0.2°, 22.44° ⁇ 0.2°, 23.49° ⁇ 0.2°.
  • room temperature refers to a temperature from about 10° C. to about 40° C. In some embodiments, “room temperature” refers to a temperature from about 20° C. to about 30° C.; in other embodiments, “room temperature” refers to 20° C., 22.5° C., 25° C., 27.5° C., etc.
  • the pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, adjuvant, or excipient, which, as used in the present invention, includes any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a specific target dosage form.
  • a pharmaceutically acceptable carrier includes any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc.
  • the crystal form of the present invention can be used as an active ingredient and uniformly combined in a mixture with a drug carrier according to conventional drug compounding technology.
  • a drug carrier can be in a variety of forms.
  • any conventional drug medium can be used, for example, water, ethylene glycol, oil, alcohol, fragrance, preservative, colorant, etc.
  • oral liquid medicaments such as suspensions, elixirs and solutions
  • oral solid preparations such as powders, hard capsules, soft capsules and tablets, starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, adhesives, disintegrants, etc. are used, wherein solid oral preparations are more preferred than liquid medicaments.
  • the crystalline forms of the present invention may also be administered parenterally.
  • Solutions or suspensions of these active substances may be prepared in water by suitable mixing with a surfactant such as hydroxypropylcellulose.
  • Dispersants may also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof, and in oils. Under normal conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms.
  • the pharmaceutical form suitable for injection purposes includes sterile aqueous solution or dispersant and the sterile powder for instant preparation of sterile injectable solution or dispersant.
  • the pharmaceutical form must be sterile and must be a fluid in the form of easy injection. It must be stable under the conditions of manufacture and storage and must be preserved under the conditions of antimicrobial such as antibacterial and fungal contamination.
  • Carrier can be a solvent or a dispersion medium, which contains, for example: water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol), their applicable mixtures and vegetable oils.
  • any suitable method of administration can be used to provide an effective dose of the crystalline form of the present invention to a mammal, especially a human.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal and other administration methods can be used.
  • Dosage forms include tablets, lozenges, dispersants, suspensions, solutions, capsules, emulsions, ointments, aerosols, etc.
  • the crystalline form of the present invention is administered orally.
  • the compounds of the present invention or their crystalline forms are administered at a daily dose of about 0.1 mg to about 100 mg/kg of animal body weight, preferably in a single daily dose, or in 2 to 6 divided doses per day, or in a continuous release form.
  • the total daily dose is about 1.0 mg to about 1000 mg, preferably about 1 mg to about 50 mg.
  • the total daily dose is generally 7 mg to about 350 mg. This dosage regimen can be adjusted to provide the best therapeutic effect.
  • the crystal form or pharmaceutical composition thereof disclosed in the present invention can be effectively used to prevent, treat, cure or alleviate FXR-mediated diseases in patients, and can particularly effectively treat non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), obesity, hypertriglyceridemia, atherosclerosis, chronic intrahepatic cholestasis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), progressive familial cholestasis (PFIC), drug-induced bile duct damage, gallstones, cirrhosis, hepatitis B, sebaceous gland disease, alcohol-induced cirrhosis, cystic fibrosis, biliary obstruction, cholelithiasis, liver fibrosis, dyslipidemia, atherosclerosis, type II diabetes, diabetic nephropathy, diabetic neuropathy, Diabetic retinopathy, peripheral arterial occlusive disease (PAOD), colitis,
  • FIG1 is an X-ray powder diffraction (XRPD) pattern of Form II of the compound represented by formula (I).
  • FIG2 is a differential scanning calorimetry (DSC) diagram of Form II of the compound represented by formula (I).
  • FIG4 is an X-ray powder diffraction (XRPD) pattern of Form III of the compound represented by formula (I).
  • FIG5 is a differential scanning calorimetry (DSC) diagram of Form III of the compound represented by formula (I).
  • FIG7 is an X-ray powder diffraction (XRPD) pattern of Form VII of the compound represented by formula (I).
  • FIG8 is a differential scanning calorimetry (DSC) diagram of Form VII of the compound represented by formula (I).
  • FIG9 is a thermogravimetric analysis (TGA) diagram of Form VII of the compound represented by formula (I).
  • FIG10 is an X-ray powder diffraction (XRPD) pattern of Form VIII of the compound represented by formula (I).
  • FIG11 is a differential scanning calorimetry (DSC) diagram of Form VIII of the compound represented by formula (I).
  • FIG12 is a thermogravimetric analysis (TGA) diagram of Form VIII of the compound represented by formula (I).
  • FIG13 is an X-ray powder diffraction (XRPD) pattern of Form IX of the compound represented by formula (I).
  • FIG14 is a differential scanning calorimetry (DSC) diagram of Form IX of the compound represented by formula (I).
  • FIG15 is an X-ray powder diffraction (XRPD) pattern of Form I of the compound represented by formula (I).
  • the X-ray powder diffraction analysis method used in the present invention is: Empyrean diffractometer, using Cu-K ⁇ radiation (45KV, 40mA) to obtain X-ray powder diffraction patterns.
  • the powdered sample is prepared into a thin layer on a single crystal silicon sample holder, placed on a rotating sample stage, and analyzed in a range of 3°-40° with a step size of 0.0168°.
  • Data Collector software is used to collect data
  • HighScore Plus software is used to process data
  • Data Viewer software is used to read data.
  • the differential scanning calorimetry (DSC) analysis method used in the present invention is: differential scanning calorimetry is performed using a TA Q2000 module with a thermal analysis controller. Data is collected and analyzed using TA Instruments Thermal Solutions software. About 1-5 mg of sample is accurately weighed into a special aluminum crucible with a lid, and a linear heating device of 10°C/min is used to analyze the sample from room temperature to about 300°C. During use, the DSC chamber is purged with dry nitrogen.
  • the compound 2-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy-10,11-dihydrobenzo[6,7]oxazo[3,2-b]pyridine-7-carboxylic acid i.e., the compound of formula (I)
  • the compound of formula (I) in the following examples is prepared by referring to the synthesis method of Example 3 in patent applications WO 2016127924A1 and CN 105884758A, and is identified by Empyrean X-ray powder diffraction (XRPD) analysis as Form I, having an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 15, as described in Example 6 of the present invention.
  • Method 1 Add the compound 2-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy-10,11-dihydrobenzo[6,7]oxazo[3,2-b]pyridine-7-carboxylic acid (900.0 mg) to methyl acetate (22.0 mL), heat under reflux until the solid is completely dissolved, then cool to room temperature, and then add n-heptane (22.0 mL), and solid precipitates. Filter by suction, and dry the filter cake under vacuum at room temperature to obtain a white solid (685.0 mg, yield 76.11%).
  • TGA Thermogravimetric analysis
  • Method 1 Add the compound 2-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy-10,11-dihydrobenzo[6,7]oxazo[3,2-b]pyridine-7-carboxylic acid (30.0 g) to dimethyl sulfoxide (150.0 mL), and the solid is completely dissolved. After stirring for 4 hours, water (450.0 mL) is added, and stirring is continued for 40 hours. Filter with suction, and the filter cake is vacuum dried at 60°C for 16 hours to obtain a white solid (29.51 g, yield 98.38%).
  • Method 2 Add the compound 2-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy-10,11-dihydrobenzo[6,7]oxazo[3,2-b]pyridine-7-carboxylic acid (1.0 g) to dimethyl sulfoxide (2.0 mL), the solid is completely dissolved, N,N-dimethylacetamide (2.0 mL) is added and heated to 60°C, kept warm for 2 hours and then slowly cooled to room temperature, water (12.0 mL) is added and stirred for 16 hours. Filter by suction, and dry the filter cake under vacuum at 60°C for 4 hours to obtain a white solid (0.93 g, yield 93.00%).
  • Method 3 Add the compound 2-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy-10,11-dihydrobenzo[6,7]oxazo[3,2-b]pyridine-7-carboxylic acid (52.0 mg) to N,N-dimethylacetamide (0.5 mL), heat to 90°C and then slowly cool to room temperature, add water (1.5 mL), and solid precipitates. Filter by suction, and dry the filter cake under vacuum at room temperature to obtain a white solid (42.1 mg, yield 80.96%).
  • Method 4 Add the compound 2-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy-10,11-dihydrobenzo[6,7]oxazo[3,2-b]pyridine-7-carboxylic acid (50.0 mg) to N,N-dimethylformamide (0.5 mL), heat to 60°C, keep warm for 2 hours, then slowly cool to room temperature, add water (1.5 mL) to crystallize, filter, and dry the filter cake in vacuo at room temperature to obtain a white solid (46.6 mg, yield 93.20%).
  • Method 5 Add 2-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy-10,11-dihydrobenzo[6,7]oxazo[3,2-b]pyridine-7-carboxylic acid (5.08 g) and isopropanol (84.0 mL) into a 100 mL two-necked bottle, heat to 79°C, wait until the solid is completely dissolved, add the above solution into 5-10°C water (198.0 mL), continue stirring for 1 hour after the addition, then stir at room temperature overnight, filter, and dry the filter cake under vacuum at room temperature for 6 hours to obtain an off-white solid (4.33 g, yield 85.23%).
  • TGA Thermogravimetric analysis

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Abstract

L'invention concerne une forme cristalline d'un composé tricyclique et son utilisation. Spécifiquement, l'invention concerne une forme cristalline d'un composé acide 2-((5-cyclopropyl-3-(2,6-dichlorophényl)isoxazol-4-yl)méthoxy-10,11-dihydrobenzo[6,7]oxazole[3,2-b]pyridine-7-carboxylique, une composition pharmaceutique comprenant la forme cristalline, et son utilisation dans la préparation d'un médicament pour prévenir, traiter ou soulager des maladies médiées par FXR chez des patients.
PCT/CN2023/142570 2022-12-30 2023-12-28 Forme cristalline d'un composé tricyclique et son utilisation Ceased WO2024140868A1 (fr)

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Citations (4)

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EP1182200A1 (fr) * 1999-06-03 2002-02-27 Nippon Suisan Kaisha, Ltd. Composes heterocycliques condenses a trois cycles, procede de preparation correspondant et utilisation de tels composes
CN105884758A (zh) * 2015-02-13 2016-08-24 广东东阳光药业有限公司 三环化合物及其在药物中的应用
CN107686486A (zh) * 2016-08-05 2018-02-13 广东东阳光药业有限公司 含氮三环化合物及其在药物中的应用
CN110128432A (zh) * 2018-02-02 2019-08-16 广东东阳光药业有限公司 含氮三环化合物及其在药物中的应用

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EP1182200A1 (fr) * 1999-06-03 2002-02-27 Nippon Suisan Kaisha, Ltd. Composes heterocycliques condenses a trois cycles, procede de preparation correspondant et utilisation de tels composes
CN105884758A (zh) * 2015-02-13 2016-08-24 广东东阳光药业有限公司 三环化合物及其在药物中的应用
CN107686486A (zh) * 2016-08-05 2018-02-13 广东东阳光药业有限公司 含氮三环化合物及其在药物中的应用
CN110128432A (zh) * 2018-02-02 2019-08-16 广东东阳光药业有限公司 含氮三环化合物及其在药物中的应用

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CAO SHENGTIAN, YANG XINYE, ZHANG ZHENG, WU JUNWEN, CHI BO, CHEN HONG, YU JIANGHONG, FENG SHANSHAN, XU YULIN, LI JING, ZHANG YINGJU: "Discovery of a tricyclic farnesoid X receptor agonist HEC96719, a clinical candidate for treatment of non-alcoholic steatohepatitis", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER MASSON, vol. 230, 1 February 2022 (2022-02-01), pages 114089, XP093187243, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2021.114089 *

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