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WO2025167362A1 - Forme cristalline b de 6-((5,6-diphényl-1,2,4-triazin-3-yl)(isopropyl)amino)-n-(méthylsulfonyl)hexanamide, son utilisation et son procédé de préparation - Google Patents

Forme cristalline b de 6-((5,6-diphényl-1,2,4-triazin-3-yl)(isopropyl)amino)-n-(méthylsulfonyl)hexanamide, son utilisation et son procédé de préparation

Info

Publication number
WO2025167362A1
WO2025167362A1 PCT/CN2024/141737 CN2024141737W WO2025167362A1 WO 2025167362 A1 WO2025167362 A1 WO 2025167362A1 CN 2024141737 W CN2024141737 W CN 2024141737W WO 2025167362 A1 WO2025167362 A1 WO 2025167362A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
crystallization
solvent
crystalline form
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/141737
Other languages
English (en)
Chinese (zh)
Inventor
孙立杰
孙晓飞
郭志强
杨娴
曹柳
李磊
张紫莹
刘丽娟
赵方红
陶宇凡
朱树杰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shijiazhuang No 4 Pharmaceutical Co Ltd
Hebei Guolong Pharmaceutical Co Ltd
Original Assignee
Shijiazhuang No 4 Pharmaceutical Co Ltd
Hebei Guolong Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shijiazhuang No 4 Pharmaceutical Co Ltd, Hebei Guolong Pharmaceutical Co Ltd filed Critical Shijiazhuang No 4 Pharmaceutical Co Ltd
Publication of WO2025167362A1 publication Critical patent/WO2025167362A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • 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
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • 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
    • 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

  • the present application belongs to the field of pharmacy, and specifically relates to a crystalline form of the compound 6-((5,6-diphenyl-1,2,4-triazin-3-yl)(isopropyl)amino)-N-(methylsulfonyl)hexanamide, its pharmaceutical composition, use and preparation method.
  • Pulmonary arterial hypertension is a rare, incurable pulmonary vascular disease that can gradually lead to right heart failure and ultimately death.
  • PAH is characterized by pulmonary microvascular remodeling, which leads to a progressive increase in pulmonary artery resistance (PVR), which in turn causes right heart failure. This makes PAH a progressive and fatal disease. 75% of PAH patients die within 5 years of diagnosis, with an average survival of 1.9 years after symptom onset. It is often referred to as the "malignant tumor of the cardiovascular and pulmonary vascular system.”
  • PGI2 is an important endothelial relaxing factor that stimulates cyclic adenosine monophosphate (cAMP) production, causing pulmonary vascular smooth muscle relaxation and inhibiting smooth muscle growth. PGI2 deficiency can cause pulmonary hypertension, making PGI2 drugs the most active treatment for PAH.
  • PGI2 drugs include PGI2 analogs and PGI2 receptor agonists.
  • PGI2 analogs which share a native PGI2 backbone, are rapidly metabolized and have a very short biological half-life. They require frequent dosing or intravenous infusion, leading to poor patient compliance. Furthermore, PGI2 analogs have poor target selectivity, making it difficult to separate their therapeutic effects from other effects and prone to adverse reactions.
  • the compound of formula I also known as Compound I, has the chemical name 6-((5,6-diphenyl-1,2,4-triazin-3-yl)(isopropyl)amino)-N-(methylsulfonyl)hexanamide, and its structural formula is shown in Formula I. It is a PGI2 receptor agonist with a novel structure and good drugability. Compound I has strong target selectivity, and its agonist activity at the prostacyclin IP receptor is more than 1,000 times that of the other seven prostacyclin receptor targets.
  • IP receptor mainly activates the IP receptor to promote the production of cAMP in pulmonary artery smooth muscle cells, thereby inhibiting abnormal contraction of the pulmonary artery, inhibiting the proliferation of pulmonary artery smooth muscle cells, and reducing pulmonary artery pressure, thereby achieving the treatment of pulmonary hypertension.
  • IP receptor to promote the production of cAMP in pulmonary artery smooth muscle cells, thereby inhibiting abnormal contraction of the pulmonary artery, inhibiting the proliferation of pulmonary artery smooth muscle cells, and reducing pulmonary artery pressure, thereby achieving the treatment of pulmonary hypertension.
  • it has higher efficacy and safety.
  • Compound I exists in various crystalline forms. Extensive research has been conducted on the crystalline forms of Compound I to identify and prepare crystalline forms that meet pharmaceutical requirements. Based on these studies, this application provides Compound I Form B, which is non-hygroscopic and exhibits excellent storage stability, making it suitable for formulation development. This application also provides pharmaceutical compositions and uses of Compound I Form B, as well as a method for preparing Compound I Form B, which operates under mild process conditions and is suitable for large-scale production.
  • One object of the present application is to provide a crystalline form B of compound I, whose X-ray powder diffraction pattern expressed in 2 ⁇ angles has diffraction peaks at 3.36 ⁇ 0.2°, 10.07 ⁇ 0.2°, 13.90 ⁇ 0.2°, 16.51 ⁇ 0.2°, 20.20 ⁇ 0.2°, and 21.10 ⁇ 0.2°.
  • the crystalline form B of compound I has an X-ray powder diffraction pattern expressed in 2 ⁇ angles having characteristic peaks at 3.36 ⁇ 0.2°, 6.72 ⁇ 0.2°, 10.07 ⁇ 0.2°, 13.90 ⁇ 0.2°, 16.51 ⁇ 0.2°, 17.67 ⁇ 0.2°, 19.50 ⁇ 0.2°, 20.20 ⁇ 0.2°, and 21.10 ⁇ 0.2°.
  • the crystalline form B of Compound I has an X-ray powder diffraction pattern expressed in 2 ⁇ angles as shown in FIG1 .
  • Form B of Compound 1 when characterized by TGA/DSC, its TGA graph can confirm that Form B does not contain crystalline water or solvate.
  • Form B of Compound I when Form B of Compound I is characterized by TGA/DSC, its DSC graph shows that the melting point (extrapolated onset temperature) of Form B is 140.5 ⁇ 2°C.
  • the TGA/DSC graph of Form B of Compound 1 is shown in FIG2 .
  • the second object of the present application is to provide a method for preparing Form B of Compound I, which comprises the following steps: dissolving Compound I by heating in a solvent, cooling to 50°C to 60°C, keeping warm until solid precipitates, continuing crystallization, separation, and drying to obtain Form B.
  • the solvent is one or a mixed solvent of alcohols, ethers, esters, alkanes, ketones, acetonitrile, and water.
  • the solvent is one or a mixed solvent of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, ethyl acetate, n-hexane, acetone, and water.
  • the solvent is one or a mixed solvent of isopropanol, ethanol, water, tetrahydrofuran and n-hexane.
  • the solvent is isopropyl alcohol.
  • the mass volume ratio (g/mL) of the compound I to the solvent is 1:3.5-15.
  • the heating and dissolving may be performed in a single solvent or a mixed solvent, or may be performed by first heating and dissolving in one solvent and then adding another one or more solvents.
  • the heating condition is heating under reflux.
  • the temperature is lowered to 50°C to 60°C.
  • the method may be to turn off the heating and cool the temperature slowly naturally, or to add other solvents to cool the temperature slowly under heating or non-heating conditions. As long as the temperature range of the cooling can be guaranteed, various cooling methods can be selected.
  • the temperature is lowered to 50°C to 60°C, and a more preferred temperature range is 55°C to 60°C.
  • the heat preservation is carried out until solids precipitate, and the crystallization method can be static crystallization or crystallization under stirring, such as paddle stirring, suspension stirring, etc. Stirring crystallization is preferred, as stirring can crystallize faster than static crystallization.
  • the heat preservation is carried out until solids precipitate, and the heat preservation temperature fluctuates by 1° C. to 2° C. based on the previous cooling temperature.
  • the crystallization is continued after the solid precipitates.
  • crystallization can be carried out by naturally cooling the temperature, and then the temperature can be further reduced to 0°C to 10°C and kept warm for crystallization.
  • the natural cooling crystallization is carried out at room temperature.
  • the natural cooling crystallization can be performed by standing still or by stirring, such as paddle stirring, suspension stirring, etc. Stirring crystallization is preferred, as stirring can crystallize faster than standing still.
  • the natural cooling crystallization has a crystallization time of 1 to 15 hours, preferably 1 to 2 hours.
  • the temperature is further lowered to 0°C to 10°C in a cold water bath, an ice bath, or an ice salt bath.
  • Various cooling conditions can be selected as long as the temperature range of the cooling can be ensured.
  • the temperature is lowered to 0°C to 10°C and then kept warm for crystallization.
  • the crystallization can be performed by standing still or under stirring, such as paddle stirring, suspension stirring, etc. Stirring crystallization is preferred, as stirring can crystallize faster than standing still.
  • the temperature is lowered to 0°C to 10°C and then kept warm for crystallization, and the crystallization time is 1 to 15 hours, preferably 1 to 2 hours.
  • the heat preservation is continued until solid precipitates and then crystallization is continued.
  • the crystallization method can also be to start heating, heat to 55°C ⁇ 60°C, keep stirring, cool naturally to crystallize, and then continue to cool to 0°C ⁇ 10°C and keep warm to crystallize.
  • the heat-insulating stirring has a stirring time of 20 min to 3 h, preferably 30 min to 1 h.
  • the natural cooling crystallization is to turn off the heating and cool down naturally and slowly in a hot oil bath.
  • the natural cooling crystallization can be performed by standing still or by stirring, such as paddle stirring, suspension stirring, etc. Stirring crystallization is preferred, as stirring can crystallize faster than standing still.
  • the natural cooling crystallization has a crystallization time of 5 to 24 hours, preferably 5 to 8 hours.
  • the temperature is further lowered to 0°C to 10°C in a cold water bath, an ice bath, or an ice salt bath.
  • Various cooling conditions can be selected as long as the temperature range of the cooling can be ensured.
  • the heat preservation crystallization can be performed by standing still or by stirring, such as paddle stirring, suspension stirring, etc. Stirring crystallization is preferred, as stirring can crystallize faster than standing still.
  • the crystallization time during the heat preservation is 1 to 20 hours, preferably 1 to 2 hours.
  • the crystallization is continued after the heat preservation until solid precipitates, and the crystallization method can also be natural cooling crystallization.
  • the natural cooling crystallization can be performed by removing the oil bath and naturally cooling at room temperature, or by naturally cooling in a hot oil bath.
  • the natural cooling crystallization can be performed by standing still or by stirring, such as paddle stirring, suspension stirring, etc. Stirring crystallization is preferred, as stirring can crystallize faster than standing still.
  • the natural cooling crystallization has a crystallization time of 5 to 24 hours, preferably 10 to 20 hours.
  • seed crystals of Compound I may be further added.
  • the amount of the seed crystal added is 0.1% to 5% by mass of Compound I.
  • seed crystals of Compound I can be added to further accelerate the precipitation of Form B.
  • the seed crystals may be various crystalline forms of Compound I, such as seed crystals of Form A, seed crystals of Form B, etc.
  • the Form A of Compound I is described in the patent "6-((5,6-diphenyl-1,2,4-triazin-3-yl)(isopropyl)amino)-N-(methylsulfonyl)hexanamide Form A, its pharmaceutical composition, use and preparation method" filed by the present applicant on the same filing date.
  • the separation can be performed by conventional methods, such as centrifugation or filtration.
  • the drying is a conventional drying method, such as vacuum drying.
  • the drying entails drying to constant weight.
  • the third object of the present application is to provide a pharmaceutical composition comprising a therapeutically effective dose of Compound I Form B and a pharmaceutically acceptable carrier and excipient.
  • the pharmaceutical composition can be formulated into a variety of dosage forms for easy administration, for example, oral preparations (such as tablets, capsules, solutions or suspensions); injectable preparations (such as injectable solutions or suspensions, or injectable dry powders that can be used immediately after adding a pharmaceutical solvent before injection).
  • oral preparations such as tablets, capsules, solutions or suspensions
  • injectable preparations such as injectable solutions or suspensions, or injectable dry powders that can be used immediately after adding a pharmaceutical solvent before injection.
  • the fourth object of the present application is to provide a therapeutically effective dose of Compound I Form B or the pharmaceutical composition for use in the preparation of a drug for preventing and/or treating a disease or condition.
  • the disease or condition is associated with PGI2 receptor agonism.
  • the disease or condition is selected from: pulmonary hypertension, platelet aggregation-related cardiovascular and cerebrovascular diseases, and diabetic nephropathy.
  • the fifth object of the present application is to provide a therapeutically effective dose of Compound I Form B or the use of the pharmaceutical composition in the preparation of PGI2 receptor agonist drugs.
  • room temperature or "RT” refers to an ambient temperature of 20 to 25°C (68 to 77°F).
  • Form B of Compound I of the present application has low hygroscopicity, a higher melting point, and outstanding thermal stability. Furthermore, it is highly pure and less susceptible to impurities. It exhibits strong drug stability and crystal form stability in forced degradation tests, making it suitable for formulation development. Furthermore, its mild preparation process conditions make it suitable for large-scale production. Therefore, Form B offers significant advantages in terms of drugability and industrial production, and is of great significance for drug development.
  • FIG1 shows the XRPD spectrum of Compound 1 Form B prepared in Example 1;
  • FIG3 shows the 1 H-NMR spectrum of Compound I Form B prepared in Example 1;
  • FIG4 shows the IR spectrum of Compound 1 Form B prepared in Example 1;
  • FIG5 shows the XRPD overlay of Compound I Form B prepared in Example 1 at high temperature, high humidity, and light exposure for 30 days and on day 0;
  • FIG6 shows the average concentration-time curve of Compound I in plasma of Group 1 animals after intravenous administration in the bioavailability study of Experimental Example 7;
  • FIG7 shows the average concentration-time curve of Compound I in plasma after oral administration to the second group of animals in the bioavailability test of Experimental Example 7.
  • thermogravimetric-differential scanning calorimetry (TGA/DSC) spectrum is shown in FIG2 .
  • Atmosphere AIR(80/20)--/NITROGEN/50/NITROGEN/20
  • Test results The infrared spectrum of the sample has characteristic peaks at 3105 ⁇ 5cm -1 , 2952 ⁇ 5cm -1 , 1684 ⁇ 5cm -1 , 1532 ⁇ 5cm -1 , 1473 ⁇ 5cm -1 , 1457 ⁇ 5cm -1 , 1441 ⁇ 5cm -1 , 1370 ⁇ 5cm -1 , 1150 ⁇ 5cm -1 , 1137 ⁇ 5cm -1 , 697 ⁇ 5cm - 1 , and 688 ⁇ 5cm -1 .
  • the thickness of the test sample is generally about 1 mm. Accurately weigh the weight (m 2 ).
  • the homogeneity and concentration of the drug formulations were analyzed using a validated HPLC-UV analytical method.
  • concentration of Compound I in plasma samples was determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method.
  • LC-MS/MS liquid chromatography-tandem mass spectrometry
  • the Compound I Form B samples prepared in Examples 2 to 9 have comparable properties to the Compound I Form B sample prepared in Example 1, including hygroscopicity, stability, and bioavailability.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente demande concerne une forme cristalline B du composé I (6-((5,6-diphényl-1,2,4-triazin-3-yl)(isopropyl)amino)-N-(méthylsulfonyl)hexanamide) et une composition pharmaceutique de celui-ci, son utilisation et son procédé de préparation. La forme cristalline B du composé I selon la présente demande présente au moins des pics de diffraction aux angles de diffraction suivants : 2θ 3,36 ± 0,2°, 10,07 ± 0,2°, 13,90 ± 0,2°, 16,51 ± 0,2°, 20,20 ± 0,2° et 21,10 ± 0,2° dans son motif de diffraction de rayons X sur poudre. La forme cristalline B du composé I selon la présente demande présente des pics de diffraction dans son motif de diffraction de rayons X sur poudre au moins aux angles de diffraction suivants : 2θ 3,36 ± 0,2°, 10,07 ± 0,2°, 13,90 ± 0,2°, 16,51 ± 0,2°, 20,20 ± 0,2° et 21,10 ± 0,2°.
PCT/CN2024/141737 2024-02-06 2024-12-24 Forme cristalline b de 6-((5,6-diphényl-1,2,4-triazin-3-yl)(isopropyl)amino)-n-(méthylsulfonyl)hexanamide, son utilisation et son procédé de préparation Pending WO2025167362A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202410169645.1 2024-02-06
CN202410169645 2024-02-06
CN202410898642.1A CN118852042B (zh) 2024-02-06 2024-07-05 6-((5,6-二苯基-1,2,4-三嗪-3-基)(异丙基)氨基)-n-(甲基磺酰基)己酰胺晶型b及其用途和制备方法
CN202410898642.1 2024-07-05

Publications (1)

Publication Number Publication Date
WO2025167362A1 true WO2025167362A1 (fr) 2025-08-14

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Family Applications (3)

Application Number Title Priority Date Filing Date
PCT/CN2024/130940 Pending WO2025167237A1 (fr) 2024-02-06 2024-11-08 Composé de diphényltriazine, son procédé de préparation et son utilisation
PCT/CN2024/141731 Pending WO2025167361A1 (fr) 2024-02-06 2024-12-24 Forme cristalline a de 6- ((5,6-diphényl -1,2,4-triazine-3-yl) (isopropyl) amino)-n- (méthylsulfonyl) hexanamide, et son utilisation et son procédé de préparation
PCT/CN2024/141737 Pending WO2025167362A1 (fr) 2024-02-06 2024-12-24 Forme cristalline b de 6-((5,6-diphényl-1,2,4-triazin-3-yl)(isopropyl)amino)-n-(méthylsulfonyl)hexanamide, son utilisation et son procédé de préparation

Family Applications Before (2)

Application Number Title Priority Date Filing Date
PCT/CN2024/130940 Pending WO2025167237A1 (fr) 2024-02-06 2024-11-08 Composé de diphényltriazine, son procédé de préparation et son utilisation
PCT/CN2024/141731 Pending WO2025167361A1 (fr) 2024-02-06 2024-12-24 Forme cristalline a de 6- ((5,6-diphényl -1,2,4-triazine-3-yl) (isopropyl) amino)-n- (méthylsulfonyl) hexanamide, et son utilisation et son procédé de préparation

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CN (3) CN118598820B (fr)
WO (3) WO2025167237A1 (fr)

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CN118598820B (zh) * 2024-02-06 2025-07-08 石家庄四药有限公司 一种二苯基三嗪类化合物及其制备方法和应用

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CN118619893A (zh) * 2023-12-27 2024-09-10 石家庄四药有限公司 Pgi2受体激动剂化合物、药物组合物和应用

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CN118598820B (zh) 2025-07-08
CN118598820A (zh) 2024-09-06
CN118852042B (zh) 2025-07-08
WO2025167237A1 (fr) 2025-08-14
CN118852042A (zh) 2024-10-29
WO2025167361A1 (fr) 2025-08-14
CN118852041B (zh) 2025-07-08
CN118852041A (zh) 2024-10-29

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