[go: up one dir, main page]

WO2025167362A1 - 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 - Google Patents

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

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)
French (fr)
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/zh
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.

Landscapes

  • 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

本申请公开了一种化合物I(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及其药物组合物、用途和制备方法。本申请中所述的化合物I晶型B在其X-射线粉末衍射图中至少在下述衍射角2θ：3.36±0.2°、10.07±0.2°、13.90±0.2°、16.51±0.2°、20.20±0.2°、21.10±0.2°处有衍射峰。本申请的化合物I晶型B具有引湿性低和稳定性好等优点，对于药物开发具有非常重要的意义。

Description

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
相关申请的交叉引用
本申请要求申请日为2024年2月6日的中国专利申请CN202410169645.1的优先权，本申请要求申请日为2024年7月5日的中国专利申请CN2024108986421的优先权，本申请引用上述中国专利申请的全文。
技术领域
本申请属于药学领域，具体涉及化合物6-((5,6-二苯基-1,2,4-三嗪-3-基)(异丙基)氨基)-N-(甲基磺酰基)己酰胺的晶型及其药物组合物、用途和制备方法。
背景技术
肺动脉高压(Pulmonary arterial hypertension,PAH)是一种罕见的，难以治愈的肺血管病变，可逐渐导致右心衰并最终死亡。PAH的特点是肺微血管重构，导致肺动脉阻力(PVR)进行性增加从而导致右心衰竭，使其成为一种进行性和致命性疾病，PAH患者中75％病人死于诊断后5年内，症状出现后平均生存期为1.9年，因此又被称为“心肺血管领域的恶性肿瘤”。
目前，全球针对PAH的治疗方法包括常规治疗和靶向治疗，常规治疗往往仅能改善症状，不能有效阻止病程的进展。靶向治疗方面，PAH的靶向药物有三条途径，即一氧化氮途径、内皮素途径及前列环素途径(prostacyclin,PGI2)。PGI2是重要的血管内皮舒张因子，其通过刺激环磷酸腺苷(cAMP)的生成引起肺血管平滑肌舒张并抑制平滑肌的生长。PGI2缺乏可引起肺动脉高压，因此PGI2类药物是目前治疗PAH最积极的方法。PGI2类药物包括PGI2类似物和PGI2受体激动剂。PGI2类似物在结构上存在天然PGI2骨架，在体内代谢速度快，生物半衰期非常短，需要高频次给药或者静脉输注给药，患者依从性较差。另外，PGI2类似物的靶点选择性差，治疗作用与其他作用很难分开，易产生不良反应。
式I化合物，也称化合物I，其化学名称为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，结构式如式I所示，是一种PGI2受体激动剂，其结构新颖、成药性良好。化合物I的靶点选择性强，前列环素IP受体的激动活性是其余7个前列环素受体靶点的1000倍以上，其主要通过激活IP受体，促进肺动脉平滑肌细胞内cAMP生成，进而抑制肺动脉的异常收缩、抑制肺动脉平滑肌细胞增殖、降低肺动脉压力，达到治疗肺动脉高压作用，与已上市的同类药物相比，具有更高的药效及安全性。
目前，尚未有化合物I的晶型情况公开，本申请重点基于化合物I在药物开发过程中的晶型研究，提供出一种稳定性好的药物晶型，及其药物组合物、用途和制备方法。
技术问题
经过大量探索研究，结果发现化合物I存在不同结晶型态，对化合物I的晶型进行大量研究，用来确定并制备得到符合药用需求的结晶型态。基于这些研究，本申请提供了化合物I的晶型B，其无引湿性、保存稳定性良好，适合用于制剂开发。本申请同时还提供了化合物I晶型B的药物组合物和用途，并提供了化合物I晶型B的制备方法，其制备工艺条件温和，适合大规模生产。
技术解决方案
为实现本申请目的，采用以下技术方案：
本申请的一个目的是提供一种化合物I的晶型B，其以2θ角度表示的X-射线粉末衍射图在3.36±0.2°、10.07±0.2°、13.90±0.2°、16.51±0.2°、20.20±0.2°、21.10±0.2°处有衍射峰。
在一些实施方案中，化合物I的晶型B，其以2θ角度表示的X-射线粉末衍射图在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°、21.10±0.2°处有特征峰。
在一些实施方案中，化合物I的晶型B，其以2θ角度表示的X-射线粉末衍射图如图1所示。
在一些实施方案中，化合物I的晶型B，采用TGA/DSC表征时，其TGA图可确定晶型B不含有结晶水或溶剂化物。
在一些实施方案中，化合物I的晶型B，采用TGA/DSC表征时，其DSC图显示晶型B的熔点(外推起始温度)为140.5±2℃。
在一些实施方案中，化合物I的晶型B，其TGA/DSC图如图2所示。
本申请的第二个目的是提供化合物I晶型B的制备方法，其包含以下步骤：将化合物I在溶剂中加热溶解，降温至50℃～60℃后，保温直至有固体析出后，继续析晶，分离，干燥，得到晶型B。
在一些实施方案中，所述溶剂为醇类、醚类、酯类、烷类、酮类、乙腈、水的一种或混合溶剂。
在一些实施方案中，所述溶剂为甲醇、乙醇、异丙醇、乙腈、四氢呋喃、乙酸乙酯、正己烷、丙酮、水的一种或混合溶剂。
在某些优选方案中，所述溶剂为异丙醇、乙醇、水、四氢呋喃和正己烷的一种或混合溶剂。
在某些优选方案中，所述溶剂为异丙醇。
在一些实施方案中，所述化合物I与所述溶剂的质量体积比(g/mL)为1：3.5～15。
在一些实施方案中，所述加热溶解，可以是在单一溶剂或混合溶剂中加热溶解，也可以是先在一种溶剂中加热溶解后再加入另外一种或两种以上溶剂。
在一些实施方案中，所述加热的条件为加热回流。
在一些实施方案中，所述降温至50℃～60℃，降温方式有多种，可以是关闭加热自然缓慢降温，也可以是在加热或非加热条件下通过加入其他溶剂来缓慢降温，只要能保证所述降温的温度范围，各种降温方式都是可以选择的。
在一些实施方案中，所述降温至50℃～60℃，更优选的降温范围是降温至55～60℃。
在一些实施方案中，所述保温直至有固体析出，析晶的方式可以是静置析晶，也可以是在搅拌下进行析晶，如桨式搅拌、悬浮搅拌等。优选搅拌析晶，搅拌比静置能更快析晶。
在一些实施方案中，所述保温直至有固体析出，保温的温度是在前面降温温度的基础上上下浮动1℃～2℃。
在一些实施方案中，所述保温直至有固体析出后继续析晶，析晶的方式有多种，常规的析晶方法都是可以采用的。例如，可以是自然降温析晶，再继续降温至0℃～10℃，保温析晶。
进一步地，所述自然降温析晶是在室温下进行。
进一步地，所述自然降温析晶，析晶的方式可以是静置析晶，也可以是在搅拌下进行析晶，如桨式搅拌、悬浮搅拌等。优选搅拌析晶，搅拌比静置能更快析晶。
进一步地，所述自然降温析晶，析晶时间是1～15h，优选1～2h。
进一步地，所述继续降温至0℃～10℃，降温条件是在冷水浴或冰浴或冰盐浴中进行降温，只要能保证所述降温的温度范围，各种降温条件都是可以选择的。
进一步地，所述降温至0℃～10℃后保温析晶，析晶的方式可以是静置析晶，也可以是在搅拌下进行析晶，如桨式搅拌、悬浮搅拌等。优选搅拌析晶，搅拌比静置能更快析晶。
进一步地，所述降温至0℃～10℃后保温析晶，析晶时间为1～15h，优选1～2h。
在一些实施方案中，所述保温直至有固体析出后继续析晶，析晶的方式还可以是启动加热，升温至55℃～60℃保温搅拌，自然降温析晶，再继续降温至0℃～10℃，保温析晶。
进一步地，所述保温搅拌，搅拌时间是20min～3h，优选30min～1h。
进一步地，所述自然降温析晶是关闭加热，在热油浴中自然缓慢降温。
进一步地，所述自然降温析晶，析晶的方式可以是静置析晶，也可以是在搅拌下进行析晶，如桨式搅拌、悬浮搅拌等。优选搅拌析晶，搅拌比静置能更快析晶。
进一步地，所述自然降温析晶，析晶时间为5～24h，优选5～8h。
进一步地，所述继续降温至0℃～10℃，降温条件是在冷水浴或冰浴或冰盐浴中进行降温，只要能保证所述降温的温度范围，各种降温条件都是可以选择的。
进一步地，所述保温析晶，析晶的方式可以是静置析晶，也可以是在搅拌下进行析晶，如桨式搅拌、悬浮搅拌等。优选搅拌析晶，搅拌比静置能更快析晶。
进一步地，所述保温析晶，析晶时间为1～20h，优选1～2h。
在一些实施方案中，所述保温直至有固体析出后继续析晶，析晶的方式还可以是自然降温析晶。
进一步地，所述自然降温析晶，可以是移走油浴，在室温下自然降温，还可以是在热油浴中自然降温。
进一步地，所述自然降温析晶，析晶的方式可以是静置析晶，也可以是在搅拌下进行析晶，如桨式搅拌、悬浮搅拌等。优选搅拌析晶，搅拌比静置能更快析晶。
进一步地，所述自然降温析晶，析晶时间为5～24h，优选10～20h。
在一些实施方案中，还可以进一步加入化合物I的晶种。
在一些实施方案中，所述晶种的加入量为化合物I质量的0.1％～5％。
在一些实施方案中，在所述加热溶解后，在所述降温至50℃～60℃过程中或在所述降温至50℃～60℃后保温过程中，可以加入化合物I的晶种，来进一步加快析出晶型B。
进一步地，所述晶种可以是化合物I的各种晶型，如晶型A的晶种、晶型B的晶种等。所述化合物I的晶型A记载在本申请人在同一个申请日申请的专利“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A及其药物组合物、用途和制备方法”中。
在一些实施方案中，所述分离，可以是常规方法，如离心或过滤等。
在一些实施方案中，所述干燥为常规干燥方法，如真空干燥。
在一些实施方案中，所述干燥需要干燥至恒重。
本申请第三个目的是提供了一种药物组合物，其包含治疗有效剂量的化合物I晶型B及药学上可接受的载体、赋形剂。
进一步地，所述药物组合物可配制成多种剂型，便于给药，例如，口服制剂(如片剂、胶囊剂、溶液或混悬液)；可注射的制剂(如可注射的溶液或混悬液，或者是可注射的干燥粉末，在注射前加入药物溶媒后可立即使用)。
本申请第四个目的是提供了一种治疗有效剂量的化合物I晶型B或所述的药物组合物在制备预防和/或治疗疾病或病症的药物中的用途。
在某些优选方案中，所述疾病或病症与PGI2受体激动作用相关。
在某些优选方案中，所述疾病或病症选自：肺动脉高压、血小板聚集相关的心脑血管疾病和糖尿病性肾病等。
本申请第五个目的是提供了一种治疗有效剂量的化合物I晶型B或所述的药物组合物在制备PGI2受体激动剂药物中的用途。
术语定义和说明
本文所用的术语″室温″或″RT″是指20至25℃(68～77°F)的环境温度。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本申请各较佳实例。
有益效果
本申请积极进步效果在于：本申请化合物I晶型B的引湿性低，晶型B的熔点更高，其热稳定性更突出，且其纯度高，不易产生杂质，在强制降解试验中表现出极强的药品稳定性和晶型稳定性，适合用于制剂开发。同时其制备工艺条件温和，适合大规模生产。因此，晶型B在成药和利于工业生产等方面具备明显优势，对于药物开发具有非常重要的意义。
附图说明
图1表示实施例1所制备的化合物I晶型B的XRPD谱图；
图2表示实施例1所制备的化合物I晶型B的TGA/DSC谱图；
图3表示实施例1所制备的化合物I晶型B的1H-NMR谱图；
图4表示实施例1所制备的化合物I晶型B的IR谱图；
图5表示实施例1所制备的化合物I晶型B的高温、高湿、光照30天与第0天的XRPD叠加图；
图6表示实验例7生物利用度试验中第1组动物静脉给药后血浆中化合物I的平均药时曲线图；
图7表示实验例7生物利用度试验中第2组动物口服给药后血浆中化合物I的平均药时曲线图。
本发明的实施方式
下面通过具体实施方式对本申请作进一步详细说明，但只是用于帮助理解本申请，使本领域专业技术人员能够实现或使用本申请，不对本申请构成任何限制。
实施例1
将10g化合物I原料药在120mL异丙醇中加热回流溶解，关闭油浴锅加热，自然缓慢降温至58℃，保温58±1℃搅拌直至有固体析出，随后在室温下自然降温，搅拌析晶2h，再继续在冷水浴中降温至10℃，保温搅拌析晶1.5h，过滤，真空干燥至恒重，得到化合物I晶型B样品，收率93.5％。
实施例2
将10g化合物I原料药在80mL无水乙醇中加热回流溶解，关闭油浴锅加热，自然缓慢降温至52℃，保温52±1℃搅拌直至有固体析出，随后在室温下自然降温，搅拌析晶1.5h，再在冰浴中降温至5℃，保温搅拌析晶2.0h，过滤，真空干燥至恒重，得到化合物I晶型B样品，收率85.3％。此方法所得样品的X-射线粉末衍射图谱与实施例1中所得化合物I晶型B样品图谱一致。
实施例3
将10g化合物I原料药在50mL甲醇中加热回流溶解，关闭油浴锅加热，自然缓慢降温至50℃，加入0.1g晶型B晶种，保温50±1℃搅拌直至有固体析出，随后开启加热，升温至58±2℃并保温搅拌30min，关闭油浴锅加热，在热油浴中自然缓慢降温，搅拌析晶5h，再继续在冰盐浴中降温至0℃，保温搅拌析晶1h，过滤，真空干燥至恒重，得到化合物I晶型B样品，收率77.4％。此方法所得样品的X-射线粉末衍射图谱与实施例1中所得化合物I晶型B样品图谱一致。
实施例4
将10g化合物I原料药在50mL无水乙醇和50mL的异丙醇中加热回流溶解，关闭油浴锅加热，自然缓慢降温至53℃，保温53±1℃搅拌直至有固体析出，随后在室温下自然降温，静置析晶13h，再在冰浴中降温至3℃，保温搅拌析晶1h，过滤，真空干燥至恒重，得到化合物I晶型B样品，收率88.7％。此方法所得样品的X-射线粉末衍射图谱与实施例1中所得化合物I晶型B样品图谱一致。
实施例5
将10g化合物I原料药在40mL乙酸乙酯中加热回流溶解，关闭油浴锅加热，自然缓慢降温至50℃，保温50±1℃搅拌直至有固体析出，随后开启加热，升温至55±2℃并保温搅拌1h，关闭加热，在热油锅中自然缓慢降温，静置析晶20h，再在冰浴中降温至2℃，保温静置析晶18h，过滤，真空干燥至恒重，得到化合物I晶型B样品，收率68.8％。此方法所得样品的X-射线粉末衍射图谱与实施例1中所得化合物I晶型B样品图谱一致。
实施例6
将10g化合物I原料药在90mL 95％乙醇中加热回流溶解，关闭油浴锅加热，自然缓慢降温至55℃，保温55±1℃搅拌直至有固体析出，随后在室温下自然降温，搅拌析晶1h，再在冰浴中降温至5℃，保温搅拌析晶2.0h，过滤，真空干燥至恒重，得到化合物I晶型B样品，收率86.2％。此方法所得样品的X-射线粉末衍射图谱与实施例1中所得化合物I晶型B样品图谱一致。
实施例7
将10g化合物I原料药在60mL乙腈和40mL水中加热回流溶解，关闭油浴锅加热，自然缓慢降温至51℃，保温51±1℃搅拌直至有固体析出，随后在室温下自然降温，搅拌析晶1.5h，再在冰浴中降温至3℃，保温搅拌析晶1h，过滤，真空干燥至恒重，得到化合物I晶型B样品，收率76.1％。此方法所得样品的X-射线粉末衍射图谱与实施例1中所得化合物I晶型B样品图谱一致。
实施例8
将10g化合物I原料药在20mL丙酮和15mL水的混合溶剂中加热回流溶解，关闭油浴加热，自然缓慢降温至55℃，保温55±1℃搅拌直至有固体析出，随后在室温下自然降温，搅拌析晶1h，再在冰浴下降温至3℃，保温静置析晶15h，过滤，真空干燥至恒重，得到化合物I晶型B样品，收率80.3％。此方法所得样品的X-射线粉末衍射图谱与实施例1中所得化合物I晶型B样品图谱一致。
实施例9
将10g化合物I原料药在30mL四氢呋喃中加热回流溶解，缓慢加入120mL正己烷，降温至60℃，随后保温60±2℃搅拌直至有固体析出，移走油浴，在室温下自然降温，搅拌析晶16h，过滤，真空干燥至恒重，得到化合物I晶型B样品，收率89.3％。此方法所得样品的X-射线粉末衍射图谱与实施例1中所得化合物I晶型B样品图谱一致。
实验例1：X-射线粉末衍射峰的衍射角(2θ)的测定
关于实施例1所制备的化合物I晶型B样品，其X-射线粉末衍射(XRPD)谱图示于图1，其X-射线粉末衍射峰的衍射角(2θ)的值示于表1。
需要说明的是，实验例1中记载各结晶的物性数据通过以下条件测定。
检测仪器：日本理学SmartLab SE全自动多功能X-射线衍射仪。
操作条件：X线管球：对阴极：铜；管压：40kV；管流：30mA；扫描模式：一维扫描；扫描速率：10°/min；扫描轴：θ/2θ；扫描范围：3～35°；步进间隔：0.01°。
检测结果：晶型B通过X-射线粉末衍射发生在衍射角2θ为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°、21.10±0.2°处有特征峰。
表1 实施例1所制备的化合物I晶型B样品X-射线粉末衍射峰的衍射角(2θ)的值
实验例2：热重-差示扫描量热分析
关于实施例1所制备的化合物I晶型B样品，其热重-差示扫描量热分析(TGA/DSC)谱图示于图2。
检测仪器型号：同步热分析仪STA449F3
测试条件：温度：25℃，湿度：35％RH
坩埚：DSC/TG pan Al2O3
气氛：AIR(80/20)--/NITROGEN/50/NITROGEN/20
检测结果：TGA图可确定晶型B不含有结晶水或溶剂化物；DSC图可确认晶型B的熔点(外推起始温度)为140.5±2℃。
实验例3：核磁共振谱(1H-NMR)
关于实施例1所制备的化合物I晶型B样品，其核磁共振(1H-NMR)谱图示于图3。
测定条件：在Bruker 500MHz核磁共振仪上采集，CDCl3作为溶剂。
测试结果：1H-NMR：δ：10.181(br，1H)，7.493～7.439(m，4H)，7.392～7.378(m，1H)，7.317～7.261(m，5H)，5.072(m，1H)，3.608(m，2H)，3.230(s，3H)，2.376(m，2H)，1.729(m，4H)，1.460(m，2H)，1.303～1.289(m，6H)，ppm。
实验例4：红外光谱(IR)
关于实施例1所制备的化合物I晶型B样品，其红外(IR)谱图示于图4。
仪器型号：Nicolet。
检测方法：取本品适量(约1～2mg)，取研磨后干燥的溴化钾适量，置玛瑙研钵中，将样品和溴化钾混合研磨均匀，取适量研磨好的混合物放入压片模具中压片，测定红外谱图。
测试结果：样品的红外谱图在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、688±5cm-1处有特征峰。
实验例5：引湿性
关于实施例1所制备的化合物I晶型B样品，参照2020年版《中国药典》四部通则9103药物引湿性试验指导原则测定其引湿性。具体试验方法如下：
取干燥的具塞玻璃称量瓶(外径为50mm，高为15mm)，于试验前一天置于适宜的25℃±1℃恒温恒湿干燥器内，精密称定重量(m1)。
取供试品适量，平铺于上述称量瓶中，供试品厚度一般约为1mm，精密称定重量(m2)。
将称量瓶敞口，并与瓶盖同置于上述恒温恒湿条件下24h，盖好称量瓶盖，精密称定重量(m3)。
测试结果：如表2所示，3批次样品的引湿增重均小于0.2％，表明本申请所得晶型B无引湿性。
表2 引湿性结果汇总
实验例6：稳定性试验
关于实施例1所制备的化合物I晶型B样品进行稳定性研究，将样品在高温(60℃)、高湿(RH90±5％)、光照(4500Lx±500Lx)条件下分别放置30天，然后分别测定样品的XRPD谱图，通过与第0天测定的XRPD谱图比较，以确定晶型变化情况，同时采用高效液相色谱法测定其纯度，以考察有关物质的变化情况。
晶型B样品在0天与高温、高湿、光照30天的稳定性实验结果见表3，其晶型B样品的高温、高湿、光照30天末与第0天的XRPD叠加图见图5。
图5结果显示，晶型B在高温(60℃)、高湿(RH90±5％)、光照(4500Lx±500Lx)条件下放置30天检测的XRPD图谱，与第0天检测的XRPD图谱进行对比，晶型保持不变，说明晶型B是一种稳定的晶型。
根据表3数据显示，晶型B样品在高温、高湿、光照30天后，有关物质无显著变化，晶型B的纯度很高且稳定。稳定性研究结果表明，该晶型适合用于制剂开发。
表3 晶型B样品高温、高湿、光照30天稳定性实验结果

实验例7：生物利用度试验
关于实施例1所制备的化合物I晶型B样品进行生物利用度试验，先将化合物I晶型B样品采用常规方法分别制备成澄明溶液和混悬液。
本研究采用12只Beagle犬(雌雄各半)，随机分为2组，每组雄性和雌性动物各3只。第1组动物未禁食，单次静脉注射给予0.5mg/kg的化合物I(澄明溶液)，采集血样至给药后24h，具体采集时间点为给药前、给药后0.083、0.25、0.5、1、2、3、4、5、6、8、12和24h；第2组动物禁食后单次经口灌胃给予0.5mg/kg的化合物I(混悬液)，采集血样至给药后24h，具体采集时间点为给药前、给药后0.25、0.5、1、2、3、4、5、6、8、12和24h；采用已验证过的HPLC-UV分析方法进行给药制剂均一性和浓度分析。采用验证过的液相色谱-串联质谱法(LC-MS/MS)分析方法检测血浆样品中化合物I的浓度。通过血药浓度数据，运用Phoenix7.0软件采用非房室模型计算其生物利用度。
生物利用度试验中第1组动物静脉给药后血浆中化合物I的平均药时曲线图和第2组动物口服给药后血浆中化合物I的平均药时曲线图分别见图6和图7。
结果显示，晶型B生物利用度为67.48％，生物利用度一般，但生物利用度达到60％～90％之间，可满足基本的体内吸收及发挥药效的需求。
实施例2～9制备的化合物I晶型B样品与实施例1制备的化合物I晶型B样品具备相当的性质，包括引湿性、稳定性和生物利用度等。
以上所述仅为本申请的较佳实施例而已，并不用以限制本申请，凡在本申请的精神和原则之内所作的任何修改、等同替换或改进等，均应包含在本申请的保护范围之内。

Claims (18)

  1. 一种式I化合物的晶型B，其特征在于，所述的式I化合物游离碱晶型B，其以2θ角度表示的X-射线粉末衍射图在3.36±0.2°、10.07±0.2°、13.90±0.2°、16.51±0.2°、20.20±0.2°、21.10±0.2°处有衍射峰，
  2. 如权利要求1所述的式I化合物的晶型B，其特征在于，所述的式I化合物游离碱晶型B，其以2θ角度表示的X-射线粉末衍射图在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°、21.10±0.2°处有衍射峰。
  3. 如权利要求2所述的式I化合物的晶型B，其特征在于，所述的式I化合物游离碱晶型B，其以2θ角度表示的X-射线粉末衍射图具有图1表示的图谱。
  4. 如权利要求1所述的式I化合物的晶型B，其特征在于，所述的式I化合物游离碱晶型B，其采用差示扫描量热法测定的熔点为138℃-143℃。
  5. 如权利要求1所述的式I化合物的晶型B，其特征在于，所述的式I化合物游离碱晶型B，其热重-差示扫描量热分析谱图具有图2表示的图谱。
  6. 根据权利要求1-5中任意一项所述的晶型B的制备方法，其特征在于，包括：将化合物I在溶剂中加热溶解，降温至50℃～60℃后，保温直至有固体析出后，继续析晶，分离，干燥，得到晶型B。
  7. 根据权利要求6所述的晶型B的制备方法，其特征在于，所述溶剂为醇类、醚类、酯类、烷类、酮类、乙腈或水的一种或混合溶剂。
  8. 根据权利要求7所述的晶型B的制备方法，其特征在于，所述溶剂为甲醇、乙醇、异丙醇、乙腈、四氢呋喃、乙酸乙酯、正己烷、丙酮或水的一种或混合溶剂。
  9. 根据权利要求8所述的晶型B的制备方法，其特征在于，所述溶剂为异丙醇、乙醇、水、四氢呋喃和正己烷的一种或混合溶剂。
  10. 根据权利要求9所述的晶型B的制备方法，其特征在于，所述溶剂为异丙醇。
  11. 根据权利要求6所述的晶型B的制备方法，其特征在于，所述式I化合物与所述溶剂的质量体积比(g/mL)为1：3.5～15。
  12. 根据权利要求6所述的晶型B的制备方法，其特征在于，所述加热溶解为：在单一溶剂或混合溶剂中加热溶解，或者先在一种溶剂中加热溶解、再加入其他一种或两种以上溶剂。
  13. 根据权利要求6所述的晶型B的制备方法，其特征在于，所述降温至50℃～60℃的降温范围是降温至55℃～60℃。
  14. 根据权利要求6所述的晶型B的制备方法，其特征在于，所述保温直至有固体析出后继续析晶中，继续析晶的步骤为：自然降温析晶，再继续降温至0℃～10℃，保温析晶；或是启动加热，升温至55℃～60℃保温搅拌，自然降温析晶，再继续降温至0℃～10℃，保温析晶；或是自然降温析晶。
  15. 根据权利要求6所述的晶型B的制备方法，其特征在于，在所述制备过程中还可以进一步加入化合物I的晶种。
  16. 一种药物组合物，其特征在于，包含药学上可接受的载体、赋形剂，以及治疗有效剂量的权利要求1-5任一项所述的式I化合物晶型B。
  17. 一种治疗有效剂量的如权利要求1-5任一项所述的式I化合物晶型B或如权利要求16所述的药物组合物在制备预防和/或治疗肺动脉高压、血小板聚集相关的心脑血管疾病或糖尿病性肾病的药物中的用途。
  18. 一种治疗有效剂量的如权利要求1-5任一项所述的式I化合物晶型B或如权利要求16所述的药物组合物在制备PGI2受体激动剂药物中的用途。
PCT/CN2024/141737 2024-02-06 2024-12-24 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 Pending WO2025167362A1 (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202410169645.1 2024-02-06
CN202410169645 2024-02-06
CN202410898642.1 2024-07-05
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

Publications (1)

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

Family

ID=92562691

Family Applications (3)

Application Number Title Priority Date Filing Date
PCT/CN2024/130940 Pending WO2025167237A1 (zh) 2024-02-06 2024-11-08 一种二苯基三嗪类化合物及其制备方法和应用
PCT/CN2024/141737 Pending WO2025167362A1 (zh) 2024-02-06 2024-12-24 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
PCT/CN2024/141731 Pending WO2025167361A1 (zh) 2024-02-06 2024-12-24 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a及其用途和制备方法

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/130940 Pending WO2025167237A1 (zh) 2024-02-06 2024-11-08 一种二苯基三嗪类化合物及其制备方法和应用

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/141731 Pending WO2025167361A1 (zh) 2024-02-06 2024-12-24 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a及其用途和制备方法

Country Status (2)

Country Link
CN (3) CN118598820B (zh)
WO (3) WO2025167237A1 (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118955410B (zh) * 2023-12-27 2025-08-26 石家庄四药有限公司 二苯基吡嗪类化合物及其组合物、应用和制备方法
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

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1516690A (zh) * 2001-04-26 2004-07-28 �ձ���ҩ��ʽ���� 杂环衍生物及医药品
CN118598820A (zh) * 2024-02-06 2024-09-06 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
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

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA94598C2 (ru) * 2005-11-10 2011-05-25 Баер Шеринг Фарма Акциэнгезельшафт Диарилмочевины для лечения легочной гипертензии
CN1970552A (zh) * 2005-11-25 2007-05-30 中国科学院上海药物研究所 取代[1,3,5]三嗪类化合物及其制备方法和应用
WO2007095812A1 (en) * 2006-02-27 2007-08-30 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Substituted [1,3,5] triazine compounds, their processes for preparation and uses thereof
DE102011078715A1 (de) * 2011-07-06 2013-01-10 Bayer Pharma AG Heteroaryl-substituierte Pyrazolopyridine und ihre Verwendung
KR102259938B1 (ko) * 2012-11-14 2021-06-03 바이알 - 포르텔라 앤드 씨에이 에스에이 폐동맥 고혈압 및 폐 손상의 치료에 이용하기 위한 1,3-디히드로이미다졸-2-티온 유도체
US10815204B2 (en) * 2016-04-01 2020-10-27 Honour (R&D) Process for the preparation of diphenylpyrazine derivatives
CN107569476A (zh) * 2017-09-13 2018-01-12 无锡市人民医院 含有乙酰紫草素的药物组合物及其在肺动脉高压药物中的应用
CN108530348B (zh) * 2018-04-08 2021-11-05 哈尔滨博达森虎医药科技有限公司 一种治疗慢性阻塞性肺疾病的药物及其制备方法
CN108863955B (zh) * 2018-08-03 2021-08-13 成都苑东生物制药股份有限公司 二苯基吡嗪类化合物或其药学上可接受的盐、异构体及其制备方法和用途
CN115583908B (zh) * 2021-07-05 2024-08-06 西北农林科技大学 一种吲哚甲酰胺类化合物及其制备方法和用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1516690A (zh) * 2001-04-26 2004-07-28 �ձ���ҩ��ʽ���� 杂环衍生物及医药品
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
CN118598820A (zh) * 2024-02-06 2024-09-06 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
CN118852041A (zh) * 2024-02-06 2024-10-29 石家庄四药有限公司 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a及其用途和制备方法
CN118852042A (zh) * 2024-02-06 2024-10-29 石家庄四药有限公司 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

Also Published As

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

Similar Documents

Publication Publication Date Title
WO2025167362A1 (zh) 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
CN105452227B (zh) {[1-氰基-5-(4-氯苯氧基)-4-羟基-异喹啉-3-羰基]-氨基}-乙酸的晶形
WO2009121228A2 (zh) 鲁比前列酮晶体、其制备方法及用途
CN116583503A (zh) Fxr激动剂的多晶型物
KR20200138283A (ko) 결정질 형태, 및 결정질 형태의 화합물을 제조하는 방법
CN113754596B (zh) 一种吉非替尼的共晶体
US20210363101A1 (en) Crystalline forms of gft-505, processes for preparation and use thereof
US11192882B2 (en) Crystal form of small molecule immune compound, preparation method thereof and pharmaceutical composition containing the same
US9593117B2 (en) Crystalline form of N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide for the treatment of myeloproliferative disorders
WO2023193563A1 (zh) 一种噻吩并吡啶化合物的晶型a、制备方法及其药物组合物
US9593116B2 (en) Crystalline forms of N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide for the treatment of myeloproliferative disorders
CN116375634A (zh) 卡瑞斯汀对甲苯磺酸盐的晶型和无定型
CN102770416B (zh) 美他沙酮共晶体
US9464086B2 (en) Crystalline forms of N,N-dicyclopropyl-4-(1,5-dimethyl-1 H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-D]pyrrolo[2,3-B]pyridine-7-carboxamide for the treatment of myeloproliferative disorders
US9598413B2 (en) Crystalline form of N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-D]pyrrolo[2,3-B]pyridine-7-carboxamide for the treatment of myeloproliferative disorders
TW202248189A (zh) 芬戈莫德藥用鹽、製備方法、含其的藥物組合物及應用
TW201739750A (zh) 一種鈉依賴性葡萄糖共轉運蛋白抑制劑的胺溶劑合物及其製備方法和應用
WO2015035817A1 (zh) 一种肌醇晶体及其制备方法和用途
WO2017152846A1 (zh) 2-[(2r)-2-甲基-2-吡咯烷基]-1h-苯并咪唑-7-甲酰胺二盐酸盐的晶型a及其制备方法
WO2025147497A1 (en) Solid forms comprising (5r,6s)-10,11-difluoro-12-((2-fluoro-4-iodophenyl)amino)-5,6-dihydroxy-4,5,6,7-tetrahydro-1h-spiro[benzo[b][1,5,4]oxathiazecine-3,1'-cyclopropane] 2,2-dioxide, and compositions comprising and methods of using the same
WO2017076358A1 (zh) 咪唑基联苯基化合物盐的新晶型及其制备方法
CN114656448A (zh) 一种托匹司他-氨基磺酸共晶
WO2025035486A1 (zh) 一种酪氨酸激酶抑制剂的可药用盐、结晶形式及其制备方法
TW202333694A (zh) 稠環衍生物的晶型、其製備方法及其應用
WO2018130226A1 (zh) 利奥西呱的新晶型及其制备方法和用途

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: 24923564

Country of ref document: EP

Kind code of ref document: A1