[go: up one dir, main page]

WO2021023271A1 - Forme cristalline d'un composé en tant qu'agoniste du récepteur de la prostacycline et son procédé de préparation - Google Patents

Forme cristalline d'un composé en tant qu'agoniste du récepteur de la prostacycline et son procédé de préparation Download PDF

Info

Publication number
WO2021023271A1
WO2021023271A1 PCT/CN2020/107470 CN2020107470W WO2021023271A1 WO 2021023271 A1 WO2021023271 A1 WO 2021023271A1 CN 2020107470 W CN2020107470 W CN 2020107470W WO 2021023271 A1 WO2021023271 A1 WO 2021023271A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal form
compound
preparation
water
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2020/107470
Other languages
English (en)
Chinese (zh)
Inventor
钱文远
杨纯道
徐光海
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.)
Medshine Discovery Inc
Original Assignee
Medshine Discovery Inc
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 Medshine Discovery Inc filed Critical Medshine Discovery Inc
Publication of WO2021023271A1 publication Critical patent/WO2021023271A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the invention relates to a crystal form of a PGI 2 receptor agonist and a preparation method thereof, and to its application in the preparation of drugs for treating diseases related to the PGI 2 receptor.
  • Prostacyclin is one of the metabolites of arachidonic acid (AA), mainly produced by vascular endothelial cells.
  • arachidonic acid into the cyclooxygenase under the action of prostaglandin G 2 (prostaglandin G 2, PGG 2), which prostaglandin H 2 (prostaglandin H 2 under the action of peroxidase, PGH 2 ), prostaglandin H 2 is an important metabolic intermediate, through which a series of different prostaglandins can be obtained through different pathways.
  • prostaglandin H 2 is converted into prostacyclin.
  • the main target of prostacyclin is the prostacyclin receptor (IP receptor).
  • the prostacyclin receptor couples with regulatory proteins and activates adenylate cyclase (AC), which in turn makes the target cell cyclic phosphoric acid
  • AC adenylate cyclase
  • cAMP adenosine
  • Pulmonary arterial hypertension refers to a group of clinical pathophysiological syndromes in which the average pressure of the pulmonary artery ⁇ 25mmHg detected by the right catheter under the resting state of the sea level, mainly including vasospasm, intimal hyperplasia, and remodeling of pulmonary arterioles Characteristic, leading to a continuous increase in pulmonary vascular resistance, which will eventually lead to right heart failure and death of the patient.
  • the synthesis of prostacyclin in patients with pulmonary hypertension is reduced. Therefore, the use of prostacyclin and its analogues is a viable alternative therapy.
  • the present invention provides crystal form A of the compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 14.80 ⁇ 0.2°, 19.26 ⁇ 0.2°, 22.02 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 10.64 ⁇ 0.2°, 14.80 ⁇ 0.2°, 18.54 ⁇ 0.2°, 19.26 ⁇ 0.2°, 20.82 ⁇ 0.2°, 22.02 ⁇ 0.2°, 23.92 ⁇ 0.2°, 24.88 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 7.301°, 9.243°, 10.637°, 11.601°, 14.803°, 15.483°, 17.258°, 18.540 °, 19.261°, 19.920°, 20.819°, 21.300°, 22.019°, 23.219°, 23.917°, 24.241°, 24.879°, 26.439°, 27.561°, 28.941°, 29.859°, 30.300°, 31.560°, 31.919°, 33.360°, 34.900°, 36.622°, 36.958°, 38.199°, 38.898°, 39.403°.
  • the XRPD pattern of the above crystal form A is shown in FIG. 1.
  • the XRPD pattern analysis data of the above-mentioned crystal form A is shown in Table 1:
  • the differential scanning calorimetry curve of the above-mentioned crystal form A has the starting point of an endothermic peak at 151.24 ⁇ 3°C.
  • the DSC spectrum of the above crystal form A is shown in FIG. 2.
  • thermogravimetric analysis curve of the above-mentioned crystal form A has a weight loss of 0.1501% at 200.00 ⁇ 3°C.
  • the TGA spectrum of the above-mentioned crystal form A is shown in FIG. 3.
  • the present invention provides a method for preparing the crystal form of compound A of formula (I), which comprises adding the compound of formula (I) into a solvent, heating and beating or recrystallization.
  • the above-mentioned solvent is selected from: methanol, ethanol, isopropanol, acetonitrile, acetone, methanol: water (1:1), ethanol: water (1:1), acetonitrile: water (1:1) , Acetonitrile: water (2:1), acetone: water (1:1), ethyl acetate and tetrahydrofuran.
  • the above-mentioned beating temperature is 25°C to 45°C.
  • the above-mentioned beating time is 12 hours to 24 hours.
  • the above-mentioned weight-volume ratio of the compound to the solvent is 1:6-12 g/mL.
  • the above-mentioned weight-volume ratio of the compound to the solvent is 1:10-15 g/mL.
  • the present invention also provides the application of the above compound or crystal form A or the crystal form prepared according to the above method in the preparation of drugs for treating PGI2 related diseases.
  • the compound of formula (I) mentioned in the present invention has good crystal form stability and is easy to prepare medicine; the present invention is a new type of prostacyclin agonist with high activity, good solubility, suitable for oral administration and the like.
  • the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • the present invention uses the following abbreviations: DCM stands for dichloromethane; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOH stands for ethanol; MeOH stands for methanol; TFA stands for trifluoroacetic acid; TsOH stands for P-toluenesulfonic acid; mp represents melting point; EtSO 3 H represents ethanesulfonic acid; MeSO 3 H represents methanesulfonic acid; ATP represents adenosine triphosphate; HEPES represents 4-hydroxyethylpiperazine ethanesulfonic acid; EGTA represents ethylene glycol bis(2 -Aminoethyl ether) tetraacetic acid; MgCl 2 stands for magnesium dichloride; MnCl 2 stands for manganese dichloride; DTT stands for dithiothreitol.
  • Test method Approximately 10-20mg sample is used for XRPD detection.
  • Light tube voltage 40kV
  • light tube current 30mA
  • the first solar slit 28mm
  • the second solar slit 28mm
  • Test method Take a sample (2-5mg) and place it in a DSC high-pressure gold-plated crucible for testing. Heat the sample from 40°C to 350°C at a heating rate of 10°C/min.
  • Thermogravimetric analysis (Thermal Gravimetric Analyzer, TGA) method of the present invention
  • Test method Take a sample (5-10mg) and place it in a TGA alumina crucible for testing. Under the condition of 50mL/min and N2, heating the sample from 40°C to 200°C at a heating rate of 10°C/min.
  • the analysis method is as follows:
  • Figure 1 is an XRPD spectrum of Cu-K ⁇ radiation of the crystal form of compound A of formula (I).
  • Figure 2 is the DSC spectrum of the crystal form of compound A of formula (I).
  • Figure 3 is the TGA spectrum of the crystal form of compound A of formula (I).
  • Methyl tert-butyl ether 2.32 >1000 ⁇ 2.32 Tetrahydrofuran 1.91 ⁇ 80 >23.8 Toluene 2.23 >1000 ⁇ 2.23 N-heptane 2.06 >1000 ⁇ 2.06 N-hexane 2.26 >1000 ⁇ 2.26 1,4-dioxane 2.23 ⁇ 300 >7.4 water 2.10 >1000 ⁇ 2.10 Methanol: water (1:1) 2.31 >1000 ⁇ 2.31 Ethanol: water (1:1) 2.00 >1000 ⁇ 2.00 Acetonitrile: water (2:1) 1.98 ⁇ 400 >4.95 Acetone: Water (1:1) 1.80 >1000 ⁇ 1.80
  • the crystal form of compound A of formula (I) has good solubility in common solvents such as methanol, ethanol, acetone, acetonitrile and tetrahydrofuran.
  • Use Echo to transfer 50nL DMSO or the sample to be tested to PE 384-well OptiPlate Use an electric discharge gun to transfer the cell suspension to the test plate, 10 ⁇ L cells/well. Centrifuge the test plate at 1000 rpm for 5 seconds. Incubate the test plate at room temperature for 60 minutes. Add 2 kinds of detection reagents to the experiment plate, 5 ⁇ L/well. Centrifuge the test plate at 1000 rpm for 1 minute. Seal the experiment plate with TopSeal-A film and incubate at room temperature for 60 minutes. Remove TopSeal-A and read on EnVision.

Landscapes

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

Abstract

La présente invention concerne une forme cristalline d'un agoniste du récepteur PGI2, son procédé de préparation et son utilisation dans la préparation d'un médicament pour le traitement de maladies associées au récepteur PGI2.
PCT/CN2020/107470 2019-08-06 2020-08-06 Forme cristalline d'un composé en tant qu'agoniste du récepteur de la prostacycline et son procédé de préparation Ceased WO2021023271A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910722125 2019-08-06
CN201910722125.8 2019-08-06

Publications (1)

Publication Number Publication Date
WO2021023271A1 true WO2021023271A1 (fr) 2021-02-11

Family

ID=74503911

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/107470 Ceased WO2021023271A1 (fr) 2019-08-06 2020-08-06 Forme cristalline d'un composé en tant qu'agoniste du récepteur de la prostacycline et son procédé de préparation

Country Status (1)

Country Link
WO (1) WO2021023271A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102459198A (zh) * 2009-06-26 2012-05-16 日本新药株式会社 晶体
CN107325040A (zh) * 2016-04-28 2017-11-07 广州市恒诺康医药科技有限公司 环己烯类衍生物或其药学上可接受的盐及其用途
CN108069914A (zh) * 2016-11-17 2018-05-25 江苏艾立康药业股份有限公司 一种西里帕格晶型的制备方法
CN109125325A (zh) * 2018-09-25 2019-01-04 中国人民解放军总医院 前列环素受体激动剂的医药用途
WO2019065792A1 (fr) * 2017-09-28 2019-04-04 日本新薬株式会社 Cristaux
WO2019154363A1 (fr) * 2018-02-07 2019-08-15 南京明德新药研发有限公司 Agoniste du récepteur de la prostacycline

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102459198A (zh) * 2009-06-26 2012-05-16 日本新药株式会社 晶体
CN107325040A (zh) * 2016-04-28 2017-11-07 广州市恒诺康医药科技有限公司 环己烯类衍生物或其药学上可接受的盐及其用途
CN108069914A (zh) * 2016-11-17 2018-05-25 江苏艾立康药业股份有限公司 一种西里帕格晶型的制备方法
WO2019065792A1 (fr) * 2017-09-28 2019-04-04 日本新薬株式会社 Cristaux
WO2019154363A1 (fr) * 2018-02-07 2019-08-15 南京明德新药研发有限公司 Agoniste du récepteur de la prostacycline
CN109125325A (zh) * 2018-09-25 2019-01-04 中国人民解放军总医院 前列环素受体激动剂的医药用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LAO FANG : "Learn From Patent Invalidation and Patent Litigation Cases to Consider Polymorphic Drugs Inventive Step and Non-Obviousness", CHINA INVENTION & PATENT, no. 2, 31 December 2016 (2016-12-31), pages 110 - 115, XP009525893, ISSN: 1672-6081 *

Similar Documents

Publication Publication Date Title
EP4361141A1 (fr) Agent de dégradation de protéine
CN111892578B (zh) 一种靶向降解黏着斑激酶的化合物及应用
US11634388B2 (en) Crystal form of lenvatinib mesylate and preparation method therefor
JP2024547113A (ja) Ｇｌｐ－１受容体作動薬の薬学的に許容される塩、結晶形及びその調製方法
TW202328115A (zh) Glp-1受體激動劑的結晶形式及其製備方法
WO2025140518A1 (fr) Composé à cycles fusionnés, composition pharmaceutique le comprenant et leur utilisation
US20200361913A1 (en) Salt form and crystal form serving as fgfr and vegfr inhibitor compounds, and preparation method therefor
WO2021023271A1 (fr) Forme cristalline d'un composé en tant qu'agoniste du récepteur de la prostacycline et son procédé de préparation
CN113166121B (zh) 一种fxr激动剂的固体形式、结晶形式、a晶型及其制备方法和应用
KR20250116731A (ko) 갑상선 호르몬 β 수용체 작용제, 그 결정형, 제조 방법 및 용도
WO2022262841A1 (fr) Forme de sel et forme cristalline de composé spiro et son procédé de préparation
WO2024088400A1 (fr) Composés contenant du phosphore, composition pharmaceutique et leur utilisation
WO2018214958A1 (fr) Forme cristalline de l'inhibiteur de l'ido1 et son procédé de préparation
JP7244487B2 (ja) ステロイド系誘導体ｆｘｒアゴニストの結晶又は非晶質、その製造方法及び使用
TWI822716B (zh) 作為ppar促效劑的吡咯啶衍生物的非晶形及其製備方法
RU2804320C2 (ru) Твердая форма, кристаллическая форма и кристаллическая форма а агониста fxr, и способ их получения, и их применение
RU2800751C2 (ru) Кристаллическая или аморфная форма агонистов fxr, представляющих собой производные стероидов, способ их получения и их применение
US20210230188A1 (en) Crystal form of tri-cycle compound and application thereof
WO2020192637A1 (fr) Composé inhibiteur de brd4 sous forme solide, son procédé de préparation et son application
US20240246985A1 (en) Crystal form of triazolopyridine-substituted indazole compound and preparation method therefor
HK40050754A (en) Solid form, crystalline form, and crystal form a of fxr agonist, and preparation method therefor and application thereof
HK40050754B (en) Solid form, crystalline form, and crystal form a of fxr agonist, and preparation method therefor and application thereof
WO2024213088A1 (fr) Cristal de dérivé tricyclique de pyrimidine et son utilisation
KR20250112264A (ko) 퀴놀린아민계 화합물의 결정형 및 이의 제조 방법
JP2022533237A (ja) ピリミジンスルホンアミド系化合物の結晶形及びその製造方法

Legal Events

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

Ref document number: 20849789

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20849789

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 20849789

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 29/08/2022)

122 Ep: pct application non-entry in european phase

Ref document number: 20849789

Country of ref document: EP

Kind code of ref document: A1