WO2020073984A1 - Forme cristalline d'un agoniste du récepteur opioïde (mor) et son procédé de préparation - Google Patents

Forme cristalline d'un agoniste du récepteur opioïde (mor) et son procédé de préparation Download PDF

Info

Publication number
WO2020073984A1
WO2020073984A1 PCT/CN2019/110560 CN2019110560W WO2020073984A1 WO 2020073984 A1 WO2020073984 A1 WO 2020073984A1 CN 2019110560 W CN2019110560 W CN 2019110560W WO 2020073984 A1 WO2020073984 A1 WO 2020073984A1
Authority
WO
WIPO (PCT)
Prior art keywords
solvent
crystal form
formula
compound represented
ray powder
Prior art date
Application number
PCT/CN2019/110560
Other languages
English (en)
Chinese (zh)
Inventor
邵启云
杜振兴
Original Assignee
江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 江苏恒瑞医药股份有限公司, 上海恒瑞医药有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to CN201980053702.7A priority Critical patent/CN112638906B/zh
Publication of WO2020073984A1 publication Critical patent/WO2020073984A1/fr

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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present disclosure provides (1S, 4S) -4-ethoxy-N- (2-((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-9-yl) Ethyl) -1,2,3,4-tetrahydronaphthalene-1-amine fumarate II crystal form and preparation method, application of the II crystal form in the pharmaceutical composition and the II crystal form, composition in Use in the preparation of a medicament for the treatment and / or prevention of diseases associated with opioid receptor (MOR) agonists.
  • MOR opioid receptor
  • Opioid receptors are an important class of G protein-coupled receptors (GPCRs). They are targets for the binding of endogenous opioid peptides and opioids. After activation, opioid receptors are immune to the nervous system and endocrine system. With regulatory effects, opioids are currently the strongest and most commonly used central analgesics. Endogenous opioid peptides are naturally-occurring opioid-like active substances in mammals, and currently known endogenous opioid peptides are roughly divided into enkephalins, endorphins, dynorphins, and neomorphin (Pharmacol Rev 2007 ; 59: 88-123).
  • MOR is the target of opioid analgesics such as endogenous enkephalin and morphine.
  • the crystalline structure as a medicinal active ingredient often affects the chemical and physical stability of the drug. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by the production of other crystalline forms.
  • amorphous drug products do not have a regular crystal structure, and often have other defects, such as poor product stability, difficult filtration, easy caking, and poor fluidity. Therefore, it is necessary to improve various properties of the compound represented by formula (II).
  • the disclosure provides an II crystal form of the compound represented by formula (I), an X-ray powder diffraction pattern expressed at a diffraction angle of 2 ⁇ , whose diffraction angle is 2 ⁇ at 6.07, 10.70, 13.28, 16.22, 22.02 And characteristic peaks at 24.43,
  • Some embodiments provide the II crystal form, the X-ray powder diffraction pattern expressed at a diffraction angle of 2 ⁇ , at 6.07, 8.08, 10.7, 12.15, 13.28, 14.45, 15.03, 15.20, 15.50, 16.22, 17.83, 18.26 , 18.87, 20.99, 21.21, 22.02, 23.05, 24.43, 25.02, 29.62 and 31.14 have characteristic peaks.
  • Some embodiments provide the II crystal form, the X-ray powder diffraction pattern expressed at a diffraction angle of 2 ⁇ , at 6.07, 8.08, 10.7, 12.15, 13.28, 14.45, 15.03, 15.2, 15.5, 16.22, 17.23, 17.83 , 18.26, 18.87, 20.99, 21.21, 22.02, 23.05, 24.43, 25.02, 25.95, 26.75, 27.98, 29.62, 31.14 and 35.60 have characteristic peaks.
  • the II crystal form is provided, and the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ is shown in FIG. 1.
  • the present disclosure also provides a method of preparing the II crystal form, the method selected from
  • the compound represented by formula (I) is dissolved in a solvent (I) and crystallized to obtain crystal form II;
  • the solvent (I) is preferably an ether type or alcohol type solvent, and the ether type solvent is preferably diethyl ether,
  • the alcohol solvent is preferably methanol or isopropanol, and the crystallization method is preferably room temperature crystallization, cooling crystallization or adding seed crystals to induce crystallization;
  • the volume (ml) of the solvent (I) used in this method is 1 to 50 times the weight (g) of the compound, which can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times.
  • the compound represented by formula (I) is added to the solvent (II) to obtain the crystal form II by beating;
  • the solvent (II) is selected from alcohols or ester solvents;
  • the ester solvent is selected from ethyl acetate, Isopropyl acetate or butyl acetate,
  • the alcohol solvent is selected from methanol or isopropyl alcohol;
  • the volume (ml) of the solvent (II) used in this method is 1 to 50 times the weight (g) of the compound, which can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times.
  • the solvent (III) is preferably an alcohol A solvent or a mixed solvent of ethers and alcohols, the alcoholic solvent is preferably methanol or isopropanol, and the mixed solvent of the ethers and alcohols is preferably a mixed solvent of ether and methanol;
  • the volume (ml) of the solvent (II) used in this method is 1 to 50 times the weight (g) of the compound, which can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 , 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 times.
  • the method for preparing the crystalline form of the present disclosure further includes steps such as filtration, washing, or drying.
  • the present disclosure provides a pharmaceutical composition prepared from the compound II crystal form represented by the aforementioned formula (I) and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the crystalline form II or pharmaceutical preparation of the compound represented by formula (I) of the present disclosure can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, injections Use sterile powders and concentrated solutions for injection), suppositories, inhalants or sprays.
  • the pharmaceutical composition of the present disclosure can also be administered to patients or subjects in need of such treatment by any suitable method of administration, such as oral, parenteral, rectal, pulmonary or local administration.
  • the pharmaceutical composition When used for oral administration, the pharmaceutical composition can be made into oral preparations, such as oral solid preparations, such as tablets, capsules, pills, granules, etc .; or, oral liquid preparations, such as oral solutions, oral mixtures Suspension, syrup, etc.
  • oral preparations such as oral solid preparations, such as tablets, capsules, pills, granules, etc .; or, oral liquid preparations, such as oral solutions, oral mixtures Suspension, syrup, etc.
  • the pharmaceutical preparation may further contain suitable fillers, binders, disintegrating agents, lubricants and the like.
  • the pharmaceutical preparation When used for parenteral administration, the pharmaceutical preparation can be made into injections, including injections, sterile powders for injection and concentrated solutions for injection.
  • the pharmaceutical composition When prepared as an injection, the pharmaceutical composition can be produced using conventional methods in the existing pharmaceutical field. When preparing an injection, no additional agent may be added to the pharmaceutical preparation, or an appropriate additional agent may be added according to the nature of the drug.
  • the pharmaceutical preparation When used for rectal administration, the pharmaceutical preparation can be made into suppositories and the like. When used for pulmonary administration, the pharmaceutical preparations can be made into inhalants or sprays.
  • the crystalline form II of the compound represented by formula (I) of the present disclosure is present in the pharmaceutical composition or drug in a therapeutically and / or prophylactically effective amount. In certain preferred embodiments, the crystalline form II of the compound represented by formula (I) of the present disclosure is present in the pharmaceutical composition or drug in unit dosage form.
  • the present disclosure also provides a method for preparing a pharmaceutical composition, including the step of mixing the aforementioned II crystal form or the II crystal form obtained by the foregoing method with a pharmaceutically acceptable carrier, diluent or excipient.
  • the present disclosure also provides the use of the crystalline form II and the crystalline form II pharmaceutical composition in the preparation of a medicament for treating diseases related to opioid receptor (MOR) agonists.
  • MOR opioid receptor
  • the related diseases mediated by the MOR receptor agonist described in the present disclosure are selected from pain, immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric diseases, urinary and reproductive diseases, cardiovascular diseases and respiratory diseases, preferably pain.
  • the present disclosure also provides the use of the crystalline form II and the crystalline form II of the compound represented by formula (I) in the preparation of a medicament for preventing or treating pain and pain-related diseases.
  • the pain described in the present disclosure is selected from postoperative pain, cancer-induced pain, neuropathic pain, traumatic pain, or inflammation-induced pain.
  • the cancer described in the present disclosure is selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia, and leukemia.
  • the present disclosure also provides the use of the crystalline form II and the crystalline form II of the compound represented by the formula (I) in the preparation of a medicament for agonizing or antagonizing the MOR receptor.
  • the present application also provides a method of inhibiting a disease associated with an opioid receptor (MOR) agonist, which includes administering to a subject in need thereof a therapeutically and / or prophylactically effective amount of the disclosed formula ( I) Form II of the compound, or the pharmaceutical composition of the present disclosure.
  • MOR opioid receptor
  • the disease is a disease associated with an opioid receptor (MOR) agonist, selected from pain.
  • MOR opioid receptor
  • the X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC) of the obtained compound represented by formula (I) were used for structure determination and crystal form study.
  • the method of recrystallization of the crystal form II is not particularly limited, and can be carried out by a general recrystallization operation method.
  • the compound represented by the raw material formula (I) can be dissolved in an organic solvent and then added to an anti-solvent for crystallization. After the crystallization is completed, the desired crystal can be obtained by filtration and drying.
  • the crystallization methods of the present disclosure include volatile crystallization, room temperature crystallization, cooling crystallization, and addition of seed crystals to induce crystallization.
  • the starting material used in the crystalline form preparation method of the present disclosure may be any form of the compound represented by formula (I), and specific forms include but are not limited to: amorphous, any crystalline form, and the like.
  • C 1-6 alkyl group in the present disclosure means a linear or branched alkyl group containing 1-6 carbon atoms, and specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl , N-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3 -Methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc.
  • hydroxyl group in the present disclosure refers to a group such as -OH.
  • cyano in this disclosure refers to a group such as -CN.
  • ether solvent refers to a chain compound or a cyclic compound containing an ether bond -O- and having 1 to 10 carbon atoms. Specific examples include but are not limited to: tetrahydrofuran, diethyl ether, and propylene glycol methyl ether , Methyl tert-butyl ether or 1,4-dioxane.
  • the "alcoholic solvent” described in the present disclosure refers to a group derived from one or more "hydroxyl groups” in place of one or more hydrogen atoms on the "C 1-6 alkyl group".
  • the "hydroxyl group” and “C “1-6 alkyl” is as defined above, and specific examples include but are not limited to: methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol, or trifluoroethanol.
  • ester solvent refers to a combination of a lower organic acid having 1 to 4 carbon atoms and a lower alcohol having 1 to 6 carbon atoms. Specific examples include but are not limited to: acetic acid Ethyl acetate, isopropyl acetate or butyl acetate.
  • the “mixed solvent” in the present disclosure refers to a solvent in which one or more different kinds of organic solvents are mixed in a certain ratio, or a solvent in which an organic solvent and water are mixed in a certain ratio;
  • the mixed solvent is preferably A mixed solvent of alcohols and ethers;
  • the mixed solvent of alcohols and ethers is preferably a mixed solvent of methanol and ether, and the ratio is preferably 1:10.
  • the "X-ray powder diffraction pattern" described in this disclosure is measured using Cu-K ⁇ radiation. among them,
  • the “differential scanning calorimetry or DSC” mentioned in this disclosure refers to the measurement of the temperature difference and heat flow difference between the sample and the reference substance during the sample heating or constant temperature to characterize all physical changes and chemistry related to the thermal effect Change, get the phase change information of the sample.
  • the "2 ⁇ or 2 ⁇ angle" mentioned in the present disclosure refers to the diffraction angle, ⁇ is the Bragg angle, the unit is ° or degree, and the error range of 2 ⁇ is ⁇ 0.3, which can be -0.30, -0.29, -0.28, -0.27,- 0.26, -0.25, -0.24, -0.23, -0.22, -0.21, -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11 , 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22
  • crystal plane spacing or crystal plane spacing (d value) means that the spatial lattice selects three non-parallel unit vectors a, b, and c that connect two adjacent lattice points, and they will point
  • the array is divided into juxtaposed parallelepiped units, called interplanar spacing.
  • the space lattice is divided according to the determined parallelepiped unit connection to obtain a set of straight-line grids, called space grids or lattices.
  • the lattice and lattice reflect the periodicity of the crystal structure with geometric dots and lines, respectively. Different crystal planes have different surface spacings (ie, the distance between two adjacent parallel crystal planes); the unit is Or Egypt.
  • the drying temperature in the present disclosure is generally 25 ° C to 100 ° C, preferably 40 ° C to 70 ° C, and can be dried under normal pressure or under reduced pressure. Preferably, the drying is done under reduced pressure.
  • the crystalline form II of the compound represented by the formula (I) obtained by the technical scheme of the present disclosure can meet the pharmaceutical requirements for production, transportation and storage.
  • the production process is stable, repeatable and controllable, and can be adapted to industrial production.
  • Fig. 1 is an XRPD pattern of the compound II crystal form represented by formula (I).
  • Fig. 2 is a DSC chart of the crystal form of Compound II represented by formula (I).
  • FIG. 3 is a TGA pattern of the crystal form of compound II represented by formula (I).
  • FIG. 4 is an XRPD pattern of the crystal form of Compound I represented by formula (I).
  • FIG. 5 is a DVS pattern of the crystal form of Compound II represented by formula (I).
  • FIG. 6 is a XRPD pattern before and after DVS of the compound II crystal form of formula (I) (the upper picture is the XRPD picture after the moisture absorption experiment, and the lower picture is the XRPD picture before the moisture absorption experiment).
  • Heating rate 10.0 °C / min
  • Heating rate 10.0 °C / min
  • Humidity change 0-95-0-95-0% RH, the step is 10%, the judgment standard is that the quality change within 10000min is less than 0.01%
  • reaction solution was washed successively with water (100 mL), saturated sodium bicarbonate solution (100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product 11a (5.6 g, light yellow oil), product The next step was carried out without purification.
  • reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using n-hexane and ethyl acetate as eluents to obtain the title product 11b (3.1 g, off-white solid), yield: 52%.
  • the crude compound 19a (698 mg, 2.4 mmol) was dissolved in 4 mL of dichloromethane, 8 mL of 4M hydrogen chloride in 1,4-dioxane was added, and the reaction was stirred for 2 hours.
  • the reaction solution was filtered, and the filter cake was rinsed with ether (5 mL ⁇ 3).
  • the filter cake was collected and dried in vacuo to obtain a white solid product (160 mg, yield 70%).
  • the crystal sample was confirmed to be Form II by XRPD characterization.
  • Example 1 The product of Example 1 (50 mg) was placed in a reaction flask, isopropyl acetate (0.5 mL) was added, pulped at room temperature for 48 h, filtered and dried, and the yield was 62%. The sample was characterized by X-ray powder diffraction, and the product was determined to be the II crystal form.
  • Example 1 The product of Example 1 (50 mg) was placed in a reaction flask, isopropanol (0.5 mL) was added, pulped at room temperature for 48 h, filtered and dried, and the yield was 65%. The sample was characterized by X-ray powder diffraction, and the product was determined to be the II crystal form.
  • Example 1 The product of Example 1 (50 mg) was placed in a reaction bottle, isopropanol (0.5 mL) was added, and the slurry was beaten at 40 ° C for 48 h, filtered and dried, and the yield was 70%. The sample was characterized by X-ray powder diffraction, and the product was determined to be the II crystal form.
  • the crystal form I 50 mg of the product obtained in Comparative Example 2 was placed in a reaction bottle, isopropanol (0.5 mL) was added, beaten at room temperature for 48 h, filtered and dried, and the yield was 63%.
  • the sample was characterized by X-ray powder diffraction, and the product was determined to be the II crystal form, which indicated that the II crystal form was more stable than the I crystal form.
  • Test product Compound (free state), crystal form II of formula (II) obtained in Comparative Example 1;
  • Solubility test of crystal form II sample Weigh 53.55mg of the sample in a vial, add 1.5mL of aqueous solution, add a stirrer, and after magnetic stirring for 24hr, the sample is not completely dissolved and centrifuge at 12000rpm for 40min. The supernatant was diluted 1000-fold and transferred to HPLC analysis.
  • Solubility detection of the compound (free state) shown in formula (II) Weigh 1.29 mg of the sample in a vial, add 1.0 mL of aqueous solution, add a stirrer, and stir the sample magnetically for 24 hr. The sample is not completely dissolved. Centrifuge at 12000 rpm for 40 min. The liquid was transferred to HPLC analysis.
  • HPLC chromatographic conditions fluidity is acetonitrile-0.1% TFA aqueous solution (50:50), detection wavelength 264nm, injection volume 10 ⁇ L, flow rate 1.0mL / min.
  • the solubility of crystal form II in water is better than that in the free state.
  • Example 12 the stability of factors affecting the II crystal form
  • Example 1 Place the sample of Form II obtained in Example 1 flat and open to investigate the chemical stability of the sample under the conditions of light (4500 Lux), high temperature (40 ° C, 60 ° C), and high humidity (RH75%, RH90%).
  • Sampling time is 5 days, 10 days, check the chemical purity and chiral purity of the sample, HPLC detection purity is shown in the table below.
  • the crystal form II is exposed to light and high temperature (40 ° C, 60 ° C) for 10 days, and the chemical purity and chiral purity decrease significantly. When exposed to high humidity (RH75%, RH90%) for 10 days, the chemical The purity and chiral purity changes little; XRPD detection II crystal form is placed for 10 days under the conditions of light (4500 Lux), high temperature (40 ° C, 60 ° C), high humidity (RH75%, RH90%), and the crystal form has not changed , Indicating that the II crystal form has better stability.
  • Example 13 the long-term, accelerated stability of the II crystal form
  • the sample of Form II obtained in Example 1 was protected from light and placed in a sealed flat position, and the stability of the sample under long-term (25 ° C, 60% RH) and acceleration (40 ° C, 75% RH) was investigated.
  • the sampling time was 0.5 Months, 1 months, 2 months, 3 months, XRPD detects whether the crystal form has changed.
  • the II crystal form obtained in Example 1 has good stability under long-term (25 ° C, 60% RH) and accelerated (40 ° C, 75% RH) storage for 3 months under the condition of light shielding and sealing, and the XRPD peak of the II crystal form The type has not changed, and the crystal form is stable.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Rheumatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une forme cristalline d'un agoniste du récepteur opioïde (MOR) et son procédé de préparation. En particulier, l'invention concerne la forme cristalline II du fumarate de (1S,4S)-4-éthoxy-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)éthyl)-1,2,3,4-tétrahydronaphthalèn-1-amine (un composé représenté par la formule (I)) et son procédé de préparation. La forme cristalline II du composé de formule (I) a une bonne stabilité cristalline et peut être mieux utilisé dans un traitement clinique.
PCT/CN2019/110560 2018-10-12 2019-10-11 Forme cristalline d'un agoniste du récepteur opioïde (mor) et son procédé de préparation WO2020073984A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201980053702.7A CN112638906B (zh) 2018-10-12 2019-10-11 一种阿片样物质受体(mor)激动剂的结晶形式及制备方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811186669 2018-10-12
CN201811186669.9 2018-10-12

Publications (1)

Publication Number Publication Date
WO2020073984A1 true WO2020073984A1 (fr) 2020-04-16

Family

ID=70163625

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/110560 WO2020073984A1 (fr) 2018-10-12 2019-10-11 Forme cristalline d'un agoniste du récepteur opioïde (mor) et son procédé de préparation

Country Status (3)

Country Link
CN (1) CN112638906B (fr)
TW (1) TWI745764B (fr)
WO (1) WO2020073984A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113624898B (zh) * 2021-08-23 2023-08-25 成都诺和晟泰生物科技有限公司 一种手性镇痛类多肽药物的纯化方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103702561A (zh) * 2011-03-23 2014-04-02 特维娜有限公司 阿片样物质受体配体以及使用和制备其的方法
WO2017063509A1 (fr) * 2015-10-15 2017-04-20 江苏恒瑞医药股份有限公司 Dérivé oxa spiro, son procédé de préparation, et ses applications dans des médicaments
WO2018188643A1 (fr) * 2017-04-14 2018-10-18 江苏恒瑞医药股份有限公司 Sel agoniste du récepteur opioïde (mor), forme cristalline du sel de fumarate i correspondante et procédé de préparation de celui-ci

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103702561A (zh) * 2011-03-23 2014-04-02 特维娜有限公司 阿片样物质受体配体以及使用和制备其的方法
WO2017063509A1 (fr) * 2015-10-15 2017-04-20 江苏恒瑞医药股份有限公司 Dérivé oxa spiro, son procédé de préparation, et ses applications dans des médicaments
WO2018188643A1 (fr) * 2017-04-14 2018-10-18 江苏恒瑞医药股份有限公司 Sel agoniste du récepteur opioïde (mor), forme cristalline du sel de fumarate i correspondante et procédé de préparation de celui-ci

Also Published As

Publication number Publication date
TWI745764B (zh) 2021-11-11
TW202014188A (zh) 2020-04-16
CN112638906A (zh) 2021-04-09
CN112638906B (zh) 2022-05-27

Similar Documents

Publication Publication Date Title
TWI682929B (zh) 一種阿片樣物質受體（mor）激動劑的鹽、其富馬酸鹽i晶型及製備方法
CN108727347B (zh) 一种阿片样物质受体(mor)激动剂的晶型及其制备方法
WO2018086608A1 (fr) Forme cristalline d'antagoniste du récepteur de gnrh et son procédé de préparation
WO2018210302A1 (fr) Formes cristallines du chlore libre dérivé du benzofurane et son procédé de préparation
WO2018072742A1 (fr) Forme cristalline de base libre de dérivé d'imidazo-isoindole et son procédé de préparation
WO2018082687A1 (fr) Polymorphe antagoniste du récepteur cellulaire gnrh et son procédé de préparation
WO2020073984A1 (fr) Forme cristalline d'un agoniste du récepteur opioïde (mor) et son procédé de préparation
WO2018133823A1 (fr) Forme cristalline de bisulfate d'inhibiteur de kinase jak et son procédé de préparation
WO2023193563A1 (fr) Forme cristalline d'un composé thiénopyridine, son procédé de préparation et composition pharmaceutique associée
WO2017041622A1 (fr) Forme cristalline d'un inhibiteur de récepteur d'androgène et son procédé de préparation
WO2017219994A1 (fr) Forme cristalline de 9-aminométhyle substitués des composés de tetracycline et leur procédé de préparation
WO2020073985A1 (fr) Structure cristalline d'un agoniste des récepteurs aux opiacés mu (mor) et son procédé de préparation
WO2016050134A1 (fr) Composé l-proline d'un inhibiteur du cotransporteur sodium-glucose de type 2, ainsi que monohydrate et cristal du composé l-proline
RU2779119C2 (ru) Соль агониста опиоидного рецептора (mor), кристаллическая форма i его фумаратной соли и способ их получения
US20130143846A1 (en) Polymorphic form of a calcimimetic compound
WO2023134723A1 (fr) Forme cristalline d'un composé promédicament antagoniste de la neurokinine-1
WO2023222103A1 (fr) Formes cristallines d'un dérivé de triazine-dione et leur procédé de préparation
WO2015161730A1 (fr) Cristal eutectique de lorcasérine et procédé de préparation, composition pharmaceutique le contenant et utilisation
WO2019001551A1 (fr) Forme cristalline de base libre de dérivé d'imidazo-isoindole et son procédé de préparation

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: 19871718

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: 19871718

Country of ref document: EP

Kind code of ref document: A1