WO2020073984A1 - Crystal form of opioid receptor (mor) agonist and preparation method thereof - Google Patents

Crystal form of opioid receptor (mor) agonist and preparation method thereof Download PDF

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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
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solvent
crystal form
formula
compound represented
ray powder
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PCT/CN2019/110560
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French (fr)
Chinese (zh)
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邵启云
杜振兴
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN201980053702.7A priority Critical patent/CN112638906B/en
Publication of WO2020073984A1 publication Critical patent/WO2020073984A1/en

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    • 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.

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Abstract

A crystal form of an opioid receptor (MOR) agonist and a preparation method thereof. In particular, provided are crystal form II of (1S,4S)-4-ethoxy-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine fumarate (a compound represented by formula (I)) and a preparation method thereof. The crystal form II of the compound of formula (I) has good crystal stability and can be better used in clinical treatment.

Description

一种阿片样物质受体(MOR)激动剂的结晶形式及制备方法Crystal form and preparation method of opioid receptor (MOR) agonist
本申请要求申请日为2018/10/12的中国专利申请201811186669.9的优先权。本申请引用上述中国专利申请的全文。This application requires the priority of Chinese patent application 201811186669.9 with an application date of 2018/10/12. This application refers to the entire text of the aforementioned Chinese patent application.
技术领域Technical field
本公开提供了(1S,4S)-4-乙氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙基)-1,2,3,4-四氢萘-1-胺富马酸盐的II晶型及制备方法，II晶型在药物组合物中的应用以及该II晶型、组合物在制备治疗和/或预防与阿片样物质受体(MOR)激动剂有关疾病的药物中的用途。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.
背景技术Background technique
阿片受体是一类重要的G蛋白偶联受体(G protein coupled receptor,GPCR)，是内源性阿片肽及阿片类药物结合的靶点，阿片受体激活后对神经***免疫及内分泌***具有调节作用，阿片类药物是目前最强且常用的中枢镇痛药。内源性阿片肽是哺乳动物体内天然生成的阿片样活性物质，目前已知的内源性阿片肽大致分为脑啡肽、内啡肽、强啡肽和新啡肽几类(Pharmacol Rev 2007；59:88-123)。中枢神经***中存在其相应的阿片受体，即μ(MOR)、δ(DOR)、κ(KOR)受体等。MOR是内源性脑啡肽和***等阿片类镇痛药物的作用靶点。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). There are corresponding opioid receptors in the central nervous system, namely μ (MOR), δ (DOR), and κ (KOR) receptors. MOR is the target of opioid analgesics such as endogenous enkephalin and morphine.
阿片类药物长期使用会产生耐受以及呼吸抑制、便秘等副作用，而这些副作用被证明与β-arrestin的功能密切相关。为了减小阿片类药物的副作用，可基于MOR的负性β-arrestin偏爱性配体设计药物，使β-arrestin介导的副作用降低，增强治疗效果，对于本公开的氧杂螺环类衍生物在作为MOR选择性药物的研究中，TrevenaInc公司研究发现芳基苄位取代时活性较差(J.Med.Chem.2013,56,8019-8031)，但WO2017063509发现了一种芳基苄位成环后却表现出高活性、Emax显著提高、hERG明显改善、单一构型的MOR化合物，结构如式(II)所示：Long-term use of opioids will produce side effects such as tolerance, respiratory depression, and constipation. These side effects have been shown to be closely related to the function of β-arrestin. In order to reduce the side effects of opioids, the drugs can be designed based on the negative β-arrestin preference ligand of MOR to reduce the side effects mediated by β-arrestin and enhance the therapeutic effect. For the oxaspiro derivatives of the present disclosure In the study as a MOR selective drug, Trevena Inc research found that the activity of aryl benzyl substitution is poor (J. Med. Chem. 2013, 56, 8019-8031), but WO2017063509 discovered an aryl benzyl After the ring, it shows high activity, Emax is significantly improved, hERG is significantly improved, and the single-configuration MOR compound has the structure shown in formula (II):
Figure PCTCN2019110560-appb-000001
Figure PCTCN2019110560-appb-000001
作为药用活性成分的晶型结构往往影响到该药物的化学和物理稳定性，结晶条件及 储存条件的不同有可能导致化合物的晶体结构的变化，有时还会伴随着产生其他形态的晶型。一般来说，无定形的药物产品没有规则的晶体结构，往往具有其它缺陷，比如产物稳定性较差，过滤较难，易结块，流动性差等。因此，改善式(II)所示化合物的各方面性质是很有必要的。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. In general, 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).
发明内容Summary of the invention
本公开(The disclosure)提供一种式(I)所示化合物的II晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，其衍射角2θ角在6.07、10.70、13.28、16.22、22.02和24.43处有特征峰，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 2θ, whose diffraction angle is 2θ at 6.07, 10.70, 13.28, 16.22, 22.02 And characteristic peaks at 24.43,
Figure PCTCN2019110560-appb-000002
Figure PCTCN2019110560-appb-000002
一些实施方案中提供所述的II晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在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和31.14处有特征峰。Some embodiments provide the II crystal form, the X-ray powder diffraction pattern expressed at a diffraction angle of 2θ, 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.
一些实施方案中提供所述的II晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱，在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和35.60处有特征峰。Some embodiments provide the II crystal form, the X-ray powder diffraction pattern expressed at a diffraction angle of 2θ, 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.
另一些实施方案中提供所述的II晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图1所示。In other embodiments, the II crystal form is provided, and the X-ray powder diffraction pattern represented by the diffraction angle 2θ is shown in FIG. 1.
本公开还提供一种制备II晶型的方法，所述方法选自The present disclosure also provides a method of preparing the II crystal form, the method selected from
(1)将式(I)所示化合物溶解于溶剂(I)中，析晶得II晶型；所述溶剂(I)优选醚类、醇类溶剂，所述醚类溶剂优选***，所述醇类溶剂优选甲醇或异丙醇，所述析晶方法优选室温析晶、冷却析晶或加入晶种诱导析晶；(1) 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;
本法所述溶剂(I)所用体积(ml)为化合物重量(g)的1～50倍，可以为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倍。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.
(2)将式(I)所示化合物加入溶剂(II)中，打浆得II晶型；所述溶剂(II)选自醇类或酯类溶剂；所述酯类溶剂选自乙酸乙酯、乙酸异丙酯或乙酸丁酯，所述醇类溶剂选自甲醇或异丙醇；(2) 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;
本法所述溶剂(II)所用体积(ml)为化合物重量(g)的1～50倍，可以为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倍。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.
(3)将式(I)所示化合物的游离态溶解于溶剂(III)中，加入富马酸，析出固体或加入晶种，析晶得目标II晶型；所述溶剂(III)优选醇类溶剂或醚类与醇类的混合溶剂，所述醇类溶剂优选甲醇或异丙醇，所述醚类与醇类的混合溶剂优选***与甲醇的混合溶剂；(3) Dissolve the free state of the compound represented by formula (I) in the solvent (III), add fumaric acid, precipitate solids or add seed crystals, and crystallize to obtain the target II crystal form; 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;
本法所述溶剂(II)所用体积(ml)为化合物重量(g)的1～50倍，可以为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倍。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.
另一方面，在一些实施方案中，本公开中晶型的制备方法中还包括过滤，洗涤或干燥等步骤。On the other hand, in some embodiments, the method for preparing the crystalline form of the present disclosure further includes steps such as filtration, washing, or drying.
本公开中提供了一种药物组合物，由前述式(I)所示化合物II晶型，以及一种或多种药学上可接受的载体、稀释剂或赋形剂制备而成。例如，本公开的式(I)所示化合物的II晶型或药物制剂可以配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。此外，本公开所述药物组合物还可以以任何合适的给药方式，例如口服、肠胃外、直肠、经肺或局部给药等方式施用于需要这种治疗的患者或受试者。当用于口服给药时，所述药物组合物可制成口服制剂，例如口服固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；或，口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。当制成口服制剂时，所述药物制剂还可包含适宜的填充剂、粘合剂、崩解剂、润滑剂等。当用于肠胃外给药时，所述药物制剂可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。当制成注射剂时，所述药物组合物可采用现有制药领域中的常规方法来进行生产。当配制注射剂时，所述药物制剂中可以不加入附加剂，也可根据药物的性质加入适宜的附加剂。当用于直肠给药时，所述药物制剂可制成栓剂等。用于经肺给药时，所述药物制剂可制成吸入剂或喷雾剂等。在某些优选的实施方案中，本公开的式(I)所示的化合物的II晶型以治疗和/ 或预防有效量存在于药物组合物或药物中。在某些优选的实施方案中，本公开式(I)所示的化合物的II晶型以单位剂量的形式存在于药物组合物或药物中。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. For example, 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. In addition, 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. 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. When prepared as an oral preparation, the pharmaceutical preparation may further contain suitable fillers, binders, disintegrating agents, lubricants and the like. When used for parenteral administration, the pharmaceutical preparation can be made into injections, including injections, sterile powders for injection and concentrated solutions for injection. 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. 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. 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 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.
本公开还提供了一种药物组合物的制备方法，包括将前述II晶型或由前述方法制备获得的II晶型与药学上可接受的载体、稀释剂或赋形剂混合的步骤。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.
本公开还提供所述的II晶型、II晶型的药物组合物在制备治疗与阿片样物质受体(MOR)激动剂介导的相关疾病的药物中的用途。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.
本公开所述MOR受体激动剂介导的相关疾病选自疼痛、免疫功能障碍、炎症、食管回流、神经和精神疾病、泌尿和生殖疾病、心血管疾病和呼吸道疾病，优选疼痛。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.
本公开还提供式(I)所示化合物的II晶型、II晶型的药物组合物在制备预防或治疗疼痛和疼痛相关疾病的药物中的用途。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.
本公开所述的疼痛选自术后疼痛、癌症引起的疼痛、神经性疼痛、创伤性疼痛或炎症引起的疼痛。The pain described in the present disclosure is selected from postoperative pain, cancer-induced pain, neuropathic pain, traumatic pain, or inflammation-induced pain.
本公开所述的癌症选自乳腺癌、子宫内膜癌、***、皮肤癌、***癌、卵巢癌、输卵管肿瘤、卵巢瘤、血友病和白血病。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.
本公开还提供式(I)所示化合物的II晶型、II晶型的药物组合物在制备激动或拮抗MOR受体的药物中用途。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.
此外，本申请还提供了一种抑制与阿片样物质受体(MOR)激动剂有关的疾病的方法，其包括给有此需要的受试者施用治疗和/或预防有效量的本公开式(I)化合物的II晶型，或者本公开的药物组合物。In addition, 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.
在某些优选的实施方案中，所述疾病为与阿片样物质受体(MOR)激动剂有关的疾病，选自疼痛。通过X-射线粉末衍射图谱(XRPD)、差示扫描量热分析(DSC)对所得到式(I)所示化合物的II晶型进行结构测定、晶型研究。II晶型重结晶的方法没有特别限定，可以用通常的重结晶操作方法进行。例如，可以用原料式(I)所示化合物在有机溶剂中溶解后加入反溶剂析晶，结晶完成后，经过滤干燥，即可得到所需要的结晶。In certain preferred embodiments, the disease is a disease associated with an opioid receptor (MOR) agonist, selected from pain. 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. For example, 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.
本公开析晶的方法有挥发析晶、室温析晶、冷却析晶、加入晶种诱导析晶等。The crystallization methods of the present disclosure include volatile crystallization, room temperature crystallization, cooling crystallization, and addition of seed crystals to induce crystallization.
本公开晶型制备方法中所用的起始原料可以是任意形式的式(I)所示化合物，具体形式包括但不限于：无定形、任意晶型等。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.
披露详述Disclosure details
在本申请的说明书和权利要求书中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。然而，为了更好地理解本公开，下面提供 了部分相关术语的定义和解释。另外，当本申请所提供的术语的定义和解释与本领域技术人员所通常理解的含义不一致时，以本申请所提供的术语的定义和解释为准。In the description and claims of this application, unless otherwise stated, the scientific and technical terms used herein have the meanings generally understood by those skilled in the art. However, in order to better understand the present disclosure, definitions and explanations of some related terms are provided below. In addition, when the definitions and interpretations of the terms provided in this application are inconsistent with the meanings generally understood by those skilled in the art, the definitions and interpretations of the terms provided in this application shall prevail.
本公开所述“C 1-6烷基”表示直链或支链的含有1-6个碳原子的烷基，具体实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。 The "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.
本公开所述“羟基”是指-OH等基团。The "hydroxyl group" in the present disclosure refers to a group such as -OH.
本公开所述“氰基”是指-CN等基团。The "cyano" in this disclosure refers to a group such as -CN.
本公开所述的“醚类溶剂”是指含有醚键-O-且碳原子数为1至10个的链状化合物或环状化合物，具体实例包括但不限于：四氢呋喃、***、丙二醇甲醚、甲基叔丁基醚或1,4-二氧六环。The "ether solvent" described in the present disclosure 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.
本公开所述的“醇类溶剂”是指一个或多个“羟基”取代“C 1-6烷基”上的一个或多个氢原子所衍生的基团，所述“羟基”和“C 1-6烷基”如前文所定义，具体实例包括但不限于：甲醇、乙醇、异丙醇、正丙醇、异戊醇或三氟乙醇。 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.
本公开所述的“酯类溶剂”是指含碳原子数为1至4个的低级有机酸与含碳原子数为1至6个的低级醇的结合物，具体实例包括但不限于：乙酸乙酯、乙酸异丙酯或乙酸丁酯。The "ester solvent" described in the present disclosure 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.
本公开所述的“混合溶剂”是指一种或多种不同种类的有机溶剂按照一定比例混合而成的溶剂，或有机溶剂与水按照一定比例混合而成的溶剂；所述混合溶剂优选为醇类与醚类的混合溶剂；所述醇类与醚类的混合溶剂优选为甲醇与***的混合溶剂，所述比例优选1:10。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.
本公开中所述的“X-射线粉末衍射图谱”为使用Cu-Kα辐射测量得到。其中，
Figure PCTCN2019110560-appb-000003
Figure PCTCN2019110560-appb-000004
The "X-ray powder diffraction pattern" described in this disclosure is measured using Cu-Kα radiation. among them,
Figure PCTCN2019110560-appb-000003
Figure PCTCN2019110560-appb-000004
本公开所述的“X-射线粉末衍射图谱或XRPD”是指根据布拉格公式2d sinθ＝nλ(式中，λ为X射线的波长，
Figure PCTCN2019110560-appb-000005
衍射的级数n为任何正整数，一般取一级衍射峰，n＝1)，当X射线以掠角θ(入射角的余角，又称为布拉格角)入射到晶体或部分晶体样品的某一具有d点阵平面间距的原子面上时，就能满足布拉格方程，从而测得了这组X射线粉末衍射图。本公开所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。 The “X-ray powder diffraction pattern or XRPD” described in this disclosure refers to the Bragg formula 2d sinθ = nλ (where, λ is the wavelength of X-ray,
Figure PCTCN2019110560-appb-000005
The order of diffraction n is any positive integer, generally the first order diffraction peak is taken, n = 1), when X-rays enter the crystal or part of the crystal sample at a grazing angle θ (coincidence of incident angle, also known as Bragg angle) When an atomic plane with a d-lattice plane spacing meets the Bragg equation, the X-ray powder diffraction pattern is measured. 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.
本公开所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度，2θ的误差范围为±0.3，可以为-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、0.23、0.24、0.25、0.26、0.27、0.28、0.29、0.30，更优选±0.2。The "2θ or 2θ angle" mentioned in the present disclosure refers to the diffraction angle, θ is the Bragg angle, the unit is ° or degree, and the error range of 2θ 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, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, more preferably ± 0.2.
本公开所述的“晶面间距或晶面间距(d值)”是指空间点阵选择3个不相平行的连结相邻两个点阵点的单位矢量a，b，c，它们将点阵划分成并置的平行六面体单位，称为晶面间距。空间点阵按照确定的平行六面体单位连线划分，获得一套直线网格，称为空间格子或晶格。点阵和晶格是分别用几何的点和线反映晶体结构的周期性，不同的晶面，其面间距(即相邻的两个平行晶面之间的距离)各不相同；单位为
Figure PCTCN2019110560-appb-000006
或埃。 The "crystal plane spacing or crystal plane spacing (d value)" described in this disclosure 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
Figure PCTCN2019110560-appb-000006
Or Egypt.
本公开中所述干燥温度一般为25℃～100℃，优选40℃～70℃，可以常压干燥，也可以减压干燥。优选的，干燥在减压下干燥。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.
本公开的有益效果The beneficial effects of the present disclosure
与现有技术相比，本公开的技术方案具有以下优点：Compared with the prior art, the technical solution of the present disclosure has the following advantages:
经研究表明，本公开制备的式(I)所示化合物的II晶型溶解性良好、纯度较高，在高温、高湿、光照的条件下晶型经XRPD检测均未发生改变、晶型稳定性良好；本公开技术方案得到的式(I)所示化合物的II晶型能够满足生产运输储存的药用要求，生产工艺稳定、可重复可控，能够适应于工业化生产。Studies have shown that the compound of formula (I) prepared by the present disclosure has good solubility and high purity of the crystal form II, and the crystal form has not been changed by XRPD detection and the crystal form is stable under the conditions of high temperature, high humidity and light. 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.
附图说明BRIEF DESCRIPTION
图1为式(I)所示化合物II晶型的XRPD图谱。Fig. 1 is an XRPD pattern of the compound II crystal form represented by formula (I).
图2为式(I)所示化合物II晶型的DSC图谱。Fig. 2 is a DSC chart of the crystal form of Compound II represented by formula (I).
图3为式(I)所示化合物II晶型的TGA图谱。FIG. 3 is a TGA pattern of the crystal form of compound II represented by formula (I).
图4为式(I)所示化合物I晶型的XRPD图谱。FIG. 4 is an XRPD pattern of the crystal form of Compound I represented by formula (I).
图5为式(I)所示化合物II晶型的DVS图谱。FIG. 5 is a DVS pattern of the crystal form of Compound II represented by formula (I).
图6为式(I)所示化合物II晶型的DVS前后XRPD图谱(上图为引湿性实验后的XRPD图，下图为引湿性实验前的XRPD图)。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).
具体实施方式detailed description
以下将结合实施例更详细地解释本公开，本公开的实施例仅用于说明本公开的技术方案，并非限定本公开的实质和范围。The present disclosure will be explained in more detail in conjunction with embodiments below. The embodiments of the present disclosure are only used to illustrate the technical solutions of the present disclosure, and do not limit the essence and scope of the present disclosure.
实验所用仪器的测试条件：Test conditions of the instrument used in the experiment:
1、差示扫描量热仪(Differential Scanning Calorimeter,DSC)1. Differential Scanning Calorimeter (DSC)
仪器型号：Mettler Toledo DSC3 + Stare e System Instrument model: Mettler Toledo DSC3 + Stare e System
吹扫气：氮气(50mL/min)Purge gas: nitrogen (50mL / min)
升温速率：10.0℃/minHeating rate: 10.0 ℃ / min
温度范围：20-250℃Temperature range: 20-250 ℃
2、X-射线粉末衍射谱(X-ray Powder Diffraction,XRPD)2. X-ray powder diffraction spectrum (X-ray Powder Diffraction, XRPD)
仪器型号：Rigaku UltimaIV X-射线粉末衍射仪Instrument model: Rigaku Ultima IV X-ray powder diffractometer
射线：单色Cu-Kα射线
Figure PCTCN2019110560-appb-000007
Ray: Monochrome Cu-Kα Ray
Figure PCTCN2019110560-appb-000007
扫描方式：θ/2θ，扫描范围：3-45°Scanning method: θ / 2θ, scanning range: 3-45 °
电压：40kV，电流：40mAVoltage: 40kV, current: 40mA
3、热重分析仪(Thermogravimetric Analysis,TGA)3. Thermogravimetric Analysis (TGA)
仪器型号：Mettler Toledo TGA2STAR e System Instrument model: Mettler Toledo TGA2STAR e System
吹扫气：氮气Purge gas: nitrogen
升温速率：10.0℃/minHeating rate: 10.0 ℃ / min
温度范围：20-250℃Temperature range: 20-250 ℃
4、动态蒸汽吸附(Dynamic Vapour Sorption,DVS)4. Dynamic Vapor Sorption (DVS)
仪器型号：TAQ5000VSAInstrument model: TAQ5000VSA
温度：25℃Temperature: 25 ℃
溶剂：水Solvent: water
湿度变化：0-95-0-95-0％RH，步进为10％，判断标准为10000min之内质量变化小于0.01％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%
对比例1(1S,4S)-4-乙氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙基)-1,2,3,4-四氢萘-1-胺(化合物19的无定形)的制备Comparative Example 1 (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 (amorphous compound 19)
Figure PCTCN2019110560-appb-000008
Figure PCTCN2019110560-appb-000008
Figure PCTCN2019110560-appb-000009
Figure PCTCN2019110560-appb-000009
第一步first step
(S)-1,2,3,4-四氢萘-1-氨基甲酸叔丁酯11a(S) -1,2,3,4-Tetrahydronaphthalene-1-carbamic acid tert-butyl ester 11a
将(S)-1,2,3,4-四氢-1-萘胺10a(3g，20.41mmol，采用“Angewandte Chemie-International Edition,45(28),4641-4644,2006”公开的方法制备而得)溶解于100mL二氯甲烷中，加入三乙胺(5.7mL，40.82mmol)，加入二叔丁基二碳酸酯(4.9g，22.45mmol)，搅拌反应12小时。反应液依次用水(100mL)，饱和碳酸氢钠溶液洗涤(100mL)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物11a(5.6g，淡黄色油状物)，产物不经纯化直接进行下步反应。(S) -1,2,3,4-Tetrahydro-1-naphthylamine 10a (3g, 20.41mmol, prepared by the method disclosed in "Angewandte Chemie-International Edition, 45 (28), 4641-4644, 2006" (Acquired) was dissolved in 100 mL of dichloromethane, triethylamine (5.7 mL, 40.82 mmol) was added, di-tert-butyl dicarbonate (4.9 g, 22.45 mmol) was added, and the reaction was stirred for 12 hours. The 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.
MS m/z(ESI):248.3[M+1]MS m / z (ESI): 248.3 [M + 1]
第二步Second step
(S)-4-羰基-1,2,3,4-四氢萘-1-氨基甲酸叔丁酯11b(S) -4-Carbonyl-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester 11b
将粗品(S)-1,2,3,4-四氢萘-1-氨基甲酸叔丁酯11a(5.6g，20.41mmol)溶解于90mL丙酮和水(V/V＝2:1)混合溶剂中，加入硫酸镁(5.5g，45.66mmol)，搅拌下缓慢加入高锰酸钾(7.22g，45.66mmol)，搅拌反应12小时。反应液减压浓缩，用硅胶柱色谱法以正己烷和乙酸乙酯为洗脱剂纯化所得残余物，得到标题产物11b(3.1g，类白色固体)，产率：52％。Dissolve crude (S) -1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester 11a (5.6 g, 20.41 mmol) in 90 mL of acetone and water (V / V = 2: 1) mixed solvent In it, magnesium sulfate (5.5g, 45.66mmol) was added, potassium permanganate (7.22g, 45.66mmol) was slowly added with stirring, and the reaction was stirred for 12 hours. The 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%.
MS m/z(ESI):262.3[M+1]MS “m / z (ESI): 262.3 [M + 1]
第三步third step
(1S,4S)-4-羟基-1,2,3,4-四氢萘-1-氨基甲酸叔丁酯14a(1S, 4S) -4-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester 14a
将(S)-4-羰基-1,2,3,4-四氢萘-1-氨基甲酸叔丁酯11b(100mg，0.883mmol)溶解于5mL 甲苯中，降温至0℃，加入(R)-2-甲基-CBS-恶唑硼烷(0.1ml，0.076mmol)，搅拌5分钟，加入硼烷甲基硫醚(0.88ml，0.76mmol)，搅拌反应2小时。加入50ml饱和氯化钠溶液淬灭反应，用乙酸乙酯萃取(30mL×3)，合并有机相，有机相用饱和氯化钠溶液洗涤(30mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法以二氯甲烷和甲醇为洗脱剂纯化所得残余物，得到标题产物14a(60mg，白色固体)，产率60％。Dissolve (S) -4-carbonyl-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester 11b (100 mg, 0.883 mmol) in 5 mL of toluene, cool to 0 ° C, and add (R) -2-Methyl-CBS-oxazolylborane (0.1 ml, 0.076 mmol), stirred for 5 minutes, added borane methyl sulfide (0.88 ml, 0.76 mmol), and stirred to react for 2 hours. The reaction was quenched by adding 50 ml of saturated sodium chloride solution, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined. The organic phase was washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate It was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography using dichloromethane and methanol as eluents to obtain the title product 14a (60 mg, white solid) in 60% yield.
MS m/z(ESI):208.3[M-55]MS “m / z (ESI): 208.3 [M-55]
第四步the fourth step
(1S,4S)-4-乙氧基-1,2,3,4-四氢萘-1-氨基甲酸叔丁酯19a(1S, 4S) -4-ethoxy-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester 19a
将粗品(1S)-4-羟基-1,2,3,4-四氢萘-1-氨基甲酸叔丁酯14a(850mg，3.23mmol)，氧化银(76mg，0.33mmol)和碘乙烷(1.3mL，16.15mmol)溶解于二氯甲烷(30mL)中，搅拌反应48小时。过滤，滤液减压浓缩，得到粗品标题产物19a(800mg，黄色油状物)，产物不经纯化直接进行下步反应。The crude (1S) -4-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester 14a (850 mg, 3.23 mmol), silver oxide (76 mg, 0.33 mmol) and iodoethane ( 1.3 mL, 16.15 mmol) was dissolved in dichloromethane (30 mL), and the reaction was stirred for 48 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude title product 19a (800 mg, yellow oil). The product was directly subjected to the next step without purification.
MS m/z(ESI):236.1[M-55]MS “m / z (ESI): 236.1 [M-55]
第五步the fifth step
(1S,4S)-4-乙氧基-1,2,3,4-四氢萘-1-胺19b(1S, 4S) -4-ethoxy-1,2,3,4-tetrahydronaphthalene-1-amine 19b
将粗品化合物19a(698mg，2.4mmol)溶解于4mL二氯甲烷中，加入8mL 4M氯化氢的1,4-二氧六环溶液，搅拌反应2小时。反应液减压浓缩，乙酸乙酯打浆(30mL)，过滤，滤饼溶于二氯甲烷和甲醇(20mL，V:V＝5:1)的混合溶剂中，用饱和碳酸氢钠溶液调节反应液pH为7～8，反应液减压浓缩，用二氯甲烷和甲醇(V:V＝5:1)的混合溶剂洗涤(30mL×2)，过滤，滤液减压浓缩，得到粗品标题产物19b(310mg，黄色液体)，产物不经纯化直接进行下步反应。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 concentrated under reduced pressure, slurried with ethyl acetate (30 mL), filtered, and the filter cake was dissolved in a mixed solvent of dichloromethane and methanol (20 mL, V: V = 5: 1), and the reaction solution was adjusted with saturated sodium bicarbonate solution The pH is 7-8. The reaction solution is concentrated under reduced pressure, washed with a mixed solvent of dichloromethane and methanol (V: V = 5: 1) (30 mL × 2), filtered, and the filtrate is concentrated under reduced pressure to obtain the crude title product 19b ( 310 mg, yellow liquid), the product was directly subjected to the next reaction without purification.
MS m/z(ESI):191.1[M+1]MS m / z (ESI): 191.1 [M + 1]
第六步The sixth step
(1S,4S)-4-乙氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氢萘-1-胺19(1S, 4S) -4-ethoxy-N- (2-((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-9-yl) ethyl) -1,2,3,4-tetrahydronaphthalene-1-amine 19
将(R)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙醛5a(500mg，1.85mmol，采用专利申请“WO2012129495”公开的方法制备而得)，粗品化合物19b(310mg，1.85mmol)溶解于二氯乙烷(30mL)中，搅拌反应40分钟，加入三乙酰氧基硼氢化钠(980mg，4.63mmol)，搅拌反应2小时。依次用饱和碳酸氢钠溶液(30mL×3)，用饱和氯化钠溶液洗涤(30mL×3)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法以二氯甲烷和甲醇为洗脱剂纯化所得残余物，得到标题产物19(280mg，黄色粘稠固体)，产率：35％。(R) -2- (9- (pyridin-2-yl) -6-oxaspiro [4.5] decane-9-yl) acetaldehyde 5a (500mg, 1.85mmol, using the patent application "WO2012129495" published (Prepared by the method), the crude compound 19b (310mg, 1.85mmol) was dissolved in dichloroethane (30mL), the reaction was stirred for 40 minutes, sodium triacetoxyborohydride (980mg, 4.63mmol) was added, and the reaction was stirred for 2 hours . It was sequentially washed with saturated sodium bicarbonate solution (30 mL × 3), washed with saturated sodium chloride solution (30 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, using thin layer chromatography with dichloromethane The resulting residue was purified using methane and methanol as eluents to obtain the title product 19 (280 mg, yellow sticky solid), yield: 35%.
对比例2、Comparative example 2.
(1S,4S)-4-乙氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙基)-1,2,3,4-四氢萘-1-胺富马酸盐(I晶型)的制备(1S, 4S) -4-ethoxy-N- (2-((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-9-yl) ethyl)- Preparation of 1,2,3,4-tetrahydronaphthalene-1-amine fumarate (Form I)
将(1S,4S)-4-乙氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙基)-1,2,3,4-四氢萘-1-胺富马酸盐(50mg，0.09mmol)和四氢呋喃(0.5mL)加入反应瓶中，升温至微沸搅拌溶清。自然冷却至室温，搅拌反应16小时。反应液过滤，滤饼用乙酸乙酯淋洗(1mL×3)，收集滤饼，真空干燥，得到固体(25mg，产率50％)，该结晶样品的XRPD图谱见图4，其2θ特征峰位置如下表所示：(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 (50 mg, 0.09 mmol) and tetrahydrofuran (0.5 mL) were added to the reaction flask, and the temperature was raised to slightly boiling and stirred to dissolve. It was naturally cooled to room temperature, and the reaction was stirred for 16 hours. The reaction solution was filtered, and the filter cake was rinsed with ethyl acetate (1 mL × 3). The filter cake was collected and dried in vacuo to obtain a solid (25 mg, yield 50%). The XRPD pattern of the crystalline sample is shown in FIG. 4 and its 2θ characteristic peak The location is shown in the table below:
表1、I晶型特征峰Table 1. I-shaped characteristic peaks
Figure PCTCN2019110560-appb-000010
Figure PCTCN2019110560-appb-000010
Figure PCTCN2019110560-appb-000011
Figure PCTCN2019110560-appb-000011
实施例1Example 1
(1S,4S)-4-乙氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙基)-1,2,3,4-四氢萘-1-胺富马酸盐(II晶型)的制备(1S, 4S) -4-ethoxy-N- (2-((R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] dec-9-yl) ethyl)- Preparation of 1,2,3,4-tetrahydronaphthalene-1-amine fumarate (crystal form II)
Figure PCTCN2019110560-appb-000012
Figure PCTCN2019110560-appb-000012
将(1S,4S)-4-乙氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙基)-1,2,3,4-四氢萘-1-胺(88mg，0.2mmol)溶于***(2.5mL)中，将富马酸(23.2mg，0.2mmol)溶于甲醇(0.25mL)中，滴加到上述溶液中，滴加过程中析出白色固体，搅拌后澄清，继续搅拌析出大量白色固体，搅拌反应16小时。反应液过滤，滤饼用***淋洗(2mL×3)，收集滤饼，真空干燥得到白色固体产物(70mg，产率60％)，该结晶样品的XRPD图谱见图1，其DSC谱图见图2，起始熔化温度为161.45℃，峰值约为163.17℃，TGA图谱如图3，表明II晶型为无水物；其特征峰位置如下表所示：(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 (88mg, 0.2mmol) was dissolved in ether (2.5mL), fumaric acid (23.2mg, 0.2mmol) was dissolved in methanol (0.25mL) , Dropwise added to the above solution, white solid precipitated during the dropwise addition, cleared after stirring, continued stirring to precipitate a large amount of white solid, and stirred to react for 16 hours. The reaction solution was filtered, and the filter cake was rinsed with ether (2mL × 3). The filter cake was collected and dried in vacuo to give a white solid product (70mg, yield 60%). The XRPD pattern of the crystal sample is shown in Figure 1, and the DSC spectrum is shown in Figure 2, the initial melting temperature is 161.45 ℃, the peak value is about 163.17 ℃, the TGA spectrum is shown in Figure 3, indicating that the crystal form II is anhydrous; its characteristic peak position is shown in the following table:
MS m/z(ESI):435.5[M+1]MS m / z (ESI): 435.5 [M + 1]
1H-NMR(400MHz,DMSO-d 6)δ8.43-8.66(m,1H),7.69-7.80(m,1H),7.42-7.52(m,1H),7.28-7.36(m,1H),7.23(s,4H),6.51(s,2H),4.26-4.35(m,1H),3.85-3.97(m,1H),3.60(m,3H),3.39-3.51(m,1H),2.52-2.61(m,1H),2.30-2.45(m,2H),2.07-2.20(m,1H),1.85-2.07(m,3H),1.20-1.84(m,12H),1.11(t,3H),0.93-1.03(m,1H),0.57-0.72(m,1H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.43-8.66 (m, 1H), 7.69-7.80 (m, 1H), 7.42-7.52 (m, 1H), 7.28-7.36 (m, 1H), 7.23 (s, 4H), 6.51 (s, 2H), 4.26-4.35 (m, 1H), 3.85-3.97 (m, 1H), 3.60 (m, 3H), 3.39-3.51 (m, 1H), 2.52- 2.61 (m, 1H), 2.30-2.45 (m, 2H), 2.07-2.20 (m, 1H), 1.85-2.07 (m, 3H), 1.20-1.84 (m, 12H), 1.11 (t, 3H) 0.93-1.03 (m, 1H), 0.57-0.72 (m, 1H).
表2、II晶型特征峰Table 2. Characteristic peaks of crystal form II
Figure PCTCN2019110560-appb-000013
Figure PCTCN2019110560-appb-000013
实施例2Example 2
将(1S,4S)-4-乙氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙基)-1,2,3,4-四氢萘-1-胺(176mg，0.4mmol)溶于***(5mL)中，将富马酸(46.4mg，0.4mmol)溶于甲醇(0.5 mL)中，滴加到上述溶液中，滴加过程中析出白色固体，搅拌后澄清，继续搅拌析出大量白色固体，搅拌反应16小时。反应液过滤，滤饼用***淋洗(5mL×3)，收集滤饼，真空干燥得到白色固体产物(160mg，产率70％)，该结晶样品经XRPD表征确认为II晶型。(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 (176mg, 0.4mmol) was dissolved in ether (5mL), fumaric acid (46.4mg, 0.4mmol) was dissolved in methanol (0.5mL), It was added dropwise to the above solution, and a white solid precipitated during the dropwise addition. It was clarified after stirring, and a large amount of white solid was precipitated by continuing stirring, and the reaction was stirred for 16 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.
实施例3Example 3
将(1S,4S)-4-乙氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙基)-1,2,3,4-四氢萘-1-胺富马酸盐(50mg，0.09mmol)和异丙醇(0.5mL)加入反应瓶中，升温至60℃搅拌溶清。自然冷却至室温，搅拌反应16小时。反应液过滤，滤饼用乙酸乙酯淋洗(1mL×3)，收集滤饼，真空干燥，得到白色固体化合物(II晶型)(30mg，产率60％)，经XRPD表征确认为II晶型；(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 (50 mg, 0.09 mmol) and isopropanol (0.5 mL) were added to the reaction flask, and the temperature was raised to 60 ° C and stirred to dissolve. It was naturally cooled to room temperature, and the reaction was stirred for 16 hours. The reaction solution was filtered, and the filter cake was rinsed with ethyl acetate (1 mL × 3). The filter cake was collected and dried in vacuo to obtain a white solid compound (crystal form II) (30 mg, yield 60%), which was confirmed to be crystal II by XRPD characterization. type;
DVS表征，样品在25℃的条件下，在0％RH～80％RH之间随着湿度的增加吸水量也在增加，重量变化为0.033％，小于0.2％，该样品无或几乎无引湿性；对比DVS检测前后的XRPD谱图，该样品在测定DVS前后晶型未发生转变；DVS characterization, under 25 ℃ condition, the water absorption also increases with the increase of humidity between 0% RH and 80% RH, the weight change is 0.033%, less than 0.2%, the sample has no or almost no moisture ; Compare the XRPD spectrum before and after DVS detection, the sample did not change the crystal form before and after DVS determination;
DVS谱图见图5，DVS前后X-粉末衍射对比图显示DVS前后晶型未发生转变(见图6)。The DVS spectrum is shown in Figure 5, and the X-powder diffraction comparison chart before and after DVS shows that the crystal form has not changed before and after DVS (see Figure 6).
实施例4Example 4
将实施例1产物(50mg)置于反应瓶中，加入乙酸异丙酯(0.5mL)，室温打浆48h，过滤、干燥，产率为62％。样品经X-射线粉末衍射表征，确定产物为II晶型。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.
实施例5Example 5
将实施例1产物(50mg)置于反应瓶中，加入异丙醇(0.5mL)，室温打浆48h，过滤、干燥，产率为65％。样品经X-射线粉末衍射表征，确定产物为II晶型。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.
实施例6Example 6
将实施例1产物(50mg)置于反应瓶中，加入异丙醇(0.5mL)，40℃打浆48h，过滤、干燥，产率为70％。样品经X-射线粉末衍射表征，确定产物为II晶型。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.
实施例7Example 7
将(1S,4S)-4-乙氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙基)-1,2,3,4-四氢萘-1-胺(88mg，0.2mmol)溶于异丙醇(2.5mL)中，将富马酸(23.2mg，0.2mmol)加入异丙醇(0.25mL)中，滴加到上述溶液中，加热至80℃反应2h，冷却至40℃无沉淀产生，继续冷却至25℃加入晶种析出白色固体，过滤，滤饼用***淋洗(5mL×3)，收集滤饼，真空干燥得到白色固体产物(68mg，产率78.1％)，该结晶样品经XRPD表征确认为II晶型。(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 (88mg, 0.2mmol) was dissolved in isopropanol (2.5mL), fumaric acid (23.2mg, 0.2mmol) was added to isopropanol (0.25 mL), added dropwise to the above solution, heated to 80 ℃ for 2h, cooled to 40 ℃ without precipitation, continue to cool to 25 ℃, add a seed crystal to precipitate a white solid, filter, rinse the filter cake with ether (5mL × 3 ), The filter cake was collected and dried in vacuo to give a white solid product (68 mg, yield 78.1%). The crystal sample was confirmed to be Form II by XRPD characterization.
实施例8Example 8
将(1S,4S)-4-乙氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙基)-1,2,3,4-四氢 萘-1-胺(88mg，0.2mmol)溶于异丙醇(2.5mL)中，将富马酸(23.2mg，0.2mmol)加入异丙醇(0.25mL)中，滴加到上述溶液中，加热至80℃反应2h，冷却至室温析出固体，过滤，滤饼用***淋洗(5mL×3)，收集滤饼，真空干燥得到白色固体产物(67mg，产率76.9％)，该结晶样品经XRPD表征确认为II晶型。(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 (88mg, 0.2mmol) was dissolved in isopropanol (2.5mL), fumaric acid (23.2mg, 0.2mmol) was added to isopropanol (0.25 mL), added dropwise to the above solution, heated to 80 ℃ for 2h, cooled to room temperature to precipitate solid, filtered, the filter cake was rinsed with ether (5mL × 3), the filter cake was collected, and dried in vacuo to give a white solid product (67mg , Yield 76.9%), the crystalline sample confirmed by XRPD characterization of the II crystal form.
实施例9Example 9
将(1S,4S)-4-乙氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙基)-1,2,3,4-四氢萘-1-胺(88mg，0.2mmol)溶于异丙醇(2.5mL)中，将富马酸(23.2mg，0.2mmol)加入异丙醇(0.25mL)中，滴加到上述溶液中，室温反应4h，析出固体，过滤，滤饼用***淋洗(5mL×3)，收集滤饼，真空干燥得到白色固体产物(65mg，产率74.6％)，该结晶样品经XRPD表征确认为II晶型。(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 (88mg, 0.2mmol) was dissolved in isopropanol (2.5mL), fumaric acid (23.2mg, 0.2mmol) was added to isopropanol (0.25 mL), added dropwise to the above solution, reacted at room temperature for 4h, precipitated a solid, filtered, the filter cake was rinsed with ether (5mL × 3), the filter cake was collected and dried in vacuo to give a white solid product (65mg, yield 74.6%) The X-ray crystallographic sample was confirmed to be Form II by XRPD characterization.
实施例10Example 10
将对比例2所得产物I晶型(50mg)置于反应瓶中，加入异丙醇(0.5mL)，室温打浆48h，过滤、干燥，产率为63％。样品经X-射线粉末衍射表征，确定产物为II晶型，由此说明II晶型比I晶型稳定。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.
实施例11、II晶型与式(II)所示化合物的溶解度比较Example 11. Comparison of the solubility of the crystal form II and the compound represented by formula (II)
供试品：对比例1所得的式(II)所示化合物(游离态)、II晶型；Test product: Compound (free state), crystal form II of formula (II) obtained in Comparative Example 1;
溶剂：纯水；Solvent: pure water;
实验方法：experimental method:
II晶型样品溶解度检测：精密称取样品53.55mg于西林瓶中，加入1.5mL水溶液，加入搅拌子，磁力搅拌24hr后，样品未完全溶解，在12000rpm离心40min。上清液稀释1000倍转移至HPLC分析。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.
式(II)所示化合物(游离态)溶解度检测：精密称取样品1.29mg于西林瓶中，加入1.0mL水溶液，加入搅拌子，磁力搅拌24hr后，样品未完全溶解，在12000rpm离心40min，上清液转移至HPLC分析。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色谱条件：流动性为乙腈-0.1％TFA水溶液(50:50)、检测波长264nm、进样量10μL、流速1.0mL/min。HPLC chromatographic conditions: fluidity is acetonitrile-0.1% TFA aqueous solution (50:50), detection wavelength 264nm, injection volume 10μL, flow rate 1.0mL / min.
试验结果：test results:
表3、II晶型与游离态溶解性比较Table 3. Comparison of solubility of crystal form II and free state
Figure PCTCN2019110560-appb-000014
Figure PCTCN2019110560-appb-000014
试验结论：Test Conclusions:
II晶型在水中的溶解性优于游离态。The solubility of crystal form II in water is better than that in the free state.
实施例12、II晶型影响因素稳定性考察Example 12, the stability of factors affecting the II crystal form
将实施例1所得的II晶型样品敞口平摊放置，考察在光照(4500Lux)、高温(40℃，60℃)、高湿(RH75％，RH90％)条件下样品的化学稳定性，考察取样时间为5天、10天，考察样品化学纯度和手性纯度，HPLC检测纯度见下表。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.
试验结果：test results:
表4、II晶型样品的影响因素稳定性(HPLC纯度)Table 4. Factors affecting the crystal form II stability (HPLC purity)
Figure PCTCN2019110560-appb-000015
Figure PCTCN2019110560-appb-000015
试验结论：Test Conclusions:
II晶型在光照、高温(40℃，60℃)条件下敞口放置10天，化学纯度和手性纯度下降明显，在高湿(RH75％，RH90％)条件下敞口放置10天，化学纯度和手性纯度变化较小；XRPD检测II晶型在光照(4500Lux)、高温(40℃，60℃)、高湿(RH75％，RH90％)条件下放置10天，晶型均未发生改变，说明II晶型稳定性较好。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.
实施例13、II晶型长期、加速稳定性考察Example 13, the long-term, accelerated stability of the II crystal form
将实施例1所得的II晶型样品避光、密封平摊放置，考察在长期(25℃、60％RH)和加速(40℃、75％RH)下样品的稳定性，考察取样时间为0.5个月、1个月、2个月、3个月，XRPD检测晶型是否发生转变。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.
试验结果：test results:
表5、II晶型样品的稳定性(HPLC纯度)Table 5. Stability of crystalline sample II (HPLC purity)
Figure PCTCN2019110560-appb-000016
Figure PCTCN2019110560-appb-000016
试验结论：Test Conclusions:
实施例1所得的II晶型在避光、密封情况下，长期(25℃、60％RH)、加速(40℃、75％RH)放置3个月稳定性良好，同时II晶型的XRPD峰型未发生变化，晶型稳定。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.

Claims (10)

  1. 一种式(I)所示化合物的II晶型，其特征在于：以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.07、10.70、13.28、16.22、22.02和24.43处有特征峰，A crystal form II of a compound represented by formula (I), characterized by an X-ray powder diffraction pattern expressed at a diffraction angle of 2θ, having characteristic peaks at 6.07, 10.70, 13.28, 16.22, 22.02, and 24.43,
    Figure PCTCN2019110560-appb-100001
    Figure PCTCN2019110560-appb-100001
  2. 根据权利要求1所述的II晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.07、8.08、10.70、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和31.14处有特征峰。The crystal form II according to claim 1, wherein the X-ray powder diffraction pattern expressed at a diffraction angle of 2θ is 6.07, 8.08, 10.70, 12.15, 13.28, 14.45, 15.03, 15.20, 15.50, 16.22, There are characteristic peaks at 17.83, 18.26, 18.87, 20.99, 21.21, 22.02, 23.05, 24.43, 25.02, 29.62 and 31.14.
  3. 根据权利要求2所述的II晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱，在6.07、8.08、10.70、12.15、13.28、14.45、15.03、15.20、15.50、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和35.60处有特征峰。The II crystal form according to claim 2, characterized in that the X-ray powder diffraction pattern expressed at a diffraction angle of 2θ is 6.07, 8.08, 10.70, 12.15, 13.28, 14.45, 15.03, 15.20, 15.50, 16.22, There are characteristic peaks at 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.
  4. 根据权利要求1-3中至少一项所述的II晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱如图1所示。The crystal form II according to at least one of claims 1 to 3, characterized in that the X-ray powder diffraction pattern represented by the diffraction angle 2θ is shown in Fig. 1.
  5. 根据权利要求1-4中至少一项所述的II晶型，其特征在于，所述2θ角误差范围为±0.30。The II crystal form according to at least one of claims 1 to 4, characterized in that the 2θ angle error range is ± 0.30.
  6. 一种制备如权利要求1-5中至少一项所述II晶型的方法，其特征在于，所述方法选自A method for preparing the crystal form II according to at least one of claims 1-5, characterized in that the method is selected from
    (1)将式(I)所示化合物溶解于溶剂(I)中，析晶得II晶型；所述溶剂(I)优选醚类、醇类溶剂，所述醚类溶剂优选***，所述醇类溶剂优选甲醇或异丙醇，所述析晶方法优选室温析晶、冷却析晶或加入晶种诱导析晶；(1) 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;
    (2)将式(I)所示化合物加入溶剂(II)中，打浆得II晶型；所述溶剂(II)选自醇类或酯类溶剂；所述酯类溶剂选自乙酸乙酯、乙酸异丙酯或乙酸丁酯，所述醇类溶剂选自甲醇或异丙醇；(2) 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;
    (3)将式(I)所示化合物的游离态溶解于溶剂(III)中，加入富马酸，析出固体或加入 晶种，析晶得目标II晶型；所述溶剂(III)优选醇类溶剂或醚类与醇类的混合溶剂，所述醇类溶剂优选甲醇或异丙醇，所述醚类与醇类的混合溶剂优选***与甲醇的混合溶剂。(3) Dissolve the free state of the compound represented by formula (I) in the solvent (III), add fumaric acid, precipitate solids or add seed crystals, and crystallize to obtain the target II crystal form; 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.
  7. 一种药物组合物，由权利要求1-5中至少一项所述II晶型，以及一种或多种药学上可接受的载体、稀释剂或赋形剂制备而成。A pharmaceutical composition is prepared from the crystal form II according to at least one of claims 1 to 5, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  8. 一种药物组合物的制备方法，包括将权利要求1-5中至少一项所述的II晶型或由权利要求6方法制备的II晶型与药学上可接受的载体、稀释剂或赋形剂混合的步骤。A method for preparing a pharmaceutical composition, comprising combining the crystalline form II of at least one of claims 1-5 or the crystalline form II prepared by the method of claim 6 with a pharmaceutically acceptable carrier, diluent or excipient The step of mixing agent.
  9. 一种根据权利要求1-5中至少一项所述的II晶型、或根据权利要求7所述II晶型的药物组合物在制备治疗与阿片样物质受体(MOR)激动剂介导的相关疾病的药物中的用途。A pharmaceutical composition according to at least one of claims 1 to 5 or the pharmaceutical composition according to claim 7 in preparation for treatment and opioid receptor (MOR) agonist-mediated Use in medicine for related diseases.
  10. 根据权利要求9所述的用途，其中所述MOR受体激动剂介导的相关疾病选自疼痛、免疫功能障碍、炎症、食管回流、神经和精神疾病、泌尿和生殖疾病、心血管疾病和呼吸道疾病，优选疼痛。The use according to claim 9, wherein the related diseases mediated by the MOR receptor agonist are selected from pain, immune dysfunction, inflammation, esophageal reflux, neurological and mental diseases, urinary and reproductive diseases, cardiovascular diseases and respiratory tract Disease, preferably pain.
PCT/CN2019/110560 2018-10-12 2019-10-11 Crystal form of opioid receptor (mor) agonist and preparation method thereof WO2020073984A1 (en)

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WO2017063509A1 (en) * 2015-10-15 2017-04-20 江苏恒瑞医药股份有限公司 Oxa spiro derivative, preparation method therefor, and applications thereof in medicines
WO2018188643A1 (en) * 2017-04-14 2018-10-18 江苏恒瑞医药股份有限公司 Opioid receptor (mor) agonist salt, fumarate salt i crystal form thereof and preparation method thereof

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WO2018188643A1 (en) * 2017-04-14 2018-10-18 江苏恒瑞医药股份有限公司 Opioid receptor (mor) agonist salt, fumarate salt i crystal form thereof and preparation method thereof

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