WO2020073985A1 - Structure cristalline d'un agoniste des récepteurs aux opiacés mu (mor) et son procédé de préparation - Google Patents

Structure cristalline d'un agoniste des récepteurs aux opiacés mu (mor) et son procédé de préparation Download PDF

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WO2020073985A1
WO2020073985A1 PCT/CN2019/110563 CN2019110563W WO2020073985A1 WO 2020073985 A1 WO2020073985 A1 WO 2020073985A1 CN 2019110563 W CN2019110563 W CN 2019110563W WO 2020073985 A1 WO2020073985 A1 WO 2020073985A1
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iii
crystal form
mor
ray powder
present disclosure
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PCT/CN2019/110563
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English (en)
Chinese (zh)
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王林
杜振兴
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江苏恒瑞医药股份有限公司
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Priority to CN201980053697.XA priority Critical patent/CN112638907B/zh
Publication of WO2020073985A1 publication Critical patent/WO2020073985A1/fr

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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
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 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) ethane Group) -1,2,3,4-tetrahydronaphthalene-1-amine fumarate III crystal form and preparation method, application of the III crystal form in the pharmaceutical composition and preparation of the III crystal form and composition Use in medicine 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 a crystal form III of the compound represented by formula (I), an X-ray powder diffraction pattern expressed at a diffraction angle of 2 ⁇ , at 6.44, 10.16, 11.99, 13.65, 14.00, 16.43, 17.05, There are characteristic peaks at 19.56, 21.40 and 22.64,
  • Some embodiments provide the III crystal form, the X-ray powder diffraction pattern expressed at a diffraction angle of 2 ⁇ , at 6.44, 10.16, 11.99, 13.22, 13.65, 14.00, 14.38, 16.08, 16.43, 17.05, 17.63, 17.98 , 18.90, 19.56, 20.12, 20.58, 21.40, 22.64, 22.91, 23.94 and 29.26 have characteristic peaks.
  • the III crystal form is provided, and the diffraction angle 2 ⁇ angle is 6.44, 7.11, 9.78, 10.16, 11.99, 12.90, 13.22, 13.65, 14.00, 14.38, 14.82, 15.32, 16.08, 16.43, 17.05, 17.63 , 17.98, 18.90, 19.56, 20.12, 20.58, 20.92, 21.40, 22.64, 22.91, 23.18, 23.94, 24.50, 25.32, 25.88, 26.67, 28.47, 29.26, 30.16, 30.96, 32.52, 33.38, 35.74, 37.02, 40.38 And 42.41 have characteristic peaks.
  • the III 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 III crystal form, the method including:
  • the free state of the compound represented by formula (I) is dissolved in a solvent, fumaric acid is added, heated to a slight boiling, and crystallized by cooling to obtain crystal form III; the slight boiling temperature is selected from 40 ° C-the boiling point of the solvent, and the solvent is preferably An alcohol-based solvent, and the alcohol-based solvent is preferably isopropyl alcohol.
  • 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 III crystal form represented by the aforementioned formula (I), and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the crystalline form III 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.
  • 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 preparation may further contain suitable fillers, binders, disintegrating agents, lubricants and the like.
  • 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. 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 III 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 III 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 III crystal form or the III 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 III and the crystalline form III pharmaceutical composition in the preparation of medicaments for treating diseases related to opioid receptor (MOR) agonists.
  • MOR opioid receptor
  • 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 diseases, Preferably pain.
  • the present disclosure also provides use of the crystalline form III and the crystalline form III 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 III and the crystalline form III of the compound represented by 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) Compound III crystal form, 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 structure III of the obtained compound of formula (I) was determined by X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC).
  • the method of recrystallization of the III crystal form 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 crystallizing methods of the present disclosure include room temperature crystallizing, cooling crystallizing, and adding seed crystals to induce crystallizing.
  • 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.
  • 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 “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 compound III of the formula (I) prepared by the present disclosure has a high melting point, good solubility, and high purity.
  • the crystal form has not been changed by XRPD detection under the conditions of high temperature, high humidity, and light. 3.
  • the crystal form has good stability; the III crystal form 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.
  • Fig. 1 is an XRPD pattern of the compound III crystal form represented by formula (I).
  • FIG. 2 is a DSC chart of the crystal form of compound III represented by formula (I).
  • Fig. 3 is a TGA pattern of the compound III crystal form represented by formula (I).
  • Fig. 4 is an XRPD pattern of the compound III crystal form represented by formula (I) at 25 ° C and 60% RH for 3 months.
  • FIG. 5 is an XRPD pattern of the compound III crystal form represented by formula (I) at 40 ° C. and 75% RH for 3 months.
  • Heating rate 10.0 °C / min
  • Heating rate 10.0 °C / min
  • 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 reaction was quenched by adding 50ml of saturated sodium chloride solution, extracted with ethyl acetate (30mL ⁇ 3), the organic phases were combined, the organic phase was washed with saturated sodium chloride solution (30mL ⁇ 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.
  • 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 isopropyl alcohol (2 mL ⁇ 5) and ethyl acetate (2 mL ⁇ 3) in sequence.
  • the filter cake was collected and dried in vacuo to give a white solid product (2.0 g, yield 60%).
  • the XRPD pattern of the sample is shown in Figure 1, and its DSC spectrum is shown in Figure 2.
  • the starting point of the endothermic peak is near 175.44 °C, and the peak value is about 176.65 °C.
  • the TGA pattern is shown in Figure 3, indicating that the crystal form III is anhydrous; its characteristic peak
  • the location is shown in the table below:
  • Example 1 Place the III crystal sample 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%).
  • the sampling time is 10 days and 17 days.
  • the chemical purity and chiral purity of the samples are investigated.
  • the HPLC detection purity is shown in the table below.
  • the III crystal form is exposed to light and high temperature (40 ° C, 60 ° C) for 17 days, and the chemical purity and chiral purity decrease significantly. Under high humidity (RH75%, RH90%), it is exposed for 17 days, chemical The purity and chiral purity change little; XRPD detection III crystal form is placed under light (4500Lux), high temperature (40 °C, 60 °C), high humidity (RH75%, RH90%) conditions for 17 days, the crystal form has not changed , Indicating that the III crystal form has better stability.
  • the III crystal sample obtained in Example 1 was placed in a light-proof, sealed flat position, and the stability of the sample under long-term (25 ° C, 60% RH) and acceleration (40 ° C, 75% RH) was investigated, and the sampling time was 0.5 Months, 1 months, 2 months, 3 months, XRPD detects whether the crystal form has changed.
  • the III crystal form has good stability under long-term (25 ° C, 60% RH) and accelerated (40 ° C, 75% RH) conditions when protected from light and sealed for 3 months.
  • the XRPD pattern is shown in Fig. 4 and the XRPD pattern at 40 ° C and 75% RH for 3 months is shown in Fig. 5.
  • the XRPD peak shape of the III crystal form is basically unchanged, and the crystal form is stable.

Abstract

L'invention concerne une structure cristalline d'un agoniste des récepteurs aux opiacés mu (MOR) et son procédé de préparation. L'invention concerne particulièrement un (1S4S)-4-éthoxy-N-(2-((R)-9-(pyridine-2-yl)-6-oxaspiro [4.5] décano-9-yl) éthyl) -1,2,3,4-tétrahydronaphthalène-1-amine fumarate et son procédé de préparation. La forme cristalline présente une bonne stabilité en termes de forme cristalline et est plus indiquée pour un usage clinique.
PCT/CN2019/110563 2018-10-12 2019-10-11 Structure cristalline d'un agoniste des récepteurs aux opiacés mu (mor) et son procédé de préparation WO2020073985A1 (fr)

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CN201980053697.XA CN112638907B (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

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CN201811186743 2018-10-12

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012129495A1 (fr) * 2011-03-23 2012-09-27 Trevena, Inc. Ligands de récepteurs opïoides, et leurs procédés d'utilisation et de production
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
WO2012129495A1 (fr) * 2011-03-23 2012-09-27 Trevena, Inc. Ligands de récepteurs opïoides, et leurs procédés d'utilisation et de production
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEN, XIAOTAO ET AL.: "Structure-Activity Relationships and Discovery of a G Protein Biased µ Opioid Receptor Ligand, [(3-Methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6- oxaspiro-[4.5]decan-9-yl]ethyl})amine (TRV130), for the Treatment of Acute Severe Pain", JOURNAL OF MEDICINAL CHEMISTRY, vol. 56, 24 September 2013 (2013-09-24), pages 8019 - 8031, XP055375432, DOI: 10.1021/jm4010829 *

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CN112638907B (zh) 2022-04-12
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TWI717859B (zh) 2021-02-01

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