WO2019109802A1 - Procédé de préparation de composé de borate substitué et forme cristalline associée - Google Patents

Procédé de préparation de composé de borate substitué et forme cristalline associée Download PDF

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WO2019109802A1
WO2019109802A1 PCT/CN2018/116623 CN2018116623W WO2019109802A1 WO 2019109802 A1 WO2019109802 A1 WO 2019109802A1 CN 2018116623 W CN2018116623 W CN 2018116623W WO 2019109802 A1 WO2019109802 A1 WO 2019109802A1
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compound
formula
cancer
crystalline form
solvent
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Chinese (zh)
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王义汉
刘志强
赵九洋
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Shenzhen Targetrx Inc
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Shenzhen Targetrx Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the technical field of medicine, in particular to a high-purity substituted borate compound, a preparation method thereof and a crystal form, and the invention also provides a pharmaceutical composition comprising the compound of the invention, and a composition for treating various diseases. method.
  • the proteasome is a large multivalent complex enzyme involved in many important physiological and biochemical processes in the cell, such as DNA repair, cell cycle function, signal transduction, antigen presentation, protein transmembrane localization, etc. Balancing important intracellular enzymes plays a major role.
  • the function of the proteasome is achieved by the ubiquitin-proteasome pathway (UPP). UPP not only catalyzes the degradation of abnormal proteins, but also participates in many regulation and protein renewal and processing processes. The catalytic process of these proteins involves an important biochemical mechanism for the pathogenesis of human disease.
  • UPP ubiquitin-proteasome pathway
  • Proteasome inhibitors inhibit the expression of cell growth-related proteins, cytokines and signaling molecules by inhibiting the activity of proteasomes, interfering with the original proliferation, differentiation and apoptosis of cells, and inhibiting the growth of tumor cells. It is obvious.
  • Proteasome inhibitors are mainly peptide aldehydes, peptide boric acids, peptide epoxy ketones, peptide vinyl sulfones, beta lactones and other compounds.
  • the peptide borate proteasome inhibitor bortezomib (trade name VELCADE) was the first proteasome inhibitor for clinical use and was approved by the US Food and Drug Administration (FDA) in 2003 and 2006, respectively.
  • FDA US Food and Drug Administration
  • the peptide epoxiphenone peptide proteasome inhibitor Carfilzomib (trade name Kyprolis) was approved by the FDA in 2012 for the treatment of multiple myeloma and became the second marketed proteasome antitumor drug.
  • the peptide borate proteasome inhibitor Ixazomib citrate (trade name Ninlaro) was approved by the FDA in 2015 for the treatment of multiple myeloma and became the second marketed peptide borate proteasome inhibitor.
  • Listed drugs and reported boric acid proteasome inhibitors such as WO2005/021558, WO2005/016859, WO2006/086600, WO2009/02044, WO2010/012222, WO2011/109355, WO2011/026349, WO2011/087822, WO2013/092979, etc.
  • Peptide backbone proteasome inhibitors have low stability in vivo, short half-life in plasma, and rapid clearance (Miller et al. J Med Chem, 2015, 58: 2036-41).
  • the invention relates to a process for the preparation of a compound of formula (A) or a crystalline form thereof:
  • n, m are independently selected from 0 or 1; and n and m are not the same,
  • the method includes the following steps:
  • the invention relates to a compound of formula (A-1), or a crystalline form thereof, a pharmaceutically acceptable hydrate or solvate, or a pharmaceutically acceptable salt.
  • the present invention is also directed to a crystalline form of the compound of formula (A-1),
  • the present invention provides a crystalline form of the compound of formula (A-2),
  • the present invention provides a process for the preparation of a pharmaceutical composition as described above, comprising the steps of: pharmaceutically acceptable excipients with a compound of the invention, or a crystalline form, pharmaceutically acceptable hydration
  • the solvate or pharmaceutically acceptable salt is mixed to form a pharmaceutical composition.
  • the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient.
  • a compound of the invention is provided in the pharmaceutical composition in an effective amount.
  • the compounds of the invention are provided in a therapeutically effective amount.
  • the compounds of the invention are provided in a prophylactically effective amount.
  • the pharmaceutical composition is an injection, a sachet, a tablet, a pill, a powder or a granule.
  • the pharmaceutical composition further comprises an additional therapeutic agent, the additional therapeutic agent being a medicament for cancer, cardiovascular disease, inflammation, immune disease, kidney disease, angiogenesis, prostate disease.
  • the compounds can be used to treat and prevent diseases associated with proteasome targets.
  • the pharmaceutical composition is for treating and preventing a disease: cancer, cardiovascular disease, inflammation, immune disease, kidney disease, angiogenesis, or prostate disease.
  • the cancer includes, but is not limited to, multiple myeloma, non-small cell lung cancer, uterine cancer, rectum, brain cancer, head cancer, neck cancer, skin cancer, prostate cancer, breast cancer, solid tumor, solid tumor.
  • kidney cancer blood cancer, liver cancer, stomach cancer, or pancreatic cancer.
  • the invention provides a method of treatment comprising the steps of administering a compound of the invention, or a crystalline form thereof, a pharmaceutically acceptable hydrate or solvate thereof, or a A pharmaceutically acceptable salt, or a pharmaceutical composition as described in the present invention, is administered to inhibit the proteasome.
  • the disease comprises: cancer, cardiovascular disease, inflammation, immune disease, kidney disease, angiogenesis or prostate disease.
  • the cancer includes, but is not limited to, multiple myeloma, non-small cell lung cancer, uterine cancer, rectum, brain cancer, head cancer, neck cancer, skin cancer, prostate cancer, breast cancer, solid tumor, kidney cancer. , blood cancer, liver cancer, stomach cancer, or pancreatic cancer.
  • the invention relates to a process for the preparation of a compound of formula (A) or a crystalline form thereof:
  • n, m are independently selected from 0 or 1; and n and m are not the same,
  • the method includes the following steps:
  • the invention relates to a process for the preparation of a compound of formula (A-1) or a crystalline form thereof:
  • the method includes the following steps:
  • the solvent of step a) is 1,4-dioxane.
  • the reaction temperature of step a) is from 40 ° C to the boiling temperature of dioxane (101.1 ° C), preferably from 40 ° C to 80 ° C.
  • reaction temperature of step a) is 80 °C.
  • step a) is to add the compound of formula (B) and citric acid to the solvent, the reaction is stirred at 80 ° C until the starting reaction is complete.
  • step b) the solvent of step a) is removed, and ethyl acetate is added at room temperature to stir to precipitate a solid.
  • ethyl acetate is added at room temperature for 12 hours, a solid is precipitated, and suction filtration is carried out.
  • the invention relates to a process for the preparation of a compound of formula (A-2) or a crystalline form thereof:
  • the method includes the following steps:
  • the reaction temperature of step a) is from 40 ° C to the boiling temperature of the solvent, preferably from 40 ° C to, for example, 80 ° C.
  • step a) is to add the compound of formula (B) and citric acid to the solvent, and the reaction is stirred until the starting material is completely reacted.
  • step b) the solvent of step a) is removed, and ethyl acetate is added at room temperature to stir to precipitate a solid.
  • the solvent of step a) is ethyl acetate.
  • reaction temperature of step a) is 70 °C.
  • the compound of the formula (B) and citric acid are added to the solvent, the reaction is stirred at 70 ° C for 10 minutes, and the mixture is cooled to room temperature and stirred until a solid precipitates.
  • the mixture is cooled to room temperature and stirred for 12 hours, and a solid is precipitated and suction filtered.
  • the invention relates to a compound of formula (A) or a crystal thereof prepared by any of the above methods.
  • the invention relates to a compound of formula (A-1), or a crystalline form thereof, a pharmaceutically acceptable hydrate or solvate thereof, or a pharmaceutically acceptable salt
  • the invention relates to the crystalline form I of the compound of formula (A-1),
  • the X-ray powder diffraction pattern comprises the following peaks: 6.361, 8.06, 16.137, 17.56, 19.001, 20.201, 24.88, 25.358 ° 2 ⁇ ⁇ 0.2 ° 2 ⁇ , which is used at a wavelength of the diffractometer. Determination of Cu-K ⁇ radiation.
  • the invention relates to Form I of the compound of formula (A-1), characterized in that the X-ray powder diffraction pattern comprises the following peaks: 6.361, 8.06, 10.599, 14.80, 16.137, 17.56, 19.001, 20.201, 21.02, 24.88. , 25.358 ° 2 ⁇ ⁇ 0.2 ° 2 ⁇ , which uses a wavelength on the diffractometer Determination of Cu-K ⁇ radiation.
  • the invention relates to Form I of the compound of formula (A-1), characterized in that the X-ray powder diffraction pattern comprises the following peaks: 6.361, 8.06, 10.079, 10.599, 12.719, 13.356, 14.8, 15.319, 16.137, 17.119 , 17.56, 18.04, 19.001, 20.201, 21.02, 22.041, 24.88, 25.358, 26.241, 26.618, 27.901, 32.56, 33.94, 35.163 ° 2 ⁇ ⁇ 0.2 ⁇ 2 ⁇ , which is used at the wavelength of the diffractometer Determination of Cu-K ⁇ radiation.
  • the invention relates to Form I of the compound of formula (A-1), wherein said diffraction pattern is substantially as shown in Figure 1.
  • the invention relates to Form I of the compound of formula (A-1), characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 197.9 ° C and about 249.7 ° C.
  • DSC differential scanning calorimetry
  • the invention relates to Form I of the compound of formula (A-1), wherein said DSC curve is substantially as shown in Figure 2.
  • the invention relates to the crystalline form I of the compound of formula (A-2),
  • the X-ray powder diffraction pattern comprises the following peaks: 5.740, 7.517, 11.458, 19.438, 19.801 and 22.262 ° 2 ⁇ ⁇ 0.2 ° 2 ⁇ , which are used on the diffractometer at a wavelength of Determination of Cu-K ⁇ radiation.
  • the invention relates to Form I of the compound of formula (A-2), characterized in that the X-ray powder diffraction pattern comprises the following peaks: 5.740, 7.517, 11.458, 12.439, 16.5878, 19.438, 19.801, 22.262 and 22.999° 2 ⁇ ⁇ 0.2° 2 ⁇ , which uses a wavelength on the diffractometer Determination of Cu-K ⁇ radiation.
  • the invention relates to Form I of the compound of formula (A-2), characterized in that the X-ray powder diffraction pattern comprises the following peaks: 5.74, 7.517, 11.458, 11.819, 12.439, 14.278, 16.5878, 17.2, 18.119, 19.438 , 19.801, 20.279, 21.621, 22.262, 22.999, 26.34, 29.262, 29.759, 31.38, 34.2, and 34.840° 2 ⁇ ⁇ 0.2 ⁇ 2 ⁇ , which are used at the wavelength of the diffractometer Determination of Cu-K ⁇ radiation.
  • the invention relates to Form I of the compound of formula (A-2), wherein said diffraction pattern is substantially as shown in FIG.
  • the invention relates to Form I of the compound of formula (A-2), characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 224.6 ° C, about 237.0 ° C and about 253.5 ° C.
  • DSC differential scanning calorimetry
  • the invention relates to Form I of the compound of formula (A-2), wherein said DSC curve is substantially as shown in Figure 4.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (A) or a crystal thereof prepared by the preparation method described in the present invention, or formula (A-1) Compound Form I or Form I of formula (A-2).
  • the present invention relates to a compound of the formula (A) or a crystal thereof prepared by the preparation method of the present invention, or a crystalline form I of the compound of the formula (A-1) or a crystalline form I of the compound of the formula (A-2) in the preparation treatment And the use of drugs to prevent proteasome-related diseases.
  • the invention relates to a compound of formula (A) or a crystal thereof, or a crystalline form I of compound of formula (A-1), or a crystalline form I of compound of formula (A-2), prepared by the process of the invention Use in the manufacture of a medicament for the treatment and prevention of cancer, cardiovascular disease, inflammation, immune disease, kidney disease, angiogenesis or prostate disease.
  • the cancer is selected from the group consisting of multiple myeloma, non-small cell lung cancer, uterine cancer, rectum, brain cancer, head cancer, neck cancer, skin cancer, prostate cancer, breast cancer, solid tumor, kidney cancer, blood cancer. , liver cancer, stomach cancer, or pancreatic cancer.
  • Figure 1 shows X-ray powder diffraction (XRPD) of Form I of the compound of formula (A-1).
  • Figure 2 shows a differential scanning calorimetry (DSC) curve and a thermogravimetric analysis (TGA) curve for Form I of the compound of formula (A-1).
  • Figure 3 shows X-ray powder diffraction (XRPD) of Form I of the compound of formula (A-2).
  • Figure 4 shows a differential scanning calorimetry (DSC) curve and a thermogravimetric analysis (TGA) curve for Form I of the compound of formula (A-2).
  • deuterated means that one or more hydrogens in the compound or group are replaced by deuterium; deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuterated is used interchangeably with “one or more deuterated”.
  • the strontium isotope content of strontium in the deuterated position is at least 0.015%, preferably greater than 30%, more preferably greater than 50%, and even more preferably greater than 75%, more preferably greater than the natural strontium isotope content.
  • the ground is greater than 95%, more preferably greater than 99%.
  • non-deuterated compound means a compound containing a proportion of germanium atoms not higher than the natural helium isotope content (0.015%).
  • the term "independently selected from” is that a plurality of groups are respectively selected from certain substituents, and each group is not related to each other, for example, "m, n is independently selected from 0 or 1", meaning m It is selected from 0 or 1, n is selected from 0 and 1, and there is no correlation between m and n.
  • compound of the invention refers to a compound of formula (I).
  • the term also encompasses various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (I).
  • pharmaceutically acceptable salt means that it is suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergies, etc., and with reasonable benefits, within the scope of sound medical judgment. / Those dangerous proportions of those salts.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., pharmaceutically acceptable salts as described in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and inorganic and organic bases.
  • non-toxic acid addition salts examples include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or salts with organic acids such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Also included are salts formed using conventional methods in the art, for example, ion exchange methods.
  • adipic acid salts alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphor Acid salt, camphor sulfonate, citrate, cyclopentanoate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerol Phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate , malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate Salt, pectin
  • Pharmaceutically acceptable salts derived from suitable bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like.
  • other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed with counterions, counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, Nitrate, lower alkyl sulfonate and aryl sulfonate.
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio.
  • Hydrophilate means a complex formed by the coordination of a compound of the invention with water.
  • the invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein.
  • isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. , 31 P, 32 P, 35 S, 18 F and 36 Cl. a compound, or an enantiomer, a diastereomer, an isomer, or a pharmaceutically acceptable salt or solvate of the present invention, wherein an isotope or other isotopic atom containing the above compound is within the scope of the present invention .
  • isotopically-labeled compounds of the present invention such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates. ⁇ , ie 3 H and carbon-14, ie 14 C, are easier to prepare and detect and are preferred in isotopes.
  • Isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • HBTU O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate
  • HCTU 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate
  • TCTU O-(6-chlorobenzotriazol-1-yl)-1,1,3,3-N,N,N',N'-tetramethyluronium tetrafluoroborate
  • HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • DIPEA N,N-diisopropylethylamine
  • Typical embodiments of the compounds according to the invention can be synthesized using the general reaction schemes described below. As will be apparent from the description herein, the general scheme can be altered by replacing the starting materials with other materials having similar structures to produce correspondingly different products. Given the desired product in which the substituent is defined, the desired starting material can usually be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. To synthesize the compounds of the embodiments of the present disclosure, detecting the structure of the compound to be synthesized will provide for the identification of each substituent. In view of the examples herein, the nature of the final product will typically reveal the characteristics of the desired starting materials through a simple inspection process.
  • the compounds of the present disclosure can be prepared from readily available starting materials using, for example, the general methods and procedures below. It should be understood that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can be used unless otherwise stated. Optimum reaction conditions can vary with the particular reactants or solvents employed, but one skilled in the art can determine the conditions by routine optimization procedures.
  • the compounds of the present disclosure may contain one or more chiral centers.
  • the compound can be prepared as a pure stereoisomer or isolated as a pure stereoisomer, either as a separate enantiomer or diastereomer or as a stereoisomeric A mixture of rich bodies. All such stereoisomers (and enriched mixtures) are included within the scope of the invention unless otherwise stated. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optional active starting materials or stereoselective reagents well known in the art. Alternatively, the racemic mixture of the compound can be isolated using, for example, chiral column chromatography, chiral resolving agents, and the like.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known methods or by obvious modifications thereof.
  • many starting materials are available from commercial suppliers such as Shanghai Tebo Chemical Technology Co., Ltd. (Shanghai, China), Saen Chemical Technology (Shanghai) Co., Ltd. (Shanghai, China), Shanghai Houyi Chemical Technology Co., Ltd. (Shanghai, China) ), Shanghai Jinlu Pharmaceutical Technology Co., Ltd. (Shanghai, China), Anhui Dexinjia Biomedical Co., Ltd. (Anhui, China), Tianjin Famosi Pharmaceutical Technology Co., Ltd. (Tianjin, China), Hunan Hezhong Pharmaceutical Technology Co., Ltd. (Hunan, China) ).
  • reaction products from each other and/or from the starting materials.
  • the desired product of each step or series of steps is separated and/or purified (hereinafter referred to as separation) by the techniques common in the art to the desired degree of homogeneity.
  • separations include multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation or chromatography.
  • Chromatography can include any number of methods including, for example, reverse phase and normal phase chromatography; size exclusion chromatography; ion exchange chromatography; high, medium and low pressure liquid chromatography and equipment; small scale analytical chromatography; Bed (SMB) and preparative thin or thick layer chromatography, as well as small-scale thin layer and flash chromatography techniques.
  • Another type of separation process involves treating the mixture with an agent that is selected to bind or separate from the product, unreacted starting materials, reaction byproducts, and the like.
  • agents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, and the like.
  • the reagent may be an acid (in the case of a basic substance), a base (in the case of an acidic substance), a binding reagent such as an antibody, a binding protein, a selective chelating agent such as a crown ether, a liquid/liquid example extraction reagent (LIX). )Wait.
  • a single stereoisomer, such as an enantiomer, substantially free of its stereoisomers can be obtained by resolution of the externally-spinning mixture, for example, using optically active resolving agents to form diastereomeric Method of conformation (Stereochemistry of Carbon Compounds, (1962), EL Eliel, McGraw Hill; Lochmuller, CH, (1975) J. Chromatogr., 113: (3) 283-302).
  • the racemic mixture of the chiral compound of the present invention can be isolated and resolved by any suitable method, including: (1) formation of an ionic diastereomeric salt with a chiral compound, and fractional crystallization Or other methods of separation; (2) formation of diastereomeric compounds with chiral derivatization reagents, separation of diastereomers, and conversion to pure stereoisomers; and (3) direct in chiral conditions Substantially pure or enriched stereoisomers are separated.
  • the present disclosure provides, in some embodiments, a method of preparing a compound of formula (A).
  • the present invention provides a process for the preparation of the compound of formula (A) or a crystalline form thereof,
  • n, m are independently selected from 0 or 1; and n and m are not the same,
  • the method includes the following steps:
  • n and m are independently selected from 0 or 1; and n and m are not the same.
  • the reaction conditions of step a) comprise a solvent, preferably the solvent is selected from the group consisting of methyl isobutyl ketone, acetone, acetonitrile, 2-methyltetrahydrofuran, anisole, ethyl acetate, isopropyl acetate, Dimethoxyethane, tetrahydrofuran, dioxane, dichloromethane, toluene, heptane, methyl-cyclohexane, ethylene glycol dimethyl ether, tert-butyl methyl ether, and mixtures thereof; more preferably, the solvent is Dioxane; more preferably, the solvent is ethyl acetate.
  • the reaction conditions of step a) are carried out at a temperature of from about 40 ° C to about the boiling temperature of the solvent (preferably from about 40 ° C to about 80 ° C); more preferably, the temperature is about 80 ° C; more preferably The temperature is 70 °C.
  • the Applicant has unexpectedly found that for the deuterated compound of the present invention (the compound of the formula (B)), it is difficult to form the compound of the formula (A-1) according to the method of the prior art.
  • the reaction solution was slowly cooled to about 60 ° C and reacted for 3 hours, and then cooled to 25 ° C at a rate of 0.12 ° C / min, and only the compound of the formula (A-2) was obtained.
  • Applicants have also tried a variety of other solvents, all of which also give compounds of formula (A-2).
  • the reaction solvent of step a) is selected from the group consisting of methyl isobutyl ketone, acetone, acetonitrile, 2-methyltetrahydrofuran, anisole, ethyl acetate, isopropyl acetate, dimethoxy
  • the compound of the formula (B) is reacted with citric acid to form a formula Compound of (A-2).
  • reaction solvent of step a) is a dioxane such as 1,4-dioxane
  • the compound of formula (B) reacts with citric acid to form A compound of the formula (A-1).
  • the above method for preparing a compound of formula (A) or a crystalline form thereof of the present invention further comprises the steps of:
  • the reaction conditions of step c) comprise an organoboron reagent; preferably, the organoboron reagent is isobutylboronic acid.
  • the reaction conditions of step c) comprise a lower alkanol; preferably, the lower alkanol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol or pentane Alcohol; more preferably, the lower alkanol is methanol.
  • the reaction conditions of step c) comprise an aqueous mineral acid solution; preferably, the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid; more preferably, the inorganic acid is selected from the group consisting of hydrochloric acid.
  • the above method for preparing a compound of formula (A) or a crystalline form thereof of the present invention further comprises the steps of:
  • the reaction conditions of step d) comprise a peptide coupling reagent; preferably, the peptide coupling reagent is selected from the group consisting of EDC and HOBT, TBTU, DCC and HOBT, HBTU, HCTU, TCTU, HATU or PyBOP; more preferably, the peptide
  • the coupling reagent is selected from the group consisting of TBTU, HBTU, HCTU, TCTU, HATU; most preferably, the peptide coupling reagent is TBTU.
  • the reaction conditions of step d) comprise a base; preferably, the base is selected from the group consisting of NMM, TEA, and DIPEA; more preferably, the base is selected from the group consisting of DIPEA.
  • the reaction conditions of step d) comprise a solvent; preferably, the solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, toluene, benzene, acetonitrile, dioxane, and N,N-dimethylformamide, or a mixture of the above
  • the reaction conditions of step d) are carried out at a temperature of from about -20 ° C to about 50 ° C; preferably, the temperature is selected from about -20 ° C to about 10 ° C; more preferably, the temperature is 0 ° C.
  • the above method for preparing a compound of formula (A) or a crystalline form thereof of the present invention further comprises the steps of:
  • the reaction conditions of step e) comprise a base; preferably, the base is selected from the group consisting of NaOH and KOH; more preferably, the base is NaOH.
  • the reaction conditions of step e) comprise a solvent; preferably, the solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, acetone, DMF, and DMSO; more preferably, the solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, and DMF; most preferably, the solvent is selected from the group consisting of tetrahydrofuran.
  • the above method for preparing a compound of formula (A) or a crystalline form thereof of the present invention further comprises the steps of:
  • the reaction conditions of step f) comprise a chlorinating agent; preferably, the chlorinating agent is selected from the group consisting of thionyl chloride, oxalyl chloride, PCl 3 or PCl 5 with or without DMF; more preferably, chlorine
  • the catalyzing agent is selected from thionyl chloride or oxalyl chloride; most preferably, the chlorinating agent is selected from the group consisting of thionyl chloride.
  • the present invention provides a crystalline form of a compound of formula (A-1) and a compound of formula (A-2) as specified herein.
  • Crystalline Form (A-1) Compound Form I is characterized by an X-ray powder diffraction pattern comprising the following peaks: 6.361, 8.06, 10.079, 10.599, 12.719, 13.356, 14.8, 15.319, 16.137, 17.119, 17.56, 18.04, 19.001 , 20.201, 21.02, 22.041, 24.88, 25.358, 26.241, 26.618, 27.901, 32.56, 33.94, 35.163 ° 2 ⁇ 0.2 ⁇ 2 ⁇ , which is passed through a diffractometer using Cu-K ⁇ radiation Determination of the wavelength.
  • the crystalline form I of the compound of formula (A-1) is also characterized by its full X-ray powder diffraction pattern substantially as shown in FIG.
  • the crystalline form I of the compound of formula (A-1) is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 197.9 °C, and an endotherm at about 249.7 °C.
  • DSC differential scanning calorimetry
  • Form I of the compound of formula (A-1) is also characterized by a DSC curve substantially as shown in FIG.
  • Crystalline Form (A-2) Compound Form I is characterized by an X-ray powder diffraction pattern comprising the following peaks: 5.74, 7.517, 11.458, 11.819, 12.439, 14.278, 16.5878, 17.2, 18.119, 19.438, 19.801, 20.279, 21.621 , 22.262, 22.999, 26.34, 29.262, 29.759, 31.38, 34.2, and 34.840° 2 ⁇ ⁇ 0.2 ⁇ 2 ⁇ , which are passed through a diffractometer using Cu-K ⁇ radiation. Determination of the wavelength.
  • the crystalline form I of the compound of formula (A-2) is also characterized by its full X-ray powder diffraction pattern substantially as shown in FIG.
  • the crystalline form I of the compound of formula (A-2) is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm at about 224.6 ° C and 237.0 ° C, and an endotherm at about 253.5 ° C.
  • DSC differential scanning calorimetry
  • Form I of the compound of formula (A-2) is also characterized by a DSC curve substantially as shown in FIG.
  • the compound of the present invention has an excellent inhibitory activity against the proteasome
  • the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable hydrates or solvates thereof, or pharmaceutically acceptable salts, and compounds containing the present invention are mainly Pharmaceutical compositions of the active ingredients are useful for the treatment, prevention, and alleviation of diseases mediated by the proteasome.
  • the compounds of the invention are useful in the treatment of diseases such as cancer, cardiovascular disease, obesity, diabetes and the like.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 10 to 200 mg of the compound of the invention per agent.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity.
  • “compatibility” it is meant herein that the components of the composition are capable of blending with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • carrier used interchangeably herein and include any and all solvents, diluents and other liquid carriers, dispersion or suspension aids, surfactants, pH adjusters, Isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc., are suitable for the particular dosage form desired.
  • any conventional carrier medium is incompatible with a compound of the invention, for example, by causing any undesirable biological effects or interaction with any other component of the pharmaceutical composition to render the compound ineffective or ineffective, or to produce a hazardous substance, its use is It is considered to be within the scope of the invention.
  • Pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, carbonates, magnesium hydroxide and aluminum glycine, Sorbic acid or potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, no heat source water, salts or electrolytes such as protamine sulfate, disodium phosphate, disodium hydrogen phosphate, sodium chloride and zinc salts, colloidal dioxide Silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, polyethylene-polyoxypropylene block polymer, lanolin, sugars such as lactose, glucose, sucrose and mannitol, starches such as corn starch and potato starch, cellulose And derivatives thereof such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate, powdered yellow gum: malt, gelatin,
  • compositions of the present invention can be prepared by methods well known in the art, such as conventional granulation, mixing, dissolving, encapsulating, lyophilizing or emulsifying methods and the like.
  • the compositions can be produced in a variety of forms including granules, pellets or granules, powders, including freeze-dried, spin-dried or spray-dried powders, amorphous powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, mashes, and mixtures. Suspending agent or solution.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and according to a preferred embodiment, the composition of the present invention is formulated for administration to a mammal, preferably to a human.
  • These pharmaceutical compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implantable kit.
  • the term "digestive administration" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic and intracranial injection or infusion techniques.
  • the composition is administered orally, intravenously or subcutaneously.
  • the formulations of the invention can be designed to be short acting, fast release or long lasting. Additionally, the compounds can be administered in a local rather than systemic manner, such as at the site of a tumor (eg, by injection).
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzyl benzoate, propylene glycol, 1,3-butanediol, cyclodextrin, dimethylformamide, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin , tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters, sorbitan and mixtures thereof.
  • the oral compositions may also contain adj
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or solubilizer, for example, starch , lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example , glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) slow solvent, such as paraffin; (f) absorption acceleration Agents, for example, quaternary amine compounds; (g) lubricants, for example,
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • Injectable preparations for example, sterile injectable aqueous or oily suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, a compound sodium chloride injection, and an isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium, and any of the ⁇ RTIgt; Further, a fatty acid such as oleic acid is used for the preparation of an injection.
  • the injectables can be sterilized by, for example, filtration by bacteria or by incorporation of a sterilizing agent in the form of a sterile solid composition which is dissolved or dispersed in sterile water or other sterile injectables before use. In the medium.
  • Compositions formulated for parenteral administration may be administered by bolus injection or by timed bolus injection, or may be administered by continuous infusion.
  • Dosage forms for topical or transdermal administration of a compound of the invention include ointments, powders, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives or buffers which may be required.
  • Ophthalmic formulations, ear drops and eye drops are also considered to be within the scope of the invention.
  • the present invention contemplates the use of transdermal patches that have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the invention provides pharmaceutical compositions of the compounds and other excipients described herein. In some other embodiments, the invention provides a pharmaceutical composition of a compound of formula (A) and other excipients described herein.
  • the pharmaceutical formulations of the present invention are prepared by using excipients having low or low moisture content and using dry or non-aqueous formulation methods to provide a stable solid oral dosage form of the active compound.
  • the present invention provides a method of preventing and/or treating a condition associated with proteasome mediated (such as cancer, cardiovascular disease, inflammation, immune disease, kidney disease, angiogenesis, or prostate), which comprises the steps of: providing The subject to be treated administers a compound of the invention, or a crystalline form thereof, a pharmaceutically acceptable hydrate or solvate thereof, or a pharmaceutically acceptable salt, or a pharmaceutical composition of the invention.
  • proteasome-mediated condition includes any condition, disease or condition caused by or increased by proteasome expression or activity, or which requires proteasome activity.
  • proteasome-mediated condition also includes any condition, disease or condition in which inhibition of proteasome activity is advantageous.
  • the present invention compounds and pharmaceutical compositions useful for treating regulated by proteasome activity of a protein (e.g., NFkB, p27 kip, p21 WAF / CIPI, p 53) mediated disorders.
  • Related conditions include inflammatory conditions (eg rheumatoid arthritis, inflammatory bowel disease, asthma, chronic obstructive pulmonary disease (COPD), osteoarthritis, skin diseases (eg atopic dermatitis, psoriasis)), vascular proliferative disorders (eg, atherosclerosis, restenosis), proliferative eye disease (eg, diabetic retinopathy), benign proliferative disorders (eg, hemangiomas), autoimmune diseases (eg, multiple sclerosis, tissue and organ rejection), and infections
  • inflammation eg, immune response
  • neurodegenerative disorders eg, Alzheimer's disease, Parkinson's disease, motor neuron disease, neuropathic pain, triplet repeat disease, astrocytoma, and
  • cancer refers to a cell characteristic characterized by uncontrolled or regulated abnormal cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissues, and/or the ability to establish a new body at an ectopic site. Illness.
  • the term cancer includes, but is not limited to, solid tumors and blood-borne tumors.
  • the term cancer encompasses diseases of the skin, tissues, organs, bones, cartilage, blood and blood vessels.
  • the term cancer further encompasses primary and metastatic cancer.
  • Non-limiting examples of solid tumors that can be treated with the disclosed proteasome inhibitors or pharmaceutical compositions include multiple myeloma, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer (including metastatic breast cancer), prostate cancer (including male) Hormone-dependent and androgen-independent prostate cancer), renal cancer (including metastatic renal cell carcinoma), hepatocellular carcinoma, lung cancer (including non-small cell lung cancer, bronchioloalveolar carcinoma, lung adenocarcinoma, ovarian cancer) Sexual epithelium or primary peritoneal cancer), cervical cancer, stomach cancer, head and neck cancer (including squamous cell carcinoma of the head and neck, melanoma, neuroendocrine cancer (including metastatic neuroendocrine tumors), brain tumors (including nerve glue) Tumor, anaplastic oligodendroglioma, adult glioblastoma multiforme and adult anaplastic astrocytoma, bone cancer and soft tissue sarcoma.
  • breast cancer including metastatic breast
  • Non-limiting examples of hematologic malignancies that can be used in the disclosed proteasome inhibitors or pharmaceutical compositions include dosage form myeloid leukemia (AML); chronic myelogenous leukemia (CML), including accelerated CML and CML blast phase (CML-BP) Acute lymphoblastic leukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease (HD); non-Hodgkin's lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma B-cell lymphoma; T-cell lymphoma; multiple myeloma; Waldenstrom's macroglobulinemia; myelodysplastic syndrome (MDS), including refractory anemia (RA), with a ring Refractory anemia of iron red blood cells (RARS), refractory anemia with blasts (RAEB) and RAEB (RAEB-T) in transition; and myeloproliferative syndrome.
  • AML
  • a compound or pharmaceutical composition of the invention is for use in treating a patient having or at risk of developing or experiencing a recurrence of a cancer selected from the group consisting of multiple myeloma and mantle cell lymphoma Group.
  • a compound or pharmaceutical composition of the invention is administered in combination with other therapeutic agents.
  • the other therapeutic agents can also inhibit the proteasome or be manipulated by different mechanisms.
  • other therapeutic agents are typically administered to a therapeutic agent in a patient having the disease or condition being treated.
  • the proteasome inhibitors of the invention can be administered in a single dosage form or in separate dosage forms with other therapeutic agents. When administered in separate dosage forms, other therapeutic agents can be administered prior to, concurrently with, or subsequent to administration of the proteasome inhibitor of the present invention.
  • a proteasome inhibitor of formula (A) or a pharmaceutical composition of a compound of formula (A) is administered in combination with an anticancer agent.
  • an anticancer agent refers to any agent that is administered to an individual having cancer for the purpose of cancer.
  • the compounds of the invention may be combined with a medicament for the treatment of cancer, cardiovascular disease, inflammation, immune disease, kidney disease, angiogenesis, prostate disease.
  • the therapeutic agents include, but are not limited to, 5-fluorouracil, AV412, avastin(abstin, bevacizumab), bexarotene, bortezomib, calcitriol ( Calcitriol), canertinib, capecitabine, carboplatin, celecoxib, cetuximab, CHR-2797, cisplatin ), dasatinib, digoxin, enzastaurin, erlotinib, etoposide, everolimus, fulvestrant, Gefitinib, 2,2-difluorodeoxycytidine (gemcitabine), genistein, imatinib, irinotecan, rapa Latatinib, lenalidomide, letrozole, leu
  • the compounds of the present invention can be prepared using the methods disclosed herein and in routine variations that are apparent from the present disclosure, as well as methods well known in the art. In addition to the teachings herein, conventional well-known synthetic methods can also be used. The synthesis of the compounds described herein can be accomplished as described in the Examples below. If commercially available, the reagents can be purchased commercially, for example, from Saan Chemical Technology (Shanghai) Co., Ltd. or other chemical suppliers. Starting materials for the following reactions can be obtained from commercial sources unless otherwise stated.
  • Chlorinated compound (G) forms compound (F)
  • Compound (B) reacts with citric acid to form compound (A-1)
  • Compound (A-2) can also be produced by the following method:
  • the crystalline form of the compound (A) was analyzed by XRPD, DSC and TGA.
  • the XRPD pattern was collected using a PANalytical X'Pert PRO MPD diffractometer, using the following experimental setup: 40 kV, 40 mA, The scan range is 4-40°2 ⁇ , and the step size is 0.02°2 ⁇ .
  • DSC analysis was performed on a NETZSCH STA 449F3 STA449F3A-1029-M differential scanning calorimeter-thermogravimetric analyzer using a sample of about 3 to 6 mg at a heating rate of 10 ° C/min in the range of 25 ° C to 400 ° C. And TGA analysis.
  • the crystalline form I of the compound of the formula (A-1) was prepared as in Example 1 to give a crystalline form as an ethyl acetate solvent system.
  • Form I of the compound of formula (A-1) is characterized by XRPD, DSC and TGA.
  • the XRPD pattern is shown in Figure 1, and the XRPD pattern analysis data is shown in Table 1.
  • the TGA showed no weight loss below about 50 °C, and a weight loss of about 0.9% was observed at about 50 ° C to about 200 ° C, followed by decomposition (Figure 2).
  • the DSC thermogram shows a sharp endotherm at about 197.9 °C and then a sharp endotherm at about 249.7 °C ( Figure 2).
  • the crystalline form I of the compound of the formula (A-2) was prepared as in Example 1 to give a crystalline form in an ethyl acetate solvent system.
  • Form I of the compound of formula (A-2) is characterized by XRPD, DSC and TGA.
  • the XRPD pattern is shown in Figure 3, and the XRPD pattern analysis data is shown in Table 2.
  • TGA showed no weight loss below about 50 °C, and a weight loss of about 0.9% was observed at about 50 ° C to about 200 ° C, followed by decomposition (Figure 4).
  • the DSC thermogram shows a sharp endotherm at about 224.6 ° C, 237.0 ° C, and then a sharp endotherm at about 253.5 ° C ( Figure 4).
  • the in vitro antiproliferative activity of the compounds of the present invention against tumor cells cultured in vitro was examined by the MTS method.
  • Cell line Myeloma cells MM.1s (purchased from the American Standard Collection of Biological Products (ATCC)) were cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100 U/ml penicillin, and 100 ⁇ g/ml streptomycin.
  • Reagents and consumables RPMI-1640 (GIBCO, catalog number A10491-01); fetal bovine serum (GIBCO, catalog number 10099141); 0.25% trypsin-EDTA (GIBCO, catalog number 25200); penicillin-streptomycin; GIBCO, Cat. No. 15140-122); DMSO (Sigma, Cat. No. D2650); MTS Test Kit (Promega, Cat. No. G3581), 96-well plate (Corning, Cat. No. 3365).
  • test compound preparation The test compound was dissolved in DMSO to prepare a 20 mM mother liquor and stored at -20 °C. Dilute 3 times with a gradient of DMSO and the like, and dilute 10 times. The drug medium was diluted 4 times with the drug.
  • MTS cell viability assay 0.25% trypsin-EDTA digested logarithmic growth phase cells, inoculated with 150 ⁇ l in 96-well plates at an optimized density, and added to the medium 4 times after dilution for 4 hours, 50 ⁇ l/well (generally 10 Concentrations: 100, 33.3, 11.1, 3.70, 1.23, 0.412, 0.137, 0.0457, 0.0152, 0.00508 ⁇ M). A well of the same volume of 0.5% DMSO was added as a control. After the cells were cultured for 72 hours, MTS was assayed for cell viability.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).
  • phosphate buffer 100 mM, pH 7.4.
  • the pH of the solution was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 ⁇ L of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 ⁇ L of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • the metabolic stability of human and rat liver microsomes was evaluated by comparing the compounds of formula (A) of the present invention and their compound Ixazomib without deuteration.
  • the half-life of the compound of formula (A-1) and the compound of formula (A-2) was significantly longer than Ixazomib, and the clearance rate was also significantly less than that of Ixazomib.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at the last time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube, indicating the name and time of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.
  • the medicament of the present invention may take, but is not limited to, the following pharmaceutical composition:
  • Dosage per unit dose (mg) Dosage (%w/w or w/w) Compound of formula (A) 4 1.3 Silicified microcrystalline cellulose 292.4 97.5 talcum powder 0.6 0.2 Magnesium stearate 3 1 Content weight 300 100
  • Dosage per unit dose (mg) Dosage (%w/w or w/w) Compound of formula (A) 4 1.3 Microcrystalline cellulose 231.8 77.8 Pregelatinized starch 60 20 Silica 1.2 0.1 Magnesium stearate 3 1 Content weight 300 100
  • Dosage per unit dose (mg) Dosage (%w/w or w/w) Compound of formula (A) 4 1.3 Microcrystalline cellulose 246.8 82.3 Mannitol 45 15 talcum powder 1.2 0.4 Magnesium stearate 3 1 Content weight 300 100
  • Dosage per unit dose (mg) Dosage (%w/w or w/w) Compound of formula (A) 3 1.5 Mannitol 120 60 lactose 45 37.5 Magnesium stearate 2 1 Content weight 200 100
  • Dosage per unit dose (mg) Dosage (%w/w or w/w) Compound of formula (A) 3 1.5 Mannitol 100 50 Microcrystalline cellulose 95 47.5 Magnesium stearate 2 1 Content weight 200 100
  • Dosage per unit dose (mg) Dosage (%w/w or w/w) Compound of formula (A) 2.3 1.15 Silicified microcrystalline cellulose 155 77.5 Mannitol 40 20 talcum powder 0.7 0.35 Magnesium stearate 2 1 Content weight 200 100
  • the above pharmaceutical composition was uniformly mixed in a usual manner, and then placed in an opaque white gelatin capsule.
  • the "compound of the formula (A)” includes the compound (A-1) and the compound (A-2).
  • the present invention relates to the following technical solutions:
  • n, m are independently selected from 0 or 1; and n and m are not the same,
  • the method includes the following steps:
  • reaction temperature of step a) is from 40 ° C to 101.1 ° C.
  • reaction temperature of step a) is 80 °C.
  • step a) is to add the compound of formula (B) and citric acid to the solvent, and the reaction is stirred at 80 ° C until the starting reaction is complete.
  • step b) removes the solvent of step a), and adds ethyl acetate at room temperature to stir to precipitate a solid.
  • step b) ethyl acetate is added at room temperature for 12 hours, and a solid is precipitated and suction filtered.
  • reaction solvent of step a) comprises methyl isobutyl ketone, acetone, acetonitrile, 2-methyltetrahydrofuran, anisole, ethyl acetate, isopropyl acetate, dimethyl Oxyethane, tetrahydrofuran, dichloromethane, toluene, heptane, methyl-cyclohexane, ethylene glycol dimethyl ether, methyl tert-butyl ether, and mixtures thereof,
  • the product of formula (A) is a compound of formula (A-2)
  • reaction temperature of step a) is from 40 °C to 80 °C.
  • step a) is to add the compound of the formula (B) and citric acid to the solvent, and the reaction is stirred until the starting material is completely reacted.
  • step b) removes the solvent of step a), and adds ethyl acetate at room temperature to stir to precipitate a solid.
  • reaction temperature of step a) is 70 °C.
  • a compound of formula (A) or a crystal thereof prepared by the process of any one of claims 1-16.
  • the X-ray powder diffraction pattern comprises the following peaks: 6.361, 8.06, 16.137, 17.56, 19.001, 20.201, 24.88, 25.358 ° 2 ⁇ ⁇ 0.2 ° 2 ⁇ , which is used at a wavelength of the diffractometer. Determination of Cu-K ⁇ radiation.
  • the X-ray powder diffraction pattern comprises the following peaks: 5.740, 7.517, 11.458, 19.438, 19.801 and 22.262 ° 2 ⁇ ⁇ 0.2 ° 2 ⁇ , which are used on the diffractometer at a wavelength of Determination of Cu-K ⁇ radiation.
  • DSC differential scanning calorimetry
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the formula (A) as described in claim 17 or a crystal thereof, a compound of the formula (A-1) of the technical scheme 18, or a technical solution 19
  • the crystalline form I of the compound of the formula (A-1), or the crystalline form I of the formula (A-2) according to any one of claims 25 to 30.
  • cancer is selected from the group consisting of multiple myeloma, non-small cell lung cancer, uterine cancer, rectum, brain cancer, head cancer, neck cancer, skin cancer, prostate cancer, breast cancer, and entity. Tumor, kidney cancer, blood cancer, liver cancer, stomach cancer, or pancreatic cancer.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé de formule (A), une forme cristalline associée, et une préparation correspondante. La présente invention concerne également une composition pharmaceutique comprenant le composé de formule (A) et une méthode de traitement d'une maladie liée au protéasome par l'utilisation de la composition.
PCT/CN2018/116623 2017-12-05 2018-11-21 Procédé de préparation de composé de borate substitué et forme cristalline associée Ceased WO2019109802A1 (fr)

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