WO2022166792A1 - 苯并氮杂卓衍生物的盐、溶剂合物、多晶型物、制备方法及应用 - Google Patents

苯并氮杂卓衍生物的盐、溶剂合物、多晶型物、制备方法及应用 Download PDF

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WO2022166792A1
WO2022166792A1 PCT/CN2022/074486 CN2022074486W WO2022166792A1 WO 2022166792 A1 WO2022166792 A1 WO 2022166792A1 CN 2022074486 W CN2022074486 W CN 2022074486W WO 2022166792 A1 WO2022166792 A1 WO 2022166792A1
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compound
formula
angle
crystal form
acetic acid
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French (fr)
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付敏
刘晓斌
赵坤
蔡丽朋
古亮
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上海迪诺医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to salts, solvates, polymorphs, preparation methods and applications of benzazepine derivatives.
  • TLRs Toll-like receptors
  • Regulatory T cells have a potent immune response suppressing ability and are a major obstacle to effective cancer immunotherapy.
  • the TLR8 signaling pathway was shown to be a necessary and sufficient condition to reverse the suppressive function of Treg cells leading to strong tumor suppression.
  • TLR8 selective agonists potently activate a variety of immune cells, including mDCs and monocytes (Gorden, et al, 2005), and promote the generation of adaptive immune responses against cancer cells (Krug, et al, 2003; Schnurr, et al, 2005).
  • Activated mDCs engulf apoptotic and dying tumor cells, and then, more efficiently cross-present tumor-associated antigens to CD8 + CTLs than pDCs (Berard, et al, 2000; Dalgaard, et al, 2005).
  • activation of mDCs resulting in the release of TNF ⁇ and interleukin 12 (IL-12), can stimulate the activation of T cells and NK cells.
  • IL-12 interleukin 12
  • ADCC antibody-mediated cytotoxicity
  • TLR8 agonists can directly exert anti-tumor effects independent of its immunomodulatory function (Ignatz-Hoover, et al, 2015). Therefore, TLR8 agonists can not only act as monotherapy, but also improve the efficacy of various chemotherapy and targeted anticancer drugs by enhancing the host immune response.
  • TLR7 and TLR8 have high homology, and can recognize some artificially synthesized small molecules with antiviral effects, such as Imidazoquinolines imidazoquinoline small molecule compounds (ligands of TLR7 and TLR8) .
  • Imidazoquinolines were studied in a guinea pig genital herpes model infected with HSV, and it was found that the compound had little effect on virus replication in vitro, but had a strong effect in vivo, indicating that these compounds promote immune cells to produce pro-inflammatory factors and regulate cytokines , leading to an antiviral response (Int Immunopharmacol 2002;2:443-451).
  • TLR7 and TLR8 can recognize viral ssRNA.
  • ssRNA viruses are natural ligands for TLR7 and TLR8, such as human immunodeficiency virus type I (HIV), influenza virus, Sendai virus, dengue virus, Newcastle disease virus (NDV), vesicular stomatitis virus (VSV), Hepatitis B virus (HBV) and Hepatitis C virus (HCV).
  • HAV human immunodeficiency virus type I
  • influenza virus Sendai virus
  • NDV Newcastle disease virus
  • VSV vesicular stomatitis virus
  • HBV Hepatitis B virus
  • HCV Hepatitis C virus
  • TLR8 can recognize antiviral compounds, ssRNA viruses, synthetic oligonucleotides, etc., induce Th1 through MyD88-dependent signaling pathway, inhibit Th2 cytokine secretion and Tregs proliferation, mediate antiviral immunity, and exert anti-infection and anti-allergic effects.
  • the present invention provides a benzoazepine derivative Compound: 2-amino-8-(2-(2-(methylsulfonyl)ethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N,N-diisopropyl -3H-benzazepine-4-carboxamide salts, solvates, polymorphs, preparation methods and applications.
  • the crystal form obtained by the present invention has better solubility and stability, and is more suitable for the preparation and storage of pharmaceutical preparations.
  • the present invention provides compounds represented by formula (I):
  • X is H 2 O, CH 3 CH 2 OH, CH 3 C(O)OH, CH 3 C(O)OCH 2 CH 3 , CH 3 C(O)CH 3 or (CH 3 ) 2 CHOH;
  • the X is preferably H 2 O, CH 3 CH 2 OH or CH 3 C(O)OH, more preferably H 2 O.
  • n can be 0 or 1, preferably 1.
  • the m may be 0, 1, 1.5, 2, 2.5 or 3, preferably 0, 1, 1.5 or 2, more preferably 1, 1.5 or 2.
  • n is 1 and m is 1.5 or 2; alternatively, n is 0 and m is 1 or 2.
  • n 1 and m is 0.
  • the compound represented by the formula (I) is selected from any of the following compounds:
  • the crystalline form of the compound represented by formula (I) is hydrochloride hydrate crystal form I; using Cu-K ⁇ radiation , which has an X-ray powder diffraction pattern expressed in 2 ⁇ angles with diffraction peaks at 9.8 ⁇ 0.2°, 10.5 ⁇ 0.2°, 17.4 ⁇ 0.2°, 19.7 ⁇ 0.2° and 22.7 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the hydrochloride hydrate Form I may also have diffraction peaks at one or more of the following 2 theta angles: 7.1 ⁇ 0.2°, 12.5 ⁇ 0.2°, 14.0 ⁇ 0.2°, 15.7 ⁇ 0.2°, 18.0 ⁇ 0.2° and 20.3 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the hydrochloride hydrate Form I expressed at 2 theta angles, also has diffraction peaks at one or more of the following 2 theta angles: 12.9 ⁇ 0.2°, 21.5 ⁇ 0.2°, 22.0 ⁇ 0.2°, 25.2 ⁇ 0.2°, 26.0 ⁇ 0.2°, 26.8 ⁇ 0.2° and 29.3 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the hydrochloride hydrate Form I expressed at 2 theta angles, also has diffraction peaks at one or more of the following 2 theta angles: 18.7 ⁇ 0.2°, 19.0 ⁇ 0.2°, 24.8 ⁇ 0.2°, 29.9 ⁇ 0.2° and 34.1 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the hydrochloride hydrate crystal form I expressed at 2 ⁇ angle, its diffraction peaks and relative intensities can also be shown in the following table:
  • the X-ray powder diffraction pattern at 2 theta angles of the hydrochloride hydrate Form I can also be substantially as shown in FIG. 18 using Cu-K ⁇ radiation.
  • the differential scanning calorimetry (DSC) of the hydrochloride hydrate Form I has an absorption peak at 136.3 ⁇ 5°C (eg, 136.3 ⁇ 3°C).
  • the differential scanning calorimetry of the hydrochloride hydrate Form I can also be substantially as shown in FIG. 19 .
  • thermogravimetric analysis profile of the hydrochloride hydrate Form I has a weight loss between 70°C and 100°C, and the weight loss may be 6 ⁇ 0.5% (eg, 6 ⁇ 0.2%).
  • thermogravimetric analysis plot (TGA) of the hydrochloride hydrate Form I can also be substantially as shown in FIG. 20 .
  • the crystalline form of the compound represented by formula (I) is hydrochloride acetic acid solvate crystalline form I;
  • the X-ray powder diffraction pattern of the hydrochloride acetic acid solvate Form I in 2 theta angles is also substantially as shown in FIG. 16 using Cu-K ⁇ radiation.
  • the crystalline form of the compound represented by formula (I) is hydrochloride ethanol solvate crystal form I;
  • the X-ray powder diffraction pattern of the hydrochloride ethanol solvate Form I in 2 theta angles is also substantially as shown in FIG. 14 using Cu-K ⁇ radiation.
  • thermogravimetric analysis profile of the hydrochloride ethanol solvate Form I has a weight loss between 50°C and 125°C, and the weight loss may be 12.7 ⁇ 0.5% (eg, 12.7 ⁇ 0.2%). ).
  • thermogravimetric analysis profile (TGA) of the hydrochloride ethanol solvate Form I can also be substantially as shown in FIG. 15 .
  • the crystal form of the compound represented by formula (I) is acetic acid solvate crystal form I; using Cu-K ⁇ radiation, which has an X-ray powder diffraction pattern expressed in 2 ⁇ angles, has diffraction peaks at 5.3 ⁇ 0.2°, 8.5 ⁇ 0.2°, 10.8 ⁇ 0.2°, 18.7 ⁇ 0.2° and 20.4 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the acetic acid solvate Form I at 2 theta angles further has diffraction peaks at one or more of the following 2 theta angles: 4.9 ⁇ 0.2°, 10.1 ⁇ 0.2°, 11.8 ⁇ 0.2°, 12.8 ⁇ 0.2°, 14.0 ⁇ 0.2°, 15.2 ⁇ 0.2°, 15.8 ⁇ 0.2°, 17.1 ⁇ 0.2°, 17.6 ⁇ 0.2°, 21.7 ⁇ 0.2°, 23.7 ⁇ 0.2° and 25.9 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the acetic acid solvate crystal form I expressed at 2 ⁇ angle, its diffraction peaks and relative intensities can also be shown in the following table:
  • the X-ray powder diffraction pattern of the acetic acid solvate Form I in 2 theta angles can also be substantially as shown in FIG. 6 using Cu-K ⁇ radiation.
  • the acetic acid solvate Form I has a differential scanning calorimetry (DSC) at 167.2 ⁇ 5°C (eg, 167.2 ⁇ 3°C) and 238.5 ⁇ 5°C (eg, 238.5 ⁇ 3°C), respectively. There is an absorption peak at °C).
  • DSC differential scanning calorimetry
  • the differential scanning calorimetry of the acetic acid solvate Form I can also be substantially as shown in FIG. 7 .
  • thermogravimetric analysis profile of the acetic acid solvate Form I has a weight loss at 100°C to 160°C, the weight loss may be 10 ⁇ 0.5% (eg, 10 ⁇ 0.2%).
  • thermogravimetric analysis plot (TGA) of the acetic acid solvate Form I can also be substantially as shown in FIG. 8 .
  • the crystalline form of the compound represented by formula (I) is acetic acid solvate crystal form II; using Cu-K ⁇ radiation, which has an X-ray powder diffraction pattern expressed in 2 ⁇ angles, has diffraction peaks at 6.5 ⁇ 0.2°, 7.1 ⁇ 0.2°, 7.5 ⁇ 0.2°, 13.7 ⁇ 0.2° and 24.5 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the acetic acid solvate Form II expressed at 2 theta angles, also has diffraction peaks at one or more of the following 2 theta angles: 19.4 ⁇ 0.2°, 20.8 ⁇ 0.2°, 23.1 ⁇ 0.2° and 24.8 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the acetic acid solvate crystal form II expressed at 2 ⁇ angle, its diffraction peaks and relative intensities can also be shown in the following table:
  • the X-ray powder diffraction pattern of the acetic acid solvate Form II in 2 theta angles can also be substantially as shown in FIG. 10 using Cu-K ⁇ radiation.
  • the differential scanning calorimetry (DSC) of the acetic acid solvate crystalline form II has an absorption peak at 115.8 ⁇ 5°C (eg, 115.8 ⁇ 3°C).
  • the differential scanning calorimetry of the acetic acid solvate Form II can also be substantially as shown in FIG. 11 .
  • thermogravimetric analysis profile of the acetic acid solvate crystalline form II may have a weight loss at 100°C to 160°C; the weight loss may be 11.6 ⁇ 0.5% (eg, 11.6 ⁇ 0.2%).
  • thermogravimetric analysis plot (TGA) of the acetic acid solvate Form II can also be substantially as shown in FIG. 12 .
  • the present invention also provides a crystalline form of Compound A:
  • the crystalline form of the compound A is the crystalline form I of the compound A; using Cu-K ⁇ radiation, its X-ray powder diffraction pattern expressed at 2 ⁇ angle, at 6.3 ⁇ 0.2°, 7.4 ⁇ 0.2°, 8.7 ⁇ 0.2°, There are diffraction peaks at 15.3 ⁇ 0.2° and 17.5 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the Form I of Compound A at 2 theta angles may also have diffraction peaks at one or more of the following 2 theta angles: 12.4 ⁇ 12.4 ⁇ 0.2°, 14.9 ⁇ 0.2°, 15.7 ⁇ 0.2°, 17.3 ⁇ 0.2°, 18.9 ⁇ 0.2°, 20.5 ⁇ 0.2°, 21.6 ⁇ 0.2°, 22.3 ⁇ 0.2°, 22.9 ⁇ 0.2°, 23.1 ⁇ 0.2°, 24.0 ⁇ 0.2° and 26.0 ⁇ 0.2°.
  • the X-ray powder diffractogram of Form I of Compound A at 2 theta angles may also have diffraction peaks at one or more of the following 2 theta angles: 20.7 ⁇ 0.2°, 21.9 ⁇ 0.2°, 23.7 ⁇ 0.2°, 24.3 ⁇ 0.2° and 25.4 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form I of Compound A in 2 theta angles can also be substantially as shown in FIG. 2 using Cu-K ⁇ radiation.
  • the Form I of Compound A has an absorption peak at 235.1 ⁇ 5°C (eg, 235.1 ⁇ 3°C) in a Differential Scanning Calorimetry (DSC).
  • DSC Differential Scanning Calorimetry
  • the differential scanning calorimetry map of Form I of Compound A can also be substantially as shown in FIG. 3 .
  • thermogravimetric analysis plot (TGA) of Form I of Compound A can also be substantially as shown in FIG. 4 .
  • the present invention provides a preparation method of a compound represented by formula (I), which comprises the following method one, method two or method three:
  • n is 0, and the definitions of m and X are as described above;
  • n is 1, and m is any value from 0 to 3; the definition of X is as described above;
  • n is any value from 0 to 1
  • m and m' are any value from 0 to 3 independently, and both n and m are not 0;
  • X is H 2 O;
  • Y is CH 3 CH 2 OH, CH3C (O)OH, CH3C (O) OCH2CH3 , CH3C (O) CH3 or ( CH3 ) 2CHOH .
  • the process of dissolving the compound A in X can be achieved by the following methods: dissolving the compound A in an organic solvent to form a mixture, and then dissolving the mixture in X; or, placing the compound A in X Heat in medium until it dissolves.
  • the type of the organic solvent can be conventional in the art, as long as it can dissolve compound A and be miscible with X, for example, when X is acetic acid , the organic solvent may be dichloromethane and/or methanol.
  • the amount of the organic solvent is not limited, so long as compound A is dissolved.
  • compound A when compound A is placed in X and heated, preferably, it is heated to a temperature conventional in the art, such as 60°C to 120°C, for example, 60°C to 85°C, and for example, 79.5°C. °C or 80°C.
  • a temperature conventional in the art such as 60°C to 120°C, for example, 60°C to 85°C, and for example, 79.5°C. °C or 80°C.
  • the reaction when compound A is heated in X to dissolve it, the amount of X may not be limited, so long as compound A is dissolved.
  • the reaction when X is H 2 O, the reaction further includes alcohols and/or ketone solvents; the types of the alcohols can be conventional in the field, for example: isopropanol and/or ethanol , preferably isopropanol; the type of the ketone solvent can be conventional in the field, such as acetone.
  • the temperature at which the compound A is placed in X can be conventional in the art, for example, 10°C to 85°C, and for example, 10°C to 30°C or 60°C.
  • the HCl can be hydrogen chloride gas, hydrochloric acid (for example: concentrated hydrochloric acid), hydrochloric acid alcohol solution (for example: hydrochloric acid ethanol solution, hydrochloric acid methanol solution, hydrochloric acid isopropanol solution), hydrochloric acid ketone solution (for example: hydrochloric acid solution) acetone solution), hydrogen chloride alcohol solution (for example: hydrogen chloride ethanol solution, hydrogen chloride methanol solution, hydrogen chloride isopropanol solution), hydrogen chloride ketone solution (hydrogen chloride acetone solution), etc., preferably ethanol solution of hydrochloric acid, concentrated hydrochloric acid, hydrogen chloride ethanol solution (eg 2M hydrogen chloride in ethanol) or hydrochloric acid in isopropanol.
  • hydrochloric acid for example: concentrated hydrochloric acid
  • hydrochloric acid alcohol solution for example: hydrochloric acid ethanol solution, hydrochloric acid methanol solution, hydrochloric acid is
  • the molar ratio of the compound A and HCl can be conventional in the art, such as 1:(1-15), and another example is 1:1, 1:1.2, 1:1.5, 1:2, 1:3 or 1:10.
  • the type of the organic solvent can be conventional in the field, so as to be able to dissolve the compound shown in formula (II) and to be miscible with water, preferably dichloromethane and methanol, isopropanol and One or more of acetone.
  • the amount of the organic solvent-water mixed solution is not limited, as long as the compound represented by the formula (II) is completely dissolved.
  • the volume percentage of the organic solvent may be conventional in the field, preferably 50% to 98%, such as 50%, 75%, 85% or 95%. .
  • the compound represented by the formula (II) can also be dissolved in a mixed solution of organic solvent-water by heating; 80°C), preferably 30°C to 80°C, for example 50°C.
  • Y is preferably CH 3 CH 2 OH, CH 3 C(O)OH or (CH 3 ) 2 CHOH.
  • the compound represented by the formula (II) can be prepared by the second method.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of an active component and a pharmaceutically acceptable adjuvant; the active component includes a compound represented by formula (I).
  • the active ingredient may also include other therapeutic agents for cancer, viral infections or autoimmune diseases.
  • the pharmaceutically acceptable adjuvants may include pharmaceutically acceptable carriers, diluents and/or excipients.
  • the pharmaceutical composition can be made into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (including injections, injections Sterile powder (powder injection) and concentrated solution for injection), etc., preferably liquid, suspension, emulsion, suppository and injection (solution and suspension) and the like.
  • administration unit dosage forms such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (including injections, injections Sterile powder (powder injection) and concentrated solution for injection), etc., preferably liquid, suspension, emulsion, suppository and injection (solution and suspension) and the like.
  • any of the excipients known and widely used in the art can be used.
  • carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, etc.
  • binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrating agents such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Calcium, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceryl stearate, starch and lactose, etc.
  • disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil, and hydrogenated Oils
  • adsorption promoters such as lactose, white sugar,
  • any excipient known and widely used in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oils, kaolin and talc, etc.; binders , such as gum arabic powder, tragacanth powder, gelatin and ethanol, etc.; disintegrating agents, such as agar and kelp powder.
  • carriers such as lactose, starch, coconut oil, hardened vegetable oils, kaolin and talc, etc.
  • binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, etc.
  • disintegrating agents such as agar and kelp powder.
  • any excipient known and widely used in the art can be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides and the like .
  • any known and widely used carriers or excipients in the art can be used.
  • the carriers or excipients used include water for injection, Ringer's solution and isotonic sodium chloride solution.
  • suitable additives such as antioxidants, solubilizers, pH adjusters and bacteriostatic agents.
  • the content of the active component in the pharmaceutical composition is not particularly limited, and can be selected within a wide range, usually 5-95% by mass, preferably 30% by mass ⁇ 80%.
  • the administration method of the pharmaceutical composition is not particularly limited.
  • Various dosage forms can be selected for administration according to the patient's age, sex and other conditions and symptoms. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules are administered orally; injections can be administered alone, or mixed with injectable delivery fluids (such as glucose solutions and amino acid solutions) for intravenous, intramuscular or Local injection into the lesion; suppository for administration into the rectum.
  • injectable delivery fluids such as glucose solutions and amino acid solutions
  • the present invention also provides the use of the compound represented by formula (I) or the pharmaceutical composition in the preparation of a TLRs modulator.
  • the TLRs modulators include TLRs full agonists or TLRs partial agonists.
  • the TLRs are preferably one or more of TLR7, TLR8 and TLR9, more preferably TLR8.
  • the present invention also provides the use of the compound represented by formula (I), or the pharmaceutical composition, in the preparation of a drug for regulating T cells.
  • the present invention also provides the use of the compound represented by formula (I) or the pharmaceutical composition in the preparation of a medicament for treating, relieving and/or preventing related diseases mediated by TLRs.
  • the TLRs Drugs for related diseases mediated by TLR8 are drugs for related diseases mediated by TLR8; the diseases include tumors and non-tumor diseases.
  • the diseases include, but are not limited to, cancer, viral infection, and autoimmune diseases, etc.
  • the cancer is preferably an immunologic agent-related cancer, and the immunosuppression refers to tumor-specific immunosuppression.
  • the compound represented by the formula (I) or the pharmaceutical composition is used in the preparation of medicines for treating and/or alleviating cancer, viral infections and autoimmune diseases.
  • the present invention further provides a method for treating, relieving and/or preventing cancer, viral infection or autoimmune disease by using the compound represented by formula (I) or the pharmaceutical composition, comprising: administering to a mammal for the treatment of A desired dose of a compound of formula (I), or a pharmaceutical composition.
  • Said mammal preferably human.
  • the present invention further provides that the compound represented by formula (I), or the pharmaceutical composition and one or more other types of therapeutic agents and/or therapeutic methods are used in combination for the treatment, alleviation and/or prevention of Related diseases mediated by TLRs, especially related diseases mediated by TLR8.
  • TLR8-mediated related diseases refer to diseases caused by TLR8-mediated immunosuppression, and the diseases may include cancer, viral infection or autoimmune diseases.
  • the present invention preferably uses the compound represented by formula (I), or the pharmaceutical composition in combination with one or more other kinds of therapeutic agents for the treatment and/or alleviation of diseases mediated by TLR8, the diseases Cancer is preferred.
  • the present invention further provides the compound represented by formula (I), or the pharmaceutical composition and one or more other kinds of therapeutic agents in combination for the treatment and/or alleviation of cancer, viral infection and autoimmunity disease.
  • the present invention further provides that the compound represented by formula (I), or the pharmaceutical composition and one or more other kinds of therapeutic agents are used in combination for treating and/or alleviating cancer.
  • the other kinds of therapeutic agents can be combined with the compound represented by the formula (I) to form a single-administered therapeutic dosage form, or a treatment that is administered separately and sequentially dosage form.
  • the viral infection may include: influenza virus, Sendai virus, Coxsackie virus, Dengue virus, Newcastle disease virus (NDV), vesicular stomatitis virus (VSV), Hepatitis B virus (HBV), Hepatitis C virus virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), poliovirus, herpes virus (HSV) (eg: varicella zoster virus, Infections caused by viruses such as herpes simplex virus and other human herpes viruses) or human immunodeficiency virus type I (HIV).
  • influenza virus Sendai virus, Coxsackie virus, Dengue virus, Newcastle disease virus (NDV), vesicular stomatitis virus (VSV), Hepatitis B virus (HBV), Hepatitis C virus virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), Epstein-Barr
  • Said cancer includes metastatic and non-metastatic cancer, also includes familial hereditary and sporadic cancer, and also includes solid tumor and non-solid tumor.
  • solid tumors may include, but are not limited to, eye cancer, bone cancer, lung cancer, stomach cancer, pancreatic cancer, breast cancer, prostate cancer, brain cancer (including glioblastoma, medulloblastoma), ovarian cancer cancer, bladder cancer, cervical cancer, testicular cancer, kidney cancer (including adenocarcinoma and Wilms cell carcinoma), oral cancer (including squamous cell carcinoma), tongue cancer, throat cancer, nasopharyngeal cancer, head and neck cancer, colon cancer , one or more of small bowel cancer, rectal cancer, parathyroid cancer, thyroid cancer, esophageal cancer, gallbladder cancer, bile duct cancer, cervical cancer, liver cancer, lung cancer, sarcoma, and skin cancer.
  • eye cancer including glioblastoma, medulloblastoma
  • ovarian cancer cancer bladder cancer
  • cervical cancer testicular cancer
  • kidney cancer including adenocarcinoma and Wilms cell carcinoma
  • oral cancer including
  • non-solid tumors may include, but are not limited to: lymphocytic leukemia (including acute lymphocytic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin's One or more of gold lymphoma, T-cell chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia), myeloid-related leukemia (including acute myeloid leukemia, chronic myeloid leukemia), and AIDs-related leukemia.
  • lymphocytic leukemia including acute lymphocytic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin's
  • gold lymphoma including T-cell chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia
  • myeloid-related leukemia including acute myeloid le
  • the autoimmune diseases may include, but are not limited to: rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease (MCTD), systemic scleroderma (including: CREST syndrome), dermatomyositis, nodular vasculitis, nephropathy (including: pulmonary hemorrhagic nephritic syndrome, acute glomerulonephritis, primary membranous proliferative glomerulonephritis, etc.), endocrine-related diseases (including: type I diabetes, gonadal insufficiency, malignant anemia, hyperthyroidism, etc.), liver disease (including: primary biliary cirrhosis, autoimmune cholangitis, autoimmune hepatitis, primary sclerosing cholangitis, etc.) and autoimmune reactions due to infection ( For example: one or more of AIDS, malaria, etc.).
  • MCTD mixed connective tissue disease
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive improvement effect of the present invention is that the crystal form of the compound represented by formula (I) of the present invention has better solubility and stability, is more suitable for the preparation of pharmaceutical dosage forms, and is prepared from the compound represented by formula (I) The drug has better absorption and metabolism in the body.
  • Fig. 1 is the XRPD pattern of compound 1-8-5 disclosed in CN107344931A.
  • FIG. 2 is the XRPD pattern of the crystal form I of Compound A in Example 2.
  • FIG. 3 is the DSC chart of the crystal form I of Compound A in Example 2.
  • FIG. 4 is the TGA spectrum of the crystal form I of Compound A in Example 2.
  • FIG. 5 is the 1 H NMR spectrum of the crystal form I of compound A in Example 2.
  • FIG. 6 is the XRPD pattern of the acetic acid solvate crystal form I of Compound A in Example 3.
  • FIG. 6 is the XRPD pattern of the acetic acid solvate crystal form I of Compound A in Example 3.
  • FIG. 7 is the DSC spectrum of the acetic acid solvate crystal form I of Compound A in Example 3.
  • FIG. 7 is the DSC spectrum of the acetic acid solvate crystal form I of Compound A in Example 3.
  • FIG. 8 is the TGA spectrum of the acetic acid solvate crystal form I of Compound A in Example 3.
  • FIG. 8 is the TGA spectrum of the acetic acid solvate crystal form I of Compound A in Example 3.
  • FIG. 9 is the 1 H NMR spectrum of the acetic acid solvate crystal form I of Compound A in Example 3.
  • FIG. 9 is the 1 H NMR spectrum of the acetic acid solvate crystal form I of Compound A in Example 3.
  • FIG. 10 is the XRPD pattern of the acetic acid solvate crystal form II of Compound A in Example 4.
  • FIG. 10 is the XRPD pattern of the acetic acid solvate crystal form II of Compound A in Example 4.
  • FIG. 11 is the DSC chart of the acetic acid solvate crystal form II of Compound A in Example 4.
  • FIG. 11 is the DSC chart of the acetic acid solvate crystal form II of Compound A in Example 4.
  • FIG. 12 is the TGA spectrum of the acetic acid solvate crystal form II of Compound A in Example 4.
  • FIG. 12 is the TGA spectrum of the acetic acid solvate crystal form II of Compound A in Example 4.
  • FIG. 13 is the 1 H NMR spectrum of the acetic acid solvate crystal form II of Compound A in Example 4.
  • FIG. 14 is the XRPD pattern of the hydrochloride ethanol solvate crystal form I of Compound A in Example 5.
  • FIG. 14 is the XRPD pattern of the hydrochloride ethanol solvate crystal form I of Compound A in Example 5.
  • FIG. 16 is the XRPD pattern of the hydrochloride acetic acid solvate crystal form I of Compound A in Example 6.
  • FIG. 16 is the XRPD pattern of the hydrochloride acetic acid solvate crystal form I of Compound A in Example 6.
  • FIG. 18 is the XRPD pattern of the hydrochloride hydrate crystal form I of Compound A in Example 8.
  • FIG. 18 is the XRPD pattern of the hydrochloride hydrate crystal form I of Compound A in Example 8.
  • FIG. 21 is the 1 H NMR spectrum of the hydrochloride hydrate crystal form I of Compound A in Example 8.
  • FIG. 21 is the 1 H NMR spectrum of the hydrochloride hydrate crystal form I of Compound A in Example 8.
  • FIG. 22 is the XRPD overlay diagram before and after the stability test of the hydrochloride hydrate crystal form I of Compound A in Example 8.
  • FIG. 22 is the XRPD overlay diagram before and after the stability test of the hydrochloride hydrate crystal form I of Compound A in Example 8.
  • FIG. 23 is the XRPD overlay diagram before and after the stability test of the acetic acid solvate crystal form II of Compound A in Example 4.
  • FIG. 23 is the XRPD overlay diagram before and after the stability test of the acetic acid solvate crystal form II of Compound A in Example 4.
  • FIG. 24 is the XRPD overlay diagram before and after the long-term stability test of the hydrochloride hydrate crystal form I of Compound A in Example 8.
  • FIG. 24 is the XRPD overlay diagram before and after the long-term stability test of the hydrochloride hydrate crystal form I of Compound A in Example 8.
  • FIG. 25 is the 1 H NMR spectrum of the hydrochloride salt of Compound A in Example 7.
  • Solid samples were analyzed with a powder X-ray diffraction analyzer (Bruker D8 advance).
  • the instrument is equipped with an SSD160 detector, and the 2 ⁇ scan angle of the sample ranges from 3° to 40° with a scan step size of 0.02°.
  • the light tube voltage and light tube current when measuring the sample were 40KV and 40mA, respectively.
  • the instrument model for differential scanning calorimetry was TA Discovery DSC 250.
  • the sample is accurately weighed and placed in a capped Tzero sample pan, and the exact mass of the sample is recorded.
  • the sample was heated to the final temperature at a ramp rate of 10°C/min.
  • thermogravimetric analysis was Discovery TGA 550.
  • the sample is placed in an equilibrated sample pan and the sample amount is automatically weighed in a TGA oven.
  • the sample was heated to the final temperature at a rate of 10°C/min.
  • GC gas analytical chromatography
  • K-F moisture was detected using the 870 KF Titrino plus moisture titrator.
  • Ion chromatography uses Thermo Fisher ICS-1100 ion chromatograph, chromatographic column: AS11-HC 4*250mm, eluent 25mmol potassium hydroxide aqueous solution, flow rate: 1mL/min.
  • compound 1-8-5 refers to compound 1-8-5 obtained by referring to the method in Example 52 of Patent CN107344931A.
  • the product was analyzed by powder X-ray diffraction analyzer (Bruker D8 advance), and its XRPD The spectrum is shown in Figure 1, and the results show that the compound prepared by this method is an amorphous (amorphous) compound.
  • Step 1 To a solution of compound 1.10 (2.1 g, 1 eq) in tetrahydrofuran (90 mL) under nitrogen protection, compound 22.7 (2.7 g, 1.5 eq), aqueous sodium carbonate (29.2 mL, 2.0 M) and Pd(dppf) were sequentially added 2 Cl 2 (369 mg, 0.1 equiv) was added, the reaction system was replaced with nitrogen three times, and the reaction system was stirred at 70°C until the reaction was complete by TLC (about 1.5 hours).
  • Step 2 Trifluoroacetic acid (3.24 mL) was added to a solution of intermediate 1 (2.16 g) in dichloromethane (22 mL) under ice bath condition, and the reaction system was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure, the obtained residue was re-added to dichloromethane (50 mL), and activated carbon (2 g) was added to stir for 10 minutes after dissolving, filtered, and the filtrate was concentrated under reduced pressure, and the obtained solid was redissolved in dichloromethane (50 mL). ) and methanol (5 mL), added saturated aqueous sodium bicarbonate solution (20 mL), stirred for 10 minutes, and allowed to stand to separate the layers.
  • Method 2 Add dichloromethane (210 mL) and absolute ethanol (105 mL) to the hydrochloride acetic acid solvate of compound A (15 g), respectively, and stir to dissolve at room temperature; add saturated aqueous sodium bicarbonate solution (113 mL) to adjust The pH was about 8, and the liquids were separated; the organic layer was washed once with saturated sodium chloride solution (200 mL), the organic layer was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure at 40° C. to obtain compound A ( 12.5 g) as a pale yellow solid.
  • the 1 H NMR results showed that the sample had no solvent residue and that the ratio of free base to acetic acid was approximately 1:1.
  • TGA had a weight loss of 10.16% before 175°C.
  • the DSC spectrum shows that the temperature of its endothermic peak is about 167.21°C and 238.50°C.
  • XRPD detection proved to be the acetic acid solvate crystal form I of compound A.
  • the XRPD diffraction peaks of the acetic acid solvate crystal form I of Compound A are shown in Table 1.
  • Method 1 Take compound A (506 mg), add acetic acid (1.25 mL), heat up to 79.5 ° C to dissolve the clear, immediately add ethyl acetate (10 mL) dropwise, and finish adding in about 30 seconds, a white solid is precipitated during the addition process, and immediately The mixture was stirred and crystallized at room temperature for 2.5 hours, filtered, and the filter cake was rinsed with ethyl acetate (1 mL). The obtained solid was dried under vacuum at 40°C for 4 hours to obtain the corresponding acetic acid solvate crystal form II of compound A. The sample is an off-white powder.
  • Method 2 Take compound A (7.26g), add acetic acid (18mL), heat up to 80°C to dissolve, keep at 80°C, add ethyl acetate (180mL) dropwise, add it in about 30 seconds, and a white solid is precipitated during the addition process , immediately placed at room temperature for 0.5 hour stirring and crystallization, ice-water bath for 0.5 hour, filtered, and the filter cake was rinsed with ethyl acetate (20 mL). The obtained solid was dried under vacuum at 45°C for 1.5 hours to obtain the corresponding acetic acid solvate crystal form II of compound A. The sample is an off-white powder.
  • the detection results of the acetic acid solvate crystal form II of Compound A are as follows: As shown in Figure 13, 1 H NMR results show that the sample has no solvent residue, and the ratio of free base to acetic acid is about 1:2. As shown in Figure 12, TGA had a weight loss of 11.58% before 175°C. As shown in Figure 11, the DSC spectrum shows that the temperature of its endothermic peak is about 115.79°C. As shown in Figure 10, XRPD detection proved to be the acetic acid solvate crystal form II of Compound A. The XRPD diffraction peaks of the acetic acid solvate crystal form II of Compound A are shown in Table 2. As shown in Figure 23, the crystal form remained unchanged after being placed under the conditions of 4500 lux illumination and 40 °C-92.5% RH with packaging for 31 days.
  • TGA had a weight loss of 12.74% before 125 °C
  • the ethanol content detected by GC chromatography was about 10.5%
  • the ratio of free base to ethanol was about 1:1.5, as shown in Figure 14.
  • XRPD detection proved to be compound A
  • Table 3 shows the XRPD diffraction peaks of the hydrochloride ethanol solvate crystal form of Compound A, and the hydrochloride ethanol solvate crystal form I of Compound A.
  • Method 1 Take compound A (300mg, 1eq), add acetic acid (6mL), heat to 60°C, stir for ten minutes, add concentrated hydrochloric acid (60mg, 1.05eq), cool to room temperature to precipitate solids, then stir at room temperature for 1 day , filtered, and the filter cake was air-dried at 45° C. for 4 hours to obtain the hydrochloride acetic acid solvate crystal form I of compound A.
  • the sample is a white powder.
  • Method 2 Take compound 1-8-5 (100 g, 1 eq), add acetic acid (750 mL), and heat to 60°C. Add activated carbon (10g) and stir for 10 minutes, filter (repeated twice), add ethanolic hydrogen chloride solution (10%, 112g, 2eq) under stirring at 40°C, add acetic acid (100mL), cool down to precipitate solids, filter, add to filter cake Add to preheated acetic acid (500 mL), add acetic acid (500 mL) to the system, stir at 90° C. for 1 hour, cool to room temperature for crystallization. After filtration, the filter cake was dried by air at 45°C for 6 hours to obtain the crystalline form I of the hydrochloride acetic acid solvate of Compound A. The sample is an off-white powder.
  • the detection results of the hydrochloride acetic acid solvate crystal form I of Compound A are as follows: As shown in Figure 17, 1 H NMR shows that the ratio of Compound A and acetic acid is 1:2. As shown in Figure 16, XRPD detection proved to be the hydrochloride acetic acid solvate crystal form I of Compound A, and the XRPD diffraction peaks of the hydrochloride acetic acid solvate crystal form I of Compound A are shown in Table 4.
  • Method 1 Add water (3 mL) to the hydrochloride ethanol solvate of compound A (1 g), heat to 65°C, dissolve it, add isopropanol (3 mL) to the system, and the system is cooled to room temperature and stirred for 1 hour After cooling in an ice bath, crystallize, filter, and dry the obtained solid at 45° C. for 2 hours to obtain the corresponding crystalline form I of the hydrochloride salt of Compound A.
  • the sample is an off-white powder.
  • Method 2 Add 75% isopropanol-water mixed solution (0.8 mL) to the hydrochloride acetic acid solvate of Compound A (100 mg), dissolve it first, then continue stirring for about 0.5 hours to precipitate a solid, filter to obtain a solid Blow drying at 45°C for 2 hours to obtain the corresponding crystalline form I of the hydrochloride salt of Compound A.
  • the sample is a white powder.
  • Method 3 Add 85% isopropanol-water mixed solution (0.9 mL) to the hydrochloride acetic acid solvate of compound A (100 mg), heat to 50°C to dissolve, immediately take out the crystal slurry and place it at room temperature for about After 10 minutes, a solid was precipitated, which was filtered, and the obtained solid was air-dried at 45° C. for 2 hours to obtain the corresponding crystalline form I of the hydrochloride salt of Compound A.
  • the sample is a white powder.
  • Method 4 Add 75% isopropanol-water mixed solution (0.8 mL) to the hydrochloride of compound A (100 mg), dissolve it first, then continue stirring for about 1 hour to precipitate a solid, filter, and the obtained solid is blown at 45°C Drying for 2 hours gave the corresponding Compound A hydrochloride hydrate Form I.
  • the sample is an off-white powder.
  • Method 5 Dissolve compound A (1 g, 1 eq) in a mixed solvent of dichloromethane (8 mL) and methanol (4 mL), add ethanolic hydrogen chloride solution (30%, 0.45 g, 2 eq), add ethyl acetate after dissolving (20 mL), a solid was precipitated, concentrated under reduced pressure to remove the solvent, and then a mixed solution of dichloromethane and methanol (5 mL, 2/1) was added, then water (20 mL) and acetone (20 mL) were added, and the resulting solid was vacuum-dried at 50° C. The corresponding Compound A hydrochloride hydrate Form I was obtained in 4 hours. The sample was an off-white solid.
  • Method 6 To compound A (12.47g, 1eq) was added isopropanol (36mL), the resulting turbid solution was kept in an ice-water bath, and a mixture of concentrated hydrochloric acid (2.46g, 1.05eq) and water (5mL) was added under stirring , add water (31 mL) after adding, remove the ice-water bath, stir at room temperature, dissolve clear, stir at room temperature for 10 minutes, then add about 5 mg of seed crystals (the seed crystals are compounds prepared according to any of the above-mentioned methods 1 to 5).
  • A's hydrochloric acid hydrate crystal form I slowly a large amount of solids are precipitated, add 50% isopropanol-water mixed solution (10 mL) after 1 hour, continue to stir for about 45 minutes, filter, filter cake with a small amount of 50% isopropyl
  • the alcohol-water mixture was rinsed, and the obtained solid was air-dried at 35° C. for 5 hours to obtain the corresponding crystalline form I of the hydrochloride salt of Compound A.
  • the sample is an off-white powder.
  • the detection results of the hydrochloride hydrate crystal form I of Compound A are as follows: As shown in Figure 21, 1 H NMR results show that the sample has no solvent residue. As shown in Figure 20, TGA has a weight loss of 6.052% before 125°C (which is basically consistent with the theoretical value (5.93%) of 2 molecules of crystal water in the structure). KF moisture test, the moisture content is about 6.2%, and the ratio of free alkali and water is about 1:2. As shown in Figure 19, the DSC spectrum shows that the temperature of its endothermic peak is about 136.25°C. The average % of chloride ion content determined by ion chromatography was 5.81 (the theoretical value was 5.83%), indicating that the ratio of free base and hydrochloric acid was 1:1.
  • XRPD detection proved to be the hydrochloride hydrate crystalline form.
  • the samples were placed for 31 days under the conditions of high temperature 60°C, light 4500lux, high humidity 92.5%RH, 40°C-92.5%RH bare and 40°C-92.5%RH packed for 31 days, and there was no obvious crystal form. Variety.
  • the crystal form of the sample has no obvious change after being placed for 12 months under the conditions of a temperature of 25 °C ⁇ 2 °C and a relative humidity of 60% ⁇ 5%.
  • the XRPD diffraction peak list of the hydrochloride hydrate crystal form I of Compound A is shown in Table 5.
  • High temperature 60°C Take an appropriate amount of sample, spread it in a petri dish with a thickness of no more than 3mm, and place it in a 60°C high temperature box.
  • High humidity 92.5% RH Take an appropriate amount of sample, spread it in a petri dish with a thickness of no more than 3 mm, and place the open mouth in a desiccator saturated with potassium nitrate saturated solution.
  • Illumination 4500 lux Take an appropriate amount of the sample, spread it in a petri dish with a thickness of no more than 3 mm, and place the open opening in a light box with an intensity of 4500 lux.
  • Chromatographic column waters Xselect CSH TM C18, 4.6mm*250mm, 5 ⁇ m.
  • Mobile phase A 10 mM potassium dihydrogen phosphate (adjust pH to 2.5 with phosphoric acid); mobile phase B: acetonitrile; flow rate: 1.0 ml/min; column temperature: 35 °C; wavelength: 262 nm; injection volume: 10 ⁇ L; Table 6 shows the elution gradient:
  • test items include character, moisture, related substances, content, microbial limit and bacterial endotoxin .
  • Test purpose To investigate the solubility of the crystalline form of compound A solvate and the crystalline form of compound A hydrochloride solvate in water.
  • Test method Take about 10 mg of the crystal form of Compound A, the crystal form of Compound 1-8-5 disclosed in CN107344931A and the solvate of Compound A, and the crystal form of the hydrochloride solvate of Compound A.
  • the Cecillin bottle add about 5 mL of water and 5% ethanol aqueous solution to each vial to make it a supersaturated solution, shake it in a water bath shaker at 25°C or magnetically stir it at 2-8°C for 2 hours, The supersaturated solution was taken in 24 hours (one solution was prepared at each time point), and centrifuged at 3000 rpm/min for 15 min. Take the supernatant as the test solution.
  • the chromatographic analysis method is as follows:
  • Chromatographic column waters Xselect CSH TM C18, 4.6mm*150mm, 3.5 ⁇ m.
  • Mobile phase A 10 mM potassium dihydrogen phosphate (adjust pH to 2.5 with phosphoric acid); mobile phase B: acetonitrile; flow rate: 1.0 ml/min; column temperature: 35 °C; wavelength: 262 nm; injection volume: 10 ⁇ L; Table 8 shows the elution gradient:
  • Drugs and reagents are shown in Table 10: the compounds to be tested are prepared into solutions with the following solvents, and other reagents are of analytical grade:
  • Test animals male SPF SD rats (3 rats in each group), purchased from Shanghai Sipple-Bikai Laboratory Animal Co., Ltd., and the range of animal body weight before administration is: 206.9-222.6 g.
  • SC subcutaneous injection
  • Pharmacokinetic test The compound to be tested was administered to SD male rats by subcutaneous injection. , 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h after administration.
  • the blood samples were placed on ice after collection, and the plasma was separated by centrifugation (centrifugation conditions: 8000 rpm, 6 minutes, 2-8°C).
  • the collected plasma was stored at -80°C until analysis.
  • Plasma samples were analyzed by LC-MS/MS (API5500), and the area under the drug-time curve (AUC) of the test product was calculated using the pharmacokinetic calculation software WinNonlin5.2 non-compartmental model according to the blood concentration data of the drug. , half-life (t 1/2 ), time to peak (T max ), peak concentration (C max ), mean residence time (MRT). The results are shown in Table 11:

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Abstract

一种苯并氮杂卓衍生物的盐、溶剂合物、多晶型物、制备方法及应用。具体公开了如式(I)所示化合物，所述如式(I)所示化合物的晶型具有较佳的溶解度和稳定性，更适用于药物剂型的制备，且由如式(I)所示化合物制备得到的药物在体内具有较佳的吸收和代谢效果。

Description

苯并氮杂卓衍生物的盐、溶剂合物、多晶型物、制备方法及应用
本申请要求申请日为2021年2月5日的中国专利申请2021101636940和申请日为2022年1月24日的中国专利申请2022100800656的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及苯并氮杂卓衍生物的盐、溶剂合物、多晶型物、制备方法及应用。
背景技术
Toll样受体家族(TLRs)是识别病原相关分子模式重要蛋白家族，可以感应并启动固有免疫应答并促进适应性免疫应答的发展。TLR8在不同亚型的免疫细胞中均有表达。调节性T细胞(Treg)具有强有力的免疫应答抑制能力，是有效的癌症免疫治疗的主要障碍。TLR8信号通路被证明是逆转Treg细胞抑制功能导致强烈肿瘤抑制所必要且充分的条件。TLR8选择性激动剂有效的激活多种免疫细胞，包括mDCs及单核细胞(Gorden,et al,2005)，可促进针对癌症细胞的适应性免疫应答的产生(Krug,et al,2003；Schnurr,et al,2005)。激活的mDCs吞噬凋亡及死亡的肿瘤细胞，接着，与pDCs相比，更有效的向CD8 +CTLs交叉呈递肿瘤相关抗原(Berard,et al,2000；Dalgaard,et al,2005)。此外，mDCs激活，导致TNFα及白介素12(IL-12)的释放可刺激T细胞及NK细胞的活化。NK细胞的激活是抗体介导的细胞毒性(ADCC)的主要机制。因而，通过ADCC加强对肿瘤细胞的杀伤可能为TLR8选择性抑制剂呈现出重要的治疗机遇(Lu,et al,2011)。一些单克隆抗体疗法被广泛用于癌症患者的治疗，如利妥昔单抗及曲妥单抗，它们可通过ADCC起到治疗作用(Ferris,et al,2010)。事实上，在mAb治疗方法中加入TLR8激动剂可增强ADCC从而增加mAb治疗的疗效(Ferris,et al,2015)。此外，最近的研究还表明TLR8激动剂可直接起到抗肿瘤的作用，而不依赖于它的免疫调节功能(Ignatz-Hoover,et al,2015)。因此，TLR8激动剂不仅可作为单药治疗而起作用，还可通过增强宿主免疫应答提高多种化疗及靶向抗癌药物的疗效。
在识别病原微生物核酸的TLRs家族成员中，TLR7和TLR8具有很高同源性，可以识别一些人工合成的具有抗病毒作用的小分子，例如Imidazoquinolines咪唑喹啉类小分子化合物(TLR7和TLR8的配体)。在由HSV感染的天竺鼠生殖器疱疹模型中对Imidazoquinolines进行研究，发现该化合物对体外病毒复制效果较小，但在体内有较强的 效果，表明该类化合物促进免疫细胞生成前炎因子及调节细胞因子，导致抗病毒反应(Int Immunopharmacol 2002；2:443-451)。更重要的是TLR7和TLR8可以识别病毒ssRNA。研究证明，ssRNA病毒是TLR7和TLR8的天然配体，例如I型人类免疫缺陷病毒(HIV)、流感病毒、仙台病毒、登革热病毒、新城疫病毒(NDV)、水泡性口炎病毒(VSV)、乙肝病毒(HBV)及丙型肝炎病毒(HCV)等。TLR8能识别抗病毒化合物、ssRNA病毒、人工合成的寡核苷酸等，通过MyD88依赖信号通路诱导Th1、抑制Th2细胞因子分泌和Tregs增殖，介导抗病毒免疫，发挥抗感染、抗过敏效应。
中国专利申请CN107344931A中披露了一系列作为TLR8激动剂的苯并氮杂卓类化合物，特别是披露了以下化合物(CN107344931A中公开的化合物1-8-5)：
Figure PCTCN2022074486-appb-000001
根据CN107344931A化合物1-8-5的制备方法得到的是非晶形化合物，稳定性较差，不适合工业化生产及保存。
发明内容
本发明所要解决的技术问题是现有技术中作为TLR8激动剂的苯并氮杂卓类化合物是非晶形化合物，溶解度和稳定性较差，为此，本发明提供了一种苯并氮杂卓衍生物：2-氨基-8-(2-(2-(甲磺酰基)乙基)-1-氧代-1,2-二氢酞嗪-6-基)-N,N-二异丙基-3H-苯并氮杂卓-4-甲酰胺的盐、溶剂合物、多晶型物、制备方法及应用。本发明得到的晶型具有较佳的溶解度和稳定性，更适用于药物制剂的制备及存储。
本发明提供了如式(I)所示化合物：
Figure PCTCN2022074486-appb-000002
其中，X为H 2O、CH 3CH 2OH、CH 3C(O)OH、CH 3C(O)OCH 2CH 3、CH 3C(O)CH 3或(CH 3) 2CHOH；
n为0-1的任意数值；m为0-3的任意数值；且m和n不同时为0。
本发明中，所述X优选为H 2O、CH 3CH 2OH或CH 3C(O)OH，更优选为H 2O。
本发明中，所述n可为0或1，优选为1。
本发明中，所述m可为0、1、1.5、2、2.5或3，优选为0、1、1.5或2，更优选为1、1.5或2。
在某一实施方案中，n为1，m为1.5或2；或者，n为0，m为1或2。
在某一实施方案中，n为1，m为0。
本发明中，所述如式(I)所示化合物选自如下任一化合物：
Figure PCTCN2022074486-appb-000003
在某一实施方案中，当n为1，m为2，X为H 2O时，所述如式(I)所示化合物的结晶形式为盐酸盐水合物晶型I；使用Cu-Kα辐射，其以2θ角表示的X-射线粉末衍射图，在9.8±0.2°、10.5±0.2°、17.4±0.2°、19.7±0.2°和22.7±0.2°处具有衍射峰。
在某一实施方案中，使用Cu-Kα辐射，所述盐酸盐水合物晶型I以2θ角表示的X-射线粉末衍射图，还可在如下一个或多个2θ角处有衍射峰：7.1±0.2°、12.5±0.2°、14.0±0.2°、15.7±0.2°、18.0±0.2°和20.3±0.2°。
在某一实施方案中，使用Cu-Kα辐射，所述盐酸盐水合物晶型I以2θ角表示的X-射线粉末衍射图，还可在如下一个或多个2θ角处有衍射峰：12.9±0.2°、21.5±0.2°、22.0±0.2°、25.2±0.2°、26.0±0.2°、26.8±0.2°和29.3±0.2°。
在某一实施方案中，使用Cu-Kα辐射，所述盐酸盐水合物晶型I以2θ角表示的X- 射线粉末衍射图，还可在如下一个或多个2θ角处有衍射峰：18.7±0.2°、19.0±0.2°、24.8±0.2°、29.9±0.2°和34.1±0.2°。
在某一实施方案中，使用Cu-Kα辐射，所述盐酸盐水合物晶型I以2θ角表示的X-射线粉末衍射图，其衍射峰和相对强度还可如下表所示：
角度2θ/° 相对强度％ 角度2θ/° 相对强度％ 角度2θ/° 相对强度％
7.082 9.7 9.793 100.0 10.477 54.9
12.470 20.7 12.834 6.9 13.987 15.5
15.635 23.8 17.404 33.69 17.937 14.8
18.686 6.8 19.027 16.6 19.674 48.6
20.294 15.8 21.534 9.8 22.000 11.0
22.669 70.2 23.613 6.5 24.438 10.6
24.803 15.1 25.191 22.0 26.005 9.6
26.815 26.3 29.283 11.3 29.937 6.0
32.029 5.2 34.121 9.1    
。
在某一实施方案中，使用Cu-Kα辐射，所述盐酸盐水合物晶型I以2θ角表示的X-射线粉末衍射图还可基本上如图18所示。
在某一实施方案中，所述盐酸盐水合物晶型I的差示扫描量热图(DSC)中在136.3±5℃(例如136.3±3℃)处有吸收峰。
在某一实施方案中，所述盐酸盐水合物晶型I的差示扫描量热图还可基本上如图19所示。
在某一实施方案中，所述盐酸盐水合物晶型I的热重分析图在70℃至100℃有重量损失，所述重量损失可为6±0.5％(例如6±0.2％)。
在某一实施方案中，所述盐酸盐水合物晶型I的热重分析图(TGA)还可基本上如图20所示。
在某一实施方案中，当n为1，m为2，X为CH 3C(O)OH时，所述如式(I)所示化合物的结晶形式为盐酸盐醋酸溶剂合物晶型I；使用Cu-Kα辐射，其以2θ角表示的X-射线粉末衍射图的衍射峰和相对强度如下表所示：
角度2θ/° 相对强度％ 角度2θ/° 相对强度％ 角度2θ/° 相对强度％
6.539 100.0 7.019 2.8 7.534 4.6
15.942 1.6 18.416 1.9 18.763 3.8
19.441 2.9 19.739 4.4 20.700 3.4
20.898 6.3 21.741 2.0 22.720 2.0
24.505 2.7 24.878 3.3 26.421 4.2
。
在某一实施方案中，使用Cu-Kα辐射，所述盐酸盐醋酸溶剂合物晶型I以2θ角表示的X-射线粉末衍射图还可基本上如图16所示。
在某一实施方案中，当n为1，m为1.5，X为CH 3CH 2OH时，所述如式(I)所示化合物的结晶形式为盐酸盐乙醇溶剂合物晶型I；使用Cu-Kα辐射，其以2θ角表示的X-射线粉末衍射图谱的衍射峰和相对强度如下表所示：
角度2θ/° 相对强度％ 角度2θ/° 相对强度％ 角度2θ/° 相对强度％
6.454 100.0 7.239 27.0 9.157 11.9
11.702 12.5 12.966 7.2 13.417 4.9
16.183 4.5 19.496 7.5 20.229 10.5
20.679 7.3 21.964 12.8 22.397 6.7
23.545 8.8 25.181 9.0 26.068 9.5
。
在某一实施方案中，使用Cu-Kα辐射，所述盐酸盐乙醇溶剂合物晶型I以2θ角表示的X-射线粉末衍射图还可基本上如图14所示。
在某一实施方案中，所述盐酸盐乙醇溶剂合物晶型I的热重分析图在50℃至125℃有重量损失，所述重量损失可为12.7±0.5％(例如12.7±0.2％)。
在某一实施方案中，所述盐酸盐乙醇溶剂合物晶型I的热重分析图(TGA)还可基本上如图15所示。
在某一实施方案中，当n为0，m为1，X为CH 3C(O)OH时，所述如式(I)所示化合物的结晶形式为醋酸溶剂合物晶型I；使用Cu-Kα辐射，其以2θ角表示的X-射线粉末衍射图，在5.3±0.2°、8.5±0.2°、10.8±0.2°、18.7±0.2°和20.4±0.2°处具有衍射峰。
在某一实施方案中，使用Cu-Kα辐射，所述醋酸溶剂合物晶型I以2θ角表示的X-射线粉末衍射图，还可在如下一个或多个2θ角处有衍射峰：4.9±0.2°、10.1±0.2°、11.8±0.2°、12.8±0.2°、14.0±0.2°、15.2±0.2°、15.8±0.2°、17.1±0.2°、17.6±0.2°、21.7±0.2°、23.7±0.2°和25.9±0.2°。
在某一实施方案中，使用Cu-Kα辐射，所述醋酸溶剂合物晶型I以2θ角表示的X-射线粉末衍射图，其衍射峰和相对强度还可如下表所示：
角度2θ/° 相对强度％ 角度2θ/° 相对强度％ 角度2θ/° 相对强度％
4.911 26.0 5.337 38.6 5.849 6.8
8.467 55.7 10.129 50.2 10.761 100.0
11.803 49.8 12.851 9.6 13.953 21.5
15.184 20.9 15.766 30.2 17.074 19.9
17.605 10.5 18.738 41.4 20.442 30.7
21.671 24.5 23.670 10.3 23.940 9.1
25.875 12.6        
。
在某一实施方案中，使用Cu-Kα辐射，所述醋酸溶剂合物晶型I以2θ角表示的X-射线粉末衍射图还可基本上如图6所示。
在某一实施方案中，所述醋酸溶剂合物晶型I的差示扫描量热图(DSC)中分别在167.2±5℃(例如167.2±3℃)和238.5±5℃(例如238.5±3℃)处有吸收峰。
在某一实施方案中，所述醋酸溶剂合物晶型I的差示扫描量热图还可基本上如图7所示。
在某一实施方案中，所述醋酸溶剂合物晶型I的热重分析图在100℃至160℃有重量损失，所述重量损失可为10±0.5％(例如10±0.2％)。
在某一实施方案中，所述醋酸溶剂合物晶型I的热重分析图(TGA)还可基本上如图8所示。
在某一实施方案中，当n为0，m为2，X为CH 3C(O)OH时，所述如式(I)所示化合物的结晶形式为醋酸溶剂合物晶型II；使用Cu-Kα辐射，其以2θ角表示的X-射线粉末衍射图，在6.5±0.2°、7.1±0.2°、7.5±0.2°、13.7±0.2°和24.5±0.2°处具有衍射峰。
在某一实施方案中，使用Cu-Kα辐射，所述醋酸溶剂合物晶型II以2θ角表示的X-射线粉末衍射图，还可在如下一个或多个2θ角处有衍射峰：19.4±0.2°、20.8±0.2°、23.1±0.2°和24.8±0.2°。
在某一实施方案中，使用Cu-Kα辐射，所述醋酸溶剂合物晶型II以2θ角表示的X-射线粉末衍射图，其衍射峰和相对强度还可如下表所示：
角度2θ/° 相对强度％ 角度2θ/° 相对强度％ 角度2θ/° 相对强度％
6.518 100.0 7.081 62.3 7.491 6.1
13.700 9.1 14.739 3.9 15.059 3.8
18.501 3.9 18.759 3.8 19.404 5.7
20.099 18.2 20.799 4.5 21.838 3.6
23.081 4.0 24.543 6.8 24.835 5.2
。
在某一实施方案中，使用Cu-Kα辐射，所述醋酸溶剂合物晶型II以2θ角表示的X-射线粉末衍射图还可基本上如图10所示。
在某一实施方案中，所述醋酸溶剂合物晶型II的差示扫描量热图(DSC)中在115.8±5℃(例如115.8±3℃)处有吸收峰。
在某一实施方案中，所述醋酸溶剂合物晶型II的差示扫描量热图还可基本上如图11所示。
在某一实施方案中，所述醋酸溶剂合物晶型II的热重分析图可在100℃至160℃有重量损失；所述重量损失可为11.6±0.5％(例如11.6±0.2％)。
在某一实施方案中，所述醋酸溶剂合物晶型II的热重分析图(TGA)还可基本上如图12所示。
本发明还提供了化合物A的结晶形式：
Figure PCTCN2022074486-appb-000004
所述化合物A的结晶形式为化合物A的晶型I；使用Cu-Kα辐射，其以2θ角表示的X-射线粉末衍射图，在6.3±0.2°、7.4±0.2°、8.7±0.2°、15.3±0.2°和17.5±0.2°处具有衍射峰。
在某一实施方案中，使用Cu-Kα辐射，所述化合物A的晶型I以2θ角表示的X-射线粉末衍射图，还可在如下一个或多个2θ角处有衍射峰：12.4±0.2°、14.9±0.2°、15.7±0.2°、17.3±0.2°、18.9±0.2°、20.5±0.2°、21.6±0.2°、22.3±0.2°、22.9±0.2°、23.1±0.2°、24.0±0.2°和26.0±0.2°。
在某一实施方案中，使用Cu-Kα辐射，所述化合物A的晶型I以2θ角表示的X-射线粉末衍射图，还可在如下一个或多个2θ角处有衍射峰：20.7±0.2°、21.9±0.2°、23.7±0.2°、24.3±0.2°和25.4±0.2°。
在某一实施方案中，使用Cu-Kα辐射，所述化合物A的晶型I以2θ角表示的X-射线粉末衍射图还可基本上如图2所示。
在某一实施方案中，所述化合物A的晶型I的差示扫描量热图(DSC)中在235.1±5℃(例如235.1±3℃)处有吸收峰。
在某一实施方案中，所述化合物A的晶型I的差示扫描量热图还可基本上如图3所示。
在某一实施方案中，所述化合物A的晶型I的热重分析图(TGA)还可基本上如图4所示。
本发明提供了如式(I)所示化合物的制备方法，其包括以下方法一、方法二或方法三：
方法一：
将化合物A溶于X中，析晶，得到如式(I)所示化合物，
Figure PCTCN2022074486-appb-000005
方法一中，n为0，m和X的定义如前所述；
方法二：
将化合物A置于X中和HCl反应，析晶，得到如式(I)所示化合物，
Figure PCTCN2022074486-appb-000006
方法二中，n为1，m为0-3的任意数值；X的定义如前所述；
方法三：
将如式(II)所示化合物溶于有机溶剂-水的混合溶液中，析晶，得到如式(I)所示化合物，
Figure PCTCN2022074486-appb-000007
方法三中，n为0-1的任意数值，m和m’独立地为0-3的任意数值，且n和m均不为0；X为H 2O；Y为CH 3CH 2OH、CH 3C(O)OH、CH 3C(O)OCH 2CH 3、CH 3C(O)CH 3或(CH 3) 2CHOH。
所述方法一中，所述化合物A溶于X的过程可通过如下方法实现：将化合物A溶解在有机溶剂中形成混合物，再将所述混合物溶解于X中；或者，将化合物A置于X中加热，使其溶清即可。
所述方法一中，当化合物A溶解在有机溶剂中形成混合物时，所述有机溶剂的种类可为本领域常规，以能溶解化合物A并能和X混溶即可，例如，当X为醋酸时，所述有机溶剂可为二氯甲烷和/或甲醇。
所述方法一中，当化合物A溶解在有机溶剂中形成混合物时，所述有机溶剂的量可不做限定，以使化合物A溶解即可。
所述方法一中，当将化合物A置于X中并加热时，较佳地，将其加热至本领域常规的温度，例如60℃～120℃，又例如60℃～85℃，再例如79.5℃或80℃。
所述方法一中，当将化合物A置于X中加热使其溶清时，所述X的量可不做限定，以使化合物A溶清即可。所述方法二中，当X为H 2O时，所述反应还进一步包含醇类和/或酮类溶剂；所述醇类溶剂的种类可为本领域常规，例如：异丙醇和/或乙醇，优选为异丙醇；所述酮类溶剂的种类可为本领域常规，例如丙酮。所述方法二中，所述化合物A置于X中的温度可为本领域常规，例如10℃～85℃，又例如10℃～30℃或60℃。
所述方法二中，所述HCl可为氯化氢气体、盐酸(例如：浓盐酸)、盐酸醇溶液(例如：盐酸乙醇溶液、盐酸甲醇溶液、盐酸异丙醇溶液)、盐酸酮溶液(例如：盐酸丙酮溶液)、氯化氢醇溶液(例如：氯化氢乙醇溶液、氯化氢甲醇溶液、氯化氢异丙醇溶液)、氯化氢酮溶液(氯化氢丙酮溶液)等，较佳地为盐酸的乙醇溶液、浓盐酸、氯化氢乙醇溶液(例如2M的氯化氢乙醇溶液)或盐酸异丙醇溶液。所述化合物A和HCl的摩尔比可为本领域常规，例如1：(1～15)，又例如1:1、1:1.2、1:1.5、1:2、1:3或1:10。所述方法三中，所述有机溶剂的种类可为本领域常规，以使能溶解如式(II)所示化合物以及能与水混溶即可，优选为二氯甲烷和甲醇、异丙醇和丙酮的一种或多种。
所述方法三中，所述有机溶剂-水的混合溶液的量可不做限定，以使如式(II)所示化合物溶清即可。
所述方法三中，所述有机溶剂-水的混合溶液中，所述有机溶剂的体积百分数可为本领域常规，优选为50％～98％，例如50％、75％、85％或95％。
所述方法三中，所述如式(II)所示化合物还可经加热溶解于有机溶剂-水的混合溶液中；较佳地，将其加热至本领域常规的温度(例如：10℃～80℃)，优选30℃～80℃，例如50℃。
所述方法三中，Y优选为CH 3CH 2OH、CH 3C(O)OH或(CH 3) 2CHOH。
所述方法三中，所述如式(II)所示化合物可由所述方法二制备得到。
本发明还提供了一种药物组合物，其包括治疗有效量的活性组分以及药学上可接受的辅料；所述活性组分包括如式(I)所示化合物。
所述药物组合物中，所述活性组分还可包括癌症、病毒感染或自身免疫疾病的其它治疗剂。
所述药物组合物中，所述药学上可接受的辅料可包括药学上可接受的载体、稀释剂和/或赋形剂。
根据治疗目的，可将药物组合物制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、胶囊、栓剂和注射剂(包括注射液、注射用无菌粉末(粉针)与注射用浓溶液)等，优选液体、悬浮液、乳液、栓剂和针剂(溶液及悬浮液)等。
为了使片剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋形剂。例如，载体，如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素和硅酸等；粘合剂，如水、乙醇、丙醇、普通糖浆、葡萄糖溶液、淀粉溶液、明胶溶液，羧甲基纤维素、紫胶、甲基纤维素和磷酸钾、聚乙烯吡咯烷酮等；崩解剂，如干淀粉、藻酸钠、琼脂粉和海带粉，碳酸氢钠、碳酸钙、聚乙烯脱水山梨醇的脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘酯、淀粉和乳糖等；崩解抑制剂，如白糖、甘油三硬脂酸酯、椰子油和氢化油；吸附促进剂，如季胺碱和十二烷基硫酸钠等；润湿剂，如甘油、淀粉等；吸附剂，如淀粉、乳糖、高岭土、膨润土和胶体硅酸等；以及润滑剂，如纯净的滑石，硬脂酸盐、硼酸粉和聚乙二醇等。还可以根据需要选用通常的涂渍材料制成糖衣片剂、涂明胶膜片剂、肠衣片剂、涂膜片剂、双层膜片剂及多层片剂。
为了使丸剂形式的药物组合物成形，可使用本领域任何已知的并广泛使用的赋形剂，例如，载体，如乳糖，淀粉，椰子油，硬化植物油，高岭土和滑石粉等；粘合剂，如阿 拉伯树胶粉，黄蓍胶粉，明胶和乙醇等；崩解剂，如琼脂和海带粉等。
为了使栓剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋性剂，例如，聚乙二醇，椰子油，高级醇，高级醇的酯，明胶和半合成的甘油酯等。
为了制备注射剂形式的药物组合物，可使用本领域任何已知并广泛使用的载体或赋性剂，所用载体或赋形剂包含注射用水、林格氏液和等渗氯化钠溶液，也可根据药物的性质加入适宜的附加剂例如抗氧化剂、增溶剂、PH调节剂和抑菌剂。
本发明中，所述药物组合物中的所述活性组分的含量无特殊限制，可在很宽的范围内进行选择，通常可为质量百分比的5～95％，较佳的为质量百分比30～80％。
本发明中，所述药物组合物的给药方法没有特殊限制。可根据病人年龄、性别和其它条件及症状，选择各种剂型的制剂给药。例如，片剂、丸剂、溶液、悬浮液、乳液、颗粒剂或胶囊口服给药；注射剂可以单独给药，或者和注射用输送液(如葡萄糖溶液及氨基酸溶液)混合进行静脉注射、肌肉注射或病灶局部注射；栓剂为给药到直肠。
本发明还提供了如式(I)所示化合物、或所述药物组合物在制备TLRs调节剂中的应用。
所述在制备TLRs调节剂中的应用中，所述TLRs调节剂包括TLRs完全激动剂或者TLRs部分激动剂。所述TLRs优选TLR7、TLR8和TLR9中的一种或者多种，更优选为TLR8。
本发明还提供了如式(I)所示化合物、或所述药物组合物在制备调节T细胞药物中的应用。
本发明还提供了如式(I)所示化合物、或所述药物组合物在制备治疗、缓解和/或预防由TLRs介导的相关疾病的药物中的应用。
本发明中，所述如式(I)所示化合物、或所述药物组合物在制备治疗和/或缓解由TLRs介导的相关疾病的药物中的应用中，较佳地，所述由TLRs介导的相关疾病的药物为由TLR8介导的相关疾病的药物；所述疾病包括肿瘤和非肿瘤性疾病。所述疾病包括但不限于：癌症、病毒感染，以及自身免疫性疾病等；所述癌症优选免疫制剂相关的癌症，所述免疫抑制是指肿瘤特异性地免疫抑制。
本发明中，所述如式(I)所示化合物、或所述药物组合物在制备治疗和/或缓解癌症、病毒感染以及自身免疫性疾病的药物中的应用。
本发明还进一步提供了用所述如式(I)所示化合物，或所述药物组合物治疗、缓解和/或预防癌症、病毒感染或自身免疫性疾病的方法，包括：给予哺乳动物治疗所需剂量的如式(I)所述化合物，或药物组合物。
所述哺乳动物，优选人。
本发明还进一步提供了所述如式(I)所示化合物、或所述药物组合物和一种或多种其它种类的治疗剂和/或治疗方法联合用于治疗、缓解和/或预防由TLRs介导的相关疾病，尤其指由TLR8介导的相关疾病。所述的TLR8介导的相关疾病是指由TLR8介导的免疫抑制而引起的疾病，所述的疾病可包括：癌症、病毒感染或自身免疫性疾病等。
本发明优选用所述如式(I)所示化合物，或所述药物组合物和一种或多种其它种类的治疗剂联合用于治疗和/或缓解由TLR8介导的疾病，所述疾病优选为癌症。
本发明还进一步提供了所述如式(I)所示化合物、或所述药物组合物和一种或多种其它种类的治疗剂联合用于治疗和/或缓解癌症、病毒感染以及自身免疫性疾病。
本发明还进一步提供了所述如式(I)所示化合物、或所述药物组合物和一种或多种其它种类的治疗剂联合用于治疗和/或缓解癌症。
所述其它种类的治疗剂(例如：用于治疗癌症的其它种类的治疗剂)可以和所述的如式(I)所示化合物做成单一给药的治疗剂型，或者分别先后给药的治疗剂型。
所述病毒感染可包括：由流感病毒、仙台病毒、柯萨奇病毒、登革热病毒、新城疫病毒(NDV)、水泡性口炎病毒(VSV)吧、乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)、人类乳头状瘤病毒(HPV)、巨细胞病毒(CMV)、爱泼斯坦-巴尔病毒(EBV)、脊髓灰质炎病毒、疱疹病毒(HSV)(例如：水痘带状疱疹病毒、单纯疱疹病毒及其他人类疱疹病毒)或I型人类免疫缺陷病毒(HIV)等病毒引起的感染。
所述的癌症包括转移性的和非转移性的癌症，也包括家族遗传性的和偶发性的癌症，还可包括固体肿瘤和非固体肿瘤。
所述固体肿瘤的具体例子可包括但不限于：眼癌、骨癌、肺癌、胃癌、胰腺癌、乳腺癌、前列腺癌、脑癌(包括噁性胶质瘤、成神经管细胞瘤)、卵巢癌、膀胱癌、子宫颈癌、睾丸癌、肾癌(包括腺癌和肾母细胞癌)、口腔癌(包括鳞状细胞癌)、舌癌、喉癌、鼻咽癌、头颈癌、结肠癌、小肠癌、直肠癌、甲状旁腺癌、甲状腺癌、食管癌、胆囊癌、胆管癌、宫颈癌、肝癌、肺癌、肉瘤、和皮肤癌中的一种或多种。
所述非固体肿瘤(包括血液学肿瘤)的具体例子可包括但不限于：淋巴性白血病(包括急性淋巴细胞白血病、淋巴瘤、骨髓瘤、慢性淋巴细胞白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、T细胞慢性淋巴性白血病、B细胞慢性淋巴性白血病)、髓性相关的白血病(包括急性髓性白血病、慢性髓性白血病)和AIDs相关的白血病中的一种或多种。
所述的自身免疫性疾病可包括但不限于：类风湿性关节炎、全身性红斑狼疮、混合性结缔组织病(MCTD)、系统硬皮病(包括：CREST综合症)、皮肌炎、结节性脉管炎、 肾病(包括：肺出血肾炎综合症、急性肾小球肾炎、原发性膜增殖性肾小球肾炎等)、内分泌相关疾病(包括：I型糖尿病、性腺机能不全、噁性贫血、甲状腺机能亢进等)、肝病(包括：原发性胆汁性肝硬化、自身免疫性胆管炎、自身免疫性肝炎、原发性硬化性胆管炎等)和由于感染引起的自身免疫反应(例如：艾滋病、疟疾等)中的一种或多种。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明如式(I)所示化合物的晶型具有较佳的溶解度和稳定性，更适用于药物剂型的制备，且由如式(I)所示化合物制备得到的药物在体内具有较佳地吸收和代谢效果。
附图说明
图1为CN107344931A公开的化合物1-8-5的XRPD图谱。
图2为实施例2中化合物A的晶型I的XRPD图谱。
图3为实施例2中化合物A的晶型I的DSC图谱。
图4为实施例2中化合物A的晶型I的TGA图谱。
图5为实施例2中化合物A的晶型I的 1H NMR图谱。
图6为实施例3中化合物A的醋酸溶剂合物晶型I的XRPD图谱。
图7为实施例3中化合物A的醋酸溶剂合物晶型I的DSC图谱。
图8为实施例3中化合物A的醋酸溶剂合物晶型I的TGA图谱。
图9为实施例3中化合物A的醋酸溶剂合物晶型I的 1H NMR图谱。
图10为实施例4中化合物A的醋酸溶剂合物晶型II的XRPD图谱。
图11为实施例4中化合物A的醋酸溶剂合物晶型II的DSC图谱。
图12为实施例4中化合物A的醋酸溶剂合物晶型II的TGA图谱。
图13为实施例4中化合物A的醋酸溶剂合物晶型II的 1H NMR图谱。
图14为实施例5中化合物A的盐酸盐乙醇溶剂合物晶型I的XRPD图谱。
图15为实施例5中化合物A的盐酸盐乙醇溶剂合物晶型I的TGA图谱。
图16为实施例6中化合物A的盐酸盐醋酸溶剂合物晶型I的XRPD图谱。
图17为实施例6中化合物A的盐酸盐醋酸溶剂合物晶型I的 1H NMR图谱。
图18为实施例8中化合物A的盐酸盐水合物晶型I的XRPD图谱。
图19为实施例8中化合物A的盐酸盐水合物晶型I的DSC图谱。
图20为实施例8中化合物A的盐酸盐水合物晶型I的TGA图谱。
图21为实施例8中化合物A的盐酸盐水合物晶型I的 1H NMR图谱。
图22为实施例8中化合物A的盐酸盐水合物晶型I晶型稳定性测试前后的XRPD叠加图。
图23为实施例4中化合物A的醋酸溶剂合物晶型II晶型稳定性测试前后的XRPD叠加图。
图24为实施例8中化合物A的盐酸盐水合物晶型I长期稳定性测试前后的XRPD叠加图。
图25为实施例7中化合物A的盐酸盐的 1H NMR图谱。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
1H NMR化学位移(δ)以PPM记录(10 -6)。NMR通过Bruker Avance III HD 400光谱仪进行。合适的溶剂是氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，氘代二甲亚砜(DMSO-d6)，四甲基硅烷作为内标(TMS)。
固体样品用粉末X射线衍射分析仪(Bruker D8 advance)进行分析。该仪器配备了SSD160探测器，样品的2θ扫描角度范围为3°到40°，扫描步长为0.02°。测定样品时的光管电压和光管电流分别为40KV和40mA。
示差扫描量热分析(DSC)的仪器型号为TA Discovery DSC 250。样品经精确称重后置于加盖Tzero样品盘中，并记录下样品的准确质量。样品以10℃/min的升温速率加热至最终温度。
热重分析(TGA)的仪器型号为Discovery TGA 550。将样品置于已平衡的样品盘中，样品量在TGA加热炉内自动称量。样品以10℃/min的速率加热至最终温度。
气相分析色谱(GC)的仪器型号为安捷伦7890B气相色谱仪。
K-F水分检测使用870 KF Titrino plus水分滴定仪。
离子色谱使用Thermo Fisher ICS-1100离子色谱仪，色谱柱：AS11-HC 4*250mm，淋洗液25mmol的氢氧化钾水溶液，流速：1mL/分钟。
以下实施例中，化合物1-8-5指参照专利CN107344931A实施例52的方法制得的化合物1-8-5，用粉末X射线衍射分析仪(Bruker D8 advance)对其产物进行分析，其XRPD 图谱如图1所示，结果显示，该方法制得的化合物为非晶形(无定形)化合物。
实施例1 2-氨基-8-(2-(2-(甲磺酰基)乙基)-1-氧代-1,2-二氢酞嗪-6-基)-N,N-二异丙基-3H-苯并氮杂卓-4-甲酰胺(化合物A)的合成
方法1：
Figure PCTCN2022074486-appb-000008
步骤1：氮气保护下，向化合物1.10(2.1g，1eq)的四氢呋喃(90mL)溶液中依次加入化合物22.7(2.7g，1.5eq)、碳酸钠水溶液(29.2mL，2.0M)和Pd(dppf) 2Cl 2(369mg，0.1当量)，加毕，反应体系用氮气置换三次，反应体系在70℃下搅拌直到TLC检测反应完成(约1.5小时)。向反应体系中加入水(50mL)淬灭反应，混合物用乙酸乙酯(150mL×3)萃取，合并有机相，有机相用饱和食盐水洗涤，分离有机相，用无水硫酸钠干燥，过滤、浓缩，得到的残留物用硅胶柱层析(石油醚/乙酸乙酯＝4/1～1/1)纯化得到中间体1(3.16g)为浅黄色泡沫状固体。
步骤2：冰浴条件下，向中间体1(2.16g)的二氯甲烷(22mL)溶液中加入三氟乙酸(3.24mL)，加毕，反应体系在室温下搅拌4小时。减压除去溶剂，得到的残留物重新加入到二氯甲烷(50mL)中，溶清后加入活性炭(2g)搅拌10分钟，过滤，滤液减压浓缩，得到的固体重新溶解在二氯甲烷(50mL)和甲醇(5mL)中，加入饱和的碳酸氢钠水溶液(20mL)，搅拌10分钟，静置分层。分离有机相，水相用二氯甲烷萃取(20mL×2)，合并有机相并用无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物A(1.01g)为类白色固体。
方法2：向化合物A的盐酸盐醋酸溶剂合物(15g)中分别加入二氯甲烷(210mL)和无水乙醇(105mL)，室温搅拌溶清；加入饱和碳酸氢钠水溶液约(113mL)调pH至8左右，分液；有机层用饱和氯化钠溶液(200mL)洗涤1次，分离有机层并用无水硫酸钠干燥，过滤，滤液在40℃下减压浓缩至干，得到化合物A(12.5g)为浅黄色固体。
实施例2化合物A的晶型I
将化合物A(1g)加入无水乙醇(40mL)，溶清后超声5-10分钟，析出固体后继续搅拌1小时，过滤，滤饼室温下真空干燥过夜得到化合物A，其为类白色固体，为化合物A的晶型I。并分别进行了XRPD、DSC、TGA和 1H NMR表征，其结果分别如图2、图3、图4和图5所示。
实施例3化合物A的醋酸溶剂合物晶型I
将化合物A(1g，1eq)溶解在二氯甲烷(8mL)和甲醇(4mL)的混合溶剂中，加入醋酸(224mg，2eq)，得到的溶液室温搅拌0.5小时后加入乙酸乙酯(20mL)继续搅拌1h析晶，过滤，得到的固体50℃真空干燥4小时得到相应的化合物A的醋酸溶剂合物晶型I。样品为类白色粉末，并分别进行了XRPD、DSC、TGA和 1H NMR表征。
如图9所示， 1H NMR结果显示样品无溶剂残留，且游离碱和醋酸的比例约为1:1。如图8所示，TGA在175℃之前有10.16％的失重。如图7所示，DSC图谱显示其吸热峰的温度约在167.21℃和238.50℃。如图6所示XRPD检测证明为化合物A的醋酸溶剂合物晶型I。化合物A的醋酸溶剂合物晶型I的XRPD衍射峰如表1所示。
表1.化合物A的醋酸溶剂合物晶型I的XRPD衍射峰列表
角度2θ/° 相对强度％ 角度2θ/° 相对强度％ 角度2θ/° 相对强度％
4.911 26.0 5.337 38.6 5.849 6.8
8.467 55.7 10.129 50.2 10.761 100.0
11.803 49.8 12.851 9.6 13.953 21.5
15.184 20.9 15.766 30.2 17.074 19.9
17.605 10.5 18.738 41.4 20.442 30.7
21.671 24.5 23.670 10.3 23.940 9.1
25.875 12.6        
实施例4化合物A的醋酸溶剂合物晶型II
方法1：取化合物A(506mg)，加入醋酸(1.25mL)，升温至79.5℃溶清，立刻滴加乙酸乙酯(10mL)，约30秒加完，加的过程即有白色固体析出，立刻置于室温下搅拌析晶2.5小时，过滤，滤饼用乙酸乙酯(1mL)淋洗。得到的固体40℃真空干燥4小时得到相应的化合物A的醋酸溶剂合物晶型II。样品为类白色粉末。
方法2：取化合物A(7.26g)，加入醋酸(18mL)，升温至80℃溶清，保温80℃滴加乙酸乙酯(180mL)，约30秒加完，加的过程即有白色固体析出，立刻置于室温下搅拌析晶0.5小时，冰水浴0.5小时，过滤，滤饼用乙酸乙酯(20mL)淋洗。得到的固体45℃真空干燥1.5小时得到相应的化合物A的醋酸溶剂合物晶型II。样品为类白色粉末。
化合物A的醋酸溶剂合物晶型II的检测结果如下：如图13所示， 1H NMR结果显示样品无溶剂残留，且游离碱和醋酸的比例约为1:2。如图12所示，TGA在175℃之前有11.58％的失重。如图11所示，DSC图谱显示其吸热峰的温度约在115.79℃。如图10所示XRPD检测证明为化合物A的醋酸溶剂合物晶型II。化合物A的醋酸溶剂合物晶型II的XRPD衍射峰如表2所示。如图23所示，光照4500lux和40℃-92.5％RH带包装条件下放置31天，晶型均不变。
表2.化合物A的醋酸溶剂合物晶型II的XRPD衍射峰列表
角度2θ/° 相对强度％ 角度2θ/° 相对强度％ 角度2θ/° 相对强度％
6.518 100.0 7.081 62.3 7.491 6.1
13.700 9.1 14.739 3.9 15.059 3.8
18.501 3.9 18.759 3.8 19.404 5.7
20.099 18.2 20.799 4.5 21.838 3.6
23.081 4.0 24.543 6.8 24.835 5.2
实施例5化合物A的盐酸盐乙醇溶剂合物晶型I
取实施例1制备的化合物A(100mg)，加入乙醇(4mL)，得到的浑浊液在室温搅拌下加入浓盐酸(21mg)的乙醇溶液，析出固体，室温下搅拌3天，过滤，滤饼45℃鼓风干燥2小时得到化合物A的盐酸盐乙醇溶剂合物晶型I。样品为白色粉末。并分别进行了XRPD和TGA表征。
如图15所示，TGA在125℃之前有12.74％的失重，GC色谱检测乙醇含量约为10.5％，游离碱和乙醇的比例约为1:1.5，如图14所示XRPD检测证明为化合物A的盐酸盐乙醇溶剂合物晶型，化合物A的盐酸盐乙醇溶剂合物晶型I的XRPD衍射峰如表3所示。
表3.化合物A的盐酸盐乙醇溶剂合物晶型I的XRPD衍射峰列表
角度2θ/° 相对强度％ 角度2θ/° 相对强度％ 角度2θ/° 相对强度％
6.454 100.0 7.239 27.0 9.157 11.9
11.702 12.5 12.966 7.2 13.417 4.9
16.183 4.5 19.496 7.5 20.229 10.5
20.679 7.3 21.964 12.8 22.397 6.7
23.545 8.8 25.181 9.0 26.068 9.5
实施例6化合物A的盐酸盐醋酸溶剂合物晶型I
方法1：取化合物A(300mg，1eq)，加入醋酸(6mL)，加热至60℃，搅拌十分钟后加入浓盐酸(60mg，1.05eq)，降至室温析出固体，然后在室温下搅拌1天，过滤，滤 饼45℃鼓风干燥4小时得到化合物A的盐酸盐醋酸溶剂合物晶型I。样品为白色粉末。
方法2：取化合物1-8-5(100g，1eq)，加入醋酸(750mL)，加热至60℃。加入活性炭(10g)搅拌10分钟，过滤(重复两次)，搅拌下40℃条件下加入氯化氢乙醇溶液(10％，112g，2eq)，加入醋酸(100mL)后降温析出固体，过滤，滤饼加入到预热的醋酸(500mL)中，加毕，向体系中继续加入醋酸(500mL)，90℃下搅拌1小时，冷却至室温析晶体。过滤，滤饼45℃鼓风干燥6小时得到化合物A的盐酸盐醋酸溶剂合物晶型I。样品为类白色粉末。
化合物A的盐酸盐醋酸溶剂合物晶型I的检测结果如下：如图17所示， 1H NMR显示化合物A和醋酸比例为1:2。如图16所示XRPD检测证明为化合物A的盐酸盐醋酸溶剂合物晶型I，化合物A的盐酸盐醋酸溶剂合物晶型I的XRPD衍射峰如表4所示。
表4.化合物A的盐酸盐醋酸溶剂合物晶型I的XRPD衍射峰列表
角度2θ/° 相对强度％ 角度2θ/° 相对强度％ 角度2θ/° 相对强度％
6.539 100.0 7.019 2.8 7.534 4.6
15.942 1.6 18.416 1.9 18.763 3.8
19.441 2.9 19.739 4.4 20.700 3.4
20.898 6.3 21.741 2.0 22.720 2.0
24.505 2.7 24.878 3.3 26.421 4.2
实施例7化合物A的盐酸盐的制备
向化合物A(200mg，1eq)中加入乙醇(4mL)，向得到的浑浊液中加入氯化氢乙醇溶液(2M，0.6mL，3.2eq)，继续搅拌1小时，加入水(20mL)后直接冷冻干燥得到化合物A的盐酸盐，为类白色粉末。如图25所示， 1H NMR结果显示样品无乙醇溶剂残留。
m/z:[M+H] +535.8； 1H NMR(400MHz,DMSO-d 6):δ12.39(s,1H),9.93(s,1H),9.10(s,1H),8.57(s,1H),8.40(d,J＝8.4Hz,1H),8.35(d,J＝1.2Hz,1H),8.22(dd,J＝8.4Hz,J＝1.6Hz,1H),7.88-7.74(m,3H),7.07(s,1H),4.60(d,J＝6.8Hz,2H),3.66(d,J＝6.8Hz,2H),3.36(6H,被溶剂峰覆盖),3.10(s,3H),1.59(d,J＝7.2Hz,4H),0.91-0.82(m,6H)。
实施例8化合物A的盐酸盐水合物晶型I
方法1：向化合物A的盐酸盐乙醇溶剂合物(1g)中加入水(3mL)，加热至65℃，溶清，向体系中加入异丙醇(3mL)，体系降至室温搅拌1小时后冰浴冷却下析晶，过滤，得到的固体45℃鼓风干燥2小时得到相应的化合物A的盐酸盐水合物晶型I。样品为类白色粉末。
方法2：向化合物A的盐酸盐醋酸溶剂合物(100mg)中加入75％异丙醇-水混合溶 液(0.8mL)，先溶清后继续搅拌约0.5小时析出固体，过滤，得到的固体45℃鼓风干燥2小时得到相应的化合物A的盐酸盐水合物晶型I。样品为白色粉末。
方法3：向化合物A的盐酸盐醋酸溶剂合物(100mg)中加入85％异丙醇-水混合溶液(0.9mL)，加热至50℃溶清，立即取出置于室温下晶浆，约10分钟后析出固体，过滤，得到的固体45℃鼓风干燥2小时得到相应的化合物A的盐酸盐水合物晶型I。样品为白色粉末。
方法4：向化合物A的盐酸盐(100mg)中加入75％异丙醇-水混合溶液(0.8mL)，先溶清后继续搅拌约1小时析出固体，过滤，得到的固体45℃鼓风干燥2小时得到相应的化合物A的盐酸盐水合物晶型I。样品为类白色粉末。
方法5：将化合物A(1g，1eq)溶解在二氯甲烷(8mL)和甲醇(4mL)的混合溶剂中，加入氯化氢乙醇溶液(30％，0.45g，2eq)，溶清后加入乙酸乙酯(20mL)，析出固体，减压浓缩除去溶剂后加入二氯甲烷和甲醇混合溶液(5mL，2/1)，再加入水(20mL)和丙酮(20mL)，过滤，得到的固体50℃真空干燥4小时得到相应的化合物A的盐酸盐水合物晶型I。样品为类白色固体。
方法6：向化合物A(12.47g，1eq)中加入异丙醇(36mL)，得到的浑浊液用冰水浴保温，搅拌下加入浓盐酸(2.46g，1.05eq)和水(5mL)的混合液，加完后再加入水(31mL)，除去冰水浴，室温搅拌，溶清，室温搅拌10分钟后加入约5mg左右的晶种(晶种是根据上述方法1～5任一方案制备得到的化合物A的盐酸水合物晶型I)，慢慢大量固体析出，1小时后补加50％异丙醇-水混合溶液(10mL)，继续搅拌约45分钟，过滤，滤饼用少量50％异丙醇-水混合液淋洗，得到的固体35℃鼓风干燥5小时得到相应的化合物A的盐酸盐水合物晶型I。样品为类白色粉末。
化合物A的盐酸盐水合物晶型I的检测结果如下：如图21所示， 1H NMR结果显示样品无溶剂残留。如图20所示，TGA在125℃之前有6.052％的失重(与结构中含2分子结晶水的理论值(5.93％)基本相符)。K-F水分检测，含水量约为6.2％，游离碱和水的比例约为1:2。如图19所示，DSC图谱显示其吸热峰的温度约在136.25℃。离子色谱分析检测氯离子含量测定平均值％为5.81(理论值为5.83％)，说明游离碱和盐酸的比例为1:1。如图18所示，XRPD检测证明为盐酸盐水合物晶型。如图22所示，样品分别在高温60℃、光照4500lux、高湿92.5％RH、40℃-92.5％RH裸放和40℃-92.5％RH带包装条件下放置31天，晶型均无明显变化。如图24所示，样品在温度25℃±2℃，相对湿度为60％±5％条件下放置12个月晶型无明显变化。化合物A的盐酸盐水合物晶型I的XRPD衍射峰列表如表5所示。
表5.化合物A的盐酸盐水合物晶型I的XRPD衍射峰列表
角度2θ/° 相对强度％ 角度2θ/° 相对强度％ 角度2θ/° 相对强度％
7.082 9.7 9.793 100.0 10.477 54.9
12.470 20.7 12.834 6.9 13.987 15.5
15.635 23.8 17.404 33.69 17.937 14.8
18.686 6.8 19.027 16.6 19.674 48.6
20.294 15.8 21.534 9.8 22.000 11.0
22.669 70.2 23.613 6.5 24.438 10.6
24.803 15.1 25.191 22.0 26.005 9.6
26.815 26.3 29.283 11.3 29.937 6.0
32.029 5.2 34.121 9.1    
实施例9稳定性试验
为考察化合物A的溶剂合物的晶型以及化合物A的盐酸盐溶剂合物的晶型的稳定性，分别测试，
1)高温60℃、光照4500lux和高湿92.5％RH条件下对样品稳定性的影响，影响因素测试条件如下：
高温60℃：取样品适量，平铺于培养皿中，厚度不超过3mm，敞口置于60℃高温箱内。
高湿92.5％RH：取样品适量，平铺于培养皿中，厚度不超过3mm，敞口置于硝酸钾饱和溶液饱和的干燥器内。
光照4500lux：取样品适量，平铺于培养皿中，厚度不超过3mm，敞口置于4500lux强度的光照箱内。
分别在第0天、5天、10天和30天通过HPLC测试样品纯度。
色谱分析方法示例如下：
色谱柱：waters Xselect CSH TM C18，4.6mm*250mm，5μm。
流动相A：10mM磷酸二氢钾(用磷酸调pH值至值2.5)；流动相B：乙腈；流速：1.0毫升/分钟；柱温：35℃；波长：262nm；进样量：10μL；如表6所示为洗脱梯度：
表6
时间(min) A(％) B(％)
0 85 15
15 65 35
25 50 50
30 30 70
30.1 85 15
45 85 15
如表7所示为CN107344931A公开的化合物1-8-5、化合物A的溶剂合物的晶型以及化合物A的盐酸盐溶剂合物的晶型的影响因素检测结果：
表7
Figure PCTCN2022074486-appb-000009
Figure PCTCN2022074486-appb-000010
2)25℃±2℃；60％RH±5％RH条件下模拟市售包装的长期稳定性测试(12个月)，测试项包括性状、水分、有关物质、含量、微生物限度及细菌内毒素。
结果显示：盐酸盐水合物晶型I长期试验条件下放置12个月，已知杂质、单杂和总杂无明显变化，其余检测指标(性状、水分、含量)与0天相比，无明显变化；微生物限度及细菌内毒素检测符合规定限度(需氧菌总数不得过10 3cfu/g、霉菌和酵母菌总数不得过10 2cfu/g、大肠埃希菌：不得检出/g、细菌内毒素：<10EU/mg)。
实施例10溶解度测试
测试目的：考察化合物A的溶剂合物的晶型以及化合物A的盐酸盐溶剂合物的晶型在水中溶解度。
测试方法：取化合物A的晶型I、CN107344931A公开的化合物1-8-5和化合物A的溶剂合物的晶型以及化合物A的盐酸盐溶剂合物的晶型样品约10mg，置20mL具塞西林瓶中，在各西林瓶中分别加入水、5％乙醇水溶液约5mL，使其成为过饱和溶液，于25℃水浴振荡器中振摇或2-8℃磁力搅拌，分别于2小时、24小时取过饱和溶液(每个时间点对应配制一份溶液)，3000rpm/min离心15min。取上清液作为供试品溶液。另取化合物A的晶型I、CN107344931A公开的化合物1-8-5和化合物A的溶剂合物的晶型以及化合物A的盐酸盐溶剂合物的晶型样品约10mg，精密称定于20mL容量瓶中，用30％乙腈水溶液溶解并稀释至刻度线，作为对照溶液。分别精密量取空白溶液(30％乙腈水溶液)、对照溶液、供试品溶液各10μl注入液相色谱仪，记录色谱图。
色谱分析方法如下：
色谱柱：waters Xselect CSH TM C18，4.6mm*150mm，3.5μm。
流动相A：10mM磷酸二氢钾(用磷酸调pH值至值2.5)；流动相B：乙腈；流速：1.0毫升/分钟；柱温：35℃；波长：262nm；进样量：10μL；如表8所示为洗脱梯度：
表8
时间(min) A(％) B(％)
0 85 15
15 65 35
25 50 50
30 30 70
30.1 85 15
35 85 15
如表9所示为化合物A的晶型I、CN107344931A公开的化合物1-8-5、化合物A的溶剂合物的晶型以及化合物A的盐酸盐溶剂合物的晶型在水中溶解度的结果：
表9
Figure PCTCN2022074486-appb-000011
实施例11药代动力学测试
如表10所示为药物及试剂：待测化合物分别用以下溶媒配成溶液，其它试剂均为分析纯：
表10
Figure PCTCN2022074486-appb-000012
备注：表10中“40％PEG400+60％葡萄糖(5％)”中的百分数均为体积百分数。
测试用动物：雄性SPF级别SD大鼠(每组3只)，购于上海西普尔-必凯实验动物有限公司，给药前动物体重范围为：206.9～222.6g。
给药剂量：皮下注射(SC)10mg/Kg，给药浓度：2mg/Kg，给药体积：5mL/kg。
药代动力学测试：将待测化合物通过皮下注射给药方式给予SD雄性大鼠，血样经颈静脉穿刺采血，每个样品采集约0.25mL，肝素钠抗凝，采血时间点如下：给药前，给药后0.083h，0.25h，0.5h，1h，2h，4h，6h，8h，12h，24h。血液样本采集后置于冰上，离心分离血浆(离心条件：8000转/分钟，6分钟，2-8℃)。收集的血浆分析前存放于-80℃。血浆样品采用LC-MS/MS(API5500)进行分析，根据药物的血药浓度数据，使用药代动力学计算软件WinNonlin5.2非房室模型分别计算供试品的药时曲线下面积(AUC)、半衰期(t 1/2)、达峰时间(T max)、峰浓度(C max)、平均驻留时间(MRT)。结果见表11：
表11
Figure PCTCN2022074486-appb-000013
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (26)

  1. 一种如式(I)所示化合物，
    Figure PCTCN2022074486-appb-100001
    其中，X为H 2O、CH 3CH 2OH、CH 3C(O)OH、CH 3C(O)OCH 2CH 3、CH 3C(O)CH 3或(CH 3) 2CHOH；
    n为0-1的任意数值；m为0-3的任意数值；且m和n不同时为0。
  2. 如权利要求1所述的如式(I)所示化合物，其特征在于，X为H 2O、CH 3CH 2OH或CH 3C(O)OH，优选为H 2O；
    和/或，n为0或1，优选为1；
    和/或，m为0、1、1.5、2、2.5或3，优选为0、1、1.5或2。
  3. 如权利要求1所述的如式(I)所示化合物，其特征在于，n为1，m为1.5或2；或者，n为0，m为1或2；或者，n为1，m为0。
  4. 如权利要求1所述的如式(I)所示化合物，其特征在于，所述如式(I)所示化合物选自如下任一化合物：
    Figure PCTCN2022074486-appb-100002
    Figure PCTCN2022074486-appb-100003
  5. 如权利要求1-4至少一项所述的如式(I)所示化合物，其特征在于，当n为1，m为2，X为H 2O时，所述如式(I)所示化合物的结晶形式为盐酸盐水合物晶型I，使用Cu-Kα辐射，其以2θ角表示的X-射线粉末衍射图，在9.8±0.2°、10.5±0.2°、17.4±0.2°、19.7±0.2°和22.7±0.2°处具有衍射峰。
  6. 如权利要求5所述的如式(I)所示化合物，其特征在于，使用Cu-Kα辐射，所述盐酸盐水合物晶型I以2θ角表示的X-射线粉末衍射图，还在如下一个或多个2θ角处有衍射峰：7.1±0.2°、12.5±0.2°、14.0±0.2°、15.7±0.2°、18.0±0.2°和20.3±0.2°。
  7. 如权利要求6所述的如式(I)所示化合物，其特征在于，使用Cu-Kα辐射，所述盐酸盐水合物晶型I以2θ角表示的X-射线粉末衍射图，还在如下一个或多个2θ角处有衍射峰：12.9±0.2°、21.5±0.2°、22.0±0.2°、25.2±0.2°、26.0±0.2°、26.8±0.2°和29.3±0.2°。
  8. 如权利要求7所述的如式(I)所示化合物，其特征在于，使用Cu-Kα辐射，所述盐酸盐水合物晶型I以2θ角表示的X-射线粉末衍射图，还在如下一个或多个2θ角处有衍射峰：18.7±0.2°、19.0±0.2°、24.8±0.2°、29.9±0.2°和34.1±0.2°。
  9. 如权利要求8所述的如式(I)所示化合物，其特征在于，使用Cu-Kα辐射，所述盐酸盐水合物晶型I以2θ角表示的X-射线粉末衍射图，其衍射峰和相对强度如下表所示：
    角度2θ/° 相对强度％ 角度2θ/° 相对强度％ 角度2θ/° 相对强度％ 7.082 9.7 9.793 100.0 10.477 54.9 12.470 20.7 12.834 6.9 13.987 15.5 15.635 23.8 17.404 33.69 17.937 14.8 18.686 6.8 19.027 16.6 19.674 48.6 20.294 15.8 21.534 9.8 22.000 11.0 22.669 70.2 23.613 6.5 24.438 10.6 24.803 15.1 25.191 22.0 26.005 9.6 26.815 26.3 29.283 11.3 29.937 6.0 32.029 5.2 34.121 9.1    
    ；进一步地，所述盐酸盐水合物晶型I以2θ角表示的X-射线粉末衍射图基本上如图18所示；
    和/或，所述盐酸盐水合物晶型I的差示扫描量热图中在136.3±5℃(例如136.3±3℃)处有吸收峰；较佳地，所述盐酸盐水合物晶型I的差示扫描量热图基本上如图19所示；
    和/或，所述盐酸盐水合物晶型I的热重分析图在70℃至100℃有重量损失，所述重量损失为6±0.5％(例如6±0.2％)；较佳地，所述盐酸盐水合物晶型I的热重分析图基本上如图20所示。
  10. 如权利要求1-4至少一项所述的如式(I)所示化合物，其特征在于，当n为1，m为2，X为CH 3C(O)OH时，所述如式(I)所示化合物的结晶形式为盐酸盐醋酸溶剂合物晶型I，
    使用Cu-Kα辐射，其以2θ角表示的X-射线粉末衍射图的衍射峰和相对强度如下表所示：
    角度2θ/° 相对强度％ 角度2θ/° 相对强度％ 角度2θ/° 相对强度％ 6.539 100.0 7.019 2.8 7.534 4.6 15.942 1.6 18.416 1.9 18.763 3.8 19.441 2.9 19.739 4.4 20.700 3.4 20.898 6.3 21.741 2.0 22.720 2.0 24.505 2.7 24.878 3.3 26.421 4.2
    ；较佳地，所述盐酸盐醋酸溶剂合物晶型I以2θ角表示的X-射线粉末衍射图基本上如图16所示。
  11. 如权利要求1-4至少一项所述的如式(I)所示化合物，其特征在于，当n为1，m为1.5，X为CH 3CH 2OH时，所述如式(I)所示化合物的结晶形式为盐酸盐乙醇溶剂合物晶型I，使用Cu-Kα辐射，其以2θ角表示的X-射线粉末衍射图谱的衍射峰和相对强度如下表所示：
    角度2θ/° 相对强度％ 角度2θ/° 相对强度％ 角度2θ/° 相对强度％ 6.454 100.0 7.239 27.0 9.157 11.9 11.702 12.5 12.966 7.2 13.417 4.9 16.183 4.5 19.496 7.5 20.229 10.5 20.679 7.3 21.964 12.8 22.397 6.7 23.545 8.8 25.181 9.0 26.068 9.5
    ；较佳地，所述盐酸盐乙醇溶剂合物晶型I以2θ角表示的X-射线粉末衍射图基本上 如图14所示；
    和/或，所述盐酸盐乙醇溶剂合物晶型I的热重分析图基本上如图15所示。
  12. 如权利要求1-4至少一项所述的如式(I)所示化合物，其特征在于，当n为0，m为1，X为CH 3C(O)OH时，所述如式(I)所示化合物的结晶形式为醋酸溶剂合物晶型I，使用Cu-Kα辐射，其以2θ角表示的X-射线粉末衍射图，在5.3±0.2°、8.5±0.2°、10.8±0.2°、18.7±0.2°和20.4±0.2°处具有衍射峰。
  13. 如权利要求12所述的如式(I)所示化合物，其特征在于，使用Cu-Kα辐射，所述醋酸溶剂合物晶型I以2θ角表示的X-射线粉末衍射图，还在如下一个或多个2θ角处有衍射峰：4.9±0.2°、10.1±0.2°、11.8±0.2°、12.8±0.2°、14.0±0.2°、15.2±0.2°、15.8±0.2°、17.1±0.2°、17.6±0.2°、21.7±0.2°、23.7±0.2°和25.9±0.2°。
  14. 如权利要求13所述的如式(I)所示化合物，其特征在于，使用Cu-Kα辐射，所述醋酸溶剂合物晶型I以2θ角表示的X-射线粉末衍射图，其衍射峰和相对强度如下表所示：
    角度2θ/° 相对强度％ 角度2θ/° 相对强度％ 角度2θ/° 相对强度％ 4.911 26.0 5.337 38.6 5.849 6.8 8.467 55.7 10.129 50.2 10.761 100.0 11.803 49.8 12.851 9.6 13.953 21.5 15.184 20.9 15.766 30.2 17.074 19.9 17.605 10.5 18.738 41.4 20.442 30.7 21.671 24.5 23.670 10.3 23.940 9.1 25.875 12.6        
    ；进一步地，所述醋酸溶剂合物晶型I以2θ角表示的X-射线粉末衍射图基本上如图6所示；
    和/或，所述醋酸溶剂合物晶型I的差示扫描量热图中分别在167.2±5℃(例如167.2±3℃)和238.5±5℃(例如238.5±3℃)处有吸收峰；较佳地，所述醋酸溶剂合物晶型I的差示扫描量热图基本上如图7所示；
    和/或，所述醋酸溶剂合物晶型I的热重分析图在100℃至160℃有重量损失，所述重量损失为10±0.5％(例如10±0.2％)；较佳地，所述醋酸溶剂合物晶型I的热重分析图基本上如图8所示。
  15. 如权利要求1-4至少一项所述的如式(I)所示化合物，其特征在于，当n为0，m为2，X为CH 3C(O)OH时，所述如式(I)所示化合物的结晶形式为醋酸溶剂合物晶 型II，使用Cu-Kα辐射，其以2θ角表示的X-射线粉末衍射图，在6.5±0.2°、7.1±0.2°、7.5±0.2°、13.7±0.2°和24.5±0.2°处具有衍射峰。
  16. 如权利要求15所述的如式(I)所示化合物，其特征在于，使用Cu-Kα辐射，所述醋酸溶剂合物晶型II以2θ角表示的X-射线粉末衍射图，还在如下一个或多个2θ角处有衍射峰：19.4±0.2°、20.8±0.2°、23.1±0.2°和24.8±0.2°。
  17. 如权利要求16所述的如式(I)所示化合物，其特征在于，使用Cu-Kα辐射，所述醋酸溶剂合物晶型II以2θ角表示的X-射线粉末衍射图，其衍射峰和相对强度如下表所示：
    角度2θ/° 相对强度％ 角度2θ/° 相对强度％ 角度2θ/° 相对强度％ 6.518 100.0 7.081 62.3 7.491 6.1 13.700 9.1 14.739 3.9 15.059 3.8 18.501 3.9 18.759 3.8 19.404 5.7 20.099 18.2 20.799 4.5 21.838 3.6 23.081 4.0 24.543 6.8 24.835 5.2
    ；进一步地，所述醋酸溶剂合物晶型II以2θ角表示的X-射线粉末衍射图基本上如图10所示；
    和/或，所述醋酸溶剂合物晶型II的差示扫描量热图中在115.8±5℃(例如115.8±3℃)处有吸收峰；较佳地，所述醋酸溶剂合物晶型II的差示扫描量热图基本上如图11所示；
    和/或，所述醋酸溶剂合物晶型II的热重分析图在100℃至160℃有重量损失；所述重量损失可为11.6±0.5％(例如11.6±0.2％)；较佳地，所述醋酸溶剂合物晶型II的热重分析图基本上如图12所示。
  18. 一种化合物A的结晶形式，其特征在于，所述化合物A的结晶形式为化合物A的晶型I；使用Cu-Kα辐射，其以2θ角表示的X-射线粉末衍射图，在6.3±0.2°、7.4±0.2°、8.7±0.2°、15.3±0.2°和17.5±0.2°处具有衍射峰，
    Figure PCTCN2022074486-appb-100004
  19. 如权利要求18所述的化合物A的结晶形式，其特征在于，使用Cu-Kα辐射，所述化合物A的晶型I以2θ角表示的X-射线粉末衍射图，还在如下一个或多个2θ角处 有衍射峰：12.4±0.2°、14.9±0.2°、15.7±0.2°、17.3±0.2°、18.9±0.2°、20.5±0.2°、21.6±0.2°、22.3±0.2°、22.9±0.2°、23.1±0.2°、24.0±0.2°和26.0±0.2°；较佳地，所述化合物A的晶型I以2θ角表示的X-射线粉末衍射图，还在如下一个或多个2θ角处有衍射峰：20.7±0.2°、21.9±0.2°、23.7±0.2°、24.3±0.2°和25.4±0.2°；更佳地，所述化合物A的晶型I以2θ角表示的X-射线粉末衍射图基本上如图2所示；
    和/或，所述化合物A的晶型I的差示扫描量热图中在235.1±5℃(例如235.1±3℃)处有吸收峰；较佳地，所述化合物A的晶型I的差示扫描量热图基本上如图3所示；
    和/或，所述化合物A的晶型I的热重分析图基本上如图4所示。
  20. 如权利要求1～17至少一项所述的如式(I)所示化合物的制备方法，其特征在于，其包括以下方法一、方法二或方法三：
    方法一：
    将化合物A溶于X中，析晶，得到如式(I)所示化合物，
    Figure PCTCN2022074486-appb-100005
    方法一中，n为0，m和X的定义如权利要求1～3至少一项所述；
    方法二：
    将化合物A置于X中和HCl反应，析晶，得到如式(I)所示化合物，
    Figure PCTCN2022074486-appb-100006
    方法二中，n为1，m为0-3的任意数值；X的定义如权利要求1～3至少一项所述；
    方法三：
    将如式(II)所示化合物溶于有机溶剂-水的混合溶液中，析晶，得到如式(I)所示化合物，
    Figure PCTCN2022074486-appb-100007
    方法三中，n为0-1的任意数值，m和m’独立地为0-3的任意数值，且n和m均不为0；X为H 2O；Y为CH 3CH 2OH、CH 3C(O)OH、CH 3C(O)OCH 2CH 3、CH 3C(O)CH 3或(CH 3) 2CHOH。
  21. 如权利要求20所述的如式(I)所示化合物的制备方法，其特征在于，所述方法一中，所述化合物A溶于X的过程通过如下方法实现：将化合物A溶解在有机溶剂中形成混合物，再将所述混合物溶解于X中；或者，将化合物A置于X中加热，使其溶清即可；较佳地，所述方法一中，当化合物A溶解在有机溶剂中形成混合物时，所述有机溶剂以能溶解化合物A并能和X混溶即可；例如当X为醋酸时，所述有机溶剂为二氯甲烷和/或甲醇；当将化合物A置于X中并加热时，将其加热至60℃～120℃，例如60℃～85℃，又例如79.5℃或80℃；
    和/或，所述方法二中，当X为H 2O时，所述反应还进一步包含醇类和/或酮类溶剂；所述醇类溶剂可为异丙醇和/或乙醇，优选为异丙醇；所述酮类溶剂可为丙酮；
    和/或，所述方法二中，所述化合物A置于X中的温度为10℃～85℃，例如10℃～30℃或60℃；
    和/或，所述方法二中，所述化合物A和HCl的摩尔比为1：(1～15)，又例如1:1、1:1.2、1:1.5、1:2、1:3或1:10；
    和/或，所述方法三中，所述有机溶剂以使能溶解如式(II)所示化合物以及能与水混溶即可，优选为异丙醇和/或丙酮；
    和/或，所述方法三中，所述有机溶剂-水的混合溶液中，所述有机溶剂的体积百分数可为50％～98％，例如50％、75％、85％或95％；
    和/或，所述方法三中，所述如式(II)所示化合物经加热溶解于有机溶剂-水的混合溶液中；较佳地，将其加热至30℃～80℃，例如50℃；
    和/或，所述方法三中，Y为CH 3CH 2OH、CH 3C(O)OH或(CH 3) 2CHOH；
    和/或，所述方法三中，所述如式(II)所示化合物由所述方法二制备得到。
  22. 一种药物组合物，其特征在于，其包括治疗有效量的活性组分以及药学上可接受的辅料；所述活性组分包括如权利要求1～17至少一项所述的如式(I)所示化合物。
  23. 如式(I)所示化合物或药物组合物在制备治疗、缓解和/或预防由TLRs介导的相关疾病的药物中的应用，其中，所述如式(I)所示化合物如权利要求1～17至少一项所述；所述药物组合物如权利要求22所述。
  24. 如权利要求23所述的如式(I)所示化合物或药物组合物在制备治疗和/或缓解由TLRs介导的相关疾病的药物中的应用，其特征在于，所述由TLRs介导的相关疾病的药物为由TLR8介导的相关疾病的药物；
    和/或，所述由TLRs介导的相关疾病包括癌症、病毒感染以及自身免疫性疾病。
  25. 如式(I)所示化合物或药物组合物在制备治疗和/或缓解癌症、病毒感染以及自身免疫性疾病的药物中的应用，其中，所述如式(I)所示化合物如权利要求1～17至少一项所述；所述药物组合物如权利要求22所述。
  26. 如权利要求25所述的如式(I)所示化合物或药物组合物在制备治疗和/或缓解癌症、病毒感染以及自身免疫性疾病的药物中的应用，其特征在于，所述如式(I)所示化合物、或所述药物组合物和一种或多种其它种类的治疗剂联合用于治疗和/或缓解癌症、病毒感染以及自身免疫性疾病。
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CN107344931A (zh) * 2016-05-06 2017-11-14 上海迪诺医药科技有限公司 苯并氮杂卓衍生物、其制备方法、药物组合物及应用
CN109721597A (zh) * 2017-10-30 2019-05-07 上海迪诺医药科技有限公司 吡啶并氮杂卓衍生物、其药物组合物及应用

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* Cited by examiner, † Cited by third party
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CN102753542A (zh) * 2009-08-18 2012-10-24 文蒂雷克斯药品公司 作为toll样受体调节剂的取代的苯并氮杂*
CN107344931A (zh) * 2016-05-06 2017-11-14 上海迪诺医药科技有限公司 苯并氮杂卓衍生物、其制备方法、药物组合物及应用
CN109721597A (zh) * 2017-10-30 2019-05-07 上海迪诺医药科技有限公司 吡啶并氮杂卓衍生物、其药物组合物及应用

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