WO2021136488A1 - 一种吡啶并嘧啶类衍生物的结晶形式及其制备方法 - Google Patents

一种吡啶并嘧啶类衍生物的结晶形式及其制备方法 Download PDF

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WO2021136488A1
WO2021136488A1 PCT/CN2020/142037 CN2020142037W WO2021136488A1 WO 2021136488 A1 WO2021136488 A1 WO 2021136488A1 CN 2020142037 W CN2020142037 W CN 2020142037W WO 2021136488 A1 WO2021136488 A1 WO 2021136488A1
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crystal form
formula
compound represented
compound
solvent
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PCT/CN2020/142037
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English (en)
French (fr)
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吴琪
杜振兴
王捷
王林
陆伟栋
邵启云
冯君
贺峰
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to MX2022008286A priority Critical patent/MX2022008286A/es
Priority to EP20909539.7A priority patent/EP4085914A4/en
Priority to JP2022540974A priority patent/JP2023509175A/ja
Priority to CN202080091758.4A priority patent/CN114929232B/zh
Priority to US17/757,946 priority patent/US20230058425A1/en
Priority to KR1020227026482A priority patent/KR20220123437A/ko
Priority to AU2020416484A priority patent/AU2020416484A1/en
Priority to CA3163386A priority patent/CA3163386A1/en
Publication of WO2021136488A1 publication Critical patent/WO2021136488A1/zh

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    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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 disclosure relates to a crystal form of a pyridopyrimidine derivative and a preparation method thereof, in particular to a crystal form of a compound of formula (I) and a preparation method thereof.
  • TLRs Toll-like receptors
  • TLR8 is a member of the subgroup of TLRs (TLRs 3, 7, 8 and 9) and is limited to the endosomal compartment of cells that specifically recognize non-self nucleic acids. TLR8 is mainly expressed in humans by monocytes, NK cells and myeloid dendritic cells (mDC). TLR8 agonists can cause the release of various pro-inflammatory cytokines, such as IL-6, IL-12, TNF- ⁇ and IFN- ⁇ .
  • TLR8 plays an important role in the body's innate immunity and acquired immunity.
  • TLR8 agonists can be used for the treatment of various immune-related diseases, such as ovarian cancer, melanoma, non-small cell lung cancer, hepatocellular carcinoma, basal cell carcinoma, and renal cell carcinoma , Myeloma, allergic rhinitis, asthma, chronic obstructive pneumonia (COPD), ulcerative colitis, liver fibrosis, HBV, Flaviviridae virus, HCV, HPV, RSV, SARS, HIV or epidemic Viral infection of colds, etc.
  • various immune-related diseases such as ovarian cancer, melanoma, non-small cell lung cancer, hepatocellular carcinoma, basal cell carcinoma, and renal cell carcinoma , Myeloma, allergic rhinitis, asthma, chronic obstructive pneumonia (COPD), ulcerative colitis, liver fibrosis, HBV, Flaviviridae virus, HCV, HPV, RSV,
  • TLR8 and TLR7 are highly homologous, TLR8 agonists are also TLR7 agonists in most cases. Therefore, dual agonists of TLR8 and TLR7 have been reported in many patents, such as WO2009111337, WO2011017611, WO2011068233, WO2011139348, WO2012066336, WO2013033345 and WO2017046112.
  • TLR8 selective agonists mainly VentiRX’s VTX-2337 (WO2007024612) and Gilead’s GS-9688 (WO2016141092), but these two compounds still have a certain degree of activity on TLR7, and have a certain effect on Cyp and hERG. The selectivity is also poor. Therefore, it is still necessary to continue to develop safe and therapeutically more effective TLR8 agonists.
  • WO2020007275 (application number: PCT/CN/2019/094310) relates to a compound represented by formula (I), the chemical name is (R)-2-((2-amino-7-(6-((4-methyl) Piperazin-1-yl)methyl)pyridin-3-yl)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexane-1-ol, this compound is a novel TLR8 Agonists have been improved in terms of clinical efficacy, indications, and safety, and their structure is as follows:
  • the crystal structure of medicinal active ingredients often affects the chemical stability of the drug.
  • the difference in crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by the production of other crystalline forms.
  • amorphous drug products have no regular crystal structure and often have other defects, such as poor product stability, finer crystallization, difficult filtration, easy agglomeration, and poor fluidity. Therefore, it is necessary to improve the properties of the above-mentioned products. We need in-depth research to find new crystal forms with higher crystal purity and good chemical stability.
  • the purpose of the present disclosure is to provide a new crystal form of the compound represented by formula (I), which has good stability and can be better applied in clinics.
  • One aspect of the present disclosure provides a crystal form A of the compound represented by formula (I), whose X-ray powder diffraction pattern at 2 ⁇ angles is 8.610, 9.740, 13.903, 15.313, 16.354, 17.675, 17.879, 19.184, 19.905, 20.901 There are characteristic peaks at, 21.365, 22.319 and 23.057,
  • the present disclosure provides a crystal form A of the compound represented by formula (I), whose X-ray powder diffraction pattern at 2 ⁇ angles is 8.610, 9.740, 10.949, 13.314, 13.903, 15.313, 16.060, 16.354 There are characteristic peaks at, 16.794, 17.675, 17.879, 19.184, 19.905, 20.901, 21.365, 22.319, 23.057, 23.748, 24.430, 25.428, 26.576, 27.270, 27.863, 28.957, 29.842 and 31.506.
  • the present disclosure provides a crystal form A of the compound represented by formula (I), and its X-ray powder diffraction pattern is shown in FIG. 2.
  • the present disclosure further provides a method for preparing the above-mentioned crystal form A of the compound represented by formula (I), the method comprising:
  • the solvent can be one or more of methanol, n-heptane, cyclohexane, n-hexane, petroleum ether, and n-propanol; or ,
  • the compound represented by formula (I) is mixed with an appropriate amount of solvent, dissolved at elevated temperature, and crystallized at lowered temperature.
  • the solvent may be ethyl acetate.
  • One aspect of the present disclosure provides a crystal form B of the compound represented by formula (I), and its X-ray powder diffraction pattern at 2 ⁇ angles is 4.60, 8.77, 9.90, 13.86, 15.45, 16.44, 17.74, 18.03, 19.31, 19.91 There are characteristic peaks at, 21.07, 21.52, 22.48 and 23.22,
  • the present disclosure provides a crystal form B of the compound represented by formula (I), and its X-ray powder diffraction pattern at 2 ⁇ angles is 4.60, 8.77, 9.20, 9.90, 11.17, 13.86, 14.51, 15.45 Available at, 16.44, 17.74, 18.03, 18.19, 18.51, 19.31, 19.91, 20.07, 21.07, 21.52, 22.48, 23.22, 24.00, 24.61, 25.64, 26.78, 27.43, 28.04, 29.31, 31.21, 32.09, 32.57, 33.23 and 34.01 Characteristic peaks.
  • the present disclosure provides a crystal form B of the compound represented by formula (I), and its X-ray powder diffraction pattern is shown in FIG. 4.
  • the present disclosure further provides a method for preparing the above-mentioned crystal form B of the compound represented by formula (I), the method comprising:
  • the compound represented by formula (I) is mixed with an appropriate amount of solvent to volatilize and crystallize.
  • the solvent can be water, isopropanol, ethyl acetate, acetonitrile, acetophenone, dichloromethane, N,N-dimethylformaldehyde One or more of amide and 1,2-dichloroethane; or,
  • the compound represented by formula (I) is mixed with an appropriate amount of solvent, dissolved at elevated temperature, and crystallized at lowered temperature.
  • the solvent may be isopropanol or dimethyl sulfoxide.
  • the structure determination and crystal form study of the crystal form obtained in the present disclosure are carried out by X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC).
  • XRPD X-ray powder diffraction pattern
  • DSC differential scanning calorimetry
  • the mixed crystals of crystal form A and crystal form B can be prepared by using certain solvents.
  • the compound represented by formula (I) and an appropriate amount of solvent such as acetone, isopropyl acetate, methyl Tert-butyl ether, 2-butanone, methyl isobutyl ketone, nitromethane, ethyl acetate/n-heptane, butyl acetate, p-xylene, propylene glycol monomethyl ether, isoamyl alcohol, water/ethanol , Water/acetone, ethyl acetate/ethanol, trichloromethane, etc.) mixed, volatilized and crystallized.
  • solvents such as acetone, isopropyl acetate, methyl Tert-butyl ether, 2-butanone, methyl isobutyl ketone, nitromethane, ethyl acetate/n-heptane, butyl acetate, p-x
  • the crystallization method of the crystal form in the present disclosure is conventional, such as volatilization crystallization, cooling crystallization or crystallization at room temperature.
  • the starting material used in the method for preparing the crystal form of the present disclosure can be any form of the compound represented by formula (I), and the specific form includes, but is not limited to: amorphous, any crystal form, hydrate, solvate, and the like.
  • the present disclosure further provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned crystal form A and/or crystal form B of the compound represented by formula (I), and one or more pharmaceutically acceptable carriers or excipients.
  • the present disclosure further provides a pharmaceutical composition, which is prepared by mixing the above-mentioned crystal form A and/or crystal form B of the compound represented by formula (I) with one or more pharmaceutically acceptable carriers or excipients .
  • the present disclosure further provides a method for preparing a pharmaceutical composition, which comprises combining the above-mentioned crystal form A and/or crystal form B of the compound represented by formula (I) with one or more pharmaceutically acceptable carriers or excipients Mixed steps.
  • the present disclosure further provides the use of the crystal form A or crystal form B or the pharmaceutical composition of the compound represented by formula (I) described in the present disclosure in the preparation of a medicament for agonizing TLR8.
  • the present disclosure further provides the use of the crystal form A or crystal form B or the pharmaceutical composition of the compound represented by formula (I) described in the present disclosure in the preparation of a medicament for the treatment of infection caused by a virus, and the virus is preferably form B One or more of hepatitis virus, hepatitis C virus, influenza virus, herpes virus and HIV.
  • the present disclosure further provides the use of the crystal form A or crystal form B or the pharmaceutical composition of the compound represented by formula (I) described in the present disclosure in the preparation of drugs for regulating the immune system.
  • the present disclosure further provides the use of the crystal form A or crystal form B or the pharmaceutical composition of the compound represented by the formula (I) described in the present disclosure in the preparation of a medicine for treating or preventing tumors.
  • the “beating” mentioned in the present disclosure refers to a method of purifying substances with poor solubility in solvents but good solubility in solvents.
  • the beating purification can remove color, change crystal form, or remove a small amount of impurities.
  • the "X-ray powder diffraction pattern or XRPD" described in the present disclosure is a pattern obtained by using Cu-K ⁇ radiation in an X-ray powder diffractometer.
  • the “differential scanning calorimetry or DSC” mentioned in the present disclosure refers to the measurement of the temperature difference and heat flow difference between the sample and the reference material during the temperature rise or constant temperature process of the sample to characterize all the physical changes and chemistry related to the thermal effect. Change, get the phase change information of the sample.
  • the "2 ⁇ or 2 ⁇ angle" mentioned in the present disclosure refers to the diffraction angle, ⁇ is the Bragg angle, and the unit is ° or degree, and the error range of 2 ⁇ is ⁇ 0.3 or ⁇ 0.2 or ⁇ 0.1.
  • interplanar spacing or interplanar spacing (d value) means that the spatial lattice selects three non-parallel unit vectors a, b, and c that connect two adjacent lattice points.
  • the matrix is divided into juxtaposed parallelepiped units, called interplanar spacing.
  • the spatial lattice is divided according to the determined parallelepiped unit lines to obtain a set of linear grids, called spatial lattices or lattices.
  • Lattice and crystal lattice use geometric points and lines to reflect the periodicity of the crystal structure.
  • the interplanar spacing that is, the distance between two adjacent parallel crystal planes
  • the unit is Or angstrom.
  • the crystal form A and crystal form B of the compound represented by formula (I) prepared by the present disclosure have high purity, good stability of the crystal form under the conditions of light, high temperature, and high humidity, small changes in HPLC purity, high physical and chemical stability, and more Conducive to the storage and use of raw materials.
  • Figure 1 is the amorphous XRPD pattern of the compound represented by formula (I).
  • Figure 2 is the XRPD pattern of the crystal form A of the compound represented by formula (I).
  • Figure 3 is a DSC chart of the crystal form A of the compound represented by formula (I).
  • Figure 4 is the XRPD pattern of the crystal form B of the compound represented by formula (I).
  • Figure 5 is a DSC chart of the crystal form B of the compound represented by formula (I).
  • Fig. 6 is an XRPD pattern of a mixed crystal of crystal form A and crystal form B of the compound represented by formula (I).
  • Purge gas nitrogen.
  • Heating rate 10.0°C/min.
  • Purge gas nitrogen.
  • Heating rate 10.0°C/min.
  • Cu-K ⁇ 1 wavelength is The wavelength of Cu-K ⁇ 2 is Cu-K ⁇ wavelength is the weighted average of K ⁇ 1 and K ⁇ 2 ).
  • Cu-K ⁇ 1 wavelength is The wavelength of Cu-K ⁇ 2 is Cu-K ⁇ wavelength is the weighted average of K ⁇ 1 and K ⁇ 2 ).
  • the 2 ⁇ data with 2 decimal places is measured by the BRUKER D8 Focus X-ray powder diffractometer.
  • reaction can be carried out in an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction uses the CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the examples adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used in the purification of the compound, and the developing reagent system of thin layer chromatography include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system
  • A Dichloromethane/methanol system
  • B n-hexane/ethyl acetate system
  • C petroleum ether/ethyl acetate system
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and acetic acid can also be added Wait for alkaline or acidic reagents to adjust.
  • Test Example 1 Determination of the agonistic activity of the compounds of the present disclosure on human TLR8 and TLR7
  • HEK-Blue TM hTLR8 cell line (InvivoGen, hkb-hTLR8), or HEK-Blue TM hTLR7 cell line (InvivoGen, hkb-hTLR7),
  • PBS Phosphate buffered saline
  • HEK-Blue detection medium Take a bag of HEK-Blue detection dry powder, add 50ml of endotoxin-free water to dissolve it, then put it into the 37°C incubator, and filter aseptically after 10 minutes.
  • the compound is first prepared into a 20 mM stock solution; then diluted with pure DMSO to a maximum concentration of 6 ⁇ 10 6 nM, and then diluted in a 3-fold gradient, a total of 10 points; the compound is diluted 20 times with the culture medium, and then 20 ⁇ l is added to each well. After the compound.
  • HEK-Blue TM hTLR8 cells Take HEK-Blue TM hTLR8 cells, first remove the supernatant, add 2-5ml of pre-warmed PBS, put them in the incubator for 1-2 minutes, gently pipette the cells, trypan blue staining and counting. Resuspend the cells with HEK-Blue detection medium to adjust the concentration to 2.2 ⁇ 10 5 cells/ml, add 180 ⁇ l cells to the aforementioned 96-well cell culture plate to which 20 ⁇ l drugs have been added, and culture at 37° C. for 6-16 h.
  • the wavelength is 620nm.
  • the corresponding OD value can be obtained, and the EC 50 value of the drug can be calculated by Graphpad Prism.
  • HEK-Blue detection medium Take a bag of HEK-Blue detection dry powder, add 50ml of endotoxin-free water to dissolve it, then put it into the 37°C incubator, and filter aseptically after 10 minutes.
  • the compound was first prepared into a 20 mM stock solution; then diluted with pure DMSO to a maximum concentration of 6 ⁇ 10 6 nM, and then diluted by a 3-fold gradient for a total of 10 points.
  • the compound prepared above is first diluted 20 times with culture medium, and then 20 ⁇ l of the diluted compound is added to each well.
  • HEK-Blue TM hTLR7 cells Take HEK-Blue TM hTLR7 cells, first remove the supernatant, then add 2-5ml of pre-warmed PBS, put them in the incubator for 1-2 minutes, gently pipette the cells, trypan blue staining and counting. Resuspend the cells with HEK-Blue detection medium to adjust the concentration to 2.2 ⁇ 10 5 cells/ml, add 180 ⁇ l cells to the aforementioned 96-well cell culture plate to which 20 ⁇ l drugs have been added, and culture at 37° C. for 6-16 h.
  • the wavelength is 620nm.
  • the corresponding OD value can be obtained, and the EC 50 value of the drug can be calculated by Graphpad Prism.
  • the activating effect of the compounds of the present disclosure on human TLR8 and TLR7 can be determined by the above test, and the measured EC 50 values are shown in Table 1-1.
  • Table 1-1 EC 50 of the compounds of the present disclosure on human TLR8 and TLR7
  • the compound of the present disclosure has a good activating effect on human TLR8, but has no activating effect on human TLR7, indicating that the compound of the present disclosure is selective for TLR8.
  • Test Example 2 The inhibitory effect of the compound of the present disclosure on the enzyme activity of the metabolite site of human liver microsome CYP3A4 midazolam
  • PBS Phosphate buffered saline
  • CYP probe substrate (15 ⁇ M midazolam, SIGMA UC429) and positive control inhibitor (ketoconazole, SIGMA K1003).
  • the value is calculated by Graphpad Prism to obtain the IC 50 value of the drug to the metabolite site of CYP3A4 midazolam, shown in Table 1-2.
  • Table 1-2 IC 50 values of the compounds of the present disclosure on the metabolism site of CYP3A4 midazolam
  • the compound of the present disclosure has no inhibitory effect on the midazolam metabolism site of human liver microsomes CYP3A4, and shows better safety, suggesting that there will be no metabolic drug interaction based on the midazolam metabolism site of CYP3A4 metabolism. effect.
  • Test Example 3 The inhibitory effect of the compound of the present disclosure on the enzyme activity of human liver microsomes CYP2D6
  • the enzyme activity of the compounds of the present disclosure on human liver microsomes CYP2D6 was determined by the following experimental method:
  • PBS Phosphate buffered saline
  • CYP probe substrate (20 ⁇ M dextromethorphan, SIGMA Q0750) and positive control inhibitor (quinidine, SIGMA D9684).
  • Table 1-3 IC 50 values of the compounds of the present disclosure on the metabolic sites of CYP2D6
  • the compound of the present disclosure has weak inhibitory effect on the enzyme activity of human liver microsomes CYP2D6, and shows better safety, suggesting that there will be no metabolic drug interactions based on CYP2D6.
  • Test Example 4 The inhibitory effect of the compound of the present disclosure on the enzyme activity of human liver microsome CYP3A4 testosterone metabolism site
  • the enzymatic activity of the compounds of the present disclosure on the testosterone metabolism site of human liver microsome CYP3A4 was determined by the following experimental method:
  • PBS Phosphate buffered saline
  • CYP probe substrate testosterone/100 ⁇ M, SIGMA K1003
  • positive control inhibitor ketoconazole, Dr. Ehrenstorfer GmbH, C17322500
  • the values are calculated by Graphpad Prism to obtain the IC 50 value of the drug to the CYP3A4 testosterone metabolism site, shown in Table 1-4.
  • Table 1-4 IC 50 values of the compounds of the present disclosure on CYP3A4 testosterone metabolism sites
  • the compound of the present disclosure has no inhibitory effect on the testosterone metabolism site of human liver microsome CYP3A4, and shows better safety, suggesting that there will be no metabolic drug interaction based on the testosterone metabolism site of CYP3A4.
  • Test Example 5 Determination of the ability of the compounds in the present disclosure to stimulate peripheral blood mononuclear cells (PBMC) to secrete IL12 and IFN ⁇
  • PHERAStar multifunctional microplate reader BMG, PHERAStar.
  • the compound was diluted with pure DMSO, the highest concentration was 5 mM, and it was diluted 4-fold with a total of 9 points. Then take 4 ⁇ l of the compound and add it to 196 ⁇ l of RMPI 1640 medium containing 10% FBS, and mix well. Take 50 ⁇ l to a new 96-well cell culture plate.
  • All reagents are equilibrated to room temperature, take a 250ml culture flask, add 60ml blood and equal volume of PBS+2% FBS to it, gently pipette to mix and dilute. Take 50ml PBMC separation tube SepMateTM-50, add 15ml lymphocyte separation fluid Ficoll-Paque PREMIUM, and then add 30ml diluted blood. Centrifuge at 1200g for 10 minutes at room temperature. Take the supernatant and centrifuge at 300g for 8 minutes.
  • RMPI 1640 medium containing 10% FBS Resuspend and count in RMPI 1640 medium containing 10% FBS, adjust the number of PBMCs to 3.33 ⁇ 10 6 cells/ml, and transfer 150 ⁇ l to the cell culture plate to which the compound has been added, 37°C, 5.0% CO2 in an incubator Cultivate for 24h. Put the cell culture plate in a centrifuge, centrifuge at 1200 rpm for 10 minutes at room temperature, and take out 150 ⁇ l of supernatant from each well.
  • the maximum concentration of the standard is 2000pg/ml, with a total of 8 points of double-gradient dilution.
  • the sample to be tested is diluted 20 times. Then 100 ⁇ l/well was added to the pre-coated plate. Incubate at 37°C for 90 min. .Wash the plate and add 100 ⁇ l/well of antibioticized antibody. Incubate at 37°C for 60 min. Wash the plate and add 100 ⁇ l/well of HRP binding enzyme. Incubate at 37°C for 30 minutes and wash the plate; add TMB and incubate at room temperature for 5 minutes. Finally, stop solution was added to stop the reaction, and the absorbance value at 450nm was read by the microplate reader.
  • Table 1-5 The compounds of the present disclosure stimulate PBMC to secrete IL12 and IFN ⁇ MEC
  • Fully automatic patch clamp was used to test the blocking effect of the compounds of the present disclosure on hERG potassium currents on stable cell lines transfected with hERG potassium channels.
  • the HEK293-hERG stable cell line was passaged in MEM/EBSS medium (10% FBS, 400 ⁇ g/ml G418, 1% MEM non-essential amino acid solution (100 ⁇ ), 1% sodium pyruvate solution) at a density of 1:4 Cultivate, and perform fully automatic patch clamp experiments within 48-72 hours of incubation.
  • MEM/EBSS medium 10% FBS, 400 ⁇ g/ml G418, 1% MEM non-essential amino acid solution (100 ⁇ ), 1% sodium pyruvate solution
  • the cells were digested with 0.25% trypsin on the day of the experiment, the cells were collected by centrifugation , and resuspended in extracellular fluid (140mM NaCl, 4mM KCl, 1mM MgCl 2 , 2mM CaCl 2 , 5mM D glucose monohydrate, 10mM Hepes, pH7.4, 298mOsmol)
  • extracellular fluid 140mM NaCl, 4mM KCl, 1mM MgCl 2 , 2mM CaCl 2 , 5mM D glucose monohydrate, 10mM Hepes, pH7.4, 298mOsmol
  • the cells are made into a cell suspension.
  • the cell suspension is placed on the cell bank of the Patchliner instrument.
  • the Patchliner instrument uses a negative pressure controller to add cells to the chip (NPC-16), and the negative pressure attracts single cells to the small holes of the chip.
  • the instrument When the whole-cell mode is formed, the instrument will obtain the hERG current according to the set hERG current and voltage program, and then the instrument will automatically change from low concentration to high concentration for compound perfusion.
  • the data analysis software provided by HEAK Patchmaster, HEAK EPC10 Patch Clamp Amplifier (Nanion) and Pathlinersoftware and Pathcontrol HTsoftware were used to analyze the currents at each concentration of the compound and the blank control current.
  • Table 1-6 IC of the present disclosure compound hERG potassium current blocking effect of 50
  • the compound of the present disclosure has a weak inhibitory effect on hERG and can reduce the side effects caused by the hERG pathway.

Abstract

一种吡啶并嘧啶类衍生物的结晶形式及其制备方法，具体而言，涉及式(I)化合物的结晶形式及制备方法。新晶型具备良好的理化性质，更有利于临床治疗。

Description

一种吡啶并嘧啶类衍生物的结晶形式及其制备方法
本申请要求申请日为2020年1月2日的中国专利申请CN202010002822.9的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开涉及一种吡啶并嘧啶类衍生物的结晶形式及其制备方法，具体地涉及式(I)化合物的结晶形式及制备方法。
背景技术
Toll样受体(toll-like receptors；TLRs)是参与先天免疫的一类重要受体。TLRs是单体跨膜的非催化性受体，通常在岗哨细胞如巨噬细胞和树突状细胞中表达，可以识别由微生物产生的结构保守的分子。一旦这些微生物突破如皮肤或肠道粘膜的物理屏障，就会被TLRs识别，继而激活免疫细胞应答(Mahla,R S.等人,Front Immunol.4:248(2013))。免疫系统之所以具有广泛识别病原微生物的能力，某种程度上是由于Toll样免疫受体的广泛存在。
在哺乳动物中至少有10种不同的TLRs。一些此类受体的配体和相应的信号级联放大已经被鉴定出。TLR8是TLRs(TLRs 3、7、8和9)亚组的成员，局限于专门识别非己核酸的细胞的内涵体隔室。TLR8在人身上主要通过单核细胞，NK细胞和髓样树突细胞(mDC)表达。TLR8激动剂可以导致各种不同的促炎细胞因子的释放，如IL-6，IL-12，TNF-α和IFN-γ。
TLR8在机体的固有免疫和获得性免疫都起着重要的作用。TLR8激动剂作为免疫调节剂，可以用于各种不同与免疫相关的疾病的治疗，如卵巢癌、黑色素瘤、非小细胞肺癌、肝细胞癌、基底细胞癌(basal cell carcinoma)、肾细胞癌、骨髓瘤、变应性鼻炎、哮喘、慢性阻塞性肺炎(COPD)、溃疡性结肠炎、肝纤维化，HBV、黄病毒科(Flaviviridae)病毒、HCV、HPV、RSV、SARS、HIV或流行性感冒的病毒感染等。
由于TLR8和TLR7高度同源，因此TLR8激动剂在大多数情况下也是TLR7激动剂。因此TLR8和TLR7的双重激动剂在很多专利里都有报道，如WO2009111337，WO2011017611，WO2011068233，WO2011139348，WO2012066336，WO2013033345和WO2017046112。TLR8选择性的激动剂报道的比较少，主要有VentiRX公司的VTX-2337(WO2007024612)和Gilead公司的GS-9688(WO2016141092)，但这两个化合物对TLR7 仍然有一定的活性，对Cyp和hERG选择性也较差。所以仍有必要继续研发安全的和治疗上更有效的TLR8激动剂。
WO2020007275(申请号：PCT/CN/2019/094310)涉及一种式(I)所示化合物，化学名为(R)-2-((2-氨基-7-(6-((4-甲基哌嗪-1-基)甲基)吡啶-3-基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2-甲基己烷-1-醇，该化合物为新型TLR8激动剂，在临床疗效或适应症，及安全性等方面均有所改善，其结构如下所示：
Figure PCTCN2020142037-appb-000001
药用的活性成分的晶型结构往往影响到该药物的化学稳定性，结晶条件及储存条件的不同有可能导致化合物的晶型结构的变化，有时还会伴随着产生其他形态的晶型。一般来说，无定型的药物产品没有规则的晶型结构，往往具有其它缺陷，比如产物稳定性较差，析晶较细，过滤较难，易结块，流动性差等。因此，改善上述产物的各方面性质是很有必要的，我们需要深入研究找到晶型纯度较高并且具备良好化学稳定的新晶型。
发明内容
本公开的目的在于提供一种式(I)所示化合物新的晶型，其具备良好的稳定性，可更好地应用于临床。
本公开一方面提供了一种式(I)所示化合物的A晶型，其X-射线粉末衍射图谱在2θ角为8.610、9.740、13.903、15.313、16.354、17.675、17.879、19.184、19.905、20.901、21.365、22.319和23.057处有特征峰，
Figure PCTCN2020142037-appb-000002
在某些实施方式中，本公开提供一种式(I)所示化合物的A晶型，其X-射线粉末衍射 图谱在2θ角为8.610、9.740、10.949、13.314、13.903、15.313、16.060、16.354、16.794、17.675、17.879、19.184、19.905、20.901、21.365、22.319、23.057、23.748、24.430、25.428、26.576、27.270、27.863、28.957、29.842和31.506处有特征峰。
在某些的实施方案中，本公开提供一种式(I)所示化合物的A晶型，其X-射线粉末衍射图谱如图2所示。
本公开进一步提供一种制备上述的式(I)所示化合物的A晶型的方法，所述方法包括：
将式(I)所示化合物与适量的溶剂混合，挥发结晶，所述溶剂可以为甲醇、正庚烷、环己烷、正己烷、石油醚、正丙醇中的一种或多种；或，
将式(I)所示化合物与适量的溶剂混合，升温溶解，降温结晶，所述溶剂可以为乙酸乙酯。
本公开一方面提供了一种式(I)所示化合物的B晶型，其X-射线粉末衍射图谱在2θ角为4.60、8.77、9.90、13.86、15.45、16.44、17.74、18.03、19.31、19.91、21.07、21.52、22.48和23.22处有特征峰，
Figure PCTCN2020142037-appb-000003
在某些实施方式中，本公开提供一种式(I)所示化合物的B晶型，其X-射线粉末衍射图谱在2θ角为4.60、8.77、9.20、9.90、11.17、13.86、14.51、15.45、16.44、17.74、18.03、18.19、18.51、19.31、19.91、20.07、21.07、21.52、22.48、23.22、24.00、24.61、25.64、26.78、27.43、28.04、29.31、31.21、32.09、32.57、33.23和34.01处有特征峰。
在某些的实施方案中，本公开提供一种式(I)所示化合物的B晶型，其X-射线粉末衍射图谱如图4所示。
本公开进一步提供一种制备上述的式(I)所示化合物的B晶型的方法，所述方法包括：
将式(I)所示化合物与适量的溶剂混合，挥发结晶，所述溶剂可以为水、异丙醇、乙酸乙酯、乙腈、苯乙酮、二氯甲烷、N,N-二甲基甲酰胺和1,2-二氯乙烷中的一种或多种；或，
将式(I)所示化合物与适量的溶剂混合，升温溶解，降温结晶，所述溶剂可以为异丙醇或二甲亚砜。
通过X-射线粉末衍射图谱(XRPD)、差示扫描量热分析(DSC)对本公开所得到晶型进 行结构测定、晶型研究。
在某些的实施方案中，采用某些溶剂制备可得到A晶型与B晶型的混晶，例如，将式(I)所示化合物与适量的溶剂(例如丙酮、乙酸异丙酯、甲基叔丁基醚、2-丁酮、甲基异丁基酮、硝基甲烷、乙酸乙酯/正庚烷、乙酸丁酯、对二甲苯、丙二醇单甲醚、异戊醇、水/乙醇、水/丙酮、乙酸乙酯/乙醇、三氯甲烷等)混合，挥发结晶可得。其X-射线粉末衍射图谱如图6所示。
本公开中晶型的析晶方法是常规的，例如挥发析晶、降温析晶或室温下析晶。
本公开晶型制备方法中所用的起始原料可以是任意形式的式(I)所示化合物，具体形式包括但不限于：无定形、任意晶型、水合物、溶剂合物等。
本公开进一步提供一种药物组合物，其包含上述的式(I)所示化合物的A晶型和/或B晶型，以及一种或多种药学上可接受的载体或赋形剂。
本公开进一步提供一种药物组合物，其通过上述的式(I)所示化合物的A晶型和/或B晶型与一种或多种药学上可接受的载体或赋形剂混合制备得到。
本公开进一步提供一种制备药物组合物的方法，包括将上述的式(I)所示化合物的A晶型和/或B晶型与一种或多种药学上可接受的载体或赋形剂混合的步骤。
本公开进一步提供本公开所述的式(I)所示化合物的A晶型或B晶型或药物组合物在制备用于激动TLR8的药物中的用途。
本公开进一步提供本公开所述的式(I)所示化合物的A晶型或B晶型或药物组合物在制备用于治疗由病毒引起的感染的药物中的用途，所述病毒优选乙型肝炎病毒、丙型肝炎病毒、流感病毒、疱疹病毒和艾滋病毒中的一种或多种。
本公开进一步提供本公开所述的式(I)所示化合物的A晶型或B晶型或药物组合物在制备用于调节免疫系统的药物中的用途。
本公开进一步提供本公开所述的式(I)所示化合物的A晶型或B晶型或药物组合物在制备用于治疗或预防肿瘤的药物中的用途。
在本申请的说明书和权利要求书中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。然而，为了更好地理解本公开，下面提供了部分相关术语的定义和解释。另外，当本申请所提供的术语的定义和解释与本领域技术人员所通常理解的含义不一致时，以本申请所提供的术语的定义和解释为准。
本公开所述的“打浆”是指利用物质在溶剂中溶解性差，但杂质在溶剂中溶解性好的特性进行纯化的方法，打浆提纯可以去色、改变晶型或去除少量杂质。
本公开所述的“X-射线粉末衍射图谱或XRPD”是指根据布拉格公式2d sinθ＝nλ(式 中，λ为X射线的波长，衍射的级数n为任何正整数，一般取一级衍射峰，n＝1)，当X射线以掠角θ(入射角的余角，又称为布拉格角)入射到晶体或部分晶体样品的某一具有d点阵平面间距的原子面上时，就能满足布拉格方程，从而测得了这组X射线粉末衍射图。
本公开所述的“X-射线粉末衍射图谱或XRPD”是通过在X-射线粉末衍射仪中使用Cu-Kα辐射得到的图谱。
本公开所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
本公开所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度，2θ的误差范围为±0.3或±0.2或±0.1。
本公开所述的“晶面间距或晶面间距(d值)”是指空间点阵选择3个不相平行的连结相邻两个点阵点的单位矢量a，b，c，它们将点阵划分成并置的平行六面体单位，称为晶面间距。空间点阵按照确定的平行六面体单位连线划分，获得一套直线网格，称为空间格子或晶格。点阵和晶格是分别用几何的点和线反映晶体结构的周期性，不同的晶面，其面间距(即相邻的两个平行晶面之间的距离)各不相同；单位为
Figure PCTCN2020142037-appb-000004
或埃。
发明的有益效果
本公开制备的式(I)所示化合物的A晶型、B晶型纯度高，在光照、高温、高湿的条件下晶型稳定性良好，HPLC纯度变化小、物理化学稳定性高，更有利于原料的存储和使用。
附图说明
图1为式(I)所示化合物的无定形的XRPD图谱。
图2为式(I)所示化合物的A晶型的XRPD图谱。
图3为式(I)所示化合物的A晶型的DSC图谱。
图4为式(I)所示化合物的B晶型的XRPD图谱。
图5为式(I)所示化合物的B晶型的DSC图谱。
图6为式(I)所示化合物的A晶型与B晶型的混晶的XRPD图谱。
具体实施方式
以下将结合实施例更详细地解释本公开，本公开的实施例仅用于说明本公开的技术 方案，并非限定本公开的实质和范围。
试验所用仪器的测试条件：
1、差示扫描量热仪(Differential Scanning Calorimeter,DSC)
仪器型号：Mettler Toledo DSC 1 STAR e System。
吹扫气：氮气。
升温速率：10.0℃/min。
温度范围：40-300℃。
2、差示扫描量热仪(Differential Scanning Calorimeter,DSC)
仪器型号：Mettler Toledo DSC 3+。
吹扫气：氮气。
升温速率：10.0℃/min。
温度范围：25-300℃。
3、X-射线衍射谱(X-ray Powder Diffraction,XRPD)
仪器型号：BRUKER D8 DISCOVERY X-射线粉末衍射仪。
射线：单色Cu-Kα射线(Cu-Kα1波长为
Figure PCTCN2020142037-appb-000005
Cu-Kα2波长为
Figure PCTCN2020142037-appb-000006
Cu-Kα波长取Kα1与Kα2的加权平均值
Figure PCTCN2020142037-appb-000007
)。
扫描方式：θ/2θ，扫描范围：5-48°。
电压：40KV，电流：40mA。
4、X-射线衍射谱(X-ray Powder Diffraction,XRPD)
仪器型号：BRUKER D8 Focus X-射线粉末衍射仪。
射线：单色Cu-Kα射线(Cu-Kα1波长为
Figure PCTCN2020142037-appb-000008
Cu-Kα2波长为
Figure PCTCN2020142037-appb-000009
Cu-Kα波长取Kα1与Kα2的加权平均值
Figure PCTCN2020142037-appb-000010
)。
扫描方式：θ/2θ，扫描范围：2-40°。
电压：40KV，电流：40mA。
其中，2θ保留2位小数的数据通过BRUKER D8 Focus X-射线粉末衍射仪测得。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：石油醚/乙酸乙酯体系溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
Figure PCTCN2020142037-appb-000011
第一步
(R)-2-((7-溴-2-氯吡啶并[3,2-d]嘧啶-4-基)氨基)-2-甲基己烷-1-醇1c
将化合物1a(400mg,1.434mmol,采用专利申请WO2014022728公开的方法制备而得)加入到10mL四氢呋喃中，加入(R)-2-氨基-2-甲基己烷-1-醇1b(377mg,2.873mmol)，加入N,N-二异丙基乙胺(556mg,4.302mmol),100℃封管搅拌反应16小时，反应结束，冷却到室温，过滤去不溶物，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系A纯化所得残余物，得到标题产物1c(4.0g，产率：55.3％)。
MS m/z(ESI):373.1[M+1]。
第二步
(R)-2-((7-溴-2-((2,4-二甲氧基苄基)氨基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2-甲基己烷-1-醇1d
将化合物1c(250mg,0.669mmol)加入到10mL四氢呋喃中，加入2,4-二甲氧基苯甲胺(560mg,3.349mmol)，加入N,N-二异丙基乙胺(259mg,2.004mmol)，封管100℃搅拌16小时，向反应液中加入20mL水，用二氯甲烷萃取(20mL×3)，合并有机相，有机相分别用水(20mL)，饱和氯化钠溶液(20mL)洗涤，无水硫酸镁干燥，过滤除去干燥剂，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物1d(295mg，产率：87.5％)。
MS m/z(ESI):504.1[M+1]
第三步
(R)-2-((2-((2,4-二甲氧基苄基)氨基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2-甲基己烷-1-醇1e
将化合物1d(295mg,0.54mmol)加入到5mL乙二醇二甲醚中，加入联硼酸频那醇酯(223mg,878.169μmol)，加入1,1'-双二苯基膦二茂铁二氯化钯(43mg,0.059mmol)，加入乙酸钾(173mg,1.76mmol)，置换氩气三次，升温到80℃搅拌反应2小时。反应液减压浓缩后，向体系中加入水20ml，用二氯甲烷萃取(10mL×3)，合并有机相，有机相分别用水(20mL)，饱和氯化钠溶液(20mL)洗涤，无水硫酸镁干燥，过滤除去干燥剂，滤液减压浓缩得到粗品标题产物1e(322mg，产率：100％)。
第四步
(R)-2-((2-((2,4-二甲氧基苄基)氨基)-7-(6-((4-甲基哌嗪-1-基)甲基)吡啶-3-基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2-甲基己烷-1-醇1g
将化合物1e(650mg，1.178mmol)加入到20mL 1,4-二氧六环和4mL水中，加入1-((5-溴吡啶-2-基)甲基)-4-甲基哌嗪1f(318mg，1.170mmol,采用专利申请WO20020026052公开的方法制备而得)，加入1,1'-双二苯基膦二茂铁二氯化钯(86mg,0.117mmol)，加入碳酸钾(489mg,3.538mmol)，置换氩气三次，升温到80℃搅拌反应2小时。反应液减压浓缩后，向体系中加入水30ml，用二氯甲烷萃取(30mL×3)，合并有机相，有机相分别用水(30mL)，饱和氯化钠溶液(30mL)洗涤，无水硫酸镁干燥，过滤除去干燥剂，滤液减压浓缩用硅胶柱色谱法以洗脱剂体系B纯化所得残余物得到标题产物1g(650mg，产率：89.70％)。
MS m/z(ESI):615.1[M+1]。
第五步
(R)-2-((2-氨基-7-(6-((4-甲基哌嗪-1-基)甲基)吡啶-3-基)吡啶并[3,2-d]嘧啶-4-基)氨基)-2-甲基己烷-1-醇I
将化合物1g(650mg,0.138mmol)加入到5mL三氟乙酸，室温反应3小时，反应液减压浓缩，向反应液中加入20mL饱和碳酸氢钠，用二氯甲烷(20mL×3)萃取，合并有机相，用饱和氯化钠溶液(30mL)洗涤，无水硫酸镁干燥，过滤除去干燥剂，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到产物I(320mg产率：65.14％)。经X-射线粉末衍射检测，该化合物为无定形，XRPD谱图如图1。
MS m/z(ESI):465.1[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.87-8.88(d,1H),8.60-8.61(m,1H),8.14-8.16(d,1H),7.79-7.80(s,1H),7.51-7.53(d,1H),7.20(s,1H),6.36(br,2H),5.12-5.15(t,1H),3.66(s,2H),3.68-3.70(m,1H),3.48-2.53(m,1H),2.32-3.42(m,8H),2.12(s,3H),1.90-1.92(m,2H),1.40(s,3H),1.22-1.23(m,4H),0.80-0.84(m,3H)。
实施例2
将实施例1得到的式(I)所示化合物(200mg，0.43mmol)加入到10mL乙酸乙酯中，升温至回流，搅拌溶解，然后溶液缓慢降至室温搅拌，过滤，滤饼用乙酸乙酯洗涤，收集滤饼，真空干燥，得到100mg式(I)所示化合物的A晶型，其特征峰位置如下表所示：
表1：A晶型的XRD特征峰位置
Figure PCTCN2020142037-appb-000012
Figure PCTCN2020142037-appb-000013
实施例3
将式(I)所示化合物(400mg，0.86mmol)加入到8mL异丙醇中，加热回流至固体溶清，然后自然冷却至室温搅拌，过滤，滤饼用异丙醇洗涤，收集滤饼，真空干燥，得到200mg式(I)所示化合物的B晶型，其特征峰位置如下表所示：
表2：B晶型的XRD特征峰位置
Figure PCTCN2020142037-appb-000014
Figure PCTCN2020142037-appb-000015
实施例4
取式(I)所示化合物的A晶型与B晶型于开口的洁净称量瓶中，考察在加热(40℃、60℃)、光照(4500lx±500lx)、高湿(90％±5％、75％±5％)条件下样品的稳定性，取样考察期为30天。
表3：A晶型影响因素30天试验结果
Figure PCTCN2020142037-appb-000016
Figure PCTCN2020142037-appb-000017
表4：B晶型影响因素30天试验结果
Figure PCTCN2020142037-appb-000018
Figure PCTCN2020142037-appb-000019
实施例5
取式(I)所示化合物的B晶型进行3个月的长期(25℃、60％RH)、加速(40℃、75％RH)稳定性考察，结果如下表：
表5：式(I)所示化合物的B晶型长期加速稳定性
Figure PCTCN2020142037-appb-000020
实验结果显示：式(I)所示化合物的B晶型长期(25℃、60％RH)、加速(40℃、75％RH)稳定性条件下放置3个月，物理化学稳定性较好。
测试例：
生物学评价
测试例1、本公开化合物对人源TLR8和TLR7激动活性的测定
本公开化合物对HEK-Blue TM hTLR8稳转株细胞表达的hTLR8激活作用采用如下实验方法测定：
一、实验材料及仪器
1.DMEM(Gibco，10564-029),
2.胎牛血清(GIBCO,10099),
3.台盼蓝溶液(Sigma,T8154-100ML),
4.Flexstation 3多功能酶标仪(Molecμlar Devices),
5.HEK-Blue TM hTLR8细胞系(InvivoGen,hkb-hTLR8),或HEK-Blue TM hTLR7细胞系(InvivoGen,hkb-hTLR7),
6.HEK-Blue检测试剂(InvivoGen,hb-det3),
7.磷酸盐缓冲液(PBS)pH7.4(上海源培生物科技股份有限公司，B320)。
二、实验步骤
a.对人源TLR8激动活性的测定
配置HEK-Blue检测培养基，取HEK-Blue检测干粉一袋，加入50ml去内毒素水溶解，再放入37℃培养箱，10分钟后无菌过滤。化合物先配制成20mM的原液；再用纯DMSO稀释至最高浓度为6×10 6nM，然后3倍梯度稀释，共10个点；用培养基先把化 合物稀释20倍，然后每孔加入20μl稀释后的化合物。
取HEK-Blue TM hTLR8细胞，先去掉上清，加入2-5ml预热的PBS，放入培养箱1-2分钟，轻轻吹打细胞，台盼蓝染色计数。用HEK-Blue检测培养基重悬细胞调整浓度为2.2×10 5个细胞/ml，加180μl细胞至上述已加入20μl药物的96孔细胞培养板中，37℃，培养6-16h。
酶标仪读数，波长为620nm。可获得相应的OD值，经Graphpad Prism计算得到药物的EC 50值。
b.对人源TLR7激动活性的测定
配置HEK-Blue检测培养基，取HEK-Blue检测干粉一袋，加入50ml去内毒素水溶解，再放入37℃培养箱，10分钟后无菌过滤。化合物先配制成20mM的原液；再用纯DMSO稀释至最高浓度为6×10 6nM，经3倍梯度稀释，共10个点。
用培养基先把上述配制好的化合物稀释20倍，然后每孔加入20μl稀释后的化合物。
取HEK-Blue TM hTLR7细胞，先去掉上清，再加入2-5ml预热的PBS，放入培养箱1-2分钟，轻轻吹打细胞，台盼蓝染色计数。用HEK-Blue检测培养基重悬细胞调整浓度为2.2×10 5个细胞/ml，加180μl细胞至上述已加入20μl药物的96孔细胞培养板中，37℃，培养6-16h。
酶标仪读数，波长为620nm。可获得相应的OD值，经Graphpad Prism计算得到药物的EC 50值。
本公开化合物对人源TLR8和TLR7激活作用可通过以上的试验进行测定，测得的EC 50值见表1-1。
表1-1：本公开化合物对人源TLR8和TLR7的EC 50
Figure PCTCN2020142037-appb-000021
结论：本公开化合物对人源TLR8具有较好的激活作用，对人源TLR7没有激活作用，说明本公开化合物对TLR8具有选择性。
测试例2、本公开化合物对人肝微粒体CYP3A4咪达唑仑代谢位点的酶活性的抑制作用
本公开化合物对人肝微粒体CYP3A4咪达唑仑代谢位点的酶活性采用如下实验方法测定：
一、实验材料及仪器
1.磷酸缓冲液(PBS),
2.NADPH(Sigma N-1630),
3.人肝微粒体(Corning Gentest),
4.ABI QTrap 4000液质两用仪(AB Sciex),
5.Inertsil C8-3柱,4.6×50mm,5μm(美国迪马公司),
6.CYP探针底物(15μM的咪达唑仑，SIGMA UC429)和阳性对照抑制剂(酮康唑，SIGMA K1003)。
二、实验步骤
配置100mM的PBS缓冲液，用该缓冲液配制2.5mg/ml的微粒体溶液和5mM的NADPH溶液，用PBS梯度稀释5X浓度的化合物工作液(150、50、15、5、1.5、0.15、0.015、0μM)。用PBS梯度稀释5X浓度的酮康唑工作液(150、50、15、5、1.5、0.15、0.015、0μM)。用PBS稀释至15μM浓度的咪达唑仑工作液。
分别取2.5mg/ml的微粒体溶液、15μM的咪达唑仑工作液、MgCl 2溶液和化合物工作液(150、50、15、5、1.5、0.15、0.015、0μM，每个浓度设置不同的反应体系)各20μl，混合均匀。阳性对照组用相同浓度的酮康唑代替化合物。同时将5mM的NADPH溶液一起在37℃预孵育5分钟。5分钟之后取20μl NADPH加入到个孔中，启动反应，孵育30分钟。所有孵育样品设双样本。30分钟后向所有样本中加入250μl含内标的乙腈，混匀，800rpm摇10分钟，然后3700rpm离心10分钟。取80μl的上清液，转移至LC-MS/MS分析。
数值经Graphpad Prism计算得到药物对CYP3A4咪达唑仑代谢位点的IC 50值见表1-2。
表1-2：本公开化合物对CYP3A4咪达唑仑代谢位点的IC 50值
实施例编号 IC 50(μM)
1 >30
结论：本公开化合物对人肝微粒体CYP3A4的咪达唑仑代谢位点没有抑制作用，表现出更好的安全性，提示不会发生基于CYP3A4代谢咪达唑仑代谢位点的代谢性药物相互作用。
测试例3、本公开化合物对人肝微粒体CYP2D6酶活性的抑制作用
本公开化合物对人肝微粒体CYP2D6酶活性采用如下实验方法测定：
一、实验材料及仪器
1.磷酸缓冲液(PBS),
2.NADPH(Sigma N-1630),
3.人肝微粒体(Corning Gentest),
4.ABI QTrap 4000液质两用仪(AB Sciex),
5.Inertsil C8-3柱,4.6×50mm,5μm(美国迪马公司),
6.CYP探针底物(20μM的右美沙芬，SIGMA Q0750)和阳性对照抑制剂(奎尼丁，SIGMA D9684)。
二、实验步骤
配置100mM的PBS缓冲液，用该缓冲液配制2.5mg/ml的微粒体溶液和5mM的NADPH溶液，用PBS梯度稀释5X浓度的化合物工作液(150、50、15、5、1.5、0.15、0.015、0μM)。用PBS梯度稀释5X浓度的奎尼丁工作液(150、50、15、5、1.5、0.15、0.015、0μM)。用PBS稀释至20μM浓度的右美沙芬工作液。
分别取2.5mg/ml的微粒体溶液、20μM的右美沙芬工作液、MgCl 2溶液和化合物工作液(150、50、15、5、1.5、0.15、0.015、0μM，每个浓度设置不同的反应体系)各20μl，混合均匀。阳性对照组用相同浓度的奎尼丁代替化合物。同时将5mM的NADPH溶液一起在37℃预孵育5分钟，5分钟之后取20μl NADPH加入到个孔中，启动反应，孵育30分钟。所有孵育样品设双样本。30分钟后向所有样本中加入250μl含内标的乙腈，混匀，800rpm摇10分钟。3700rpm离心10分钟。取80μl的上清液，转移至LC-MS/MS分析。
数值经Graphpad Prism计算得到药物对CYP2D6代谢位点的IC 50值见表1-3。
表1-3：本公开化合物对CYP2D6代谢位点的IC 50值
实施例编号 IC 50(μM)
1 >30
结论：本公开化合物对人肝微粒体CYP2D6的酶活性抑制作用弱，表现出更好的安全性，提示不会发生基于CYP2D6发生代谢性药物相互作用。
测试例4、本公开化合物对人肝微粒体CYP3A4睾酮代谢位点的酶活性的抑制作用
本公开化合物对人肝微粒体CYP3A4睾酮代谢位点的酶活性采用如下实验方法测定：
一、实验材料及仪器
1.磷酸缓冲液(PBS),
2.NADPH(Sigma N-1630),
3.人肝微粒体(Corning Gentest),
4.ABI QTrap 4000液质两用仪(AB Sciex),
5.Inertsil C8-3柱,4.6×50mm,5μm(美国迪马公司),
6.CYP探针底物(睾酮/100μM，SIGMA K1003)和阳性对照抑制剂(酮康唑，Dr.Ehrenstorfer GmbH,C17322500)。
二、实验步骤
配置100mM的PBS缓冲液，用该缓冲液配制2.5mg/ml的微粒体溶液和5mM的NADPH溶液，用PBS梯度稀释5X浓度的化合物工作液(150、50、15、5、1.5、0.15、0.015、0μM)。用PBS梯度稀释5X浓度的酮康唑工作液(150、50、15、5、1.5、0.15、0.015、0μM)。用PBS稀释至50μM浓度的右美沙芬工作液。
分别取2.5mg/ml的微粒体溶液、50μM的睾酮工作液、MgCl 2溶液和化合物工作液(150、50、15、5、1.5、0.15、0.015、0μM，每个浓度设置不同的反应体系)各20μl，混合均匀。阳性对照组用相同浓度的酮康唑代替化合物。同时将5mM的NADPH溶液一起在37℃预孵育5分钟。5分钟之后取20μl NADPH加入到个孔中，启动反应，孵育30分钟。所有孵育样品设双样本。30分钟后向所有样本中加入250μl含内标的乙腈，混匀，800rpm摇10分钟。3700rpm离心10分钟。取80μl的上清液，转移至LC-MS/MS分析。
数值经Graphpad Prism计算得到药物对CYP3A4睾酮代谢位点的IC 50值见表1-4。
表1-4：本公开化合物对CYP3A4睾酮代谢位点的IC 50值
实施例编号 IC 50(μM)
1 >30
结论：本公开化合物对对人肝微粒体CYP3A4的睾酮代谢位点没有抑制作用，表现出更好的安全性，提示不会发生基于CYP3A4的睾酮代谢位点的代谢性药物相互作用。
测试例5、本公开中化合物刺激外周血单个核细胞(PBMC)分泌IL12和IFNγ能力的测定
本公开中化合物刺激PBMC分泌IL12和IFNγ能力采用如下实验方法测定：
一、实验材料及仪器
1.RPMI 1640(Invitrogen,11875),
2.FBS(Gibco,10099-141),
3.Ficoll-Paque PREMIUM(GE,17-5442-02),
4.台盼蓝溶液(Sigma,T8154-100ML),
5.SepMateTM-50(Stemcell,15460),
6.Bright-Line TM血细胞计数仪(Sigma,Z359629-1EA),
7. 96孔平底板(Corning,3599),
8. 96孔v底板(Corning,3894),
9.Human IL-12 ELISA kit(欣博盛,EHC152.96),
10.Human IFNγkit(cisbio,62HIFNGPEG)
11.PHERAStar多功能酶标仪(BMG，PHERAStar).
二、实验步骤
化合物用纯DMSO稀释，最高浓度为5mM，4倍梯度稀释，共9个点。然后取4μl化合物，加入到196μl含10％FBS的RMPI 1640培养基中，混匀。取50μl至新的96孔细胞培养板。
所有试剂平衡到室温，取250ml培养瓶，将60ml血液和等体积的PBS+2％FBS加入其中，轻轻吹打混匀稀释。取50ml PBMC分离管SepMateTM-50，加入15ml淋巴细胞分离液Ficoll-Paque PREMIUM，然后加入30ml稀释后血液。1200g室温离心10分钟。取上清，然后300g，离心8分钟。用含10％FBS的RMPI 1640培养基重悬并计数，调整PBMC数量至3.33×10 6个细胞/ml，取150μl至已加入化合物的细胞培养板中，37℃，5.0％CO2的培养箱中培养24h。将细胞培养板放入离心机中，1200rpm，室温离心10分钟，每孔取出150μl上清。
平衡Human IL-12检测试剂盒的试剂至常温，根据试剂盒说明书，标准品的最高浓度为2000pg/ml，二倍梯度稀释共8个点。待测样本稀释20倍。然后100μl/well加入预包被好的板子内。37℃孵育90min。.洗板，加入抗生素化抗体100μl/well。37℃孵育60min。洗板，加入HRP结合酶100μl/well。37℃孵育30min，洗板；加入TMB，室温孵育5min。最后加入终止液终止反应，酶标仪读取450nm处的吸光值。
平衡Human IFNγ检测试剂盒的试剂至常温，在避光条件下根据试剂盒说明书，配制标准品及检测抗体。每孔加入16μl的离心取得的上清液，再每孔加入4μl现配的混合检测抗体，震荡混匀，室温避光孵育过夜，PHERAStar使用htrf程序读数
我们将能刺激PBMC产生比未加化合物组平均值高3倍SD(未加化合物组的SD)所对应化合物浓度，定义为该化合物的MEC(Minimal Effective Concentration)值。
本公开化合物刺激PBMC分泌IL12和IFNγ的能力通过以上的试验进行测定，测得的MEC值见表1-5。
表1-5：本公开化合物刺激PBMC分泌IL12和IFNγ的MEC
实施例编号 IL12 MEC(nM) IFNγMEC(nM)
1 41 -
结论：从刺激PBMC分泌IL12和IFNγ的活性的数据上看，本公开化合物具有起效浓度较低的优势。
测试例6
1、实验目的
应用全自动膜片钳在转染hERG钾通道的稳定细胞株上测试本公开化合物对hERG钾电流的阻断作用。
2、实验方法
2.1实验材料与仪器
2.1.1实验材料：
Figure PCTCN2020142037-appb-000022
2.1.2实验仪器：
Figure PCTCN2020142037-appb-000023
2.2全自动膜片钳实验步骤
HEK293-hERG稳定细胞株按照1:4的密度在MEM/EBSS培养基(10％FBS，400μg/ml G418,1％MEM非必需氨基酸溶液(100×),1％丙酮酸钠溶液)中进行传代培养，培养48-72小时之内进行全自动膜片钳实验。实验当天将细胞用0.25％胰酶消化后，离心收集细 胞，用细胞外液(140mM NaCl，4mM KCl，1mM MgCl 2，2mM CaCl 2，5mMD一水葡萄糖，10mM Hepes,pH7.4,298mOsmol)重悬细胞制成细胞悬液。将细胞悬液放置在Patchliner仪器的细胞库上，Patchliner仪器利用负压控制器将细胞加到芯片(NPC-16)上，负压将单个细胞吸引在芯片的小孔上。当形成全细胞模式后，仪器将按照设定的hERG电流电压程序得到hERG电流，然后仪器自动的由低浓度到高浓度，进行化合物灌流。通过HEAK Patchmaster,HEAK EPC10膜片钳放大器(Nanion)和Pathlinersoftware以及Pathcontrol HTsoftware提供的数据分析软件，对化合物各浓度下的电流以及空白对照电流进行分析。
2.3测试结果
本公开化合物对hERG钾电流的阻断作用通过以上的试验进行测定，测得的IC 50值见表1-6。
表1-6：本公开化合物对hERG钾电流的阻断作用的IC 50
实施例编号 IC 50(μM)
1 26
结论：本公开化合物对hERG的抑制作用弱，可降低由hERG通路引起的副作用。

Claims (16)

  1. 一种式(I)所示化合物的A晶型，其X-射线粉末衍射图谱在2θ角为8.610、9.740、13.903、15.313、16.354、17.675、17.879、19.184、19.905、20.901、21.365、22.319和23.057处有特征峰，
    Figure PCTCN2020142037-appb-100001
  2. 根据权利要求1所述的式(I)所示化合物的A晶型，其X-射线粉末衍射图谱在2θ角为8.610、9.740、10.949、13.314、13.903、15.313、16.060、16.354、16.794、17.675、17.879、19.184、19.905、20.901、21.365、22.319、23.057、23.748、24.430、25.428、26.576、27.270、27.863、28.957、29.842和31.506处有特征峰。
  3. 根据权利要求1所述的式(I)所示化合物的A晶型，其X-射线粉末衍射图谱如图2所示。
  4. 一种式(I)所示化合物的B晶型，其X-射线粉末衍射图谱在2θ角为4.60、8.77、9.90、13.86、15.45、16.44、17.74、18.03、19.31、19.91、21.07、21.52、22.48和23.22处有特征峰，
    Figure PCTCN2020142037-appb-100002
  5. 根据权利要求4所述的式(I)所示化合物的B晶型，其X-射线粉末衍射图谱在2θ角为4.60、8.77、9.20、9.90、11.17、13.86、14.51、15.45、16.44、17.74、18.03、18.19、18.51、19.31、19.91、20.07、21.07、21.52、22.48、23.22、24.00、24.61、25.64、26.78、27.43、28.04、29.31、31.21、32.09、32.57、33.23和34.01处有特征峰。
  6. 根据权利要求4所述的式(I)所示化合物的B晶型，其X-射线粉末衍射图谱如图4 所示。
  7. 根据权利要求1-6任意一项所述的式(I)所示化合物的晶型，其中所述2θ角的误差范围为±0.2。
  8. 一种制备如权利要求1-3任意一项所述的式(I)所示化合物的A晶型的方法，所述方法包括：将式(I)所示化合物与适量的溶剂混合，挥发结晶，所述溶剂选自甲醇、正庚烷、环己烷、正己烷、石油醚和正丙醇中的一种或多种；或将式(I)所示化合物与适量的溶剂混合，升温溶解，降温结晶，所述溶剂为乙酸乙酯。
  9. 一种制备如权利要求4-6任意一项所述的式(I)所示化合物的B晶型的方法，所述方法包括：将式(I)所示化合物与适量的溶剂混合，挥发结晶，所述溶剂选自水、异丙醇、乙酸乙酯、乙腈、苯乙酮、二氯甲烷、N,N-二甲基甲酰胺和1,2-二氯乙烷中的一种或多种；或将式(I)所示化合物与适量的溶剂混合，升温溶解，降温结晶，所述溶剂选自异丙醇或二甲亚砜。
  10. 一种药物组合物，其包含如权利要求1-3任意一项所述的式(I)所示化合物的A晶型和/或如权利要求4-6任意一项所述的式(I)所示化合物的B晶型，以及一种或多种药学上可接受的载体或赋形剂。
  11. 一种药物组合物，其通过如权利要求1-3任意一项所述的式(I)所示化合物的A晶型和/或如权利要求4-6任意一项所述的式(I)所示化合物的B晶型与一种或多种药学上可接受的载体或赋形剂混合制备得到。
  12. 一种如权利要求1-7任意一项所述的式(I)所示化合物的A晶型或B晶型或权利要求10、11所述的药物组合物在制备用于激动TLR8的药物中的用途。
  13. 一种如权利要求1-7任意一项所述的式(I)所示化合物的A晶型或B晶型或权利要求10、11所述的药物组合物在制备用于治疗由病毒引起的感染的药物中的用途，所述病毒优选乙型肝炎病毒、丙型肝炎病毒、流感病毒、疱疹病毒和艾滋病毒中的一种或多种。
  14. 一种如权利要求1-7任意一项所述的式(I)所示化合物的A晶型或B晶型或权利要求10、11所述的药物组合物在制备用于调节免疫系统的药物中的用途。
  15. 一种如权利要求1-7任意一项所述的式(I)所示化合物的A晶型或B晶型或权利要求10、11所述的药物组合物在制备用于治疗或预防肿瘤的药物中的用途。
  16. 一种制备如权利要求10或11所述的药物组合物的方法，其包括将式(I)所示化合物的A晶型和/或B晶型与一种或多种药学上可接受的载体或赋形剂混合的步骤。
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