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WO2020007355A1 - 噻唑类化合物的晶型及其应用 - Google Patents

噻唑类化合物的晶型及其应用 Download PDF

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WO2020007355A1
WO2020007355A1 PCT/CN2019/094824 CN2019094824W WO2020007355A1 WO 2020007355 A1 WO2020007355 A1 WO 2020007355A1 CN 2019094824 W CN2019094824 W CN 2019094824W WO 2020007355 A1 WO2020007355 A1 WO 2020007355A1
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compound
formula
pattern
present
crystal form
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French (fr)
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石卫华
江志赶
贺海鹰
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Medshine Discovery Inc
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Medshine Discovery Inc
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Priority to JP2021500202A priority Critical patent/JP7150368B2/ja
Priority to KR1020217003759A priority patent/KR102535452B1/ko
Priority to US17/258,011 priority patent/US11964969B2/en
Priority to AU2019297214A priority patent/AU2019297214B2/en
Priority to ES19831293T priority patent/ES2982663T3/es
Priority to CN201980043942.9A priority patent/CN112384512B/zh
Priority to EP19831293.6A priority patent/EP3819297B1/en
Publication of WO2020007355A1 publication Critical patent/WO2020007355A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/54—Nitrogen and either oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a compound A of the formula (I), a compound of the formula (II) and its B form, and a compound of the formula (I), a compound of the formula (II) and its B form in the preparation and treatment of herpes simplex Application of drugs for virus-related diseases.
  • Zidovudine is the main species that has been approved for the treatment of human immunodeficiency virus.
  • Ganciclovir, acyclovir and phosphonic acid are currently used to treat herpes virus infections.
  • these treatments have considerable side effects because they impair the replication of host cell DNA or affect only a limited number of viral infections.
  • viruses can develop resistance to treatment, causing the therapeutic effect to decrease.
  • the herpesvirus family is a family of DNA viruses, including herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), cytomegalovirus (CMV), chickenpox-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV6), human herpesvirus-7 (HHV7), human herpesvirus-8 (HHV8), pseudorabies virus and rhinotracheitis virus.
  • HSV-1 herpes simplex virus-1
  • HSV-2 herpes simplex virus-2
  • CMV cytomegalovirus
  • VZV chickenpox-zoster virus
  • Epstein-Barr virus Epstein-Barr virus
  • human herpesvirus-6 HHV6
  • HHV7 human herpesvirus-7
  • HHV8 human herpesvirus-8
  • the present invention provides an X-ray powder diffraction pattern of Form A of the compound of formula (I) with characteristic diffraction peaks at the following 2 ⁇ angles: 10.81 ⁇ 0.2 °, 15.97 ⁇ 0.2 °, 21.69 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the above-mentioned Form A has a characteristic diffraction peak at the following 2 ⁇ angle:
  • the X-ray powder diffraction pattern of the above-mentioned Form A has characteristic diffraction peaks at the following 2 ⁇ angles: 6.581 °, 10.807 °, 13.031 °, 15.301 °, 15.637 °, 15.971 °, 17.253 °, 18.160 ° , 18.475 °, 20.076 °, 20.644 °, 21.688 °, 22.381 °, 23.782 °, 25.141 °, 26.167 °, 26.959 °, 29.108 °, 31.492 °, 31.904 °, 32.061 °, 33.385 °, and 36.623 °.
  • the XRPD pattern of the above-mentioned Form A is shown in FIG. 1.
  • the differential scanning calorimetry curve of the above-mentioned Form A has a starting point of an endothermic peak at 216.04 ⁇ 3 ° C.
  • the DSC spectrum of the above-mentioned Form A is shown in FIG. 2.
  • thermogravimetric analysis curve of the above-mentioned crystal form A has a weight loss of 0.4442% at 120 ⁇ 3 ° C and a weight loss of 2.4492% at 204 ⁇ 3 ° C.
  • the TGA spectrum of the above-mentioned Form A is shown in FIG. 3.
  • the invention also provides compounds of formula (II).
  • the invention also provides an X-ray powder diffraction pattern of the B-form of the compound of formula (II) with characteristic diffraction peaks at the following 2 ⁇ angles:
  • the X-ray powder diffraction pattern of the above-mentioned Form B has a characteristic diffraction peak at the following 2 ⁇ angle:
  • the X-ray powder diffraction pattern of the above-mentioned Form B has characteristic diffraction peaks at the following 2 ⁇ angles: 8.460 °, 10.174 °, 11.535 °, 11.850 °, 13.982 °, 15.935 °, 19.110 °, 19.464 ° , 19.939 °, 20.391 °, 21.888 °, 23.309 °, 23.780 °, 24.517 °, 24.929 °, 26.034 °, 26.367 °, 26.959 °, 27.352 °, 28.772 °, 30.626 °, 31.297 °, 32.067 °, 33.845 °, and 38.235 °.
  • the XRPD pattern of the above-mentioned Form B is shown in FIG. 4.
  • the differential scanning calorimetry curve of the above B-form has a starting point of an endothermic peak at 185.89 ⁇ 3 ° C.
  • the DSC spectrum of the B-form is shown in FIG. 5.
  • thermogravimetric analysis curve of the above-mentioned Form B is 0.7160% at 187.16 ⁇ 3 ° C.
  • the TGA spectrum of the B-form is shown in FIG. 6.
  • the invention also provides the application of the above-mentioned Form A in the preparation of a medicament for treating a herpes simplex virus-related disorder.
  • the invention also provides the application of the compound of formula (II) and its B crystal form in the preparation of a medicament for treating a herpes simplex virus-related disorder.
  • the compound of the present invention has good antiviral activity against herpes simplex virus (HSV); in vivo pharmacokinetic studies, the plasma exposure at the same effective dose is lower and the safety is better.
  • the crystal form A of the compound of the formula (I) and the crystal form B of the compound of the formula (II) of the present invention are stable, little affected by light, heat, and humidity, and have good in vivo drug efficacy.
  • the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalent alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • the present invention uses the following abbreviations: EtOH stands for ethanol; MeOH stands for methanol; TFA stands for trifluoroacetic acid; TsOH stands for p-toluenesulfonic acid; mp stands for melting point; EtSO 3 H stands for ethanesulfonic acid; MeSO 3 H stands for methanesulfonic acid; THF stands for tetrahydrofuran; EtOAc stands for ethyl acetate; NBS stands for N-bromosuccinimide; AIBN stands for azobisisobutyronitrile; DMSO stands for dimethylsulfoxide; DMF stands for N, N-dimethylformamide; EDCI stands for carbodiimide; HOBt stands for 1-hydroxybenzotriazole.
  • XRPD X-ray powder diffraction
  • Test method about 10 ⁇ 20mg sample is used for XRPD detection.
  • Light tube voltage 40kV
  • light tube current 40mA
  • Anti-scattering slit 7.10mm
  • DSC Differential thermal analysis
  • Test method Take a sample ( ⁇ 1mg) in a DSC aluminum pan for testing. Under 50mL / min N 2 condition, heat the sample from 30 °C (room temperature) to 300 °C (or 350) ° C).
  • Thermogravimetric (Analyzer, TGA) method of the present invention is thermogravimetric (Analyzer, TGA) method of the present invention
  • Test method Take a sample (2 ⁇ 5mg) and place it in a TGA platinum pot for testing. Under the condition of 25mL / min N 2 , heat the sample from room temperature to 350 °C or lose weight by 20% at a heating rate of 10 °C / min.
  • Test conditions Take samples (10-15mg) and place them in the DVS sample tray for testing.
  • the hygroscopicity evaluation is classified as follows:
  • Hygroscopic classification Moisture gain and weight gain * deliquescence Absorb a sufficient amount of water to form a liquid
  • Very hygroscopic ⁇ W% ⁇ 15% Hygroscopic 15%> ⁇ W% ⁇ 2%
  • FIG. 1 is an XRPD spectrum of Cu-K ⁇ radiation of crystal form A of compound (I);
  • FIG. 2 is a DSC spectrum of a crystal form of the compound of formula (I);
  • FIG. 4 is an XRPD spectrum of Cu-K ⁇ radiation of Form B of the compound of formula (II);
  • Fig. 7 is a DVS isotherm of the crystal form B of the compound of formula (II).
  • the compound of formula (I) (56.5 g, 131.85 mmol) was weighed into a 3 L round bottom flask, 2 L of anhydrous tetrahydrofuran was added, and the mixture was heated to 50 to 55 ° C. to completely dissolve it. After filtration, the methanesulfonic acid (12.67 g, 131.85 mmol) diluted with 50 mL of anhydrous tetrahydrofuran was added dropwise to the filtrate at 55 ° C, a solid was precipitated, and stirring was continued for 2 hours. It was filtered and the filtrate was dried under reduced pressure.
  • the hygroscopic weight gain of the crystal form B of the compound of formula (II) at 25 ° C and 80% RH is 1.158%, which is slightly hygroscopic.
  • CPE Cytopathic (CPE) experiments were used to determine the antiviral activity of the compound against herpes simplex virus type 1 (HSV-1) GHSV-UL 46 strain.
  • Microplate reader Molecular DeviceSpectraMax340PC384.
  • Cell growth medium 500ml DMEM medium + 50ml fetal bovine serum + 5ml double antibody + 5ml non-essential amino acids.
  • Cytopathic experimental medium 500ml DMEM medium + 10ml fetal bovine serum + 5ml double antibody + 5ml non-essential amino acids.
  • the inoculation amount is 1.5TCID 90 / well, 30 ⁇ l.
  • Multidrop was used to add the experimental medium to the cell control wells, 30 ⁇ l per well, and the diluted virus was added to the compound test wells and virus control wells, 30 ⁇ l per well.
  • Sample is the absorbance value of the compound test well
  • cell control is the average value of the cell control well
  • virus control is the average value of the virus control well.
  • the compounds of the present invention have good antiviral activity against herpes simplex virus (HSV).
  • mice Male, 18-22g, 6-8 weeks old, Shanghai Slark
  • Candidate compounds are formulated as corresponding solutions and given as a single intravenous injection (1.0 mg / kg, 5% DMSO / 95% 20% hydroxypropyl- ⁇ -cyclodextrin) or by intragastric administration (1.0 mg / kg, 0.5% methyl Cellulose MC4000).
  • Samples, LC-MS / MS analysis method was used to quantitatively analyze blood drug concentration, and calculate pharmacokinetic parameters, such as peak concentration, peak time, clearance rate, half-life, area under the curve of drug time, bioavailability, etc.
  • the compounds of the present invention have lower plasma exposure and better safety in the same pharmacokinetic study of mice administered intragastrically.

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Abstract

本发明公开了式(Ⅰ)化合物的A晶型，式(Ⅱ)化合物及其B晶型，以及式(Ⅰ)化合物的A晶型、式(Ⅱ)化合物及其B晶型在制备治疗单纯疱疹病毒相关疾病的药物的应用。

Description

噻唑类化合物的晶型及其应用
本申请主张如下优先权：
CN201810738963.X，申请日：2018.07.06。
技术领域
本发明涉及式(Ⅰ)化合物的A晶型，式(Ⅱ)化合物及其B晶型，以及式(Ⅰ)化合物的A晶型、式(Ⅱ)化合物及其B晶型在制备治疗单纯疱疹病毒相关疾病的药物的应用。
背景技术
在治疗病毒性疾病方面，对新的治疗方法有很大的需求。虽然在开发各种细菌感染的治疗方法方面已经取得了很大的进展，但是对于病毒的治疗还鲜有可行的治疗方法。齐多夫定是已经得到认可的用于治疗人类免疫缺损病毒的主要品种。目前使用更昔洛韦、阿昔洛韦和膦甲酸来治疗疱疹病毒感染。然而，由于这些治疗方法损害宿主细胞DNA的复制或者只对有限数量的病毒感染发生作用，因而具有相当大的副作用。另外，已知病毒能发展出对治疗的抗性，使得治疗效果日益下降。
疱疹病毒科是一族DNA病毒，包括单纯疱疹病毒-1型(HSV-1)、单纯疱疹病毒-2型(HSV-2)、巨细胞病毒(CMV)、水痘-带状疱疹病毒(VZV)、Epstein-Barr病毒、人类疱疹病毒-6(HHV6)、人类疱疹病毒-7(HHV7)、人类疱疹病毒-8(HHV8)、假狂犬病毒和鼻气管炎病毒等。
发明内容
本发明提供了式(Ⅰ)化合物的A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.81±0.2°、15.97±0.2°、21.69±0.2°。
Figure PCTCN2019094824-appb-000001
本发明的一些方案中，上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：
10.81±0.2°、13.03±0.2°、15.97±0.2°、18.48±0.2°、21.69±0.2°、23.78±0.2°、25.14±0.2°、26.96±0.2°。
本发明的一些方案中，上述A晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：6.581°、10.807°、13.031°、15.301°、15.637°、15.971°、17.253°、18.160°、18.475°、20.076°、20.644°、21.688°、22.381°、23.782°、25.141°、26.167°、26.959°、29.108°、31.492°、31.904°、32.061°、33.385°和36.623°。
本发明的一些方案中，上述A晶型的XRPD图谱如图1所示。
本发明的一些方案中，上述A晶型的XRPD图谱解析数据如表1所示：
表1.A晶型的XRPD图谱解析数据
Figure PCTCN2019094824-appb-000002
Figure PCTCN2019094824-appb-000003
本发明的一些方案中，上述A晶型的差示扫描量热曲线在216.04±3℃处具有一个吸热峰的起始点。
本发明的一些方案中，上述A晶型的DSC图谱如图2所示。
本发明的一些方案中，上述A晶型的热重分析曲线在120±3℃时失重达0.4442％；在204±3℃时失重达2.4492％。
本发明的一些方案中，上述A晶型的TGA图谱如图3所示。
本发明还提供了式(Ⅱ)化合物。
Figure PCTCN2019094824-appb-000004
本发明还提供了式(Ⅱ)化合物的B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：
10.17±0.2°、11.85±0.2°、15.94±0.2°。
本发明的一些方案中，上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：
8.46±0.2°、10.17±0.2°、11.85±0.2°、13.98±0.2°、15.94±0.2°、20.39±0.2°、21.32±0.2°、23.78±0.2°。
本发明的一些方案中，上述B晶型的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.460°、10.174°、11.535°、11.850°、13.982°、15.935°、19.110°、19.464°、19.939°、20.391°、21.888°、23.309°、23.780°、24.517°、24.929°、26.034°、26.367°、26.959°、27.352°、28.772°、30.626°、31.297°、32.067°、33.845°和38.235°。
本发明的一些方案中，上述B晶型的XRPD图谱如图4所示。
本发明的一些方案中，上述B晶型的XRPD图谱解析数据如表2所示：
表2.B晶型的XRPD图谱解析数据
Figure PCTCN2019094824-appb-000005
Figure PCTCN2019094824-appb-000006
本发明的一些方案中，上述B晶型的差示扫描量热曲线在185.89±3℃处具有一个吸热峰的起始点。
本发明的一些方案中，上述B晶型的DSC图谱如图5所示。
本发明的一些方案中，上述B晶型的热重分析曲线在187.16±3℃时失重达0.7160％。
本发明的一些方案中，上述B晶型的TGA图谱如图6所示。
本发明还提供了上述A晶型在制备治疗单纯疱疹病毒相关病症的药物上的应用。
本发明还提供了上述式(Ⅱ)化合物及其B晶型在制备治疗单纯疱疹病毒相关病症的药物上的应用。
技术效果
作为新型的噻唑类化合物，本发明化合物对抗单纯疱疹病毒(HSV)的抗病毒活性良好；在体内药代动力学研究中，相同起效剂量下的血浆暴露量更低，安全性更好。本发明式(Ⅰ)化合物的A晶型及式(Ⅱ)化合物的B晶型，稳定、受光热湿度影响小且具有良好的体内给药药效，成药前景广阔。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文出现商品名时，旨在指代其对应的商品或其活性成分。
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
下面会通过实施例具体描述本发明，这些实施例并不意味着对本发明的任何限制。
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：EtOH代表乙醇；MeOH代表甲醇；TFA代表三氟乙酸；TsOH代表对甲苯磺酸；mp代表熔点；EtSO 3H代表乙磺酸；MeSO 3H代表甲磺酸；THF代表四氢呋喃；EtOAc代表乙酸乙酯；NBS代表N-溴代琥珀酰亚胺；AIBN代表偶氮二异丁腈；DMSO代表二甲基亚砜；DMF代表N,N-二甲基甲酰胺；EDCI代表碳化二亚胺；HOBt代表1-羟基苯并三唑。
本发明X-射线粉末衍射(X-ray powder diffractometer,XRPD)方法
仪器型号：布鲁克D8advance X-射线衍射仪
测试方法：大约10～20mg样品用于XRPD检测。
详细的XRPD参数如下：
光管：Cu,kα,
Figure PCTCN2019094824-appb-000007
光管电压：40kV，光管电流：40mA
发散狭缝：0.60mm
探测器狭缝：10.50mm
防散射狭缝：7.10mm
扫描范围：4-40deg
步径：0.02deg
步长：0.12秒
样品盘转速：15rpm
本发明差热分析(Differential Scanning Calorimeter,DSC)方法
仪器型号：TA Q2000差示扫描量热仪
测试方法：取样品(～1mg)置于DSC铝锅内进行测试，在50mL/min N 2条件下，以10℃/min的升温速率，加热样品从30℃(室温)到300℃(或350℃)。
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法
仪器型号：TA Q5000IR热重分析仪
测试方法：取样品(2～5mg)置于TGA铂金锅内进行测试，在25mL/min N 2条件下，以10℃/min的升温速率，加热样品从室温到350℃或失重20％。
动态蒸汽吸附分析(Dynamic Vapor Sorption,DVS)方法
仪器型号：SMS DVS Advantage动态蒸汽吸附仪
测试条件：取样品(10～15mg)置于DVS样品盘内进行测试。
详细的DVS参数如下：
温度：25℃
平衡：dm/dt＝0.01％/min(最短：10min，最长：180min)
干燥：0％RH下干燥120min
RH(％)测试梯级：10％
RH(％)测试梯级范围：0％-90％-0％
引湿性评价分类如下：
引湿性分类 引湿增重*
潮解 吸收足量水分形成液体
极具引湿性 ΔW％≥15％
有引湿性 15％>ΔW％≥2％
略有引湿性 2％>ΔW％≥0.2％
无或几乎无引湿性 ΔW％<0.2％
*在25±1℃和80±2％RH下的引湿增重
附图说明
图1为式(I)化合物A晶型的Cu-Kα辐射的XRPD谱图；
图2为式(I)化合物A晶型的DSC谱图；
图3为式(I)化合物A晶型的TGA谱图；
图4为式(Ⅱ)化合物B晶型的Cu-Kα辐射的XRPD谱图；
图5为式(Ⅱ)化合物B晶型的DSC谱图；
图6为式(Ⅱ)化合物B晶型的TGA谱图；
图7为式(Ⅱ)化合物B晶型的DVS等温线。
具体实施方式
为了更好的理解本发明的内容，下面结合具体实施例来做进一步的说明，但具体的实施方式并不是对本发明的内容所做的限制。
实施例1：式(Ⅰ)化合物的制备
Figure PCTCN2019094824-appb-000008
Figure PCTCN2019094824-appb-000009
步骤1：化合物2的合成
向化合物1(30.00g,162.11mmol)的四氯化碳(400.00mL)溶液加NBS(57.70g,324.22mmol)和AIBN(5.32g,32.42mmol)，体系在80℃继续搅拌2小时。反应完毕，减压浓缩，残留物经柱色谱纯化得化合物2，无色油状物。 1H NMR(400MHz,CDCl 3)δ7.55(s,1H),7.47-7.45(m,1H),7.28-7.25(m,1H),4.62(s,1H),4.60(s,2H)。
步骤2：化合物3的合成
钠氢(9.60g,240.02mmol,含量60％)缓慢加入乙醇(144.00mL)和四氢呋喃(432.00mL)溶液，室温搅拌5分钟，然后向该体系加丙二酸二乙酯(18.22g,113.75mmol)和化合物2(39.00g,113.75mmol)，体系室温搅拌30分钟。反应完毕，加水淬灭并减压浓缩。残留物经柱色谱纯化得化合物3，无色油状物。 1H NMR(400MHz,DMSO-d 6)δ7.36(s,1H),7.34-7.32(m,1H),7.22-7.12(m,1H),4.13(q,J1＝14.0Hz,J2＝7.2Hz,6H),1.18-1.14(m,8H)。
步骤3：化合物4的合成
向化合物3(10.00g,29.31mmol)的水(10.00mL)和DMSO(100.00mL)溶液加氯化锂(7.45g,175.86mmol)，体系在160℃下搅拌4小时。反应完毕，加100mL水，体系用乙酸乙酯(50mL x 5)萃取，有机层经碳酸氢钠水溶液(50mL x 2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残留物经柱色谱(石油醚：乙酸乙酯＝10:1)纯化得化合物4，黄色油状物。 1H NMR(400MHz,DMSO-d 6)δ7.40(s,1H),7.29(d,J＝8.0Hz,1H),7.15(d,J＝8.0Hz,1H),4.07(t,J＝14.0Hz,2H),3.42-3.35(m,1H),3.16-3.04(m,4H),1.18(t,J＝15.6Hz,3H)。
步骤4：化合物5的合成
化合物4(3.50g,13.00mmol)和三丁基(2-吡啶)锡烷(7.18g,19.50mmol)的甲苯(50.00mL)溶液用氮气置换3次，然后向反应液加四三苯基膦钯(901.67mg,780.00μmol)，体系110℃氮气保护下搅拌5小时。反应完毕，减压浓缩。残留物经制备色谱(石油醚：乙酸乙酯＝3:1)纯化得化合物5，淡黄色固体。 1H NMR (400MHz,DMSO-d 6)δ8.62(d,J＝6.4Hz,1H),7.92-7.81(m,4H),7.29(d,J＝5.2Hz,2H),4.09(q,J1＝18.0Hz,J2＝6.8Hz,2H),3.40-3.23(m,1H),3.21-3.15(m,4H),1.20(t,J＝14.4Hz,3H)。
步骤5：化合物6的合成
20℃下向化合物5(2.00g,7.48mmol)的乙醇(20mL)和水(5mL)混合溶液中，加入氢氧化钠(1.50g,37.41mmol)，体系20℃搅拌30分钟。反应完毕，反应液浓缩至干。固体溶于20mL水，酸化pH至4-6，用乙酸乙酯萃取。有机相无水硫酸钠干燥，过滤，浓缩得化合物6，淡黄色油状物。 1H NMR(400MHz,DMSO-d 6)δ8.63(d,J＝4.4Hz,1H),7.94-7.83(m,3H),7.34-7.31(m,2H),3.30-3.00(m,1H),3.22-3.16(m,4H)。
步骤6：化合物8的合成
向化合物6(200.00mg,835.88μmol)和化合物7(207.90mg,1.00mmol)的DMF(5.00mL)溶液加EDCI(192.29mg,1.00mmol)和HOBt(135.53mg,1.00mmol)，体系50℃搅拌6小时。反应完毕，减压浓缩，反应液浓缩至干，残留物经制备色谱纯化得化合物8，白色固体。 1H NMR(400MHz,CDCl 3)δ8.70(d,J＝4.0Hz,1H),(s,1H),7.81-7.71(m,3H),7.34(d,J＝8.0Hz,1H),7.26-7.25(m,1H),(s,2H),3.91-3.83(m,1H),3.79(s,3H),3.45-3.35(m,4H),2.60(s,3H)。
步骤7：化合物(I)的制备
将化合物8(690.00mg,1.61mmol)经超临界流体色谱手性拆分(仪器:SFC-10；手性柱:AD(250mm*50mm,10μm)；流动相:超临界CO 2/MeOH(0.1％NH 3H 2O)＝55/45，流速180mL/min；柱温:38℃，得到旋转异构体化合物(Ⅰ)，保留时间约为1.7min。 1H NMR(400MHz,DMSO-d 6)δ8.62(d,J＝3.2Hz,1H),(m,4H),7.63(s,2H),7.34-7.29(m,2H),4.09-4.06(m,1H),3.74(s,3H),(m,4H),2.45(s,3H)。
实施例2：式(Ⅰ)化合物的A晶型的制备
称量式(I)化合物约20g，加入800mL乙醇，置于磁力搅拌器搅拌过夜。将混合物过滤，滤饼用少量乙醇润洗，所得固体减压干燥。XRPD检测，得到式(I)化合物的A晶型。
实施例3：式(Ⅱ)化合物的B晶型的的制备
Figure PCTCN2019094824-appb-000010
称量式(I)化合物(56.5g,131.85mmol)加入3L圆底烧瓶，加入无水四氢呋喃2L，加热至50～55℃，使之完全溶解。过滤，滤液于55℃滴加用50mL无水四氢呋喃稀释的甲磺酸(12.67g,131.85mmol)，析出固 体，继续搅拌2小时。过滤，滤液减压干燥，所得固体加入圆底烧瓶，加入无水乙醇1L，加热至40℃搅拌14小时。过滤，滤饼真空干燥，XRPD检测，得到式(II)化合物的B晶型。
实施例4：式(II)化合物的B晶型的吸湿性研究
实验材料：
SMS DVS Advantage动态蒸汽吸附仪
实验方法：
取式(II)化合物B晶型10～15mg置于DVS样品盘内进行测试。
实验结果：
式(II)化合物B晶型的DVS谱图如图7所示，△W＝1.158％。
实验结论：
式(II)化合物B晶型在25℃和80％RH下的吸湿增重为1.158％，略有吸湿性。
实验例1：1-型单纯性疱疹病毒细胞病变实验(体外评价)
实验目的：
使用细胞病变(CPE)实验测定化合物对1型单纯性疱疹病毒(HSV-1)GHSV-UL 46株的抗病毒活性。
实验仪器：
细胞培养箱：Thermo 240I
细胞计数仪：Beckman Vi-CellTM XR
自动分液器：Thermo Multidrop
化合物移液系统：Labcyte ECHO 555 liquid handler
酶标仪：Molecular Device SpectraMax340PC384。
实验材料：
病毒：HSV-1 GHSV-UL46,ATCC#VR-1544
细胞：非洲绿猴肾细胞Vero E6，由中国科学院武汉病毒所赠与。
实验试剂：
试剂名称 品牌货号
DMEM细胞培养基 Gibco#11995-065
胎牛血清 Corning#35-076-CV
双抗 HyClone#SV30010
非必需氨基酸(NEAA) Gibco#11140050,100×
磷酸盐缓冲液 Corning#21-031-CVR
细胞活力检测试剂盒(CCK8) Biolite#35004
培养基配置方法：
细胞生长培养基:500ml DMEM培养基+50ml胎牛血清+5ml双抗+5ml非必需氨基酸。
细胞病变实验培养基:500ml DMEM培养基+10ml胎牛血清+5ml双抗+5ml非必需氨基酸。
实验步骤：
1.细胞铺板(第1天)
1.1.使用75％的酒精擦拭生物安全柜的工作台面，紫外照射生物安全柜15分钟，打开风机，拉伸玻璃窗至警戒线下缘，等待5分钟使柜内气流达到稳定。
1.2.取出1瓶(T 150细胞培养瓶)细胞密度达80％的Vero E6细胞。将生长培养基吸出，用10ml磷酸盐缓冲液清洗细胞两次，加入2ml胰酶，放入37℃，CO 2培养箱消化细胞。
1.3.待细胞分离脱落，加入15ml细胞病变实验培养基终止消化，吹打细胞数次后取1ml细胞悬液用细胞计数仪计数。
1.4.使用细胞病变实验培养基将细胞稀释至1.33×10 5cells/ml。使用Multidrop将稀释好的细胞悬液加入384孔板(Corning#3701)中，每孔加30μl，4000个细胞。
1.5.轻微震荡细胞板周围，使细胞分布均匀，放置于37℃，CO 2细胞培养箱内过夜培养。
2.化合物稀释、处理与病毒接种(第2天)
2.1.使用DMSO梯度稀释化合物，并将稀释好的化合物加入ECHO板中。
2.2.用ECHO 555液体工作站将化合物加入到接种有细胞的384孔板中。每个测试化合物测定8个浓度，双复孔。对于细胞对照孔，不加化合物与病毒。对于病毒对照孔，不加入化合物。所有孔中DMSO的终浓度均为0.5％。
2.3.用实验培养基稀释病毒，接种量为1.5TCID 90/well，30μl。用Multidrop将实验培养基加入细胞对照孔，每孔30μl，再将稀释好的病毒用Multidrop加入化合物测试孔和病毒对照孔，每孔30μl。
2.4.将细胞板放入37℃，CO 2细胞培养箱培养5天。
3.细胞活性检测(第7天)
3.1.培养5天后,观察细胞板所有孔中的细胞病变情况，细胞对照孔中的细胞应该没有发生病变，而病毒对照孔中的细胞几乎全部发生病变。
3.2.用Multidrop将CCK8加入细胞板中，每孔加入6μl。
3.3.将细胞板放入37℃，CO 2细胞培养箱孵育3小时。
3.4.用酶标仪读取细胞板每个孔的吸光值，所用波长为450nm，并使用630nm作为参比波长。原始数据值为450nm处的吸光度减去630nm处的吸光度(原始数据＝OD 450-OD 630)。
4.数据分析
4.1.使用下面的方程式计算测试化合物的抗病毒活性(％Inhibition)：
Figure PCTCN2019094824-appb-000011
其中，Sample为化合物测试孔的吸光值，cell control为细胞对照孔吸光值的平均数，virus control为病毒对照孔吸光值的平均数。
4.2.使用GraphPad Prism软件绘制剂量-效应曲线，并得出测试化合物的半数有效浓度(EC 50)。
5.实验结果见表3
表3.HSV-1细胞病变实验测试结果
化合物编号 HSV-1细胞病变实验EC 50(μM)
式(Ⅰ)化合物 0.007
6.结论：本发明化合物对抗单纯疱疹病毒(HSV)的抗病毒活性良好。
实验例2：化合物药代动力学评价
实验目的：测试化合物在小鼠体内药代动力学
实验材料：
Balb/c小鼠(雄性,18-22g,6～8周龄，上海斯莱克)
实验操作：
以标准方案测试化合物静脉注射及口服给药后的啮齿类动物药代特征。候选化合物配置成相应溶液，给予单次静脉注射(1.0mg/kg，5％DMSO/95％的20％羟丙基-β-环糊精)或灌胃(1.0mg/kg，0.5％甲基纤维素MC4000)给药。收集24小时内的全血样品，3000g离心15分钟，分离上清得血浆样品，加入4倍体积含内标的乙腈溶液沉淀蛋白，离心取上清液加入等倍体积的水再离心取上清进样，以LC-MS/MS分析方法定量分析血药浓度，并计算药代参数，如达峰浓度，达峰时间，清除率，半衰期，药时曲线下面积，生物利用度等。
实验结果如表4：
表4.药代动力学测试结果
Figure PCTCN2019094824-appb-000012
结论：本发明化合物，在小鼠灌胃给药的体内药代动力学研究中，相同起效剂量下的血浆暴露量更低，安全性更好。

Claims (17)

  1. 式(Ⅰ)化合物的A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.81±0.2°、15.97±0.2°、21.69±0.2°。
    Figure PCTCN2019094824-appb-100001
  2. 根据权利要求1所述的A晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.81±0.2°、13.03±0.2°、15.97±0.2°、18.48±0.2°、21.69±0.2°、23.78±0.2°、25.14±0.2°、26.96±0.2°。
  3. 根据权利要求2所述的A晶型，其XRPD图谱如图1所示。
  4. 根据权利要求1～3任意一项所述的A晶型，其差示扫描量热曲线在216.04±3℃处有一个吸热峰的起始点。
  5. 根据权利要求4所述的A晶型，其DSC图谱如图2所示。
  6. 根据权利要求1～3任意一项所述的A晶型，其热重分析曲线在120±3℃时失重达0.4442％；在204±3℃时失重达2.4492％。
  7. 根据权利要求6所述的A晶型，其TGA图谱如图3所示。
  8. 式(Ⅱ)化合物。
    Figure PCTCN2019094824-appb-100002
  9. 式(Ⅱ)化合物的B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.17±0.2°、11.85±0.2°、15.94±0.2°。
  10. 根据权利要求9所述的B晶型，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.46±0.2°、10.17±0.2°、11.85±0.2°、13.98±0.2°、15.94±0.2°、20.39±0.2°、21.32±0.2°、23.78±0.2°。
  11. 根据权利要求10所述的B晶型，其XRPD图谱如图4所示。
  12. 根据权利要求9～11任意一项所述的B晶型，其差示扫描量热曲线在185.89±3℃处具有一个吸热峰的起始点。
  13. 根据权利要求12所述的B晶型，其DSC图谱如图5所示。
  14. 根据权利要求9～11任意一项所述的B晶型，其热重分析曲线在187.16±3℃时失重达0.7160％。
  15. 根据权利要求14所述的B晶型，其TGA图谱如图6所示。
  16. 根据权利要求1～7任意一项所述的式(Ⅰ)化合物的A晶型在制备治疗单纯疱疹病毒相关病症的药物上的应用。
  17. 根据权利要求8所述的式(Ⅱ)化合物及其9～15任意一项所述的式(Ⅱ)化合物的B晶型在制备治疗单纯疱疹病毒相关病症的药物上的应用。
PCT/CN2019/094824 2018-07-06 2019-07-05 噻唑类化合物的晶型及其应用 Ceased WO2020007355A1 (zh)

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ES19831293T ES2982663T3 (es) 2018-07-06 2019-07-05 Formas cristalinas de un compuesto de tiazol y aplicación del mismo
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