WO2019072236A1 - 一种吡啶酮化合物的晶型、盐型及其制备方法 - Google Patents

一种吡啶酮化合物的晶型、盐型及其制备方法 Download PDF

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WO2019072236A1
WO2019072236A1 PCT/CN2018/110022 CN2018110022W WO2019072236A1 WO 2019072236 A1 WO2019072236 A1 WO 2019072236A1 CN 2018110022 W CN2018110022 W CN 2018110022W WO 2019072236 A1 WO2019072236 A1 WO 2019072236A1
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compound
production method
crystalline form
solvent
group
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PCT/CN2018/110022
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French (fr)
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张蕾
陈斌
赵阳光
黎健
陈曙辉
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石家庄智康弘仁新药开发有限公司
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Priority to CN201880066799.0A priority Critical patent/CN111278820B/zh
Priority to US16/755,386 priority patent/US11198686B2/en
Publication of WO2019072236A1 publication Critical patent/WO2019072236A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • 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

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  • the present invention relates to a crystalline form of Compound 1 and a process for the preparation thereof, and to the use of said crystalline form for the preparation of a medicament for treating diseases associated with fibrosis.
  • Idiopathic Pulmonary Fibrosis is a typical chronic, progressive and fatal fibrotic interstitial pneumonia characterized by progressive dyspnea and progressive decline in lung function, which quickly leads to respiratory failure and death. At least 5 million people worldwide were sick in 2008. In 2010, there were only 130,000 to 500,000 people in the United States. About 48,000 new cases were reported each year, and about 40,000 people died each year from IPF. The incidence of IPF is estimated to be 4.6-7.4/100,000, and 3–35,000 new cases are diagnosed each year. The incidence of smoking is much greater than that of non-smokers, and the incidence of IPF can reach nearly 2.3% in people aged 20-40 years. The male incidence rate is higher than that of females. The 5-year individual survival rate of IPF is about 20%, and the mortality rate is much higher than many cancers. It is known as a cancer that is not cancer. Potential risk factors include occupational exposure and environmental pollution such as metals, animals, wood chips, smoking and smog.
  • IPF The pathogenesis of IPF is complex and generally thought to involve interaction between pro-inflammatory and pro-fibrotic pathways, but the exact mechanism is still unknown.
  • Roche's pirfenidone and Boehringer Ingelheim's nintedanib were first approved in the United States, and the annual sales peak of pirfenidone is estimated to reach $2 billion in 2019.
  • the prognosis of IPF is poor, and the treatment plan is scarce.
  • the launch of these two new drugs gives confidence in the progress of IPF disease, and these two drugs are likely to be used to treat other fibrotic diseases.
  • the majority of patients still have unmet medical needs, so the development of better IPF new drugs is receiving more and more attention.
  • the present invention provides Form A of Compound 1, the X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 7.87 ⁇ 0.2 °, 15.69 ⁇ 0.2 °, 16.58 ⁇ 0.2 °.
  • the X crystal form of the above Compound 1 has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 7.87 ⁇ 0.2 °, 15.69 ⁇ 0.2 °, 16.58 ⁇ 0.2 °, 18.34 ⁇ 0.2 °. , 19.39 ⁇ 0.2 °, 24.97 ⁇ 0.2 °, 27.19 ⁇ 0.2 °, 31.57 ⁇ 0.2 °.
  • the X-form analysis data of the A crystal form of the above Compound 1 is shown in Table 1.
  • Table-1 A crystal form XRPD pattern analysis data
  • the crystalline form of Form A of Compound 1 above has a differential scanning calorimetry curve having an onset of an endothermic peak at 106.63 °C ⁇ 4 °C.
  • the A crystal form of the above compound 1 has a DSC pattern as shown in FIG.
  • the A crystal form of the above Compound 1 has a thermogravimetric analysis curve having a weight loss of 0.3391% at 110.00 ° C ⁇ 3 ° C.
  • the T crystal of Form A of Compound 1 above is shown in Figure 3.
  • the present invention also provides a process for the preparation of Form A of Compound 1, which comprises adding Compound 1 of any form to a mixture of esters and alkanes in an organic solvent to prepare a slurry.
  • the ester solvent is selected from the group consisting of ethyl acetate.
  • the alkane solvent is selected from the group consisting of petroleum ether, n-heptane, and cyclohexane.
  • the organic mixed solvent is selected from the group consisting of a mixed solvent of ethyl acetate and n-heptane.
  • the volume ratio of ethyl acetate to n-heptane is selected from the group consisting of 1:0.5 to 1.5.
  • the volume ratio of ethyl acetate to n-heptane is selected from the group consisting of 1:1.
  • the beating temperature is selected from the group consisting of 20 ° C to 30 ° C.
  • the beating time is selected from the group consisting of 12 hours to 36 hours.
  • the weight ratio of the above compound 1 to the organic mixed solvent is selected from 1:5 to 6.
  • the invention also provides the application of the A crystal form in the preparation of a medicament for treating idiopathic pulmonary fibrosis.
  • the crystal form A of the present invention has good stability and is easy to form a drug; its inhibitory effect on cytokines related to the TNF-NFTGF-F-related pathway is obvious, and it is found by the left unilateral pulmonary fibrosis model of SD rats, Compound 1
  • the A crystal form has a significant inhibitory effect on idiopathic pulmonary fibrosis.
  • 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, combinations thereof with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the present invention employs the following abbreviations: DMF stands for dimethylformamide; MsOH stands for methanesulfonic acid; EtOH stands for ethanol; MeOH stands for methanol; NaOH stands for sodium hydroxide; DCM stands for dichloromethane; PE stands for petroleum ether, EtOAc stands for Ethyl acetate; THF represents tetrahydrofuran.
  • XRPD X-ray powder diffractometer
  • Test method Approximately 10-20 mg samples were used for XRPD detection.
  • DSC Differential Scanning Calorimeter
  • Test method The sample ( ⁇ 1 mg) was placed in a DSC aluminum pan for testing, and the sample was heated from 25 ° C to 350 ° C at a heating rate of 10 ° C / min under 50 mL / min N 2 .
  • TGA Thermal Gravimetric Analyzer
  • Test method The sample (2-5 mg) was placed in a TGA platinum pot for testing, and the sample was heated from room temperature to weight loss by 20% at a heating rate of 10 ° C/min under 25 mL/min N 2 .
  • Figure 1 is an XRPD spectrum of Cu-K ⁇ radiation of Form A of Compound 1.
  • Figure 3 is a TGA spectrum of Form A of Compound 1.
  • reaction solution was added water (800 mL) was diluted with saturated Na 2 CO 3 aqueous solution was adjusted to pH 9-10 and then extracted with EtOAc (200mL ⁇ 4). The combined organic layers were washed with brine (50 mL) After the desiccating agent was filtered off, the solvent was evaporated, evaporated, mjjjjjjjj %).
  • the obtained white solid was subjected to HPLC (mobile phase A: 0.05% aqueous solution of trifluoroacetic acid; mobile phase) B: acetonitrile; column: Ultimate C18 3.0mm ⁇ 50mm, 3.0 ⁇ m; peak time: 8min) purity is higher than 98%, if the purity is low, repeat the beating operation until the purity reaches the requirement (generally no more than 2 times), get 122 A crystalline form of Compound A in powdery white solid.
  • HPLC mobile phase A: 0.05% aqueous solution of trifluoroacetic acid; mobile phase
  • B acetonitrile
  • column Ultimate C18 3.0mm ⁇ 50mm, 3.0 ⁇ m
  • peak time 8min
  • a sample of 16 parts of Form A was weighed in parallel on the bottom of the glass bottle, about 10 mg per part, and 8 parts of Form A sample, and about 20 mg of each sample was spread into a thin layer. Wrap all sample vials in aluminum foil and place small holes in the aluminum foil to ensure that the sample is in full contact with ambient air. Place at 40 ° C / 75% RH and 60 ° C / 75% RH, respectively. Months, 2 months, 3 months.
  • OBJECTIVE To test the effect of compound 1 on TNF- ⁇ in rat blood induced by bacterial lipopolysaccharide LPS, and to evaluate its anti-inflammatory activity in vitro.
  • Rat TNF-alpha Quantikine ELISA Kit R&D, #SRTA00
  • a test compound solution having a concentration of 5 mM or 1 mM was prepared, and 40 ⁇ L (the final concentration of the compound was 0.5 or 0.1 mM) was added to a 48-well cell culture plate, respectively. After anesthesia with isoflurane, the rats were bled in the abdominal aorta (heparin anticoagulation). Blood was added to a 48-well plate to which the test compound was added, 320 ⁇ L per well. The 48-well plate was incubated at 37 ° C, and after 30 minutes of incubation, it was taken out, 40 ⁇ L of LPS solution (final concentration 100 ⁇ g/mL) was added, mixed, and placed at 37 ° C to continue incubation.
  • LPS solution final concentration 100 ⁇ g/mL
  • the 48-well plate was taken out, and the blood sample was transferred to a 1.5 mL centrifuge tube, centrifuged in a centrifuge (4,500 rpm, 4 ° C, 5 minutes), and the upper layer of plasma was separated, and 20 ⁇ L of each well was dispensed into a 96-well sample plate. Quickly freeze and store in a -80 ° C refrigerator. The next day, according to the kit instructions, the R&D ELISA kit was used to detect TNF- ⁇ levels in plasma samples. Data analysis was performed using EXCEL and Prism statistical software.
  • pirfenidone detection concentration is 0.5 mM, compound 1 is 0.1 mM;
  • the A crystal form of Compound 1 can significantly inhibit the LPS-induced TNF- ⁇ level at the final concentration of 0.1 mM, and the inhibition rate of TNF- ⁇ is significantly higher than that of the original drug pirfenib. ketone.

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Abstract

化合物1的晶型及其制备方法，还包括所述晶型在制备治疗与纤维化相关疾病药物中的应用。

Description

一种吡啶酮化合物的晶型、盐型及其制备方法
相关申请的引用
本申请主张如下优先权：
CN201710953047.3，申请日2017-10-13；
技术领域
本发明涉及化合物1的晶型及其制备方法，还包括所述晶型在制备治疗与纤维化相关相关疾病药物中的应用。
背景技术
特发性肺纤维化Idiopathic Pulmonary Fibrosis(IPF)是典型的慢性，渐进并致命的纤维化间质性肺炎，其特征在于渐进呼吸困难和肺功能逐渐下降，很快会导致呼吸衰竭而死亡。2008年全世界至少有500万人患病，2010年仅美国就有13-50万人患病，每年新增病例约48,000例，每年约4万人死于IPF。IPF的发病率估计为4.6-7.4/100,000，每年有3–3.5万新病例被确诊。吸烟的人发病率远远大于不吸烟的人，在烟龄为(20-40年)人群中IPF发病率可达到将近2.3％。男性发病率高于女性，IPF的5年个体存活率约为20％，死亡率远远高于许多癌症，被誉为不是癌症的癌症。潜在的风险因素包括职业暴露和环境污染，如金属，动物，木屑，吸烟和霧霾。
IPF的发病机制复杂，一般认为涉及促炎和促致纤维化途径之间的互动，然而确切的机制还是一个未知数。2014年罗氏的吡非尼酮(pirfenidone)和勃林格殷格翰的nintedanib在美国首次批准，吡非尼酮的年销售高峰估计在2019年可达20亿美元。目前IPF预后诊断差，治疗方案稀缺，这两个新药的上市给了IPF疾病进展一定的信心，而且这两个药很可能可用于治疗其他纤维化疾病。但是目前广大患者还有未满足的医疗需求，所以研发更好的IPF新药日益受到重视。
发明内容
本发明提供了化合物1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：7.87±0.2°、15.69±0.2°、16.58±0.2°。
Figure PCTCN2018110022-appb-000001
本发明的一些方案中，上述化合物1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：7.87±0.2°、15.69±0.2°、16.58±0.2°，18.34±0.2°，19.39±0.2°，24.97±0.2°，27.19±0.2°，31.57±0.2°。
本发明的一些方案中，上述化合物1的A晶型，其XRPD图谱如图1所示。
本发明的一些方案中，上述化合物1的A晶型，其XRPD图谱解析数据如表1所示。
表-1 A晶型XRPD图谱解析数据
Figure PCTCN2018110022-appb-000002
本发明的一些方案中，上述化合物1的A晶型，其差示扫描量热曲线在106.63℃±4℃处具有吸热峰的起始点。
本发明的一些方案中，上述化合物1的A晶型，其DSC图谱如图2所示。
本发明的一些方案中，上述化合物1的A晶型，其热重分析曲线在110.00℃±3℃时失重达0.3391％。
本发明的一些方案中，上述化合物1的A晶型，其TGA图谱如图3所示。
本发明还提供了化合物1的A晶型的制备方法，包括将任意一种形式的化合物1加入到酯类和烷烃类有机混合溶剂中打浆制得。
本发明的一些方案中，上述酯类溶剂选自乙酸乙酯。
本发明的一些方案中，上述烷烃类溶剂选自石油醚、正庚烷和环己烷。
本发明的一些方案中，上述有机混合溶剂选自乙酸乙酯与正庚烷的混合溶剂。
本发明的一些方案中，上述乙酸乙酯与正庚烷的体积比选自1：0.5～1.5。
本发明的一些方案中，上述乙酸乙酯与正庚烷的体积比选自1:1。
本发明的一些方案中，上述打浆温度选自20℃～30℃。
本发明的一些方案中，上述打浆时间选自12小时～36小时。
本发明的一些方案中，上述化合物1与有机混合溶剂的重量比选自1:5～6。
本发明还提供了A晶型在制备治疗特发性肺纤维化相关药物上的应用。
技术效果
本发明化合物1的A晶型稳定性好，易于成药；其对与TNF-NFTGF-F相关通路的细胞因子的抑制作用明显，并通过SD大鼠左侧单侧肺纤维化模型发现，化合物1的A晶型对特发性肺纤维化的抑制作用显著。
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。
本发明采用下述缩略词：DMF代表二甲基甲酰胺；MsOH代表甲磺酸；EtOH代表乙醇；MeOH代表甲醇；NaOH代表氢氧化钠；DCM代表二氯甲烷；PE代表石油醚、EtOAc代表乙酸乙酯；THF代表四氢呋喃。
化合物经手工或者
Figure PCTCN2018110022-appb-000003
软件命名，市售化合物采用供应商目录名称。
本发明粉末X-射线衍射(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 PCTCN2018110022-appb-000004
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25℃到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，加热样品从室温到失重20％。
附图说明
图1为化合物1的A晶型的Cu-Kα辐射的XRPD谱图。
图2为化合物1的A晶型的DSC谱图。
图3为化合物1的A晶型的TGA谱图。
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：化合物1的合成
Figure PCTCN2018110022-appb-000005
第一步：化合物b的制备
在氮气保护下于10℃，向悬浮着钠氢(1.99g,49.83mmol)的无水DMF(75mL)溶液中滴加丙二酸二乙酯(6.57g,41.00mL)。滴加完成后，室温下搅拌反应0.5小时，然后滴加5-氯-2-硝基吡啶(5.00g,31.54mmol)的无水DMF(25mL)溶液。反应混合物缓慢升温至80℃，继续搅拌12小时。反应完成后，反应液用水(2300mL)稀释，然后EtOAc萃取(500mL×4)。合并有机相，饱和食盐水(100mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂，所得残留物经层析柱分离纯化(洗脱剂：PE/EtOAc＝10/1到5/1)，得到桔红色固体化合物b(5.40g，收率60.66％)。 1H NMR(400MHz,CDCl 3)δ:8.63(d,J＝2.0Hz,1H),8.33-8.28(m,1H),8.26(d,J＝2.0Hz,1H),4.81(s,1H),4.33-4.21(m,4H),1.33-1.28(m,6H).
第二步：化合物c的制备
室温下，将化合物b(5.00g,17.71mmol)溶于无水DMF(50mL)中，加入碳酸钾固体(4.90g,35.42mmol)后，滴加碘甲烷(5.03g,35.42mmol)。混合物在25℃下搅拌1小时。反应完成后，反应液用水(900mL)稀释后，EtOAc萃取(200mL×3)。合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂，所得残留物经层析柱分离纯化(洗脱剂：PE/EtOAc＝10/1)，得到黄色固体化合物c(5.25g，收率100％)。 1H NMR(400MHz,CDCl 3)δ:8.67(d,J＝2.0Hz,1H),8.25(d,J＝8.5Hz,1H),8.10(dd,J＝2.5,8.5Hz,1H),4.27(dq,J＝2.0,7.1Hz,4H),1.94(s,3H),1.28(t,J＝7.0Hz,6H).
第三步：化合物d的制备
室温下，将化合物c(17.00g,60.23mmol)溶于EtOAc(150mL)中，加入10％湿钯碳(3.20g,3.01mmol)， 混合物在40℃下于氢气氛围中(50psi)搅拌12小时。反应完成后，反应液过滤除去不溶物，催化剂用少量EtOAc(20mL×3)洗涤，滤液减压浓缩，所得桔黄色固体化合物d(13.70g，收率85.42％)可直接用于下一步合成，无需进一步纯化。 1H NMR(400MHz,CDCl 3)δ:7.83(d,J＝2.5Hz,1H),7.34(dd,J＝2.5,8.8Hz,1H),6.45-6.39(m,1H),5.99(s,2H),4.15(q,J＝7.0Hz,4H),1.74-1.66(m,3H),1.17(t,J＝7.0Hz,6H).
第四步：化合物e的制备
室温下，将化合物d(13.70g,51.45mmol)溶于70％的硫酸(92.00g,50.00mL)水溶液中，混合物降温到-5℃，慢慢滴加亚硝酸钠(4.30g,62.25mmol)的水(3.5mL)溶液，保证反应内温在0℃以下，混合物在-5℃下搅拌0.5小时，然后升温至室温，继续搅拌3小时。反应完成后，反应液加水(800mL)稀释，饱和Na 2CO 3水溶液调节pH至9～10，然后用EtOAc(200mL×4)萃取。合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，旋蒸除去溶剂，所得残留物经层析柱分离纯化(洗脱剂：PE/EtOAc＝5/1至纯EtOAc)，得到棕黄色固体化合物e(11.00g，收率80％)。 1H NMR(400MHz,CDCl 3)δ:12.88(br.s.,1H),7.60(dd,J＝2.8,9.8Hz,1H),7.38(d,J＝3.0Hz,1H),6.57(d,J＝9.5Hz,1H),4.23(q,J＝6.9Hz,4H),1.76(s,3H),1.26(t,J＝7.0Hz,6H).
第五步：化合物f的制备
室温于氮气保护下，向化合物e(500.00mg,1.87mmol)和3-溴噻吩(304.88mg,1.87mmol)的无水二氧六环(12mL)溶液中加入碘化亚铜(356.14mg,1.87mmol)，N,N’-二甲基-trans-环己二胺(427.07mg,3.74mmol)和碳酸钾(516.91mg,3.74mmol)，混合物在100℃下搅拌12小时。反应完毕后，反应液用水(50mL)稀释，EtOAc(50mL)萃取。有机相用5％的氨水(20mL×3)洗涤，至有机相成为亮黄色，且水相无蓝色洗出为止。水相再次用EtOAc(30mL×2)萃取，有机相合并，减压浓缩至干。残余物用层析柱纯化(洗脱剂：PE/EtOAc，从10/1至3/1)，得到黄色固体化合物f(550.00mg，收率：84.18％)。 1H NMR(400MHz,CDCl 3)δ:7.49(dd,J＝2.6,9.7Hz,1H),7.44-7.37(m,3H),7.25(br d,J＝5.3Hz,1H),6.63(d,J＝9.8Hz,1H),4.25(q,J＝7.2Hz,4H),1.77(s,3H),1.28(t,J＝7.2Hz,6H).
第六步：化合物g的制备
0℃于氮气保护下，向化合物f(2.95g，8.44mmol)的MeOH(45mL)溶液中分批加入硼氢化钠(1.60g，42.20mmol)，混合物缓慢升温至25℃搅拌12小时。反应完成后，反应液倒入DCM(450mL)中，并于室温搅拌1小时。过滤除去不溶物，滤液减压浓缩至干。残余物用层析柱纯化(洗脱剂：DCM/MeOH＝50/1至10/1)，得到白色固体粉末状化合物g(950.00mg，收率42.42％)。 1H NMR(400MHz,DMSO-d 6)δ:7.76-7.72(m,1H),7.67-7.58(m,2H),7.42(d,J＝2.5Hz,1H),7.31-7.27(m,1H),6.45(d,J＝9.5Hz,1H),4.65(br s,2H),3.56-3.49(m,2H),3.48-3.42(m,2H),1.11(s,3H).
第七步：化合物1的制备
室温于氮气保护下，向化合物g(900.00mg,3.39mmol)，三苯基磷(1.78g,6.78mmol)和福美锌(1.60g,5.22mmol)的无水THF(25mL)溶液中滴加偶氮二甲酸二乙酯DEAD(1.18g,6.78mmol)，混合物在30℃下搅拌20小时。反应完毕后，反应液中加入MeOH(50mL)，过滤除去不溶物，固体用MeOH(10mL×2)洗涤。滤液合并后，减压浓缩至干。残余物用层析柱纯化(洗脱剂：PE/EtOAc，从10:1到纯EtOAc)，得到混有少量三苯氧磷的黄色固体粗产物。粗产物用混合溶剂PE/EtOAc(1:1,10mL)打浆1小时，过滤收集固体，滤饼用PE(5mL×2)洗涤，所得固体真空干燥，得到化合物1。 1H NMR(400MHz,CDCl 3)δ:7.60(dd,J＝2.5,9.5Hz,1H),7.46-7.39(m,2H),7.27-7.22(m,2H),6.78(d,J＝9.5Hz,1H),4.80(d,J＝6.0Hz,2H),4.63(d,J＝5.8Hz,2H),1.72-1.65(m,1H),1.69(s,2H).
实施例2：A晶型的制备
向化合物1(163g)中加入乙酸乙酯(800mL)，稍微加热使固体溶解完全，用6号砂芯漏斗抽滤除去杂质及不溶物，滤液旋蒸至干。残余物中加入正庚烷/乙酸乙酯(1:1，800mL)室温搅拌打浆12小时，不溶物过滤收集，所得白色固体经HPLC检测(流动相A:0.05％三氟乙酸的水溶液；流动相B:乙腈；色谱柱:Ultimate C18 3.0mm×50mm，3.0μm；出峰时间：8min)纯度高于98％，如纯度低需重复打浆操作至纯度达到要求(一般不超过2次)，得到122克白色固体粉末状化合物1的A晶型。 1H NMR(400MHz,DMSO-d 6)δ:1.07(s,3H),3.37-3.44(m,2H),3.44-3.52(m,2H),6.40(d,J＝9.48Hz,1H),7.25(dd,J＝5.18,1.43Hz,1H),7.38(d,J＝2.65Hz,1H),7.54-7.63(m,2H),7.67-7.71(m,1H).
实验例1：A晶型在高温，高湿条件下的固体稳定性试验
平行称取16份A晶型样品平铺于玻璃瓶底部，每份约10mg，以及8份A晶型样品，每份约20mg样品，摊成薄薄一层。将所有样品瓶用铝箔纸包好瓶口并在铝箔纸上扎些小孔，保证样品与环境空气充分接触，放置于40℃/75％RH和60℃/75％RH条件下，分别放置1个月，2个月，3个月。
分析方法：使用Agilent 1260高效液相仪配置DAD检测器或Waters 2695高效液相仪配置PDA检测器，色谱柱：Waters Atlantis d C18(4.6mm×150mm，3.0μm)，柱温：40℃，流速：1.0mL/分钟，检测波长：230nm，进样体积：10μL，配制样品浓度：0.5mg/ml，稀释剂：乙腈：水＝1:1(v/v)，采用以下流动相梯度进行分析。
梯度：时间(min) 流动相A：0.04％TFA in water(％) 流动相B：ACN(％)
0.00 95 5
50.00 50 50
55.00 30 70
55.01 95 5
60.00 95 5
表-2 A晶型的固体稳定性试验
Figure PCTCN2018110022-appb-000006
实验结论：各条件下三个月内A晶型性质稳定，成药性很好。
实验例2：A晶型在不同温度和湿度及光照条件下固体物理稳定性试验
平行称取4份A晶型固体，每份大约100mg，放置于玻璃样品瓶的底部，摊成薄薄一层，铝箔纸封瓶口，并在铝箔纸上扎些小孔，保证样品能与环境空气充分接触。把制备的4份样品分别放置于25℃/92.5％的相对湿度，60℃，40℃/75％及光照条件下，考察样品第10天的物理稳定性。同时，单独称取一份大约100mg A晶型固体，放置于玻璃样品瓶的底部，用螺纹瓶盖密封后，保存于-20℃条件下，作为对照品使用。在第10天，取出所有样品，恢复至室温，观察样品外观变化，并用XRPD检测样品晶型。通过对加速样品与对照样品的比较，判断化合物1的A晶型的固体物理稳定性。下表-3为A晶型固体物理稳定性实验结果。
表-3 A晶型在不同温度和湿度条件下及光照下固体物理稳定性试验
Figure PCTCN2018110022-appb-000007
实验结论：各条件下10天内A晶型性质稳定，成药性很好。
实验例3：化合物1的多晶型研究
称取大约50mg样品分别加入到不同的4.0mL玻璃小瓶中，分别加入适量的溶剂或溶剂混合(见下表)使其成悬浊液。40℃条件下振摇2天后，将所有样品取出置于8000r/min的离心机中离心5min，吸取上清液丢弃，将剩余固体置于35℃真空干燥箱中干燥两天。将干燥好的样品取出铺板进行XRPD检测。
表-4化合物1的多晶型研究结果
编号 溶剂 晶型
1 乙醇 A晶型
2 乙腈 A晶型
3 丙酮 A晶型
4 乙酸乙酯 A晶型
5 丙酮：水(1:2) A晶型
6 水 A晶型
实验结论：由上表可知，在上述溶剂条件下，化合物1的A晶型稳定。
实验例4：A晶型在不用溶剂中的溶解度
本实验是在常温条件下采用手动逐级稀释的方法并同时观察溶解情况进行测定的。大约2mg的化合物1的A晶型加入到不同的液相小瓶中，然后少量多次加入有机溶剂或溶剂混合物(表5)，观察化合物的溶解情况。化合物的溶解度试验结果见表5。
表-5 A晶型在不用溶剂中的大致溶解度
编号 溶剂 溶解度(mg/mL)
1 甲醇 >104
2 乙醇 51-102
3 异丙醇 34-52
4 正丁醇 50-100
5 乙腈 >100
6 丙酮 52-103
7 甲基乙基酮 52-104
8 甲基异丁基酮 34-51
9 乙酸乙酯 34-51
10 乙酸异丙酯 20-34
11 甲基叔丁基醚 <2
12 四氢呋喃 51-102
13 2-甲基四氢呋喃 34-51
14 甲苯 35-52
15 庚烷 <2
16 环己烷 <2
17 1,4-二氧六环 >102
18 水 10-21
19 甲醇-水(1:1) >102
20 甲醇-水(3:1) >104
21 乙醇-水(1:1) >100
22 乙醇-水(3:1) >104
23 乙腈-水(1:1) >100
24 丙酮-水(1:2) 52-103
25 异丙醇-水(1:1) >102
实验例5：体外评价化合物对内毒素(LPS)诱导大鼠血液中TNF-α的影响
实验目的：检测化合物1对细菌脂多糖LPS诱导的大鼠血液中TNF-α的影响，用于评估其体外抗炎活性。
实验材料:
Sprague Dawley大鼠(雄性,280～310g,上海斯莱克)
Rat TNF-alpha Quantikine ELISA Kit(R&D,#SRTA00)
实验操作：
配制浓度为5mM或1mM的待测化合物溶液，分别在48孔细胞培养板中加入40μL(化合物终浓度为0.5或0.1mM)。大鼠用异氟烷麻醉后，于腹主动脉采血(肝素抗凝)。将血液加入已加好待测化合物的48孔板中，每孔320μL。48孔板放置于37℃孵育，孵育30分钟后取出，加入40μL LPS溶液(终浓度100μg/mL)，混匀后放置于37℃中继续孵育。5小时后取出48孔板，血样转移至1.5mL离心管中，置于离心机中离心(4,500rpm,4℃,5分钟)，分离上层得血浆，20μL每孔分装于96孔样品板后速冻，保存在-80℃冰箱。第二天按照试剂盒说明书操作用R&D ELISA试剂盒进行血浆样品中TNF-α水平检测。用EXCEL和Prism统计软件进行数据分析。
实验结果总结：
表-6
实施例 体外TNF-α抑制率
吡非尼酮 53.51％±5.73
化合物1(A晶型) 80.78％±5.67
注：吡非尼酮检测浓度为0.5mM，化合物1为0.1mM；
结论：在体外TNF-α抑制活性检测实验中，化合物1的A晶型在0.1mM终浓度能够显著抑制LPS诱导的TNF-α水平，对TNF-α的抑制率显著高于原研药吡非尼酮。

Claims (17)

  1. 化合物1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：7.87±0.2°、15.69±0.2°、16.58±0.2°。
    Figure PCTCN2018110022-appb-100001
  2. 根据权利要求1所述化合物1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：7.87±0.2°、15.69±0.2°、16.58±0.2°，18.34±0.2°，19.39±0.2°，24.97±0.2°，27.19±0.2°，31.57±0.2°。
  3. 根据权利要求2所述化合物1的A晶型，其XRPD图谱如图1所示。
  4. 根据权利要求1～3任意一项所述化合物1的A晶型，其差示扫描量热曲线在106.63℃±4℃处具有吸热峰的起始点。
  5. 根据权利要求4所述化合物1的A晶型，其DSC图谱如图2所示。
  6. 根据权利要求1～3所述化合物1的A晶型，其热重分析曲线在110.00℃±3℃时失重达0.3391％。
  7. 根据权利要求6所述化合物1的A晶型，其TGA图谱如图3所示。
  8. 化合物1的A晶型的制备方法，包括将任意一种形式的化合物1加入到酯类和烷烃类有机混合溶剂中打浆制得。
  9. 根据权利要求8所述的制备方法，其中，酯类溶剂选自乙酸乙酯。
  10. 根据权利要求8所述的制备方法，其中，烷烃类溶剂选自石油醚、正庚烷和环己烷。
  11. 根据权利要求8所述的制备方法，其中，有机混合溶剂选自乙酸乙酯与正庚烷的混合溶剂。
  12. 根据权利要求11所述的制备方法，其中，乙酸乙酯与正庚烷的体积比选自1：0.5～1.5。
  13. 根据权利要求12所述的制备方法，其中，乙酸乙酯与正庚烷的体积比选自1:1。
  14. 根据权利要求8所述的制备方法，其中，打浆温度选自20℃～30℃。
  15. 根据权利要求8所述的制备方法，其中，打浆时间选自12小时～36小时。
  16. 根据权利要求8所述的制备方法，其中，化合物1与有机混合溶剂的重量比选自1:5～6。
  17. 根据权利要求1～7任意一项所述的A晶型在制备治疗特发性肺纤维化相关药物上的应用。
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WO2017177974A1 (zh) * 2016-04-14 2017-10-19 南京明德新药研发股份有限公司 用于治疗纤维化和炎性疾病的含杂原子环丁烷取代基的吡啶酮衍生物

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WO2023217239A1 (zh) * 2022-05-12 2023-11-16 广州嘉越医药科技有限公司 一种药物组合及其应用
WO2024012531A1 (zh) * 2022-07-14 2024-01-18 广州嘉越医药科技有限公司 一种吡啶酮衍生物的应用

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