CN106397408B - 5-甲基-2(1h)吡啶酮衍生物及其制备方法和用途 - Google Patents
5-甲基-2(1h)吡啶酮衍生物及其制备方法和用途 Download PDFInfo
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- CN106397408B CN106397408B CN201510460618.0A CN201510460618A CN106397408B CN 106397408 B CN106397408 B CN 106397408B CN 201510460618 A CN201510460618 A CN 201510460618A CN 106397408 B CN106397408 B CN 106397408B
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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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
- C07D417/10—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 carbon chain containing aromatic rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了式Ⅰ所示5‑甲基‑2(1H)吡啶酮衍生物或其晶型、药学上可接受的盐、水合物、溶剂合物或前体药物:其中,X选自S或NH;R1~R4分别或同时选自氢、卤素、C1~C6的烷基、C1~C6的烷氧基。本发明提供了一种新的5‑甲基‑2(1H)吡啶酮衍生物,对成纤维细胞增殖以及成纤维细胞分泌纤维结合蛋白(Fn)均具有明显的抑制作用,可以用于制备治疗或预防纤维化疾病、肿瘤等药物;本发明式Ⅰ所示化合物的制备方法,具有工序少、步骤简便、反应条件温和、能耗低、效率高、成本低、绿色环保等优点,非常适合产业上的应用。
Description
技术领域
本发明涉及一种5-甲基-2(1H)吡啶酮衍生物及其制备方法和用途。
背景技术
5-甲基-2(1H)吡啶酮,别名:5-甲基吡啶-2-醇、2-羟基-5-甲基吡啶,CAS号:1003-68-5,其化学结构如式A所示,主要用于有机合成等领域。
美国专利US3839346A公开了式B所示的吡啶酮类化合物,该化合物具有抗炎、解热、降低血清尿酸水平、止痛等作用;其中,取代基R数目为0或1,R代表硝基、氯原子、烷基、甲氧基;当R为0时,式B所示化合物为1-苯基-5-甲基-2-(1H)吡啶酮(即吡非尼酮)。美国专利US4052509A也公开了吡非尼酮,其具有良好的抗炎和镇痛作用。
中国专利CN 1386737 A公开了一种式C所示的抗纤维化吡啶酮药物,它为1-多取代苯基-5-甲基-2-(1H)吡啶酮化合物;其中,n为1或2,R为F、Cl、Br、I、饱和直链烃基、氧代饱和直链烃基或卤代饱和直链烃基。
中国专利CN 102786467 A公开了一种式D所示的N-取代芳基吡啶酮化合物,它是以吡非尼酮为先导化合物,保留吡啶酮母核,在N-取代芳基的4位上引入不同的胺亚甲基醚结构,得到N-(4-胺亚甲基醚)芳基吡啶酮;其中,X3为Y(CH2)nR4,Y为O或S,n为1-10;所述的R4是开链或环状的叔胺结构NR5R6,R5、R6独立地选自含1-3个碳原子的直链或支链烷烃,或R5、R6与R4中的N构成五元、六元或七元环,所述的五元、六元或七元环为恶唑、吡咯、咪唑、吡唑、哌啶、哌嗪、甲基哌嗪、吗啉或高哌啶。
中国专利CN 101842355 A公开了式E所示取代的N-芳基吡啶酮;其中,R1、R2、R3、R4、R5、R6、R7、R8、R9、R10和R11独立选自由氢和氘组成的组;R1、R2、R3、R4、R5、R6、R7、R8、R9、R10和R11中的至少一个是氘;且如果R7、R8、R9、R10和R11是氘,则R1、R2、R3、R4、R5和R6中的至少一个是氘。
目前,未见有本发明式Ⅰ所示5-甲基-2(1H)吡啶酮衍生物的报道;也未见有式Ⅰ所示5-甲基-2(1H)吡啶酮衍生物的制备方法和用途的报道。
发明内容
本发明的目的在于提供一种新的5-甲基-2(1H)吡啶酮衍生物。
本发明提供的式Ⅰ所示5-甲基-2(1H)吡啶酮衍生物或其晶型、药学上可接受的盐、水合物、溶剂合物或前体药物:
其中,X选自S或NH;R1~R4分别或同时选自氢、卤素、C1~C6的烷基、C1~C6的烷氧基。
进一步的,R1~R4同时为氢。
本发明的另一目的在于提供上述式Ⅰ所示5-甲基-2(1H)吡啶酮衍生物的制备方法。
本发明提供的一种5-甲基-2(1H)吡啶酮衍生物的制备方法,所述制备方法的合成路线为:
其中,X选自S或NH;R1~R4分别或同时选自氢、卤素、C1~C6的烷基、C1~C6的烷氧基;
所述制备方法包括以下步骤:
a、化合物1与化合物2在醇溶剂中进行回流反应,薄层色谱监控反应完毕,得到反应液,步骤a中,催化剂为冰乙酸;
化合物1与化合物2的重量比比为0.2:0.11~0.15;化合物1与醇溶剂的质量体积比为0.2:13~15g/ml;
醇溶剂选自无水乙醇、甲醇中的任意一种或两种;
b、对步骤a所得反应液进行分离纯化,得到式Ⅰ所示的化合物。
进一步的,步骤a中,化合物1的合成路线为:
化合物1按照如下步骤制备得到:
①、取5-甲基-2(1H)吡啶酮、无机碱、对溴苯甲醛和催化剂,在有机溶剂中进行回流反应,薄层色谱监控反应完毕,得到反应液;
5-甲基-2(1H)吡啶酮与无机碱的重量比为0.1:0.14~0.20;5-甲基-2(1H)吡啶酮与对溴苯甲醛的重量比为0.1:0.17~0.20;5-甲基-2(1H)吡啶酮与催化剂的重量比为0.1:0.02~0.05;5-甲基-2(1H)吡啶酮与有机溶剂的质量体积比为0.02~0.05g/ml;
无机碱选自碳酸钾、碳酸钠、碳酸铯、氢氧化钾、氢氧化钠中的任意一种或两种以上;
催化剂选自碘化亚铜、铜中的任意一种或两种;
有机溶剂选自N,N-二甲基甲酰胺、四氢呋喃、吡啶中的任意一种或两种以上;
②、对步骤①所得反应液进行分离纯化,得到化合物1。
进一步的,步骤①中,5-甲基-2(1H)吡啶酮的合成路线为:
5-甲基-2(1H)吡啶酮按照如下步骤制备得到:
i、取2-氨基-5-甲基吡啶和硫酸水溶液,混匀,加入亚硝酸钠水溶液进行反应,薄层色谱监控反应完毕后,加入水,回流搅拌反应15min~30min,得到反应液;
2-氨基-5-甲基吡啶与硫酸水溶液的质量体积比为1:3.2~3.6g/ml;2-氨基-5-甲基吡啶与亚硝酸钠水溶液的质量体积比为1:3.0~1:3.5g/ml;2-氨基-5-甲基吡啶与水的质量体积比为1:7.5~1:8.0g/ml;
硫酸水溶液是由等体积的水和浓硫酸混合而成;亚硝酸钠水溶液的浓度为0.55~0.65g/ml;
ii、对步骤i所得反应液进行分离纯化,得到5-甲基-2(1H)吡啶酮。
进一步的,步骤ii中,对步骤i所得反应液进行分离纯化的方法为:反应液冷却后,加入无机碱,调节pH约为7,过滤,得到滤液,除去滤液中的溶剂,得到粗品,重结晶,得到5-甲基-2(1H)吡啶酮;
所述无机碱选自碳酸钠、碳酸钾、氢氧化钾、氢氧化钠中的任意一种或两种以上。
进一步的,步骤②中,对步骤①所得反应液进行分离纯化的方法为:对反应液进行过滤,得到滤液;滤液用乙酸乙酯萃取,将有机相浓缩过柱,洗脱液为石油醚:乙酸乙酯=3:1,除去溶剂,干燥,得到化合物1。
进一步的,步骤a中,化合物2为邻苯二胺或2-氨基苯硫酚;催化剂为冰乙酸。
进一步的,步骤b中,对步骤a所得反应液进行分离纯化的方法为:用氢氧化钠水溶液调节反应液的pH=7~8,除去溶剂,过柱,洗脱液为石油醚:乙酸乙酯=1:1,收集洗脱液,除去溶剂,干燥,即得式Ⅰ所示的化合物。
本发明还提供了上述的式Ⅰ所示5-甲基-2(1H)吡啶酮衍生物或其晶型、药学上可接受的盐、水合物、溶剂合物或前体药物,在制备治疗和/或预防纤维化疾病、肿瘤的药物中的用途。
上述的式Ⅰ所示5-甲基-2(1H)吡啶酮衍生物或其晶型、药学上可接受的盐、水合物、溶剂合物或前体药物在制备治疗和/或预防纤维化疾病或肿瘤疾病的药物中的用途。
进一步的,所述的纤维化疾病包括特发性肺纤维化、肺纤维化、间质性肺病、非特异性间质性肺炎、普通型间质性肺炎、心内膜心肌纤维化、纵隔纤维化、骨髓纤维化、腹膜后纤维化、进行性块状纤维化、肾性全身纤维化症、克罗恩氏病、陈旧性心肌梗塞、硬皮病/系统性硬化、神经纤维瘤、Hermansky-Pudlak综合征、糖尿病性肾病、肾纤维化、肥厚型心肌病、高血压相关肾病、局灶性节段性肾小球硬化、放射诱导的纤维化、子宫平滑肌瘤、酒精性肝病、肝性脂肪变性、肝纤维变性、肝硬化、丙型肝炎病毒感染、慢性器官移植排异反应、皮肤纤维化病症、瘢痕疙瘩、掌筋膜挛缩病、Ehlers-Danlos综合征、营养不良性大疱性表皮松解、口腔黏膜下纤维化或纤维增殖性病症中的任意一种或多种。
上述纤维化疾病的含义,参考中国专利CN 104093408 A,或者根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
本发明还提供了一种药物组合物,所述的药物组合物是以上述的式Ⅰ所示5-甲基-2(1H)吡啶酮衍生物或其晶型、药学上可接受的盐、水合物、溶剂合物或前体药物为活性成分,加上药学上可接受的辅料或辅助性成分制备而成的制剂。
本发明提供了一种新的5-甲基-2(1H)吡啶酮衍生物,对成纤维细胞增殖以及成纤维细胞分泌纤维结合蛋白(Fn)均具有明显的抑制作用,可以用于制备治疗或预防纤维化疾病、肿瘤等药物;本发明式Ⅰ所示化合物的制备方法,具有工序少、步骤简便、反应条件温和、能耗低、效率高、成本低、绿色环保等优点,非常适合产业上的应用。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社,Columbus,OH)命名系统命名。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀(Ca~b)烷基表明任何含“a”至“b”个碳原子的烷基。因此,例如,C1~C4烷基是指包含1~4个碳原子的烷基。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料,和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体,与无机和/或有机酸和碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
本发明的某些实施方式中,本发明包括了同位素标记的化合物,所述同位素标记化合物是指与本文中所列化合物相同,但是其中的一个或多个原子被另一个原子取代,该原子的原子质量或质量数不同于自然界中常见的原子质量或质量数。可以引入式(I)化合物中的同位素包括氢、碳、氮、氧、硫,即2H,3H、13C、14C、15N、17O、18O、35S。含有上述同位素和/或其它原子同位素的式(I)的化合物及其立体异构体,以及该化合物、立体异构体的可药用的盐均应包含在本发明范围之内。
本发明中的关键中间体和化合物进行分离和纯化,所使用的方式是有机化学中常用的分离和纯化方法且所述方法的实例包括过滤、萃取、干燥、旋干和各种类型的色谱。可选择地,可以使中间体不经纯化即进行下一步反应。
在某些实施方式中,本发明的一种或多种化合物可以彼此联合使用。也可选择将本发明的化合物与任何其它的活性试剂结合使用,用于制备调控细胞功能或治疗疾病的药物或药物组合物。如果使用的是一组化合物,则可将这些化合物同时、分别或有序地对受试对象进行给药。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明所述药学上可接受的辅料,是指除活性成分以外包含在剂型中的物质。
本发明所述药学上可接受的辅助性成分,它具有一定生理活性,但该成分的加入不会改变上述药物组合物在疾病治疗过程中的主导地位,而仅仅发挥辅助功效,这些辅助功效仅仅是对该成分已知活性的利用,是医药领域惯用的辅助治疗方式。若将上述辅助性成分与本发明药物组合物配合使用,仍然应属于本发明保护的范围。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
实施例1
其中,“rf”为reflux的缩写,其中文含义为“回流”。
在25ml反应瓶中,先加入3.4ml由17ml H2O和17ml浓硫酸组成的溶液(50%,体积分数),然后加入1g(0.01mol)2-氨基-5-甲基吡啶,用冰盐浴冷却至10℃以下,搅拌几分钟后,反应液变为乳白色。然后缓慢滴加由(1.72g NaNO2与3mLH2O)混合组成的溶液,滴加时,产生刺激性气体,滴加完毕,反应液变为淡黄色溶液,TCL(薄层色谱)监控至反应完毕(约40min)。然后加入8mL H2O,回流搅拌反应15min,冷却,搅拌下加入无水Na2CO3,使反应液呈中性(产生黄棕色固体),过滤,将所得滤液旋干,再用无水乙醇溶解过滤,再次将所得滤液旋干,即得到黄棕色固体(5-甲基-2(1H)吡啶酮)0.87g。
单口瓶中加入0.1g(1mmol)5-甲基-2(1H)吡啶酮,0.14g K2CO3,0.17g对溴苯甲醛,0.05g CuI,5ml DMF作为溶剂,进行回流搅拌反应,TCL监控至反应完毕,停止反应,过滤,滤液用EA(乙酸乙酯)萃取,将有机层浓缩过柱(PE:EA=3:1,体积比,PE为石油醚),得到类黄色或白色片状固体0.08g,即为化合物1。
在25ml反应瓶中加入0.2g化合物1溶于10ml无水乙醇中,加入2滴冰乙酸作催化剂,搅拌下缓慢滴入溶有0.12g邻苯二胺的5ml无水乙醇溶液,滴加完毕,加热回流反应,TLC跟踪至反应完全,反应完后,加入稀NaOH溶液调至PH至8,减压蒸出溶剂,过柱(PE:EA=1:1),即得黄色产品,收率为75%。
黄色产品;熔点(mp)为180-182℃;
1H NMR(400MHz,DMSO-d6)δ:13.02(s,1H,NH),8.30(d,J=8.4Hz,2H,ArH),7.61(d,J=8.0Hz,4H,ArH),7.53(s,1H,CH),7.41(d,J=9.2Hz,1H,CH),7.24(s,2H,ArH),6.47(d,J=9.6Hz,1H,CH),2.07(s,3H,CH3);
13C NMR(100MHz,DMSO-d6)160.38,150.40,143.19,141.92,135.73,129.66,127.29,126.93,120.22,114.30,16.29;IR(KBr,n,cm-1):3426,1667,1592,1439,1280,1033,825,723;
HRMS(ESI)calcd for C19H15N3O[M+Na]+301.1215found 324.1107。
实施例2
在25mL反应瓶中依次加入0.15g化合物1、0.11g 2-氨基苯硫酚和10mL无水乙醇,搅拌,使其溶解,再加入3滴冰乙酸作催化剂,加料完毕,回流反应,TLC监控至反应结束,停止反应;加入稀NaOH溶液调至pH≈8,减压蒸出溶剂,残夜加入硅胶旋干,过柱(PE:EA=1:1),收集洗脱液,旋干,得黄色固体0.15g,收率为68%。
黄色产品;熔点(mp)为90-91℃;
1H NMR(400MHz,DMSO-d6)δ:8.22(d,2H,J=8.4Hz,ArH),8.18(d,1H,J=8.0Hz,CH),7.63(d,2H,J=8.4Hz,ArH),7.48~7.60(m,4H,ArH),7.42(dd,J1=2.0Hz,J2=9.2Hz,1H,CH),6.47(d,1H,J=9.2Hz,CH),2.08(s,3H,CH3);
13C NMR(100MHz,DMSO-d6)166.62,160.26,153.55,143.25,143.13,135.49,134.64,132.24,127.71,126.74,125.70,122.99,120.26,114.38,39.53,16.32;IR(KBr,n,cm-1):3422,3054,1672,1594,1534,1516,1484,1414,1291,964,823;
HRMS(ESI)calcd for C19H14N2OS[M]+318.0824found 318.3024。
为了说明本发明的有益效果,本发明提供以下试验例:
实验材料和仪器
1、主要实验仪器
生化培养箱(SANYO);
酶标仪(biorad);
2、主要实验材料与试剂
MRC-5细胞株(人胚肺成纤维细胞);
MTT(sigma,Cat.No.M5655);
DMSO,(sigma,Cat.No.67685);
Fn ELISA Kit:博士德(Cat.No.EK0349);
试验例1
检测化合物对人肺成纤维细胞增殖的影响(MTT法:24小时持续作用组与48小时持续作用组);检测化合物对人肺成纤维细胞分泌Fn的影响(ELISA法)。
参考文献:
陶立坚,张军,胡高云,陈卓,龚娟.1-(3-氟苯基)-5-甲基-2-(1H)吡啶酮对鼠肾成纤维细胞的影响.中南大学学报(医学版),2004,29(2):139~141.
Xianchai Lin,Minbin Yu,Kaili Wu,Hongzhi Yuan,and Hua Zhong.Effects ofPirfenidone on Proliferation,Migration,and Collagen Contraction of HumanTenon’s Fibroblasts In Vitro.Investigative Ophthalmology&Visual Science,August 2009,Vol.50,No.8:3763~3770.
样品处理:
分别用DMSO溶解吡非尼酮以及本发明式Ⅰ所示化合物,0.22μm滤膜过滤除菌,制成不同浓度的溶液,-20℃保存,临用前解冻。
细胞培养:
将MRC-5细胞(人胚肺成纤维细胞)接种于含10%胎牛血清的DMEM培养液(100U/ml青霉素、100U/ml链霉素)的培养皿中,置于5%CO2、37℃培养箱中培养。待细胞生长汇合后,以0.25%胰酶消化传代,取3-10代的MRC-5细胞用于试验。
1、MTT法检测抑制率
MTT法,又称MTT比色法,是一种检测细胞存活和生长的方法。
用含10%胎牛血清的DMEM培养液调整MRC-5细胞浓度为8×103/孔,接种于96孔板,于5%CO2、37℃培养箱中培养24h,分别加入不同浓度的本发明式Ⅰ所示化合物的DMSO溶液(100μg/ml,500μg/ml,1000μg/ml),以不同浓度的吡非尼酮的DMSO溶液(100μg/ml,500μg/ml,1000μg/ml)为阳性对照,空白对照组只加等量的DMEM培养液,每组设5个平行孔,将培养板置于5%CO2、37℃培养箱中,继续培养24h,48h后加入20μl MTT(5mg/ml),再置于培养箱中孵育4h,弃上清后每孔加入150μl DMSO,混匀10min,于酶标仪570nm处读取各孔吸光度A值。
根据吸光度A值计算出细胞增生抑制率,公式如下:
抑制率(%)=(空白对照组A值-试验组A值)/空白对照组A值×100%
采用统计软件SPSS 17.0进行统计分析,所有定量数据均以均数±标准差(mean±s)表示,组间比较采用单因素方差分析,以P<0.05为差异有统计学意义,P<0.01为存在差异性显著。
MTT法检测结果见表1。
表1、本发明式Ⅰ所示化合物对MRC-5细胞的影响
与空白对照组比较,*表示P<0.05,**表示P<0.01;与吡非尼酮500μg/mL比较,△表示P<0.05,△△表示P<0.01。
试验结果表明,本发明式Ⅰ所示化合物对成纤维细胞增殖具有明显的抑制作用,并且随着用量的增加,其抑制率也随之增大。
2、纤维结合蛋白(Fn)表达的检测
采用ELISA试剂盒测定Fn的表达。
用含10%胎牛血清的DMEM培养液调整MRC-5细胞浓度为8×103/孔,接种于96孔板,于5%CO2、37℃培养箱中培养24h,分别加入不同浓度的本发明式Ⅰ所示化合物的DMSO溶液(100μg/ml,500μg/ml,1000μg/ml),以不同浓度的吡非尼酮(PF是指吡非尼酮)的DMSO溶液(100μg/ml,500μg/ml,1000μg/ml)为阳性对照,空白对照组只加等量的DMEM培养液,将培养板置于5%CO2、37℃培养箱中,继续培养48h后取细胞上清液加入测试孔中,按照Fn试剂盒提供的方法进行操作。酶标仪测定吸光度A值后,与标准曲线对照,得出Fn含量。
采用统计软件SPSS 17.0进行统计分析,所有定量数据均以均数±标准差(mean±s)表示,组间比较采用单因素方差分析,以P<0.05为差异有统计学意义,P<0.01为存在差异性显著。
Fn表达的试验结果见表2。
表2、本发明式Ⅰ所示化合物对Fn表达的影响
与空白对照组比较,*表示P<0.05,**表示P<0.01。
试验结果表明,本发明式Ⅰ所示化合物能够抑制成纤维细胞分泌纤维结合蛋白(Fn),并且随着用量的增加,其抑制作用也随之提高。
综上所述,本发明提供了一种新的5-甲基-2(1H)吡啶酮衍生物,对成纤维细胞增殖以及成纤维细胞分泌纤维结合蛋白(Fn)均具有明显的抑制作用,可以用于制备治疗或预防纤维化疾病、肿瘤等药物;本发明式Ⅰ所示化合物的制备方法,具有工序少、步骤简便、反应条件温和、能耗低、效率高、成本低、绿色环保等优点,非常适合产业上的应用。
Claims (11)
1.式Ⅰ所示5-甲基-2(1H)吡啶酮衍生物或其药学上可接受的盐:
其中,X选自S或NH;R1~R4同时选自氢。
2.一种5-甲基-2(1H)吡啶酮衍生物的制备方法,其特征在于:所述制备方法的合成路线为:
其中,X选自S或NH;R1~R4同时选自氢;
所述制备方法包括以下步骤:
a、化合物1与化合物2在醇溶剂中进行回流反应,薄层色谱监控反应完毕,得到反应液,步骤a中,催化剂为冰乙酸;
化合物1与化合物2的重量比为0.2:0.11~0.15;化合物1与醇溶剂的质量体积比为0.2:13~15 g/ml;
醇溶剂选自无水乙醇、甲醇中的任意一种或两种;
b、对步骤a所得反应液进行分离纯化,得到式Ⅰ所示的化合物。
3.根据权利要求2所述的制备方法,其特征在于:步骤a中,化合物1的合成路线为:
化合物1按照如下步骤制备得到:
①、取5-甲基-2(1H)吡啶酮、无机碱、对溴苯甲醛和催化剂,在有机溶剂中进行回流反应,薄层色谱监控反应完毕,得到反应液;
5-甲基-2(1H)吡啶酮与无机碱的重量比为0.1:0.14~0.20;5-甲基-2(1H)吡啶酮与对溴苯甲醛的重量比为0.1:0.17~0.20;5-甲基-2(1H)吡啶酮与催化剂的重量比为0.1:0.02~0.05;5-甲基-2(1H)吡啶酮与有机溶剂的质量体积比为0.02~0.05 g/ml;
无机碱选自碳酸钾、碳酸钠、碳酸铯、氢氧化钾、氢氧化钠中的任意一种或两种以上;
催化剂选自碘化亚铜、铜中的任意一种或两种;
有机溶剂选自N,N-二甲基甲酰胺、四氢呋喃、吡啶中的任意一种或两种以上;
②、对步骤①所得反应液进行分离纯化,得到化合物1。
4.根据权利要求3所述的制备方法,其特征在于:步骤①中,5-甲基-2(1H)吡啶酮的合成路线为:
5-甲基-2(1H)吡啶酮按照如下步骤制备得到:
i、取2-氨基-5-甲基吡啶和硫酸水溶液,混匀,加入亚硝酸钠水溶液进行反应,薄层色谱监控反应完毕后,加入水,回流搅拌反应15min~30min,得到反应液;
2-氨基-5-甲基吡啶与硫酸水溶液的质量体积比为1:3.2~3.6 g/ml;2-氨基-5-甲基吡啶与亚硝酸钠水溶液的质量体积比为1:3.0~1:3.5 g/ml;2-氨基-5-甲基吡啶与水的质量体积比为1:7.5~1:8.0 g/ml;
硫酸水溶液是由等体积的水和浓硫酸混合而成;亚硝酸钠水溶液的浓度为0.55~0.65g/ml;
ii、对步骤i所得反应液进行分离纯化,得到5-甲基-2(1H)吡啶酮。
5.根据权利要求4所述的制备方法,其特征在于:步骤ii中,对步骤i所得反应液进行分离纯化的方法为:反应液冷却后,加入无机碱,调节pH约为7,过滤,得到滤液,除去滤液中的溶剂,得到粗品,重结晶,得到5-甲基-2(1H)吡啶酮;
步骤ii中加入的无机碱选自碳酸钠、碳酸钾、氢氧化钾、氢氧化钠中的任意一种或两种以上。
6.根据权利要求3所述的制备方法,其特征在于:步骤②中,对步骤①所得反应液进行分离纯化的方法为:对反应液进行过滤,得到滤液;滤液用乙酸乙酯萃取,将有机相浓缩过柱,洗脱液为石油醚:乙酸乙酯=3:1,除去溶剂,干燥,得到化合物1。
7.根据权利要求2所述的制备方法,其特征在于:步骤a中,化合物2为邻苯二胺或2-氨基苯硫酚;催化剂为冰乙酸。
8.根据权利要求2所述的制备方法,其特征在于:步骤b中,对步骤a所得反应液进行分离纯化的方法为:用氢氧化钠水溶液调节反应液的pH=7~8,除去溶剂,过柱,洗脱液为石油醚:乙酸乙酯=1:1,收集洗脱液,除去溶剂,干燥,即得式Ⅰ所示的化合物。
9.权利要求1所述的式Ⅰ所示5-甲基-2(1H)吡啶酮衍生物或其药学上可接受的盐在制备治疗和/或预防纤维化疾病或肿瘤疾病的药物中的用途。
10.根据权利要求9所述的用途,其特征在于:所述的纤维化疾病包括特发性肺纤维化、间质性肺病、非特异性间质性肺炎、普通型间质性肺炎、心内膜心肌纤维化、纵隔纤维化、骨髓纤维化、腹膜后纤维化、进行性块状纤维化、肾性全身纤维化症、克罗恩氏病、陈旧性心肌梗塞、硬皮病/ 系统性硬化、神经纤维瘤、Hermansky-Pudlak 综合征、糖尿病性肾病、肾纤维化、肥厚型心肌病、高血压相关肾病、局灶性节段性肾小球硬化、放射诱导的纤维化、子宫平滑肌瘤、酒精性肝病、肝性脂肪变性、肝纤维变性、肝硬化、丙型肝炎病毒感染、慢性器官移植排异反应、皮肤纤维化病症、瘢痕疙瘩、掌筋膜挛缩病、Ehlers-Danlos 综合征、营养不良性大疱性表皮松解、口腔黏膜下纤维化或纤维增殖性病症中的任意一种或两种以上。
11.一种药物组合物,其特征在于:所述的药物组合物是以权利要求1所述的式Ⅰ所示5-甲基-2(1H)吡啶酮衍生物或其药学上可接受的盐为活性成分,加上药学上可接受的辅料或辅助性成分制备而成的制剂。
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