CN101429181A - 对羟基苯丙烯酸衍生物及其应用 - Google Patents
对羟基苯丙烯酸衍生物及其应用 Download PDFInfo
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- CN101429181A CN101429181A CNA2008102385499A CN200810238549A CN101429181A CN 101429181 A CN101429181 A CN 101429181A CN A2008102385499 A CNA2008102385499 A CN A2008102385499A CN 200810238549 A CN200810238549 A CN 200810238549A CN 101429181 A CN101429181 A CN 101429181A
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- Prior art keywords
- hydrocarbyl
- och
- group
- sulfonylaminophenyl
- acid derivative
- Prior art date
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Abstract
本发明公开了一类对羟基苯丙烯酸衍生物,其化学结构如通式(I)所示。本发明还公开了所述的对羟基苯丙烯酸衍生物在制备COX-2选择性抑制剂药物中的应用,以及含有治疗有效量的本发明所述的对羟基苯丙烯酸衍生化合物或其可药用的盐的治疗和预防疼痛、炎症、类风湿性关节炎、骨性关节炎或痛经疾病的药物组合物或治疗和预防病毒细菌感染的抗病毒抗菌的药物组合物或治疗和预防动脉粥样硬化、血栓形成、中风或局部缺血性脑血管疾病的药物组合物。
Description
技术领域
本发明涉及一种对羟基苯丙烯酸衍生物及其应用,尤其涉及通式(I)的化合物、药理学允许的盐以及水合物,及其制备方法,和含有一个或多个这些化合物的组合物,以及该化合物在制备COX—2选择性抑制剂药物中的应用。
背景技术
非甾体抗炎药(NSAIDs)药物由于其具有确定的抗炎、镇痛效果,被广泛应用于风湿性疾病、炎性疾病、疼痛、软组织疾病和运动损伤的治疗,但肠胃并发症是长期服用NSAIDs药物最常见的副作用,新开发的环氧合酶(COX2)抑制剂在治疗炎症、疼痛的同时,可以明显降低肠胃并发症的发生。
万络是一种上市后很快被广泛使用的环氧合酶抑制剂,在该药研究表明引发心脏病后,2004年默克公司对其进行了召回。美国心脏学会宣布,心脏病患者服用万络,心脏病复发或死亡的风险是未服用的2.7倍,服用西乐葆的风险为2倍,服用双氯芬酸的风险为1.9倍,服用布洛芬的风险为1.3倍。
2008年10月,英国医学杂志《柳叶刀》报道了环氧合酶抑制剂的最新研究结果,研究人员表示,环氧化酶-2(Cox-2)抑制剂等同类药物增加患中风和心脏病的几率。2500多名病人参加了试验,研究人员对其中的84%病人进行了长期跟踪。病人被分成两组,其中一组每天服用万络,另一组服用不含有效成分的安慰剂,与不服用任何药物相比,患者服用万络后,患心脏病和中风的风险增加了将近一倍。但研究发现,患者停止服用万络一年后,患病风险基本消失。
Thomson公司对默克公司将万络撤离后的镇痛药市场进行了考察,结果发现,如果万络仍然留在市场上进行销售,那么,即使知道万络有引发心血管副作用的危险,47%的曾经使用过万络的病人也会继续使用该药。
在美国,西乐葆是唯一仍被允许销售的环氧合酶抑制剂药物。到2006年,60%以前用过西乐葆的病人已经放弃了该药。在万络召回事件发生之前,西乐葆在2005年的销售收入曾经预计达到40亿美元,而现在,西乐葆每年在全球的销售额只有20亿美元,而且还带上了黑框警告标签。但最近市场预测表明,到2010年,西乐葆的销售收入将达到27亿美元,比目前的销售水平要高出7亿多美元,显然,该药还有着相当的销售活力。
事实上,大型制药公司并没有放弃开发治疗骨关节炎和类风湿性关节炎的新药物。辉瑞公司研发的5个候选药物已经处于II期试验阶段,分别被用来治疗骨关节炎或类风湿性关节炎,另有3个用来治疗类风湿性关节炎的药物处于I期试验阶段。诺华公司研制的SMC021用来治疗骨关节炎,该药已经完成了II期试验。NicOx公司正在开发一种Naproxcinod,其为第一个COX抑制性一氧化氮供体类抗炎化合物,由于其有良好的心血管潜在特性,该药已经通过了III期临床试验,公司希望Naproxcinod不会引发许多镇痛药都会产生的增高血压的副作用。CombinatoRx公司研制的CRx-102药物正处于II期试验阶段,该药被用来治疗骨关节炎疼痛。
研究人员表示,疼痛和发炎是两大重要研究目标,因此需要进行系统性治疗,而系统性药物会引起系统性副作用,治疗疼痛和发炎这类药物有着广阔的市场,制药公司仍在寻找新的药物。
发明内容
针对现有技术的不足,本发明的目的在于提供一种对羟基苯丙烯酸衍生物;
本发明的另一目的在于提供一种制备对羟基苯丙烯酸衍生物的方法;
本发明的再一目的在于提供一种含有一个或多个所述对羟基苯丙烯酸衍生化合物的药物组合物;
本发明的又一目的在于提供一种所述对羟基苯丙烯酸衍生化合物在制备COX—2选择性抑制剂药物中的应用。
本专利的化合物是对羟基苯丙烯酸衍生物。4-羟基苯乙烯能与多种酶活性中心亲水性基团相作用,认为与芳环连接的侧链α,β-不饱和共扼体系能与花生四烯酸相契合并增强药效,而烯烃上的β-芳环对位的羟基是必需基团且可干扰酶的活性,羧基可能会使它在滑液中有较长的持续时间。
咖啡酸和阿魏酸都是具有对羟基苯丙烯酸结构的中药活性成分,其中咖啡酸是3,4-二羟基苯丙烯酸,阿魏酸是3-甲氧基4-羟基苯丙烯酸。
咖啡酸它存在于许多中药中,如野胡萝卜、光叶水苏、荞麦、木半夏等。咖啡酸有广泛的抑菌和抗病毒活性,体外使用效果较强,对腺病毒和副流感都有抑制作用,低浓度可抑制胶原酶活性,有防龋牙效用,它对牛痘和腺病毒抑制作用较强,其次为脊髓灰质炎I型和副流感III型病毒。咖啡酸还有缩短血凝及出血时间的作用,对内脏的止血效果较好,毒性较小。还可以抑制过氧化脂质,可以抑制鼠脑组织匀浆脂质过氧化物的生成。
咖啡酸苯乙酯是蜂巢蜡胶中的活性成分,是咖啡酸所形成的酯,它具有抗病毒,抗炎,抗氧化、调节免疫的功能。可以抑制肿瘤细胞增殖和诱导细胞凋亡等。(参见文献《咖啡酸苯乙酯对激活的大鼠血管平滑肌细胞增殖的抑制作用》)
绿原酸是金银花的抗菌有效成分之一,也是咖啡酸所形成的酯,它具有显著的药理活性,如抗菌,抗病毒、抗诱变、抗肿瘤和保肝等,另外还可以提高中枢神经兴奋性,增强小肠蠕动、增进胆汁分泌、利胆,以及止血、增高白细胞作用、缩短血凝及出血时间和抗氧化剂活性等。美国专利US6632459和US7288271中指出,绿原酸可以提高人体的免疫力,提高对疱疹病毒,腺病毒,流感病毒,艾滋病毒,冠状病毒,EB病毒,肺炎球菌,金黄色葡萄球菌等的抵抗力。US5788971阐述了绿原酸抗氧化作用对清除氧自由基,治疗炎症反应的作用。
阿魏酸是当归、川芍等中药材提取物中的活性成分,除了具有抗炎、抗菌作用以外,在降血脂、抗血栓、防治冠心病方面也具有优良的活性,且毒副作用较小。现在发现,阿魏酸有以下生理作用:抗菌消炎、抗动脉粥样硬化、抗血小板凝集和血栓、抗肿瘤、抗突变,清除亚硝酸盐、氧自由基、过氧化亚硝基,增加免疫功能、人体精于活力和运动性等,阿魏酸能为人体吸收并易于从尿中排出,不会在体内累积,因此是一种安全性极高的药物。(《阿魏酸的抗炎作用》;《利脉胶囊(复方阿魏酸钠)的抗血小板聚集和抗血栓作用》;《阿魏酸钠对缺氧性肺动脉高压大鼠血小板聚集率和……》等)。在30例冠心病充血性心力衰竭治疗研究中,总有效率96.7%。(何秀兰,王传中.注射用阿魏酸钠治疗冠心病充血性心力衰竭疗效观察.河北医学.2004;10:982-984),在对36例脑梗塞治疗中,总有效率为83.3%(朱江,林飞英,钟秀丹.阿魏酸钠治疗脑梗塞36例.海南医学.2007;18:1-2)
在相关化合物的调查当中,
(1刘鹰祥、计志忠等人对阿魏酸的结构进行了改造(如结构式2),考查了羟基取代后,当R1为乙酰基,尤其是肉桂酰基时有较好的抗癌活性(刘鹰翔,计志忠,牟孝硕等.(E)-4-酰氧基苯基丙烯酸类衍生物的合成及抑癌活性.中国药物化学杂志,11(2):7279)和抗炎活性(刘鹰翔,马玉卓,计志忠等.(E)-4-桂皮酰氧基苯乙烯衍生物的合成及抗炎活性.中国药物化学杂志.1999,9(3):186-191.);将乙酸基团成酯以后,取代苯环R2上的取代基不同,则表现出不同的活性(刘鹰翔,计志忠,徐颖等.4-肉桂酰阿魏酸苯酚酯衍生物的合成及其抗炎活性.中国药物化学杂志,1997,7(1):18-22)。
(2牟丽媛等发现类似结构化合物(如结构式3)具有较强的扩血管活性,同时表现出一定的钾通道开放活性,该化合物结构新颖,不同于已知的各类型钾通道开放剂的结构类型,对于预防和治疗高血压病很有前途(牟丽媛,林紫云,朱莉亚等.α-苯基取代肉桂酰胺类化合物的合成及其钾通道开放活性.药学学报,2001,36(7):502506)。
结构式2 结构式3 结构式4
(3朱崇泉等发现此系列化合物(如结构式4)具有较好的抗生育活性,尤其化合物(R1=3-CH3O-,4-HO-,R2=H)具有很强的抗生育活性(朱崇全,张奕华,曹观坤等.非甾体抗生育药物的研究II对-羟基苯丙烯酸衍生物的合成及抗生育活性.南京药学院学报,1982,20(3):50-56)。
迄今,开发上市的环氧合酶抑制剂主要为二芳基杂环类化合物,如吡唑环类的化合物如塞来昔布(celecoxib),呋喃环类的化合物如罗非昔布(rofecoxib),异噁唑环类的化合物如戊地昔布(valdecoxib)和帕瑞昔布(Parecoxib),这一类药物的结构特点主要是中心环为杂环的二芳基杂环化合物,两个苯环位于连接桥的同一侧,在其中1个芳环的对位带有-SO2CH3基或-SO2NH2基。氯美昔布(lumiracoxib)以N原子为中间桥连接。
本发明的基本设计思路是:将中药提取物活性成分的核心结构——对羟基苯丙烯酸,引入环氧合酶抑制剂中,在对羟基苯丙烯酸衍生物的α位上有一个苯环,与β位上的苯环位于杂环或烯键的同一侧,在α位的苯环上有环氧合酶抑制剂的构效基团。实验表明此类化合物在降低肠胃副作用的同时,降低其心血管方面的副作用。预示此类化合物做为环氧合酶抑制剂的前体药物将有很好的前途。
实现本发明目的的一类对羟基苯丙烯酸衍生物,其化学结构如通式(I)所示:
其中,
R1是H、-C1-C6烃基、-芳基C1-C6烃基、-C(O)(C1-C6烃基)或-C(O)(芳基C1-C6烃基);其中所述基团任选地被-OH、卤素、-NH2、-NO2、-CN、-C(O)OH、-C1-C6烃氧基、芳基、杂芳基、-NH-环C3-C6烃基、-C(O)(C0-C6烃基)或-OC(O)(C0-C6烃基)中的1-5个取代基取代;
R2、R3是H、-OH、卤素、C1-C6烃基或-C1-C6烃氧基;
或者:R2、R3任选地通过氧基或C1-C4烃氧基与R1桥连接成稠合二环系统;
或者:R2、R3通过氧基或C1-C4烃氧基桥连接成稠合二环系统;
X是H、-CH2-或CH2CH2-;
Y是H、-OH、O-、-NH2、-C1-C6烃基、环C3-C6烃基、-C1C6烃氧基、-环C3-C6烃氧基、杂环C5-C7胺基、-NH-环C3-C6烃基或N(C0-C6烃基)(C0-C6烃基);其中所述基团任选地被-OH、卤素、-NH2、-NO2、-CN、-C(O)OH、C1-C6烃基、-环C3-C6烃基、-C1-C6烃氧基、芳基、杂芳基、-C(O)(C0-C6烃基)、-C(O)O(C0C6烃基)、-OC(O)(C0C6烃基)或-C(O)-N(C0-C6烃基)(C0-C6烃基)中的1-5个取代基取代;
或者:X、Y通过氧基、C1-C4烃基或C1-C4烃氧基桥连接起来;
R4是H、卤素、-C1-C6烃基、-C1-C6烃氧基、-SO2NH2、SO2-(C1-C6烃基)、-SO2NH(C1-C6烃基)或-NH-SO2-(C1-C6烃基);
R5是SO2NH2、-SO2-(C1-C6烃基)、-SO2NH(C1-C6烃基)、-SO2NH(芳基)、-SO2NH(芳基C1-C6烃基)或NH-SO2-(C1-C6烃基);其中所述基团任选地被-OH、卤素、-NH2、-NO2、-CN、-C(O)OH、芳基、杂芳基、C1-C6烃氧基、-C(O)(C0-C6烃基)、OC(O)(C0-C6烃基)或-C(O)-N(C0-C6烃基)(C0-C6烃基)中的1-5个取代基取代;并当R5是-SO2CH3时,不包含X为H,且Y为OH、OK、ONa、OCH3或OCH2CH3,R1为H、-CH3、-C(O)CH3或-C(O)CH=CHC6H5。
上述对羟基苯丙烯酸衍生物进一步优选的化合物形式是:
所述R1是H、-CH3、-CH2CH3、-C(O)CH3或-C(O)CH=CHC6H5;其中所述基团任选地被-OH、卤素、-NH2、-NO2或-OCH3中的1-5个取代基取代;
R2、R3是H、-OH、-CH3、-CH2CH3、-CH(CH3)2、-C(CH3)3或-OCH3;
或者:R2、R3任选地通过氧基与R1桥连接成苯并二氧杂环;
或者:R2、R3通过氧基桥连接成苯并二氧杂环;
X是H或-CH2-;
Y是H、-OH、-O-、-NH2、-OCH3、-OCH2CH3、-OCH2C6H5、-OCH2CH2C6H5、奎尼酸基或六氢吡嗪基;其中所述基团任选地被-OH、卤素、-NH2、-NO2、-CH3、-OCH3、-C(O)CH3或-C(O)OCH2CH3中的1-5个取代基取代;
或者:X、Y通过—CH2-O-或—CH2CH2-O-桥连接起来;
R4为H;
R5为-SO2NH2或-SO2CH3,且在苯环的对位或邻位;其中当R5是-SO2CH3时,不包含X为H,且Y为OH、OK、ONa、OCH3或OCH2CH3,R1为H、-CH3、-C(O)CH3或-C(O)CH=CHC6H5。
上述对羟基苯丙烯酸衍生物再进一步优选的化合物形式是:
所述R1是H、-CH3、-CH2CH3、-C(O)CH3或-C(O)CH=CHC6H5;其中所述基团任选地被-OH、卤素、-NH2、-NO2或-OCH3中的1-5个取代基取代;
R2、R3是H、-OH、-CH3、-CH2CH3、-CH(CH3)2、-C(CH3)3或-OCH3;
或者:R2和R1通过—O-CH2-桥连接成苯并二氧杂环;
X是H或-CH2-;
Y是H、-OH、-O-、-NH2、-OCH3、-OCH2CH3、-OCH2C6H5、-OCH2CH2C6H5、奎尼酸基或六氢吡嗪基;其中所述基团任选地被-OH、卤素、-NH2、-NO2、-CH3、-OCH3、-C(O)CH3或-C(O)OCH2CH3中的1-5个取代基取代;
或者:X、Y通过—CH2-O-桥连接起来;
R4为H;
R5为-SO2NH2,且在苯环的对位或邻位。
上述对羟基苯丙烯酸衍生物最优选如下化合物之一:
(E)-2-(4-磺酰胺基苯基)-3-(3-甲氧基4-羟基苯基)丙烯酸,
(E)-2-(4-磺酰胺基苯基)-3(3甲氧基-4乙酰氧基苯基)丙烯酸,
(E)-2-(4磺酰胺基苯基)-3-(3甲氧基-4肉桂酰氧基苯基)丙烯酸,
(E)-2(4-磺酰胺基苯基)-3(3-甲氧基4-羟基苯基)丙烯酸乙酯,
(E)-2-(4磺酰胺基苯基)-3-(3-甲氧基-4乙酰氧苯基)丙烯酸乙酯,
(E)-2-(4-磺酰胺基苯基)-3-(3,4-二羟基苯基)丙烯酸,
(E)-2-(4-磺酰胺基苯基)-3-(3,4-二羟基苯基)丙烯酸苯乙酯,
(E)-2(4-磺酰胺基苯基)-3(4-羟基苯基)丙烯酸,
(E)-2-(4磺酰胺基苯基)-3-(4-乙酰氧基苯基)丙烯酸,
3-(4-磺酰胺基苯基)-4-(3-甲氧基-4-羟基苯基)-2(5H)-呋喃酮,
3-(4-磺酰胺基苯基)-4(3,4-二羟基苯基)-2(5H)-呋喃酮,
(E)-2-(4-磺酰胺基苯基)-3-(3,4-亚甲基二氧苯)丙烯酸。
其中:上述对羟基苯丙烯酸衍生物精选如下化学结构式的化合物:
上述陈述中,术语烃基、烃氧基,其中“烃”可以是烷基,链烯基,链炔基等,其碳链可以是直链或支链或其联合形式。烷基的实例包括甲基、乙基、丙基、异丙基、丁基、仲和叔丁基、戊基、己基、庚基等。“链烯基”、“链炔基”及其它类似术语包括含至少一个不饱和C—C健的碳链。
术语“环烃基”指不含杂原子的碳环,并包括单、双和三环饱和碳环,以及稠环系。这样的稠环体系可以包括部分或完全不饱和的一个环如苯环,以形成稠合环系如苯并稠合碳环。环烃基包括螺稠合的环系那样的稠合环系。环烃基的实例包括环丙基、环丁基、环戊基、环己基、环己烯基、十氢萘基、金刚烷基、二氢茚基、茚基、芴基、1,2,3,4—四氢萘基等。
术语“烃氧基”,除非另行说明,包括连接到氧基连接原子的烃基。
术语“环烃氧基”,除非特别另行说明,包括连接到氧基连接原子的环烃基。
术语“芳基”,除非另行说明,包括多环系及单环系,例如,苯基或萘基。
术语“C0—C6烃基”包括含6、5、4、3、2、1或不含碳原子的烃基。不含碳原子的烃基是氢原子取代基或者—直接的健,这根据所述烃基是末端或桥部分而定。
术语“杂”,除非另行说明,包括一个或多个O、S或N原子。例如,杂环烷基,杂芳基和杂环胺基包括环中含有一个或多个O、S或N原子(包括此类原子的混合)的环系。该杂原子代替环碳原子。因此,例如,杂环C5烷基是含5至0个碳原子的5元环。
所述杂芳基的实例如,吡啶基,喹啉基,异喹啉基,哒嗪基,嘧啶基,吡嗪基,呋喃基,苯并呋喃基,二苯并呋喃基,噻吩基,苯并噻吩基,吡咯基,吲哚基,吡唑基,吲唑基,噁唑基,异噁唑基,噻唑基,异噻唑基,咪唑基,苯并咪唑基,噁二唑基,噻二唑基,三唑基或四唑基。
所述芳基C1-C6烃基的实例如,苯基C1-C6烷基、苯基C1-C6链烯基或萘基C1-C6烷基。
所述杂环C5-C7烃基的实例如,氮杂环丁烷基,吡咯烷基,哌啶基,哌嗪基,吗啉基,四氢呋喃基,咪唑啉基,吡咯烷—2—酮,哌啶—2—酮或硫代吗啉基。
所述杂环C5-C7胺基的实例如,六氢吡嗪,六氢哒嗪,六氢吡啶或六氢嘧啶。
术语“胺”,除非另行说明,包括伯、仲和叔胺。
术语“卤素”包括氟、氯、溴和碘原子。
术语“任选地被取代”用来包括被取代和未被取代两种情况。例如,任选地被芳基取代,其中芳基可以表示五氟苯基或苯环。进一步讲,取代可以发生在任何基团上。例如,被取代的芳基C1-C6烃基包括在苯环上的取代以及在烃基上的取代。
本文中描述的化合物含有一个或多个双健并因此可以给出Z式/E式异构体及其它构象异构体。本发明包括所有这些可能的异构体以及此类异构体的混合物。
本文中描述的化合物可以含有一个或多个不对称中心并因此可以给出非对映异构体和旋光异构体。本发明包括所有这些可能的非对映异构体以及它们的外消旋混合物、其基本上纯的拆分对映异构体、所有可能的几何异构体、及其可药用盐。
上述式(I)没有给出特定位置的确定的立体化学,本发明包括式(I)的所有立体异构体及其可药用盐。此外,还包括立体异构体的混合物以及分离的特定立体异构体。在用来制备此类化合物的合成过程中,或在使用本领域技术人员已知的外消旋化或差向异构表异构化方法中,此类方法的产物可以是立体异构体的混合物。
本发明所述对羟基苯丙烯酸衍生物的合成方法
在目标化合物的合成中发明人将茴香硫醚通过Friedel-Crafts反应在硫醚的对位引入乙酰基,然后通过氧化反应将硫醚氧化为砜,再通过Willgerodt反应使得到对甲磺酰基苯乙酸;通过Friedel-Crafts反应在乙苯的对位引入磺酰氯,再和氨水反应生成磺酰胺,然后通过重铬酸钾氧化反应将乙苯氧化为乙酮,再通过Willgerodt反应使得到对磺酰胺基苯乙酸。其反应式为:
a.AlCl3、CH3COCl、CHCl3;b.H2O2、H3PO4、CH3COOH;c.①S、吗菲林;②NaOH溶液。
a.①氯磺酸;②NH3。b.K2Cr2O7;c.①S、吗菲林;②NaOH溶液。
另据文献报道,乙苯在高压釜中快速氧化,可以被氧化成苯乙酸。发明人进行了尝试,在300mL的高压釜中,将重铬酸钾8g溶解在100ml水中,加入5g的4-乙基苯磺酰胺,在60分钟的时间升温到250℃,压力为14大气压,再快速搅拌反应1小时,快速冷却,取出反应液,为褐绿色混合物,原料被氧化分解为絮状物质,没有得到产物。
后来选择以苯乙酸为起始原料,控制合适的条件和氯磺酸反应,再和氨水反应,也可以得到对磺酰胺苯乙酸,缩短了反应路线。
其反应式为:
a.氯磺酸;b.NH3
Claisen-Schmidt缩合反应
两个羰基化合物,通过第一个化合物的羰基和第二个羰基化合物羰基α-位的氢原子进行缩合,失去一分子的水,形成α,β-不饱和羰基化合物,本发明称为羰-羰缩合反应,文献上称为Claisen-Schmidt反应。
上述缩合最常用的催化剂是氢氧化钠或氢氧化钾;醇钠、醇镁、醇铝也是有效的催化剂,不过醇镁和醇铝在一些反应条件下,可使二分子醛转化成一分子酯,又可还原醛或酮成醇;氨化钠、氨化氢甚至金属钠,也曾用做催化剂,特别在高位阻的酮进行缩合反应的时候;伯氨和仲氨是很好的催化剂,用得最为普遍,特别是与醋酸并用,效果更好;硫酸和烟酸等都曾经用做催化剂。
许多羰羰缩合反应是放热反应,常在溶液中进行,溶剂一般用乙醇、乙醚、苯、醋酸等。有时也用高沸点的溶剂以提高反应温度。许多缩合反应可以在室温下进行,一般都在溶剂回流温度进行反应。鉴于此,本发明设计了多条路线探索目标化合物的合成工艺。
将对甲磺酰基苯乙酸、香兰素和三乙胺(催化剂),在乙酸酐溶剂中,加热到130~140℃,搅拌加热2小时,然后移出油浴,降温,加入少量水,分解乙酸酐,再在室温中搅拌,析出黄色固体,但从谱图上分析,不是目标化合物。这条合程路线,苯环上的磺酰胺基可能和乙酸酐在高温下反应,生成酰胺。再要将酰胺分解得到苯磺酰胺产物,就很困难,因此对于磺酰胺来说,需要选择较温和的反应条件。
在乙醇中用乙醇钠催化,没有得到产物;在乙醇中用金属钠做催化剂,没有得到产物;在乙醇中用浓硫酸催化,没有得到产物;在二氯甲烷中用浓硫酸催化,没有得到产物;在甲苯中用NaH做催化剂反应,没有得到产物。
最后在乙腈溶剂中,乙酰香兰素、对磺酰胺苯乙酸和三乙胺混合反应一段时间后,再加入适量的催化剂DBU(1,8二氮杂环[5,4,0]十一烯-7,别名二氮杂二环),从薄层条件(乙酸乙酯:环己烷为1:1),以及谱图分析上,得到了目标化合物。
具体反应如下:在四口瓶中,将乙酰香兰素加入到乙腈溶剂中,加入三乙胺,搅拌溶解,然后加入对磺酰胺苯乙酸,搅拌反应1小时,然后加入DBU,再搅拌反应1小时,停止反应,加盐酸调节pH值,用乙酸乙酯提取产物,分层,乙酸乙酯溶液用水洗涤,干燥,浓缩,得到黄色油状物,然后将油状物溶解在乙酸乙酯中,活性炭脱色,滴加适量的环己烷,析出黄色油状产物。
在(E)-2-(4-甲磺酰基苯基)3-(3,4-亚甲基二氧苯)丙烯酸的合成中,
将对甲磺酰基苯乙酸、香兰素和三乙胺(催化剂),在乙酸酐溶剂中,加热到130~140℃反应,最后分离得到了产物。这可能是对甲磺酰基苯乙酸在乙酸酐溶剂中,甲磺酰基不和酸酐反应。将对甲磺酰基苯乙酸,3,4-亚甲基二氧苯甲醛,乙酸酐,三乙胺混合后,移入130~140℃的油浴当中,搅拌加热3小时,然后移出油浴,降温到100℃,加入适量的水,在100℃的油浴当中搅拌5分钟,然后移出油浴,在室温中搅拌,析出产物。
另外用DBU做催化剂,也得到产物。在四口瓶中,将3,4-亚甲基二氧苯甲醛加入到乙腈溶剂中,加入三乙胺,然后加入对甲磺酰基苯乙酸,搅拌反应1小时,然后加入DBU,再搅拌反应1小时,停止反应,用盐酸酸化,用乙酸乙酯提取,分层,乙酸乙酯溶液用水洗涤,干燥,浓缩,得到产物。这两种方法,得到相同的化合物。
E式和Z式烯烃
按照文献(Org Syn,CV4,730;Org Syn,CV4,777)所报道的方法,取代苯乙酸和取代苯甲醛在乙酸酐中以三乙胺催化的合成方法,得到E式异构体化合物。Ketcham(J.Org.Chem.1963,28,1034.)和Grawford(J.Chem.Soc.1955,3445)等人研究认为,在以三乙胺催化的苯乙酸和苯甲醛类化合物的缩合反应中主要产物都为E式的α-苯肉桂酸类化合物,Z式的异构体只有很少的比例,其中绝大多数反应只得到E式的异构体。
Rolf Stomberg(Journal of Chemical Crystallography,2001,31(6):321-328)等人在晶体结构研究中,从分子构象的角度发现,取代的α-苯基肉桂酸的Z式异构体中,羧基基团的平面垂直于乙烯基和芳香基所在的平面,羧基基团的孤立使得Z式异构体的稳定性降低,酸性增加;在E式异构体中,羧基、芳香基和乙烯基几乎是共平面的,它们之间的共轭使得E式异构体的酸性降低,稳定性增强。
另据文献(J Am Chem Soc,1970,92,3190)报道,以Ketcham方法合成的E式α-苯基肉桂酸类化合物在喹啉中以亚铬酸铜催化脱羧所得的产物构型不变。
利用上述方法合成的代表性化合物如下,但本专利的化合物并不限于以下化合物。
化合物1 | (E)-2-(4-磺酰胺基苯基)-3-(3-甲氧基-4-羟基苯基)丙烯酸 |
化合物2 | (E)-2-(4-磺酰胺基苯基)-3-(3-甲氧基-4-乙酰氧基苯基)丙烯酸 |
化合物3 | (E)-2-(4-磺酰胺基苯基)-3-(3-甲氧基-4-肉桂酰氧基苯基)丙烯酸 |
化合物4 | (E)-2-(4-磺酰胺基苯基)-3-(3-甲氧基-4-羟基苯基)丙烯酸甲酯 |
化合物5 | (E)-2-(4-磺酰胺基苯基)-3-(3-甲氧基-4-羟基苯基)丙烯酸乙酯 |
化合物6 | (E)-2-(4-磺酰胺基苯基)-3-(3-甲氧基-4-乙酰氧苯基)丙烯酸乙酯 |
化合物7 | (E)-2-(4-磺酰胺基苯基)-3-(3,4-二羟基苯基)丙烯酸 |
化合物8 | (E)-2-(4-磺酰胺基苯基)-3-(3,4-二羟基苯基)丙烯酸苯乙酯 |
化合物9 | (E)-2-(4-磺酰胺基苯基)-3-(4-羟基苯基)丙烯酸 |
化合物10 | (E)-2-(4-磺酰胺基苯基)-3-(4-乙酰氧基苯基)丙烯酸 |
化合物11 | (E)-2-(4-磺酰胺基苯基)-3-(3-甲氧基-4-羟基苯基)丙烯酸钠 |
化合物12 | (E)-2-(4-磺酰胺基苯基)-3-(3-甲氧基-4-羟基苯基)丙烯酸钾 |
化合物13 | (E)-2-(4-磺酰胺基苯基)-3-(3甲氧基4羟基苯基)丙烯酸钙 |
化合物14 | 3-(4甲磺酰基苯基)-4-(3-甲氧基-4-羟基苯基)-2(5H)-呋喃酮 |
化合物15 | 3-(4-磺酰胺基苯基)-4-(3-甲氧基-4-羟基苯基)-2(5H)-呋喃酮 |
化合物16 | 3-(4-磺酰胺基苯基)-4-(3,4-二羟基苯基)-2(5H)-呋喃酮 |
化合物17 | (E)-2-(4-甲磺酰基苯基)-3-(3,4-亚甲基二氧苯)丙烯酸 |
化合物18 | (E)-2-(4-磺酰胺基苯基)-3-(3,4-亚甲基二氧苯)丙烯酸 |
本专利的合成方法并不限于上述所介绍的合成途径,也包括通过分解、氧化、氢化、取代或加成等途径得到本发明的化合物。例如,由取代产物分解得到本发明化合物,以及通过氧化反应最终得到本发明化合物。
另一方面,本发明的化合物可以在哺乳动物体内系统里以代谢产物的形式形成。
本发明所述的对羟基苯丙烯酸衍生物在制备COX—2选择性抑制剂药物中的应用;其中所述药物的剂型主要是片剂、胶囊、水针剂或粉剂等。
相关的,本发明所述的对羟基苯丙烯酸衍生物在制备NSAID、5LOX选择性抑制剂、PDE4抑制剂或白三烯受体拮抗剂药物中的应用。
治疗和预防疼痛、炎症、类风湿性关节炎、骨性关节炎或痛经疾病的药物组合物,其中:所述组合物含有治疗有效量的本发明所述的对羟基苯丙烯酸衍生化合物或其可药用的盐,以及药学上可接受的载体或辅料。
治疗和预防病毒细菌感染的抗病毒抗菌的药物组合物,其中:所述组合物含有治疗有效量的本发明所述的对羟基苯丙烯酸衍生化合物或其可药用的盐,以及药学上可接受的载体或辅料。
治疗和预防动脉粥样硬化、缺血再灌注、中风、血栓形成或局部缺血性脑血管疾病的药物组合物,其中:所述组合物含有治疗有效量的本发明所述的对羟基苯丙烯酸衍生化合物或其可药用的盐,以及药学上可接受的载体或辅料。
治疗和预防肠道息肉或结肠癌的药物组合物,其中:所述组合物含有治疗有效量的本发明所述的对羟基苯丙烯酸衍生化合物或其可药用的盐,以及药学上可接受的载体或辅料。
NSAID、5-LOX选择性抑制剂、PDE4抑制剂或白三烯受体拮抗剂,其中:所述抑制剂含有治疗有效量的本发明所述的对羟基苯丙烯酸衍生化合物或其可药用的盐,以及药学上可接受的载体或辅料。
其中上述术语“可药用盐”指由可药用碱或酸制备的盐。当本发明的化合物是酸性时,其相应的盐可以由可药用碱(包括无机碱和有机碱)方便地制备。得自此类无机碱的盐包括铝盐、铵盐、钙盐、铜盐(二价和一价)、铁盐、亚铁盐、锂盐、镁盐、锰盐(三价和二价)、钾盐、钠盐、锌盐等盐。特别优选的是铵、钙、镁、钾和钠盐。得自可药用有机碱的盐包括伯、仲和叔胺以及环胺和被取代的胺如天然存在和合成的被取代的胺的盐。可以形成盐的其它可药用有机碱包括离子交换树脂,例如,精氨酸、甜菜碱、咖啡因、胆碱、N,N—二苄基亚乙基二胺、二乙基胺、2—二乙基氨基乙醇、2—二甲基氨基乙醇、乙醇胺、亚乙基二胺、N—乙基吗啉、N一乙基哌啶、葡糖胺、氨基葡糖、组胺、羟基胺、异丙基胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤类、可碱、三乙基胺、三甲基胺、三丙基胺、氨丁三醇等。当本发明的化合物是碱性时,其相应的盐可以由可药用酸(包括无机酸和有机酸)方便地制备。此类酸包括,例如,乙酸、苯磺酸、苯甲酸、樟脑磺酸、枸橼酸、乙磺酸、富马酸、葡糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘酸、硝酸、棕榈酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、奎尼酸、对甲苯磺酸盐等。特别优选苯磺酸、枸橼酸、氢溴酸、盐酸、马来酸、磷酸、硫酸、酒石酸。
本发明的药物组合物含有式(I)表示的化合物(或其可药用盐)作为活性组分、可药用载体和任选地存在的其它治疗组分或辅剂。此类其它治疗组分包括,例如,(1非甾体类杭炎药,(2 COX—2选择性抑制剂,(3 5-LOX选择性抑制剂,(4受体拮抗剂,(5CysLT1受体拮抗剂,(6选择性PAF受体拮抗剂,(7肾上腺素能受体激动剂。这些组合物包括适于口服、直肠、局部和非肠道(包括皮下、肌肉内和静脉内)给药的组合物,在任何给定的具体情况中大多数适宜的途径依赖于活性组分所给药的特定的宿主及病症的性质和严重性。药物组合物可以方便地以单位剂型的形式存在,并通过药学领域中熟知的任何方法制备。
更进一步的,含式(I)化合物的霜剂、软膏、胶凝剂、溶液剂或混悬剂可以局部施用。漱口水和含漱剂包括在出于本发明目的的局部使用范围内。
在治疗如下病症中,使用约0.001mg/Kg至约140mg/kg体重每天的剂量水平是有利的:例如,疼痛、炎症、类风湿性关节炎、骨性关节炎或痛经、动脉粥样硬化、中风、血栓形成或局部缺血性脑血管、病毒感染、细菌、真菌或病毒引起的脓毒症,阿尔茨海默氏病,治疗牛皮癣,缺血再灌注,肠道息肉和结肠癌,肿瘤生长及肿瘤对正常组织的侵入,或另一种可选择的方式为约0.05mg至约7g每天每位患者。例如,使用约0.01mg至50mg的化合物每天每千克体重或者约0.5mg至约2.5G每天每位患者,可以有效地治疗炎症。此外,应理解,本发明的环氧合酶抑制化合物可以以预防有效剂量水平施用,以预防上述病症。
可以与载体物质混合制备单一剂型的活性组分的量,根据所治疗的对象以及特定的给药方式而变化。例如,用于给人口服给药的制剂可以便利地含有约0.5mg至约5g的活性剂,其与适当并方便量的载体物质混合,载体的量可以占总组合物的约5至约95%。单位剂型一般含约0.01mg至约1000mg的活性组分,典型的量为0.01mg、0.05mg、0.25mg、1mg、5mg、25mg、50mg、100mg、200mg、300mg、400mg、500mg、600mg、800mg或1000mg。
但是应理解,对于任何特定患者的特定剂量水平依赖于多种因素,包括年龄、体重、一般健康状况、性别、饮食、给药时间、给药途径、排泄速率、联合用药和所治疗特定疾病的严重性。
在实际应用中,本发明的式(I)所表示的化合物或其可药用盐作为活性组分可以按照常规药物混合技术与药物载体紧密地混合。根据给药如口服或非肠道给药(包括静脉内)所需的制剂形式,载体可以采用多种形式。因此,本发明的药物组合物可以是适于口服给药的离散单元如胶囊、小药囊或片剂,其中各含有预定量的活性组分。此外,这些组合物可以是粉剂、颗粒剂、溶液剂、存在于含水液体中的混悬剂、非水的液体、水包油乳液或油包水液体乳液等制剂形式。除了上述普通剂型,式(I)表示的化合物或其可药用盐,还可以通过控释方式和/或传递器具给药。这些组合物可以通过任何药学方法来制备。一般来说,此类方法包括将活性物质与构成一个或多个必要组分的载体结合。一般来说,这些组合物通过将活性组分与液体载体或细分的固体载体或者与此二者均匀紧密地混合。然后,可以将产品方便地制成需要的形状。
因此,本发明的药物组合物可以包括可药用载体和式(I)化合物或可药用盐。式(I)的化合物或其可药用盐,也可以与一种或多种其它治疗活性化合物联合包括在药物组合物中。
可以使用药物载体,例如,固体、液体或气体。固体载体的实例包括乳糖、白土、蔗糖、滑石、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁和硬脂酸。液体载体的实例为糖浆、花生油、橄榄油和水。气体载体的实例包括二氧化碳和氮气。
在口服剂型组合物的制备中,可以使用任何适宜的可药用介质。例如,水、二醇、油、醇、矫味剂、防腐剂、着色剂等可以用于形成口服液体制剂如混悬剂、酏剂和溶液剂;而载体如淀粉、糖、微晶纤维素、稀释剂、成颗粒剂、润滑剂、粘合剂、崩解剂等可以用来制备口服固体制剂如粉剂、胶囊和片剂。由于其易于给药,片剂和胶囊是优选的口服剂量单位,其中使用固体药物载体。任选地,片剂可以通过标准含水或非水技术包衣。
含本发明组合物的片剂可以通过任选地与一种或多种辅助组分或辅剂压制或模塑来制备。压制片剂可以通过在适宜的机器中压制自由流动形式如粉末或颗粒的活性组分来制备,所述活性组分任选地与粘合剂、润滑剂、惰性稀释剂、表面活性剂或助分散剂混合。模塑片剂可以通过在适宜的机器中,模塑用惰性液体稀释剂湿润的粉末状化合物的混合物来制备。每个片剂优选含有约0.1mg至约500mg的活性组分,而每个小药囊或胶囊优选含有约0.1mg至约500mg的活性组分。
适于非肠道给药的本发明的药物组合物可以制备为活性化合物在水中的溶液剂或混悬剂。其中可以含有适宜的表面活性剂,如羟丙基纤维素。也可以在甘油、液体聚乙二醇及它们在油中的混合物中制备分散剂。此外,可以含有防腐剂以防止微生物的有害生长。
适宜注射用的本发明的药物组合物包括灭菌的含水溶液剂或分散剂。此外,这些组合物可以是灭菌粉末的形式,以便临时制备此类灭菌注射溶液或分散液。在所有情况下,最终的注射形式必须是灭菌的,且必须是易于注射的有效液体。药物组合物在制备和储存的条件下必须是稳定的;因此,优选的贮存应防止微生物如细菌和真菌的污染作用。载体可以是含有,例如,水、乙醇、多元醇(如甘油、丙二醇和液体聚乙二醇)、植物油及其适宜的混合物的溶剂或分散体介质.本发明的药物组合物可以是适于局部使用的形式,例如,气雾剂、霜剂、软膏、洗剂、扑粉剂等。此外,这些组合物可以是适于透皮器具中给药的形式。这些制剂可以用本发明式I表示的化合物或其可药用盐,通过常规处理方法来制备。例如,霜或软膏的制备通过混合亲水物质和水,以及约5wt%至约10wt%的化合物,来制备具有符合要求的稠度的霜或软膏。
本发明的药物组合物可以是适于直肠给药的形式,其中载体是固体。优选混合物形成单位剂量的检剂。适宜的载体包括可脂及常用于本领域的其它物质。通过先将该组合物与软化或融化的载体(一种或多种)混合,接着在模具中冷却并成形,可以方便地制备栓剂。
除了上述载体组分外,上述药物制剂可以按照需要含有一种或多种其它载体组分,如稀释剂、缓冲剂、矫味剂、粘合剂、表面活性剂、增稠剂、润滑剂、防腐剂(包括抗氧剂)等。此外,可以含有使该制剂与用药对象血液等渗的其它辅剂。含有式(I)化合物或其可药用盐的组合物,也可以制备为粉剂或液体浓缩物形式。
结构式5 结构式6
本发明所述的一类对羟基苯丙烯酸衍生物在CA检索中未发现相关的文献报道。
已上市的环氧合酶抑制剂罗非昔布(如结构式5)和塞来昔布(如结构式6)与本专利化合物的结构有相似之处,但这些药物的结构中都不存在本发明所描述的具有优异的抗炎活性和心血管安全性的核心结构——对羟基苯丙烯酸衍生物。在刘鹰翔所报道的阿魏酸系列化合物中,虽然结构相似,并有良好的抗炎或抗癌活性,但不具备环氧合酶抑制剂的特效基团——磺酰胺基等。在专利CN200510044870.X中,本发明人合成了一系列含有磺酰基二苯基乙烯桥化合物,其结构特点在于以乙烯桥连接两个苯环,苯环上的环氧合酶构效基团为甲磺酰基。而本专利进行了深入研究,明确提出了对羟基苯丙烯酸衍生物为核心结构,苯环上的环氧合酶构效基团侧重于磺酰胺基。罗非昔布的环氧合酶构效基团为甲磺酰基,而塞来昔布的构效基团为磺酰胺基,塞来昔布在心血管方面的安全性比罗非昔布好,两个药物在适应症上也有不少差异,这说明了磺酰胺基的某些特性。
本专利将对羟基苯丙烯酸衍生物,引入环氧合酶抑制剂中,在对羟基苯丙烯酸衍生物的α位上有一个苯环,与β位上的苯环位于杂环或烯键的同一侧,在α位的苯环上有和环氧合酶相关的磺酰胺基等构效基团,在降低肠胃副作用的同时,降低其心血管方面的副作用。
本发明所述对羟基苯丙烯酸衍生物中的部分化合物在动物试验中,表现出良好的抗炎活性,抑制率为(28.34%),和吲哚美辛的抑制率(29.55%)相当;并能够明显降低溃疡的发生率,溃疡面积为0.41mm2,比吲哚美辛(1.45mm2)低3倍左右。而在心肌细胞的毒性实验中,没有观察到异常情况。罗非昔布等环氧合酶抑制剂增加患中风和心脏病的几率,这是一个长期缓慢的过程,而且引发机制还不明确,很难建立一个可行的模型在短时间内对化合物进行确切的实验。但没有观察到心肌方面的毒性,这和对羟基苯丙烯酸衍生物在抗炎和心血管安全性方面的表现相符合。
具体实施方式
本发明化合物合成中涉及的中间体的合成
1.4-乙基苯磺酰胺
在三口瓶中,加入乙苯60mL(0.48mol,金属钠干燥过),用冰水浴冷却,氯磺酸100ml(1.45mol)滴加到乙苯中,温度不高于5℃,反应进行1小时,然后混合物被注入碎冰1000g中,分离有机层,水层用乙醚提取三次,合并有机层,水洗,MgSO4干燥,减压下除去乙酸乙酯得到粗品,得到浅黄绿色油状物。
取100mL28%氨水,在冰水浴中冷却,将上一步的油状物滴加到氨水中,然后在45℃水浴中搅拌反应半小时,得到白色膏状物,在室温下放置,逐渐固化。抽滤,水洗,烘干,得到固体产品77g,收率85.6%,熔点96-99℃。乙醇重结晶,熔点104.5-105.8℃(文献熔点,103-105℃)。
2.4-磺酰胺基苯乙酮
在三口瓶中,将CrO3 8g溶解在10ml水和10mL乙酸的混合溶剂中,冰水浴中冷却。4-乙基苯磺酰胺3g,加入到50mL乙酸中,加热溶解,冷却到室温,然后滴加到三氧化铬溶液中。混合物逐渐升高到室温,搅拌反应3小时,反应液为红褐色液体。然后在冰水浴中加入异丙醇50ml,混合物减压浓缩得到残余物。用水稀释,用乙酸乙酯提取,有机层用MgSO4干燥。滤去干燥剂,乙酸乙酯溶液在5℃下冷藏。析出一部分棱柱状晶体0.35g,熔点178.4-179.6℃(文献报道178-179℃,乙酸乙酯)。滤液浓缩,得到类白色固体,加入异丙醇溶解,室温放置析晶,得到针状晶体0.8g,熔点171.7-174.5℃(文献报道173-175℃,异丙醇)。滤液再浓缩,还得到一部分固体,重量0.9g,略有黄色。总收率63%。
3.4-磺酰胺基苯乙酸
在三口瓶中,加入4-磺酰胺基苯乙酮2g(0.01mol)、升华硫0.32g(0.01mol)和吗啡林3mL加热到120℃下回流8hr,冷却到50℃,然后加入4g NaOH在50mL水中的溶液,置于90℃的油浴中搅拌过夜,移出油浴,冷却到室温,过滤,加入10mL的浓盐酸,调节pH大约4左右,析出浅黄色固体,固体用乙酸乙酯重结晶,得到白色固体0.5g,收率26%,熔点173.0-175.2℃。(文献报到178179℃)。
4.4-磺酰胺基苯乙酸(苯乙酸起始)
在三口瓶中,加入氯磺酸40ml(0.6mol),在冰水浴中冷却下,将苯乙酸20.5g(0.15mol)分批加入到反应瓶中,得到黄色的液体,加热到60℃反应2小时,注入到冰水中,得到类白色固体,减压抽至半干,称湿重26.7g。
固体中加入45ml冷的氨水中,混合物在85℃水浴中搅拌加热1小时,然后冷却到室温,用100ml水稀释,再用4N盐酸酸化到中性,析出类白色固体。干燥称重9.9g,熔点173.7-177.7℃。用异丙醇重结晶,得到透明鳞片状固体,熔点179.6-181.1℃。总收率30.3%。
1H-NMR(DMSO)δ(ppm):3.68(2H,s,CH2),7.32(2H,s,NH2),7.43-7.78(4H,m,苯环上H),12.46(1H,s,—COOH)。
5.4羟基-3-甲氧基溴代苯乙酮
4-羟基-3-甲氧基苯乙酮8.3g(0.05mol),溶解在40mL乙酸中,加入3滴溴,室温下搅拌40分钟,开始有颜色,逐渐消失,然后滴液漏斗缓慢滴加溴水5.2mL(0.05mol),结束后在40℃水浴中反应1小时,反应液淡黄色,冷却到室温,加入水,析出白色固体产物,干燥称重,9.0g,收率74%。用乙醇和水重结晶,熔点77.5—79.2℃。(文献报道78-79℃)
目标化合物合成
实施例1:(E)-2-(4-磺酰胺基苯基)-3-(3-甲氧基-4-乙酰氧基苯基)丙烯酸的制备
在四口瓶中,将乙酰香兰素0.25g(0.0013mol)加入到10mL乙腈溶剂中,加入三乙胺0.4mL,搅拌溶解,然后加入对磺酰胺苯乙酸0.22g(0.001mol),搅拌反应1小时,然后加入DBU,再搅拌反应1小时,停止反应,加入1N盐酸约10mL,用乙酸乙酯提取,分层,乙酸乙酯溶液用饱和食盐水洗涤,干燥,浓缩,得到黄色固体物,重量0.06g。薄层,Rf为0.3。
1H-NMR(DMSO)δ(ppm):1.94(3H,s,COCH3),3.72(3H,s,OCH3),7.33(2H,NH2),7.14-7.80(7H,m,苯环上氢),7.58(1H,-C=C-H),12.36(1H,s,COOH);
MS(m/z):392.3[M+H]+,409.4[M+NH4]+;
IR(KBr)(v/cm-1):3434,3230(NH2,COOH);3023,2978(苯环氢);2942(OCH3);1770(υC=0,—COCH3);1676(υC=0,—CH=CCOOH);1188,1154(SO2)。
实施例2:3(4-磺酰胺基苯基)-4-(3-甲氧基4-羟基苯基)-2(5H)-呋喃酮的制备
在四口瓶中,将3-甲氧基4-羟基溴代苯乙酮0.37g(0.0015mol)加入到10mL乙腈溶剂中,加入三乙胺0.4mL,然后加入对磺酰胺基苯乙酸0.22g(0.001mol),搅拌反应1小时,然后加入DBU,再搅拌反应2小时,停止反应,加入1N盐酸约10mL,用乙酸乙酯提取,分层,乙酸乙酯溶液用水洗涤,干燥,浓缩,得到黄色固体。薄层,Rf为0.4。
1H-NMR(DMSO)δ(ppm):5.44(2H,s,CH2),7.24-7.73(7H,m,苯环氢),7.45(2H,NH2);
MS(m/z):362.2[M+H]+;
IR(KBr)(v/cm-1):3431,3230(NH2);3010(苯环氢);2940(OCH3);1740(呋喃酮);1192,1141(SO2)。
实施例3:(E)-2-(4-磺酰胺基苯基)-3-(3-甲氧基-4-羟基苯基)丙烯酸的制备
在四口瓶中,将香兰素0.23g(0.0015mol)加入到10mL乙腈溶剂中,加入三乙胺0.40mL,搅拌溶解,然后加入对磺酰胺苯乙酸0.22g(0.001mol),搅拌反应1小时,然后加入DBU,再搅拌反应2小时,停止反应,加入1N盐酸约10mL,用乙酸乙酯提取,分层,乙酸乙酯溶液用水洗涤,干燥,浓缩,得到黄色固体。薄层,Rf为0.15。
MS(m/z):350.3[M+H]+,367.4[M+NH4]+;
IR(KBr)(v/cm-1):3433,3230(NH2,COOH);3020,2977(苯环氢);2942(OCH3);1677(υC=0,—CH=CCOOH);1190,1154(SO2)。
实施例4:3-(4-甲磺酰基苯基)-4-(3-甲氧基-4-羟基苯基)-2(5H)-呋喃酮的制备
在四口瓶中,将3-甲氧基-4-乙酰氧基溴代苯乙酮0.43g(0.0015mol)加入到10mL乙腈溶剂中,加入三乙胺0.40mL,然后加入对甲磺酰基苯乙酸0.22g(0.001mol),搅拌反应1小时,然后加入DBU,再搅拌反应2小时,停止反应,加入1N盐酸约10mL,用乙酸乙酯提取,分层,乙酸乙酯溶液用水洗涤,干燥,浓缩,得白色固体。薄层,Rf为0.7。
MS(m/z):361.3[M+H]+;
IR(KBr)(v/cm-1):3433,3230(NH2);3020,2977(苯环氢);2942(OCH3);1740(呋喃酮);1416,1390,1195,1156(CH3SO2)。
实施例5:(E)-2-(4-磺酰胺基苯基)-3-(3,4-二羟基苯基)丙烯酸的制备
在四口瓶中,将2,4-二羟基苯甲醛0.21g(0.0015mol)加入到10mL乙腈溶剂中,加入三乙胺0.40mL,然后加入对磺酰胺基苯乙酸0.22g(0.001mol),搅拌反应1小时,然后加入DBU,再搅拌反应1小时,停止反应,加入1N盐酸约10mL,用乙酸乙酯提取,分层,乙酸乙酯溶液用水洗涤,干燥,浓缩,得到黄色固体。Rf为0.5。
IR(KBr)(v/cm-1):3430,3228(NH2,COOH);3010,2977(苯环氢);1682(υC=0,—CH=CCOOH);1183,1155(SO2)。
实施例6:(E)-2-(4-磺酰胺基苯基)-3-(3,4-二羟基苯基)丙烯酸苯乙酯的制备
在四口瓶中,将(E)-2-(4-磺酰胺基苯基)-3-(3,4-二羟基苯基)丙烯酸20mg加入到2mL水中,滴加5%的NaOH溶液,固体溶解,调节pH值为10,然后加入苯乙基溴10mg,搅拌反应20分钟,然后用10mL乙酸乙酯提取,浓缩,得到少量粘状残余物。
1H-NMR(DMSO)δ(ppm):2.84(2H,t,CH2),4.19(2H,t,CH2),7.31(2H,NH2),7.10-7.82(7H,m,苯环上氢),12.36(1H,s,COOH)。
实施例7:3-(4-磺酰胺基苯基)-4-(3,4-二羟基苯基)-2(5H)-呋喃酮的制备
在四口瓶中,将3,4-二羟基溴代苯乙酮0.69g(0.003mol)加入到20mL乙腈溶剂中,加入三乙胺0.75mL,然后加入对磺酰胺基苯乙酸0.43g(0.002mol),搅拌反应1小时,然后加入DBU,再搅拌反应1小时,停止反应,加入1N盐酸约20mL,用乙酸乙酯提取,分层,乙酸乙酯溶液用水洗涤,干燥,浓缩,得到黄色固体。薄层,Rf为0.5。
IR(KBr)(v/cm-1):3431,3233(NH2);2993(苯环氢);1740(呋喃酮);1192,1140(SO2)。
实施例8:(E)-2(4-甲磺酰基苯基)-3-(3,4-亚甲基二氧苯)丙烯酸的制备
方法一:
在四口瓶中,将3,4-亚甲基二氧苯甲醛0.37g(0.003mol)加入到20mL乙腈溶剂中,加入三乙胺0.75mL,然后加入对甲磺酰基苯乙酸0.43g(0.002mol),搅拌反应1小时,然后加入DBU,再搅拌反应1小时,停止反应,加入1N盐酸约20mL,用乙酸乙酯提取,分层,乙酸乙酯溶液用水洗涤,干燥,浓缩,得到白色固体。
方法二:
将对甲磺酰基苯乙酸0.43g(0.002mol),3,4-亚甲基二氧苯甲醛0.37g(0.003mol),乙酸酐5.0mL,三乙胺0.5mL混合后,移入130~140℃的油浴当中,搅拌加热3小时,然后移出油浴,降温到100℃,加入5.0m的水,在100℃的油浴当中搅拌5分钟,然后移出油浴,再加入20mL的水,在室温中搅拌,析出白色固体。
1H-NMR(DMSO)δ(ppm):3.24(3H,s,SO2CH3),5.80(2H,s),6.37(1H,s),6.80—7.96(7H,苯环上氢),12.33(1H,s,COOH).。
实施例9:(E)-2-(4-磺酰胺基苯基)-3-(3,4-亚甲基二氧苯)丙烯酸的制备
在四口瓶中,将3,4亚甲基二氧苯甲醛0.18g(0.0015mol)加入到10mL乙腈溶剂中,加入三乙胺0.40mL,然后加入对磺酰胺基苯乙酸0.22g(0.001mol),搅拌反应1小时,然后加入DBU,再搅拌反应1小时,停止反应,加入1N盐酸约10mL,用乙酸乙酯提取,分层,乙酸乙酯溶液用水洗涤,干燥,浓缩,得到产物。
1H-NMR(DMSO)δ(ppm):5.81(2H,s),7.34(2H,NH2),7.05-7.90(7H,m,苯环上氢),12.42(1H,s,COOH)。
实施例10:(E)-2-(4-磺酰胺基苯基)-3-(4-羟基苯基)丙烯酸的制备
在四口瓶中,将4-羟基苯甲醛0.18g(0.0015mol)加入到10mL乙腈溶剂中,加入三乙胺0.40mL,然后加入对磺酰胺基苯乙酸0.22g(0.001mol),搅拌反应1小时,然后加入DBU,再搅拌反应1小时,停止反应,加入1N盐酸约10mL,用乙酸乙酯提取,分层,乙酸乙酯溶液用水洗涤,干燥,浓缩,得到黄色固体。
1H-NMR(DMSO)δ(ppm):7.43(2H,NH2),6.56-6.78(4H,dd,苯酚环上氢),7.41-7.95(4H,dd,磺胺苯环上氢),12.24(1H,s,COOH)。
IR(KBr)(v/cm1):3430,3226(NH2,COOH);3012,2974(苯环氢);1680(υC=0,-CH=CCOOH);1183,1150(SO2)。
实施例11:(E)-2-(4-磺酰胺基苯基)-3-(3-甲氧基-4-羟基苯基)丙烯酸乙酯的制备
将(E)-2-(4-磺酰胺基苯基)-3-(3-甲氧基-4-羟基苯基)丙烯酸0.05g加入3mL的无水乙醇,再加入0.1mL的98%的浓硫酸,在90℃的油浴中加热回流2hr,冷却到室温,加入适量水,在0℃下冷藏,析出酯化产物。
实施例12:(E)2-(4-磺酰胺基苯基)-3-(3-甲氧基-4-羟基苯基)丙烯酸钠的制备
将(E)-2-(4-磺酰胺基苯基)-3-(3-甲氧基-4-羟基苯基)丙烯酸0.5g加入3.0mL的水,在室温下,滴加10%的NaOH溶液,调节pH为8~9,50℃下加热搅拌0.5小时,然后真空抽干,得到固体残余物,加入少量乙醇溶解,再加入乙醚析出固体,并在真空中抽干得到产物钠盐。极易溶于水。
相似的,其钾盐,钙盐,铵盐的合成方法同上。
动物试验
吲哚美辛(市售口服制剂)
化合物(2):(E)-2-(4-磺酰胺基苯基)-3-(3-甲氧基-4-乙酰氧基苯基)丙烯酸
抗炎活性实验
将昆明小鼠(18~22)g随机分为4组,即空白组、吲哚美辛组和不同剂量化合物(2)组,每组10只。受试化合物用5‰CMC-Na配成混悬液,灌胃给药。空白组为等量的5‰CMC-Na,吲哚美辛为阳性对照。小鼠末次灌胃给药1h后,于小鼠右耳二侧均匀涂布50μ1二甲苯,左耳为对照。致炎1h后沿耳廓剪下两耳,用8mm打孔器于两耳同一部位取耳片并称重,以两耳片重量差计算肿胀度,以肿胀抑制率为指标评价受试化合物的药理活性。
** P<0.01
结果表明,化合物(2)与空白组相比具有明显的抗炎活性(P<0.01),与吲哚美辛相比无显著性差异,表明其抗炎活性相当。
对大鼠胃肠道的影响
给药剂量及药物配制同1。对大鼠连续给药7天,并于末次给药后观察并比较药物对大鼠胃肠道的影响。所有大鼠禁食12小时,给药1小时后颈椎脱臼处死,立即打开腹腔,在距幽门2cm处结扎,从贲门处注入10%甲醛10ml,固定10分钟,沿胃大弯剪开,取出胃及十二指肠,以0.9%生理盐水冲洗,展平,置解剖显微镜下测溃疡面积。
** P<0.01
结果表明,吲哚美辛致大鼠胃肠道溃疡面积是化合物(2)的3-4倍,表明化合物(2)对胃肠道的伤害明显小于吲哚美辛(P<0.01)。
本发明化合物应用实例
应用例1 片剂的制备
1、处方
化合物(2) | 0.25g |
淀粉 | 1.2g |
微晶纤维素 | 1g |
2%HPMC水溶液 | 适量 |
硬脂酸镁 | 0.025g |
羧甲淀粉钠 | 0.045g |
制备数量 | 10片 |
2、具体步骤
1)按照处方量称取原料和辅料;
2)将HPMC制成2%的水溶液备用;
3)将化合物(2)、微晶纤维素混合均匀,加入2%HPMC水溶液适量,搅拌均匀,制成软材;
4)过20目筛制颗粒,在60℃条件下烘干;
5)干燥的颗粒加入硬脂酸镁,过18目筛,混合均匀;
6)按照确定的片重压片。
应用例2 胶囊剂的制备
1、处方
化合物(2) | 0.15g |
化合物(7) | 0.10g |
阿司匹林 | 1 |
淀粉 | 0.8g |
微晶纤维素 | 0.45g |
2%HPMC水溶液 | 适量 |
微粉硅胶 | 0.02g |
制备数量 | 10粒 |
2、具体步骤
以常规方法制备。
应用例3 水针剂的制备
1、处方
化合物(11) | 0.25g |
聚山梨酯80 | 0.5g |
丙二醇 | 1mL |
注射用水 | 加至20ml |
制备数量 | 10支 |
2、具体步骤
以常规方法制备。
Claims (10)
1.一类对羟基苯丙烯酸衍生物,其化学结构如通式(I)所示:
其中,
R1是H、-C1-C6烃基、-芳基C1-C6烃基、-C(O)(C1-C6烃基)或-C(O)(芳基C1-C6烃基);其中所述基团任选地被-OH、卤素、-NH2、-NO2、-CN、-C(O)OH、-C1-C6烃氧基、芳基、杂芳基、-NH-环C3-C6烃基、-C(O)(C0-C6烃基)或-OC(O)(C0-C6烃基)中的1-5个取代基取代;
R2、R3是H、-OH、卤素、-C1-C6烃基或-C1-C6烃氧基;
或者:R2、R3任选地通过氧基或C1-C4烃氧基与R1桥连接成稠合二环系统;
或者:R2、R3通过氧基或C1-C4烃氧基桥连接成稠合二环系统;
X是H、-CH2-或-CH2CH2-;
Y是H、-OH、-O-、-NH2、-C1-C6烃基、-环C3-C6烃基、-C1-C6烃氧基、-环C3-C6烃氧基、杂环C5-C7胺基、-NH-环C3-C6烃基或-N(C0-C6烃基)(C0-C6烃基);其中所述基团任选地被-OH、卤素、-NH2、-NO2、-CN、-C(O)OH、-C1-C6烃基、-环C3-C6烃基、-C1-C6烃氧基、芳基、杂芳基、-C(O)(C0-C6烃基)、-C(O)O(C0-C6烃基)、-OC(O)(C0-C6烃基)或-C(O)-N(C0-C6烃基)(C0-C6烃基)中的1-5个取代基取代;
或者:X、Y通过氧基、C1-C4烃基或C1-C4烃氧基桥连接起来;
R4是H、卤素、-C1-C6烃基、-C1-C6烃氧基、-SO2NH2、-SO2-(C1-C6烃基)、-SO2NH(C1-C6烃基)或-NH-SO2-(C1-C6烃基);
R5是-SO2NH2、-SO2-(C1-C6烃基)、-SO2NH(C1-C6烃基)、-SO2NH(芳基)、-SO2NH(芳基C1-C6烃基)或-NH-SO2-(C1-C6烃基);其中所述基团任选地被-OH、卤素、-NH2、-NO2、-CN、-C(O)OH、芳基、杂芳基、-C1-C6烃氧基、-C(O)(C0-C6烃基)、-OC(O)(C0-C6烃基)或-C(O)-N(C0-C6烃基)(C0-C6烃基)中的1-5个取代基取代;并当R5是-SO2CH3时,不包含X为H,且Y为OH、OK、ONa、OCH3或OCH2CH3,R1为H、-CH3、-C(O)CH3或-C(O)CH=CHC6H5。
2.如权利要求1所述的对羟基苯丙烯酸衍生物,其特征在于:所述R1是H、-CH3、-CH2CH3、-C(O)CH3或-C(O)CH=CHC6H5;其中所述基团任选地被-OH、卤素、-NH2、-NO2或-OCH3中的1-5个取代基取代;
R2、R3是H、-OH、-CH3、-CH2CH3、-CH(CH3)2、-C(CH3)3或-OCH3;
或者:R2、R3任选地通过氧基与R1桥连接成苯并二氧杂环;
或者:R2、R3通过氧基桥连接成苯并二氧杂环;
X是H或-CH2-;
Y是H、-OH、-O-、-NH2、-OCH3、-OCH2CH3、-OCH2C6H5、-OCH2CH2C6H5、奎尼酸基或六氢吡嗪基;其中所述基团任选地被-OH、卤素、-NH2、-NO2、-CH3、-OCH3、-C(O)CH3或-C(O)OCH2CH3中的1-5个取代基取代;
或者:X、Y通过—CH2-O-或—CH2CH2-O-桥连接起来;
R4为H;R5为-SO2NH2或-SO2CH3,且在苯环的对位或邻位;其中当R5是-SO2CH3时,不包含X为H,且Y为OH、OK、ONa、OCH3或OCH2CH3,R1为H、-CH3、-C(O)CH3或-C(O)CH=CHC6H5。
3.如权利要求2所述的对羟基苯丙烯酸衍生物,其特征在于:所述R1是H、-CH3、-CH2CH3、-C(O)CH3或-C(O)CH=CHC6H5;其中所述基团任选地被-OH、卤素、-NH2、-NO2或-OCH3中的1-5个取代基取代;
R2、R3是H、-OH、-CH3、-CH2CH3、-CH(CH3)2、-C(CH3)3或-OCH3;
或者:R2和R1通过—O-CH2-桥连接成苯并二氧杂环;
X是H或-CH2-;
Y是H、-OH、-O-、-NH2、-OCH3、-OCH2CH3、-OCH2C6H5、-OCH2CH2C3H5、奎尼酸基或六氢吡嗪基;其中所述基团任选地被-OH、卤素、-NH2、-NO2、-CH3、-OCH3、-C(O)CH3或C(O)OCH2CH3中的1-5个取代基取代;
或者:X、Y通过—CH2-O-桥连接起来;
R4为H;R5为-SO2NH2,且在苯环的对位或邻位。
4.如权利要求3所述的对羟基苯丙烯酸衍生物,其特征在于:所述对羟基苯丙烯酸衍生物是如下化合物之一:
(E)-2-(4-磺酰胺基苯基)-3-(3-甲氧基-4-羟基苯基)丙烯酸,
(E)-2-(4-磺酰胺基苯基)-3-(3-甲氧基-4-乙酰氧基苯基)丙烯酸,
(E)-2-(4-磺酰胺基苯基)-3-(3-甲氧基-4-肉桂酰氧基苯基)丙烯酸,
(E)-2-(4-磺酰胺基苯基)-3-(3-甲氧基-4-羟基苯基)丙烯酸乙酯,
(E)-2-(4-磺酰胺基苯基)-3-(3-甲氧基-4-乙酰氧基苯基)丙烯酸乙酯,
(E)-2-(4-磺酰胺基苯基)-3-(3,4-二羟基苯基)丙烯酸,
(E)-2-(4-磺酰胺基苯基)-3-(3,4-二羟基苯基)丙烯酸苯乙酯,
(E)-2-(4-磺酰胺基苯基)-3-(4-羟基苯基)丙烯酸,
(E)-2-(4-磺酰胺基苯基)-3-(4-乙酰氧基苯基)丙烯酸,
3-(4-磺酰胺基苯基)-4-(3-甲氧基-4-羟基苯基)-2(5H)-呋喃酮,
3-(4-磺酰胺基苯基)-4-(3,4-二羟基苯基)-2(5H)-呋喃酮,
(E)-2-(4-磺酰胺基苯基)-3-(3,4-亚甲基二氧苯)丙烯酸。
6.权利要求1所述的对羟基苯丙烯酸衍生物在制备COX—2选择性抑制剂药物中的应用。
7.治疗和预防疼痛、炎症、类风湿性关节炎、骨性关节炎或痛经疾病的药物组合物,其特征在于:所述组合物含有治疗有效量的权利要求1所述的对羟基苯丙烯酸衍生化合物或其可药用的盐,以及药学上可接受的载体或辅料。
8.治疗和预防病毒细菌感染的抗病毒抗菌的药物组合物,其特征在于:所述组合物含有治疗有效量的权利要求1所述的对羟基苯丙烯酸衍生化合物或其可药用的盐,以及药学上可接受的载体或辅料。
9.治疗和预防动脉粥样硬化、血栓形成、中风或局部缺血性脑血管疾病的药物组合物,其特征在于:所述组合物含有治疗有效量的权利要求1所述的对羟基苯丙烯酸衍生化合物或其可药用的盐,以及药学上可接受的载体或辅料。
10.治疗和预防肠道息肉或结肠癌的药物组合物,其特征在于:所述组合物含有治疗有效量的权利要求1所述的对羟基苯丙烯酸衍生化合物或其可药用的盐,以及药学上可接受的载体或辅料。
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Cited By (7)
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WO2010069150A1 (zh) * | 2008-12-18 | 2010-06-24 | Mao Jinlong | 对羟基苯丙烯酸衍生物及其应用 |
CN103951594A (zh) * | 2009-12-18 | 2014-07-30 | 毛近隆 | 对羟基苯丙烯酸衍生物及其应用 |
CN104447330A (zh) * | 2014-11-06 | 2015-03-25 | 四川大学 | 一种从松针中制备抗菌剂的方法 |
CN104926797A (zh) * | 2014-06-10 | 2015-09-23 | 北京元博方医药科技有限公司 | 呋喃酮衍生物、制备方法及用途 |
CN109212216A (zh) * | 2018-10-31 | 2019-01-15 | 中国药科大学 | 对羟基肉桂酸或磷脂酰乙醇胺在大肠癌早期诊断方面的应用 |
CN109456232A (zh) * | 2018-12-17 | 2019-03-12 | 苏州华道生物药业股份有限公司 | 一种对乙基苯磺酰胺的制备工艺 |
CN111108103A (zh) * | 2017-07-21 | 2020-05-05 | 港大科桥有限公司 | 影响色素生产及用于治疗细菌性疾病的化合物 |
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US5474995A (en) * | 1993-06-24 | 1995-12-12 | Merck Frosst Canada, Inc. | Phenyl heterocycles as cox-2 inhibitors |
CN100425591C (zh) * | 2005-09-26 | 2008-10-15 | 山东大学 | 含有磺酰基二苯基乙烯桥化合物及其制法和药物应用 |
WO2008140251A2 (en) * | 2007-05-14 | 2008-11-20 | University-Industry Cooperation Group Of Kyung Hee University | Cyclooxygenase-2 inhibitors |
CN101429181A (zh) * | 2008-12-18 | 2009-05-13 | 毛近隆 | 对羟基苯丙烯酸衍生物及其应用 |
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WO2010069150A1 (zh) * | 2008-12-18 | 2010-06-24 | Mao Jinlong | 对羟基苯丙烯酸衍生物及其应用 |
CN101910144B (zh) * | 2008-12-18 | 2014-04-23 | 毛近隆 | 对羟基苯丙烯酸衍生物及其应用 |
CN103951594A (zh) * | 2009-12-18 | 2014-07-30 | 毛近隆 | 对羟基苯丙烯酸衍生物及其应用 |
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CN104447330A (zh) * | 2014-11-06 | 2015-03-25 | 四川大学 | 一种从松针中制备抗菌剂的方法 |
CN104447330B (zh) * | 2014-11-06 | 2016-02-24 | 四川大学 | 一种从松针中制备抗菌剂的方法 |
CN111108103A (zh) * | 2017-07-21 | 2020-05-05 | 港大科桥有限公司 | 影响色素生产及用于治疗细菌性疾病的化合物 |
CN111108103B (zh) * | 2017-07-21 | 2023-10-20 | 港大科桥有限公司 | 影响色素生产及用于治疗细菌性疾病的化合物 |
CN109212216A (zh) * | 2018-10-31 | 2019-01-15 | 中国药科大学 | 对羟基肉桂酸或磷脂酰乙醇胺在大肠癌早期诊断方面的应用 |
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