CN103951594B - 一种中药活性成分阿魏酸的衍生物、合成及其应用 - Google Patents
一种中药活性成分阿魏酸的衍生物、合成及其应用 Download PDFInfo
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- CN103951594B CN103951594B CN201410116059.7A CN201410116059A CN103951594B CN 103951594 B CN103951594 B CN 103951594B CN 201410116059 A CN201410116059 A CN 201410116059A CN 103951594 B CN103951594 B CN 103951594B
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Abstract
本申请是针对申请号为200980101704.5，申请日为2009年12月18日，名称为“对羟基苯丙烯酸衍生物及其应用”的发明专利申请的分案申请。本发明涉及对羟基苯丙烯酸衍生物及其可药用盐，所述对羟基苯丙烯酸衍生物是如下化合物：(E)-2-(4-氨基磺酰基苯基)-3-(3,4-二乙酰氧基苯基)丙烯酸，(E)-2-(4-甲磺酰基苯基)-3-(3,4-二乙酰氧基苯基)丙烯酸和(E)-2-(4-(N-乙酰基氨基磺酰基)苯基)-3-(3,4-二乙酰氧基苯基)丙烯酸，包含其成分的药物组合物以及在制备治疗和预防炎症或炎症相关的病症的药物中的应用，特别是在制备环氧合酶和/或脂氧化酶选择性抑制药物中的应用。
Description
技术领域
本申请是针对申请号为200980101704.5，申请日为2009年12月18日，名称为“对羟基苯丙烯酸衍生物及其应用”的发明专利申请的分案申请。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、其水合物，其可药用盐，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治疗和预防炎症或炎症相关的病症的药物中的应用，特别是在制备环氧合酶和/或脂氧化酶选择性抑制药物中的应用。
背景技术
非甾体抗炎(NSAIDs)药物由于其具有确定的抗炎、镇痛效果，被广泛应用于炎症、疼痛、风湿性疾病和运动损伤的治疗，但肠胃并发症是长期服用非甾体抗炎药物最常见的副作用，包括威胁生命的溃疡，限制了非甾体抗炎药物的应用。新开发的环氧合酶(COX-2)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，这类药物在上市后很快被广泛使用，代表性的药物有默克公司的罗非昔布和辉瑞公司的塞来昔布等。
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，环氧合酶抑制药物会增加患中风和心脏病的几率，服用罗非昔布，心脏病复发或死亡的风险是未服用的2.7倍，服用塞来昔布的风险为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。
本发明的化合物是对羟基苯丙烯酸衍生物及其可药用盐。对羟基苯丙烯酸衍生物有良好的心血管安全性，其结构特征为对羟基苯丙烯酸衍生物的α位上的苯环和β位上的苯环位于不饱和杂环的同一侧，在α-位苯环的对位上有氨基磺酰基等，在β-位苯环的对位上有氧原子可与不饱和键形成对羟基苯丙烯酸结构。本发明的化合物结构中的对羟基苯乙烯能与多种酶活性中心相作用，苯环对位上的羟基与抑制前列腺素(PGs)有关，去掉羟基后其活性会明显降低(Chem.Pharm.Bull.34(1986):121-129)；与苯环共轭的烯烃双键，也能够提高抑制前列腺素的活性，如果还原为饱和烷烃，则活性会消失(Chem.Pharm.Bull.34(1986):1619-1627.)；另一个苯环上的磺酰基是对环氧合酶进行选择性抑制的药效基团(J.Med.Chem.40(1997):1347-1365.)；对羟基苯丙烯酸结构具有较强的抗炎活性和心血管安全性。另外对羟基苯乙烯也表现出较强的脂氧化酶(LOX)选择性抑制活性(US4440784；US4971996)，对环氧合酶和脂氧化酶的协同抑制作用有利于降低心血管风险(Cancer Prev.Res.2(2009):288-290.)。
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。
咖啡酸具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。咖啡酸还有广泛的抑菌和抗病毒活性，对腺病毒和副流感都有较强的抑制作用。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(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.心脏杂志,05(2007):513-516)。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。
阿魏酸除了抗炎、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。研究表明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、抗突变等，能被人体吸收并易于从尿中排出，不会在体内累积，因此是一种安全性很高的药物。在30例冠心病充血性心力衰竭治疗研究中，总有效率96.7％(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,10(2004):982-984)，在对36例脑梗塞治疗中，有效率为83.3％(阿魏酸钠治疗脑梗塞36例.海南医学,18(2007):1-2)。
对羟基苯丙烯酸衍生物还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，对于治疗和预防高血压病很有前途(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,36(2001):502-506)。
本发明提供一种新型的对羟基苯丙烯酸衍生物及其可药用盐，实验表明对羟基苯丙烯酸衍生物在治疗炎症的同时，降低肠胃的副作用，在心血管方面也有较好的安全性，本发明的化合物做为治疗炎症或炎症相关的病症的前体药物将有很好的前途。
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新型对羟基苯丙烯酸衍生物、其互变异构体、其药物可接受的盐、其药物可接受的水合物和其药物可接受的溶剂化物；
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、其互变异构体、其药物可接受的盐或其药物可接受的水合物的方法；
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物、其可药用盐、其可药用的水合物和含有该化合物或其混合物的药物组合物；
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物及其可药用盐，在治疗和预防炎症或炎症相关的病症中的应用。
本发明的再一目的在于提供一种所述对羟基苯丙烯酸衍生物及其可药用盐，在制备治疗和预防炎症或炎症相关的病症的药物中的应用，特别是在制备环氧合酶和/或脂氧化酶选择性抑制药物中的应用。
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：
或其可药用盐，其中
R1选自：氢、甲基或乙酰基；
R2、R2’、R3、R3’各自独立地选自氢、羟基或甲氧基；
G选自二取代的苯基，优选自基团(M)：
或其可药用盐，其中
R4选自氨基、甲基或乙酰基氨基；
R5选自氢、卤素或甲氧基；n是2；
X选自：氢；
Y选自：羟基、氨基、甲氧基、乙氧基、甲基氨基或乙基氨基；
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-氨基磺酰基苯基)-3-(3,4-二乙酰氧基苯基)丙烯酸，(E)-2-(4-(N-乙酰基氨基磺酰基)苯基)-3-(3,4-二乙酰氧基苯基)丙烯酸。
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：
术语“羟基烷基”、“烷基氧基”和“烷基氧基羰基”等中，多个基团术语组合使用时，在不产生歧义情况下，前者的“基”可以省略表示为“羟烷基”、“烷氧基”和“烷氧基羰基”等。
术语“烃基”可以是烷基，烯基，炔基等。不管是单独使用或是与其它术语联用(如“羟基烃基”、“烃基磺酰基”等)都包括烷基、烯基和炔基中的一种或两种或三种或其联合形式。
术语“烷基”不管是单独使用或是与其它术语联用(如“羟基烷基”、“烷基磺酰基”等)都包括1-10个碳原子的直链或支链基团或其联合形式。更优选的烷基基团是1-6个碳原子的低级烷基基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、己基、异己基、庚基、辛基等。
术语“烯基”包括含至少一个碳碳双键的2-10个碳原子的直链的或者支链的烷基，优选为含2-6个碳原子的烷基。这类基团的例子包括乙烯基、正丙烯基、丁烯基等。
术语“炔基”包括含至少一个碳碳三键的2-10个碳原子的直链的或者支链的烷基或烯基，优选为含2-6个碳原子的烷基。这类基团的例子包括乙炔基、正丙炔基、丁炔基等。
术语“卤素”指卤族元素如氟、氯、溴或碘原子。
术语“环烷基”包括具有3-10个碳原子的基团。更优选的环烷基基团是具有3-7个碳原子的“低级环烷基”基团。实例包括的基团如环丙基、环丁基、环戊基、环己基、环庚基及类似基团。
术语“环烯基”包括具有3-10个碳原子的不饱和环状基团，如环丁烯基、环戊烯基、环己烯基、环庚烯基及类似基团。
术语“芳基”当单独或组合使用时，包括含1、2或3个环的碳环芳香体系，其中这些环可以侧链方式连接在一起，或者可以是稠合的。该术语“芳基”包括芳香基团如苯基、萘基和联苯基。
术语“羟基”表示-OH。术语“氧基”表示从羟基中去掉氢原子后的-O-，可以单独或与其它基团组合使用，例如烷基氧基，是由上述定义的烷基基团连接在氧基基团上。
术语“羟基烷基”包括含1-10个碳原子的直链或支链的烷基基团，其中该烷基上的任何一个碳原子可被一个或多个羟基基团取代。更优选的羟烷基基团是具有1-6个碳原子的和一个或多个羟基基团的"低级羟烷基"基团。这类基团的例子包括羟甲基、羟乙基、羟丙基、羟丁基、羟戊基和羟己基。
术语“烷基氧基”包括连接有直链或支链的含氧基团，每个基团的烷基部分为1-10个碳原子。优选的烷氧基基团是含1-6个碳原子的“低级烷氧基”基团。这类基团的例子包括甲氧基、乙氧基、丙氧基、丁氧基和叔丁氧基。
术语“芳基烷基”包括含1-6个碳原子的烷基基团上连接有芳基基团的“低级芳烷基”基团。这类基团的例子包括苄基、二苯基甲基、三苯基甲基、苯乙基、二苯基乙基及类似基团。
术语“羧基”表示-CO2H。
术语“酰基”都表示从有机酸中除去羟基后剩下的残基提供的基团，且包括但不限于取代的或未取代的基团其选自甲酰基、乙酰基、丙酰基、丁酰基或类似基团。术语“酰氧基”表示包括连接有酰基的含氧基团，“酰胺基”表示包括连接有酰基的含氨基团。
术语“羰基”表示-(C＝O)-，包括单独使用或是与其它术语联合形式。术语“烷基羰基”包括羰基上连有烷基取代基团(如上述酰基或烷酰基)的基团。术语“烷氧基羰基”表示含有上述烷氧基的基团，其中该烷氧基通过氧原子连接在羰基基团上。优选地，“低级烷氧基羰基”包括含1-6个碳原子的烷氧基基团。
术语“磺酰基”，无论是单独使用或与其它术语组合使用(如烷基磺酰基)，该术语都表示二价基团-SO2-。术语“亚磺酰基”，无论是单独使用或与其它术语组合使用(如烷基亚磺酰基)，该术语都表示二价基团-SO-。“烷基磺酰基”包括在磺酰基基团上连接如上述定义的烷基基团。更优选的烷基磺酰基基团是1-6个碳原子的低级烷基磺酰基基团。这类低级烷基磺酰基基团的例子包括甲基磺酰基、乙基磺酰基和丙基磺酰基。
术语“氨基”表示-NH2，术语“N-烷基氨基”和“N,N-二烷基氨基”分别表示具有一个烷基取代基团和具有两个烷基取代基团的氨基基团。优选的烷氨基基团是在氮原子上连接有一个或两个含1-6个碳原子的烷基基团的“低级烷氨基”基团。适合的“烷氨基”可以是N,N-二甲氨基、N,N-二乙氨基或类似基团。
术语“二取代的苯基，二取代的萘基或二取代的杂芳基”表示苯环、萘环或杂芳环上的两个取代基，可以是邻位，间位或对位，其中一个取代基的例子包括但不限于磺酰基、亚磺酰基、亚砜亚胺基、磷酰基或亚磷酰基，上述基团被氢、氨基、肼基、烷基、酰胺基或烷基磺酰胺基取代，优选地为甲磺酰基、氨基磺酰基、乙酰基氨基磺酰基或三氟乙酰基氨基磺酰基，优选地在苯环的对位。另一个取代基的例子包括但不限于氢、羟基、卤素、氨基、肼基、硝基、三氟甲基、羧基、烷基或烷基氧基，优选地为氢或卤素。
术语“取代的苯乙酸”，“取代的苯乙酰胺”表示乙酸和乙酰胺连接有上述的“二取代的苯基”。类似地，“取代的萘乙酸”，“取代的萘乙酰胺”表示乙酸和乙酰连接有上述的“二取代的萘基”。
术语“取代的α-卤代苯乙酮”，“取代的α-卤代苯乙酮”，“取代的α-羟基苯乙酮”和“取代的苯甲醛”表示苯乙酮或者苯甲醛的对位有羟基、巯基、取代的氧基或取代的巯基等取代基，取代基的例子包括但不限于羟基、巯基、甲氧基、乙氧基、乙酰氧基和肉桂酰氧基；苯乙酮或者苯甲醛的邻位或者间位可以有1至4个相同或不相同的取代基，取代基的例子包括但不限于羟基、卤素、氨基、肼基、叠氮基、硝基、氰基、三卤甲基、羧基、烷基、烯基、烷基氧基或烷基硫基，优选自羟基和卤素。
术语“可药用盐”是指由可药用的无毒碱(包括无机碱和有机碱)制备的盐。由无机碱得到的盐包括，例如钠、钾、铵、钙、镁、锌盐、铝、铜、铁、亚铁、锂、锰和二价锰，特别优选钠、钾、铵、钙和镁盐。由可药用的有机无毒碱得到的盐包括下列碱的盐：伯、仲和叔胺，取代的胺包括天然存在的取代的胺，环胺和碱性离子交换树脂，此类碱包括，例如精氨酸、甜菜碱、咖啡因、胆碱、N,N二苄基乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗琳、N-乙基哌啶、葡糖胺、氨基葡糖、组氨酸、哈胺、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺和氨基三丁醇。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，例如盐酸、氢溴酸、硫酸、磷酸、硝酸、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、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘酸、棕榈酸、泛酸、琥珀酸、酒石酸、奎尼酸和对甲苯磺酸等，特别优选盐酸、氢溴酸、硫酸、磷酸、苯磺酸、马来酸、枸橼酸、酒石酸和奎尼酸。本发明的药物组合物包括作为活性成分的式(Ⅰ)化合物或其可药用盐，也可含有可药用载体以及任选的其它治疗成分，应当理解在下面讨论的治疗方法中，涉及式(Ⅰ)化合物时也包括其可药用盐。
本文中描述的一些化合物含有一个或多个双健，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。
本文中描述的一些化合物含有一个或多个不对称中心，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)化合物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。
本发明的目的是提供式(Ⅰ)化合物及其可药用盐在制备治疗和预防炎症或炎症相关的病症的药物中的应用，特别是在制备环氧合酶和/或脂氧化酶选择性抑制药物中的应用，其中所述药物的剂型主要是片剂、胶囊、水针剂或粉剂等。
本发明的另一目的是提供式(Ⅰ)化合物及其可药用盐在治疗和预防哺乳动物的普通感冒、发热、疼痛、头痛、牙痛、颈痛、扭伤和拉伤、痛经、月经痛性痉挛、关节炎、类风湿性关节炎、骨性关节炎、脊椎关节病、痛风关节炎、全身性红斑狼疮，抑制类前列腺素引起的平滑肌收缩或者预防结肠直肠癌、卵巢癌、宫颈癌、前列腺癌、膀胱癌、小肠癌、胰腺癌、胃癌、胸癌、肺癌、唇癌、口腔癌、食道癌或皮肤的癌症的药物生产中的用途。
本发明的又一目的是提供在哺乳动物的治疗方法中应用的式(Ⅰ)化合物及其可药用盐，特别应用在治疗和预防哺乳动物的普通感冒、发热、疼痛、头痛、牙痛、颈痛、扭伤和拉伤、痛经、月经痛性痉挛、关节炎、类风湿性关节炎、骨性关节炎、脊椎关节病、痛风关节炎、全身性红斑狼疮，抑制类前列腺素引起的平滑肌收缩或者预防结肠直肠癌、卵巢癌、宫颈癌、前列腺癌、膀胱癌、小肠癌、胰腺癌、胃癌、胸癌、肺癌、唇癌、口腔癌、食道癌或皮肤的癌症。
本发明的式(Ⅰ)化合物用于治疗和预防炎症和炎症相关的病症，方法是对患者施用治疗剂量的式(Ⅰ)化合物。炎症与许多疾病情况相关联，这些情况包括风湿病引起的发热、流感或其它病毒感染的相关症状、普通感冒、下背痛和颈痛、痛经、头痛、牙痛、扭伤和拉伤、月经痛性痉挛、早产。此类化合物也可用于治疗关节炎，包括但不限于类风湿性关节炎、脊椎关节病、痛风关节炎、骨关节炎、全身性红斑狼疮和幼年型关节炎。它们还可用于治疗皮肤炎类病症如牛皮癣、湿疹、烧伤和皮炎。
此外，本发明的式(Ⅰ)化合物可抑制细胞的肿瘤转形和转移瘤的生长，因而用于癌症的治疗和预防。特别地，本发明提供一种治疗产生前列腺素的肿瘤的方法，即使用治疗剂量的式(Ⅰ)化合物对患者进行治疗。因此本发明的化合物可用于预防和治疗癌症如结肠直肠癌、卵巢癌、宫颈癌、前列腺癌、膀胱癌、小肠癌、胰腺癌、胃癌、胸癌、肺癌、唇癌、口腔癌、食道癌或皮肤的癌症等。这类化合物也可用于治疗下列疾病的炎症例如血管疾病、偏头痛、结节性动脉外膜炎、甲状腺炎、再生障碍性贫血、何杰金氏病、硬皮病、风湿病引起的发热、I型糖尿病、神经肌肉接点疾病(包括重症肌无力)、白质疾病(包括多发性硬化)、类肉瘤病、肾病并发症、贝切特氏并发症、多肌炎、齿银炎、肾炎、过敏症、损伤后的肿胀、心肌局部缺血等等。所述化合物也可用于眼科疾病(如视网膜炎、视网膜病、葡萄膜炎、畏光症)和急性眼组织损伤的治疗。它们也可用于肺部炎症(如与病毒感染有关的炎症)和膀胱纤维化的治疗。
本发明的式(Ⅰ)化合物可以是治疗和预防处于血栓形成的心血管事件的患者的药物组合物，处于血栓形成的心血管事件的情况，例如卒中、心肌缺血、心肌梗塞、心绞痛、短暂性缺血发作(TIA；一时性黑朦)、可逆性缺血性神经障碍和任何血管床(内脏、肾脏、主动脉等)中任何相似血栓形成事件。而且，有证据显示具有慢性炎症状况(如类风湿性关节炎和全身性红斑狼疮)的患者处于血栓形成的心血管事件的增加的危险中。也可用于治疗和预防痴呆包括早老性痴呆和老年性痴呆，特别是与阿尔茨海默病有关的痴呆(即阿尔茨海默痴呆)。
本发明的式(Ⅰ)化合物还可作为常用NSAIDs的替代物，特别在那些忌用非甾体抗炎药的场合，如治疗有胃肠疾病的溃疡、胃炎、局部肠炎、溃疡性结膜炎、憩室炎、克罗恩氏病、肠炎并发症和应激性肠并发症、胃肠出血和凝血病症、肾病(如肾功能不全))的病人，手术前或服用抗凝血剂的病人，以及对NSAIDs敏感的病人。
在实际应用中，本发明的式(Ⅰ)化合物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，本发明的式(Ⅰ)化合物，还可以通过控释方式和/或传递器具给药。
适宜口服用的本发明的药物组合物可按本领域公知的制备药物组合物的任意方法制备，为了提供美观可口的药物制剂，这些组合物可含有一种或多种选自甜味剂、调味剂、着色剂和防腐剂的试剂。片剂含有本发明的活性组分以及与之混合的适合制备片剂的无毒可药用赋形剂。这些赋形剂例如为惰性稀释剂，例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；成粒剂和崩解剂，例如玉米淀粉或藻酸；粘合剂，例如淀粉、明胶或阿拉伯胶；润滑剂，例如硬脂酸镁，硬脂酸或滑石粉，片剂可不被包衣或用已知方法包衣，以便在胃肠道中延缓崩散和吸收，从而在较长的期限内提供持续的作用。例如可使用时间延缓物质，如甘油一硬脂酸酯或甘油二硬脂酸酯。口服使用的制剂也可采用硬胶囊形式，其中本发明的活性组分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合，或采用软胶囊形式，其中活性成分本发明的活性组分与水或油状介质例如花生油、液体石腊或橄榄油混合。
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水悬浮液或油悬浮液。水悬浮液含有本发明的活性组分以及与之混合的适合制备水悬浮液的赋形剂。这些斌形剂为悬浮剂，例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮、西黄耆胶和阿拉伯胶；分散剂或湿润剂可以是天然存在的磷脂，例如卵磷脂，或氧化烯与脂肪酸的缩合产物，例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链脂肪醇的缩合产物，例如十七乙烯氧基十六烷醇，或环氧乙烷与脂肪酸和己糖醇所得的部分酯的缩合产物，例如聚氧乙烯山梨糖醇单油酸酯，或环氧乙烷与脂肪酸和己糖醇酐所得的部分酯的缩合产物，例如聚乙烯山梨糖醇酐单油酸酯。水悬浮液也可含有一种或多种防腐剂，例如对羟基苯甲酸乙酯或正丙酯，一种或多种着色剂，一种或多种调味剂，以及一种或多种甜味剂，例如蔗糖、糖精或阿斯巴甜。油悬浮液可通过将活性成分悬浮于植物油例如花生油、橄榄油、芝麻油、椰子油，或矿物油如液体石腊中来制备。油悬浮液可含有增稠剂，例如蜂蜡、硬石腊或鲸蜡醇。可加入如上所述的甜味剂和调味剂以得到可口的口服制剂。可通过加入抗氧化剂如抗坏血酸使这些组合物防腐。本发明的药物组合物也可以水包油的乳剂形式存在。油相可为植物油，例如橄揽油或花生油，或矿物油，如液体石腊或它们的混合物。合适的乳化剂可以是天然存在的磷脂，例如大豆，卵磷脂，脂肪酸和己糖醇酐所得的酯或部分酯。
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。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。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栓剂。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，可以制备栓剂。
在治疗和预防下述病症中，包括但不局限于普通感冒、发热、疼痛、头痛、牙痛、颈痛、扭伤和拉伤、痛经、月经痛性痉挛、关节炎、类风湿性关节炎、骨性关节炎、脊椎关节病、痛风关节炎、全身性红斑狼疮，抑制类前列腺素引起的平滑肌收缩或者预防结肠直肠癌、卵巢癌、宫颈癌、前列腺癌、膀胱癌、小肠癌、胰腺癌、胃癌、胸癌、肺癌、唇癌、口腔癌、食道癌或皮肤的癌症，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，每位患者每天使用约0.01mg/Kg至50mg/Kg的化合物或者约0.5mg/Kg至约2.5g/Kg，可以有效地治疗炎症。
本发明的药物组合物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的活性组分，其与适量的载体物质混合，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、lmg、5mg、25mg、50mg、100mg、200mg、300mg、400mg、500mg、600mg、800mg或1000mg。
但是应当理解，对于任何具体患者的特定剂量取决于各种因素，包括年龄、体重、一般的健康状况、性别、饮食、给药时间、给药途径、排泄速度、药物的配合和所治疗的具体疾病的严重程度。
制备方法
本发明所述对羟基苯丙烯酸衍生物可由下述方法制备：
取代的苯甲醛和取代的苯乙酸在三乙胺、DBU、氢氧化钠、乙醇钠等催化下，在乙酸酐中反应，得到羧酸类的对羟基苯丙烯酸衍生物(Ketcham R,Jambotkar D,J.Org.Chem.28(1963)1034-1037；J.Chem.Soc.1955,3445)，再和醇或者卤代烃反应得到酯类的对羟基苯丙烯酸衍生物(J.Am.Chem.Soc.77(1955):6214-6215；J.Med.Chem.38(1995):4171-4178)。缩合反应所用的溶剂有乙酸酐，乙腈，乙醇，甲醇，水，二氯甲烷，氯仿等，反应温度在0～150℃之间，反应时间在15分钟至15小时。
(R为烷基、烯基、芳基或芳烷基等基团。)
Ketcham研究发现，在乙酸酐中用三乙胺催化，主要得到E式构型产物。由双键上的孤立氢的位移也可以确定本方法得到E式构型产物(Org.Syn.CV4,777；Can.J.Chem.73(1990)1660-1665；J.Org.Chem.46(1981)2514-2520)。
本发明的式(Ⅰ)化合物的具体制备方法可参考文献中以及其引用的参考文献中描述的常规方法制备，所述说明书的各个部分通过引用结合到本文中并形成本发明的一部分。
在所有的方法当中，所有的R1～R8、G的详细描述以及其他符号与权利要求1中的式(Ⅰ)的定义一致。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：
本发明的合成方法并不限于上述所介绍的合成途径，也包括呋喃酮或者吡咯酮通过取代等得到本发明的化合物，糖苷化合物或者其他形式化合物通过水解得到本发明的化合物，在哺乳动物体内以代谢产物的方式形成本发明的化合物等。
生物活性
本发明所述对羟基苯丙烯酸衍生物的生物活性可由下列方法试验：
对小鼠的抗炎活性
根据文献(中国药物化学杂志,38(2000):242-246)中描述的方案，将昆明小鼠(18～22g)随机分组，每组6～8只。实验包括空白对照组，吲哚美辛(市售口服制剂)阳性对照组和测试化合物组。测试化合物组用5‰CMC-Na配成混悬液，灌胃给药，空白组用等量的5‰CMC-Na，阳性对照用吲哚美辛。小鼠末次灌胃给药1小时后，于小鼠右耳二侧均匀涂布50μl二甲苯，左耳为对照。致炎1小时后沿耳廓剪下两耳，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测试化合物的药理活性。实验结果在表1中。
肿胀度＝右耳片重-左耳片重
表1抗炎活性实验
对本发明进行举例说明，化合物NMYY和CPY的经灌胃给药100mg/kg与空白组相比具有明显的抗炎活性，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
根据(中国药科大学学报,33(2002):460-465)中描述的方案，将SD大鼠(180～200g)随机分组，每组6～8只。实验包括空白对照组和测试化合物组。药物配制及给药剂量同抗炎活性实验。大鼠连续灌胃给药7天，末次灌胃给药前禁食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分钟后，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，置解剖显微镜下测量并计算胃及十二指肠(距幽门1cm)溃疡总面积，观察并比较药物对大鼠胃肠道的影响。实验结果在表2中。
表2胃肠道影响实验
(n＝8，x±SD)*与空白组比较：*：P＜0.05，**：P＜0.01
对本发明进行举例说明，化合物CPY和NMYY经口服给予100mg/kg基本没有明显的致胃溃疡作用。
对大鼠的心肌细胞安全
根据(中国病理生理杂志,19(2003):386-390)中描述的方案，将SD大鼠(180～200g)随机分组，每组6～8只。实验包括空白对照组和测试化合物组。药物配制及给药剂量同抗炎活性实验。大鼠灌胃给药隔日1次，共6次(11天)。观察大鼠的毒性反应包括体重、行为、进食、皮毛、呼吸、四肢活动等。在第12天，大鼠用戊巴比妥钠麻醉，然后脱颈处死，打开心包腔，取出心脏用磷酸缓冲液冲洗，沿心脏长轴取左心室游离壁中部心室肌，按常规制作透射电镜标本，光镜及透射电镜常规观察心肌组织的变化。实验结果在表3中。
表3心肌细胞安全实验
对本发明进行举例说明，化合物CPY和NMYY与空白组相比较，除化合物NMYY组出现1例死亡外，其余大鼠的体重、进食，活动无异常，也未出现其它毒性反应。心肌组织的光镜观察没有发现显著不同或者异常变化。
在专利WO9500501中，对式(Ⅸ)化合物进行了研究，罗非昔布(如式(Ⅹ))对环氧合酶(COX-2)有较强的选择抑制活性，但和本发明化合物的区别在于：在呋喃环的3-位苯环上，烷氧基氧原子的对位没有丙烯酸结构，而是乙酸结构，并不具备对羟基苯丙烯酸衍生物的特征。在专利CN200510044870.X中，对式(Ⅺ)化合物进行了研究，合成了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，但对呋喃环等杂环桥连接并未进行研究，其研究的核心结构是乙烯桥，而不是对羟基苯丙烯酸衍生物。
本发明的式(Ⅰ)化合物在对羟基苯丙烯酸的基础上进行了深入研究，明确提出了对羟基苯丙烯酸衍生物为核心结构，两个苯环以不饱和的杂环桥连接，也包括杂环开环后的情况，苯环上的环氧合酶构效基团为氨基磺酰基和甲磺酰基，脂氧化酶的构效基团为对羟基苯乙烯。本发明的结构特征是对羟基苯丙烯酸衍生物的α位上的苯环和β位上的苯环位于不饱和杂环的同一侧，在α-位苯环的对位上有氨基磺酰基等，在β-位苯环的对位上有氧原子可与不饱和键形成对羟基苯丙烯酸结构，而与不饱和键以及羰基则形成对羟基苯丙烯酸结构。
罗非昔布的环氧合酶构效基团为甲磺酰基，并且在呋喃环的4-位苯环上，而构效基团在3-位苯环上时也具有很好的选择活性(Bioorg.Med.Chem.Lett.14(2004):1957-1960)。另外塞来昔布(如式(Ⅻ))的环氧合酶构效基团为氨基磺酰基，氨基磺酰基和甲磺酰基相比较，有较好的细胞凋亡诱导活性，塞来昔布在心血管方面的安全性比罗非昔布较好，这也说明了氨基磺酰基的某些特性(J.Natl.Cancer Inst.94(23):1745-1757)。
本发明的式(Ⅰ)化合物的药物组合物治疗和预防炎症及炎症相关的疾病，在降低肠胃副作用的同时，降低其心血管方面的副作用。
具体实施方式
下面的实施例详细解释本发明，实施例仅以说明方式提供，因而不会对本发明的范围构成限制。
熔点数据，由RY-1熔点仪测定，未经过校正。质谱，由美国Applied Biosystems公司API4000型质谱仪测定。红外吸收谱图，由美国Nicolet公司NEXUS 470型傅立叶变换红外光谱仪，溴化钾压片法测定。1H和13C NMR数据，用美国Bruker AVANCE-300记录，除非特别说明，一般使用DMSO为溶剂，四甲基硅烷作为内标，以δ为标度。信号峰的缩写：s,单峰；d,双峰；t,单峰；m,多重峰；化学符号的缩写具有其通用含义，使用下列缩写：m.p.(熔点)，ml(毫升)，g(克)，mol(摩尔)，mmol(毫摩尔)，DBU(1,8-二氮杂双环[5.4.0]十一碳-7-烯)等。
实施例1：(E)-2-(4-(N-乙酰基氨基磺酰基)苯基)-3-(3-甲氧基-4-乙酰氧基苯基)丙烯酸
步骤一：4-氨基磺酰基苯乙酸
在三口瓶中，加入氯磺酸(26ml,0.4mol)，在冰水浴中冷却下，将苯乙酸(13.6g,0.10mol)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。将上一步固体中加入35ml冷的氨水中，混合物在80℃水浴中搅拌加热1小时，然后冷却到室温，用水稀释，再用5％HCl酸化到中性，析出类白色固体，用异丙醇重结晶，得到透明鳞片状固体，重5.6g，m.p.180-181℃。
1H-NMRδ(ppm):3.68(2H,s),7.32(2H,s),7.45(2H,d),7.78(2H,d),12.46(1H,s)。
步骤二：(E)-2-(4-(N-乙酰基氨基磺酰基)苯基)-3-(3-甲氧基-4-乙酰氧基苯基)丙烯酸
将4-氨基磺酰基苯乙酸(0.22g,1mmol)、3-甲氧基-4-羟基苯甲醛(0.25g,1.3mmol)和三乙胺0.4ml加入到5mL的乙酸酐中，在130℃下搅拌反应4小时，然后加入5mL水，再搅拌反应5分钟，室温下放置，析出固状物，过滤，干燥，用乙酸重结晶，得到黄色固体，m.p.213-215℃。
1H-NMRδ(ppm):1.95(3H,s),2.20(3H,s),3.28(3H,s),6.54(1H,s),6.82(2H,d,J＝8.2),7.00(2H,d,J＝8.0),7.48(2H,d,J＝8.0),7.83(1H,s),7.94(2H,d,J＝8.0)；13C-NMRδ(ppm):20.78,23.69,55.43,113.93,123.46,124.46,128.27(2C),130.94(2C),132.22,132.94,139.08,139.84,140.52,142.44,150.71,167.99,168.70,169.32；MS(m/z):434.3[M+H]+。
实施例2：(E)-2-(4-甲磺酰基苯基)-3-(3,4-二乙酰氧基苯基)丙烯酸
将4-甲磺酰基苯乙酸(0.22g,1mmol)、3,4-二羟基苯甲醛(0.20g,1.4mmol)和三乙胺0.4ml加入到5mL的乙酸酐中，在130℃下搅拌反应4小时，然后加入5mL水，再搅拌反应5分钟，室温下放置，过滤，干燥，用乙酸重结晶，得到白色固体，m.p.214-216℃。
1H-NMRδ(ppm):2.17(3H,s),2.22(3H,s),3.24(3H,s),6.86(1H,s),6.96(2H,d,J＝8.6),7.14(2H,d,J＝8.5),7.47(2H,d,J＝8.0),7.82(1H,s),7.93(2H,d,J＝8.0)。
实施例3：(E)-2-(4-(N-乙酰基氨基磺酰基)苯基)-3-(3,4-二乙酰氧基苯基)丙烯酸
制备方法类似实施例1。将4-氨基磺酰基苯乙酸和3,4-二羟基苯甲醛混合反应，得到白色固体，m.p.225-227℃。
1H-NMRδ(ppm):1.95(3H,s),2.19(3H,s),2.22(3H,s),6.82(1H,s),6.95(1H,s),7.13(1H,d),7.44(2H,d),7.81(1H,s),7.90(2H,d),12.16(1H,s),13.02(1H,s)。
实施例4：(E)-2-(4-(N-乙酰基氨基磺酰基)苯基)-3-(4-乙酰氧基苯基)丙烯酸
制备方法类似实施例1。将4-氨基磺酰基苯乙酸和4-羟基苯甲醛混合反应，得到淡黄色固体，m.p.207-209℃。
1H-NMRδ(ppm):1.95(3H,s),2.21(3H,s),6.98(2H,d),7.04(2H,d),7.44(2H,d),7.85(1H,s),7.90(2H,d),12.15(1H,s),12.94(1H,s)。
实施例5：(E)-2-(4-氨基磺酰基苯基)-3-(4-羟基苯基)丙烯酸
在三口瓶中，加入实施例11的化合物0.2g和蒸馏水5ml，滴加5％的NaOH溶液0.5ml，在80℃的水浴中搅拌反应2小时，然后用5％的HCl溶液调节至酸性，析出沉淀，过滤，得到淡黄色固体，m.p.220-222℃。
1H-NMRδ(ppm):6.57(2H,d),6.88(2H,d),7.35(2H,d),7.40(2H,s),7.72(1H,s),7.81(2H,d),9.94(1H,s),12.64(1H,s)。
实施例6：(E)-2-(4-氨基磺酰基苯基)-3-(3-甲氧基-4-羟基苯基)丙烯酸
在三口瓶中，加入实施例3的化合物0.2g和蒸馏水5ml，再滴加浓硫酸6滴，在80℃的水浴中搅拌反应2小时，室温冷却，过滤，得到类白色固体，m.p.207-209℃。
1H-NMRδ(ppm):3.28(3H,s),6.34(1H,s),6.65(2H,d),6.82(2H,d),7.38(2H,d),7.41(2H,s),7.71(1H,s),7.84(2H,d),9.57(1H,s),12.18(1H,s)。
实施例7：(E)-2-(4-(N-乙酰基氨基磺酰基)苯基)-3-(3-甲氧基-4-乙酰氧基苯基)丙烯酸钠
将(E)-2-(4-(N-乙酰基氨基磺酰基)苯基)-3-(3-甲氧基-4-乙酰氧基苯基)丙烯酸0.1g加入3ml的水，在室温下，滴加5％的NaOH溶液，调节pH为10左右，50℃下加热搅拌10分钟，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。类似地，其钾盐，钙盐，铵盐的合成方法同上。
Claims (5)
1.一种对羟基苯丙烯酸衍生物或其可药用盐，其特征在于：所述对羟基苯丙烯酸衍生物是如下化合物：
(E)-2-(4-氨基磺酰基苯基)-3-(3,4-二乙酰氧基苯基)丙烯酸，(E)-2-(4-(N-乙酰基氨基磺酰基)苯基)-3-(3,4-二乙酰氧基苯基)丙烯酸。
2.如权利要求1所述的对羟基苯丙烯酸衍生物或其可药用盐，其特征在于：所述对羟基苯丙烯酸衍生物是如下化学结构式的化合物：
3.一种权利要求1所述的对羟基苯丙烯酸衍生物或其可药用盐在制备治疗和预防炎症或炎症相关的病症的药物中的应用。
4.一种药物组合物，其包括治疗有效量的权利要求1所述的对羟基苯丙烯酸衍生物或其可药用盐，以及药学上可接受的辅料。
5.如根据权利要求4所述的药物组合物在制备用于治疗和预防哺乳动物的普通感冒、发热、头痛、牙痛、颈痛、扭伤和拉伤、痛经、月经痛性痉挛、类风湿性关节炎、骨性关节炎、脊椎关节病、痛风关节炎、全身性红斑狼疮疾病方面的药物中的应用。
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