CN103044477A - 三甲基硅取代苯并吡喃类化合物及其应用 - Google Patents
三甲基硅取代苯并吡喃类化合物及其应用 Download PDFInfo
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- CN103044477A CN103044477A CN2012105283493A CN201210528349A CN103044477A CN 103044477 A CN103044477 A CN 103044477A CN 2012105283493 A CN2012105283493 A CN 2012105283493A CN 201210528349 A CN201210528349 A CN 201210528349A CN 103044477 A CN103044477 A CN 103044477A
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- trifluoromethyl
- chromene
- carboxylic acid
- silicon based
- trimethyl silicon
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Abstract
本发明公开了一种具有式(I)、(II)和(III)结构特征的三甲基硅取代苯并吡喃类化合物或者其药学上可接受的盐或立体异构体或其前药分子。该类化合物具有优良的抗炎止痛疗效,并可以抑制肿瘤细胞的生长,是一类新型的COX-2选择性抑制剂。本发明所涉及的化合物及其药学上可接受的盐可用于制备抗炎止痛及治疗或预防肿瘤的药物。
Description
技术领域
本发明属于化学医药领域,特别是涉及一种三甲基硅取代苯并吡喃类化合物及其应用。
背景技术
传统非甾体类抗炎药(传统NSAIDs或非选择性NSAIDs)是主要的治疗关节炎的消炎止痛药物,包括布洛芬、双氯芬酸、美洛昔康、萘丁美酮、萘普生等。这类药物就象一把“双刃剑”,一方面有消炎止痛作用;而另一方面,又会引发多种严重消化道不良反应及并发症,如:上腹不适、溃疡、消化道出血、穿孔和肠梗阻等。在美国,1997年死于因传统非甾体类抗炎药引起的胃肠道出血的人数约16500人,与艾滋病致死的人数相当,加重了社会和家庭的医疗负担。所以,寻求一种既可以保持消炎止痛方面的强大疗效,又能够减少严重不良反应发生的抗炎镇痛药物,成为全球医学界的共同关注的问题之一。
非甾体类抗炎止痛药物能够选择性地抑制COX-1和COX-2酶活性,成为研发抗炎止痛药物的主流。多数学者认为NSAIDs药理作用和不良反应取决于其分别对COX-1和COX-2抑制程度:对COX-1的抑制作用越强,导致消化道、肾等不良反应就越大;而对COX-2的抑制作用越强,其抗炎、镇痛效果就越显著。昔布类NSAIDs(选择性COX-2抑制剂)即在此理论背景下应运而生,代表药物为塞莱昔布(celecoxib)、罗非昔布(rofecoxib)、伐地昔布(valdecoxib),其主要优势为胃肠道不良反应少。一般认为选择性环氧合酶2抑制剂,由于不作用于COX-1,不影响对胃肠道及肾脏有保护作用的PGI2的合成,胃肠道副作用及肾毒性均比一般非甾体抗炎药小。选择性COX-2抑制剂例如塞来昔布对慢性炎症的疗效与NSAIDs相当,但它们的急性镇痛效果不及布洛芬,并会产生较大的心血管副作用。随着使用时间的延长,更多不良反应也得到进一步认识,其中包括对选择性COX-2抑制剂对血小板上COX-1及血栓素A2(TXA2)无抑制作用导致的心血管不良事件的认识。
对COX-2抑制剂的临床研究,达成了共识:由于化学结构不同,即便是同一类药,其安全性也是完全不同的;有的COX-2抑制剂对心血管还有潜在保护作用。对于COX-2选择性抑制剂来说,最重要的一点是它比传统非甾体抗炎药物能够带来更多的益处,尤其是减少对胃肠道的副作用。因此,COX-2选择性抑制剂仍然是抗炎止痛药物研发的重要方向。
苯并吡喃类化合物作为一类新型的COX-2选择性抑制剂,本身具有羧酸基团但并不与COX-2活性位点的疏水集合带相互作用。苯并吡喃类的候选药物是从双芳基杂环昔布类化合物分化出来的,具有与双芳基杂环昔布类化合物相同的药效和选择性,在神经病理大鼠疼痛模型上表现出能够降低触觉上的异常疼痛。苯并吡喃类化合物不仅证明对炎症和疼痛治疗优于现有的昔布类化合物,而且此类化合物具有潜在的肾脏保留能力,降低了由于化合物内在的结构上以及药理学和生理学上的性质而引起高血压的可能性。因此开发此类COX-2选择性抑制剂作为抗炎止痛药物,意义重大。
发明内容
基于此,本发明的目的是提供一种COX-2选择性抑制剂。
具体的技术方案如下:
具有式(I)、(II)和(III)结构特征的三甲基硅取代苯并吡喃类化合物或者其药学上可接受的盐或立体异构体或其前药分子:
X任选为O或S或NRa;
Ra任选自:
1)H;
2)C1-C3烷基;
3)C3-C6环烷基;
4)被1或2个卤素取代的C1-C5烷基;
5)芳基;
R任选自:
1)羧基;
2)酰胺基;
3)烷磺酰基;
4)烷氧羰基;
R1任选自:
1)卤代烷基;
2)烷基;
3)芳烷基;
4)环烷基;
R2任选自以下一个或多个基团:
1)氢;
2)卤素;
3)烷基;
4)芳烷基;
5)环己烷;
6)烷氧基;
7)芳氧基;
8)杂芳氧基;
9)芳烷氧基;
10)杂芳烷氧基;
11)卤代烷基;
12)卤代烷氧基;
13)胺基;
14)取代胺基;
15)磺酰胺基;
16)取代磺酰胺基;
17)羰基;
18)取代羰基。
在其中一些实施例中,所述X为O或S;
R选自羧基、C1-C3烷氧羰基;
R1选自卤代烷基,环烷基,苯基;
R2任选自以下一个或多个基团:
1)氢;
2)卤素;
3)烷基;
4)烷氧基;
5)环己烷;
6)卤代烷基;
7)烷胺基;
8)硝基;
9)烷化磺酰胺基;
10)酰基;
11)芳基。
在其中一些实施例中,所述X为O或S;R为羧基;R1为三氟甲基或五氟己基;
所述R2任选自以下一个或多个基团:
1)氢;
2)卤素;
3)甲基、乙基、丙基、异丙基、叔丁基、环己基;
4)三氟甲基,三氟甲氧基;
5)卤代烷基;
6)烷化磺酰胺基;
7)甲磺酰基;
8)芳酰基;
9)芳基。
在其中一些实施例中,所述X为O;R为羧基;R1为三氟甲基;
所述R2任选自以下一个或多个基团:
1)氢;
2)卤素;
3)甲基、乙基、丙基、异丙基、叔丁基、环己基;
4)三氟甲基;
5)甲氧基;
6)卤代烷基;
7)芳基、芳烷基、氟代芳基。
在其中一些实施例中,具有式(II)结构特征的三甲基硅取代苯并吡喃类化合物,所述X为O;R为羧基;R1为三氟甲基;
所述R2处于8位并任选自以下基团:
1)氢;
2)卤素。
在其中一些实施例中,所述的三甲基硅取代苯并吡喃类化合物或者其药学上可接受的盐或立体异构体或其前药分子,选自:
2-三氟甲基-7-三甲基硅基-2H-苯并吡喃-3-羧酸、
2-三氟甲基-5-三甲基硅基-2H-苯并吡喃-3-羧酸、
2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-氟-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-甲基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-甲氧基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-氯-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-溴-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-三氟甲基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-乙基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-丙基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-异丙基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-叔丁基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-环己基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-苯基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-(4-氟苯基)-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-(对甲苯基)-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸。
本发明还提供上述三甲基硅取代苯并吡喃类化合物或者其药学上可接受的盐或立体异构体或其前药分子的应用。
上述三甲基硅取代苯并吡喃类化合物或者其药学上可接受的盐或立体异构体或其前药分子在制备抗炎止痛的药物或制备预防或治疗肿瘤的药物中的应用。
在其中一些实施例中,所述炎症主要包括类风湿性关节炎、痛风性关节炎、骨关节炎、脊柱炎,也包括全身性红斑狼疮、牛皮癣、湿疹、皮下炎和产后炎症、肠病、克罗恩病、胃炎、肠易激综合征、溃疡性结肠炎、偏头痛与头痛、动脉外膜炎、甲状腺炎、再生障碍性贫血、霍奇金病、风湿热、I型糖尿病、神经肌肉官能症、视网膜炎、结膜炎、视网膜病、眼色素层炎、昼盲症、眼部组织的急性损伤、病毒感染和囊性纤维化肺炎、中风、缺血、精神创伤、变应性鼻炎、呼吸窘迫综合征、内毒素休克综合征、肝病、产后痛疼、牙痛、肌肉痛、癌症引起的疼痛、老年痴呆症、多元性痴呆症、非老年痴呆症、酒精痴呆症、衰老痴呆症血管疾病、冠心病、动脉瘤、动脉硬化、动脉粥样硬化、心肌梗死、栓塞、中风、血栓症、心绞痛、冠状动脉斑块炎症、细菌引起的炎症、病毒引起的炎症、手术引起的炎症、眼部血管增生症、视网膜血管增生症、胃溃疡中的一种。
在其中一些实施例中,所述肿瘤为血管瘤、子宫内膜异位症、胃肠间质瘤、组织细胞性淋巴癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、前列腺癌、鼻咽癌、白血病中一种。
本发明还提供一种治疗抗炎止痛或治疗肿瘤的药物组合物。
一种药物组合物,其由上述三甲基硅取代苯并吡喃类化合物或者其药学上可接受的盐或立体异构体或其前药分子与药学可接受的载体组成。
本发明所述化合物中,当任何变量(例如R1、R等)在任何组分中出现超过一次,则其每次出现的定义独立于其它每次出现的定义。同样,允许取代基及变量的组合,只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环,其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易的合成的化合物。如果取代基自身被超过一个基团取代,应理解这些基团可在相同碳原子上或不同碳原子上,只要使结构稳定。
本文所用术语“氢”意指单一氢原子,氢自由基附着在碳原子或氧原子上形成化合物。本发明所用术语“烷基”和“亚烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如,“C1-C5烷”中“C1-C5”的定义包括以直链或支链排列的具有1、2、3、4或5个碳原子的基团。例如,“C1-C5烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基等。术语“环烷基”指具有特定碳原子数目的单环饱和脂肪烃基。例如“环烷基”包括环丙基、甲基-环丙基、2,2-二甲基-环丁基、2-乙基-环戊基、环己基等。
“烷氧基”代表通过氧桥连接的指明数目的碳原子的环状的或非环状的烷基。因此“烷氧基”包括上述烷基和环烷基的定义.
本发明所用“芳基”是指环中多达7个原子的任何稳定的单环或每个环中多达7个原子双环碳环,其中至少一个环为芳香环。这种芳基的实例包括苯基、萘基、四氢萘基、茚满基及联苯基。在芳基取代基是双环的且一个环为非芳香性的例子中,应理解经芳香环而连接。
本发明所用术语“杂芳基”代表环中多达7个原子的稳定的单环或每个环中多达7个原子双环碳环,其中至少一个环为芳香环且含有1-4个选自O、N和S的杂原子。本定义范围内的杂芳基包括但不限于:丫啶基、咔唑基、噌啉基、喹噁啉基、吡唑基(pyrrazolyl)、吲哚基、苯并三唑基、吠喃基、噻吩基、苯并噻吩基、苯并吠喃基、喹啉基、异喹啉基、噁唑基、异噁唑基、吲哚基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、四氢喹啉。对于下列杂芳基的定义,“杂芳基”也理解为包括任何含有氮的杂芳基的N-氧化物衍生物。在杂芳基取代基是双环的且含有一个环为非芳香性或不含有杂原子的例子中,应理解各自经芳香环或经含杂原子环连接。
本文中所用术语“磺酰胺基”是指“-SO2NH2-”。正如本领域技术人员所理解的,本文中所用“卤素”(“halo”)或“卤素”意指包括氯、氟、溴和碘。
除非另有定义,烷基、环烷基、芳基、杂芳基和杂环基取代基可为未被取代的或取代的。例如,(C1-C6)烷基可被一个、两个或三个选自OH、卤素、烷氧基、二烷基氨基或杂环基例如吗啉基、哌啶基等的取代基取代。
本发明包括式I、II和III化合物的游离形式,也包括其药学上可接受的盐及立体异构体。本文中一些特定的示例性化合物为胺类化合物的质子化了的盐。术语“游离形式”指以非盐形式的胺类化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐,也包括所有式I、II和III化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如,可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别,但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常,通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的,通过和适当的无机或有机碱反应形成酸性化合物的盐。
因此,本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如,常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐,也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2一乙酰氧基一苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明化合物为酸性的,则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐。得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐,所述碱包括伯胺、仲胺和叔胺的盐,取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N ′-二苄基乙二胺、二乙胺、2一二乙基氨基乙醇、2一二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N一乙基吗啉、N一乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪、哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
由于在生理条件下化合物中脱质子化的酸性部分例如竣基可为阴离子的,而这种带有的电荷然后可被内部带有阳离子的质子化了的或烷基化的碱性部分例如四价氮原子平衡抵消,所以应注意本发明化合物是潜在的内盐或两性离子。
本发明涉及具有式I、II和III结构特征的苯并吡喃类化合物。该类化合物具有优良的抗炎止痛疗效,并可以抑制肿瘤细胞的生长,是一类新型的COX-2选择性抑制剂。本申请所涉及的化合物及其药学上可接受的盐可用于制备抗炎止痛及治疗或预防肿瘤的药物。
具体实施方式
除在文献中已知的或在实验程序中例证的标准方法外,可采用如下列方案中显示的反应制备本发明化合物。因此,下列说明性方案是为说明的目的而不是局限于所列化合物或任何特定的取代基。方案中显示的取代基数目并不必需符合权利要求中所用的数目,且为清楚起见,显示单取代基连接到在上文中式I、II和III的定义下允许有多取代基的化合物上。
方案
如方案A中所示式(III)中化合物可以由溴代苯酚为起始原料通过4步反应合成。
方案A
本申请所设计的化合物及其药学可接受的盐可以与目前应用的或正处开发阶段的其它传统的抗炎药物,如类固醇类、非类固醇类、iNOS抑制剂、LTB4受体激动剂、LTA4水解酶抑制剂等药物联合用药增加其抗炎止痛临床效果,也可以与目前应用的或正处开发阶段的抗生素、烷基化药物、抗代谢物药物、激素药物、免疫药物、干扰素药物和其它一些混合药物联合用药增加其治疗或抑制肿瘤的临床效果。
服用方式与剂量范围
根据标准药学技术,本发明化合物可单独或在药用组合物中与药学上可接受的受体、辅料或稀释剂组合给予哺乳动物,优选人。可口服或皮下、肌注、腹膜内、静脉、直肠及局部、眼睛、肺部、鼻腔、胃肠外给予化合物。
利用式I、II和III化合物用于抗炎止痛或治疗癌症患者时,服用剂量范围为在口服0.1~500毫克/天/公斤体重。适当的给药方式为每日单剂量给药或每日二次、三次、四次等多次给药或利用缓释技术给药。对于多种大型哺乳动物,其优选的剂量范围为0.1~1500毫克/天/公斤体重,优选于0.5-100毫克/天/公斤体重。对于平均体重为70公斤的病人,其每日剂量为1-500毫克。对于一些特别高活性化合物,成年病人每日剂量可低达0.1毫克/天。
剂型:
这种含有活性成分的药用组合物可制成适于口服给药形式,例如片剂、含片、锭剂、水或油混悬液、可分散粉剂或颗粒剂、乳剂、硬胶囊剂或软胶囊剂、或糖浆剂或酏剂。可根据药用组合物制造领域中任何已知方法制备预期口服给予的组合物,并且为提供药学上精制的及适口的制剂,这种组合物可含有一种或多种选自甜味剂、调味剂、着色剂和防腐剂的药剂。片剂含有活性成分与无毒的适用于制造片剂的药学上可接受的辅料。这些辅料可为例如,惰性稀释剂例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;制粒剂(granulating)和崩解剂例如微晶纤维素、交联羧甲纤维素钠(sodium crosscarmellose)、玉米淀粉或海藻酸;粘合剂例如淀粉、明胶、聚乙烯吡咯烷酮或阿拉伯胶;及润滑剂例如硬脂酸镁、硬脂酸或滑石粉。片剂可不包衣或通过已知技术包衣从而掩盖药物的不良味道或延长在胃肠道中崩解和吸收且因而提供持续更长时间的药物效应。例如,可采用水溶性掩盖味道的原料例如羟丙基-甲基纤维素或羟丙纤维素,或采用延时原料例如乙基纤维素、醋酸丁酸纤维素。片剂剂型可为0.1毫克/片、0.2毫克/片、0.25毫克/片、0.5毫克/片,1毫克/片,2毫克/片,5毫克/片,10毫克/片,25毫克/片,50毫克/片,100毫克/片,and 250毫克/片。其它剂型如胶囊等可作相似剂量参考。
口服使用的制剂也可制成硬明胶胶囊剂,其中活性成分混合于惰性固体稀释剂,例如碳酸钙、磷酸钙或白陶土中;或制成软明胶胶囊剂,其中活性成分混合于水溶性载体例如聚乙烯二醇或油性介质如花生油、液体石蜡或橄榄油中。
水混悬液含有与适于制造水混悬液的辅料混合的活性材料。这种辅料为助悬剂例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、西黄蓍胶及阿拉伯胶;分散剂或湿润剂可为天然存在的磷脂例如卵磷脂,或烯化氧与脂肪酸的缩合产物例如聚氧乙烯硬脂酸酯,或烯化氧与长链脂肪醇的缩合产物例如十七碳乙烯氧基十六醇(heptadecaethyleneoxycetanol),或烯化氧与得自脂肪酸和己糖醇的偏酯的缩合产物例如聚氧乙烯山梨醇一油酸,或烯化氧与得自脂肪酸和己糖醇酐的偏酯的缩合产物例如聚乙烯脱水山梨糖醇单油酸酯。此水混悬液也可含有一种或多种防腐剂例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙基酯,一种或多种着色剂,一种或多种调味剂,和一种或多种甜味剂例如蔗糖、糖精或阿司帕坦。
可通过将活性成分混悬于植物油例如花生油、橄榄油、麻油或椰子油中,或矿物油例如液体石蜡中制备油性混悬液。这种油性混悬液可含有增稠剂例如蜂蜡、固体石蜡或鲸蜡醇。可加入上文所述的甜味剂和调味剂以提供适合口服的制剂。可通过加入抗氧化剂例如丁羟茴醚(butylated hydroxyanisol)或α生育酚储存这些组合物。
可分散粉剂或颗粒剂适于通过加入水制备水混悬液而提供与分散剂或湿润剂、助悬剂和一种或多种防腐剂混合的活性成分。适当的分散剂或湿润剂及助悬剂已通过上文涉及的例子说明。也可存在其他辅料例如甜味剂、调味剂和着色剂。这些组合物可通过加入抗氧化剂例如抗坏血酸而储存。
本发明组合物也可制成水包油乳状液的形式。油相可为植物油例如橄榄油或花生油,或矿物油例如液体石蜡或其混合物。适当的乳化剂可为天然存在的磷脂例如大豆卵磷脂,及酯类或得自脂肪酸和己糖醇酐混合物的偏酯,例如去水山梨糖醇单油酸酯,及所述偏酯和烯化氧的缩合产物例如聚氧乙烯去水山梨糖醇单油酸酯。此乳剂也可含有甜味剂、调味剂、防腐剂和抗氧化剂。
可使用甜味剂例如甘油、丙二醇、山梨醇或蔗糖制备糖浆剂和酏剂。这种制剂也可含有湿润剂、防腐剂、调味剂和着色剂及抗氧化剂。
药用组合物可制成无菌可注射的水溶液。在可接受的载体和溶剂中可采用水、林格氏液和等渗氯化钠溶液。
这种无菌可注射制剂也可制成活性成分溶于油相中的无菌可注射水包油微乳剂。例如,首先将活性成分溶于豆油和卵磷脂的混合物中,然后将油溶液放入水和甘油的混合物中并处理而制成微乳剂。
这种可注射的溶液或微乳剂可通过局部单次快速静脉注射(local bolus injection)导入患者血流中。可选择的,以这种方法给予溶液或微乳有利于维持化合物的恒定循环浓度。为维持这种恒定浓度,可利用连续静脉注射递送装置。这种装置的一个实施例为DeltecCADD-PLUSTM model 5400静脉注射泵。
这种药用组合物可制成用于肌内或皮下给药的无菌可注射溶液或油状混悬液形式。可根据已知技术使用上文中提到的分散剂或湿润剂及助悬剂制备这种混悬液。无菌可注射制剂也可制成在无毒胃肠外可接受的稀释剂或溶剂中的无菌可注射溶液或混悬液,例如作为在1,3-丁二醇中的溶液。另外,常规采用非挥发油作为溶剂或混悬介质。为此目的,可采用任何无刺激性的非挥发油包括合成的甘油一酯或甘油二酯。另外,发现在可注射制剂中使用脂肪酸例如油酸。
式I、II和III化合物也可以直肠给药的栓剂形式给药。可通过混合药物与适当的无刺激性辅料而制备这些组合物,其在常温下为固体但在直肠温度下为液体并因此在直肠中熔化从而释放药物。这种原料包括可可脂、甘油明胶、氢化的植物油、各种分子量聚乙二醇的混合物和聚乙二醇脂肪酸酯。
为局部使用,采用含有式I、II和III化合物的乳膏、软膏剂、凝胶剂、溶液剂或混悬液等(为这种应用目的,局部应用包括口腔洗剂和漱口剂)。
本发明化合物可经适当的鼻内载体和递送装置的局部使用以鼻内形式给药,或经皮肤使用本领域普通技术人员熟知的皮肤贴剂的形式给药。以经皮肤递送系统形式给药后,整个给药方案的给药剂量理所当然比间歇给药连续。本发明化合物也可以栓剂递送,采用的基质例如可可脂、甘油明胶、氢化的植物油、各种分子量聚乙二醇的混合物和聚乙二醇脂肪酸酯。
如果给予受试人本发明化合物,正常由开处方医师通常根据每个患者的年龄、体重、性别和反应,及患者症状严重性相应改变剂量而确定日剂量。
药物代谢物及前药:
本申请所涉及的化合物及其药学可接受的盐的代谢产物,以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药,也包含在本申请的权利要求中。
联合用药:
式I、II和III化合物可以与已知的治疗或改进相似病状的其它药物联用。联合给药时,原来药物的给药方式&剂量保持不变,而同时或随后服用式I、II和III化合物。当式I、II和III化合物与其它一种或几种药物同时服用时,优选使用同时含有一种或几种已知药物和式I、II和III化合物的药用组合物。药物联用也包括在重叠的时间段服用式I、II和III化合物与其它一种或几种已知药物。当式I、II和III化合物与其它一种或几种药物进行药物联用时,式I、II和III化合物或已知药物的剂量可能比它们单独用药时的剂量较低。
可以与式I、II和III化合物进行药物联用的药物或活性成分包括但不局限为:
1)传统的类固醇类抗炎止痛药物,如地塞米松、己烯雌酚;
2)非类固醇类抗炎止痛药物,如双氯灭痛、氯灭酸、安乃近、氨基比弗、阿司匹林、保泰松、吡罗昔康、消炎痛、萘普生、布洛芬、吡罗昔康、塞米昔布、萘丁美酮、酮基布洛芬、酮咯酸、四氯芬那酸、舒林酸、水杨酸镁、水杨酸钠、水杨酸胆碱镁、二氟尼柳、双水杨酸酯;
3)LTB4受体拮抗剂,如CGS-25019C,ETH-615,T-0757,LY-213024,LY-210073,LY223982,LY233469,ONO-LB457,ONO-4057,ONO-LB-448,SC-53228,SC-41930,SC-50605,SC-51146,SB-209247;
4)5-LO抑制剂,如A-76745,78773,ABT761,CMI-392,E-3040,ML-3000,PF-5901,EF-40,F-1322,ML-3000,R-840;
5)iNOS抑制剂;
6)LTA4水解酶抑制剂,如RP-64966;
7)Mu受体拮抗剂;
8)Kappa受体拮抗剂;
9)neurokinins受体拮抗剂;
10)抗生素类抗癌药物,如Taiho 4181-A,Takeda TAN-868A,Fujisawa FK-973,Bristol-Myers BL-6859,KM-5539,KT-5432;
11)烷基化抗癌药物,如Shionogi 254-S,Sanofi CY-233,Degussa D-19-384,NCINSC-164395,NCI NSC-342215,Proter PTT-119;
12)抗代谢物药物,如Lilly DATHF,Lilly LY-188011,Lilly LY-264618,NCINSC-127716,NCI NSC-164880,NCI NSC-39661,NCI NSC-612567;
13)激素类抗癌药物;
14)免疫类抗癌药物;
15)干扰素类抗癌药物;
16)辐射防护相关药物,如AD-5,1-201,MM-159,WR-151327,FUT-187;
17)其它一些混合抗癌药物,如Biotec AD-5,Kyorin AHC-52,Ajinomoto CDAF,Chemex CHX-100,Merz D-609;
药物联用即包括式I、II和III化合物与以上药物中的一个药物联用,也包括与其中两个以上药物进行联用。
以下通过实施例对本发明做进一步的阐述。
实施例1
2-三氟甲基-7-三甲基硅基-2H-苯并吡喃-3-羧酸
2-(trifluoromethyl)-7-(trimethylsilyl)-2H-chromene-3-carboxylic acid
合成路线设计:
步骤1.4-溴-2-羟基苯甲醛
4-bromo-2-hydroxybenzaldehyde
将3-溴苯酚(3.87g,22.4mmol)溶解于30mL三氟乙酸中搅拌,加热至70°C时开始慢慢加入乌洛托品(3.77g,26.9mmol),反应2h后加入大量的水至有固体析出,继续搅拌20min后静置1h,过滤,将所得固体经柱层析得产物0.9g(20%)。
MS(MM-ES+APCI),m/z:200(M-1)
步骤2.7-溴-2-三氟甲基-2H-苯并吡喃-3-羧酸乙酯
ethyl 7-bromo-2-(trifluoromethyl)-2H-chromene-3-carboxylate
将上述产物(0.9g,4.5mmol),碳酸铯(1.47g,4.5mmol)溶解于10mL干燥的N.N-二甲基甲酰胺(DMF)中,加热至60°C时,加入4,4,4-三氟巴豆酸乙酯(1.51g,9.0mmol)后升温至120°C搅拌反应3-4h,用质谱(MS)检测到没有反应物时停止反应,加入水,用乙酸乙酯萃取,萃取所得有机相用饱和食盐水水洗,干燥,减压旋蒸,柱层析得产物1.03g(65%)。
MS(MM-ES+APCI),m/z:350(M-1)
步骤3.2-三氟甲基-7-三甲基硅基-2H-苯并吡喃-3-羧酸乙酯
ethyl 2-(trifluoromethyl)-7-(trimethylsilyl)-2H-chromene-3-carboxylate
将上述产物(1.03g,2.9mmol),dba3Pd2(57.6mg,0.09mmol),2-(二叔丁基膦)联苯(56.1mg,0.27mmol),氟化钾(0.85g,14.7mmol)置于三颈瓶中,抽真空,充氩气,重复4-5次后用注射器加入1,3-二甲基-3,4,5,6-四氢-2-嘧啶酮(DMPU)15mL,室温下搅拌5min后,用注射器注射水(104.4mg,5.8mmol),双三甲基硅(0.51g,3.5mmol),将该反应置于100°C下反应过夜,用质谱(MS)检测到没有反应物时停止反应,加入水,用乙酸乙酯萃取,萃取所得有机相用饱和食盐水水洗,干燥,减压旋蒸,柱层析得产物0.59g(59%)。
MS(MM-ES+APCI),m/z:343(M-1)
步骤4.2-三氟甲基-7-三甲基硅基-2H-苯并吡喃-3-羧酸
2-(trifluoromethyl)-7-(trimethylsilyl)-2H-chromene-3-carboxylic acid
将上述产物(0.59g,1.71mmol),氢氧化锂(0.72g,17.1mmol)溶于10mL甲醇中,加入1mL水,室温搅拌过夜,减压旋蒸至固体时加水溶解完全,慢慢滴加0.1mol/L的稀盐酸至酸性,可得大量白色固体析出,过滤,水洗后取白色固体减压旋蒸除水后即得所需最终产物530mg(98%)。
1H NMR(d6-DMSO,400MHz)δ0.23(s,9H),5.89(q,J=7.2Hz,1H),7.10(s,1H),7.18(d,J=7.2Hz,1H),7.44(t,J=7.2Hz,1H),7.84(s,1H).
MS(MM-ES+APCI),m/z:315(M-1)
实施例2
2-三氟甲基-5-三甲基硅基-2H-苯并吡喃-3-羧酸
2-(trifluoromethyl)-5-(trimethylsilyl)-2H-chromene-3-carboxylic acid
合成路线设计:
步骤1.5-溴-2-三氟甲基-2H-苯并吡喃-3-羧酸乙酯
ethyl 5-bromo-2-(trifluoromethyl)-2H-chromene-3-carboxylate
将2-溴-6-羟基苯甲醛(1.00g,5.0mmol),碳酸铯(1.63g,5.0mmol)溶解于10mL干燥的N.N-二甲基甲酰胺(DMF)中,加热至60°C时,加入4,4,4-三氟巴豆酸乙酯(1.68g,10.0mmol)后升温至120°C搅拌反应3-4h,用质谱(MS)检测到没有反应物时停止反应,加入水,用乙酸乙酯萃取,萃取所得有机相用饱和食盐水水洗,干燥,减压旋蒸,柱层析得产物1.20g(68%)。
MS(MM-ES+APCI),m/z:350(M-1)
步骤2.2-三氟甲基-5-三甲基硅基-2H-苯并吡喃-3-羧酸乙酯
ethyl 2-(trifluoromethyl)-5-(trimethylsilyl)-2H-chromene-3-carboxylate
将上述产物(1.20g,3.4mmol),dba3Pd2(78.5mg,0.10mmol),2-(二叔丁基膦)联苯(76.9mg,0.31mmol),氟化钾(0.99g,17.0mmol)置于三颈瓶中,抽真空,充氩气,重复4-5次后用注射器加入1,3-二甲基-3,4,5,6-四氢-2-嘧啶酮(DMPU)15mL,室温下搅拌5min后,用注射器注射水(122.4mg,6.8mmol),双三甲基硅(0.60g,4.1mmol),将该反应置于100°C下反应过夜,用质谱(MS)检测到没有反应物时停止反应,加入水,用乙酸乙酯萃取,萃取所得有机相用饱和食盐水水洗,干燥,减压旋蒸,柱层析得产物0.6g(51%)。
MS(MM-ES+APCI),m/z:344(M-1)
步骤3.2-三氟甲基-5-三甲基硅基-2H-苯并吡喃-3-羧酸
2-(trifluoromethyl)-5-(trimethylsilyl)-2H-chromene-3-carboxylic acid
将上述产物(0.60g,1.74mmol),氢氧化锂(0.73g,17.4mmol)溶于10mL甲醇中,加入1mL水,室温搅拌过夜,减压旋蒸至固体时加水溶解完全,慢慢滴加0.1mol/L的稀盐酸至酸性,可得大量白色固体析出,过滤,水洗后取白色固体减压旋蒸除水后即得所需最终产物533mg(97%)。
1H NMR(d6-DMSO,400MHz)δ0.33(s,9H),5.89(q,J=7.2Hz,1H),7.06(d,J=8.0Hz,1H),7.19(d,J=7.2Hz,1H),7.37(t,J=7.6Hz,1H),7.91(s,1H),13.37(brs,1H).
MS(MM-ES+APCI),m/z:315(M-1)
合成路线设计:
R′=H,CH3,OCH3,F,Cl,Br,CF3
实施例3
2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸
2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylic acid
步骤1.5-溴-2-羟基苯甲醛
5-bromo-2-hydroxybenzaldehyde
将4-溴苯酚(3.81g,22.0mmol)溶解于50mL三氟乙酸中搅拌,加热至70°C时开始慢慢加入乌洛托品(3.70g,26.4mmol),反应2h后加入大量的水至有固体析出,继续搅拌20min后静置1h,过滤,将所得固体经柱层析得产物1.59g(36%)。
1H NMR(CDCl3,400MHz)δ6.91(d,J=8.8Hz,1H),7.60(dd,J1=2.4Hz,J2=8.8Hz,1H),7.67(d,J=2.4Hz,1H),9.84(s 1H),10.92(s,1H).
MS(MM-ES+APCI),m/z:200(M-1)。
步骤2.6-溴-2-三氟甲基-2H-苯并吡喃-3-羧酸乙酯
ethyl 6-bromo-2-(trifluoromethyl)-2H-chromene-3-carboxylate
将上述产物(1.59g,7.9mmol),碳酸铯(2.61g,7.9mmol)溶解于15mL干燥的N.N-二甲基甲酰胺(DMF)中,加热至60°C时,加入4,4,4-三氟巴豆酸乙酯(2.66g,15.8mmol)后升温至120°C搅拌反应3-4h,用质谱(MS)检测到没有反应物时停止反应,加入水,用乙酸乙酯萃取,萃取所得有机相用饱和食盐水水洗,干燥,减压旋蒸,柱层析得产物1.57g(57%)。
1H NMR(CDCl3,400MHz)δ1.35(t,J=7.2Hz,3H),4.26-4.39(m,2H),5.70(q,J=6.8Hz,1H),6.87(d,J=8.4Hz,1H),7.35(d,J=1.6Hz,1H),7.40(dd,J1=1.6Hz,J2=8.4Hz,1H),7.64(s1H).
MS(MM-ES+APCI),m/z:350(M-1)
步骤3.2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸乙酯
ethyl 2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylate
将上述产物(0.99g,2.8mmol),dba3Pd2(76.7mg,0.09mmol),2-(二叔丁基膦)联苯(75.3mg,0.26mmol),氟化钾(0.82g,14.0mmol)置于三颈瓶中,抽真空,充氩气,重复4-5次后用注射器加入1,3-二甲基-3,4,5,6-四氢-2-嘧啶酮(DMPU)15mL,室温下搅拌5min后,用注射器注射水(100.8mg,5.6mmol),双三甲基硅(0.41g,3.4mmol),将该反应置于100°C下反应5h,用质谱(MS)检测到没有反应物时停止反应,加入水,用乙酸乙酯萃取,萃取所得有机相用饱和食盐水水洗,干燥,减压旋蒸,柱层析得产物0.75g(78%)。
MS(MM-ES+APCI),m/z:344(M-1)。
1H NMR(CDCl3,400MHz)δ0.26(s,9H),1.35(t,J=7.2Hz,3H),4.27-4.37(m,2H),5.73(q,J=6.8Hz,1H),6.96(d,J=8.0Hz,1H),7.36(d,J=1.6Hz,1H),7.46(dd,J1=1.6Hz,J2=8.0Hz,1H),7.77(s 1H).
步骤4.2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸
2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylic acid
将上述产物(0.75g,2.4mmol),氢氧化锂(1.01g,24.0mmol)溶于20mL甲醇中,加入2mL水,室温搅拌过夜,减压旋蒸至固体时加水溶解完全,慢慢滴加0.1mol/L的稀盐酸至酸性,可得大量白色固体析出,过滤,水洗后取白色固体减压旋蒸除水后即得所需最终产物743mg(98%)。
1H NMR(d6-DMSO,400MHz)δ0.23(s,9H),5.89(q,J=7.2Hz,1H),7.02(d,J=8.0Hz,1H),7.50(dd,J1=1.2Hz,J2=8.0Hz,1H),7.62(d,J=1.6Hz,1H),7.85(s,1H).
MS(MM-ES+APCI),m/z:315(M-1)。
实施例4
8-氟-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸
8-fluoro-2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylic acid
步骤1.5-溴-3-氟-2-羟基苯甲醛
5-bromo-3-fluoro-2-hydroxybenzaldehyde
将4-溴-2-氟苯酚(5.73g,30.0mmol)溶解于50mL三氟乙酸中搅拌,加热至70°C时开始慢慢加入乌洛托品(5.05g,36.0mmol),反应2h后加入大量的水至有固体析出,继续搅拌20min后静置1h,过滤,将所得固体经柱层析得产物3.49g(53%)。
1H NMR(CDCl3,400MHz)δ7.47-7.52(m,2H),9.87(s,1H),10.89(s,1H).
MS(MM-ES+APCI),m/z:218(M-1)
步骤2.6-溴-8-氟-2-三氟甲基-2H-苯并吡喃-3-羧酸乙酯
Ethyl 6-bromo-8-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate
将上述产物(3.49g,16mmol),碳酸铯(5.21g,16mmol)溶解于20mL干燥的N.N-二甲基甲酰胺(DMF)中,加热至60°C时,加入4,4,4-三氟巴豆酸乙酯(5.38g,32mmol)后升温至120°C搅拌反应3-4h,用质谱(MS)检测到没有反应物时停止反应,加入水,用乙酸乙酯萃取,萃取所得有机相用饱和食盐水水洗,干燥,减压旋蒸,柱层析得产物2.45g(42%)。
1H NMR(CDCl3,400MHz)δ1.35(t,J=7.2Hz,3H),2.22(s,3H),4.28-4.37(m,2H),5.74(q,J=6.8Hz,1H),7.19(d,J=2.0Hz,1H),7.29(d,J=2.0Hz,1H),7.62(s,1H).
MS(MM-ES+APCI),m/z:368(M-1)。
步骤3.8-氟-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸乙酯
Ethyl-8-fluoro-2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylate
将上述产物(1.48g,4.0mmol),dba3Pd2(92.7mg,0.12mmol),2-(二叔丁基膦)联苯(90.4mg,0.37mmol),氟化钾(1.17g,20.0mmol)置于三颈瓶中,抽真空,充氩气,重复4-5次后用注射器加入1,3-二甲基-3,4,5,6-四氢-2-嘧啶酮(DMPU)15mL,室温下搅拌5min后,用注射器注射水(144mg,8.0mmol),双三甲基硅(0.59g,4.8mmol),将该反应置于100°C下反应5h,用质谱(MS)检测到没有反应物时停止反应,加入水,用乙酸乙酯萃取,萃取所得有机相用饱和食盐水水洗,干燥,减压旋蒸,柱层析得产物0.93g(64%)。
1H NMR(CDCl3,400MHz)δ0.26(s,9H),1.36(t,J=7.2Hz,3H),4.27-4.39(m,2H),5.78(q,J=6.8Hz,1H),7.12(s,1H),7.22-7.25(m,1H),7.76(s,1H).
MS(MM-ES+APCI),m/z:362(M-1).
步骤4.8-氟-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸
8-fluoro-2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylic acid
将上述产物(0.81g,2.3mmol),氢氧化锂(0.97g,23.0mmol)溶于20mL甲醇中,加入2mL水,室温搅拌过夜,减压旋蒸至固体时加水溶解完全,慢慢滴加0.1mol/L的稀盐酸至酸性,可得大量白色固体析出,过滤,水洗后取白色固体减压旋蒸除水后即得所需最终产物723mg(94%)。
1H NMR(d6-DMSO,400MHz)δ0.24(s,9H),6.06(q,J=7.2Hz,1H),7.43-7.48(m,2H),7.94(s,1H),13.41(brs,1H).
MS(MM-ES+APCI),m/z:329(M-1).
实施例5
8-甲基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸
8-methyl-2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylic acid
合成方法同实施例4
1H NMR(d6-DMSO,400MHz)δ0.23(s,9H),2.19(s,3H),5.94(q,J=7.2Hz,1H),7.38(s,1H),7.45(s,1H),7.85(s,1H).
MS(MM-ES+APCI),m/z:329(M-1).
实施例6
8-甲氧基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸
8-methoxy-2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylic acid
合成方法同实施例4
1H NMR(d6-DMSO,400MHz)δ0.25(s,9H),3.84(s,3H),5.93(q,J=7.2Hz,1H),7.17(s,1H),7.21(s,1H),7.85(s,1H),13.24(brs,1H).
MS(MM-ES+APCI),m/z:345(M-1).
实施例7
8-氯-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸
8-chloro-2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylic acid
合成方法同实施例4
1H NMR(d6-DMSO,400MHz)δ0.24(s,9H),6.09(q,J=7.2Hz,1H),7.56(s,1H),7.61(s,1H),7.90(s,1H).
MS(MM-ES+APCI),m/z:350(M-1).
实施例8
8-溴-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸
8-bromo-2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylic acid
合成方法同实施例4
1H NMR(d6-DMSO,400MHz)δ0.25(s,9H),6.09(q,J=7.2Hz,1H),7.65-7.69(m,2H),7.90(s,1H),13.38(brs,1H).
MS(MM-ES+APCI),m/z:394(M-1).
实施例9
8-三氟甲基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸
8-(trifluoromethyl)-2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylic acid
合成方法同实施例4
1H NMR(d6-DMSO,400MHz)δ0.27(s,9H),6.12(q,J=7.2Hz,1H),7.71(s,1H),7.97-7.98(m,2H).
MS(MM-ES+APCI),m/z:383(M-1).
合成路线设计:
R″=CH2CH3,CH2CH2CH3,CH(CH3)2,C(CH3)3,cyclohexyl,Ph
实施例10
8-乙基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸
8-ethyl-2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylic acid
步骤1.4-溴-2-乙基苯酚
4-bromo-2-ethylphenol
将2-乙基苯酚(4.0g,32.8mmol)溶解于30mL二氯甲烷冰浴下搅拌,将液溴(Br2)(5.8g,32.8mmol)溶于30mL二氯甲烷置于恒压滴液漏斗中,慢慢滴加至反应瓶中,维持冰浴至滴加完成后半小时,撤去冰浴,室温搅拌过夜。用质谱(MS)检测到没有反应物时停止反应,室温下减压旋蒸,柱层析得产物6.09g(92%)。
1H NMR(CDCl3,400MHz)δ1.21(t,J=7.2,3H),2.60(q,J=7.2Hz,2H),5.39(brs,1H),6.65(d,J=2.0Hz,1H),7.14-7.17(m,1H),7.24(d,J=2.0Hz,1H).
MS(MM-ES+APCI),m/z:200(M-1)
步骤2.5-溴-3乙基-2-羟基苯甲醛
5-bromo-3-ethyl-2-hydroxybenzaldehyde
将4-溴-2-乙基苯酚(6.09g,30.0mmol)溶解于50mL三氟乙酸中搅拌,加热至70°C时开始慢慢加入乌洛托品(5.05g,36.0mmol),反应2h后加入大量的水至有固体析出,继续搅拌20min后静置1h,过滤,将所得固体经柱层析得产物2.38g(35%).
1H NMR(CDCl3,400MHz)δ1.22(t,J=7.2,3H),2.67(q,J=7.2Hz,2H),7.48-7.51(m,2H),9.82(s,1H),11.20(s,1H).
MS(MM-ES+APCI),m/z:228(M-1)
步骤3.6-溴-8-乙基-2-三氟甲基-2H-苯并吡喃-3-羧酸乙酯
ethyl 6-bromo-8-ethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate
将上述产物(2.38g,10.4mmol),碳酸铯(3.39g,10.4mmol)溶解于20mL干燥的N.N-二甲基甲酰胺(DMF)中,加热至60°C时,加入4,4,4-三氟巴豆酸乙酯(3.50g,20.8mmol)后升温至120°C搅拌反应3-4h,用质谱(MS)检测到没有反应物时停止反应,加入水,用乙酸乙酯萃取,萃取所得有机相用饱和食盐水水洗,干燥,减压旋蒸,柱层析得产物3.04g(77%)。
1H NMR(CDCl3,400MHz)δ1.19(t,J=7.6,3H),1.35(t,J=7.2Hz,3H),2.54-2.71(m,2H),4.28-4.37(m,2H),5.74(q,J=6.8Hz,1H),7.20(d,J=2.4Hz,1H),7.29(d,J=2.4Hz,1H),7.63(s,1H).
MS(MM-ES+APCI),m/z:378(M-1).
步骤4.8-乙基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸乙酯
Ethyl-8-ethyl-2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylate
将上述产物(1.52g,4.0mmol),dba3Pd2(92.7mg,0.12mmol),2-(二叔丁基膦)联苯(90.4mg,0.37mmol),氟化钾(1.17g,20.0mmol)置于三颈瓶中,抽真空,充氩气,重复4-5次后用注射器加入1,3-二甲基-3,4,5,6-四氢-2-嘧啶酮(DMPU)20mL,室温下搅拌5min后,用注射器注射水(144.0mg,8.0mmol),双三甲基硅(0.59g,4.8mmol),将该反应置于100°C下反应过夜,用质谱(MS)检测到几乎没有反应物时停止反应,加入水,用乙酸乙酯萃取,萃取所得有机相用饱和食盐水水洗,干燥,减压旋蒸,柱层析得产物1.0g(67%)。
MS(MM-ES+APCI),m/z:371(M-1)
步骤5.8-乙基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸
8-ethyl-2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylic acid
将上述产物(0.75g,2.0mmol),氢氧化锂(0.84g,20.0mmol)溶于20mL甲醇中,加入2mL水,室温搅拌过夜,减压旋蒸至固体时加水溶解完全,慢慢滴加0.1mol/L的稀盐酸至酸性,可得大量白色固体析出,过滤,水洗后取白色固体减压旋蒸除水后即得所需最终产物654mg(95%)。
1H NMR(d6-DMSO,400MHz)δ0.23(s,9H),1.14(t,3H),2.54-2.67(m,2H),5.94(q,J=7.2Hz,1H),7.36(s,1H),7.44-7.45(m,1H),7.82(s,1H).
MS(MM-ES+APCI),m/z:343(M-1).
实施例11
8-丙基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸
8-propyl-2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylic acid
合成方法同实施例10
1H NMR(d6-DMSO,400MHz)δ0.23(s,9H),0.89(t,J=7.2Hz,3H),1.51-1.60(m,2H),2.57-2.64(m,2H),5.92(q,J=7.2Hz,1H),7.35(m,1H),7.45(s,1H),7.85(s,1H).
MS(MM-ES+APCI),m/z:357(M-1).
实施例12
8-异丙基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸
8-isopropyl-2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylic acid
合成方法同实施例10
1H NMR(d6-DMSO,400MHz)δ0.22(s,9H),1.19(dd,J1=2.4Hz,J2=6.8Hz,6H),3.17-3.24(m,1H),5.92(q,J=7.2Hz,1H),7.38-7.43(m,2H),7.83(s,1H).
MS(MM-ES+APCI),m/z:357(M-1).
实施例13
8-叔丁基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸
8-tert-butyl-2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylic acid
合成方法同实施例10
1H NMR(d6-DMSO,400MHz)δ0.23(s,9H),1.36(s,9H),6.01(q,J=7.2Hz,1H),7.43(d,J=1.2Hz,1H),7.49(d,J=1.2Hz,1H),7.84(s,1H).
MS(MM-ES+APCI),m/z:371(M-1).
实施例14
8-环己基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸
8-cyclohexyl-2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylic acid
合成方法同实施例10
1H NMR(d6-DMSO,400MHz)δ0.23(s,9H),1.23-1.53(m,5H),1.71-1.81(m,5H),5.93-5.94(m,1H),7.39(s,1H),7.44(s,1H),7.85(s,1H).
MS(MM-ES+APCI),m/z:397(M-1).
实施例15
8-苯基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸
8-phenyl-2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylic acid
合成方法同实施例10
1H NMR(d6-DMSO,400MHz)δ0.27(s,9H),5.91(q,J=7.2Hz,1H),7.34-7.39(m,1H),7.43-7.49(m,5H),7.66(d,J=0.8Hz,1H),7.85(s,1H),7.94(s,1H).
MS(MM-ES+APCI),m/z:391(M-1).
合成路线设计:
R″′=4-fluorophenyl,4-methylphenyl
实施例16
8-(4-氟苯基)-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸
8-(4-fluorophenyl)-2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylic acid
步骤1.4'-氟-2-甲氧基联苯
4'-fluoro-2-methoxybiphenyl
将邻溴苯甲醚(3.7g,20mmol),4-氟苯硼酸(3.1g,22mmol),四三苯基膦钯(2.3g,2mmol),碳酸钾(8.3g,60mmol)置于100mL的反应瓶中,氩气保护下,针头注射50mL乙二醇二甲醚,110°C下反应18h。过滤,将液减压旋蒸,柱层析得产物3.64g(90%)。
1H NMR(CDCl3,400MHz)δ3.83(s,3H),6.70-7.14(m,4H),7.30-7.37(m,2H),7.50-7.52(m,2H).
步骤2.4'-氟联苯-2-酚
4'-fluorobiphenyl-2-ol
将4'-氟-2-甲氧基联苯(3.64g,18mmol)溶解于30mL二氯甲烷冰浴下搅拌,将三溴化硼(BBr3)(9.0g,36mmol)溶于30mL二氯甲烷置于恒压滴液漏斗中,慢慢滴加至反应瓶中,维持冰浴至滴加完成后半小时,撤去冰浴,室温2h。反应结束后在冰浴下慢慢滴加冰水至将剩余的BBr3全部出去,水洗两次,再用饱和食盐水洗一遍。干燥,减压旋蒸,柱层析得产物3.0g(90%)。
MS(MM-ES+APCI),m/z:187(M-1)
步骤3.5-溴-4'-氟联苯-2-酚
5-bromo-4'-fluorobiphenyl-2-ol
将4'-氟联苯-2-酚(3.0g,16mmol)溶解于30mL二氯甲烷冰浴下搅拌,将液溴(Br2)(2.8g,16mmol)溶于30mL二氯甲烷置于恒压滴液漏斗中,慢慢滴加至反应瓶中,维持冰浴至滴加完成后半小时,撤去冰浴,室温搅拌过夜。用质谱(MS)检测到没有反应物时停止反应,室温下减压旋蒸,柱层析得产物3.1g(73%)。
1H NMR(CDCl3,400MHz)δ5.29(brs,1H),3.84-6.86(m,1H),7.15-7.19(m,2H),7.32-7.35(m,2H),7.41-7.47(m,2H).
MS(MM-ES+APCI),m/z:266(M-1)
步骤4.5-溴-4'-氟--2-羟基联苯-3-甲醛
5-bromo-4'-fluoro-2-hydroxybiphenyl-3-carbaldehyde
将5-溴-4'-氟联苯-2-酚(3.1g,11.6mmol)溶解于30mL三氟乙酸中搅拌,加热至70°C时开始慢慢加入乌洛托品(1.95g,14.0mmol),反应2h后加入大量的水至有固体析出,继续搅拌20min后静置1h,过滤,将所得固体经柱层析得产物1.6g(47%).
1H NMR(CDCl3,400MHz)δ7.11-7.17(m,2H),7.52-7.57(m,2H),7.67-7.68(m,2H),9.89(s,1H),11.47(s,1H).
MS(MM-ES+APCI),m/z:294(M-1).
步骤5.6-溴-8-(4-氟苯基)-2-三氟甲基-2H-苯并吡喃-3-羧酸乙酯
Ethyl-6-bromo-8-(4-fluorophenyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate
将上述产物(1.6g,5.4mmol),碳酸铯(1.8g,5.4mmol)溶解于15mL干燥的N.N-二甲基甲酰胺(DMF)中,加热至60°C时,加入4,4,4-三氟巴豆酸乙酯(1.8g,10.8mmol)后升温至120°C搅拌反应4h,用质谱(MS)检测到没有反应物时停止反应,加入水,用乙酸乙酯萃取,萃取所得有机相用饱和食盐水水洗,干燥,减压旋蒸,柱层析得产物1.88g(78%)。
1H NMR(CDCl3,400MHz)δ1.35(t,J=7.2Hz,3H),4.27-4.39(m,2H),5.71(q,J=6.8Hz,1H),7.10-7.14(m,2H),7.35(d,J=2.4Hz,1H),7.43-7.46(m,3H),7.69(s,1H).
MS(MM-ES+APCI),m/z:444(M-1)
步骤6.8-(4-氟苯基)-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸乙酯
Ethyl-8-(4-fluorophenyl)-2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylate
将上述产物(1.4g,3.1mmol),dba3Pd2(73mg,0.10mmol),2-(二叔丁基膦)联苯(71mg,0.29mmol),氟化钾(0.90g,15.5mmol)置于三颈瓶中,抽真空,充氩气,重复4-5次后用注射器加入1,3-二甲基-3,4,5,6-四氢-2-嘧啶酮(DMPU)20mL,室温下搅拌5min后,用注射器注射水(112mg,6.2mmol),双三甲基硅(0.45g,3.7mmol),将该反应置于100°C下反应过夜,用质谱(MS)检测到几乎没有反应物时停止反应,加入水,用乙酸乙酯萃取,萃取所得有机相用饱和食盐水水洗,干燥,减压旋蒸,柱层析得产物1.05g(77%)。
1H NMR(CDCl3,400MHz)δ0.33(s,9H),1.37(t,J=7.2Hz,3H),4.30-4.3(m,2H),5.76(q,J=6.8Hz,1H),7.13-7.17(m,2H),7.40(d,J=1.2Hz,1H),7.48-7.54(m,3H),7.86(s,1H).
MS(MM-ES+APCI),m/z:438(M-1)
步骤7.8-(4-氟苯基)-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸
8-(4-fluorophenyl)-2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylic acid
将上述产物(0.66g,1.5mmol),氢氧化锂(0.63g,15mmol)溶于20mL甲醇中,加入2mL水,室温搅拌过夜,减压旋蒸至固体时加水溶解完全,慢慢滴加0.1mol/L的稀盐酸至酸性,可得大量白色固体析出,过滤,水洗后取白色固体减压旋蒸除水后即得所需最终产物585mg(95%)。
1H NMR(d6-DMSO,400MHz)δ0.26(s,9H),5.92(q,J=7.2Hz,1H),7.26-7.30(m,2H),7.45(d,J=1.6Hz,1H),7.50-7.53(m,2H),7.65(d,J=1.6Hz,1H),7.93(s,1H).
MS(MM-ES+APCI),m/z:409(M-1).
实施例17
8-(对甲苯基)-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸
8-p-tolyl-2-(trifluoromethyl)-6-(trimethylsilyl)-2H-chromene-3-carboxylic acid
合成方法同实施例16
1H NMR(d6-DMSO,400MHz)δ0.26(s,9H),2.35(s,3H),5.87(q,J=7.2Hz,1H),7.24-7.26(m,2H),7.36-7.38(m,3H),7.53(s,1H),7.70(s,1H).
MS(MM-ES+APCI),m/z:405(M-1).
实施例18
用不同浓度的三甲基硅取代苯并吡喃类化合物(1×10-10~1×10-4)分别与ovine COX-1和human recombinant COX-2混匀孵育15min,,然后加入Heme和ADHP,再孵育2分钟,最后加入底物花生四烯酸,立刻用酶标仪检测在530nm的激发光下,反应产物在595nm处的发射光强度。结果发现,三甲基硅取代苯并吡喃类化合物可显著抑制COX-2的酶反应速率,且具有较好的选择性。我们计算出其半数抑制浓度(IC50)值如表1所描述。(所用化合物分别为实施例1~17所制备的化合物,在表1中用Drug No.标号表示,GIBH-1039、GIBH-1040、GIBH-1041、GIBH-1055、GIBH-1056、GIBH-1057、GIBH-1058、GIBH-1059、GIBH-1060、GIBH-1063、GIBH-1064、GIBH-1065、GIBH-1075、GIBH-1077这14个是对应于实施例1-17所制备的化合物中挑选出来,并完成生物活性测试。
表1.部分化合物对COXs两种异构体的抑制IC50
由表中的酶活性实验可知,本发明的一系列含三甲基硅取代的苯并吡喃类化合物对人的重组COX-2酶的活性抑制IC50值达到纳摩尔级,而相应的对COX-1酶的抑制活性就较差,表明其对COX-2具有较好的先择抑制性。根据在实施例1-17所列化合物的生物活性数据表明,对COX-2酶的抑制活性与化合物取代基团的位置和吸电子强度密切相关。对于7位三甲基硅取代的苯并吡喃类化合物,表现出对COX-2较好的抑制活性,但是在合成时选择性较差,极易生成6位三甲基硅取代的苯并吡喃类化合物。对于6位三甲基硅取代的苯并吡喃类化合物,当8位为强吸电子氟时,化合物对COX-2抑制活性都高于其它给电子基团化合物。其中以7位三甲基硅取代的苯并吡喃化合物GIBH-1039选择性活性最强,其COX-2酶IC50值为241.8纳摩尔,而COX-1的IC50值大于100微摩尔,其对COX-2与COX-1的选择性比值大于415倍,化合物GIBH-1057对COX-2与COX-1的选择性比值大于372倍。
实施例19
大鼠药代动力学和生物利用度试验。雄性SD大鼠4只/组,单次给药,口服2.5-25mg/kg,静脉1-5mg/kg,给药后在合适的时间点采集动物血样,肝素抗凝,3000rpm*10min,取上清,-20°C保存备LC/MS分析。血样采用乙腈沉淀蛋白,16000rpm*30min,上清用于LC/MS分析。数据采用DAS2.0进行参数拟合,根据AUC数据计算化合物的口服生物利用度。通过分析三甲基硅取代的苯并吡喃类化合物的体外测试结果,选择性的将化合物GIBH-1039和GIBH-1041进行药代动力学研究,测试结果见下表2。
表2.部分化合物药代动力学研究结果。
AUC(Area Under the Curve):血药浓度-时间曲线下的面积,代表药物的生物利用度(药物在人体中被吸收利用的程度),AUC大则生物利用度高,反之则低。AUC全称为area underconcentration-time curve。例如GIBH-1039的AUC值最高,其生物利用度也最高。
Cmax:药峰浓度(Peak Concentration)系指血药浓度——时间曲线上的最大血药浓度值,即用药后所能达到的最高血浆药物浓度。药峰浓度与药物的临床应用密切相关。药峰浓度达到有效浓度才能显效,而如高出了安全的范围则可显示毒性的反应。此外,药峰浓度还是衡量制剂吸收和安全性的重要指标。化合物GIBH-1039的药峰浓度达到4860ug/L,远远好于化合物GIBH-1041,其药峰浓度仅为1907.5ug/L。
T1/2(half life time):半衰期。是指体内药物浓度下降一半所需要的时间,反映药物通过生物转化或排泄从体内消除的快慢。化合物GIBH-1039的半衰期为4.5小时,比较容易控制给药时间,远远好于化合物GIBH-1041,该化合物的半衰期仅为0.8小时。
Tmax:(Peak Time)药峰时间,系指在给药后人体血浆药物浓度曲线上达到最高浓度(药峰浓度)所需的时间。药峰时间短,表示药物吸收快、起效迅速,但同时消除也快;而药峰时间长,则表明药物吸收和起效较慢,药物作用持续时间也往往延长。药峰时间是应用药物和研究制剂的一个重要指标。化合物GIBH-1039的药峰时间达到0.6小时,而化合物GIBH-1041药峰时间为0.3小时。
BA(bioavailability):生物利用度。是指药物吸收进入大循环的速度和程度。生物利用度分为绝对生物利用度和相对生物利用度。绝对生物利用度是指该药物静脉注射时100%被利用,该药物的其它剂型与其剂量相等时被机体吸收利用的百分率;相对生物利用度则是以某种任意指定的剂型(如口服水制剂)为100%被利用,然后测定该药物其它剂型在相同条件下的百分利用率。化合物GIBH-1039的生物利用度达到76%,远远好于化合物GIBH-1041,其生物利用度仅为49%。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (10)
1.具有式(I)、(II)和(III)结构特征的三甲基硅取代苯并吡喃类化合物或者其药学上可接受的盐或立体异构体或其前药分子:
X任选为O或S或NRa;
Ra任选自:
1)H;
2)C1-C3烷基;
3)C3-C6环烷基;
4)被1或2个卤素取代的C1-C5烷基;
5)芳基;
R任选自:
1)羧基;
2)酰胺基;
3)烷磺酰基;
4)烷氧羰基;
R1任选自:
1)卤代烷基;
2)烷基;
3)芳烷基;
4)环烷基;
R2任选自以下一个或多个基团:
1)氢;
2)卤素;
3)烷基;
4)环己烷
5)芳烷基;
6)烷氧基;
7)芳氧基;
8)杂芳氧基;
9)芳烷氧基;
10)杂芳烷氧基;
11)卤代烷基;
12)卤代烷氧基;
13)胺基;
14)取代胺基;
15)磺酰胺基;
16)取代磺酰胺基;
17)羰基;
18)取代羰基。
2.根据权利要求1所述的三甲基硅取代苯并吡喃类化合物或者其药学上可接受的盐或立体异构体或其前药分子,其特征在于,
所述X为O或S;
R选自羧基、C1-C3烷氧羰基;
R1选自卤代烷基,环烷基,苯基;
R2任选自以下一个或多个基团:
1)氢;
2)卤素;
3)烷基;
4)烷氧基;
5)环己烷;
6)卤代烷基;
7)烷胺基;
8)硝基;
9)烷化磺酰胺基;
10)酰基;
11)芳基。
3.根据权利要求1所述的三甲基硅取代苯并吡喃类化合物或者其药学上可接受的盐或立体异构体或其前药分子,其特征在于,
所述X为O或S;R为羧基;R1为三氟甲基或五氟己基;
所述R2任选自以下一个或多个基团:
1)氢;
2)卤素;
3)甲基,乙基、丙基、异丙基、叔丁基、环己基;
4)三氟甲基,三氟甲氧基;
5)卤代烷基;
6)烷化磺酰胺基;
7)甲磺酰基;
8)芳酰基;
9)芳基。
4.根据权利要求1所述的三甲基硅取代苯并吡喃类化合物或者其药学上可接受的盐或立体异构体或其前药分子,其特征在于,
所述X为O;R为羧基;R1为三氟甲基;
所述R2任选自以下一个或多个基团:
1)氢;
2)卤素;
3)甲基,乙基、丙基、异丙基、叔丁基、环己基;
4)三氟甲基;
5)甲氧基;
6)卤代烷基;
7)芳基、芳烷基、氟代烷基。
5.根据权利要求1所述的具有式(II)结构特征的三甲基硅取代苯并吡喃类化合物或者其药学上可接受的盐或立体异构体或其前药分子,其特征在于,
所述X为O;R为羧基;R1为三氟甲基;
所述R2处于8位并任选自以下基团:
1)氢;
2)卤素。
6.根据权利要求1任一项所述的三甲基硅取代苯并吡喃类化合物或者其药学上可接受的盐或立体异构体或其前药分子,其特征在于,
2-三氟甲基-7-三甲基硅基-2H-苯并吡喃-3-羧酸、
2-三氟甲基-5-三甲基硅基-2H-苯并吡喃-3-羧酸、
2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-氟-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-甲基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-甲氧基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-氯-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-溴-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-三氟甲基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-乙基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-丙基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-异丙基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-叔丁基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-环己基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-苯基-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-(4-氟苯基)-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸、
8-(对甲苯基)-2-三氟甲基-6-三甲基硅基-2H-苯并吡喃-3-羧酸。
7.权利要求1-6任一项所述的三甲基硅取代苯并吡喃类化合物或者其药学上可接受的盐或立体异构体或其前药分子在制备抗炎止痛的药物或制备预防或治疗肿瘤的药物中的应用。
8.根据权利要求7所述的应用,所述炎症主要包括类风湿性关节炎、痛风性关节炎、骨关节炎、脊柱炎,全身性红斑狼疮、牛皮癣、湿疹、皮下炎和产后炎症、肠病、克罗恩病、胃炎、肠易激综合征、溃疡性结肠炎、偏头痛与头痛、动脉外膜炎、甲状腺炎、再生障碍性贫血、霍奇金病、风湿热、I型糖尿病、神经肌肉官能症、视网膜炎、结膜炎、视网膜病、眼色素层炎、昼盲症、眼部组织的急性损伤、病毒感染和囊性纤维化肺炎、中风、缺血、精神创伤、变应性鼻炎、呼吸窘迫综合征、内毒素休克综合征、肝病、产后痛疼、牙痛、肌肉痛、癌症引起的疼痛、老年痴呆症、多元性痴呆症、非老年痴呆症、酒精痴呆症、衰老痴呆症血管疾病、冠心病、动脉瘤、动脉硬化、动脉粥样硬化、心肌梗死、栓塞、中风、血栓症、心绞痛、冠状动脉斑块炎症、细菌引起的炎症、病毒引起的炎症、手术引起的炎症、眼部血管增生症、视网膜血管增生症、胃溃疡中的一种。
9.根据权利要求7所述的应用,其特征在于,所述肿瘤为血管瘤、子宫内膜异位症、胃肠间质瘤、组织细胞性淋巴癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、前列腺癌、鼻咽癌、白血病中一种。
10.一种药物组合物,其由权利要求1-6任一项所述的三甲基硅取代苯并吡喃类化合物或者其药学上可接受的盐或立体异构体或其前药分子与药学可接受的载体组成。
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