CN1420776A - 环氧合酶－2活性的抑制 - Google Patents

环氧合酶－2活性的抑制 Download PDF

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CN1420776A
CN1420776A CN01807481A CN01807481A CN1420776A CN 1420776 A CN1420776 A CN 1420776A CN 01807481 A CN01807481 A CN 01807481A CN 01807481 A CN01807481 A CN 01807481A CN 1420776 A CN1420776 A CN 1420776A
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dioxopiperidine
cox
amide
acid imide
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乔治·马勒
安德鲁·J·丹嫩贝格
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Abstract

本发明提供了抑制环氧合酶－2(或COX－2)酶活性的新方法。已知COX－2的抑制剂可以被用作抗炎症、止痛与抗血管生成的药剂。在本发明情况下所述的化合物是杂环取代的4－氨基戊二酰亚胺。本发明要求保护用该化合物抑制前列腺素合成的方法。

Description

环氧合酶-2活性的抑制
本申请要求2000年3月21日提交的美国临时申请60/193,981，发明名称为“环氧合酶-2活性的抑制”这一申请的优先权，该申请以引用方式并入本申请。
发明领域
本发明涉及抑制环氧合酶-2活性的方法。
背景技术
已经发现与血管内皮细胞增生、转移和入侵有关的血管生成的各组成成分部分地由多肽生长因子调节。与含有适当的生长因子的介质接触的内皮细胞可被诱发部分或全部的血管生成响应。具有离体内皮生长促进活性的多肽包括酸性或碱性的成纤维细胞生长因子、转化生长因子α和β、血小板衍生的内皮细胞生长因子、粒细胞集落刺激因子、白细胞介素-8、肝细胞生长因子、增殖蛋白、血管内皮细胞生长因子和胎盘生长因子，见Folkman等，1995，N.Engl.J.Med.，333：1757-1763。
在天然存在的内源性刺激物和血管生成抑制剂之间的平衡中抑制作用占有优势，见Rastinejad等，1989，Cell，56：345-355。在新的血管形成是在正常的生理状态下完成的那些情况下，例如外伤愈合、器官再生、胚胎发育和女性的生殖过程，血管生成被精确的调整，并且被限制在一定的空间和时间。如在以实体瘤生长为特征的病理性血管生成的条件下，对血管生成的调节控制作用就会失败。
身体中的各类细胞可以转化成良性或恶性肿瘤细胞。最常见的肿瘤部位是肺，然后是结肠、乳房、前列腺、膀胱、胰脏和卵巢。其他常见的癌症包括白血病、中枢神经系统癌症，包括脑癌、黑素瘤、淋巴癌、红白血病、子宫癌以及头部和颈部癌症。
无调节的血管生成造成许多赘生性和非赘生性疾病的发展，这些疾病包括实体瘤生长和肿瘤转移，例如参见Moses等，1991，Biotech.，9：630-634；Folkman等，1995，N.Engl.J.Med.，333：1757-1763；Auerbach等，1985，J.Microvasc.Res.，29：401-411；Folkman，1985，Advancesin Cancer Research，Klein和Weinhouse编辑，Academic Press，NewYork，p175-203；Patz，1982，J.Opthalmol.，94：715-743；Folkman等，1983，Science，221：719-725；Folkman和Klagsbrun，1987，Science，235：442-447。
发明的详细描述
环氧合酶-2，是前列腺素生物合成中的限速酶，在与肿瘤有关的巨噬细胞中表达。因为称为PEG2的前列腺素是炎症响应和血管生成的重要介质，因此，对其生物合成的抑制作用可用来抵消它们的作用。试验化合物对环氧合酶-2蛋白的抑制作用可很方便地在细胞中观测到，在所述细胞中环氧合酶-2蛋白的生成被脂多糖(LPS)诱导。已知LPS可增强环氧合酶-2的转录，并且可把此作用作为评价环氧合酶-2抑制作用的便捷模型。
现已发现环氧合酶-2的活性可被某些酰胺或酰亚胺抑制，此作用导致前列腺素生物合成的减少，特别是进而产生抗炎症响应、抗血管生成和抗赘生性疾病的作用。
可被用于本发明的酰胺和酰亚胺包括在下列专利中所公开的全部酰胺和酰亚胺：USP2,830,991、5,385,901、5,635，517、5,798,368和5,874,448，以及序号为PCT WO98/54170和1999年3月16申请的09/270,411，上述各专利公开均以引用方式并入本文。
具体地说，酰胺和酰亚胺包括下式化合物：
Figure A0180748100051
其中R是氢，1-6个碳原子的烷基，2-6个碳原子的链烯基，吗啉代甲基，苯基或苄基；和R′是：或
在一试验中，LPS介导的环氧合酶-2的诱导作用以及RAW 246.7细胞中的巨噬细胞的PEG2生物合成被低至50μM的3-苯二甲酰亚氨基-2，6-二氧代哌啶所阻断。但是，看起来LPS提高环氧合酶-2的转录，其本身不受酰胺或酰亚胺的影响。这就是说，酰胺或酰亚胺对LPS引起的环氧合酶-2的诱导作用没有影响。另一方面，酰胺或酰亚胺增强环氧合酶-2信使RNA的降解，其结果是尽管不希望局限于某种理论，但酰胺或酰亚胺对环氧合酶-2活性所产生的抑制作用很可能是通过某些转录后机制来实现的。
术语“烷基”是指具有1-6个碳原子的直链或支链的一价饱和烃基。这类烷基中有代表性的例如是甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、叔戊基、己基和异己基。
术语“链烯基”是指具有2-6个碳原子和烯烃双键的直链或支链的一价烃基。这类链烯基中有代表性的例如是乙烯基、烯丙基、丁-2-烯基、丁-3-烯基等。
有代表性的上述化合物包括3-苯二甲酰亚氨基-2，6-二氧代哌啶、1-烯丙基-3-苯二甲酰亚氨基-2，6-二氧代哌啶、1-乙基-3-苯二甲酰亚氨基-2，6-二氧代哌啶、1-苯基-3-苯二甲酰亚氨基-2，6-二氧代哌啶、1-苄基-3-苯二甲酰亚氨基-2，6-二氧代哌啶、3-琥珀酰亚氨基-2，6-二氧代哌啶和1-烯丙基-3-琥珀酰亚氨基-2，6-二氧代哌啶。优选的化合物是3-苯二甲酰亚氨基-2，6-二氧代哌啶，也称为thalidomide。
用于本发明的酰胺或酰亚胺是已知的，并可由常规方法制备，例如在上文提到的作为参考的专利和专利申请中所说明的那些。
优选将酰胺或酰亚胺口服给药。口服剂量形式可以是片剂、胶囊、糖衣丸和类似形状的压制药物形式，每单位剂量含有1-100mg药物。含有20-100mg/ml的混合物可制备成肠胃外给药的形式，包括肌内、鞘内、静脉内和动脉内给药形式。直肠内给药可通过例如使用可可脂的常规载体制成栓剂使用。
药物组合物包括与至少一种药学上可接受的载体、稀释剂或赋形剂结合的酰胺或酰亚胺。在制备该组合物时，通常将thalidomide与赋形剂混合或用赋形剂稀释，或者将其封装在制成胶囊或小袋形式的载体中。当赋形剂用作稀释剂时，它可也是固体、半固体或液体材料，其作用是活性成分的媒体、载体或活性成分的介质。因此，该组合物可以是片剂、丸剂、粉剂、酏剂、悬浮剂、乳剂、溶液、糖浆、软和硬明胶胶囊、栓剂、无菌注射溶液和无菌填充粉剂。适当的赋形剂的实例包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素，制剂中还可加入润滑剂如滑石、硬脂酸镁和矿物油，湿润剂，乳化剂和悬浮剂，防腐剂如甲基-或丙基-羟基苯甲酸酯，甜味剂和矫味剂。
优选将酰胺或亚酰胺组合物制成单位剂量形式，即物理上分离的单位，其适合作为给人或其它哺乳动物以单剂或多剂给药的单一剂量或单一剂量的预定部分，每个单位含有预定量的活性物质以及适当的药物赋型剂，所述活性物质的量可产生所需的治疗效果。可将组合物制成制剂，以便在按本领域熟知的步骤对患者给药后使活性成分即释、持续释放或缓释。
酰胺或酰亚胺可有手性中心，在此情况下可具有光学异构体。手性纯的(R)-和(S)-异构体以及这些异构体的混合物(包括但不限于外消旋混合物)均在本发明的范围之内。混合物可以其本身使用，也可以使用手性吸附剂通过色谱法将混合物物理地分离成单个的异构体。另外，单个异构体可以手性的形式制备，或用化学方法分离。
使用的剂量必须根据患者的性别、体重、疾病的严重程度和临床治疗方案认真考虑。典型的给药剂量应该足以能够产生至少为0.01μg/ml的血浓度，优选至少为0.1μg/ml的血浓度。平均体重(70kg)人体的总血量体积是大约5升，因此，有效剂量的最小量应是大约0.5mg，但也可以高达约500mg。当内脏被感染时，甚至需要更大的剂量，实际中在器官移植对宿主疾病和HIV感染的情况就是如此。已经知道对某些患者很容易患诱导神经病，因此可能需要较低的剂量。临床经验告诉我们剂量可从50mg(每周3次)直至高达每天数克，但应该注意的是，最后的实际剂量必须由主治医师决定。
下面的实施例对本发明的性质进一步典型的加以说明，但不构成对所附权利要求书定义的本发明保护范围的限制。
实施例1
片剂，每片含有50mg 3-苯二甲酰亚氨基-2，6-二氧代哌啶，可按下述方式制备：
成分(1000片)
3-苯二甲酰亚氨基-2，6-二氧代哌啶         50.0g
乳糖                                     50.7g
小麦淀粉                                 7.5g
聚乙二醇6000                               5.0g
滑石                                       5.0g
硬脂酸镁                                   1.8g
纯净水                                     适量
首先迫使固体成分通过0.6mm筛孔宽的筛25，然后将活性成分酰亚胺、乳糖、滑石、硬脂酸镁和一半的淀粉混合，另一半淀粉悬浮于40ml水，将该悬浮液加入聚乙二醇于100ml水的沸腾溶液中，将得到的糊状物加入上述粉末状物质，使混合物成粒，如果需要可加水。将颗粒物在35℃干燥过夜，然后迫使其通过1.2mm筛孔宽的筛子，压制成直径大约为6mm的片剂形式，两面都是凹形。
实施例2
片剂，每片含有100mg 1-烯丙基-3-苯二甲酰亚氨基-2，6-二氧代哌啶，可按下述方式制备：
成分(1000片)
1-烯丙基-3-苯二甲酰亚氨基-2，6-二氧代哌啶       100.0g
乳糖                                            100.0g
小麦淀粉                                        47.0g
硬脂酸镁                                        3.0g
首先迫使固体成分通过0.6mm筛孔宽的筛，然后将活性成分酰亚胺、乳糖、硬脂酸镁和一半的淀粉混合，另一半淀粉悬浮于40ml水，将该悬浮液加入100ml开水中，将得到的糊状物加入上述粉末状物质，使混合物成粒，如果需要可加水。将颗粒物在35℃干燥过夜然后迫使其通过1.2mm筛孔宽的筛子，压制成直径大约为6mm的片剂形式，两面都是凹形。
实施例3
片剂，每片含有10mg  3-琥珀酰亚氨基-2，6-二氧代哌啶，可按下述方式制备：
成分(1000片)
3-琥珀酰亚氨基-2，6-二氧代哌啶             10.0g
乳糖                                       328.5g
玉米淀粉                                   17.5g
3-琥珀酰亚氨基-2，6-二氧代哌啶             10.0g
乳糖                                       328.5g
玉米淀粉                                   17.5g
聚乙二醇6000                               5.0g
滑石                                       25.0g
硬脂酸镁                                   4.0g
纯净水                                     适量
首先迫使固体成分通过0.6mm筛孔宽的筛，然后将3-琥珀酰亚氨基-2，6-二氧代哌啶、乳糖、滑石、硬脂酸镁和一半的淀粉充分混合，另一半淀粉悬浮于65ml水，将该悬浮液加入聚乙二醇于260ml水的沸腾溶液中，将得到的糊状物加入上述粉末状物质，使所得物混合并成粒，如果需要可加水。将颗粒物在35℃干燥过夜，然后迫使其通过1.2mm筛孔宽的筛子，压制成直径大约为10mm的片剂，两面都是凹形，并且在一面上有可分开的凹槽。
实施例4
干填充的明胶胶囊，每个胶囊含有50mg 3-苯二甲酰亚氨基-2，6-二氧代哌啶，可按下述方式制备：
成分(1000个胶囊)
3-苯二甲酰亚氨基-2，6-二氧代哌啶          50.0g
乳糖                                      8.0g
通过0.2mm至0.9mm筛孔筛将十二烷基硫酸钠筛入3-苯二甲酰亚氨基-2，6-二氧代哌啶，将它们一起充分混合10分钟。最后，通过0.8mm的筛加入硬脂酸镁，再进一步混合3分钟，将混合物等分成140mg一份，各自加入0号(拉长的)大小的干填充明胶胶囊。
实施例5
制备0.2％注射或输注溶液，例如可按下述方式制备：
3-苯二甲酰亚氨基-2，6-二氧代哌啶          5.0g
氯化钠                                    22.5g
磷酸盐缓冲溶液，pH7.4                     300.0g
纯净水加至                                2500.0ml
将活性成分酰亚胺溶解于1000ml水，用微过滤器过滤，加入缓冲溶液，用水将该制剂制成总量为2500ml。制备单位剂量形式，分成1.0或2.5ml的等份，将每份装入玻璃安瓿。每一个各自含有2.0或5.0mg酰亚胺。

Claims (2)

1.抑制哺乳动物环氧合酶-2活性以减少前列腺素生物合成的方法，该方法包括给哺乳动物施用有效量的下式酰胺或酰亚胺：
Figure A0180748100021
其中R是氢，1-6个碳原子的烷基，2-6个碳原子的链烯基，吗啉代甲基，苯基或苄基；和
R′是：
Figure A0180748100022
或
Figure A0180748100023
2.按照权利要求1的方法，其中所说的酰胺或酰亚胺是3-苯二甲酰亚氨基-2，6-二氧代哌啶。
CN01807481A 2000-03-31 2001-03-30 环氧合酶－2活性的抑制 Pending CN1420776A (zh)

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CN106137986B (zh) * 2015-03-09 2019-04-16 常州制药厂有限公司 一种沙利度胺片及其制备方法

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