CN1053571C - 雷洛昔芬在制备抑制平滑肌增殖和再狭窄的药物中的应用 - Google Patents

雷洛昔芬在制备抑制平滑肌增殖和再狭窄的药物中的应用 Download PDF

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CN1053571C
CN1053571C CN94117122A CN94117122A CN1053571C CN 1053571 C CN1053571 C CN 1053571C CN 94117122 A CN94117122 A CN 94117122A CN 94117122 A CN94117122 A CN 94117122A CN 1053571 C CN1053571 C CN 1053571C
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G·J·库里南
J·P·星
D·L·伍德
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Abstract

本发明提供抑制人或其他哺乳动物平滑肌细胞增殖和再狭窄的方法，该方法包括给所述患者施用药用有效剂的式(I)或式(II)化合物及其可药用盐和溶剂化物，
(其中各代号意义详见说明书)。

Description

雷洛昔芬在制备抑制平滑肌增殖和再狭窄的药物中的应用
平滑肌细胞增殖在疾病如动脉粥样硬化和再狭窄中起着重要作用。在经皮冠状血管搭桥术(percutaneous transluminal coronaryangioplasty，PTCA)后的血管再狭窄已表明是早期和晚期的组织应答。PTCA后几小时至几天早期出现是由于带有一些血管痉挛的血栓形成，而晚期则表现为受平滑肌细胞过度增殖与迁移的支配。在此疾病中，平滑肌细胞增加的细胞能动性和移生以及巨噬细胞对该疾病的发病机理有显著的贡献。血管平滑肌细胞过度增殖和移生可能是PTCA、atherectomy、激光血管成形术和动脉分流移植术后冠状动脉再闭塞的主要机理。参见Austin等“Intimal Proliferation of SmoothMuscle Cells as an Explanation for Recurrent CoronaryArtery Stenosis after Percutaneous Transluminal CoronaryAngioplasty”，Journal of the American College ofCardiology 8：369-375(1985年8月)。
通过经皮冠状血管搭桥术(PTCA)、Atherectomy、激光血管成形术和动脉分流移植术对阻塞动脉进行外科手术后，血管再狭窄是长期存在的主要并发症。在施行PTCA的约35％患者中，术后3-6个月发生再闭塞。目前治疗血管再狭窄的策略包括用器械如固定模施行物理手术，或者进行药物治疗，这些药物包括肝素、低分子量肝素、香豆素、阿斯匹林、鱼油、钙拮抗剂、类固醇和前列环素。这些策略无法控制再闭塞速度，并且对于治疗和预防血管再狭窄无效。参见Hermans等“Prevention of Restenosis after PercutaneousTransluminal Coronary Angioplasty：The Search for a‘MagicBullet’”，American Heart Journal 122：171-187(1991年7月)。
在再狭窄发病机理中，发生细胞过度增殖与移生是血液和损伤的动脉血管壁中血胞成分产生生长因子的结果，该生长因子调节在血管再狭窄中平滑肌细胞增殖。
抑制平滑肌细胞增殖和/或移生的药物适用于治疗和预防再狭窄。本发明提供作为平滑肌细胞增殖抑制剂的化合物的用途。
本发明提供抑制人或其他哺乳动物平滑肌细胞增殖的方法，该方法包括给所述患者施用药物有效剂量的式(I)或式(II)化合物及其可药用盐和溶剂化物，
Figure C9411712200061
或其中R1和R3独立地为氢、-CH3、
Figure C9411712200072
(C1-C5烷基)或
Figure C9411712200073
，其中Ar是任意取代的苯基；R2是
Figure C9411712200074
或
Figure C9411712200075
并且R4是氢或OR1。本发明还提供了抑制再狭窄的方法。
本发明涉及下述发现：选自式I和式II的化合物可用于抑制平滑肌细胞增殖和再狭窄。本发明提供的治疗方法是：给需要治疗的人或其他乳哺动物服用抑制平滑肌细胞增殖或再狭窄有效剂量的式I或II化合物或其药学上适用的盐或溶剂化物。术语抑制定义为包括其通常可接受的含义，包括预防性地对易患平滑肌细胞增殖或再狭窄的人进行治疗，阻止和/或治疗存在的平滑肌细胞增殖和/或再狭窄。
以此种方式，本发明方法包括适宜的对症治疗和/或预防治疗。
一般来讲，可以将本发明化合物与普通的赋形剂、稀释剂或载体一起进行配制并压成片剂，或者配制成常用的口服给药酏剂或溶液剂；或者配制成肌内或静脉途径给药的注射剂。本发明化合物可以经皮给药，也可以配制成持续释放等剂型。
用于本发明方法的式I化合物可以按既定的方法制备，如美国专利4,133,814、4,418,068和4,380,635所述的方法，将它们收编在本申请中作为参考。一般，该方法用具有6-羟基和2-(4-羟苯基)的苯并[b]噻吩作为起始原料。对起始化合物保护、烷基化并脱保护，形成式I化合物。上述美国专利中提供了制备此类化合物的实例。式II化合物可以按照US 4,230,862和4,232,707中所述方法制备，这两篇专利引入本文作为参考。
本发明包括下式化合物的用途：
Figure C9411712200081
取代的苯基包括由C1-C6烷基、C1-C4烷氧基、羟基、硝基、氯、氟或三(氯或氟)甲基一次或两次取代的苯基。
用于本发明方法的化合物可以与各种有机和无机酸和碱反应生成药学上适用的酸和碱加成盐，药学上适用的酸和碱加成盐包括通常用于制药化学的生理上适用的盐。所述的盐也是本发明的一部分。生成所述盐的常用无机酸包括盐酸、氢溴酸、氢碘酸、硝酸、硫酸、磷酸、连二磷酸等。盐也可由有机酸得到，可以应用的有机酸有例如脂族一和二羧酸、苯基取代的链烷酸、羟基链烷酸和羟基链烷二酸，芳族酸、脂族和芳香族磺酸。所述药学上适用的盐包括乙酸盐、苯基乙酸盐、三氟乙酸盐、丙烯酸盐、抗坏血酸盐、苯甲酸盐、氯苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、甲基苯甲酸盐、邻-乙酰氧基苯甲酸盐、萘-2-苯甲酸盐、溴化物、异丁酸盐、苯基丁酸盐、β-羟基丁酸盐、丁炔-1，4-二酸盐、己炔-1，4-二酸盐、癸酸盐、辛酸盐、氯化物、肉桂酸盐、柠檬酸盐、甲酸盐、富马酸盐、羟基乙酸盐、庚酸盐、马尿酸盐、乳酸盐、苹果酸盐、马来酸盐、羟基马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、烟酸盐、异烟酸盐、硝酸盐、草酸盐、邻苯二甲酸盐、四邻苯二甲酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、丙炔酸盐、丙酸盐、苯基丙酸盐、水杨酸盐、癸二酸盐、琥珀酸盐、辛二酸盐、硫酸盐、硫酸氢盐、焦硫酸盐、亚硫酸盐、亚硫酸氢盐、磺酸盐、苯磺酸盐、对溴苯磺酸盐、氯苯磺酸盐、乙磺酸盐、2-羟基乙磺酸盐、甲磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、对甲苯磺酸盐、二甲苯磺酸盐、酒石酸盐等。优选的盐是盐酸盐。
药学上适用的酸加成盐通常由式I化合物与等摩尔或过量的酸反应而制得。通常使反应物于互溶剂如乙醚或苯中进行化合。盐通常约在1小时至10天内从溶液中沉淀出，经过滤分离，或按常规方法除去溶剂。
通常用于形成盐的碱包括氢氧化铵，碱金属和碱土金属氢氧化物、碳酸盐和碳酸氢盐，以及脂肪族和芳香族胺，脂肪族二胺和羟基烷胺。在制备加成盐中尤其适用的碱包括氢氧化铵、碳酸钾、碳酸氢钠、氢氧化钙、甲胺、二乙胺、1，2-乙二胺、环己胺和乙醇胺。
与衍生它的化合物比较，药学上适用的盐通常可提高溶解性能，因此常常更适用于配制如液体剂或乳剂。
药用制剂可按本技术领域已知的方法制备。例如，该化合物可与普通的赋形剂、稀释剂或载体进行配制，并制成片剂、胶囊剂、悬浮液剂、粉剂等。适用于上述制剂的赋形剂、稀释剂和载体的实例包括如下：填充剂和增量剂如淀粉、糖、甘露糖醇和硅衍生物；粘合剂如羧甲基纤维素和其他纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮；润湿剂如甘油；崩解剂如琼脂、碳酸钙和碳酸氢钠；溶解阻滞剂如石蜡；吸收促进剂如季铵化合物；表面活性剂如鲸蜡醇、单硬脂酸甘油脂；吸附载体如高岭土和膨润土；润滑剂如滑石、硬脂酸钙和硬脂酸镁，以及固态聚乙基乙二醇。
这些化合物也可配制成便于口服的酏剂或溶液剂，或适于非肠道给药的溶液剂，例如经肌内、皮下或静脉内途径给药。此外，该化合物也非常适合配制成持续释放等剂型。该制剂也可这样构成，使它们仅仅或最好在肠道的特定部位，可能在一定的时间内释放有效成分。包衣、包膜和保护基质可以由例如聚合物质或蜡制成。
根据本发明，抑制平滑肌细胞增殖和再狭窄所需要的式I化合物的具体剂量取决于疾病的严重程度、给药途径和有关因素，这些将由主治医生确定。一般来讲，每天可接受和有效剂量为约0.1～1000mg/天，更通常为约50-200mg/天。需治疗的患者服用的上述剂量可为每天1次～约3次，或为了有效地抑制平滑肌细胞增殖或再狭窄需要更经常地服用。
可以通过各种技术将抑制量的治疗再狭窄活性的化合物局部释放，这些技术将化合物施用于增殖部位或靠近增殖的部位。局部释放技术的实例不是限制、而是说明可行的技术。这些实例包括局部释放导管、位置特异性载体、移植物、直接注射或直接用药。
由导管局部释放使得药物可直接施于增殖损伤处。在EPO 383492A2和US 4,636,195(Wolinsky，1987年1月13日)中描述了用球形导管局部释放的实例。
用移植物局部释放描述了将含药物的基质手术放置于增殖损伤处。移植的基质通过渗滤、化学反应或溶剂活化剂释放药物。Lange，Scince 249：1527-1533(1990年9月)。
通过移植物局部释放的实例是使用固定模。将固定模设计为可物理预防冠状动脉萎陷和再闭塞。在固定模中加入药物，使药物直接释放到增殖部位。在Kohn的Pharmaceutical Technolugy(1990年10月)中描述了由该技术的局部释放。
在另一个释放系统实例中，将含有药物聚合物以液体形式注射到损伤部位。聚合物然后硬化，就地形成移植物。在PCT WO 90/03768(Donn，1990年4月19日)中描述了该技术。
另一个实例是通过聚合物腔内封闭释放药物。该技术用导管将聚合物移植物施放到腔内表面。由此将掺入可生物降解聚合物移植物中的药物在手术部位释出。在PCT WO 90/01969(Schindler，1989年8月23日)中描述了该方法。
通过移植物局部释放的最后一个实例是将泡囊或微粒直接注入增殖部位。这些微粒可以由例如蛋白质、类脂、碳水化合物或合成聚合物等物质组成。这些微粒贯穿于微粒当中掺有药物或者作为包衣在微粒表面包覆有药物。在Lange的Science 249：1527-1533(1990年9月)和Mathiowitz等的J.App.Poly.Sci.，26：809(1981)中描述了引入微粒的释放系统。
通过位置特异性载体局部释放的过程描述使药物附着于载体上，该载体将会使药物直接作用于增殖损伤部位。这种释放技术的实例包括使用载体例如蛋白质配体或单克隆抗体。Lange，Science 249：1527-1533(9月)。
通过直接用药的局部释放包括使用局部用药技术。直接用药进行局部释放的实例是在手术过程中将药物直接施于动脉分流移植物上。
如同服用带有碱基(如哌啶子基环)的药物的通常做法一样，通常最好服用酸加成盐形式的式I化合物。口服本发明化合物对老年人(如绝经后的妇女)也是有利的。为此目的，以下口服剂量形式是适用的。
                         制剂
在以下制剂中，  “活性成分”是指式I或式II化合物。制剂1：明胶胶囊
用下成分制备硬明明胶囊：成分                                           量(mg/胶囊)活性成分                                       0.1-1000淀粉，NF                                         0-650可流动的粉末状淀粉                               0-650硅氧烷流体(350厘沲)                              0-15
将各成分混合，通过美国45号筛，装填入硬明胶胶囊。
式I化合物(其中所述化合物是raloxifene)具体的胶囊制剂实例包括如下所示那些：制剂2：Raloxifene胶囊成分                                            量(mg/胶囊)Raloxifene                                         1淀粉，NF                                         112可流动的淀粉粉末                                 225.3硅氧烷流体(350厘沲)                                1.7制剂3：Raloxifene胶囊成分                                           量(mg/胶囊)Raloxifene                                          5淀粉，NF                                          108可流动的淀粉粉末                                  225.3硅氧烷流体(350厘沲)                                 1.7制剂4：Raloxifene胶囊成分                                           量(mg/胶囊)Raloxifene                                         10淀粉，NF                                          103可流动的淀粉粉末                                  225.3硅氧烷流体(350厘沲)                                 1.7制剂5：Raloxifene胶囊成分                                           量(mg/胶囊)Raloxifene                                         50淀粉，NF                                          150可流动的淀粉粉末                                  397硅氧烷流体(350厘沲)                                 3.0
可以对上述具体的制剂进行合理的改变。
用下列成分制备片剂：制剂6：片剂成分                                           量(mg/片)活性成分                                        0.1-1000微晶纤维素                                        0-650雾化二氧化硅                                      0-650硬脂酸                                            0-15
将各成分混合，压成片剂。
或者，每片含0.1-1000mg活性成分的片剂按以下方法制备：制剂7：片剂成分                                             量(mg/片)活性成分                                         0.1-1000淀粉                                               45微晶纤维素                                         35聚乙烯吡咯烷酮(10％水溶液)                         4羧甲基纤维素钠                                     4.5硬脂酸镁                                           0.5滑石                                               1
将活性成分、淀粉和纤维素通过美国45号筛并充分混合。聚乙烯吡咯烷酮溶液与所得的粉末混合，然后通过美国14号筛。将制备的颗粒于50°-60℃干燥，并通过美国18号筛。然后将预先通过美国60号筛的羧甲基纤维素钠、硬脂酸镁和滑石加入此颗粒中，混合后将颗粒在压片机上压片，得到片剂。
每5ml含0.1-1000mg药物的悬浮液剂按下法制备：制剂8：悬浮液剂成分                                            量(mg/5ml)活性成分                                        0.1-1000mg羧甲基纤维素钠                                     50mg糖浆                                             1.25mg苯甲酸溶液                                       0.10ml调味剂                                           适量着色剂                                           适量加纯化水                                        至 5ml
将药物通过美国45号筛，并与羧甲基纤维素钠和糖浆混合制成调匀的糊状物。苯甲酸溶液、调味剂和着色剂用一部分水稀释，并在搅拌下加入糊状物中。然后加入足够的水到所需体积。
                     试验方法
本发明化合物能够抑制血管平滑肌细胞增殖。这一点可以通过采用培养的由兔子主动脉(通过DNA合成测量已确定有增殖)得到的平滑肌细胞证实。按照Ross，J.of Cell Bio.50：172(1971)中所述方法通过移植得到细胞。将细胞铺于96孔微滴板上5天。待培养物融合以及生长停止，将细胞转入Dulbecco’s改性的Eagle’s培养基(DMEM)中，该培养基中含有0.5-2％血小板缺乏血浆、2mML-谷氨酰胺、100U/ml青霉素、100μg/ml链霉素、1μC/ml3H-胸苷、20ng/ml血小板产生的生长因子以及不同浓度的本发明化合物。在二甲亚砜中制备化合物的贮液，然后在上述分析培养基中将其稀释到合适的浓度(0.01-30μM)。于37℃、在5％CO2/95％空气下培养细胞24小时。在24小时末用甲醇固定细胞。然后按照Bonin等人在Exp.Cell Res.181：475-482(1989)中所述，通过闪烁记数测定DNA中结合的3H-胸苷。
通过测定本发明化合物对指数生长细胞的作用，进一步证实了其抑制平滑肌细胞增殖的作用。在12孔组织培养板中，将兔主动脉的平滑肌细胞接种于含10％胎牛血清、2mM L-谷氨酰胺、100U/ml青霉素和100μg/ml链霉素的DMEN中。24小时后缚紧细胞，用含10％血清、2mM L-谷氨酰胺、100U/ml青霉素、100μg/ml链霉素和指定浓度本发明化合物的DMEM培养基替换原培养基。使细胞生长4天。用胰蛋白酶处理细胞，并通过用ZM-Coulter计数器计数，测定每份培养物中的细胞数。
上述试验中的活性表明本发明化合物可用于治疗再狭窄。

Claims (8)

1.式(I)或式(II)化合物或其可药用盐或溶剂化物在制备用于抑制平滑肌细胞增殖的药物组合物中的应用：
Figure C9411712200021
或
Figure C9411712200022
其中R1和R2独立地为氢、-CH3、
Figure C9411712200023
(C1-C6烷基)或
Figure C9411712200024
其中Ar是苯基或取代的苯基，所述取代的苯基包括由C1-C6烷基、C1-C4烷氧基、羟基、硝基、氯、氟或三(氯或氟)甲基一次或两次取代的苯基；
R2是或
Figure C9411712200026
并且R4是氢或-OR1。
2.按权利要求1的应用，其中所述化合物是其盐酸盐。
3.按权利要求1的应用，其中所述药物组合物是预防性施用的。
4.按权利要求1的应用，其中所述化合物是下式化合物或其盐酸盐
Figure C9411712200031
5.式(I)或式(II)化合物或其可药用盐或溶剂化物在制备用于抑制再狭窄的药物组合物中的应用：或
Figure C9411712200033
其中R1和R3独立地为氢、-CH3、 (C1-C6烷基)或 其中Ar是苯基或取代的苯基，所述取代的苯基包括由C1-C6烷基、C1-C4烷氧基、羟基、硝基、氯、氟或三(氯或氟)甲基一次或两次取代的苯基；R2是
Figure C9411712200043
或
Figure C9411712200044
并且R4是氢或-OR1。
6.按权利要求5的应用，其中所述化合物是其盐酸盐。
7.按权利要求5的应用，其中所述药物组合物是预防性施用的。
8.按权利要求5的应用，其中所述化合物是下式化合物或其盐酸盐
Figure C9411712200045
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