CN1053102C - 苯并噻吩衍生物在制备抑制软骨退化的药物方面的用途 - Google Patents

苯并噻吩衍生物在制备抑制软骨退化的药物方面的用途 Download PDF

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CN1053102C
CN1053102C CN94117243A CN94117243A CN1053102C CN 1053102 C CN1053102 C CN 1053102C CN 94117243 A CN94117243 A CN 94117243A CN 94117243 A CN94117243 A CN 94117243A CN 1053102 C CN1053102 C CN 1053102C
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D·C·威廉斯
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Abstract

抑制软骨退化的药用组合物，它包括作为活性成分的下式(I)化合物或其药学上可接受的盐或其溶剂化物，式中R1、R2和R3的定义见说明书。

Description

苯并噻吩衍生物在制备抑制软骨退化的药物方面的用途
软骨是在哺乳动物的关节中所发现的蛋白质性质的物质，它是一种覆盖着滑液腔中的骨关节表面的弹性的海绵状物质。软骨的存在及其压缩弹性和变形性的特殊性质使得关节能够实现其两种主要的功能，即承受重量和便于运动的功能。
关节的退化出现在多种疾病情况下，所述疾病包括类风湿性关节炎、牛皮癣性关节炎、骨关节病、增殖性关节炎和骨关节炎。此外，关节急性炎症可能伴随有软骨的破坏。涉及急性关节炎症的疾病的例子有耶尔森氏菌性关节炎(yersinia arthritis)、焦磷酸盐性关节炎(pyrophosphate arthritis)、痛风性关节炎和脓毒性关节炎。此外，可能导致软骨破坏或退化的另一个因素是用可的松治疗。
本发明提供抑制人或其它哺乳动物软骨退化的方法，它包括给需要治疗的人或其它哺乳动物使用有效量的式(I)化合物或其药学上可接受的盐或溶剂化物。式(I)化合物如下：
Figure C9411724300041
式中R1和R3独立地为氢、-CH3、
Figure C9411724300051
式中的Ar是可任选地被取代的苯基；R2选自吡咯烷子基(pyrrolidino)和哌啶子基。
本发明涉及这样一个发现，即选择的一组2-苯基-3-芳酰基苯并噻吩(苯并噻吩类)，这些式(I)化合物可用于抑制软骨退化。本发明所提供的治疗方法通过给需要抑制软骨退化的人使用抑制软骨退化有效量的式(1)化合物或其药学上可接受的盐或溶剂化物来实施。术语抑制被定义为包括其一般可接受的意义，这包括预防性治疗易患软骨退化的人以及控制和/或治疗现存的软骨退化。因此，本发明方法包括医疗性和/或预防性治疗。
一般来讲，所述化合物用普通的赋形剂、稀释剂或载体来配制并压制成片剂或者配制成酏剂或溶液剂用于常规口服，或者经肌肉内或静脉内途径使用。所述化合物可以经皮肤途径来使用，而且可以被配制成缓释剂型等。
用于本发明方法中的化合物可以按照已建立的方法来制备，例如在美国专利第4133814、4418068和4380635中所述的方法，所有这些文献引入本文作参考。一般来讲，所述方法用具有6-羟基和2-(4-羟苯基)基团的苯并[b]噻吩开始。将所述起始化合物保护、酰化并去保护，制得式(I)化合物。制备这样的化合物的例子见上述的美国专利。取代的苯基包括用C1-C6烷基、C1-C4烷氧基、羟基、硝基、氯、氟或三(氯或氟)甲基取代一次或两次的苯基。
用在本发明方法中的化合物与多种有机和无机酸和碱生成药学上可接受的酸和碱加成盐，包括在药物化学中经常使用的生理上可接受的盐。这样的盐亦属于本发明范围。用来形成所述盐的典型的无机酸包括盐酸、氢溴酸、氢碘酸、硝酸、硫酸、磷酸、连二磷酸等。衍生自有机酸的盐也可以使用，所述有机酸包括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、芳香酸、脂族和芳族磺酸。因此，这样的药学上可接受的盐包括乙酸盐、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、乙醇酸盐、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、甲磺酰化物(mesylate)、烟酸盐、异烟酸盐、硝酸盐、草酸盐、邻苯二甲酸盐、对苯二甲酸盐、磷酸盐、一氢磷酸盐、二氢磷酸盐、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。
所述药学上可接受的酸加成盐一般通过将式(I)化合物与等摩尔或过量的酸反应来制备。一般将反应物在互溶剂如乙醚或苯中混合。盐通常在约1小时至10天之内从溶液中沉淀析出并可用过滤法来分离，或者可将溶剂用常规方法去除。
常用于成盐的碱包括氢氧化铵和碱金属的和碱土金属的氢氧化物碳酸盐和碳酸氢盐，以及脂肪族和芳香族胺、脂族二胺和羟基烷基胺。尤其可用于制备加成盐的碱包括氢氧化铵、碳酸钾、碳酸氢钠、氢氧化钙、甲胺、二乙胺、乙二胺、环己胺和乙醇胺。
所述药学上可接受的盐通常比衍生出该盐的化合物溶解度增大，因此常常更适于配制成液体或乳剂。
药物制剂可以用本领域已知的方法来制备。例如，可将该化合物与常规赋形剂、稀释剂或载体一起配制，并制成片剂、胶囊剂、悬浮剂、粉剂等。适合于所述制剂的赋形剂、稀释剂和载体的例子包括填充剂和增量剂，例如淀粉，糖，甘露醇和硅酸衍生物；粘合剂，例如羧甲基纤维素和其它纤维素衍生物，藻酸盐，明胶和聚乙烯吡咯烷酮；润湿剂，例如甘油；崩解剂，例如琼脂，碳酸钙和碳酸氢钠；阻溶剂，例如石蜡；吸收促进剂，例如季铵化合物；表面活性剂，例如十六烷醇，甘油一硬脂酸酯；吸附载体，例如高岭土和膨润土；以及润滑剂，例如滑石粉，硬脂酸钙和硬脂酸镁，以及固体聚乙二醇类。
所述化合物也可以被配制为常规口服用酏剂或溶液剂，或者被配制成适于肠道外注射例如肌肉内、皮下或静脉注射用溶液剂。另外，该化合物非常适于配制成缓释剂型等。可将所述制剂配制成可能在一段时间内仅仅或最好在肠道的特定部位释放活性成分的制剂。包衣、膜和保护基质可以例如用聚合物或蜡类来制备。
按照本发明，抑制软骨退化所需的式(I)化合物的特定剂量将取决于病情的严重程度、给药途径和将由执疹医生决定的相关因素。一般来讲，可接受且有效的日剂量应为约0.1-1000mg/天，更典型地为约50-200mg/天。应将所述的剂量给需要治疗的病人每天服用一至约三次，或者更常见的是根据有效地抑制软骨退化的需要来服用。
通常优选使用以酸加成盐形式存在的式(I)化合物，因为这在使用带有碱性基团例如哌啶子基环的药品上是通行的。给正步入老年的人(例如绝经后的妇女)口服这样的化合物也是有利的。为此，下列口服剂型是合用的。
在下列制剂中，“活性成分”指式(I)化合物。制剂I：明胶胶囊
用下列成分制备硬胶囊：
成分                              数量(mg/胶囊)活性成分                                0.1-1000淀粉，NF                                0-650可流动的淀粉粉末                        0-650硅氧烷液350厘沲                         0-15
将上述成分混合，过第45号筛目美国筛，然后将其装入硬胶囊中。
已经制得的式中R2是哌啶子基的式(I)化合物[拉洛西芬(ra-loxifene)]的特定胶囊制剂的例子包括以下所示制剂：制剂2：拉洛西芬胶囊
成分                            数量(mg/胶囊)拉洛西芬                                 1淀粉，NF                                 112可流动的淀粉粉末                         225.3硅氧烷液350厘沲                          1.7制剂3：拉洛西芬胶囊
成分                            数量(mg/胶囊)拉洛西芬                                 5淀粉，NF                                 108可流动的淀粉粉末                         225.3硅氧烷液350厘沲                         1.7制剂4：拉洛西芬胶囊
成分                             数量(mg/胶囊)拉洛西芬                                10淀粉，NF                                103可流动的淀粉粉末                        225.3硅氧烷液350厘沲                         1.7制剂5：拉洛西芬胶囊
成分                            数量(mg/胶囊)拉洛西芬                                50淀粉，NF                                150可流动的淀粉粉末                        397硅氧烷液350厘沲                         3.0
以上特定制剂可以按照所提供的相当的变数来变动。
用以下成分来制备片剂：制剂6：片剂
成分                              数量(mg/片)活性成分                                0.1-1000微晶纤维素                              0-650煅制二氧化硅                            0-650硬脂酸                                  0-15
将这些成分混合并压制成片剂。
或者，按下述制备各含0.1-1000mg活性成分的片剂：制剂7：片剂
成分                        数量(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                  4(为10％水溶液)羧甲基纤维素钠                  4.5硬脂酸镁                        0.5滑石粉                          1
将活性成分、淀粉和纤维素过第45号筛目美国筛并充分混合。将聚乙烯吡咯烷酮溶液与得到的粉末混合。然后过第14号筛目美国筛。将如此制得的颗粒于50-60℃干燥并过第18号筛目美国筛，然后将预先通过美国第60号筛的羧甲基纤维素钠、硬脂酸镁和滑石粉加至所述颗粒中，混合后，在压片机上压制成片剂。
每5ml剂量含0.1-1000mg药物的悬浮剂制备如下：制剂8：悬浮剂
成分                       数量(mg/5ml)活性成分                        0.1-1000mg羧甲基纤维素                    50mg糖浆                            1.25mg苯甲酸溶液                      0.10ml芳香剂                          适量着色剂                          适量净化水加至                         5ml
将所述药物通过第45号筛目美国筛并与羧甲基纤维素钠和糠浆混合形成均匀的糊状物。将苯甲酸溶液、芳香剂和着色剂用一些水稀释，搅拌下将其加至所述糊状物中。然后将足够的水加至其中以达到需要的体积。
                             测定1
将兔关节软骨细胞进行培养。将各种浓度的本发明化合物(10-9M至10-5M)和35[硫]酸钠同时加至在无血清的培养基中的培养物中。48小时后，测定结合入所述细胞和基质(用4M氯化鈲萃取)中的放射性标记的量并与对照细胞相比较，以测定化合物对蛋白多糖合成的影响。
                           测定2
将兔关节软骨细胞用各种浓度的本发明化合物(10-5M至10-9M)在有和没有恒定浓度的雌激素(10-8M)存在下处理，并按上述评价蛋白多糖合成。
                            测定3
按上述测定1分离和放射性标记兔软骨细胞。然后将所述细胞用interleukin-1β(10ng/ml)连同本发明化合物一起和无本发明化合物存在下进行处理24-72小时。观察各细胞培养物中蛋白多糖的减少。活性化合物将阻碍蛋白多糖减少。
                           测定4
将牛软骨切成5×1mm薄片并用35[硫]酸钠标记48小时，然后按测定3处理。预计活性化合物会阻止软骨的蛋白多糖减少。
                           测定5
为评价本发明化合物是否诱导TGF-βs(1，2，3)，将兔软骨细胞用各种浓度的本发明化合物处理24-72小时，测定该条件培养基中的惰性和活性TGF-βs。
                           测定6
将兔软骨细胞在无血清培养基中在本发明化合物存在或不存在的情况下用interleukin-1β(10ng/ml)处理48小时。在培养结束时，取出培养基并用3[H]-酪蛋白作中性蛋白酶活性的底物测定该酶的活性。活性化合物抑制由interleukin-1诱导的酶的生成和/或活性。
                        测定7
给C57B1小鼠从1-6个月龄开始间歇皮下注射本发明化合物。治疗过程持续6-12个月。将所述动物在18-20月龄时处死，并用它们的膝关节来评价骨关节炎的情况。骨关节炎损害的发生率降低或严重程度减轻表明治疗有效。
在以上测定中的所有活性表明本发明化合物可用于抑制软骨退化。

Claims (3)

1.式(I)化合物或其药学上可接受的盐或其溶剂化物在制备用于治疗性和/或预防性抑制软骨退化的药物方面的用途，其中所述式(I)化合物如下：
Figure C9411724300021
式中R1和R3独立地为氢、-CH3-、
Figure C9411724300022
式中的Ar是可任选地被取代的苯基；R2选自吡咯烷子基和哌啶子基。
2.按照权利要求1的用途，其中所述的化合物是其盐酸盐。
3.按照权利要求1的用途，其中所述的化合物是下式化合物或其盐酸盐：
Figure C9411724300031
CN94117243A 1993-10-15 1994-10-13 苯并噻吩衍生物在制备抑制软骨退化的药物方面的用途 Expired - Fee Related CN1053102C (zh)

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