CN1058389C - 苯并噻吩类化合物的用途 - Google Patents

苯并噻吩类化合物的用途 Download PDF

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CN1058389C
CN1058389C CN94117126A CN94117126A CN1058389C CN 1058389 C CN1058389 C CN 1058389C CN 94117126 A CN94117126 A CN 94117126A CN 94117126 A CN94117126 A CN 94117126A CN 1058389 C CN1058389 C CN 1058389C
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L·J·布拉克
G·J·库里南
M·W·德雷帕
C·D·琼斯
D·E·塞勒
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Abstract

本发明提供了抑制子宫纤维变性的方法，该方法包括给需要治疗的人或其他哺乳动物施用有效量的式I化合物及其可药用盐或溶剂化物：其中R1和R3独立地为氢、-CH3、-C(O)-(C1-C6烷基)、或-C(O)-Ar，其中Ar是任意取代的苯基；R2是选自吡咯烷子基和哌啶子基的基团。

Description

苯并噻吩类化合物的用途
子宫纤维变性是一个古老的并且始终存在的临床问题，其存在方式多种多样，包括子宫肥大、子宫平滑肌瘤、子宫肌层肥大、子宫纤维变性和纤维变性子宫炎。实际上，子宫纤维变性是纤维瘤组织在子宫壁上不适宜的沉积这样一种病症。
该病症是妇女痛经和不育症的起因。对该病症的准确起因所知甚少，但是有证据表明它是纤维瘤组织对雌激素的不适宜应答。通过每日给兔子施用雌激素，经3个月使兔子诱发了该病症。每日给豚鼠施用雌激素，经4个月诱发了豚鼠的此种病症。此外，在大鼠中雌激素引起了同样的肥大。
子宫纤维变性最通常的治疗方法包括外科手术法，该治疗方法既是昂贵的，并且有时又是造成并发症如形成腹部粘连和感染的根源。对于某些患者，开始的手术仅仅是暂时性的治疗，并且纤维瘤再次生长。在这些情况下，要进行子宫切除术，以有效地既终止纤维瘤也终止了患者的生殖寿命。也可以施用促性腺激素释放激素拮抗剂，然而由于这类拮抗剂会导致骨质疏松症，其应用是适度的。
本发明提供了抑制子宫纤维变性的方法，该方法包括给需要治疗的人或其他哺乳动物施用有效量的式I化合物及其可药用盐和溶剂化物：其中R1和R3独立地为氢、-CH3、
Figure C9411712600052
或 ，其中Ar是任意取代的苯基；
R2是选自吡咯烷子基和哌啶子基的基团。
本发明涉及发现所选的一组2-苯基-3-芳酰基苯并噻吩类(各种苯并噻吩)，即式I化合物可用于抑制子宫纤维变性。本发明提供的治疗方法是：给需要抑制子宫纤维变性的病人施用抑制子宫纤维变性有效剂量的式I化合物或其可药用盐或溶剂化物。术语抑制定义为包括其通常可接受的含义，它包括对易患子宫纤维变性的患者的预防性治疗、控制和/或治疗已存在的子宫纤维变性。因此本发明方法包括医疗和/或(如果需要)预防性治疗。
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便于口服给药的片剂，或者配制成便于口服给药的酏剂或溶液剂；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，并且可以配制成持续释放等剂型。
用于本发明方法的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。通常该方法用具有6-羟基和2-(4-羟基苯基的苯并[b]噻吩开始。将起始化合物保护、烷基化并脱保护，得到式I化合物。在上述讨论的美国专利中提供了这些化合物的制备实例。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可药用的酸和碱加成盐，可药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氢氯酸、氢溴酸、氢碘酸、硝酸、硫酸、磷酸、连二磷酸等。盐也可用有机酸得到，可以应用的有机酸有例如脂肪族一和二羧酸、苯基取代的链烷酸、羟基链烷酸和羟基链烷二酸，芳香族酸、脂肪族和芳香族磺酸。所述可药用的盐包括乙酸盐、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、经基马来酸盐、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(teraphthalate)、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、水扬酸盐、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。
可药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天内从溶液中析出，可经过滤分离，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。
与衍生它们的化合物比较，可药用盐通常具有提高的溶解性能，因此常常更适用于配制成如液体剂或乳剂。
药用制剂可按本领域已知的方法制备。例如，将所述化合物与普通的赋形剂、稀释剂或载体进行配制，并制成片剂、胶囊、悬浮液、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基他纤维素衍生物、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；阻滞溶解剂如石蜡；吸收促进剂如季铵化合物；表面活性剂如鲸蜡醇、单硬脂酸甘油酯；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类。
该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，使他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，抑制子宫纤维变性所需要的式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，可接受和有效的日剂量为约0.1～约1000mg/天，更通常为约50～约200mg/天。需治疗的患者服用的上述剂量可为每天1次～约3次，或为了有效地抑制子宫纤维变性需要更经常地服用。
本发明还提供了抑制子宫纤维变性的方法，该方法包括顺序或同时服用本发明化合物和促性腺激素释放激素拮抗剂。
正如服用带有碱基(如哌啶子基环)的药物所常用的那样，通常最好服用酸加成盐形式的式I化合物。为此目的，以下剂型是适用的。
制剂
在以下制剂中，“活性成分”是指式I化合物。制剂1：明胶胶囊
用下列成分制备硬明胶胶囊：成分                       用量(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。
已制备的其中R2是哌啶子基的式I化合物(raloxifene)的具体胶囊制剂的实例包括如下所示制剂：制剂2：Raloxifene胶囊成分                       用量(mg/胶囊)Raloxifene                        1淀粉，NF                          112可流动的粉末状淀粉                225.3硅氧烷流体(350厘沲)               1.7制剂3：Raloxifene胶囊成分                           用量(mg/胶囊)Raloxifene                        5淀粉，NF                          108可流动的粉末状淀粉                225.3硅氧烷流体(350厘沲)               1.7制剂4：Raloxifene胶囊成分                            用量(mg/胶囊)Raloxifene                           10淀粉，NF                             103可流动的粉末状淀粉                   225.3硅氧烷流体(350厘沲)                  1.7制剂5：Raloxifene胶囊成分                            用量(mg/胶囊)Raloxifene                           50淀粉，NF                             150可流动的粉末状淀粉                   397硅氧烷流体(350厘沲)                  3.0可以对上述具体的制剂进行改变以符合所提供的合理的变化。用下列成分制备片剂：制剂6：片剂成分                        用量(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，并压成片剂。
另外，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                                    用量(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。将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剂量含0.1～1000mg药物的悬浮液按下法制备：制剂8：悬浮液成分                       用量(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1
给3～20位患子宫纤维变性的妇女服用本发明化合物。服用化合物的量为0.1-1000mg/天，用药期间为3个月。
在用药期间以及停用该化合物最多达3个月观察对这些妇女子宫纤维变性的作用。试验2
采用与试验1相同的方法，不同的是用药期间为6个月。试验3
采用与试验1相同的方法，不同的是用药期间为1年。试验4
A.在豚鼠中诱发纤维瘤。
延长使用雌激素刺激，以诱发性成熟雌性豚鼠的平滑肌瘤。经注射每周给动物施用3～5次雌二醇，共2-4个月，或直到肿瘤产生。每天用本发明化合物或赋形剂治疗，共治疗3-16周，然后将动物处死，取出子宫并分析肿瘤的消退。
B.在裸鼠中植入人子宫纤维瘤组织。
将人平滑肌瘤组织植入性成熟、阉割过的雌性裸鼠腹膜腔内和/或子宫肌层中。补充外源雌激素，以诱发植入组织的生长。在某些情况下，于植入前将所得到的肿瘤细胞体外培养。通过胃管饲法每天用本发明化合物或赋形剂治疗，共治疗3-16周，取出移植物并测量生长或消退。将动物处死，取出子宫并评估该器官的状况。试验5：A.收集人子宫纤维瘤组织，并保持于试管内作为主要的非转化的培养物。使外科手术标本通过无菌筛或者筛出或者挑离周围组织，得到单细胞悬浮液。将细胞保持在含10％血清和抗菌素的培养基中。测定雌激素存在与不存在两种情况下的生长速度。分析细胞产生补体成分C3的能力及其对生长因子和生长激素的应答。在体外，对培养物进行评估，以分析用孕激素、GnRH、本发明化合物和赋形剂处理后其增殖应答。每周评估类固醇激素受体的含量，以测定是否在体外保持了重要的细胞特性。使用了5-25位患者的组织。
至少一种上述试验中的活性表明，本发明化合物能够治疗子宫纤维变性。

Claims (4)

1.式I化合物或其可药用盐或溶剂化物在制备用于抑制子宫纤维变性的药物方面的用途，
Figure C9411712600021
其中R1和R3独立地为氢、-CH3、
Figure C9411712600022
或
Figure C9411712600023
其中Ar是被C1-C6烷基、C1-C4烷氧基、羟基、硝基、氯、氟、三氯甲基或三氟甲基任选取代一次或两次的苯基；
R2是选自吡咯烷子基和哌啶子基的基团。
2.按权利要求1的用途，其中所述化合物是其盐酸盐。
3.按权利要求1的用途，其中所述化合物适用于预防性给药。
4.按权利要求1的用途，其中所述化合物是下式化合物或其盐酸盐。
Figure C9411712600031
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