CN1049335C - 苯并噻吩类化合物的制药用途 - Google Patents

苯并噻吩类化合物的制药用途 Download PDF

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CN1049335C
CN1049335C CN94117125A CN94117125A CN1049335C CN 1049335 C CN1049335 C CN 1049335C CN 94117125 A CN94117125 A CN 94117125A CN 94117125 A CN94117125 A CN 94117125A CN 1049335 C CN1049335 C CN 1049335C
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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内膜异位的方法，该方法包括给需要治疗的人施用有效量的式I化合物或其可药用盐或溶剂化物，其中R1和R3独立地为氢、-CH3、-C-(C1-C6烷基)或-C-Ar，其中Ar是任意取代的苯基；R2选自吡咯烷子基和哌啶子基。

Description

苯并噻吩类化合物的制药用途
子宫内膜异位是一种严重的痛经疾病，它伴有严重的疼痛、子宫内膜块或腹膜腔内出血，并且经常导致不育症。这种疾病症状的病因表现为异位的子宫内膜生长，这是对正常激素控制的不适当的应答，并且发生于不适当的组织。由于子宫内膜生长的位置不适当，这种组织似乎产生了引起巨噬细胞浸润的局部炎症样的应答以及一系列导致产生疼痛应答的症状。这种疾病的准确病因学不是很清楚的，并且其通过激素疗法的治疗是多种多样的、难以确定的以及会造成多种不希望的并且可能是危险的副作用。
这种疾病的一种治疗方法是使用低剂量雌激素，以通过对中枢促性腺激素释放的负反馈作用抑制子宫内膜生长以及其后的卵巢产生雌激素；但是，有时必须连续使用雌激素以控制这些症状。使用雌激素经常会导致不希望的副作用，甚至有产生子宫内膜癌的危险。
另一种治疗方法由连续服用孕激素组成，这将导致经闭，并且通过抑制卵巢雌激素产生可引起子宫内膜生长的消退。使用慢性孕激素疗法经常伴有令人不快的CNS孕激素副作用，并且由于卵巢功能的抑制导致不育症。
第三种治疗由服用弱雄激素组成，它对于控制子宫内膜异位是有效的；但是，它们会引起严重的男性化作用。几种这类治疗还引起了与连续疗法有关的中度骨损失。
因此需要新的治疗子宫内膜异位的方法。
本发明提供了抑制子宫内膜异位的方法，该方法包括给需要治疗的人施用有效量的式I化合物及其可药用盐和溶剂化物，
Figure C9411712500041
其中R1和R3独立地为氢、-CH3、
Figure C9411712500042
(C1-C5烷基)或
Figure C9411712500043
，其中Ar是任意取代的苯基；
R2选自吡咯烷子基和哌啶子基。
本发明发现选自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内膜异位。本发明提供的治疗方法是：给需要抑制子宫内膜异位的病人服用抑制子宫内膜异位有效剂量的式I化合物或其可药用盐或溶剂化物。术语抑制被定义为包括其通常可接受的含义，它包括预防性地对易患子宫内膜异位的人进行治疗、控制和/或治疗已存在的子宫内膜异位。本发明方法本身包括医疗和/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，或者配制成酏剂或溶液剂；或者通过肌内或静脉途径给药。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所详述的方法，将它们收编在本申请中作为参考。一般，该方法从具有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，形成式I化合物。上述讨论的美国专利中提供了制备此类化合物的实例。取代苯基包括由C1-C5烷基、C1-C4烷氧基、羟基、硝基、氯、氟或三(氯或氟)甲基取代一次或二次的苯基。
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。盐也可由有机酸衍生得到，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、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(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。
可药用酸加成盐通常由式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。所述盐通常约在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，以及脂肪族和伯、仲和叔胺，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，可药用盐通常具有增强的溶解性能，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，将该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活性成分。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，抑制子宫内膜异位所需要的式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，每天可接受和有效的剂量为约0.1～约1000mg/天，更通常为约50～约200mg/天。需要治疗的患者服用该剂量可为每天1次～约3次，或者(如果需要)更经常地服用以有效地抑制子宫内膜异位。
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。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)的具体的胶囊制剂的实例包括如下所示那些：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合理的改变。
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，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。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各含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。然后加入足够的水至所需体积。
                     试验方法
在试验1和2中，可以测定服用本发明化合物14天和21天对移植的子宫内膜组织生长的影响。试验1
用12-30只成熟的雌性CD大鼠作为试验动物。将其分为数目相同的三组。监测所有动物的动情周期。在动情前期对每只雌性动物施行手术。每组中的雌性动物均切除了左侧子宫角，将其切成小方块，并将这些方块松散地缝合在与肠系膜血流邻近的各个部位。另外，第2组的雌性动物切除了卵巢。
手术后第一天，给第1组和第2组动物腹膜内注射水，共14天，给第3组动物腹膜内注射1.0mg/kg体重本发明化合物，也是14天。治疗14天后将各只雌性动物杀死，取出子宫内膜移植物、肾上腺、剩余的子宫以及卵巢(如果需要)，并进行组织学检查，称量卵巢和肾上腺的重量。试验2
用12-30只成熟的雌性CD大鼠作为试验动物。将其分成相等的两组。监测所有动物的动情周期。在动情前期对每只雌性动物施行手术。每组中的雌性动物均切除了左侧子宫角，将其切成小方块，并将这些小方块松散地缝合在与肠系膜血流邻近的各个部位。
手术后约50天，给第1组动物腹膜内注射水，共21天，给第2组动物腹膜内注射1.0mg/kg体重本发明化合物，也是21天。治疗21天后将各只雌性动物杀死，取出并称量子宫内膜移植物和肾上腺。测量移植物作为生长指标。监测动情周期。试验3
A.外科手术引起子宫内膜异位
用子宫内膜组织复制物(autographs)在大鼠和/或兔中引起子宫内膜异位。对生殖成熟期的雌性动物施行双侧卵巢切除术，并且补充外源性雌激素以提供特定的恒定的激素水平。将自体固有的子宫内膜组织植入5-150只动物的腹膜中，并且补充雌激素以引起移植组织生长。每天用胃管饲法补充本发明化合物进行治疗，共治疗3-16周，取出移植物并测量其生长或消退。处死动物，收集完整的子宫角以评估子宫内膜的状况。
B.将人子宫内膜组织移植到裸鼠中
将人子宫内膜损伤的组织移植到性成熟、卵巢切除的雌性裸鼠的腹膜中。补充外源性雌激素以引起移植组织生长。在某些情况下，于移植前体外培养所收集的子宫内膜细胞。每天用胃管饲法补充本发明化合物进行治疗，共治疗3-16周，取出移植物并测量其生长或消退。处死动物，收集子宫以评估完整的子宫内膜的状况。试验4
A.收集人子宫内膜损伤组织，保存于体外作为未转化的一级培养物。将外科手术样本通过无菌筛或者从外周组织上剥离，形成单细胞悬浮液。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。在用孕激素、GnRH、本发明化合物和赋形剂治疗后对体外培养物评价其增殖应答。每周评价类固醇激素受体的含量，以检测在体外是否保持了重要的细胞特征。共采用了5-25位患者的组织。
上述任何分析中的活性表明本发明化合物适用于治疗子宫内膜异位。

Claims (3)

1.式I化合物或其可药用盐或溶剂化物在制备适用于抑制子宫内膜异位的药物方面的用途，
Figure C9411712500021
其中R1和R3独立地为氢、-CH3、 (C1-C5烷基)或 ，其中Ar是任意取代的苯基；
R2选自吡咯烷子基和哌啶子基。
2.按照权利要求1的用途，其中所述化合物是其盐酸盐。
3.按照权利要求1的用途，其中所述化合物是下式化合物或其盐酸盐。
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