CN1294913A - 化合物的制药应用 - Google Patents

化合物的制药应用 Download PDF

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CN1294913A
CN1294913A CN00124184A CN00124184A CN1294913A CN 1294913 A CN1294913 A CN 1294913A CN 00124184 A CN00124184 A CN 00124184A CN 00124184 A CN00124184 A CN 00124184A CN 1294913 A CN1294913 A CN 1294913A
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Abstract

式(Ⅰ)化合物、其可药用盐或溶剂化物在制备适于增加TGF－β在脑中表达的药物、适于抑制与阿尔茨海默症有关的炎性应答的药物、适于抑制β－淀粉样肽介导的神经毒性的药物中的应用,其中,R1、R2和R3定义如说明书所述。

Description

化合物的制药应用
本申请是1994年12月19日提交的、题为“抑制阿尔茨海默症的方法”的94119268．7号发明专利申请的分案申请。
阿尔茨海默症(AD)是一种退化性脑疾病，其临床特征在于逐渐丧失记忆、认知、推理、判断力和情绪稳定性，逐渐导致极度精神衰退并最终死亡。AD是老年人进行性精神衰退(痴呆)的常见原因，并且据信在美国它是第四位最常见的医学死因。AD已经广泛地发现于世界上不同的人种及种族中，并且表明是目前和将来主要的公共健康问题。目前估计仅在美国就有约2-3百万人患有此疾病。迄今为止证明AD是不能治愈的。
AD患者的大脑表现出神经元退化，并且具有称作成淀粉样(amyloidogenic)斑、淀粉样血管变性和神经元纤维tangles的各种损伤特性。大多数这类损伤、特别是成淀粉样斑和神经元纤维tangles一般发现于AD患者有关记忆和认知的几个重要人脑区。更有限的解剖学分布的少数这类损伤发现于大多数临床未患有AD的老年人的大脑中。成淀粉样斑和淀粉样血管变性也是21三体综合征(唐氏综合征)和具有Dutch-Type淀粉样变性的遗传性脑出血患者大脑的特征。目前，确诊AD通常需要观察患有上述疾病的已死亡患者的大脑组织、或者少数情况下观察侵入(invasive)神经外科手术中取出的少量脑组织活组织检查样品的上述损伤。
几类证据表明，具体的淀粉样基因蛋白、β-淀粉样蛋白(βAP)的进行性脑沉积在AD的发病机理中扮演了种子的作用，并且可能先于认知症状几年或几十年。参见Selkoe，(1991)Neuron 6：487。近来已表明βAP从培养基中生长的神经元细胞中释放出来，并且既存在于正常人的脑脊髓液(CFS)中也存在于AD患者的脑脊髓液中。参见Seubert等人，(1992)Nature 359：325-327。
几个团体已经揭示了这种斑的可能的病因学，这些团体证明了βAP对培养的神经元有直接神经毒性。近来报道βAP的直接神经毒性可通过用TGF-β一同处理减毒(Chao等，Soc．Neurosci．Abs．，19：1251(1993))。
最近，除了直接神经毒性，在AD脑中的炎性应答(可能由βAP引起)也对该疾病的病因学有贡献。用NBAID消炎痛进行的有限临床试验显示了阿尔茨海默痴呆进程的阻滞(Rogers等人，Science，260：1719-1720(1993))。
尽管在了解AD的根本机理方面已经取得了进展，但仍然需要寻找治疗这些疾病的组合物和方法。治疗方法可以有利地以药物为基础，这些药物能够增加TGF-β在脑中的表达，从而改善β-淀粉样肽介导的神经毒性和与AD有关的炎性应答。
本发明包括抑制阿尔茨海默症的方法，该方法包括给需要该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其中R1和R3独立地为氢、-CH3、
Figure 0012418400051
(C1-C4烷基)或 ，其中Ar是任意取代的苯基；R2选自吡咯烷基、六亚甲基亚氨基和哌啶子基。
本发明还提供了增加TGF-β在脑中表达的方法，该方法包括给需要该治疗的人施用有效量的式Ⅰ化合物。
本发明还提供了抑制β-淀粉样肽介导的神经毒性和与阿尔茨海默症(AD)有关的炎性应答的方法，该方法包括给需要该治疗的人施用有效量的式Ⅰ化合物。
本发明涉及下述发现：选自各种苯并噻吩的式Ⅰ化合物适用于抑制阿尔茨海默症的影响，尤其是据信该化合物通过增加TGF-β在脑中的表达抑制与该疾病有关的炎性应答。本发明包括给需要抑制阿尔茨海默症的人施用抑制阿尔茨海默症有效剂量的式Ⅰ化合物或其可药用盐或溶剂化物。该方法包括治疗和预防性施用。
术语“抑制”包括其通常接受的含义，包括阻止、防止、遏制和减缓、终止或逆转疾病的进程、严重程度或者所发生的症状或影响。
术语“有效量”视具体情况是指抑制阿尔茨海默症或其任何症状、抑制β-淀粉样肽介导的神经毒性或与阿尔茨海默症有关的炎性应答、或者增加TGF-β在脑中表达所需的化合物量。
通常可以将本发明化合物与普通的赋形剂、稀释剂或载体一起配制，并压成片剂、或者配制成便于口服的酏剂或溶液剂；或者通过肌内或静脉途径给药。该化合物可以经皮给药，并且可以配制成持续释放等剂型。
本发明方法所使用的化合物可以按既定的和类似的方法(例如US4，133，814、4，418，068和4，380，635中所述的方法，这些专利引入本文作为参考)制备。一般，该方法用具有6-羟基和2-(4-羟苯基)的苯并[b]噻吩开始。将起始化合物保护、烷基化或酰基化并脱保护，得到式Ⅰ化合物。在上述美国专利以及该申请的实施例中提供了这些化合物的制备实例。任意取代的苯基包括苯基和由C1-C6烷基、C1-C4烷氧基、羟基、硝基、氯、氟或三(氯或氟)甲基取代一次或二次的苯基。
本发明包括下式化合物，即雷洛昔芬：
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，所述药学上适用的盐因此包括乙酸盐、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、乙炔-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、甲磺酸盐、烟酸盐、异烟酸盐、硝酸盐、草酸盐、邻苯二甲酸盐、对苯二酸盐、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是由式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，并经过滤分离，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，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，药学上适用的盐溶解性能提高，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。
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，化合物也非常适合配制成持续释放等剂型。制剂也可这样构成，使他们仅仅或优选在肠道的特定部位，可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。
可以施用式Ⅰ化合物预防和／或治疗阿尔茨海默症。当用于治疗时，给已患有该疾病的宿主施用该化合物。
当用于预防时，给对阿尔茨海默症敏感的宿主、而不一定是已患有该疾病的宿主施用式Ⅰ化合物。这些宿主可以按照医学文献(参见例如Goate，Nature，349：704-706(1991))中所述的基因筛选和临床分析识别。对于预防或治疗目的，优选接受本发明化合物的一组人是绝经后的妇女(参见例如Paganini-Hill，Soc Neurosci Abs，19，1046)。
根据本发明，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，每天可接受的和有效的剂量为约0．1至约1000mg／天，更通常为约50-200mg／天。可以每天一次至约三次给需要治疗的患者服用上述剂量，或者根据需要，更经常地服用，用药时间达到足以抑制阿尔茨海默症的影响或其症状。
经常希望或需要将药物组合物直接或间接引入脑中。直接引入技术通常包括将药物释放导管置于宿主的室系统中以绕开血-脑屏障。间接引入技术(通常优选这种技术)包括配制该组合物，以通过亲水性药物转化为脂溶性药物使药物潜伏(latentiation)下来。一般来说，通过保护药物上存在的羟基、羰基和伯胺基，使得药物脂溶性更强并且顺利地通过血-脑屏障，实现所述潜伏。或者，可以通过动脉内输注高渗溶液(该溶液可以瞬时打开血-脑屏障)促进亲水药物的释放。
如同服用带有碱基(如哌啶子基环)的药物的做法一样，通常优选服用酸加成盐形式的式Ⅰ化合物。为此，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                          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。
已制备的化合物雷洛昔芬具体的胶囊制剂实例包括如下所示那些：
制剂2：雷洛昔芬胶囊
成分                         量(mg／胶囊)
雷洛昔芬                     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：雷洛昔芬胶囊
成分                         量(mg／胶囊)
雷洛昔芬                     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：雷洛昔芬胶囊
成分                         量(mg／胶囊)
雷洛昔芬                       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：雷洛昔芬胶囊
成分                           量(mg／胶囊)
雷洛昔芬                       50
淀粉，NF                       150
可流动的淀粉粉末               397
硅氧烷流体(350厘沲)            3．0
可以根据提供合理的变化对上述具体的制剂进行合理的改变。
用下述成分制备片剂。
制剂6：片剂
成分                           量(mg／片)
活性成分                        0．1-1000
微晶纤维素                      0-650
锻制二氧化硅               0-650
硬脂酸                     0-15
将上述成分混合，压成片剂。
另外，每片含0．1～1000mg活性成分的片剂可以按以下方法制备：
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(为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。使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药物的悬浮液剂按下法制备。
制剂8：悬浮液剂
成分                        量(mg／5ml)
活性成分                    0．1-1000
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         加至       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。
测定
实验设计
对于测定1和2，进行下列实验设计。
支链淀粉可以从Bachem，Inc．(Torrance，California)、PeninsulaLaboratories，Inc．(Belmont，California)、Sigma Chemicals(St．Louis，MO)购得，或者如上文所述合成。淀粉样蛋白-β(1-40)和逆β-淀粉样肽(40-1)可以从Bachem，Inc．购得。β2-小球蛋白可以从Sigma Chemicals(St．Louis，Missouri)购得。
用无热源无菌水即时配制肽贮液(1mM)，用确定的培养基稀释至指定浓度。将大鼠海马培养物(体外10-14天)用肽或赋形剂处理4天。通过相衬显微镜肉眼估测大鼠皮质培养物的成活力，并通过测量释放入培养基中的乳酸脱氢酶(LDH)进行定量。
测定1
用标准细胞培养技术体外培养一级大鼠海马(Primary rathippocampal)神经元。向培养的细胞中加入正常毒性浓度25-50μm的淀粉样蛋白-β(Aβ)肽。处理4天后，通过测量释放入培养基中的乳酸脱氢酶(LDH)评价成活力。在96孔板中，采用标准340nm动力LDH测定(Sig ma Catalog Number#228-20)，于20μl等分的限定条件的DMEM中测量乳酸脱氢酶。于37℃，在PC驱动的EL340 Microplate Biokinetics plate读数器(Bio-TekInstruments)上进行测定，用Delta SoftⅡ软件(V．3．30B，BioMetallics，Inc．)进行数据分析。每一测定都进行含有正常和升高的血清LDH(例如Sigma Enzyme Controls ZN和ZE)含量的质量对照标准。结果以LDH／L为单位表示，其中1单位定义为在测定条件下每分钟催化形成1微摩尔尼克酰胺腺嘌呤二核苷酸的酶的量。对于保护研究，在用淀粉样蛋白-β处理之前和／或同时，向培养物中加入式Ⅰ化合物。
与对照样相比，释放至培养基(神经毒性指示剂)中的LDH降低，说明了式Ⅰ化合物的活性。
测定2
对5-50只大鼠施行15分钟4条血管闭合，造成完全局部缺血。在15分钟闭合之前、同时和／或之后最多几小时，给实验动物或对照动物施用本发明化合物。在局部缺血损害和海马神经元损伤后3天处死动物，然后采用标准组织学技术肉眼评估纹状体。
神经元损伤的减少说明式Ⅰ化合物的活性。
测定3
选择5-50名妇女进行临床研究。这些妇女均为绝经后妇女，即在研究开始前已停止行经6-12个月，并且已诊断出患有早期阿尔茨海默症，预期在研究阶段其AD症状会恶化，但是其他方面总的来说是健康的。该研究设对照组，即将这些妇女分为两组，一组接受本发明的活性成分，另一组接受安慰剂。对患者与AD有关的记忆、认知、推理和其他症状设立基准点。试验组的妇女每天口服50-200mg活性成分。连续治疗6-36个月。准确记录各组基准点症状的情况，在研究结束时对这些结果进行比较。在每组受试者之间进行结果比较，还将每位患者自述的症状与研究开始前的症状进行比较。通过与AD有关的典型认知下降和／或行为破坏的减弱，说明了试验药物的活性。
在上述至少一个测定中的活性说明了式Ⅰ化合物的效用。

Claims (2)

1．式(Ⅰ)化合物、其可药用盐或溶剂化物在制备适于增加TGF-β在脑中表达的药物、适于抑制与阿尔茨海默症有关的炎性应答的药物、适于抑制β-淀粉样肽介导的神经毒性的药物中的应用，
Figure 0012418400021
其中，R1和R3独立地为氢、-CH3、
Figure 0012418400022
(C1-C6烷基)或 -Ar，其中Ar是任意取代的苯基；R2选自吡咯烷基、六亚甲基亚氨基和哌啶子基。
2．根据权利要求1的应用，其中所述化合物是下式化合物或其盐酸盐。
Figure 0012418400024
CN00124184A 1993-12-21 2000-08-14 化合物的制药应用 Pending CN1294913A (zh)

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