CN1109331A - 抑制强迫性神经官能症和消耗性失调的方法 - Google Patents
抑制强迫性神经官能症和消耗性失调的方法 Download PDFInfo
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Abstract
一种抑制强迫性神经官能症或消耗性失调的方
法，包括使需要治疗的患者服用有效数量的式I化合物或其药学上可接受的盐或溶剂化物，式I中的R1和R3各自独立地是氢、-CH3、
或
其中Ar是可任意取代的苯基；R2则选自吡咯烷基、六亚甲基亚氨基和哌啶子基。
Description
强迫性神经官能症是一种较少见的精神病，但是大约全部人口的六分之一有轻度的强迫性症状（Encyclopedia of Medicine，American Medical Association；Current Diagnosis，W.B.Saunders公司，1985）。其特征是以下的一种或两种症状。第一种包括反复的、侵入性的沉思默想，患者可能认识到这是无意义的，但他无法不想。其中最常见的是想象暴力、玷污、怀疑或个人的疾病。通常，患者不相信这些思想是现实的真实反映。但是，某些患者变得相信他们的强迫性反复思考是真实的、受着精神错乱的折磨。
第二种症状包括反复的仪式性的动作，患者认识到这是不需要的，但他无法停住自己不做。冼手、计数、反复查看和反复触摸是这类仪式性动作的实例。这些仪式性动作并非连续进行，而是时强时弱，反映了焦虑程度。如果阻止患者完成这些仪式性动作，通常会有惊慌和焦虑的紧张感觉。
在出现抑郁时回顾强迫性神经官能症患者的历史通常显示，强迫性观念与行为先于焦虑情绪的发生，而且抑郁感觉与强迫性观念与行为对生活的影响有关。在情形严重时，患者不能自理，完全被持续的强迫性沉思默想的困惑或完成无休止的强迫性仪式动作的要求所控制。
消耗性失调包括服用（通常是口服）的某物质数量超出正常范围、通常达到对健康有害的程度的那些失调症状。其实例是饮食或食欲失调（肥胖、食欲过盛、神经性厌食症、异食癖和心因性沉思）以及滥用或过度服用某物（吸烟、尼古丁瘾、酒精中毒、酗酒）。
众所周知，长期服用尼古丁会造成耐受性并且最终成瘾。服用烟草已在所有国家都变得极其普遍，尽管自己充分了解各种形式的烟草均有有害影响。因此很显然，烟草的服用即使不是极易耽溺也是极易成瘾的，烟草使服用者产生愉快和欢悦的感觉，虽然他们完全了解服用烟草的严重的长期有害影响。
吸烟是发达国家中可防止的发病率及早死的最主要的原因。平均说来，吸烟者比不吸烟者要早死几年，而且有更大的危险患上致命的心脏病、肺癌、口腔癌、喉癌、食道癌、胰腺癌、肾癌、膀胱癌、子宫颈癌、消化道溃疡和髋骨、腰及脊椎骨折。吸烟者的嗅觉和味觉受到损害，面部皱纹增多。吸烟的糖尿病人患蛋白尿的危险增加。
停止吸烟会有好处，即使是在生命的晚期，例如可以降低冠状动脉病患者死亡或心肌梗塞发作的危险，减缓颈动脉粥样硬化的发展和使慢性支气管炎好转。
与不吸烟者的孩子相比，吸烟者的孩子出生体重较轻，更常患呼吸道感染，肺功能效率较低，慢性耳部感染发病率高，而且本人更可能成为吸烟者。被动吸烟已证明增加宫颈癌、肺癌和心脏病的危险，而且会促成内皮损伤和血小板聚集。
最近已开展激烈的禁烟宣传，现在普遍认为，停止吸烟会产生许多不愉快的脱瘾症，例如易怒、焦虑、不安、不专心、眩晕、失眠、震颤、易饿和增重，当然还有对烟草的渴望。
酗酒和酒瘾（即，酒精中毒）是现代社会的严重的公众健康问题。根据美国政府在80年代中期进行的研究估计，仅在美国就有一千三百万成年人因过度饮酒而患有酒瘾症状，而另有七百万未显示症状的酗酒者。酒瘾和酗酒很费钱，据估计美国在1991年这方面花费远超过2000亿美元，而且没有下降或变平的趋势。由于酗酒而使个人遭受的社会和心理创伤（例如患有胎儿酒精综合症（FAS）的婴儿出生以及与饮酒有关的意外死亡、凶杀和自杀的受害者等）是巨大的。
虽然一般承认酒精中毒和酗酒与错综复杂的国际经济、社会、医学及心理影响有关，但在防止或减轻这些问题的后果方面能否成功仍然捉摸不定。只是在最近，认为只用道德规范就可以治疗酒精中毒和酗酒的公众观点才有所变化，包括意识到酒精中毒和酗酒是病因可以明白的心理失常，而且通过科学探索可以找到它的治疗方法。酗酒和酒瘾都是各式各样复杂的、而且仍然不完全清楚的过程造成的。日前，酒精问题的研究属于科学努力的主流。
本发明提供了抑制强迫性神经官能症或消耗性失调的方法，包括使需要治疗的患者服用有效数量的式I化合物或其药学上可接受的盐或溶剂化物
式I中R1和R3各自独立地是氢、-CH3、
（C1-C6烷基）或
，其中Ar是可任意取代的苯基，R2则选自吡咯烷基、六亚甲基亚氨基和哌啶子基。
本发明涉及下述发现：选自式I化合物的2-苯基-3-芳酰基苯并噻吩类（苯并噻吩）适合用于抑制强迫性神经官能症和消耗性失调及它们的症状，本发明提供的治疗和预防性处理的实施是使需要治疗的患者服用对抑制强迫性神经性官能症或消耗性失调或其症状有效的一定剂量的式I化合物或其药学上可接受的盐或溶剂化物。“抑制”一词包括它被普遍接受的含义，这包括使易患所述失调症或症状的人预防性服药，以及对已患的失调症或症状保持控制和/或治疗。因此，本发明的方法包括医药治疗和/或适当时的预防性服药。
雷洛昔芬（Raloxifene）是本发明的一种优选化合物，它是一种式I化合物的盐酸盐，其中R1和R3是氢，R2是1-哌啶基。
本发明包括用于治疗酒精中毒或酗酒、酒精过敏、消除饮酒反应、抑制饮酒冲动、诱发不耐酒性、防止对酒精中毒或酗酒敏感或不敏感的个人酒精中毒、以及限制有或没有遗传倾向的个人的酒精消耗的各种方法。
本发明的方法还包括帮助人们停止或减少服用烟草或尼古丁。最普通的服用烟草的形式是吸烟，最常见的吸烟是吸香烟。但是，本发明也有助于戒除所有各类的吸烟习惯以及使用鼻烟、嚼烟草等。本发明对于曾经用尼古丁替代物疗法替代或部分替代了烟草服用的人也有帮助。因此，可以帮助这类病人减少甚至完全戒除对所有各种形式尼古丁的依赖。
一般说来，将至少一种式I化合物与常用的赋形剂、稀释剂或载体一起配制并压制成片剂，或者配制成酏剂或溶液剂以便口服，或者通过肌内或静脉途径给药。这些化合物可以经皮给药，并且可以配制成缓释剂的剂量形式及类似形式。
本发明的方法中使用的化合物可以根据已确定的步骤制备，例如在美国专利4，133，814、4，418，068和4，380，635中详述的步骤，这些专利均在本发明中引用作为参考。通常，制备过程用有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、酰化和去保护以形成式I化合物。在上述美国专利中提供了制备这类化合物的实例。“或任意取代的苯基”包括苯基和被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。
本发明方法中使用的化合物与很多种有机和无机酸及碱形成药学上可接受的酸和碱加成盐，其中包括在药物化学中经常使用的生理上可接受的盐。这些盐也构成本发明的一部分，用来形成这些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。也可以使用由有机酸衍生得到的盐，这些酸的实例有脂族单羧酸和二羧酸、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，药学上可接受的这类盐包括乙酸盐、苯基乙酸盐、三氟乙酸盐、丙烯酸盐、抗坏血酸盐、苯甲酸盐、氯代苯甲酸盐、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、已炔-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、对苯二甲酸盐、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、丁二酸盐、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、对溴苯基磺酸盐、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。
药学上可接受的酸加成盐通常由式I化合物与等摩尔的或过量的酸反应形成。反应物通常在一种互溶剂（例如乙醚或苯）中结合。盐一般在约1小时到10天内从溶液中沉淀出来，可以用过滤法分离，或者用常规方式脱除溶剂。
通常用来形成盐的碱包括氢氧化铵和碱金属及碱土金属的氢氧化物，碳酸盐以及脂族的伯胺、仲胺和叔胺、脂族二胺。特别适合制备加成盐的碱包括氢氧化铵、碳酸钾、甲胺、二乙胺、乙二胺和环已胺。
这些药学上可接受的盐一般比它们从中衍生的化合物有更高的溶解度，因此常常更适合于象液体或乳状液这类制剂。
药物制剂可以用工艺上已知的步骤制备。例如，可以将这些化合物与常用的赋形剂、稀释剂或载体一起配制，形成片剂、胶囊、悬浮液、粉剂等。适合这些制剂的赋形剂、稀释剂和载体的实例包括以下物质：填料和增量剂（如淀粉、糖、甘露糖醇和硅酸衍生物）：粘合剂（如羧甲基纤维素和其它纤维素衍生物、藻酸盐、明胶及聚乙烯吡
咯烷酮）；增湿剂（如甘油）；崩解剂（如碳酸钙和碳酸氢钠）；延缓溶解剂（如石蜡）；再吸收加速剂（如季铵化合物）；表面活性剂（如十六烷醇、甘油单硬脂酸酯）；吸附性载体（如高岭土和膨润土）；以及润滑剂（如滑石、硬脂酸钙和镁以及固体的聚乙基乙二醇）。
这些化合物也可以配制成便于口服的酏剂或溶液，或是适合非肠道用药（例如肌内、皮下或静脉内）的溶液。另外，这些化合物很适合配制成持续释放的剂量形式及类似形式。可以将制剂做成只在或者优选在肠道的特定部位释放出活性成分，可能是在一段时间内。涂层、被膜和保护性基质可以用例如聚合物或蜡制备。
根据本发明，为抑制强迫性神经官能症或消耗性失调或它们的症状所需的式I化合物的具体剂量，取决于病症的严重性、服药途径和将由主治医师决定的有关因素。一般来说，普通使用的有效日剂量是每天约0.1到1000mg，更常用的是每天约50至约200mg。这样的剂量按照每天约1到3次对需要治疗的患者用药，或者根据有效治疗或预防失调或症状的需要增加用药次数。
通常优选服用酸加成盐形式的式I化合物，正如习惯上服用带碱性基团（如哌啶子基环）的药物一样。本发明化合物优选用于老年人（例如绝经后的妇女）。为此，提供了以下的口服剂量形式。
制剂
在以下制剂中，“活性组分”是指式I化合物。
制剂1：明胶胶囊
用以下物质制备硬明胶胶囊：
组分 数量(mg/胶囊)
活性组分 0.1-1000
淀粉(美国国家药典) 0-650
淀粉(可流动的粉末) 0-650
硅氧烷流体(350厘沲) 0-15
将各组分掺混,通过美国45目筛,装入硬明胶胶囊中。
已制得的具体的雷洛昔芬胶囊的实例包括以下列出的那些:
制剂2:雷洛昔芬胶囊
组分 数量(mg/胶囊)
雷洛昔芬 1
淀粉(美国国家药典) 112
淀粉(可流动的粉末) 225.3
硅氧烷流体(350厘沲) 1.7
制剂3:雷洛昔芬胶囊
组分 数量(mg/胶囊)
雷洛昔芬 5
淀粉(美国国家药典) 108
淀粉(可流动的粉末) 225.3
硅氧烷流体(350厘沲) 1.7
制剂4:雷洛昔芬胶囊
组分 数量(mg/胶囊)
雷洛昔芬 10
淀粉(美国国家药典) 103
淀粉(可流动的粉末) 225.3
硅氧烷流体(350厘沲) 1.7
制剂5:雷洛昔芬胶囊
组分 数量(mg/胶囊)
雷洛昔芬 50
淀粉(美国国家药典) 150
淀粉(可流动的粉末) 397
硅氧烷流体(350厘沲) 3.0
上述的具体配方可以根据所提供的合理的变化量加以改变。
用以下组分制备一种片剂
制剂6:片剂
组分 数量(mg/片)
活性组分 0.1-1000
微晶纤维素 0-650
煅制二氧化硅 0-650
硬脂酸 0-15
将各组分掺混并压制成片。
或者是,制备每片含0.1-1000mg活性组分的片剂如下:
制剂7:片剂
组分 数量(mg/片)
活性组分 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
滑石粉 1
将活性组分、淀粉和纤维素通过美国45目筛并充分混合。所形成的粉末与聚乙烯吡咯烷酮溶液混合，然后通过美国14目筛。将这样制得的颗粒在50°-60℃下干燥，通过美国18目筛。然后将事先通过60目美国筛的羧甲基纤维素钠、硬脂酸镁和滑石粉加到上述颗粒中，混合后在压片机上制成片。
制备每5ml剂量中含0.1-1000mg活性组分的悬浮液如下：
制剂8：悬浮液
组分 数量(mg/5ml)
活性组分 0.1-1000mg
羧甲基纤维素钠 50mg
糖浆 1.25mg
苯甲酸溶液 0.10mg
香味剂 适量
着色剂 适量
加纯化水至 5ml
使活性组分通过美国45目筛，与羧甲基纤维素钠和糖浆混合以形成均匀的浆体。用一些水将苯甲酸溶液、香味剂和着色剂稀释，在搅拌下加入。然后加入足量的水以达到所要求的体积。
测定
测定1
为了证实化合物在体内对酒精消耗的影响，设计了实验以测定对自由进食的金仓鼠乙醇摄取量的影响。选择金仓鼠是由于先前有报道说，与其它几种哺乳动物相比，它们能容纳并且偏爱高的乙醇摄入量。Kulkosky和Cornell（Pharmacol.Biochem.& Behav.11：439-444，1979）断定，在乙醇摄入和偏爱程度方面的物种差异与乙醇代谢方面的差别有关。
本文中所述实验使用的动物是2到6只雄性成年金仓鼠。将动物保持在每天亮14小时的亮/暗循环环境中，度过6周的适应期。动物随意接近食物和水。
为进行实验，将动物如上所述保持在带有4只250ml校正过的饮料瓶的单个大笼子中。饮料瓶装有不锈钢直吸管，用来将流体消耗量度到最接近的5ml。用装有玻璃漏斗的2盎司广口瓶收集饮料瓶中的溢出物。每3天测量一次金仓鼠的流体消耗量，以便使消耗体积大得足以得到合理的准确测量结果。
在6周适应期之后，称取动物的体重，记下水的摄入量。然后用15%的乙醇溶液代替4只饮料瓶中的2瓶水，测量水和乙醇水溶液的消耗量共2周。在开始这一自由进食阶段之后的2到3天内，金仓鼠对乙醇水溶液的爱好明显地高于水，记下最初的偏爱比（乙醇水溶液的摄取量除以水摄取量）。
作为对照，随后每天用不锈钢质动物喂食针喂食动物0.2ml水两次。根据测得的流体总摄取量，喂食水似乎对动物的吸饮习惯没有任何影响。6天之后，利用液体混合物喂食同一组金仓鼠式I化合物3到12周。喂食本发明化合物期间的偏爱比比初始偏爱比低，从而说明了式I化合物的活性。
测定2
选择5到50名妇女作临床研究。这些妇女是绝经后的，即，在研究开始之前已经停经6到12个月，健康良好，患有强迫性神经官能症或消耗性失调。由于这些失调症的特异性和主观性，此研究有一个无效剂对照组，即，将妇女分成两组，一组服用作为活性剂的雷洛昔芬，另一组则服用无效剂。试验组的妇女每日口服50-200mg药物。她们继续这样治疗3-12个月。准确记录两组中症状的数目和严重程度，在研究结束时比较这些结果。这些结果的比较包括各组的数目之间的比较，也包括每名患者与开始研究前记下的症状的对比结果。
式I化合物的效用由它们在上述测定中对一种或多种失调/症状的令人满意的作用得到了说明。
Claims (4)
1、一种适合抑制强迫性神经官能症的药物组合物，其中包括作为活性组分的式Ⅰ化合物或其药学上可接受的盐或溶剂化物
式Ⅰ中的R1和R3各自独立地是氢、-CH3、
(C1-C6烷基)或
，其中Ar是可任意取代的苯基：R2选自吡咯烷基、六亚甲基亚氨基和哌啶子基。
2、权利要求1中的药物组合物，其中所述的化合物是化学式如下的化合物或其盐酸盐。
3、一种适合抑制消耗性失调的药物组合物，其中包括作为活性组分的式I化合物或其药学上可接受的盐或溶剂化物。
式I中的R1和R3各自独立地是氢、-CH3、
（C1-C6烷基）或
，其中Ar是可任意取代的苯基；R2选自吡咯烷基、六亚甲基亚氨基和哌啶子基。
4、权利要求3的药物组合物，其中所述的化合物是化学式如下的化合物或其盐酸盐。
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| US6562862B1 (en) | 1994-10-20 | 2003-05-13 | Eli Lilly And Company | Methods of inhibiting physiological conditions associated with an excess of neuropeptide Y |
| EP0895781A3 (en) * | 1994-10-20 | 1999-07-07 | Eli Lilly And Company | Use of benzofurans, benzothiophenes or indoles for the manufacture of a medicament for the treatment of conditions associated with an excess of tachykinins |
| IL120266A (en) | 1996-02-28 | 2005-05-17 | Pfizer | Use of estrogen antagonists and estrogen agonists in the preparation of medicaments for inhibiting pathological conditions |
| TW442286B (en) * | 1996-02-28 | 2001-06-23 | Pfizer | New therapeutic uses of estrogen agonists |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4133814A (en) * | 1975-10-28 | 1979-01-09 | Eli Lilly And Company | 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents |
| US4418068A (en) * | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
-
1994
- 1994-12-19 ZA ZA9410076A patent/ZA9410076B/xx unknown
- 1994-12-19 CA CA002138458A patent/CA2138458A1/en not_active Abandoned
- 1994-12-19 KR KR1019940034930A patent/KR950016739A/ko not_active Withdrawn
- 1994-12-19 IL IL11204694A patent/IL112046A0/xx unknown
- 1994-12-19 NO NO944910A patent/NO944910L/no unknown
- 1994-12-19 EP EP94309486A patent/EP0659428A1/en not_active Withdrawn
- 1994-12-19 CN CN94119266A patent/CN1109331A/zh active Pending
- 1994-12-19 AU AU81556/94A patent/AU8155694A/en not_active Abandoned
- 1994-12-19 CZ CZ943224A patent/CZ322494A3/cs unknown
- 1994-12-19 HU HU9403656A patent/HUT71466A/hu unknown
- 1994-12-19 JP JP6314562A patent/JPH07196494A/ja active Pending
- 1994-12-19 RU RU94044323/14A patent/RU94044323A/ru unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HU9403656D0 (en) | 1995-02-28 |
| KR950016739A (ko) | 1995-07-20 |
| ZA9410076B (en) | 1996-06-19 |
| IL112046A0 (en) | 1995-03-15 |
| AU8155694A (en) | 1995-06-29 |
| NO944910L (no) | 1995-06-22 |
| NO944910D0 (no) | 1994-12-19 |
| RU94044323A (ru) | 1996-11-10 |
| CA2138458A1 (en) | 1995-06-22 |
| EP0659428A1 (en) | 1995-06-28 |
| JPH07196494A (ja) | 1995-08-01 |
| HUT71466A (en) | 1995-11-28 |
| CZ322494A3 (en) | 1995-08-16 |
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