CN104546852A - 用于治疗精神分裂症的(硫代)-氨甲酰基-环己烷衍生物和方法 - Google Patents
用于治疗精神分裂症的(硫代)-氨甲酰基-环己烷衍生物和方法 Download PDFInfo
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Abstract
本发明涉及(硫代)-氨甲酰基-环己烷衍生物、特别是反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺及其药学可接受的盐在制备用于治疗精神分裂症的药物中的应用。此外,本发明涉及治疗精神分裂症的方法,该方法通过给予(硫代)-氨甲酰基环己烷衍生物,特别是反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺及其药学可接受的盐来进行。
Description
本申请是申请日为2008年5月19日、发明名称为“用于治疗精神分裂症的(硫代)-氨甲酰基-环己烷衍生物和方法”的中国发明专利申请No.20088001717280.X的分案申请。
技术领域
本发明涉及(硫代)-氨甲酰基-环己烷衍生物、特别涉及反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺及其药学可接受的盐在制备用于治疗精神分裂症的药物中的应用。此外,本发明涉及治疗精神分裂症的方法,通过给予(硫代)-氨甲酰基环己烷衍生物,特别是反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺及其药学可接受的盐来进行。
背景技术
精神分裂症为终生使人失去能力的精神异常,其中据报导的全世界发生率约为1%,包括320万美国人(例如,参见National Instituteof Mental Health,Schizophrenia,http://www.nimh.nih.gov/healthinformation/schizophreniamenu.cfm 2006;Mueser和McGurk,Lancet 2004;363:2063-72,2004)。该病症通常在青春期或年轻的成年期过程中表现出来;主要症状分成三种范围:阳性症状,诸如妄想和幻觉;阴性症状,诸如无法驾驶和回避社交;和认知症状,诸如注意力和记忆力存在问题。它们导致社会和职业性功能障碍,不可避免地对家庭和更广泛的社会中受侵害个体的存在场所有明显影响。除精神病症状外,具有精神分裂症的患者还处于比一般群体更大的医学并存病的风险中。
使用多巴胺拮抗剂的药物治疗为控制精神分裂症的急性和后遗症期过程中的基石。目前的指导方针推荐非典型抗精神病药物,包括利培酮,奥氮平,喹硫平,齐拉西酮和阿立哌唑作为精神分裂症的第一线治疗药物。这些药物的一致性特征在于其双向作用模式:除拮抗多巴胺D2受体外,它们还成为5-羟色胺(5-HT2A)受体的有效抑制剂。
尽管其改进超过了典型的精神安定药,但是非典型抗精神病药物在有效控制所述疾病方面仍然存在缺陷。特别地,这些药物与副作用的高发生率相关(例如在高剂量下的锥体外系症状[EPS],镇静,心血管作用,诸如QTc延长,血液学改变,对性功能的作用,体重增加,代谢异常)。此外,治疗的耐受性仍然保持较高,其中10%-30%的患者对目前可利用的抗精神病药物几乎没有或完全没有响应,并且至多还有30%的患者仅存在部分治疗响应(例如,参见Lehman等,Am.J.Psychiatry,161(2Suppl),1-56,2004)。这已经导致高剂量的非典型抗精神病复方的实验应用和增加使用其它精神治疗药物的常见临床实践(例如,参见Zink等,Eur.Psychiatry,19:56-58,2004;Stahl和Grady,Curr.Med.Chem.,11,313-27,2004)。
根据美国精神病学协会对精神分裂症治疗的指导方针,60%-70%的患者在不进行维持治疗后1年内复发,并且几乎90%的患者在2年内复发(例如,参见Lehman等,Am.J.Psychiatry,161(2Suppl),1-56,2004)。
总之,在治疗精神分裂症中未得到充分满足的医学需求仍然存在,并且正在进行更多的尝试以鉴定和研发改进的抗精神病药。
在这种研发过程中,D3多巴胺受体表现为抗精神病药物治疗的可能的靶标。这种策略基于在作为所述疾病病理学的核心区域之一的复侧纹状体中具有最高密度的D3受体的脑分布和提示的作用(例如,参见Gurevich和Joyce,Neuropsychopharmacology,20,60-80,1999)。多巴胺D3受体表现为参与运动活动(例如,参见Shafer和Levant,Psychopharmacology(Berl),135,1-1,1998)和认知功能(例如,参见Ukai等,Eur.J.Pharmacol,324,147-51,1997;Smith等,Pharmacol Biochem.Behav.,63,201-11,1999)的调节。该受体的选择性拮抗剂在啮齿动物模型中调节乃至消除D2拮抗剂诱导的运动障碍(僵住症)(例如,参见Millan等,Eur.J.Pharmacol,321,R7-9,1997;Gyertyán等,[abstract].Int.J.Neuropsychopharmacol.,5 Suppl.1,174,2002),并且在单独给予时不会导致运动副作用或催乳素水平增加(例如,参见Reavill等,A.J.Pharmacol.Exp.Ther.,294,1154-65,2000;Millan等,J.Pharmacol.Exp.Ther.,293,1063-73,2000)。这提示锥体外系副作用的易发生性显著下降。经证实D3拮抗剂改善了由各种活性剂在啮齿动物(例如,参见Sigala等,Eur.J.Pharmacol,336,107-12,1997;Laszy等,Psychopharmacology(Berl),179,567-75,2005)和灵长类中导致的认知缺陷,从而提示了治疗精神分裂症中的认识障碍的有前景的方法的可能性。多巴胺D3受体拮抗剂增加了在习惯环境中的动物运动活动(例如,参见Waters等,J.Neural.Transm.Gen.Sect.,98,39-55,1994;Sautel等,J.Pharmacol Exp.Ther.,275,1239-46,1995;Gyertyán和Sághy,Behav.Pharmacol,15,253-62,2004)。这种活化作用可以证实为对所述疾病的阴性症状为有益的。
然而,迄今为止在所用的选择性D3拮抗剂在用于评价(人)抗精神病作用的各种动物模型中的作用缺乏,这提示单独使用“纯的”D3拮抗剂不能证明具有用于临床研发的充分稳固的抗精神病作用。已经证实多巴胺D2受体约60%-80%的占有率为临床上抗精神病作用必不可少的(例如,参见Nyberg等,Br.J.Psychiatry.Suppl,(29),40-4,May 1996;Seeman,Clin.Neurosci.Res.,1,53-60,2001)。后面这种现象为D2拮抗作用是抗精神病作用所必需的观点提供了基础。因此,认为给D2拮抗作用附加D3拮抗作用可以提供超过了现存抗精神病药在治疗精神分裂症中的显著优点,也就是无EPS、认知增强潜能和对阴性症状的增强作用。
美国专利公开号US2006/0229297中披露了作为D3和D2多巴胺受体亚型优选配体的(硫代)-氨甲酰基-环己烷衍生物,其具有式(I):
其中R1,R2,X和n如其中所定义。
匈牙利专利申请号HU P0700339中披露了反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺的盐。其中披露的一种具体的化合物为反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺盐酸盐,也称作反式-1{4-[2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基]-环己基}-3,3-二甲基-脲盐酸盐,其结构式如下所示:
这些(硫代)-氨甲酰基-环己烷衍生物为口服有效的并且是极为有效的多巴胺D3/D2受体拮抗剂,相对于D2受体,它们以更高的效力与D3受体结合。其D3受体拮抗作用比D2受体拮抗作用约高一个数量级,认为这种作用会抵抗D2受体拮抗剂产生的某些锥体外系副作用。除了对多巴胺D3的相对亲和力比对D2增高以外,例如,反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺盐酸盐对于其它受体位点诸如5-HT2C、组胺H1和肾上腺素能受体位点的效力较低,这提示出现副作用诸如EPS和体重增加的可能性很小。
因此,对治疗精神分裂症的症状和与精神分裂症相关的认知作用有效的、而没有与传统治疗相关的某些副作用的治疗方法存在现存和持续的需求。
发明内容
本发明涉及式(I)的(硫代)-氨甲酰基-环己烷衍生物,特别是反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺及其药学可接受的盐在制备用于治疗精神分裂症的药物中的应用。此外,本发明涉及治疗精神分裂症的方法,通过给予式(I)的(硫代)-氨甲酰基环己烷衍生物,特别是反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺及其药学可接受的盐来进行。
具体实施方式
本发明涉及式(I)的(硫代)-氨甲酰基-环己烷衍生物和/或其几何异构体和/或立体异构体和/或非对映体和/或盐和/或水合物和/或溶剂合物和/或多晶型物在制备用于治疗精神分裂症的药物中的应用:
其中
R1和R2各自独立地为氢、烷基、烯基、芳基、环烷基、芳酰基,或者R1和R2与相邻的氮原子一起形成杂环;X为O或S;n为1或2。
在某些实施方案中,当R1和/或R2表示烷基时,该烷基部分为取代或未取代的饱和烃基,其可以为直链或支链的并且包含约1-约6个碳原子(特别是1-4个碳原子),且任选被一个或多个C1-6烷氧羰基,芳基(例如苯基)或(C1-6烷氧羰基)-C1-6烷基或其组合取代。
在另外的实施方案中,R1和R2与相邻的氮原子一起形成杂环,其可以为饱和或不饱和的,任选取代的单环或双环,它们可以包含额外的选自O,N或S的杂原子。例如,杂环可以为吡咯烷,哌嗪,哌啶或吗啉。
在另外的实施方案中,当R1和/或R2表示烯基时,该烯基部分可以具有2-7个碳原子和1-3个双键。
在另外的实施方案中,当R1和/或R2表示芳基时,该芳基部分可以选自任选取代的单-,双-或三环芳基,诸如,但不限于苯基,萘基,氟壬基或蒽醌基(例如苯基或萘基)。该芳基部分可以被一个或多个C1-6烷氧基,三氟-C1-6烷氧基,C1-6烷氧羰基,C1-6烷酰基,芳基,C1-6烷硫基,卤素,氰基或其组合取代。
在另外的实施方案中,当R1和/或R2表示环烷基时,该环烷基部分可以选自任选取代的单-,双-或三环环烷基,诸如环己基或金刚烷基。
在另外的实施方案中,当R1和/或R2表示芳酰基时,其中的芳基部分如上述所定义,例如苯基。
药学可接受的盐包括通过使功能为碱的主要化合物与无机酸或有机酸反应生成的那些盐,例如盐酸盐,硫酸盐,磷酸盐,甲磺酸盐,樟脑磺酸盐,草酸盐,马来酸盐,琥珀酸盐,柠檬酸盐,甲酸盐,氢溴酸盐,苯甲酸盐,酒石酸盐,富马酸盐,水杨酸盐,扁桃酸盐和碳酸盐。药学可接受的盐还包括使功能为酸的主要化合物与适当的碱反应生成的那些盐,例如钠,钾,钙,镁,铵和胆碱的盐。本领域技术人员将会认识到,通过使要求保护的化合物与适当的无机酸或有机酸反应,经许多已知方法中的任一种都可以制备所要求保护的化合物的酸加成盐。可选择地,可以通过使本发明的化合物与适当的碱经各种已知方法反应制备碱金属盐和碱土金属盐。
下面是通过与无机酸或有机酸反应可以获得的酸式盐的其他实例:乙酸盐,己二酸盐,藻酸盐,柠檬酸盐,天冬氨酸盐,苯甲酸盐,苯磺酸盐,硫酸氢盐,丁酸盐,樟脑酸盐,二葡糖酸盐,环戊丙酸盐,十二烷基硫酸盐,乙磺酸盐,葡庚糖酸盐,甘油磷酸盐,半硫酸盐,庚酸盐,己酸盐,富马酸盐,氢溴酸盐,氢碘酸盐,2-羟基-乙磺酸盐,乳酸盐,马来酸盐,甲磺酸盐,烟酸盐,2-萘磺酸盐,草酸盐,扑酸盐,果胶酸盐,过硫酸盐,3-苯基丙酸盐,苦味酸盐,新戊酸盐,丙酸盐,琥珀酸盐,酒石酸盐,硫氰酸盐,甲苯磺酸盐,甲磺酸盐和十一酸盐。
在一个实施方案中,药学可接受的盐为盐酸盐。
本发明的某些化合物可以以不同多晶型存在。正如本领域公知的,“多晶型”是化合物结晶成一种以上不同结晶或“多晶型”种类的能力。多晶型物是固态下化合物分子具有至少两种不同排列或多晶型形式的化合物的固体结晶相。可以通过相同的化学式或组成来定义任何给定化合物的多晶型形式,由于两种不同化合物的晶体结构不同,它们的化学结构也不同。这些多晶型物的应用属于本发明的范围。
用于本发明的一些化合物可以以不同的溶剂合物的形式存在。当在结晶过程中溶剂分子掺入到化合物分子的晶格结构时,也可以形成本发明化合物的溶剂合物。例如,合适的溶剂合物包括水合物,例如一水合物,二水合物,倍半水合物和半水合物。这类溶剂合物的应用属于本发明的范围。
此外,本发明特别涉及反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺及其药学可接受的盐,更具体地说,涉及反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺盐酸盐在制备用于治疗精神分裂症的药物中的应用。
此外,本发明涉及治疗精神分裂症的方法,通过对有此需要的患者给予治疗有效量的式(I)的化合物和/或其几何异构体和/或立体异构体和/或非对映体和/或盐和/或水合物和/或溶剂合物和/或多晶型物作为活性成分来进行。此外,本发明特别涉及治疗精神分裂症的方法,通过对有此需要的患者给予治疗有效量的反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺或其药学可接受的盐,更具体地说,是给予治疗有效量的反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺盐酸盐作为活性成分来进行。
在某些实施方案中,以约0.1mg,约0.2mg,约0.3mg,约0.4mg,约0.5mg,约1mg,约1.5mg,约2mg,约2.5mg,约3mg,约3.5mg,约4mg,约4.5mg,约5mg,约5.5mg,约6mg,约6.5mg,约7mg,约7.5mg,约8mg,约8.5mg,约9mg,约9.5mg,约10mg,约10.5mg,约11mg,约11.5mg或约12mg的量给予所述活性成分。在另外的实施方案中,以这些剂量中的任意两种之间的范围的用量给予所述活性成分。例如,在一个实施方案中,以约1.5mg-约4.5mg的量给予所述活性成分。在另一个实施方案中,以约6mg-约12mg的量给予所述活性成分。在又另一个实施方案中,以约0.5mg-约12mg的量给予所述活性成分。
在典型的实施方案中,以约0.5mg,约1.0mg,约1.5mg,约3mg,约4.5mg,约6mg,约9mg或约12mg,例如约1.5mg,约3mg,约4.5mg,约6mg,约9mg或约12mg的量给予所述活性成分。
将所需的剂量作为一个或多个在适当的时间间隔给予的每日亚剂量在全天内给予,或可选择地以单剂量给予,例如在早晨或晚上给药。例如,可以将每日剂量分成1,2,3或4个分开的日剂量。
治疗期限可以为十年,数年,数月,数周或数天,只要有益作用持续。
在一个实施方案中,本发明涉及治疗精神分裂症的方法,通过对有此需要的患者给予约0.5mg的反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺或其药学可接受的盐来进行。
在一个实施方案中,本发明涉及治疗精神分裂症的方法,通过对有此需要的患者给予约1.0mg的反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺或其药学可接受的盐来进行。
在一个实施方案中,本发明涉及治疗精神分裂症的方法,通过对有此需要的患者给予约1.5mg的反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺或其药学可接受的盐来进行。
在另一个实施方案中,本发明涉及治疗精神分裂症的方法,通过对有此需要的患者给予约3mg的反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺或其药学可接受的盐来进行。
在另一个实施方案中,本发明涉及治疗精神分裂症的方法,通过对有此需要的患者给予约约4.5mg的反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺或其药学可接受的盐来进行。
在另一个实施方案中,本发明涉及治疗精神分裂症的方法,通过对有此需要的患者给予约6mg的反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺或其药学可接受的盐来进行。
在另一个实施方案中,本发明涉及治疗精神分裂症的方法,通过对有此需要的患者给予约9mg的反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺或其药学可接受的盐来进行。
在另一个实施方案中,本发明涉及治疗精神分裂症的方法,通过对有此需要的患者给予约12mg的反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺或其药学可接受的盐来进行。
在另外的实施方案中,给予的活性成分为反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺盐酸盐。
在一个实施方案中,以一个或两个分开的每日剂量给予所述活性成分。
在一个实施方案中,活性成分的给药在治疗精神分裂症的认知症状中提供了治疗效果。在另一个实施方案中,活性成分的给药在治疗精神分裂症的阳性症状中提供了治疗效果。在另一个实施方案中,活性成分的给药在治疗精神分裂症的阴性症状中提供了治疗效果。
在其它实施方案中,给药在治疗精神分裂症的情感症状、精神分裂症的后遗症或精神分裂症样精神障碍中提供了治疗效果。
可以得到描述适于给予本发明化合物的各种制剂的制备方法的大量标准参考文献。例如,在Handbook of Pharmaceutical Excipients,American Pharmaceutical Association(最新版);PharmaceuticalDosage Forms:Tablets(Lieberman,Lachman和Schwartz编辑)最新版,Marcel Dekker,Inc.出版和Remington's PharmaceuticalSciences(Arthur Osol编辑),1553-1593(最新版)中包含了可能的制品和制剂的实例。
给药方式和剂型与对指定治疗应用而言期望和有效的化合物或组合物的用量极为相关。
合适的剂型包括,但不限于口服,直肠,舌下,粘膜,鼻部,眼部,皮下,肌内,静脉内,透皮,脊柱,鞘内,关节内,动脉内,蛛网膜下,支气管,淋巴和子宫内(intra-uterille)给药和用于全身递送活性成分的其它剂型。优选适合于口服给药的制剂。
为了制备这些药物剂型,将活性成分与药用载体按照常规药物混合技术紧密混合。所述的载体可以采用各种形式,这取决于给药所需的制剂形式。
在制备口服剂型的组合物中,可以使用任意的常用药用介质。因此,就液体口服制剂而言,诸如,例如混悬液,酏剂和溶液,合适的载体和添加剂包括水,二醇类,油,醇类,矫味剂,防腐剂,着色剂等。就固体口服制剂而言,诸如,例如粉末,胶囊和片剂,合适的载体和添加剂包括淀粉,糖类,稀释剂,造粒剂,润滑剂,粘合剂,崩解剂等。由于它们易于给药,所以片剂和胶囊代表了最有利的口服单位剂型。如果需要,可以用标准技术给片剂包糖衣或肠溶衣。
就非肠道给药而言,所述的载体通常包括无菌水,不过,可以包括其它成分,例如辅助溶解或防腐的成分。还可以制备可注射溶液,在这种情况中,可以使用合适的稳定剂。
在某些应用中,有利的是使用“载体化”形式的活性剂,诸如通过将活性剂包囊在脂质体或其它胶囊用材料的介质中,或通过用共价键合,螯合或缔合连接将活性剂固定在合适的生物分子上,诸如选自蛋白质,脂蛋白,糖蛋白和多糖类的那些。
本发明的治疗方法可以使用适合于口服给药的制成分散单位的制剂,诸如胶囊,扁囊剂,片剂或锭剂,它们各自包含预定量的活性成分作为粉末或颗粒。任选可以使用在含水液体或无水液体中的混悬液,诸如糖浆剂,酏剂,乳剂或顿服剂。
可以通过压制或模制或湿法制粒,任选使用一种或多种辅助成分制备片剂。可以通过在合适的机器中使用任选混合了例如粘合剂,崩解剂,润滑剂,惰性稀释剂,表面活性剂或放电剂的能自由流动形式(诸如粉末或颗粒)的活性化合物压制制备压制片。可以通过在合适的机器中模制制备粉状活性化合物与合适载体的混合物组成的模制片。
可以通过将活性化合物加入到浓的糖例如蔗糖的水溶液中制备糖浆剂,还可以向其中加入任意的辅助成分。这类辅助成分可以包括矫味剂,合适的防腐剂,阻止糖结晶的试剂,和增加任意其它成分溶解度的试剂,诸如多元醇,例如甘油或山梨醇。
适合于非肠道给药的制剂通常包括活性化合物的无菌水制剂,其优选与接受者的血液等渗(例如生理盐水溶液)。这类制剂可以包括悬浮剂、增稠剂、和脂质体或其它为使化合物靶向血液成分或一种或多种器官而设计的微粒系统。可以将这些制剂制成单剂量或多剂量形式。
非肠道给药可以包括全身递送或直接递送至CNS的任意合适的形式。例如,给药可以为静脉内,动脉内,鞘内,肌内,皮下,肌内,腹内(例如腹膜内)等,给药可以通过输注泵(体外或可植入的)或适合于所需给药方式的任意其它合适的装置进行。
鼻部和其它粘膜喷雾剂(例如可吸入形式)可以包含活性化合物与防腐剂和等渗剂的纯水溶液。优选将这类制剂调节至与鼻或其它粘膜相容的pH和等渗状态。可选择地,它们可以为悬浮于气体载体中的分散的固体细粉形式。可以通过任意合适的装置或方法,例如用喷雾器,雾化器,计量吸入器等递送这类制剂。
可以使用可可脂,氢化脂肪或氢化脂肪羧酸这类合适的载体将用于直肠给药的制剂制成栓剂。
可以通过将活性剂掺入触变的或凝胶状载体,诸如纤维质介质(例如甲基纤维素或羟乙基纤维素)来制备透皮制剂,然后将所得制剂填充在适合于固定在与穿戴者皮肤接触的表皮上的透皮装置。
除上述成分外,本发明的制剂还可以包括一种或多种辅助成分,其选自稀释剂,缓冲剂,矫味剂,粘合剂,崩解剂,表面活性剂,增稠剂,润滑剂,防腐剂(包括抗氧化剂)等。
本发明的制剂可以具有本领域技术人员公知的速释,缓释,延迟释放或任意其它释放特性。
在本发明的一个实施方案中,将反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺或其药学可接受的盐作为一种或多种额外治疗剂(例如抗精神病药,抗抑郁药)的辅助治疗给予。在另一个实施方案中,可以将反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺或其药学可接受的盐作为联合疗法与一种或多种额外的治疗剂(例如抗精神病药,抗抑郁药)联合给予。
抗精神病药可以为非典型或典型抗精神病药,优选非典型抗精神病药。非典型抗精神病药物的实例包括,但不限于奥氮平,氯氮平,利培酮,舍吲哚,喹硫平,阿立哌唑,齐拉西酮和曲米帕明。典型抗精神病药物的实例包括,但不限于乙酰丙嗪,苯哌利多,溴西泮,溴哌利多,氯丙嗪,氯普噻吨,氯噻平,氰美马嗪,地西泮,地西拉嗪,氟哌利多,氟哌噻吨,氟奋乃静,氟司必林,氟哌啶醇,辛胺醇,异丙碘铵,左美丙嗪,左舒必利,洛沙平,美哌隆,美索达嗪,吗茚酮,奥昔哌汀,甲羟哌呤苯并噻庚,五氟利多,培拉嗪,哌氰嗪,奋乃静,匹莫齐特,匹泮哌隆,哌泊噻嗪,丙氯拉嗪,丙嗪,异丙嗪,丙硫喷地,维生素B6,舒必利,舒托必利,丁苯那嗪,硫丙拉嗪,硫利达嗪,硫必利,替沃噻吨,三氟拉嗪,三氟丙嗪,苯海索和珠氯噻醇。
定义
术语“药学可接受的”意旨在动物或人的体内应用中生物学或药理学相容的,并且优选意旨得到联邦或州政府的管理机构批准的或列入美国药典或其它公认药典中用于动物、更具体地说是用于人的。
术语“精神分裂症”包括精神障碍,其特征在于,思维和感觉受到破坏,并且包括精神分裂症(和所有其亚型;妄想狂样型,紧张型精神分裂症,分裂型,后遗症,未分化型的)和其它精神病(如Diagnosticand Statistical Manual for Mental Disorders,第4版,Washington,D.C(1994):American Psychiatric Association或The ICD-10Classification of Mental and Behavioural Disorders:ClinicalDescriptions and Diagnostic Guidelines,Geneva(1992):WorldHealth Organization中各自所述的),诸如精神分裂症样和情感性分裂症,短暂精神障碍等。
在临床评价中,精神分裂症通常被标记为“阳性症状”,诸如幻觉(尤其是通常经历为发声的幻听),分裂型思维过程和妄想;以及“阴性症状”,其包括情感冷淡,失语症,缺乏情感反应和兴趣缺失。
术语“精神分裂症的阴性症状”意旨可反映出功能、定向思维或活动的“丧失”的精神分裂症症状类型。精神分裂症的阴性症状为本领域众所周知的,包括情感冷淡(其特征在于,例如不变和/或无反应的面部表情,眼睛接触弱和身体语言减少),失语症(“言语贫乏”或简短,简洁和/或空洞答复),缺乏情感反应(其特征在于,着手和进行目标导向活动的能力下降或丧失),兴趣缺失(失去兴趣或快乐),不合群(驾车和社交减少),情感淡漠和本领域技术人员公知的其它阴性症状。可以使用本领域公知的任何方法评价精神分裂症的阴性症状,包括,但不限于简明精神病评定量表(BPRS)和阳性与阴性症状量表(PANSS)。BPRS和PANSS具有可以用于确定阴性症状的子表或要素。已经设计了其它表用来确定具体的阴性症状:例如,阴性症状的评定量表(SANS),阴性症状评价(NSA)和缺陷型精神分裂症诊断量表(SDS)。BPRS和PANSS的子表也可以用于评价阳性症状,不过,具体评价阳性症状的方法也可以得到(例如用于评价阳性症状的表或SAPS)。
术语“与精神分裂症相关的认知缺陷”意旨精神分裂症患者中的认知缺陷。精神分裂症中的认知缺损为该病的核心特征(即并非治疗结果或临床症状)。认知缺陷包括,但不限于注意力/警觉,工作记忆,言语学习和记忆力,视觉空间的记忆力,推理/解决问题和社会认知的缺陷。存在用于测定精神分裂症中认知缺陷的大量神经心理学测验,诸如威斯康辛卡片分类测验(WCST)。
术语“治疗(treat)”,“治疗(treatment)”和“治疗(treating)”意旨下列情况中的一种或多种:
(a)减轻或缓解受试者病症的至少一种症状,包括,例如过敏性和炎性病症,诸如哮喘和COPD;
(b)减轻或缓解受试者经历的病症表现的强度和/或期间,包括,但不限于对指定刺激(例如压力,组织损伤,寒冷温度等)的反应的那些;
(c)阻止,延缓发作(即在病症临床表现前的期间)和/或降低病症发展或恶化的风险。
“有效量”意旨在对患者(例如哺乳动物)给药以治疗疾病(即精神分裂症)时足以进行这种疾病的治疗或足以调节多巴胺受体(例如多巴胺D2和/或多巴胺D3受体)以达到本发明目的的活性成分的用量。“有效量”会根据化合物,疾病及其严重性和所治疗患者的年龄,体重,反应性等的不同而改变。
“有效量”意旨在对患者(例如哺乳动物)给药以治疗疾病或病症时,足以进行这种疾病或病症的治疗或足以调节多巴胺受体(例如多巴胺D2和/或多巴胺D3受体)以达到本发明目的的活性成分的用量。“有效量”会根据化合物,疾病及其严重性和所治疗患者的年龄,体重,反应性等的不同而改变。
治疗性化合物的给予为疾病或病症的有效治疗方案的受试者或患者优选为人,但也可以是任意的动物,包括上下文试验或筛选或活性实验中的实验室动物。因此,正如本领域技术人员易于理解的,本发明的方法、化合物和组合物特别适合施用于任意动物,特别是哺乳动物,包括但不限于人,家养动物(诸如猫科或犬科动物),农场动物(诸如,但不限于牛,马,山羊,绵羊和猪),野生动物(不论是户外的还是动物园中的),研究用动物(诸如小鼠,大鼠,家兔,山羊,绵羊,猪,狗,猫等),鸟类(诸如鸡,火鸡,鸣鸟)等,即,适用于兽医应用。
术语“约”或“近似”意旨在如本领域技术人员可确定的具体值的可接受的误差范围内,这部分取决于如何测量或测定该值,即测量系统的局限性。例如,“约”可以意旨本领域中每次实践操作在1或1以上的标准偏差范围内。可选择地,“约”就组合物而言可以意旨在至多±20%,优选至多±10%,更优选至多±5%范围内。可选择地,特别是对生物系统或方法而言,该术语可以意旨在数值的一个数量级范围内,优选在5-倍且更优选在2-倍范围内。如果在本说明书和权利要求中描述了具体的值,那么除非另作陈述,否则术语“约”意旨该具体值的可接受的误差范围。
实施例
下列实施例仅为了例证本发明,但不应被视为以任何作为许多变化形式和等效方案的方式限定本发明的范围,所述的变化形式和等效方案包括在本发明范围内,这对本领域技术人员而言在阅读本说明书披露的内容时显而易见。
实施例1
本临床研究以多中心、随机化、双盲、安慰剂对照、平行组的固定剂量研究进行。选择满足标准的375位住院患者,所述标准为:(i)目前满足或过去已经满足基于DSM-IV(SCID)的组织临床会诊的“诊断与统计手册”,第4版,正文修订(DSM-IV-TR)的精神分裂症标准(295.30妄想狂样型,295.10分裂型,295.20紧张型或295.90未分化型);(ii)在就诊1(第1次就诊)和就诊2(第2次就诊)时具有PANSS总分≥70且≤120;(iii)在就诊1和就诊2时对PANSS的项目P1(妄想)或P3(幻觉行为)具有评分≥4(中度);和(iv)在就诊1和就诊2时对PANSS的项目P2(概念分裂)或P6(多疑/迫害)具有评分≥4(中度)。
本研究为期10周;6-周双盲治疗和4-周安全性随访。在随机选择之前进行至多7天的无药物清除期。在筛选期过程中患者住院。在随机选择和开始双盲药物治疗后患者保持住院最少21天。
评价方案如表1中所示。
表1:评价方案
在就诊1时满足全部合格中选条件标准的患者进入至多7天的无药物清除期。在清除期后,对满足全部合格中选条件标准的患者指定就诊2时的随机号并且配发相应的双盲研究药物的泡罩包用于第1周的双盲治疗。
将全部满足合格中选条件标准的患者随机(1:1:1)分入三个治疗组之一:
(I)安慰剂;
(II)1.5-4.5mg反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺盐酸盐;或
(III)6-12mg反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺盐酸盐。
给患者提供同样形式呈现的包含1.5mg,3.0mg或6.0mg的反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺盐酸盐或安慰剂的胶囊。
将全部研究药物分配入泡罩包,每周1个泡罩包。每个卡板上包含按照10列和3行排列的30粒胶囊,足以持续该周的7天和额外3天的给药量。将泡罩包的结构提供在表2中。将全部研究药物作为每日单剂量在睡前给予。如果出现耐受问题,那么将给药改成早晨;不过,任何改变都必须在两个连续剂量之间间隔至少24小时才能允许。
表2:双盲研究给药方案
在第1天和第2天,给予全部患者来自泡罩包第1行的1粒胶囊。在第3天,如果反应不充分并且无耐受问题,那么可以将该剂量增加至2粒胶囊(第1和2行)。从第5天开始,可以根据响应和耐受性的不同将该剂量增加1粒胶囊而达到最多3粒胶囊(第1,2和3行)。就随机分入(II)组(1.5-4.5mg反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺盐酸盐)的患者而言,可以在到第5天时达到4.5mg的最大剂量,而就随机分入(III)组(6-12mg反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺盐酸盐)的患者而言,可以到第9天时达到12mg的最大剂量。任何剂量增加均按照1粒胶囊的递增量进行。
使用建立的分级方法进行的评价包括:
就诊 | 天 | 评价 |
1 | 至多7 | SCI-PANSS |
2 | 0 | SCI-PANSS,CGI-S,CDSS |
3 | 7 | SCI-PANSS,CGI-S,CGI-I |
4 | 14 | SCI-PANSS,CGI-S,CGI-I |
5 | 21 | SCI-PANSS,CGI-S,CGI-I,CDSS |
6 | 28 | SCI-PANSS,CGI-S,CGI-I |
7 | 35 | SCI-PANSS,CGI-S,CGI-I |
8 | 42 | SCI-PANSS,CGI-S,CGI-I,CDSS |
PANSS总分(例如,参见Kay等,Schizophr.Bull.,13,261-76,1987)
CGI-S:临床综合印象量表-严重性(例如,参见Guy ECDEUAssessment Manual for Psychopharmacology.Rockville,Md:USDepartment of Health,Education;和Welfare,218-22,PublicationADM 76-338,1976)
CGI-I:临床综合印象量表-改善(例如,参见Guy ECDEUAssessment Manual for Psychopharmacology.Rockville,Md:USDepartment of Health,Education,和Welfare,218-22,PublicationADM 76-338,1976)
CDSS:卡尔加里精神分裂症抑郁量表(例如,参见Addington等,Schizophr.Res.,19,205-12,1996)。
在第14,21,28,35,42,56和70天时采集血样。
可以理解上述使用反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺盐酸盐的治疗方案在治疗精神分裂症中与使用安慰剂治疗的患者相比时表现出显著的有效性。
本发明并不限于本文所述的具体实施方案的范围。实际上,除本文所述的那些外,对本发明进行各种变型对本领域技术人员而言从上述描述和附图中显而易见。这些变型也落入本发明权利要求的范围。可以进一步理解的是,所有的值均为近似的并且为描述而提供。
将上文引述的所有申请,专利和公开文献的全部披露内容完整地引入本文作为参考。
Claims (41)
1.治疗精神分裂症的方法,包括对有此需要的患者给予治疗有效量的式(I)的(硫代)-氨甲酰基-环己烷衍生物和/或其几何异构体和/或立体异构体和/或非对映体和/或盐和/或水合物和/或溶剂合物和/或多晶型物:
其中
R1和R2各自独立地为氢、烷基、烯基、芳基、环烷基、芳酰基,或者R1和R2与相邻的氮原子一起形成杂环;X为O或S;n为1或2。
2.权利要求1所述的方法,其中式(I)的化合物为反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺和/或其盐和/或水合物和/或溶剂合物和/或多晶型物。
3.权利要求1所述的方法,其中式(I)的化合物为反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺盐酸盐和/或其水合物和/或溶剂合物和/或多晶型物。
4.权利要求1所述的方法,其中式(I)化合物的治疗有效量约为0.1-12mg。
5.权利要求4所述的方法,其中式(I)化合物的治疗有效量约为0.5mg。
6.权利要求4所述的方法,其中式(I)化合物的治疗有效量约为1.0mg。
7.权利要求4所述的方法,其中式(I)化合物的治疗有效量约为1.5mg。
8.权利要求4所述的方法,其中式(I)化合物的治疗有效量约为3mg。
9.权利要求4所述的方法,其中式(I)化合物的治疗有效量约为4.5mg。
10.权利要求4所述的方法,其中式(I)化合物的治疗有效量约为6mg。
11.权利要求4所述的方法,其中式(I)化合物的治疗有效量约为9mg。
12.权利要求4所述的方法,其中式(I)化合物的治疗有效量约为12mg。
13.权利要求4-12中任一项所述的方法,其中以1,2,3或4个分开的每日剂量给予式(I)的化合物。
14.权利要求4-13中任一项所述的方法,其中式(I)的化合物在治疗精神分裂症的认知症状中提供了治疗效果。
15.权利要求4-13中任一项所述的方法,其中式(I)的化合物在治疗精神分裂症的阴性症状中提供了治疗效果。
16.权利要求4-13中任一项所述的方法,其中式(I)的化合物在治疗精神分裂症的阳性症状中提供了治疗效果。
17.权利要求4-13中任一项所述的方法,其中式(I)的化合物在治疗精神分裂症的情感症状和后遗症中提供了治疗效果。
18.权利要求4-13中任一项所述的方法,其中式(I)的化合物在治疗精神分裂症的继发性社会和职业性功能障碍中提供了治疗效果。
19.权利要求4-13中任一项所述的方法,其中式(I)的化合物在治疗精神分裂症样精神障碍和情感性分裂症中提供了治疗效果。
20.权利要求4-19中任一项所述的方法,其中将式(I)的化合物作为一种或多种额外的治疗剂的辅助治疗给予。
21.权利要求4-19中任一项所述的方法,其中将式(I)的化合物作为与一种或多种额外的治疗剂的联合疗法联合给予。
22.治疗有效量的式(I)的(硫代)-氨甲酰基-环己烷衍生物和/或其几何异构体和/或立体异构体和/或非对映体和/或盐和/或水合物和/或溶剂合物和/或多晶型物在制备用于治疗精神分裂症的药物中的应用:
其中
R1和R2各自独立地为氢、烷基、烯基、芳基、环烷基、芳酰基,或者R1和R2与相邻的氮原子一起形成杂环;X为O或S;n为1或2。
23.权利要求22所述的应用,其特征在于,式(I)的化合物为反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺和/或其盐和/或水合物和/或溶剂合物和/或多晶型物。
24.权利要求22所述的应用,其特征在于,式(I)的化合物为反式-4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-N,N-二甲基氨甲酰基-环己胺盐酸盐和/或其水合物和/或溶剂合物和/或多晶型物。
25.权利要求22-24中任一项所述的应用,其特征在于,式(I)化合物的治疗有效量约为0.1-12mg。
26.权利要求25所述的应用,其特征在于,式(I)化合物的治疗有效量约为0.5mg。
27.权利要求25所述的应用,其特征在于,式(I)化合物的治疗有效量约为1.0mg。
28.权利要求25所述的应用,其特征在于,式(I)化合物的治疗有效量约为1.5mg。
29.权利要求25所述的应用,其特征在于,式(I)化合物的治疗有效量约为3.0mg。
30.权利要求25所述的应用,其特征在于,式(I)化合物的治疗有效量约为4.5mg。
31.权利要求25所述的应用,其特征在于,式(I)化合物的治疗有效量约为6mg。
32.权利要求25所述的应用,其特征在于,式(I)化合物的治疗有效量约为9mg。
33.权利要求25所述的应用,其特征在于,式(I)化合物的治疗有效量约为12mg。
34.权利要求25-33中任一项所述的应用,其特征在于,以1,2,3或4个分开的每日剂量给予式(I)化合物的治疗有效量。
35.权利要求25-34中任一项所述的应用,其特征在于,其用于治疗精神分裂症的认知症状。
36.权利要求25-34中任一项所述的应用,其特征在于,其用于治疗精神分裂症的阴性症状。
37.权利要求25-34中任一项所述的应用,其特征在于,其用于治疗精神分裂症的阳性症状。
38.权利要求25-34中任一项所述的应用,其特征在于,其用于治疗精神分裂症的阴性症状。
39.权利要求25-34中任一项所述的应用,其特征在于,其用于治疗精神分裂症的情感症状和后遗症。
40.权利要求25-34中任一项所述的应用,其特征在于,其用于治疗精神分裂症的继发性社会和职业性功能障碍。
41.权利要求25-34中任一项所述的应用,其特征在于,其用于治疗精神分裂症样精神障碍和情感性分裂症。
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HU0700369A HUP0700369A2 (en) | 2007-05-24 | 2007-05-24 | Use of (thio)-carbamoyl-cyclohexane derivatives in the manufacture of a medicament for the treatment in the manufacture of a medicament for the treatment of schizophrenia |
HUP0700369 | 2007-05-24 |
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CN201410720780.7A Pending CN104546852A (zh) | 2007-05-24 | 2008-05-19 | 用于治疗精神分裂症的(硫代)-氨甲酰基-环己烷衍生物和方法 |
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US (1) | US20100197666A1 (zh) |
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JP (1) | JP2010527984A (zh) |
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UA (1) | UA101322C2 (zh) |
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HUP0700353A2 (en) * | 2007-05-18 | 2008-12-29 | Richter Gedeon Nyrt | Metabolites of (thio)carbamoyl-cyclohexane derivatives |
US7875610B2 (en) * | 2007-12-03 | 2011-01-25 | Richter Gedeon Nyrt. | Pyrimidinyl-piperazines useful as D3/D2 receptor ligands |
ATE552002T1 (de) * | 2008-02-21 | 2012-04-15 | Richter Gedeon Nyrt | Feste zubereitung zur oralen verabreichung |
CN102118970A (zh) | 2008-07-16 | 2011-07-06 | 吉瑞工厂 | 包含多巴胺受体配体的药物制剂 |
HU230067B1 (hu) | 2008-12-17 | 2015-06-29 | Richter Gedeon Nyrt | Új piperazin só és eljárás előállítására |
HUP0800766A2 (en) | 2008-12-18 | 2010-11-29 | Richter Gedeon Vegyeszet | Process for the preparation of piperazine derivatives |
HUP0800765A2 (en) | 2008-12-18 | 2010-11-29 | Richter Gedeon Nyrt | A new process for the preparation of piperazine derivatives and their hydrochloric salts |
HUP1200001A2 (en) | 2012-01-02 | 2013-07-29 | Gabor Dr Havas | Wind motor with rotation axis substantially at right angle to wind direction with a multistage acceleration system |
US8912197B2 (en) | 2012-08-20 | 2014-12-16 | Forest Laboratories Holdings Ltd. | Crystalline form of carbamoyl-cyclohexane derivatives |
HU231227B1 (hu) * | 2012-11-29 | 2022-03-28 | Richter Gedeon Nyrt. | Transz-4-{2-[4-(2,3-diklórfenil)-piperazin-1-il]-etil}N,N-dimetilkarbamoil-ciklohexilamin skizofrénia negatív tüneteinek kezelésére |
US11274087B2 (en) | 2016-07-08 | 2022-03-15 | Richter Gedeon Nyrt. | Industrial process for the preparation of cariprazine |
US11547707B2 (en) | 2019-04-10 | 2023-01-10 | Richter Gedeon Nyrt. | Carbamoyl cyclohexane derivatives for treating autism spectrum disorder |
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US6489341B1 (en) * | 1999-06-02 | 2002-12-03 | Sepracor Inc. | Methods for the treatment of neuroleptic and related disorders using sertindole derivatives |
HU230748B1 (hu) | 2007-05-11 | 2018-02-28 | Richter Gedeon Nyrt | Új piperazin só és előállítási eljárása |
WO2008141135A1 (en) * | 2007-05-11 | 2008-11-20 | Forest Laboratories Holdings Limited | Novel solvate and crystalline forms of carbamoyl-cyclohexane derivatives |
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