CN105792824B - 色酮衍生物作为多巴胺d3受体拮抗剂用于治疗自闭症谱系障碍的用途 - Google Patents
色酮衍生物作为多巴胺d3受体拮抗剂用于治疗自闭症谱系障碍的用途 Download PDFInfo
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Abstract
本发明要求保护为多巴胺D3受体拮抗剂的色酮衍生物和至少包含所述衍生物的药物组合物和组合用于治疗自闭症谱系障碍的用途。
Description
技术领域
本发明涉及N-(3-{4-[4-(8-氧代-8H-[1,3]间二氧杂环戊烯并[4,5-g]色烯-7-基)-丁基]-哌嗪-1-基}-苯基)-甲磺酰胺或其药学上可接受的盐，其作为用于治疗自闭症谱系障碍的药物的用途。
背景技术
专利申请WO 2011/027289公开了色酮衍生物，它们的制备方法以及它们用于治疗神经或精神疾病的治疗应用。根据WO 2011/027289的色酮衍生物为多巴胺D3受体的部分激动剂或拮抗剂。
尤其，WO 2011/027289公开了与式1相一致的N-(3-{4-[4-(8-氧代-8H-[1,3]间二氧杂环戊烯并[4,5-g]色烯-7-基)-丁基]-哌嗪-1-基}-苯基)-甲磺酰胺(WO 2011/027289的实施例21)。
在由色酮衍生物治疗的疾病中，WO 2011/027289要求保护帕金森氏病、精神病、精神分裂症、与帕金森氏病相关的运动障碍、任选与年龄或与阿尔茨海默氏病相关的认知缺陷、情绪障碍、特发性震颤、焦虑、抑郁、双相情感障碍、阳痿、早泄、醇中毒和尼古丁成瘾。尤其，WO 2011/027289既未公开也未要求保护神经发育障碍。
神经发育障碍是一组在发育期发病的病症。这些障碍典型地在儿童期显现，并且其特征在于发育缺陷，所述发育缺陷产生人格、社交、学业或职业功能损伤。残疾的范围从非常具体的学习缺陷或执行功能控制缺陷到社交能力或智力的全面损伤。
在神经发育障碍中，自闭症已被定性为一种不同于精神病的婴幼儿问题，Kanner在1943年描述了其体征和症状(L.Kanner"Autistic Disturbances of AffectiveContact",Nervous Child 2:217-50,1943)，包括各种行为和技能问题。自闭症包括典型的婴幼儿自闭症或坎纳自闭症(Kanner’s autism)、阿斯伯格综合症(Asperger’s syndrome)(其保留了语言和认知功能)、以及未另作规定的广泛性发育障碍(通常简称为PDD-NOS)(当不符合自闭症或阿斯伯格综合症的整套标准时作出该诊断)。其他分类，如世界卫生组织的疾病和有关健康问题的国际统计分类第10版(ICD-10)(the International StatisticalClassification of Diseases and Related Health Problems 10th Revision)，包括了更多的小类。症状的多变性和那些不同的诊断类别中对自闭症的描述使得难以理解对特定症状运用的治疗处理。
然而最近，自闭症的诊断已经明显改变，认识到社交缺陷将自闭症及相关障碍与其他神经发育障碍区分开来(Rapin I,Tuchman RF.Autism:definition,neurobiology,screening,diagnosis.Pediatr Clin North Am.2008；55(5):1129–46)，并将诊断统一为唯一名称自闭症谱系障碍(ASD)。根据精神疾病诊断与统计手册(Diagnostic andStatistical Manual of Mental Disorders)(DSM-5，美国精神病学协会，美国精神病学出版社，华盛顿特区，2013)，ASD的特征在于跨多环境的社交沟通和社交互动(socialinteraction)的持续性缺陷，包括社交交互性(reciprocity)的缺陷，用于社交互动的非言语交流行为缺陷，以及发展、维持和理解关系的技能的缺陷。除了社交沟通缺陷，自闭症谱系障碍的诊断需要行为、兴趣或活动的受限的、重复的模式的存在。
在ASD的诊断中，在使用描述自闭症症状及其严重性的标志语(specifier)中，注意个体的临床特征。因此，根据DSM-5，使用以下诊断标准诊断该障碍：
A：跨多环境的社交沟通和互动(需要全部3项)。
·社交-情感交互性的缺陷。
·用于社交互动的非言语交流行为的缺陷。
·发展和维持关系的缺陷。
B：受限的、重复的行为(需要任意2项)。
·刻板的或重复的言语、运动动作、或物体的使用。
·过度遵守程序，语言或非语言行为的程式化模式，或对变化的过度抗拒。
·专注度(intensity of focus)异常的、非常受限的、过分迷恋的兴趣。
·感觉输入的超或低反应性，或环境感觉方面不寻常的兴趣。
C：症状必须存在于早期发育期间。
D：症状引起社交、职业、或当前运作的其他重要方面的临床显著损伤。
E：这些病态(disturbance)不能由智力残疾或全面的发育迟缓更好地解释。
ASD是一种高度遗传性神经精神疾病：在单卵双胞胎中和合率(concordancerate)高达90％，而在双卵双胞胎中为10％(在Won等人,Front.Mol.Neurosci.2013,卷6,19章中有所评论)。然而，ASD是一种在病因学上异质性的障碍，因为在病例中没有一个基因突变占比超过1-2％(Abrahams等人,Nat.Rev.Genet.2008,vol 9,p 341–355)。迄今，连锁和候选基因分析、全基因组关联研究(GWAS)、和染色体变异评估已揭示了具有与ASD相关的素因性(predisposing)突变和多态性的各种不同的基因(Persico等人,Behav.BrainRes.2013,vol 251,p 95-112)。这些研究中没有一个已确定DRD3作为ASD的易感基因。
在2009年，de Krom和同事在144名ASD患者和404名对照个体的样本中，进行了存在于132个候选基因中的1536个单核苷酸多态性(SNP)的遗传关联研究(de Krom等人,Biol.Psychiatr.,2009,vol 65,p625-630)。他们发现了31个P值低于0.01的正相关的单核苷酸多态性，并在128名ASD患者和124名对照个体的第二样本中测试了这些正相关的单核苷酸多态性。在两个ASD样本和联合统计分析中，仅发现单核苷酸多态性rs167771是正相关的。在rs167771的风险等位基因和ASD患者中重复行为(而非其他ASD症状域(symptomaticdomain))的降低的风险之间还发现了关联，所述关联未被后续多重检验的统计校正所证实(Staal等人,J.Autism Dev.Disord.2012,vol 42,p885-888)。
单核苷酸多态性rs167771存在于多巴胺D3受体基因的第二内含子中。多巴胺D3受体几乎仅在中枢神经系统中表达，特别是在腹侧(ventral)纹状体区，该区是在情绪和认知的控制中发挥重要作用的脑区域(Sokoloff等人,Nature 1990,卷347,146-151页)。多巴胺D3受体以由编码序列中名为rs6280的单核苷酸多态性(也称作CM033372或BalI多态性)生成的两种等位基因的形式存在，其导致了在第9位含有丝氨酸(Ser)或甘氨酸(Gly)残基的两种氨基酸序列(Lannfelt等人,Psychiatric Genetics 1992,vol 2,p249-256)。Gly/Gly等位基因为功能获得性(gain-of-function)等位基因，因为其具有对多巴胺四倍更高的亲和力，并且其比Ser/Ser等位基因对多巴胺更加敏感(Jeanneteau等人,Proc.Natl.Acad.Sci.USA 2006,vol 103,p10753-10758)。如果待治疗的障碍与功能获得性(Gly/Gly等位基因)或功能失去性(loss-of-function)(Ser/Ser等位基因)相关联，则可以设想基于多巴胺D3受体干预的治疗处理。例如，多巴胺D3受体拮抗剂可以用于治疗与Gly/Gly功能获得性等位基因相关联的障碍。
e！Ensembl人类基因组遗传数据库(可从http://www.ensembl.org获得)显示，两个单核苷酸多态性rs167771和rs6280属于组件(assembly)GRCh37.p10的相同重叠群NT_005612.16，并被14540个碱基对分隔。连锁不平衡表中的数据(也可从http://www.ensembl.org获得)显示了rs167771和rs6280之间的部分连锁不平衡，在不同群体中具有0.245至0.610的r平方值(Pritchard等人,Am.J.Hum.Genet.,2001,卷69,1-14页)。这表明ASD中rs167771的遗传关联并非在形式上意味着ASD与多巴胺D3受体中的功能性单核苷酸多态性rs6280的连锁。因此，在对50例患者的小样本的另一项研究中，未发现rs6280与ASD相关联(Martineau等人,Dev Med Child Neurol,1994,36:688-697)。
ASD无法治愈。美国食品及药物管理局批准非典型抗精神病药物，如利培酮或阿立哌唑，用于治疗与自闭症有关的易怒，包括对他人的侵犯行为、故意自伤、发怒和快速的情绪变化的症状，这些症状不属于定义ASD的核心症状。患有ASD的青少年和年轻成人也容易出现焦虑和抑郁，可以使用抗抑郁药物如选择性血清素再摄取抑制剂治疗这种焦虑和抑郁。然而，没有以ASD的核心症状，即社交互动和沟通中的缺陷以及受限的兴趣为目标的治疗获得批准。
此外，遗传研究并无定论，且没有教导用于治疗ASD，尤其是社交互动中的缺陷的方法。
发明内容
本发明人令人惊讶地发现，WO 2011/027289中公开的N-(3-{4-[4-(8-氧代-8H-[1,3]间二氧杂环戊烯并[4,5-g]色烯-7-基)-丁基]-哌嗪-1-基}-苯基)-甲磺酰胺在概括(recapitulate)了ASD的核心症状的动物模型中有很大好处，所述动物模型是基于产前暴露于丙戊酸钠。
丙戊酸或其丙戊酸钠盐是抗惊厥药物，例如用于治疗癫痫，一组以无端发作为特征的常见和多样的慢性神经疾病。丙戊酸钠也用于治疗双相情感障碍，一种精神情感障碍，其呈现被称为躁狂症(或轻度躁狂，取决于严重性)的振奋或激动情绪的发作，交替有抑郁的发作。通过回顾性研究已知丙戊酸钠的致畸作用(与神经管闭合相联系的畸形)达30年。对于在妊娠期间使用过丙戊酸钠的母亲，在她们的孩子中也发现了ASD的病例，这导致了在育龄妇女中丙戊酸钠和ASD风险的警告。近期，前瞻性研究证实了与丙戊酸钠相关的风险，指出ASD风险有10倍的增加(Tomson等人,Lancet Neurol.2012,vol 11,p803-813；Bromley等人,J.Neurol.Neurosurg.Psychiatry 2013,vol 84,p 637-643)。据推测，丙戊酸钠通过在宫内发育期间干扰驱动神经管闭合的表观遗传机制而导致ASD(Kataoka等人,Int.J.Neuropsychopharmacol.2013,vol 16,p 91-103)。
在ASD大鼠模型中，在确定的胎龄，典型地第12天，将丙戊酸钠施用至怀孕雌鼠，在该物种中所述胎龄对应于神经管闭合的时间，当在婴儿期和青春期期间观察时，后代表现出明显且具体的行为异常，伴有少许体征(在Roullet等人,Neurotoxicol.Teratol.2013,卷36,47-56页中有所评论)。丙戊酸钠诱导的行为异常强烈使人想起ASD的症状，其包括：
·社交行为的损伤
·刻板的/重复的行为模式
·感觉和沟通损伤。
此外，表现型还包含ASD典型的形态重排，如前额皮质中神经元的树突棘的数量或密度降低(Bringas等人,Neuroscience 2013,卷241,170-187页)，这给予了丙戊酸钠大鼠模型以ASD病理生理动物模型的结构效度(construct validity)和表面效度(facevalidity)。
为了评估N-(3-{4-[4-(8-氧代-8H-[1,3]间二氧杂环戊烯并[4,5-g]色烯-7-基)-丁基]-哌嗪-1-基}-苯基)-甲磺酰胺盐酸盐(一种有效的多巴胺D3受体拮抗剂(参见实施例1))用于治疗ASD的可能性，本发明人已在ASD大鼠模型中评价了它(实施例2)。如实施例2所述，N-(3-{4-[4-(8-氧代-8H-[1,3]间二氧杂环戊烯并[4,5-g]色烯-7-基)-丁基]-哌嗪-1-基}-苯基)-甲磺酰胺盐酸盐作为单剂量施用时，能够逆转丙戊酸钠产前暴露的幼龄大鼠中的社会行为缺陷。因此，本发明人指出所述化合物可以用于治疗ASD。
如上所使用，术语“多巴胺D3受体”、“D3受体”或“DRD3”是指一种主要在边缘系统中表达的多巴胺受体亚型(Sokoloff P等人,Nature 1990,vol 347,p 146-151)。在国际专利申请WO 91/15513中描述了多巴胺D3受体。如上所使用，术语“D3受体部分激动剂”是指一种化合物，其与多巴胺D3受体形成复合物，并充当联合的激动剂-拮抗剂，即，其诱导强度比天然中介物多巴胺低的生理反应。在体外，在表达多巴胺D3受体的细胞中，多巴胺D3受体部分激动剂产生比由多巴胺或完全激动剂例如喹吡罗(反式(-)-4aR-4,4a,5,6,7,8,8a,9-八氢-5-丙基-1H(或2H)吡唑并[3,4g]喹啉)产生的低的最大强度的活性反应。多巴胺D3受体部分激动剂还可以部分阻止由多巴胺或其他完全激动剂所产生的反应。如上所使用，术语“多巴胺D3受体拮抗剂”是指一种分子，在表达多巴胺D3受体的细胞中，所述分子与多巴胺D3受体形成复合物，并且能够阻止由多巴胺或其激动剂触发的反应。
如本文所使用，术语“盐”是指本发明的化合物的无机酸、有机酸、无机碱或有机碱加成盐。例如，可以提及由无机酸衍生的盐，所述无机酸如盐酸、氢溴酸、磷酸、硫酸，和由有机酸衍生的那些，所述有机酸如乙酸、三氟乙酸、丙酸、琥珀酸、富马酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、谷氨酸、苯甲酸、水杨酸、甲苯磺酸、甲磺酸、硬脂酸、乳酸。优选地，所述盐是药学上可接受的，即，所述盐对于被施用的患者是无毒的。表述“药学上可接受的”是指分子实体和组合物，当其被施用至动物或人时，其不产生任何不良的变态反应或其它不期望的反应。当在本文中使用时，术语“药学上可接受的赋形剂”包括任何稀释剂、佐剂或赋形剂，如防腐剂、填充剂、崩解剂、润湿剂、乳化剂、分散剂、抗细菌剂或抗真菌剂，或还有允许延迟肠内和消化吸收及再吸收的试剂。这些介质或载体的使用是本领域熟知的。除非试剂与根据本发明的化合物化学上不相容，则可以设想其在含有根据本发明的化合物的药物组合物中的使用。
在本发明的上下文中，如本文所使用的术语“治疗”是指阻止或抑制该术语所应用的病症的表现或进展，或者该病症的一个或多个症状的表现或进展。“治疗有效量”是指根据本发明的化合物的量，所述量对于获得根据本发明的期望的治疗作用是有效的。根据本发明，术语“患者”是指患有ASD的人，或非常容易患ASD的人。
根据本发明，化合物(N-(3-{4-[4-(8-氧代-8H-[1,3]间二氧杂环戊烯并[4,5-g]色烯-7-基)-丁基]-哌嗪-1-基}-苯基)-甲磺酰胺)或其药学上可接受的盐，优选盐酸盐，被用作药物用于治疗ASD，尤其是社交互动缺陷。
本发明还涉及ASD的治疗，其包含向需要治疗的患者以治疗有效量施用化合物(N-(3-{4-[4-(8-氧代-8H-[1,3]间二氧杂环戊烯并[4,5-g]色烯-7-基)-丁基]-哌嗪-1-基}-苯基)-甲磺酰胺)或其药学上可接受的盐。
此外，本发明涉及含有化合物(N-(3-{4-[4-(8-氧代-8H-[1,3]间二氧杂环戊烯并[4,5-g]色烯-7-基)-丁基]-哌嗪-1-基}-苯基)-甲磺酰胺)或其药学上可接受的盐和药学上可接受的赋形剂的药物组合物，其作为用于治疗ASD，尤其是社交互动缺陷的药物的用途。
作为另一个实施方案，本发明涉及将化合物(N-(3-{4-[4-(8-氧代-8H-[1,3]间二氧杂环戊烯并[4,5-g]色烯-7-基)-丁基]-哌嗪-1-基}-苯基)-甲磺酰胺)或其药学上可接受的盐与已知用于治疗ASD患者的其它药物和药学上可接受的赋形剂组合的药物组合物，其作为用于治疗自闭症谱系障碍，尤其是社交互动缺陷的药物的用途。
优选地，将根据本发明的化合物与选自美金刚、金刚烷胺、巴氯芬、R-巴氯芬、非诺班(phenobam)、阿坎酸、布美他尼(bumetamide)、卡匹帕明(carpipramine)、催产素、后叶加压素的化合物和其混合物，以及药学上可接受的赋形剂组合。
可以通过经口、经皮、肠胃外、经鼻或直肠途径施用根据本发明的组合物。尤其可以以合适的制剂通过经口途径施用组合物。可以调节本发明的组合物中的化合物(N-(3-{4-[4-(8-氧代-8H-[1,3]间二氧杂环戊烯并[4,5-g]色烯-7-基)-丁基]-哌嗪-1-基}-苯基)-甲磺酰胺)的剂量以获得活性物质的量，该量对于获得特定于施用方法的组合物的期望治疗反应是有效的。因此，所选择的剂量水平取决于期望的治疗作用、施用途径、期望的治疗持续时间和其他因素如患者体重。剂量可以为0.001至10mg每kg体重。优选的剂量在0.05至2mg每kg体重的范围内。
具体实施方式
以下实施例阐明本发明而不限制其范围。
实施例1
根据本发明，在表达人重组多巴胺D3受体或人重组多巴胺D2受体的细胞中，在体外评价N-(3-{4-[4-(8-氧代-8H-[1,3]间二氧杂环戊烯并[4,5-g]色烯-7-基)-丁基]-哌嗪-1-基}-苯基)-甲磺酰胺盐酸盐作为多巴胺D3受体的配体和该受体活性的调节剂。如Cussac等人在Naunyn-Schmiedeberg's Arch.Pharmacol.2000,vol 361,p569-572中所描述，通过[3H]螺哌隆的结合的抑制测定抑制常数(Ki)。本发明人证明，根据本发明的化合物表现为有效的多巴胺D3受体配体，具有0.17纳摩尔·升-1的Ki值。该相同化合物显示了减弱71倍的对多巴胺D2受体的显著的亲和力。
通过在人重组多巴胺D3受体上使用MAP-激酶活性试验，评价根据本发明的化合物对多巴胺D3受体的激动剂、部分激动剂或拮抗剂活性(Cussac等人,Mol.Pharmacol.1999,vol 56,p1025-1030)。该化合物的固有活性为零，表明其为完全拮抗剂。
实施例2
在雌性大鼠的后代的社交互动方面测试N-(3-{4-[4-(8-氧代-8H-[1,3]间二氧杂环戊烯并[4,5-g]色烯-7-基)-丁基]-哌嗪-1-基}-苯基)-甲磺酰胺盐酸盐，所述雌性大鼠已被施用了丙戊酸的钠盐。丙戊酸自闭症大鼠模型的实验设定改编自已公布的资料(Dendrinos等人,Front.Integr.Neurosci.2011,vol 5,art 68；Markram等人,Neuropsychopharm.2007,vol 33,p 901-912；Schneider等人,Neuropsychopharm.2005,vol30,p 80-89)。
方法：
将怀孕的(最大胎龄8天)雌性斯普拉格-杜勒大鼠[OFA(SD)Charles River Lyon,法国]隔离4天。在环境受控的房间中(温度21±1℃；相对湿度55±5％)，在12h明/暗周期下(在上午07:00开灯)，在全底笼(ML-H笼,370x235x180mm,LxWxH；地板面积870cm2)中群养(每笼2只)动物，食物(A04,Safe,Augy,法国)和过滤水(0.2μm孔径)自由摄取。直到后代断奶，仅将动物每周调换(change)一次，以尽量小地打扰它们。提供环境强化(筑窝材料)。
在胎龄12和13天(E12-E13)时，雌鼠称重并接受三次2.4ml/kg丙戊酸钠(NaVPA,200mg/kg)的腹膜内注射。将丙戊酸钠溶解于0.9％盐水中以获得83.3mg/ml的浓度，pH7.3。对照组接受三次盐水(2.4ml/kg)的腹膜内注射。在第三次注射后，将雌鼠单独饲养在ML-H型笼中，并允许它们养育其幼崽。后代在出生后21至23天断奶。
将一只丙戊酸钠暴露的或盐水暴露的大鼠和一只陌生的天然大鼠放置在一块场地的对角处(黑色场地70cm x 70cm x 30cm,L x l x H)。将被测试大鼠在10min的一段时间中对陌生大鼠作出的与社交互动相关的个体行为如跟随理毛、嗅闻或咬另一只大鼠、以及爬过另一只大鼠打分。
结果：
图1总结了急性施用根据本发明的化合物对使用盐水或丙戊酸钠处理的母鼠的后代的社交互动行为的作用。
所显示的数据为n＝10只大鼠(5只雌性和5只雄性)的平均值±平均值的标准差。
根据本发明的化合物对于盐水处理的母鼠的后代的社交互动行为没有显著作用。
在0.63mg/kg，根据本发明的化合物显著减少了由丙戊酸钠产前暴露所诱导的社交互动缺陷。在2.5mg/kg，根据本发明的化合物完全逆转了这些缺陷。
根据本发明的化合物被认为是治疗自闭症谱系障碍，更特别是社交互动缺陷的有意义的产品。
Claims (4)
1.N-(3-{4-[4-(8-氧代-8H-[1,3]间二氧杂环戊烯并[4,5-g]色烯-7-基)-丁基]-哌嗪-1-基}-苯基)-甲磺酰胺或其药学上可接受的盐在制备用于治疗与自闭症谱系障碍相关的社交互动缺陷的药物中的用途。
2.根据权利要求1所述的用途，其中药学上可接受的盐为盐酸盐。
3.包含N-(3-{4-[4-(8-氧代-8H-[1,3]间二氧杂环戊烯并[4,5-g]色烯-7-基)-丁基]-哌嗪-1-基}-苯基)-甲磺酰胺或其药学上可接受的盐和药学上可接受的赋形剂的药物组合物在制备用于治疗与自闭症谱系障碍相关的社交互动缺陷的药物中的用途。
4.根据权利要求3所述的用途，其中所述药物组合物与选自美金刚、金刚烷胺、巴氯芬、R-巴氯芬、非诺班、阿坎酸、布美他尼、卡匹帕明、催产素、后叶加压素的化合物和其混合物组合。
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