CN112513047B - 芳香杂环nmda受体调节剂及其用途 - Google Patents
芳香杂环nmda受体调节剂及其用途 Download PDFInfo
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- CN112513047B CN112513047B CN201980051645.9A CN201980051645A CN112513047B CN 112513047 B CN112513047 B CN 112513047B CN 201980051645 A CN201980051645 A CN 201980051645A CN 112513047 B CN112513047 B CN 112513047B
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
提供5‑(3‑氯‑4‑氟苯基)‑7‑环丙基‑3‑(2‑(3‑氟‑3‑甲基氮杂啶‑1‑基)‑2‑氧代乙基)‑3,7‑二氢‑4H‑吡咯[2,3‑d]嘧啶‑4‑酮及其药学上可接受的盐类,以及其治疗精神病、神经疾病与神经发展疾患和神经系统疾病的用途。
Description
相关申请案
本申请案要求2018年8月3日申请的美国临时申请案第62/714,100号的优先权权益,其整体内容以引用方式并入本文中。
背景技术
如全球疾病负担所评测,神经系统疾病是人类失能的主因。甚至卫生当局已批准其治疗方法的神经系统主要疾病(包括如精神分裂症的精神疾病、如阿尔茨海默症的神经系统疾病、以及如注意缺陷与多动障碍(Attention Deficit and HyperactivityDisorder)的神经发展异常)因其核可的治疗方法疗效有限且有严重的副作用而不好处理,因而导致未被满足的医疗需求有极大负担。此外,还有许多未批准其治疗方法的主要罕见神经系统疾病,例如自闭症谱系的神经发展异常及许多智力障碍疾病,其因此与严重无法满足的医疗需求相关。
配体闸控离子通道(ligand-gated ion channel)受体的N-甲基-D-天冬氨酸(NMDA)亚型是多样化的谷氨酸受体家族,其被广泛采纳用以调控突触传递、突触可塑性的关键机制以及正常神经系统发展和功能所需的动态类神经网络连接。
NMDA受体是由四个蛋白质次单元(两个GluN1次单元及两个GluN2次单元)所组成。GluN1次单元衍生自单基因(GRIN1),其在整个神经系统中广泛表达,且常见于所有NMDA受体中。四种不同的GluN2次单元(GluN2A-D)衍生自独立的基因(GRIN2A-D),其在神经系统的不同区域中且由特定区域内的不同神经元群差异表达。GluN3次单元也已被鉴定出,但其功能尚不清楚。此外,各个神经元可以表达多于一个GluN2次单元,而由这些神经元表达的各个NMDA受体可以含有两个相同的GluN2次单元(例如,2个GluN2B次单元)或两个不同的次单元(一个GluN2A及一个GluN2B次单元)。此外,所有NMDA受体次单元都表达为多样化的mRNA剪接变异。因此,自然神经系统NMDA受体的组成有高度多样化。
对于NMDA受体功能的分子基础研究仍然是个重要的领域。由于谷氨酸是主要的兴奋性神经传导物质,故谷氨酸神经传递功能障碍和突触传递、可塑性及神经元网络连接的NMDA受体依赖性机制广泛地涉及神经系统疾病。据此,能够调控NMDA受体的化合物可以用于治疗神经系统异常和疾病,例如精神分裂症、阿尔茨海默症、注意缺陷与多动障碍、以及自闭症。
发明内容
本文中提供化合物1,5-(3-氯-4-氟苯基)-7-环丙基-3-(2-(3-氟-3-甲基氮杂啶-1-基)-2-氧代乙基)-3,7-二氢-4H-吡咯[2,3-d]嘧啶-4-酮,其具有以下结构:
化合物1是杂环吡咯并嘧啶酮(pyrrolopyrimidinone)类似物,其调控NMDA受体(例如,NMDA受体的正向异位调节)且可以治疗精神异常、神经异常与神经发展异常以及神经系统疾病。
杂环NMDA受体调节剂先前已于例如WO 2017/100591中描述。在WO 2017/100591中,公开了多种杂环核心,包括吡咯并吡嗪酮(pyrrolopyrazinone)、噻吩并吡啶酮(thienopyridinone)、咪唑并吡嗪酮(imidazopyrazinone)、吡咯并吡啶酮(pyrrolopyridinone)及吡咯并嘧啶酮。WO 2017/100591中的化合物效力是基于化合物对Ca2+反应的抑制的逆转能力来评估,其Ca2+反应的抑制是由Ro 25-6981(含有NR2B次单元的NMDA谷氨酸受体的有效选择性拮抗剂)及5,7-二氯喹啉酸(5,7-dichlorokynurenic acid,DCKA,为作用于NMDA受体络合物的甘氨酸位点的选择性NMDA受体拮抗剂)所介导。Ro 25-6981/DCKA测定中的效力以反应恢复%(例如,如WO 2017/100591的表49中所示)及/或最大测得增强%来定量。WO 2017/100591所举例的最有效的二十一种类似物(Ro 25-6981/DCKA测定中依反应恢复%排序)中,并未显示吡咯并嘧啶酮类似物。
WO 2017/100591举出四十八个吡咯[2,3-d]嘧啶-4-酮作例子。所述吡咯[2,3-d]嘧啶-4-酮核心与化合物1的杂环核心相同。WO 2017/100591所举例的最有效示例性吡咯[2,3-d]嘧啶-4-酮(基于Ro 25-6981/DCKA测定中的反应恢复%)为实例174(反应恢复91%)。请见如WO 2017/100591的表49。然而,如下表1中所示,在公开的卵母细胞NR2B PAM增强试验中,化合物1的效力比实例174高约三倍。WO 2017/100591中另一示例性吡咯[2,3-d]嘧啶-4-酮是实例181。所述化合物基于Ro 25-6981/DCKA测定中的最大测得增强(%)而确定为最有效的示例性吡咯[2,3-d]嘧啶-4-酮。请见下表1,其以Ro25-6981/DCKA测定的所述两种效力获取数据来比较实例174和181。类似于实例174的结果,再次发现化合物1在公开的卵母细胞NR2B PAM增强试验中更为有效(约2.5倍)。综合来看,这些结果证明了化合物1相对于其它吡咯[2,3-d]嘧啶-4-酮类骨架有临床上的效力优势。
就结构相关的类似物而言,WO 2017/100591公开了化合物1的组成异构体(即,实例436)以及一种氮变异体(即,实例285)。尽管结构上相似,但发现化合物1相较于此些两种化合物具有优异的水溶解性、微粒体稳定性及/或药代动力学特性。例如,表2显示化合物1的水溶解度比实例436(化合物1的组成异构体)增加约10倍。发现化合物1具有优异的细胞渗透性(A→B和B→A为32×10-6cm/s),且不是MDR1转染的MDCK细胞中外排的基质(外排率=0.99)。请见表3。表4显示化合物1展现出与实例285相比有显著改善的大鼠肝微粒体稳定性(分别为t1/2>120分钟比上37.8分钟),且还显示其大鼠体内清除率与WO 2017/100591所举例的实例285及几种其它类似物相比有显著改善(IV清除率=7.4mL/分钟/kg比上22.2mL/分钟/kg)。
上述数据确立了化合物1的许多临床优点,因而提供了寻找具有例如改善的效力、增强的溶解度、有利的微粒体稳定性与体内清除率以及优异的细胞渗透性的替代NMDA调节剂的解决方案。
附图说明
图1显示大鼠新奇事物认知(NOR)测试中口服化合物1(0.3、1.0及3.0mg/kg)对苯环利定(PCP)诱导的认知障碍的认知增强作用。
图2显示失匹配负波效力模型中的化合物1结果。
具体实施方式
1.化合物
本文中提供具有以下结构的化合物:
或其药学上可接受的盐类。
2.定义
本文所用的术语“个体”和“患者”可以互换使用,其意指需要治疗的哺乳动物,例如伴侣动物(例如犬、猫及例如此类)、农畜动物(例如牛、猪、马、绵羊、山羊及例如此类)及实验室动物(例如大鼠、小鼠、天竺鼠及例如此类)。通常,个体为需要治疗的人类。
本发明包括有本文所述化合物的药学上可接受的盐类及天然形式。对于医药用途而言,化合物的盐类是指无毒“药学上可接受的盐类”。药学上可接受的盐类形式包括药学上可接受的酸性/阴离子或碱性/阳离子盐类。药学上可接受的碱性/阳离子盐类包括钠、钾、钙、镁、二乙醇胺、N-甲基-D-葡糖胺、L-赖氨酸、L-精氨酸、铵、乙醇胺盐、哌嗪及三乙醇胺盐。药学上可接受的酸性/阴离子盐类包括如乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、酒石酸氢盐、碳酸盐、柠檬酸盐、二盐酸盐、葡糖酸盐、谷氨酸盐、乙内酰氨基苯胂酸盐(glycollylarsanilate)、己基间苯二酚盐、氢溴酸盐、盐酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、硝酸盐、水杨酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐及甲苯磺酸盐。
术语“药学上可接受的载体”是指与化合物配制而不破坏化合物药理活性的无毒载剂、佐剂或赋形剂。可以使用于本文所述组合物中的药学上可接受的载剂、佐剂或赋形剂包括,但不限制于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白质(如人类血清白蛋白)、缓冲剂物质(如磷酸盐类)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、水、盐类或电解质,例如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅溶胶、三硅酸镁、聚乙烯吡咯烷酮、纤维素类物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇及羊毛脂。
“药学上可接受”是指适当施用到动物或人类时不产生副作用、过敏或其它不利反应的分子物理及组合物。
“治疗(Treatment、treat、treating)”是指逆转、减轻、降低如本文所述的疾病或异常(disorder)或其一或更多症状(symptom)的发展可能性或抑制进展。于一些实施例中,可以于一或更多症状已发展之后给予治疗,即医疗治疗。于其它实施例中,可以在没有症状下给予治疗。例如,可以在症状开始之前(例如,鉴于症状的历史及/或鉴于基因或其它感受性因素),对易感个体给予治疗,即预防性治疗。还可以于症状已解决之后继续进行治疗,例如用以预防或延缓复发。
术语“有效量”或“治疗有效量”包括将引发个体的生物或医学反应的本文所述化合物的量,例如介于0.01-100毫克/千克体重/天的剂量。
“化合物1”与“5-(3-氯-4-氟苯基)-7-环丙基-3-(2-(3-氟-3-甲基氮杂啶-1-基)-2-氧代乙基)-3,7-二氢-4H-吡咯[2,3-d]嘧啶-4-酮”可以互换使用,其各自指具有下式的化合物:
“PAM”是指“正向异位调节剂”。
3.用途、配方及投药
于一方面中,本文所述的化合物1或其药学上可接受的盐类及组合物可以用于治疗与NMDA受体活性有关的疾病及/或异常。此些疾病及/或异常包括如精神异常、神经异常与神经发展异常以及神经系统疾病。
于另一方面中,本文所述的化合物1或其药学上可接受的盐类及组合物可以用于调控NMDA受体的活性。
于另一方面中,本文所述的化合物1或其药学上可接受的盐类及组合物可以用于治疗精神分裂症、阿尔茨海默症、注意缺陷与多动障碍、自闭症及其它神经系统相关病症。
于另一方面中,本文所述的化合物1或其药学上可接受的盐类及组合物可以用于治疗精神分裂症,包括正性、负性及认知症状。精神分裂症是一种令人衰弱的精神疾病,包括三个症状领域:正性(精神病、幻觉、妄想),负性(丧失)和认知(整体认知能力降低)。精神分裂症的正性症状通常在成年早期出现并以抗精神病药物治疗。然而,认知缺陷是严重的,在青春期前驱阶段出现,其对抗精神病药物治疗具有抗性,且依整体功能障碍评测为终身失能的主要原因(无法独立生活、失业等)。NMDA受体功能低下是精神分裂症病因的主要假设。所述假设有大量临床证据支持,包括临床药理学、电生理学、成像、认知、计算神经科学、神经解剖学研究及遗传学。尤其,几个证据显示精神分裂症中NMDA受体的功能低下。参见Frank S.Menniti,Craig W.Lindsley,P.Jeffrey Conn,Jayvardhan Pandit,PanayiotisZagouras,及Robert A.Volkmann,Allosteric Modulators for the Treatment ofSchizophrenia:Targeting Glutamatergic Networks.Curr Top Med Chem.2013;13(1):26–54。
于另一方面中,本文所述的化合物1或其药学上可接受的盐类及组合物可以用于如患有精神分裂症风险的人,以改善认知及整体功能及/或预防精神分裂症发作。
于另一方面中,本文所述的化合物1或其药学上可接受的盐类及组合物可以用于治疗认知及情绪缺陷以及与示范性精神病症(包括重度抑郁症)相关的其它症状,包括但不限于,患有分裂情感疾患、躁郁症、强迫症、情绪低落症、轻郁症、精神症忧郁、创伤后压力综合征及其它焦虑症的人。例如,本文提供了治疗所需病患的注意力缺乏症、注意缺陷与多动障碍(ADHD)、精神分裂症、焦虑、改善鸦片、尼古丁及/或酒精成瘾(例如,治疗此些成瘾或改善戒断副作用的方法)、脊髓损伤、糖尿病性视网膜病变、创伤性脑损伤及/或创伤后压力综合征的方法,其包括给予化合物1、或其药学上可接受的盐类、或其组合物。
于另一方面中,本文所述的化合物1或其药学上可接受的盐类及组合物可以用于治疗神经疾病引起的认知及情绪缺陷和其它症状,包括但不限于,患有轻度认知障碍或痴呆症、阿尔茨海默症、帕金森病、亨丁顿舞蹈症、肌萎缩侧索硬化症、多发性硬化症及癫痫症的任何类型的患者。
于另一方面中,本文所述的化合物1或其药学上可接受的盐类及组合物可以用于治疗神经发展异常引起的功能障碍,例如脑发育异常,包括但不限于,雷特氏症(RettSyndrome)、注意缺陷与多动障碍、自闭症及自闭症谱系障碍(如费伦麦克德米德综合征(Phelan-McDermid Syndrome))及其它形式的智能障碍,如脆性X染色体综合征(Fragile Xsyndrome)、结节性硬化症、史密斯-蓝利-欧比司综合征(Smith-Lemli-Opitz Syndrome)、唐氏综合征及儿童癫痫或癫痫/失语症类群障碍,如具有中央-颞部棘波的儿童良性部分性癫痫(Benign partial Epilepsy of childhood with CentroTemporal Spikes,BECTS)或蓝道克利夫症(Landau Kleffner Syndrome,LKS)。还提供了一种治疗患有由中枢神经系统感染、暴露于毒性剂或其它外来物或自然形成的毒素及/或自身免疫疾病(包括但不限于,抗NMDA受体脑炎)所引起的脑功能异常的患者的方法。
于另一方面中,本文所述的化合物1或其药学上可接受的盐类及组合物可以用于治疗患有NMDA受体功能低下的个体。
本文提供一种治疗患有本文所述疾病、异常(disorder)或病症(condition)的个体的方法,其包含给予所述个体治疗有效量的化合物1、或其药学上可接受的盐类、或其组合物。
还提供一种化合物1、或其药学上可接受的盐类、或其组合物用于制备治疗本文所述疾病、异常或病症的药物的用途。
更提供一种用于治疗本发明所述疾病、异常或病症的化合物1、或其药学上可接受的盐类、或其组合物。
于一方面中,提供了包含化合物1的药学上可接受组合物;及药学上可接受的载体。这些组合物可以用于治疗上述一或更多的疾病、异常或病症。
这些公开的组合物可以以口服、非口服、喷雾吸入、局部、经直肠、经鼻、口颊、阴道、或经由植入型药盒(implanted reservoir)等方式投药。如本文中所用的术语“非口服(parenteral)”包括皮下、静脉内、肌肉内、关节内、滑膜内、胸腔内、脊髓内、肝内、病灶内及颅内注射或输注技术。本文包括化合物的液体剂型、可注射制剂、固体分散形式及用于局部或经皮投药的剂型。
可以与载体材料组合以产生单一剂型组合物的化合物1的量将根据待治疗的患者及特定给药方式作变化。于一些实施例中,可以配制所提供的组合物,使得剂量为0.01-100毫克/千克体重/天(例如0.1-100毫克/千克体重/天)的所提供的化合物可以施用到接受这些组合物的患者。
还应当理解,任何特定患者的具体剂量及治疗方案将取决于多种因素,包括年龄、体重、一般健康、性别、饮食、给药时间,排出率、药物组成、治疗医师的判断、以及所治疗的特定疾病的严重程度。组合物中提供的化合物量还取决于组合物中的特定化合物。
本文还包括使用治疗有效量的化合物1、或其药学上可接受的盐类及有效量的一或更多额外医药活性剂的组合疗法。于一方面中,例如,提供化合物1或其药学上可接受的盐类与有效量的一或更多非典型抗精神病药用以治疗本文所述的异常或疾病的用途。非典型抗精神病药包括如鲁拉西酮(lurasidone)、喹硫平(quetiapine)、奥氮平(olanzapine)、阿塞那平(asenapine)、理思必妥(risperidone)、齐拉西酮(ziprasidone)、氯氮平(clozapine)、美哌隆(mel perone)、卡利拉嗪(cariprazine)、阿立哌唑(aripiprazole)、匹莫范色林(pimavanserin)、ITI-007、RP506及瑞莫必利(Remoxipride)。
范例
以下代表性实例为了帮助说明本发明,而非意图也不应被解释为限制本发明的范围。
实例1-5-(3-氯-4-氟苯基)-7-环丙基-3-(2-(3-氟-3-甲基氮杂啶-1-基)-2-氧代乙基)-3,7-二氢-4H-吡咯[2,3-d]嘧啶-4-酮(化合物1)的制备
步骤-1:制备4,6-二氯-5-(2,2-二乙氧基乙基)嘧啶(2):
将氯化铵加到2-(4,6-二氯嘧啶-5-基)乙醛(1,5g,26.17mmol)的乙醇(250mL)溶液中,并回流反应混合物20小时。浓缩反应混合物;用水(50mL)稀释残余物,并以乙酸乙酯(2x 100mL)萃取。将合并的有机层用无水硫酸钠进行干燥、过滤及浓缩,以得到无色油状物的标题化合物4,6-二氯-5-(2,2-二乙氧基乙基)嘧啶(2,6.9g,粗产物)。计算值(M+H):265.04;实测值(M+H):265。
步骤-2:制备4-氯-7-环丙基-7H-吡咯[2,3-d]嘧啶(3):
将环丙胺(2mL,28.62mmol)加到4,6-二氯-5-(2,2-二乙氧基乙基)嘧啶(2,6.9g,26.02mmol)与三乙胺(3.63mL,26.02mmol)的乙醇(150mL)溶液中,并回流反应混合物10小时。于真空下对反应混合物进行蒸发,并用水(100mL)稀释残余物,且以乙酸乙酯(2×200mL)萃取。将合并的有机层用无水硫酸钠进行干燥、过滤及浓缩。将残余物溶于四氢呋喃(150mL)中,加入2M盐酸(75mL),并回流反应混合物1小时。浓缩反应混合物,将残余物溶于水(100mL)中,并用氢氧化钠溶液碱化到pH 10,且以乙酸乙酯(2×200mL)萃取。将合并的有机层用无水硫酸钠进行干燥、过滤及浓缩,得到褐色半固体的标题化合物4-氯-7-环丙基-7H-吡咯[2,3-d]嘧啶(3,5g,粗产品)。计算值(M+H):194.04;实测值(M+H):194。
步骤-3:制备7-环丙基-3,7-二氢-4H-吡咯[2,3-d]嘧啶-4-酮(4):
于100℃下,加热溶于二恶烷(400mL)与2N氢氧化钠溶液(400mL)中的4-氯-7-环丙基-7H-吡咯[2,3-d]嘧啶(3,19g,98.44mmol)溶液16小时。浓缩反应混合物以除去二恶烷。用水(~200mL)稀释含水残余物,并使用1.5N盐酸溶液酸化到pH~4-6。过滤沉淀固体,用己烷洗涤并进行抽气干燥,得到褐色固体的标题化合物7-环丙基-3,7-二氢-4H-吡咯[2,3-d]嘧啶-4-酮(4,14.93g,87%产率)。计算值(M+H):176.07;实测值(M+H):176。
步骤-4:制备2-(7-环丙基-4-氧代-4,7-二氢-3H-吡咯[2,3-d]嘧啶-3-基)乙酸乙酯(5):
于室温下,将2-溴乙酸乙酯(5.1g,30.8mmol)和碳酸钾(6.2g,46.2mmol)加到7-环丙基-3,7-二氢-4H-吡咯[2,3-d]嘧啶-4-酮(4,2.7g,15.41mmol)的丙酮(60mL)溶液中,并于55℃下回流反应混合物4小时。将反应混合物冷却到室温并过滤。用乙酸乙酯(100mL)洗涤固体,并对合并的滤液进行蒸发,以得到粗产物,其以40%乙酸乙酯(于己烷中)进行硅胶柱色谱纯化,以得到灰白色固体的标题化合物2-(7-环丙基-4-氧代-4,7-二氢-3H-吡咯[2,3-d]嘧啶-3-基)乙酸酯(5,3.5g,87%产率)。计算值(M+H):262.11;实测值(M+H):262。
步骤-5:制备2-(5-溴-7-环丙基-4-氧代-4,7-二氢-3H-吡咯[2,3-d]嘧啶-3-基)乙酸乙酯(6):
将N,O-(双-三甲基硅基)乙酰胺(5.1g,25mmol)及N-溴代琥珀酰亚胺(2.02g,11.4mmol)加到2-(7-环丙基-4-氧代-4,7-二氢-3H-吡咯[2,3-d]嘧啶-3-基)乙酸乙酯(5,3g,11.4mmol)的N,N-二甲基甲酰胺(200mL)搅拌溶液中,且于室温下搅拌反应混合物2小时。用冷水(400mL)淬熄反应混合物,并以乙酸乙酯(2×200mL)萃取。将合并的有机层用无水硫酸钠进行干燥、过滤及浓缩。粗产物以35%乙酸乙酯(于己烷中)进行硅胶柱色谱纯化,以得到灰白色固体的标题化合物2-(5-溴-7-环丙基-4-氧代-4,7-二氢-3H-吡咯[2,3-d]嘧啶-3-基)乙酸乙酯(6,2.1g,54%产率)。计算值(M+H):340.02;实测值(M+H):340。
步骤-6:制备2-(5-(3-氯-4-氟苯基)-7-环丙基-4-氧代-4,7-二氢-3H-吡咯[2,3-d]嘧啶-3-基)醋酸(7):
将碳酸钾(9.15g,66.14mmol)加到2-(5-溴-7-环丙基-4-氧代-4,7-二氢-3H-吡咯[2,3-d]嘧啶-3-基)乙酸乙酯(6,7.5g,22.04mmol)与(3-氯-4-氟苯基)硼酸(5.76g,33.07mmol)的1,4-二恶烷:水混合(250mL,4:1)溶液中。用氩气吹洗反应混合物20分钟。接着,加入与二氯甲烷(0.9g,1.10mmol)络合的[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II),并于100℃下搅拌反应混合物16小时。将反应混合物通过硅藻土床过滤,用水(100mL)稀释滤液,并以乙酸乙酯(2×200mL)洗涤。丢弃有机层。用1.5N盐酸酸化水层,过滤沉淀的固体,并进行抽气干燥,以得到灰白色固体的标题化合物2-(5-(3-氯-4-氟苯基)-7-环丙基-4-氧代-4,7-二氢-3H-吡咯[2,3-d]嘧啶-3-基)乙酸(7,6g,粗产物)。计算值(M+H):362.06;实测值(M+H):362.1。
步骤-7:制备5-(3-氯-4-氟苯基)-7-环丙基-3-(2-(3-氟-3-甲基氮杂啶-1-基)-2-氧代乙基)-3,7-二氢-4H-吡咯[2,3-d]嘧啶-4-酮:
于室温下,将三乙胺(1.36mL,9.9mmol)及3-氟-3-甲基氮杂环丁烷盐酸盐(1.24g,9.9mmol)加到2-(5-(3-氯-4-氟苯基)-7-环丙基-4-氧代-4,7-二氢-3H-吡咯[2,3-d]嘧啶-3-基)醋酸(7,1.8g,4.9mmol)的二氯甲烷(70mL)溶液中。搅拌反应混合物10分钟,接着于0℃下加入丙基膦酸酐溶液(T3P)(6.33mL,9.9mmol,50%于乙酸乙酯中),并于室温下搅拌反应混合物16小时。用水(50mL)稀释反应混合物,并以二氯甲烷(3×70mL)萃取。合并的有机层用无水硫酸钠进行干燥、过滤及蒸发,以得到粗产物,其以4%甲醇(于二氯甲烷中)进行硅胶柱色谱纯化,以得到白色固体的标题化合物5-(3-氯-4-氟苯基)-7-环丙基-3-(2-(3-氟-3-甲基氮杂啶-1-基)-2-氧代乙基)-3,7-二氢-4H-吡咯[2,3-d]嘧啶-4-酮(化合物1,1.1g,51%产率)。计算值(M+H):433.12;实测值(M+H):433.1,1H NMR(400MHz,DMSO-d6)δ(ppm):8.26(d,J=6Hz,1H),8.15(s,1H),7.93-7.91(m,1H),7.58(s,1H),7.35(t,J=8.8Hz,1H),4.67(s,2H),4.45-4.32(m,2H),4.05-3.97(m,2H),3.64-3.59(m,1H).1.61(d,J=22Hz,3H),1.10-1.00(m,4H)。HPLC纯度:99.28%。
实例2-5-(3-氯-4-氟苯基)-7-环丙基-3-(2-(3-氟-3-甲基氮杂啶-1-基)-2-氧代乙基)-3,7-二氢-4H-吡咯[2,3-d]嘧啶-4-酮(化合物1)的替代制备
步骤1:制备5-溴-4-氯-7-环丙基-7H-吡咯[2,3-d]嘧啶(10):
将环丙基硼酸(7.41g,86.20mmol)、碳酸钠(10.0g,86.20mmol)及2,2'-联吡啶(6.70g,43.53mmol)加到5-溴-4-氯-7H-吡咯[2,3-d]嘧啶9(10.0g,43.10mmol)的1,2-二氯乙烷(100.0mL)溶液中。接着,将氧气注入反应混合物中30分钟,并加入醋酸铜(8.21g,45.25mmol)。于80℃下,搅拌悬浮液18小时,并在完成后,于室温下用1N盐酸淬熄反应混合物(达pH=1.0)。用二氯甲烷(4×100mL)萃取溶液,而合并的有机层用无水硫酸钠进行干燥。浓缩溶液,残余物用硅胶柱色谱纯化(使用10%乙酸乙酯的己烷溶液),以得到灰白色固体的标题化合物5-溴-4-氯-7-环丙基-7H-吡咯[2,3-d]嘧啶10。产率:8.00g,68.4%。MS(ESI):m/z 271.94[M+1]+。
步骤2:合成5-溴-7-环丙基-3,7-二氢-4H-吡咯[2,3-d]嘧啶-4-酮(11)
以95℃加热溶于二恶烷(40.00mL)与2N氢氧化钠溶液(40.00mL)中的5-溴-4-氯-7-环丙基-7H-吡咯[2,3-d]嘧啶10(8.00g,29.52mmol)溶液18小时。完成后,浓缩反应混合物以除去二恶烷。用水(约50mL)稀释含水残余物,并使用1N盐酸溶液酸化到pH约3。过滤沉淀固体,用己烷洗涤并进行抽气干燥,以得到米白色固体的标题化合物5-溴-7-环丙基-3,7-二氢-4H-吡咯[2,3-d]嘧啶-4-酮11。产率:5.80g,77.70%。MS(ESI)m/z 254.05[M+1]+。
合成中间体2-溴-1-(3-氟-3-甲基氮杂啶-1-基)乙-1-酮(12)
将NaOH(1.0M溶液,14.0g,352mmol)加到化合物A(44.0g,352mmol)的DCM(400mL)搅拌溶液中,并在室温下搅拌二相溶液30分钟。使溶液分层,且水相以DCM(50mL)萃取。将合并的有机层用无水Na2SO4进行干燥,并加入RBF中。将溶液冷却到-10℃,接着缓慢加入溴乙酰溴B(106.5mL,528mmol)(内部温度保持于-5℃),并在相同温度下搅拌2小时。完成后,用冷的饱和NaHCO3溶液淬熄反应混合物,且分成两层。有机层用无水Na2SO4干燥并进行减压浓缩。油状残余物经过硅胶快速柱色谱(20-30%EtOAc的己烷溶液),以得到浅棕色油状物的2-溴-1-(3-氟-3-甲基氮杂啶-1-基)乙-1-酮12。产率:53.0g(73%)。MS(ESI)m/z 209.98[M+1]+。
步骤3:合成5-溴-7-环丙基-3-(2-(3-氟-3-甲基氮杂啶-1-基)-2-氧代乙基)-3,7-二氢-4H-吡咯[2,3-d]嘧啶-4-酮(13)
于室温下,将2-溴-1-(3-氟-3-甲基氮杂啶-1-基)乙-1-酮12(10.9g,52mmol)及K2CO3(11.8g,86mmol)加到5-溴-7-环丙基-3,7-二氢-4H-吡咯[2,3-d]嘧啶-4-酮11(11.0g,43mmol)的丙酮(110mL)溶液中。于60℃下搅拌反应混合物16小时。完成后,将反应混合物冷却到室温,通过过滤,并用丙酮(500mL)洗涤。对合并的滤液进行蒸发,以得到粗产物,其以乙醚彻底洗涤纯化,以得到浅棕色固体的标题化合物5-溴-7-环丙基-3-(2-(3-氟-3-甲基氮杂啶-1-基)-2-氧代乙基)-3,7-二氢-4H-吡咯[2,3-d]嘧啶-4-酮13。产率:14.9g(89.7%)。MS(ESI)m/z 294.23[M+1]+。
步骤4:合成5-(3-氯-4-氟苯基)-7-环丙基-3-(2-(3-氟-3-甲基氮杂啶-1-基)-2-氧代乙基)-3,7-二氢-4H-吡咯[2,3-d]嘧啶-4-酮(化合物1)
将(3-氯-4-氟苯基)硼酸(0.22g,1.3mmol)及K2CO3(0.36g,2.6mmol,2M溶液)加到5-溴-7-环丙基-3,7-二氢-4H-吡咯[2,3-d]嘧啶-4-酮13(0.5g,1.3mmol)的1,4-二恶烷(4.0mL)溶液中。首先,用氩气对反应混合物进行脱气10分钟,接着在氩气下加入PdCl2(dppf)DCM(0.047g,0.065mmol)。在80℃下搅拌反应混合物6小时。完成后,将反应混合物冷却到室温,过滤并用DCM(30mL)洗涤。对合并的滤液进行蒸发,以得到粗产物,其通过硅胶柱色谱纯化(5-6%甲醇的DCM溶液),并用THF洗涤,以得到浅灰色固体的标题化合物5-(3-氯-4-氟苯基)-7-环丙基-3-(2-(3-氟-3-甲基氮杂啶-1-基)-2-氧代乙基)-3,7-二氢-4H-吡咯[2,3-d]嘧啶-4-酮(化合物1)。产率:0.170g(30%)。MS(ESI)m/z 433.23[M+1]+。
生物性测试
如下呈现的数据所示,化合物1是所有NR2A、NR2B、NR2C及NR2D NMDA亚型的有效正向异位调节剂。
卵母细胞2EVC NR2A PAM活性
于卵母细胞(表达hNR2A并以7μM谷氨酸和13μM甘氨酸活化)的双极电压钳(2EVC)测试中,测量化合物1的电流增强(100%增强相当于谷氨酸/甘氨酸诱导的电流加倍)及效力。EC50是指产生半最大反应的化合物浓度。
卵母细胞2EVC NR2C PAM活性
描述:于卵母细胞(表达hNR2C并以10μM谷氨酸和10μM甘氨酸活化)的双极电压钳(2EVC)测试中,测量化合物1的电流增强(100%增强相当于谷氨酸/甘氨酸诱导的电流加倍)及效力。EC50是指产生半最大反应的化合物浓度。
卵母细胞2EVC NR2D PAM活性
描述:于卵母细胞(表达hNR2D并以10μM谷氨酸和10μM甘氨酸活化)的双极电压钳(2EVC)测试中,测量化合物1的电流增强(100%增强相当于谷氨酸/甘氨酸诱导的电流加倍)及效力。EC50是指产生半最大反应的化合物浓度。
卵母细胞2EVC NR2B PAM活性
描述:于卵母细胞(表达hNR2B并以5μM谷氨酸和3μM甘氨酸活化)的双极电压钳(2EVC)测试中,测量化合物1的电流增强(100%增强相当于谷氨酸/甘氨酸诱导的电流加倍)及效力。EC50是指产生半最大反应的化合物浓度。
如下表1所示,比较化合物1与实例174(在Ro 25-6981/DCKA测定中以反应恢复%定量所测得的最有效的示例化合物)及实例181(在Ro 25-6981/DCKA测定中以%最大测得增强定量所测得的最有效的示例化合物)。如表中所示,化合物1在卵母细胞NR2B PAM增强测试中的效力分别比实例174和实例181大约高3倍及2.5倍。此改进是有利的,因为卵母细胞NR2B PAM增强测试中较高的效力在一方面来说是可预期在人体中可以提供增强的治疗效益。
表1
溶解度测定
探讨化合物1的溶解度,并与WO 2017/100591的实例436(其为化合物1的组成异构物(咪唑并哌嗪酮核,imidazopyrazinone core),于Ro 25-6981/DCKA测试中证实效力(反应恢复100%)进行比较。测试化合物的水溶解度可以通过摇瓶法于磷酸盐缓冲盐水(pH7.4)中测得。在所述测定中,将测试化合物的DMSO储备溶液加到缓冲液中,接着进行平衡(振荡)、过滤、以及通过HPLC-UV测定可溶解量。如表中所示,发现化合物1相对于组成异构物实例436有大约10倍大的水溶解度(29μM比上3μM)。提供WO 2017/100591的其它咪唑并哌嗪酮比较物作参考。所有比较类似物都具活性,可以从WO 2017/100591中获得其效力数据。此改进是有利的,因为改善水溶解度在一方面来说是可预期得以提高人体内的体内性能。
表2
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渗透率和外排测定
单层系统是由多孔载体上生长的紧密细胞层组成,以隔开两个流体隔室。它们被广泛认为是最复杂的体外工具,以用于重要药代动力屏障的中等到高通量建模,例如肠上皮、血脑屏障等(J Pharm Sci.2012年4月;101(4):1337-1354)。广泛应用于单层研究中的两种系统是人结肠线癌细胞系Caco-2与MDR1转染的MDCKII及LLC-PK1细胞。在单层测定中,测量化合物通过单层细胞的通量。通过将待测化合物施于细胞层的顶侧或基底侧,并监测其于两隔室之间的时间解析重新分布(time resolved redistribution),以测定待测化合物的单向通量。向量传输比(通常称为外排率,Efflux Ratio)通过应用双向测量[顶侧到基底侧(A-B)和基底侧到顶侧(B-A)]而测定。通常,高于2或低于0.5的比率表示主动运输过程对化合物净流量的贡献。在没有主动运输过程的情况下,所述比率约为1。
表3
如表3所示,化合物1很好穿透膜且在MDCK外排测定中不被排出。
人类与大鼠微粒体稳定性测定
肝脏是体内药物代谢最重要的部位。通过肝CYP调控的代谢可清除大约60%的上市化合物(McGinnity,D.F.;Soars,M.G.;Urbanowicz,R.A.与Riley,R.J.;DrugMetab.Disp.32,1247,(2004))。肝微粒体是次细胞群(subcellular fraction),其含有膜结合的药物代谢酶。微粒体可以用于测定化合物的体外固有清除率。利用物种特异性微粒体可以用以了解物种间差异。
如表所示,化合物1在人类肝微粒体(HLM)中表达出良好的稳定性,并且在大鼠肝微粒体(RLM)中具有优异的稳定性。
体内清除
在大鼠IV药代动力学研究中,化合物1还展现改善的体外微粒体稳定性及体内清除率。如下所示,化合物1的体内清除率显著低于WO 2017/100591(IV大鼠清除数据可以从中取得)中举例的结构相关NMDA PAM。特别值得注意的是,实例285(吡咯并吡啶酮类似物)在Ro 25-6981/DCKA测定中显示出优异的效力,且在结构上与化合物1特别相似。还提供大鼠微粒体稳定性数据。体外和体内清除的改进是有利的,因为下降的清除率在一方面来说是可预期得以提高人体内的体内性能。
表4
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药理
A.新奇事物认知测试
在大鼠新奇事物认知(NOR)测试中,针对苯环利定(PCP)诱导的认知障碍来测试口服化合物1(0.3、1.0及3.0mg/kg)的认知增强作用。此实验方案测试长期服用NMDA受体拮抗剂PCP所引起的事物认知记忆缺陷的逆转。
大鼠以盐水载体(控制组)或PCP(5mg/kg,腹膜内)每天处理两次,持续7天。在14天不处理的洗脱期(washout period)后,在NOR范例中测试大鼠。简而言之,测试涉及两个阶段(T1和T2),每个阶段持续3分钟,间隔1小时。在T1试验之前施用载体或化合物1。在T1中,将大鼠放置在具有两个相同物体的测试场地中,并允许自由探索,同时记录其在探索每个物体上所耗费的时间。在T2中,将大鼠返回到测试场所,其中一个物体保持相同而另一个物体替换成新物体。记录探索新物体所耗费的时间及探索熟悉物体所耗费的时间,并与T1物体探索时间进行比较。
与盐水控制组相比,PCP处理的动物显示在探索新物体所花费的时间显著减少,此证实了NOR中PCP诱导的缺陷。如图1中数据所示,施用化合物1(0.3及1.0mg/kg,口服)显著地逆转此缺陷,如相较于PCP处理大鼠而呈现较长的新物体探索时间。1mg/kg剂量的化合物1完全逆转PCP诱导的缺陷,因为这些剂量下的探索时间与盐水控制组动物没有显著差异。
B.失匹配负波效力模型
精神分裂症中NMDA受体功能低下的病生理生物指标包括早期听觉处理事件的EEG测量,例如“失匹配负波”,测量前注意听觉新奇检测的EEG事件相关电位(ERP)。MMN是大鼠和人类听觉新奇检测的可转换度量,其与精神分裂症患者的认知及整体功能相关。NMDA受体拮抗剂PCP、MK-801以及氯胺酮在大鼠(所有三种NMDAr拮抗剂)和人类个体(氯胺酮)中引发MMN的急性缺陷。
植入前额EEG电极的大鼠呈现不同的音频刺激,其包括听觉畸变“转置(flip-flop)”规程。简而言之,以90%概率给予1,000个6.0kHz标准音调,并以10%的概率以伪随机此序给予100个8.0kHz偏差音调(取向改变(flip)顺序),接着以8kHz音调作为标准而6kHz音调为偏差来重复所述序列(翻转(flop)顺序)。MMN的计算是于EEG记录时期(从50毫秒听觉音调开始前50毫秒到开始后150毫秒)的每1毫秒时间点从平均8kHz偏差音调反应(flip)中减去平均8kHz标准音调反应(flop)而算得的电位差。
在4向交叉设计中,对大鼠施用载体或化合物1(60mg/kg)两次,间隔4小时。接着,在测试期间前立即对大鼠施用盐水控制或MK-801(0.2mg/kg,IP)。测试期间是由三个20分钟触发器方块组成。如图2所示,相较于施用载体加盐水相比,施用载体加MK-801显著减少MMN。此外,施用化合物1(60mg/kg BID)防止MK-801造成MMN下降,使得化合物1加MK-801后所记录的MMN不再与载体和盐水后所记录的MMN不同,且比施用载体和MK-801后所记录的MMN显著更大。
虽然我们已描述本发明的许多实施例,但显然可以改变我们的基本实例以提供利用本发明化合物及方法的其它实施方式。因此,应当理解,本发明的范围是由随附的权利要求书所定义,而不是由以实例方式呈现的特定实施例所限定。
本申请案整篇所引用的所有参考数据(包括参考文献、公告专利案、公开专利申请案及同在审查中的专利申请案)内容在此以引用方式明确并入本文中。除非另外定义,否则本文使用的所有技术及科学术语均符合本技术领域具有通常知识者通常已知的涵义。
Claims (12)
1.一种如下式的化合物:
或其药学上可接受的盐类。
2.一种医药组合物,其包含:根据权利要求1所述的化合物或其药学上可接受的盐类;以及药学上可接受的载体。
3.根据权利要求1所述的化合物或其药学上可接受的盐类在制备用于治疗个体中精神异常、神经发展异常或神经异常的药物中的用途。
4.根据权利要求3所述的用途,其中所述精神异常为精神分裂症、分裂情感疾患、躁郁症或抑郁症。
5.根据权利要求3所述的用途,其中所述神经发展异常为注意力不足过动症、自闭症谱系障碍或智能障碍。
6.根据权利要求5所述的用途,其中所述障碍为费伦麦克德米德综合征、史密斯-蓝利-欧比司综合征、脆性X染色体综合征或雷特氏症。
7.根据权利要求3所述的用途,其中所述神经异常为癫痫发作或癫痫症、神经退行性疾病、失语症或脑炎。
8.根据权利要求7所述的用途,其中所述神经异常为阿尔茨海默症或抗NMDA受体脑炎。
9.根据权利要求3所述的用途,其中所述精神异常为精神分裂症.
10.根据权利要求3所述的用途,其中所述精神异常为精神分裂症的正性症状。
11.根据权利要求3所述的用途,其中所述精神异常为精神分裂症的负性症状。
12.根据权利要求3所述的用途,其中所述精神异常为精神分裂症的认知症状。
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