CN101679385A - 作为nk3受体拮抗剂的脯氨酰胺-四唑衍生物 - Google Patents
作为nk3受体拮抗剂的脯氨酰胺-四唑衍生物 Download PDFInfo
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- CN101679385A CN101679385A CN200880018987A CN200880018987A CN101679385A CN 101679385 A CN101679385 A CN 101679385A CN 200880018987 A CN200880018987 A CN 200880018987A CN 200880018987 A CN200880018987 A CN 200880018987A CN 101679385 A CN101679385 A CN 101679385A
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- phenyl
- fluoro
- compound
- tetramethyleneimine
- tetrazolium
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
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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
- A61P25/04—Centrally acting analgesics, e.g. opioids
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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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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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
- A61P25/22—Anxiolytics
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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
- A61P25/24—Antidepressants
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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
本发明涉及式I化合物或其药学适合的酸加成盐,其中R1是环烷基或是未取代或被一个或两个卤素原子取代的苯基;R2是氢或卤素;R3是氢、CN、低级烷氧基、低级烷基或卤素;n是0、1或2。已经发现,本发明化合物是高潜能的用于治疗抑郁、疼痛、精神病、帕金森病、精神分裂症、焦虑和注意力缺陷多动症(ADHD)的NK-3受体拮抗剂。
Description
本发明涉及式I化合物
其中
R1是环烷基或是未取代或被一个或两个卤素原子取代的苯基;
R2是氢或卤素;
R3是氢、CN、低级烷氧基、低级烷基或卤素;
n 是0、1或2;
或其药学适合的酸加成盐。
本发明包括式I化合物的所有立体异构形式,包括单独的非对映体和对映体,以及其外消旋和非外消旋混合物。
已经发现,本发明化合物是高度有用的NK-3受体激动剂,用于治疗抑郁、疼痛、精神病、帕金森病、精神分裂症、焦虑和注意力缺陷多动症(ADHD)。
三种主要的哺乳动物速激肽,即P物质(SP)、神经激肽A(NKA)和神经激肽B(NKB),属于共享相同的COOH-末端五肽序列Phe-X-Gly-Leu-Met-NH2的神经肽家族。作为神经递质,这些肽经由被称为NK-1、NK-2和NK-3的三种不同的神经激肽(NK)受体发挥它们的生物学活性。SP优选结合于NK-1受体,NKA优选结合于NK-2,且NKB优选结合于NK-3受体。
NK-3受体的特征在于在CNS中优势表达,已经显示其牵涉于中枢单胺能系统的调节。这些性质使得NK-3受体成为中枢神经系统病症的潜在靶标,如焦虑、抑郁、双相性精神障碍、帕金森病、精神分裂症和疼痛(Neurosci.Letters,2000,283,185-188;Exp.Opin.Ther.Patents 2000,10,939-960;Neuroscience,1996,74,403-414;Neuropeptides,1998,32,481-488)。
精神分裂症是主要的神经精神障碍之一,特征在于严重和长期的精神损害。这种破坏性的疾病影响约1%的世界人口。症状始于成人早期,随后出现人际交往和社交功能障碍时期。精神分裂症表现为听觉和视觉幻觉、偏执狂、妄想(阳性症状)、感情迟钝、抑郁、兴趣缺失、言语贫乏、记忆力和注意力缺陷,以及社交退缩(负性症状)。
数十年来,科学家和临床医生已经努力旨在发现用于药理性治疗精神分裂症的理想活性剂。但是,由于症状多样所致的该障碍的复杂性,阻碍了这些努力。对于精神分裂症的诊断而言,没有特定的病灶特征,没有单个的症状持续地存在于所有患者。因此,已经讨论了将精神分裂症的诊断作为单一病症还是作为多种不同病症,但还没有结论。开发用于精神分裂症的新药物的主要困难在于缺乏有关该疾病的起因和性质的知识。基于药理学研究已经提出了一些神经化学假设,以使相应疗法的开发合于理性:多巴胺、5-羟色胺和谷氨酸假设。但是,考虑到精神分裂症的复杂性,对阳性和负性症候和症状的功效,可能需要适合的多受体亲和性质。此外,由于精神分裂患者的坚持性差,对抗精神分裂症的理想药物将优选具有低剂量,以允许每天一次给药。
近年来,用选择性NK1和NK2受体拮抗剂的临床研究出现于文献中,显示用于治疗呕吐、抑郁、焦虑、疼痛和偏头疼(NK1)和哮喘(NK2和NK1)的结果。最令人兴奋的资料产生于用NK1受体拮抗剂治疗化学治疗诱导的呕吐、恶心和抑郁,和用NK2受体拮抗剂治疗哮喘。相比之下,直到2000年,文献中还没有出现NK3受体拮抗剂的临床资料。来自Sanofi-Synthelabo的Osanetant(SR 142,801)是首次确定的强效、选择性非肽拮抗剂,被描述用于NK3速激肽受体,用于潜在治疗精神分裂症,其在文献中报道(Current Opinion in Investigational Drugs,2001,2(7),950-956和Psychiatric Disorders Study 4,Schizophrenia,2003年6月,DecisionRecources,Inc.,Waltham,Massachusetts)。所建议的药物SR 142,801已经在II期试验中显示对精神分裂症的阳性症状有活性,如行为改变、妄想、幻觉、极端感情、兴奋性运动活性和言语散乱,但是对于负性症状的治疗无活性,其为抑郁、兴趣缺失、社会隔离或记忆力和注意力缺陷。
神经激肽-3受体拮抗剂已经描述为可用于疼痛或炎症以及精神分裂症(Exp.Opinion.Ther.Patents(2000),10(6),939-960和Current Opinion inInvestigational Drugs,2001,2(7),950-956956和Psychiatric Disorders Study4,Schizophrenia,2003年6月,Decision Recources,Inc.,Waltham,Massachusetts)。
本发明的目的是新的式I化合物、它们的制备、基于本发明化合物的药物和它们的制备,以及式I化合物在控制或预防疾病如抑郁、疼痛、双相性精神障碍、精神病、帕金森病、精神分裂症、焦虑和注意力缺陷多动症(ADHD)中的用途。
使用本发明化合物的优选适应症是抑郁、精神病、帕金森病、精神分裂症、焦虑和注意力缺陷多动症(ADHD)。
无论所讨论的术语是单独出现还是组合出现,本说明书所用的通用术语的以下定义均适用。
本文所用的术语“低级烷基”表示含有1至7个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基等。优选的低级烷基是1至4个碳原子的基团。
本文所用的术语“低级烷氧基”表示如上所述含有1至7个碳原子的直链或支链烷基,其中烷基经由氧原子键合。
术语“卤素”表示氯、碘、氟和溴。
术语“环烷基”表示含有3至7个碳原子的饱和碳环,例如环丙基、环丁基、环戊基、环己基、环庚基等。
术语“药学可接受的酸加成盐”包括与无机酸和有机酸的盐,如盐酸、硝酸、硫酸、磷酸、柠檬酸、甲酸、富马酸、马来酸、乙酸、琥珀酸、酒石酸、甲磺酸、对甲苯磺酸等。
优选其中R1是未取代或被一个或两个卤素原子取代的苯基的式I化合物,例如以下化合物:
2-(4-{(2S,4S)-1-苄基-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈,
2-{4-[(2S,4S)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-1-(2-氟-苄基)-吡咯烷-2-羰基]-哌嗪-1-基}-苄腈,
2-{4-[(2S,4S)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-1-(3-氟-苄基)-吡咯烷-2-羰基]-哌嗪-1-基}-苄腈,
2-{4-[(2S,4S)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-1-(4-氟-苄基)-吡咯烷-2-羰基]-哌嗪-1-基}-苄腈,
2-(4-{(2S,4S)-1-(2-氯-苄基)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈,
2-(4-{(2S,4S)-1-(3-氯-苄基)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈,
2-(4-{(2S,4S)-1-(4-氯-苄基)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈或
2-(4-{(2S,4S)-1-(3,4-二氟-苄基)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈。
还优选其中R1是环烷基的式I化合物,例如以下化合物
2-(4-{(2S,4S)-1-环己基甲基-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈。
本发明式I化合物的制备可以以序列或汇集合成途径进行。本发明化合物的合成示于以下方案中。进行反应和纯化所得产物所需的技术对本领域技术人员而言是已知的。以下方法描述中所用的取代基和标识具有本文给出的含义,除非另外指出。
式I化合物可通过以下给出的方法、通过实施例给出的方法或通过类似方法制备。适合于各个反应步骤的反应条件对于本领域技术人员而言是已知的。反应序列不限于方案1中所示的那些,而是取决于原料和它们各自的反应活性,可以自由改变反应步骤的顺序。原料市售可得或可通过类似于以下给出的方法、通过说明书和实施例引用的文献所述的方法或通过本领域已知的方法制备。
本发明的式I化合物和它们药学可接受的盐可通过本领域已知的方法、例如通过以下所述的方法制备,该方法包括:
使式2化合物
与R1C(O)H、乙酸和NaBH(OAc)3反应,
得到式I化合物,
其中取代基如权利要求1所述,
且如果需要将式I化合物转化为药学可接受的盐。
式I化合物的制备更详细地描述于方案I和实施例1-9中。
方案1
a)向相应的苯基-四唑在DMF中的溶液加入2-[4-(2-氰基-苯基)-哌嗪-1-羰基]-4-(甲苯-4-磺酰基氧基)-吡咯烷-1-甲酸叔丁基酯和无水碳酸钠。将混合物在约60℃搅拌过夜。将溶液用EA稀释,洗涤,干燥,浓缩,得到相应的4-[5-(苯基)-四唑-2-基]-吡咯烷-1,2-二甲酸1-叔丁基酯2-甲基酯(4)。
b)向冷却至0℃的4-[5-(苯基)-四唑-2-基]-吡咯烷-1,2-二甲酸1-叔丁基酯2-甲基酯在MeOH中的溶液加入LiOH,将混合物搅拌过夜。除去MeOH后,将残余物用HCl酸化,用EA萃取,干燥,浓缩,得到相应的4-[5-(苯基)-四唑-2-基]-吡咯烷-1,2-二甲酸1-叔丁基酯(5)。
c)向4-[5-(苯基)-四唑-2-基]-吡咯烷-1,2-二甲酸1-叔丁基酯、HOBt、EDC.HCl和Et3N在DCM中的溶液加入取代的苯基哌嗪,例如1-(2-氰基苯基)-哌嗪。将混合物搅拌过夜,然后用Na2CO3、盐水洗涤,干燥,浓缩,得到2-[4-(2-氰基-苯基)-哌嗪-1-羰基]-4-[5-(苯基)-四唑-2-基]-吡咯烷-1-甲酸叔丁基酯(6)。
d)将2-[4-(2-氰基-苯基)-哌嗪-1-羰基]-4-[5-(苯基)-四唑-2-基]-吡咯烷-1-甲酸叔丁基酯加至CF3COOH,将反应混合物搅拌约5小时。除去CF3COOH后,将残余物溶于DCM,洗涤,干燥,浓缩,得到2-(4-{4-[5-(苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈(2)。
e)将2-(4-{4-[5-(苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈、苯甲醛和乙酸(催化)溶于DCM,将溶液搅拌20分钟。然后加入NaBH(OAc)3。将所得混合物温至室温,搅拌过夜。然后将溶液用饱和NaHCO3、盐水洗涤,干燥,浓缩,得到2-(4-{1-苄基-4-[5-(苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈(I)。
盐的形成在室温、按照本身已知且为本领域技术人员熟悉的方法进行。不仅包括与无机酸的盐,也包括与有机酸的盐。这类盐的实例有盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、柠檬酸盐、乙酸盐、马来酸盐、琥珀酸盐、甲磺酸盐、对甲苯磺酸盐等。
缩写
DCM=二氯甲烷;
DMF=N,N-二甲基甲酰胺;
MS=质谱;
EA=乙酸乙酯
EDC=1-(3-二甲基氨基丙基)-3-乙基碳二亚胺
HOBt=1-羟基苯并三唑水合物
如前所提及,式I化合物和它们的药学可用加成盐具有有价值的药理学性质。已经发现,本发明化合物是神经激肽3(NK-3)受体的拮抗剂。按照下文给出的试验对化合物进行了研究。
试验描述:
按照下文给出的试验对化合物进行了研究。
[3H]SR142801竞争结合测定法
hNK3受体结合实验使用[3H]SR142801(目录号:TRK1035,比活性:74.0Ci/mmol,Amersham,GE Healthcare UK limited,Buckinghamshire,UK)和分离自瞬时表达重组人NK3受体的HEK293细胞的膜进行。融化后,将膜均浆在4℃以48,000Xg离心10分钟,将沉淀重悬于50mMTris-HCl、4mM MnCl2、1μM磷酰二肽、0.1%BSA结合缓冲液pH 7.4,最终测定浓度为5μg蛋白/孔。对于抑制实验,将膜与浓度等于放射性配体KD值的[3H]SR142801和10种浓度的抑制性化合物(0.0003-10μM)(总反应体积500μl)在室温孵育75分钟。在孵育结束时,将膜用Filtermate 196收集器(Packard BioScience)过滤到unitfilter(结合GF/C滤纸的96-孔白色微量培养板,在0.3%PEI+0.3%BSA中预孵育1小时,Packard BioScience,Meriden,CT)上,用冰冷的50mM Tris-HCl,pH 7.4缓冲液洗涤4次。对于两种放射性配体,在10μM SB222200存在下测定非特异性结合。加入45μlMicroscint 40(Canberra Packard S.A.,Zürich,瑞士)并振荡1小时后,在淬灭校正的Packard Top-count微量培养板闪烁计数仪上计数滤纸上的放射活性(5min)。使用Excel-fit 4软件(Microsoft),根据Hill方程拟合抑制曲线:y=100/(1+(x/IC50)nH),其中nH=斜率因子。IC50值得自抑制曲线,亲和性常数(Ki)值使用Cheng-Prussoff方程计算:Ki=IC50/(1+[L]/KD),其中[L]是放射性配体的浓度,KD是得自饱和等温线的在受体处的解离常数。所有试验一式两份进行,计算各个Ki值的平均值±标准误差(SEM)。
具有hNK-3受体亲和性的化合物1-9的结果示于下表1。
表1
实施例 | 数据Ki(μM) | 实施例 | 数据Ki(μM) |
1 | 0.084 | 6 | 0.295 |
2 | 0.023 | 7 | 0.208 |
3 | 0.32 | 8 | 0.696 |
4 | 0.965 | 9 | 0.387 |
5 | 0.28 |
式(I)化合物以及它们的药学可用酸加成盐可用作药物,例如以药物制剂形式。药物制剂可经口、例如以片剂、包衣片、糖衣丸、硬和软明胶胶囊、溶液、乳剂或混悬剂形式施用。但是,施用也可以经直肠进行,例如以栓剂形式,或经胃肠外进行,例如以注射溶液形式。
式(I)化合物及其药学可用酸加成盐可以用药学惰性的、无机或有机赋形剂加工以制备片剂、包衣片、糖衣丸和硬明胶胶囊。乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐等可用作这类赋形剂,例如用于片剂、糖衣丸和硬明胶胶囊。
适合用于软明胶胶囊的赋形剂有例如植物油、蜡、脂肪、半固体和液体多元醇等。
适合用于制备溶液和糖浆的赋形剂有例如水、多元醇、蔗糖、转化糖、葡萄糖等。
适合用于注射溶液的赋形剂有例如水、醇、多元醇、甘油、植物油等。
适合用于栓剂的赋形剂有例如天然或硬化油、蜡、脂肪、半液体或液体多元醇等。
此外,药物制剂可含有防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、矫味剂、用于调节渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂。它们还可以含有其他治疗有价值的物质。
剂量可在宽范围内变化,当然将适合于每一具体病例的个体需求。一般而言,口服施用的情况下,日剂量为每人约10至1000mg通式(I)化合物应当是适合的,但是必要时也可以超出上述上限。
实施例A
以常规方式制备以下组成的片剂:
mg/片
活性物质 5
乳糖 45
玉米淀粉 15
微晶纤维素 34
硬脂酸镁 1
片重100
实施例B
制备以下组成的胶囊:
mg/胶囊
活性物质 10
乳糖 155
玉米淀粉 30
滑石 5
胶囊填充重量 200
将活性物质、乳糖和玉米淀粉首先在混合器中混和,然后在粉碎机中混和。将混合物放回至混合器中,向其中加入滑石,充分混和。将混合物通过机器填充至硬明胶胶囊中。
实施例C
制备以下组成的栓剂:
mg/栓
活性物质 15
栓剂基质 1285
共计1300
将栓剂基质在玻璃或钢容器中熔融,充分混和,冷却至45℃。然后,向其中加入活性物质微细粉末,搅拌,直至其已经完全分散。将混合物倾至适合大小的栓剂模具中,使之冷却,然后从模具中除去栓剂,分别包装于蜡纸或金属箔中。
以下实施例阐释而非限制本发明。所有温度以摄氏度给出。
实施例1
2-(4-{(2S,4S)-1-苄基-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈
a)(2S,4S)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-1,2-二甲酸1-叔丁基酯2-
甲基酯
向(2,4-二氟-苯基)-四唑(0.44g,1.1mmol)在5ml DMF中的溶液加入0.1g(0.55mmol)(2S,4R)-2-[4-(2-氰基-苯基)-哌嗪-1-羰基]-4-(甲苯-4-磺酰基氧基)-吡咯烷-1-甲酸叔丁基酯和无水碳酸钠(0.15g,1.4mmol)。将混合物在60℃剧烈搅拌过夜。将溶液用30ml EA稀释,用1M Na2CO3、5%柠檬酸和盐水洗涤,干燥,浓缩,得到粗产物,为黄色油(0.14g,0.34mmol)。MSm/e=410.3[M+H]+。
b)(2S,4S)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-1,2-二甲酸1-叔丁基酯
向冷却至0℃的4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-1,2-二甲酸1-叔丁基酯2-甲基酯(0.14g,0.34mmol)在MeOH(25ml)中的溶液加入LiOH(0.06g,1.36mmol),将混合物搅拌过夜。除去MeOH后,将残余物用2M HCl酸化。水层用EA萃取,将有机溶液干燥,浓缩,得到标题产物,为黄色油(0.1g,0.25mmol)。MS m/e=396.3[M+H]+。
c)(2S,4S)-2-[4-(2-氰基-苯基)-哌嗪-1-羰基]-4-[5-(2,4-二氟-苯基)-四唑-2-
基]-吡咯烷-1-甲酸叔丁基酯
向酸(0.1g,0.25mmol)、HOBt(0.051g,0.38mmol)、EDC.HCl(0.073g,0.38mmol)和Et3N(0.07ml,0.5mmol)在DCM(20ml)中的溶液加入1-(2-氰基苯基)-哌嗪(0.056g,0.3mmol)。将混合物搅拌过夜,然后用饱和Na2CO3、盐水洗涤,干燥,浓缩,得到标题产物,为黄色油(0.184g,0.33mmol)。MS m/e=565.3[M+H]+。
d)(2S,4S)-2-(4-{4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-
基)-苄腈
将2-[4-(2-氰基-苯基)-哌嗪-1-羰基]-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-1-甲酸叔丁基酯(0.184g,0.33mmol)加至CF3COOH(0.22g,1.95mmol),将反应混合物搅拌5小时。除去CF3COOH后,将残余物溶于DCM,用饱和NaHCO3、盐水洗涤,干燥,浓缩,得到标题产物,为黄色油(0.136g,0.29mmol)。MS m/e=465.2[M+H]+。
e)(2S,4S)-2-(4-{1-苄基-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌
嗪-1-基)-苄腈
将2-(4-{4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈(0.136g,0.29mmol)、苯甲醛(0.034g,0.32mmol)和乙酸(催化)溶于DCM(20ml),将溶液搅拌20分钟。然后小心加入NaBH(OAc)3(0.12g,0.58mmol)。将所得混合物温至室温,搅拌过夜。然后将溶液用饱和NaHCO3、盐水洗涤,干燥,浓缩,得到标题产物,为黄色油(0.15g,6mmol)。MS m/e=555.4[M+H]+。
实施例2
2-{4-[(2S,4S)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-1-(2-氟-苄基)-吡咯烷-2-羰基]-哌嗪-1-基}-苄腈
如对实施例1e所述,使用2-氟-苯甲醛(17mg,0.14mmol)代替苯甲醛,将2-(4-{4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈(60mg,0.13mmol)转化为标题化合物(6.1mg,8.2%),为淡黄色油。MS m/e=573.2[M+H]+。
实施例3
2-{4-[(2S,4S)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-1-(3-氟-苄基)-吡咯烷-2-羰基]-哌嗪-1-基}-苄腈
如对实施例1e所述,使用3-氟-苯甲醛(17mg,0.14mmol)代替苯甲醛,将2-(4-{4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈(60mg,0.13mmol)转化为标题化合物(9.9mg,13.3%),为淡黄色油。MS m/e=573.1[M+H]+。
实施例4
2-{4-[(2S,4S)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-1-(4-氟-苄基)-吡咯烷-2-羰基]-哌嗪-1-基}-苄腈
如对实施例1e所述,使用4-氟-苯甲醛(17mg,0.14mmol)代替苯甲醛,将2-(4-{4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈(60mg,0.13mmol)转化为标题化合物(8.2mg,11%),为淡黄色油。MS m/e=573.1[M+H]+。
实施例5
2-(4-{(2S,4S)-1-(2-氯-苄基)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈
如对实施例1e所述,使用2-氯-苯甲醛(20mg,0.14mmol)代替苯甲醛,将2-(4-{4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈(60mg,0.13mmol)转化为标题化合物(11mg,14.4%),为淡黄色油。MS m/e=589.1(75%);591.1(25%)[M+H]+。
实施例6
2-(4-{(2S,4S)-1-(3-氯-苄基)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈
如对实施例1e所述,使用3-氯-苯甲醛(20mg,0.14mmol)代替苯甲醛,将2-(4-{4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈(60mg,0.13mmol)转化为标题化合物(7.7mg,10%),为淡黄色油。MS m/e=589.1(75%);591.1(25%)[M+H]+。
实施例7
2-(4-{(2S,4S)-1-(4-氯-苄基)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈
如对实施例1e所述,使用4-氯-苯甲醛(20mg,0.14mmol)代替苯甲醛,将2-(4-{4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈(60mg,0.13mmol)转化为标题化合物(8.3mg,11%),为淡黄色油。MS m/e=589.1(75%);591.1(25%)[M+H]+。
实施例8
2-(4-{(2S,4S)-1-环己基甲基-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈
如对实施例1e所述,使用环己烷甲醛(16mg,0.14mmol)代替苯甲醛,将2-(4-{4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈(60mg,0.13mmol)转化为标题化合物(8.5mg,11.7%),为淡黄色油。MS m/e=561.3[M+H]+。
实施例9
2-(4-{(2S,4S)-1-(3,4-二氟-苄基)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈
如对实施例1e所述,使用3,4-二氟-苯甲醛(20mg,0.14mmol)代替苯甲醛,将2-(4-{4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈(60mg,0.13mmol)转化为标题化合物(10.4mg,13.5%),为淡黄色油。MSm/e=591.2[M+H]+。
Claims (11)
2.根据权利要求1的式I化合物,其中R1是未取代或被一个或两个卤素原子取代的苯基。
3.根据权利要求2的式I化合物,其中该化合物是
2-(4-{(2S,4S)-1-苄基-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈,
2-{4-[(2S,4S)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-1-(2-氟-苄基)-吡咯烷-2-羰基]-哌嗪-1-基}-苄腈,
2-{4-[(2S,4S)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-1-(3-氟-苄基)-吡咯烷-2-羰基]-哌嗪-1-基}-苄腈,
2-{4-[(2S,4S)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-1-(4-氟-苄基)-吡咯烷-2-羰基]-哌嗪-1-基}-苄腈,
2-(4-{(2S,4S)-1-(2-氯-苄基)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈,
2-(4-{(2S,4S)-1-(3-氯-苄基)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈,
2-(4-{(2S,4S)-1-(4-氯-苄基)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈,或
2-(4-{(2S,4S)-1-(3,4-二氟-苄基)-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈。
4.根据权利要求1的式I化合物,其中R1是环烷基。
5.根据权利要求4的式I化合物,其中该化合物是2-(4-{(2S,4S)-1-环己基甲基-4-[5-(2,4-二氟-苯基)-四唑-2-基]-吡咯烷-2-羰基}-哌嗪-1-基)-苄腈。
7.根据权利要求1的式I化合物,其通过权利要求6所述的方法或通过等同方法制备。
8.药物,含有一种或多种权利要求1至5任一项所述的化合物和药学可接受的赋形剂。
9.根据权利要求8的药物,用于治疗抑郁、疼痛、精神病、帕金森病、精神分裂症、焦虑和注意力缺陷多动症(ADHD)。
10.权利要求1至5任一项所述的化合物在制备用于治疗抑郁、疼痛、精神病、帕金森病、精神分裂症、焦虑和注意力缺陷多动症(ADHD)的药物中的用途。
11.如上所述的本发明。
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