CN101111477A - 作为glyt-1抑制剂的苯甲酰基-四氢吡啶 - Google Patents
作为glyt-1抑制剂的苯甲酰基-四氢吡啶 Download PDFInfo
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- CN101111477A CN101111477A CNA2005800476568A CN200580047656A CN101111477A CN 101111477 A CN101111477 A CN 101111477A CN A2005800476568 A CNA2005800476568 A CN A2005800476568A CN 200580047656 A CN200580047656 A CN 200580047656A CN 101111477 A CN101111477 A CN 101111477A
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- Prior art keywords
- compound
- phenyl
- formula
- methylsulfonyl
- pyridine
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
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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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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Abstract
本发明涉及通式(I)化合物及其有药学活性的酸加成盐;其中,R1是非芳族杂环或OR’;R’是低级烷基、被卤素取代的低级烷基或-(CH2)n-环烷基;R2是NO2、CN或SO2R”;R”是低级烷基;Ar是苯基,其任选被卤素、氰基、被卤素取代的低级烷基或SO2R”取代;n是0、1或2;以及涉及它们在治疗神经病学和神经精神病学障碍中的用途。
Description
本发明涉及通式I化合物及其有药学活性的酸加成盐
其中
R1是非芳族杂环或OR’;
R’是低级烷基、被卤素取代的低级烷基或-(CH2)n-环烷基;
R2是NO2、CN或SO2R”;
R”是低级烷基;
Ar是苯基,其任选被卤素、氰基、被卤素取代的低级烷基或SO2R”取代;
n是0、1或2。
本发明涉及通式I化合物、制备那些化合物的方法、包含它们的药物组合物以及它们在治疗神经病学和神经精神病学障碍中的用途。
已经令人惊奇地发现通式I化合物是甘氨酸转运蛋白1(GlyT-1)的很好的抑制剂,并且它们对甘氨酸转运蛋白2(GlyT-2)抑制剂具有很高的选择性。
精神分裂症是进行性和破坏性的神经学疾病,其特征在于:短暂的阳性症状例如妄想、幻觉、思考障碍和精神病,以及持续性的阴性症状例如情感淡漠、注意力下降、社交冷淡和认知损伤(Lewis DA和Lieberman JA,Neuron,2000,28:325-33)。十年来的研究集中在“多巴胺能过兴奋”的假说,其引起了涉及阻断多巴胺能系统的治疗介入(Vandenberg RJ和AubreyKR.,Exp.Opin.Ther.Targets,2001,5(4):507-518;Nakazato A和Okuyama S等人,2000,Exp.Opin.Ther.Patents,10(1):75-98)。这种药理学方法对阴性和认知症状(功能结果的最好指示)作用微弱(Sharma T.,Br.J.Psychiatry,1999,174(suppl.28):44-51)。
在60年代中期基于拟精神病行为提出了精神分裂症补充模型,这种拟精神病行为是通过如苯环己哌啶(phencyclidine,PCP)和相关药物(氯胺酮)的化合物(它们是非竞争性NMDA受体拮抗剂)阻断谷氨酸系统引起的。有趣的是,在健康志愿者中,PCP诱导的拟精神病行为将阳性和阴性症状以及认知功能障碍合为一体,因此与患者的精神分裂症非常相似(Javitt DC等人,1999,Biol.Psychiatry,45:668-679及其参考文献)。另外,表达低水平NMDAR1亚单位的转基因小鼠显示出与在精神分裂症的药理学诱导模型中观察到的类似的行为异常,支持了降低NMDA受体活性引起类似精神分裂症行为的模型(Mohn AR等人,1999,Cell,98:427-236)。
谷氨酸神经传递、特别是NMDA受体活性在突触可塑性、学习和记忆中发挥重要作用,例如NMDA受体似乎作为门控突触可塑性和记忆形成的阈值的等级开关(Hebb DO,1949,The organization of behavior,Wiley,NY;Bliss TV和Collingridge GL,1993,Nature,361:31-39)。过表达NMDANR2B亚单位的转基因小鼠显示出突触可塑性的增强以及较好的学习和记忆能力(Tang JP等人.,1999,Nature:401-63-69)。
因此,如果精神分裂症的病理生理学涉及谷氨酸不足,那么加强谷氨酸传递,特别是通过NMDA受体的活化而加强谷氨酸传递将预示产生抗精神病和认知增强作用。
在CNS中,已知氨基酸甘氨酸至少具有两个重要功能。它与马钱子碱敏感甘氨酸受体结合用作抑制氨基酸,并且它也可以与谷氨酸一起用作N-甲基-D-天冬氨酸(NMDA)受体功能的必要的共激动剂来影响兴奋活性。当谷氨酸以活性依赖方式从突触末端释放出来时,甘氨酸显然以更恒定的水平存在并且似乎调节/控制受体对谷氨酸的响应。
控制神经递质的突触浓度的最有效方法之一是影响它们在突触中的重摄取。神经递质转运蛋白通过从胞外间隙移动神经递质可以控制它们的胞外寿命并且因此调节突触传递量(Gainetdinov RR等人,2002,Trends inPharm.Sci,23(8):367-373)。
形成部分钠和氯的神经递质转运蛋白家族的甘氨酸转运蛋白在终止突触后甘氨酸能作用以及通过甘氨酸重摄取进入突触前神经末梢和周围细微神经胶质的方法来维持低的甘氨酸胞外浓度中发挥重要作用。
两种不同的甘氨酸转运蛋白基因(GlyT-1和GlyT-2)已经从哺乳动物的脑中克隆出来,产生了两种具有~50%氨基酸序列同源性的转运蛋白。GlyT-1存在四种同种型(1a、1b、1c和1d),它们是由选择性剪接和选择性启动子的使用而产生的。在啮齿类动物的脑中仅发现了其中的两种同种型(GlyT-1a和GlyT-1b)。GlyT-2也存在一定程度的异质性。在啮齿类动物的脑中已鉴定出两种GlyT-2同种型(2a和2b)。已知GlyT-1位于CNS和外周组织中,而GlyT-2是中枢神经系统特有的。GlyT-1具有显著的神经胶质分布并且发现其不仅存在于马钱子碱敏感的甘氨酸受体相应的区域中,而且也存在于这些区域外,在这些区域中GlyT-1被认为涉及NMDA受体功能调节(Lopez-Corcuera B等人,2001,Mol.Mem.Biol.,18:13-20)。因此,提高NMDA受体活性的一个策略是通过抑制GlyT-1转运蛋白来提高甘氨酸在突触NMDA受体的局部微环境中的浓度(Bergereon R.等人,1998,Proc.Natl.Acad.Sci.USA,95:15730-15734;Chen L等人,2003,J.Neurophysiol,89(2):691-703)。
甘氨酸转运蛋白抑制剂适合治疗神经病学和神经精神病学障碍。包括的大多数疾病状态是精神病、精神分裂症(Armer RE和Miller DJ,2001,Exp.Opin.Ther.Patents,11(4):563-572)、精神病心境障碍例如严重主要抑郁障碍、伴有精神病障碍的心境障碍例如急性躁狂症或伴有双相性精神障碍的抑郁症以及伴有精神分裂症的心境障碍(Pralong ET等人,2002,Prog.Neurobiol,67:173-202)、孤独症(Carlsson ML,1998,J.Neural Transm.105:525-535)、认知障碍例如痴呆(包括年龄相关的痴呆和阿尔茨海默型老年性痴呆)、哺乳动物(包括人)的记忆障碍、注意力缺陷障碍和疼痛(Armer RE和Miller DJ,2001,Exp.Opin.Ther.Patents,11(4):563-572)。
因此,增加NMDA受体的活化(通过GlyT-1抑制)可以产生治疗以下疾病的药物:精神病、精神分裂症、痴呆以及其它认知过程受损的疾病,例如注意力缺陷障碍或阿尔茨海默病。
本发明的目的是式I化合物本身、式I化合物及其可药用盐在制备用于治疗与NMDA受体的活化(通过GlyT-1抑制)相关的疾病的药物中的用途、它们的制备方法、基于本发明化合物的药物及其制备方法以及式I化合物在控制或预防疾病中的用途,所述的疾病例如精神病、记忆和学习功能障碍、精神分裂症、痴呆以及其它认知过程受损的疾病,例如注意力缺陷障碍或阿尔茨海默病。
应用本发明的化合物的优选适应证是精神分裂症、认知损伤和阿尔茨海默病。
另外,本发明包括所有的外消旋混合物,它们所有相应的对映异构体和/或旋光异构体。
本文所用的术语“低级烷基”表示含有1至7个碳原子的饱和的直链或支链基团,例如甲基、乙基、丙基、异丙基、正丁基、异丁基、2-丁基、叔丁基等。优选的烷基是含有1-4个碳原子的基团。
本文所用的术语“环烷基”表示含有3至7个碳原子的饱和碳环,例如环丙基、环戊基或环己基。
本文所用的术语“非芳族杂环”表示含有1个或2个选自O、N或S的杂原子的五或六元杂环。优选的环是1-吡咯烷、1-哌啶、1-哌嗪或1-吗啉。
术语“卤素”表示氯、碘、氟和溴。
本文所用的术语“被卤素取代的低级烷基”表示以上定义的烷基,其中至少一个氢原子被卤素代替,例如CF3、CHF2、CH2F、CH2CF3等。
术语“可药用酸加成盐”包括与无机酸和有机酸的盐,所述的酸例如盐酸、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。
优选的式I化合物是那些其中R1是吗啉的式I化合物,例如以下化合物:4-[1-(2-吗啉-4-基-5-硝基-苯甲酰基)-1,2,3,6-四氢-吡啶-4-基]苄腈、(5-甲磺酰基-2-吗啉-4-基-苯基)-[4-(4-三氟甲基-苯基)-3,6-二氢-2H-吡啶-1-基]-甲酮或[4-(4-甲磺酰基-苯基)-3,6-二氢-2H-吡啶-1-基]-(2-吗啉-4-基-5-硝基-苯基)-甲酮。
另外优选的是其中R1是被卤素取代的-O-低级烷基的化合物,该化合物是[5-甲磺酰基-2-(2,2,2-三氟-乙氧基)-苯基]-[4-(4-三氟甲基-苯基)-3,6-二氢-2H-吡啶-1-基]-甲酮。
另外优选的是其中R1是-O-低级烷基的化合物,该化合物是3-[4-(4-氯-苯基)-3,6-二氢-2H-吡啶-1-羰基]-4-异丙氧基-苄腈。
另外优选的式I化合物是那些其中R1是-O-(CH2)n-环烷基的式I化合物,例如以下化合物:(2-环戊氧基-5-甲磺酰基-苯基)-[4-(4-甲磺酰基-苯基)-3,6-二氢-2H-吡啶-1-基]-甲酮或[4-(4-氯-苯基)-3,6-二氢-2H-吡啶-1-基]-(2-环丙基甲氧基-5-甲磺酰基-苯基)-甲酮。
本发明式I化合物及其可药用盐可以通过本领域已知的方法制备,例如通过以下描述的方法制备,该方法包括
a)将式II化合物与式III-1或式III-2化合物在式III-1化合物的活化剂、例如TBTU(2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲四氟硼酸酯)的存在下反应
生成式I化合物
其中hal是卤原子、例如氯并且Ar、R1和R2如以上定义,并且
如果需要,将获得的化合物转化为可药用酸加成盐。
式I化合物可以根据方法的变通实施方案a)和以下流程图1制备。所有的原料或者是可商购的、在文献中描述的,或者可以通过本领域众所周知的方法制备。
应用了以下缩略语:
流程图1
通式I化合物可以通过在活化剂、如TBTU的存在下将式II的4-芳基-取代的-1,2,3,6-四氢-吡啶衍生物与式III的相应的酸(A:OH)反应或与式III相应的活化的酸(A:Cl)反应而制备。式III的酸可以通过将式IV的酸与式R1H的亲核体反应而制备。式II的4-芳基-取代的-1,2,3,6-四氢-吡啶衍生物可以在Suzuki条件(Eastwood等人.tetrahedron Letters(2000),41,(19),3705-3708)下通过将硼酸酯V与ArX在钯催化剂的存在下反应,然后将保护基裂解而制备,如流程图1所示。典型的保护基是叔丁氧基羰基(Boc)。
碱性的式I化合物的酸加成盐可以通过用至少化学计算当量的适合的碱处理而转化为相应的游离碱,所述的适合的碱例如氢氧化钠或氢氧化钾、碳酸钾、碳酸氢钠、氨等。
式I化合物及其可药用加成盐具有有价值的药理学性质。特别的是,已经发现本发明化合物是甘氨酸转运蛋白1(GlyT-1)的很好的抑制剂。
根据下文给出的试验对化合物进行研究。
溶液和材料
DMEM完全培养基:营养混合物F-12(Gibco Life-technologies)、胎牛血清(FBS)5%(Gibco life technologies)、青霉素/链霉素1%(Gibco lifetechnologies)、潮霉素0.6mg/mL(Gibco life technologies)、谷氨酰胺1mM(Gibco life technologies)。
摄取缓冲液(UB):150mM NaCl、10mM Hepes-Tris(pH7.4)、1mMCaCl2、2.5mM KCl、2.5mM MgSO4、10mM(+)D-葡萄糖。
用mGlyT1b cDNA稳定转染Flp-inTM-CHO细胞(Invitrogen Cat n°R758-07)。
甘氨酸摄取抑制试验(mGlyT-1b)
第一天,将用mGlyT-1b cDNA稳定转染的哺乳动物细胞(Flp-inTM-CHO)在不含潮霉素的F-12完全培养基中以40,000个细胞/孔的密度平铺在96孔板上。第二天,抽吸培养基并且用摄取缓冲液(UB)洗涤两次。然后将细胞与(i)无潜在竞争剂、(ii)10mM非放射性甘氨酸、(iii)一定浓度的潜在抑制剂中的任一种在22℃下培养20分钟。应用一定浓度范围的潜在抑制剂以产生用于计算引起50%作用的抑制剂浓度(例如IC50,抑制50%甘氨酸摄取的竞争剂浓度)的数据。然后迅速加入含有[3H]-甘氨酸60nM(11-16Ci/mmol)和25μM非放射性甘氨酸的溶液。将板轻摇培养并且通过抽吸混合物将反应停止并且用冰冷的UB洗涤(三次)。将细胞用闪烁液裂解、振摇3小时并且应用闪烁计数器计算细胞的放射性。
优选的化合物在GlyT-1<0.9时显示IC50(μM)。
实施例号 | IC50(μM) | 实施例号 | IC50(μM) |
1 | 0.803 | 6 | 0.251 |
2 | 0.432 | 7 | 0.870 |
3 | 0.270 | 8 | 0.201 |
4 | 0.122 | 9 | 0.28 |
5 | 0.232 | 10 | 0.056 |
式I化合物和式I化合物的可药用盐可以用作药物,例如,以药物制剂的形式。药物制剂可以例如以片剂、包衣片、糖锭剂、硬和软明胶胶囊剂、溶液剂、乳剂或混悬剂的形式口服施用。但是,也可以例如以栓剂的形式直肠施用,例如以注射溶液剂的形式非肠道施用。
式I化合物可以用制备药物制剂的药用惰性的无机或有机载体进行加工。可以应用乳糖、玉米淀粉或其衍生物、滑石粉、硬脂酸或其盐等例如作为片剂、包衣片、糖锭剂和硬明胶胶囊的载体。软明胶胶囊的适合的载体是例如植物油、蜡、脂肪、半固体和液体多元醇等。但是,取决于活性物质的性质,在软明胶胶囊的情况下通常不需要载体。制备溶液剂和糖浆剂的适合的载体是例如水、多元醇、甘油、植物油等。栓剂的适合的载体是例如天然或硬化的油、蜡、脂肪、半液体或液体多元醇等。
另外,药物制剂可以包含防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、矫味剂、改变渗透压的盐、缓冲剂、掩味剂或抗氧化剂。它们也可以包含其它有治疗价值的物质。
包含式I化合物或其可药用盐以及在治疗上惰性的载体的药物也是本发明的目的,它们的制备方法也是本发明的目的,该方法包括将一种或多种式I化合物和/或可药用酸加成盐以及一种或多种其它有治疗价值的物质与一种或多种在治疗上惰性的载体(如果需要的话)一起制备成盖伦制剂施用形式。
本发明,最优选的适应证是那些包括中枢神经障碍的适应证,例如治疗或预防精神分裂症、认知损伤和阿尔茨海默病。
剂量可在较宽的限度内变化并且当然需要调节至每个特殊病例的个体需要。在口服施用的情况下,成人剂量可以从每天约0.01mg至约1000mg通式I化合物或相应量的其可药用盐变化。日剂量可以作为单剂量施用或以分剂量施用,另外,在发现需要时也可以超出上限。
片剂(湿法制粒) | |||||
项目 | 成分 | mg/片 | |||
12345 | 式IA或IB化合物无水乳糖DTGSta-Rx1500微晶纤维素硬脂酸镁总计 | 5mg | 25mg | 100mg | 500mg |
51256301167 | 251056301167 | 100306301167 | 500150301501831 |
制备方法
1.将项目1、2、3和4混合并且用纯化的水制粒。
2.在50℃下干燥颗粒。
3.将颗粒通过适合的研磨设备。
4.加入项目5并且混合3分钟;在适合的压片机上压片。
胶囊剂 | |||||
项目 | 成分 | mg/胶囊 | |||
12345 | 式IA或IB化合物含水乳糖玉米淀粉滑石粉硬脂酸镁总计 | 5mg | 25mg | 100mg | 500mg |
515925101200 | 2512335152200 | 10014840102300 | 500-70255600 |
制备方法
1.将项目1、2和3在适合的混合机中混合30分钟。
2.加入项目4和5并且混合3分钟。
3.填充入适合的胶囊中。
以下实施例用来说明本发明但不限制本发明。所有温度以摄氏温度给出。
所有的原料或者是可商购的、在文献中描述的,或者可以通过本领域众所周知的方法制备。
实施例1
(2-吗啉-4-基-5-硝基-苯基)-(4-苯基-3,6-二氢-2H-吡啶-1-基)-甲酮
1a:2-吗啉-4-基-5-硝基-苯甲酸
将吗啉(11.5mL)加入至2-氟-5-硝基苯甲酸(4.86g,26.2mmol)的二烷(50mL)溶液中。将混合物在室温下搅拌2小时。真空下除去溶剂。将残留物溶于水中并且用2NHCl将混合物酸化。将固体过滤,用水洗涤并且干燥,得到标题化合物(6.2g,93%),为黄色固体,MS(m/e):251.2(M-H,100%)。
1b:2-吗啉-4-基-5-硝基-苯甲酰氯
向2-吗啉-4-基-5-硝基苯甲酸(4.0g,16mmol)的甲苯悬浮液中加入2滴DMF和亚硫酰氯(5.7mL,79.3mmol)。将混合物加入至80℃达50分钟。真空下除去溶剂并且将产生的固体在醚中搅拌,过滤并且干燥,得到标题化合物(4.0g,93%),为黄色固体。
1c:(2-吗啉-4-基-5-硝基-苯基)-(4-苯基-3,6-二氢-2H-吡啶-1-基)-甲酮
在室温下,将40.6mg(0.15mmol)2-吗啉-4-基-5-硝基-苯甲酰氯、29mg(0.18mmol)4-苯基-1,2,3,6-四氢-吡啶(商购)和62.5μL(0.45mmol)NEt3在1mL DCM中的混合物搅拌16小时。将挥发物蒸发后,将残留物溶于1mL CH3CN/DMF/HCOOH3/5/2中并且进行制备型反相HPLC纯化,用乙腈/水梯度洗脱,蒸发后得到标题化合物。
MS(m/e):394.1(MH+,100%)
实施例2
[4-(4-氯-苯基)-3,6-二氢-2H-吡啶-1-基]-(2-吗啉-4-基-5-硝基苯基)-甲酮
根据实施例1描述的合成方法,从2-吗啉-4-基-5-硝基-苯甲酰氯和4-(4-氯-苯基)-1,2,3,6-四氢-吡啶盐酸盐(商购)合成标题化合物。MS(m/e):428.1(MH+,100%)
实施例3
4-[1-(2-吗啉-4-基-5-硝基-苯甲酰基)-1,2,3,6-四氢-吡啶-4-基]-苄腈
根据实施例1描述的合成方法,从2-吗啉-4-基-5-硝基-苯甲酰氯和4-(1,2,3,6-四氢-吡啶-4-基)-苄腈(CAS:460365-22-4)合成标题化合物。MS(m/e):417.0(M-H,100%)
实施例4
[5-甲磺酰基-2-(2,2,2-三氟-乙氧基)-苯基]-[4-(4-三氟甲基-苯基)-3,6-二氢-2H-吡啶-1-基]-甲酮
4a:2-氯-5-亚磺基-苯甲酸
在0℃下,将33.59g(267mmol)亚硫酸钠的100mL水溶液用21.2g(89mmol)2-氯-5-氟磺酰基-苯甲酸和26.6mL10M NaOH水溶液(267mmol)处理。将混合物在室温下搅拌3小时,用浓HCl酸化(pH=4)并且在真空下除去水。加入甲醇,过滤沉淀物并且浓缩滤液。加入甲醇和乙醚并且过滤沉淀物,用醚洗涤并且干燥,得到15g(76.5%)标题化合物,为白色胶状物。MS(m/e):219.1(M-H,100%)
4b:2-氯-5-甲磺酰基-苯甲酸
将1g(4mmol)2-氯-5-亚磺基-苯甲酸在20mL甲醇和20mL水中的混合物用10N NaOH处理至pH=9,然后加入1.7g(12mmol)碘代甲烷。将混合物加热48小时至80℃,偶尔加入NaOH以保持pH=9。除去所有的挥发物后加入浓盐酸并且将混合物用乙酸乙酯萃取。将合并的有机层用MgSO4干燥并且蒸干。将残留物溶于甲醇并且进行反相HPLC纯化,用乙腈/水梯度洗脱,将产物级分蒸发后得到323mg(34%)标题化合物。MS(m/e):233.0(M-H,100%)
4c:5-甲磺酰基-2-(2,2,2-三氟-乙氧基)-苯甲酸
将2.13mmol 2-氯-5-甲磺酰基-苯甲酸、0.64mmol Cu(I)Br在5mLNEt3和25mL 2,2,2-三氟-乙醇中的混合物在密封试管中加热至120℃达16小时。在真空下除去挥发物并且将残留物溶于70mL1NHCl中。用乙酸乙酯萃取、干燥合并的有机级分并且将蒸发得到的残留物用反相制备型HPLC纯化,用乙腈/水梯度洗脱,将产物级分蒸发,得到标题化合物。MS(m/e):297.0(M-H,100%)
4d:4-(4-三氟甲基-苯基)-3,6-二氢-2H-吡啶-1-甲酸叔丁酯
向0.97mmol 4-(4,4,5,5-四甲基-[1,3,2]-二氧杂环戊硼烷-2-基)-3,6-二氢-2H-吡啶-1-甲酸叔丁酯(CAS:286961-14-6)的6mL二甲基甲酰胺溶液中依次加入2.91mmol碳酸钾、1.02mmol对-溴三氟甲苯和0.06mmol二氯(1,1’二(二苯膦基)二茂铁)钯(II)二氯甲烷络合物。然后,将反应物在80℃下搅拌6小时,真空浓缩并且通过柱色谱(SiO2,20g,庚烷)纯化,得到标题化合物。MS(m/e):271.1(M-异亚丁基)
4e:4-(4-三氟甲基-苯基)-1,2,3,6-四氢-吡啶
将0.52mmol 4-(4-三氟甲基-苯基)-3,6-二氢-2H-吡啶-1-甲酸叔丁酯在2mL二氯甲烷中的混合物用0.2mL三氟乙酸处理。将混合物在40℃下搅拌3小时,然后浓缩并且用水/NaOH处理并且用二氯甲烷萃取。将合并的有机相用饱和的NaCl洗涤,用MgSO4干燥并且蒸发,得到标题化合物。MS(m/e):228.3(MH+,100%)
4f:[5-甲磺酰基-2-(2,2,2-三氟-乙氧基)-苯基]-[4-(4-三氟甲基-苯基)-3,6-
二氢-2H-吡啶-1-基]-甲酮
向0.17mmol5-甲磺酰基-2-(2,2,2-三氟-乙氧基)-苯甲酸的0.75mL二甲基甲酰胺溶液中依次加入0.19mmol TBTU、0.855mmol N-乙基二异丙基胺和0.205mmol4-(4-三氟甲基-苯基)-1,2,3,6-四氢-吡啶。然后,将反应物在室温下搅拌45分钟,真空浓缩并且通过柱色谱(SiO2,10g,庚烷,乙酸乙酯:0至100%)纯化,得到标题化合物。MS(m/e):508.6(MH+,100%)
实施例5
(5-甲磺酰基-2-吗啉-4-基-苯基)-[4-(4-三氟甲基-苯基)-3,6-二氢-2H-吡啶-1-基]-甲酮
5a:5-甲磺酰基-2-吗啉-4-基-苯甲酸
将163.8mg(0.7mmol)2-氯-5-甲磺酰基-苯甲酸(实施例4步骤b)在2mL吗啉中的混合物加热16小时至100℃。将所有挥发物蒸发后,将残留物溶于2mL甲醇/甲酸3/1中并且进行反相HPLC纯化,用乙腈/水梯度洗脱,将产物级分蒸发后得到标题化合物。MS(m/e):284.1(M-H,100%)
5b:(5-甲磺酰基-2-吗啉-4-基-苯基)-[4-(4-三氟甲基-苯基)-3,6-二氢-2H-
吡啶-1-基]-甲酮
根据实施例4步骤f描述的合成方法,从5-甲磺酰基-2-吗啉-4-基-苯甲酸和4-(4-三氟甲基-苯基)-1,2,3,6-四氢-吡啶合成标题化合物。MS(m/e):495.4(MH+,100%)
实施例6
[4-(4-甲磺酰基-苯基)-3,6-二氢-2H-吡啶-1-基]-(2-吗啉-4-基-5-硝基-苯基)-甲酮
6a:4-(4-甲磺酰基-苯基)-1,2,3,6-四氢-吡啶
根据实施例4步骤d和e描述的方法,从4-(4,4,5,5-四甲基-[1,3,2]-二氧杂环戊硼烷-2-基)-3,6-2氢-2H-吡啶-1-甲酸叔丁酯和4-溴甲基砜合成标题化合物。MS(m/e):336.0(M-H,100%)
6b:[4-(4-甲磺酰基-苯基)-3,6-二氢-2H-吡啶-1-基]-(2-吗啉-4-基-5-硝基
-苯基)-甲酮
根据实施例4步骤f描述的合成方法,从2-吗啉-4-基-5-硝基-苯甲酸和4-(4-甲磺酰基-苯基)-1,2,3,6-四氢-吡啶合成标题化合物。MS(m/e):470.1(M-H,100%)
实施例7
(2-异丙氧基-5-甲磺酰基-苯基)-[4-(4-甲磺酰基-苯基)-3,6-二氢-2H-吡啶-1-基]-甲酮
7a:2-异丙氧基-5-甲磺酰基-苯甲酸
根据实施例4步骤c描述的合成方法,从2-氯-5-甲磺酰基-苯甲酸和异丙醇合成标题化合物。MS(m/e):257.0(M-H,100%)
7b:(2-异丙氧基-5-甲磺酰基-苯基)-[4-(4-甲磺酰基-苯基)-3,6-二氢-2H-
吡啶-1-基]-甲酮
根据实施例4步骤f描述的合成方法,从2-异丙氧基-5-甲磺酰基-苯甲酸和4-(4-甲磺酰基-苯基)-1,2,3,6-四氢-吡啶合成标题化合物。MS(m/e):495.4(M+NH4+,100%)
实施例8
(2-环戊氧基-5-甲磺酰基-苯基)-[4-(4-甲磺酰基-苯基)-3,6-二氢-2H-吡啶-1-基]-甲酮
8a:2-环戊氧基-5-甲磺酰基-苯甲酸
根据实施例4步骤c描述的合成方法,从2-氯-5-甲磺酰基-苯甲酸和环戊醇合成标题化合物。MS(m/e):282.9(M-H,100%)
8b:(2-环戊氧基-5-甲磺酰基-苯基)-[4-(4-甲磺酰基-苯基)-3,6-二氢-2H-
吡啶-1-基]-甲酮
根据实施例4步骤f描述的合成方法,从2-环戊氧基-5-甲磺酰基-苯甲酸和4-(4-甲磺酰基-苯基)-1,2,3,6-四氢-吡啶合成标题化合物。MS(m/e):503.9(M+,100%)
实施例9
3-[4-(4-氯-苯基)-3,6-二氢-2H-吡啶-1-羰基]-4-异丙氧基-苄腈
根据实施例4步骤f描述的合成方法,从5-氰基-2-异丙氧基-苯甲酸(CAS:845616-14-0)和4-(4-氯-苯基)-1,2,3,6-四氢-吡啶盐酸盐(商购)合成标题化合物。MS(m/e):381.1(MH+,100%)
实施例10
[4-(4-氯-苯基)-3,6-二氢-2H-吡啶-1-基]-(2-环丙基甲氧基-5-甲磺酰基-苯基)-甲酮
根据实施例4步骤f描述的合成方法,从2-环丙基甲氧基-5-甲磺酰基-苯甲酸(CAS:845616-03-7)和4-(4-氯-苯基)-1,2,3,6-四氢-吡啶盐酸盐(商购)合成标题化合物。MS(m/e):446.0(MH+,100%)。
Claims (15)
2.权利要求1的式I化合物,其中R1是吗啉。
3.权利要求2的式I化合物,其中化合物是4-[1-(2-吗啉-4-基-5-硝基-苯甲酰基)-1,2,3,6-四氢-吡啶-4-基]苄腈、(5-甲磺酰基-2-吗啉-4-基-苯基)-[4-(4-三氟甲基-苯基)-3,6-二氢-2H-吡啶-1-基]-甲酮或[4-(4-甲磺酰基-苯基)-3,6-二氢-2H-吡啶-1-基]-(2-吗啉-4-基-5-硝基-苯基)-甲酮。
4.权利要求1的式I化合物,其中R1是被卤素取代的-O-低级烷基。
5.权利要求4的式I化合物,其中化合物是[5-甲磺酰基-2-(2,2,2-三氟-乙氧基)-苯基]-[4-(4-三氟甲基-苯基)-3,6-二氢-2H-吡啶-1-基]-甲酮。
6.权利要求1的式I化合物,其中R1是-O-低级烷基。
7.权利要求6的式I化合物,其中化合物是3-[4-(4-氯-苯基)-3,6-二氢-2H-吡啶-1-羰基]-4-异丙氧基-苄腈。
8.权利要求1的式I化合物,其中R1是-O-(CH2)n-环烷基。
9.权利要求8的式I化合物,其中化合物是(2-环戊氧基-5-甲磺酰基-苯基)-[4-(4-甲磺酰基-苯基)-3,6-二氢-2H-吡啶-1-基]-甲酮或[4-(4-氯-苯基)-3,6-二氢-2H-吡啶-1-基]-(2-环丙基甲氧基-5-甲磺酰基-苯基)-甲酮。
11.权利要求1至9中任意一项的化合物,随时通过权利要求10中要求的方法或通过相当的方法制备。
12.药物,该药物包含一种或多种权利要求1至9中任意一项要求的化合物和可药用赋形剂。
13.权利要求12的药物,其用于治疗阿尔茨海默病。
14.权利要求1至9中任意一项的化合物在制备用于治疗阿尔茨海默病的药物中的用途。
15.如以上描述的本发明。
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DE2423847A1 (de) * | 1973-05-28 | 1975-01-02 | Ciba Geigy Ag | Neue sulfamoylbenzoesaeureamide |
DE2533605A1 (de) | 1975-07-26 | 1977-02-03 | Bayer Ag | Antiparasitenmittel |
DE2611705A1 (de) * | 1976-03-18 | 1977-09-22 | Josef Dipl Chem Dr Rer N Klosa | N-5-(nitrofurfuryliden-)-1-amino- hydantoin enthaltende kristalloesungsmittel |
US4122083A (en) * | 1978-01-16 | 1978-10-24 | E. R. Squibb & Sons, Inc. | 1,2,3,4-Tetrahydropyrido[4',3':4.5]thiazolo-[3,2-a]benzimidazoles |
US4436002A (en) | 1981-12-11 | 1984-03-13 | Hughes Tool Company | Reversal mechanism for power tong |
IT1176613B (it) | 1984-08-14 | 1987-08-18 | Ravizza Spa | Derivati piperazinici farmacologicamente attivi e processo per la loro preparazione |
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CA2322136A1 (en) | 1998-03-06 | 1999-09-10 | Ludo Edmond Josephine Kennis | Glycine transport inhibitors |
CA2322164A1 (en) | 1998-03-06 | 1999-09-10 | Ludo Edmond Josephine Kennis | Glycine transport inhibitors |
US20030216385A1 (en) * | 2000-05-19 | 2003-11-20 | Takahiko Tobe | Triazole derivatives |
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JP4738421B2 (ja) | 2011-08-03 |
US20060148797A1 (en) | 2006-07-06 |
AU2005324109B2 (en) | 2011-01-20 |
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ZA200705383B (en) | 2008-09-25 |
CA2594260A1 (en) | 2006-07-13 |
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US7485637B2 (en) | 2009-02-03 |
RU2007124546A (ru) | 2009-02-20 |
EP1836168A1 (en) | 2007-09-26 |
AR052553A1 (es) | 2007-03-21 |
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AU2005324109A1 (en) | 2006-07-13 |
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