CN1131212C - 苯基-和吡啶基衍生物 - Google Patents
苯基-和吡啶基衍生物 Download PDFInfo
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Abstract
本发明涉及通式(I)的化合物,其中R是氢,低级烷基,低级烷氧基,卤素或三氟甲基;R1是氢或卤素;或R和R1可以一起为-CH=CH-CH=CH-;R2是氢,卤素,三氟甲基,低级烷氧基或氰基;R3各自独立地为氢,低级烷基或形成环烷基;R4是氢,卤素,低级烷基,低级烷氧基,-N(R5)2,-N(R5)S(O)2-低级烷基-N(R5)C(O)R5或基团(a)的环叔胺;R5各自独立地是氢,C3-6环烷基,苄基或低级烷基;R6是氢,羟基,低级烷基,-N(R5)CO-低级烷基,羟基-低级烷基,氰基,-CHO或5-或6元杂环基,任选地通过亚烷基结合,X是-C(O)N(R5)-,-(CH2)mO-,-(CH2)mN(R5)-,-N(R5)C(O)-,C(O)O-或-N(R5)(CH2)m;Y是-(CH2)n-,-O-,-S-,SO2-,-C(O)-或-N(R5)-;Z是=N-,-CH=或-C(Cl)=;n是0-4;且是1或2;及其药用酸加成盐。已证明该式(I)化合物对NK-1受体有高亲和性。
Description
本发明涉及如下通式的化合物其中R 是氢,低级烷基,低级烷氧基,卤素或三氟甲基;R1 是氢或卤素;或R和R1可以一起是-CH=CH-CH=CH-;R2 是氢,卤素,三氟甲基,低级烷氧基或氰基;R3 互相独立地是氢,低级烷基或形成环烷基;R4 是氢,卤素,低级烷基,低级烷氧基,-N(R5)2,-N(R5)S(O)2-低级烷基,-N(R5)C(O)R5或下列基团的环状三级胺R5 互相独立地是氢,C3-6-环烷基,苄基或低级烷基;R6 是氢,羟基,低级烷基,-N(R5)CO-低级烷基,羟基-低级烷基,氰基,-CHO或5-或6-员杂环基,任选地经亚烷基连接,X 是-C(O)N(R5)-,-(CH2)mO-,-(CH2)mN(R5)-,-N(R5)C(O)-,-C(O)O-或-N(R5)(CH2)m-;Y 是-(CH2)n-,-O-,-S-,-SO2-,-C(O)-或-N(R5)-;Z 是=N-,-CH=或-C(Cl)=;n 是0-4;和m 是1或2;和其药用酸加成盐。
式I化合物和其盐的特征在于其有价值的治疗性质。已经令人惊奇地发现,本发明化合物是神经激肽1(NK-1,P物质)受体拮抗剂。P物质是天然存在的,属于速激肽家族的十一肽,后者被这样命名是因为其对外血管平滑肌组织的促进收缩作用。P物质的受体是G蛋白-偶合受体的超家族。
P物质(NK-1)的神经肽受体广泛地分布在哺乳动物神经系统(尤其是脑和脊柱神经节),循环系统和外周组织(尤其是十二指肠和空肠)中,并参与调节多种生物过程。
哺乳动物速激肽P物质的中枢和外周作用与包括偏头痛,风湿性关节炎,气喘,和肠炎病以及呕吐反射的间介有关,并调节中枢神经系统(CNS)疾病如Parkinson’s病(Neurosci.Res.,1996,7,187-214),焦虑(Can.J.Phys.,1997,75,612-621)和抑郁(Science,1998,281,1640-1645)。
速激肽受体拮抗剂对于疼痛,头疼,尤其是偏头痛,Alzheimer’s病,多发性硬化,吗啡脱瘾的衰弱,心血管变化,水肿,如由烫伤引起的水肿,慢性炎症如风湿性关节炎,气喘/支气管过敏反应和其它呼吸道疾病包括过敏性鼻炎,肠线炎症包括溃疡性结肠炎和Crohn’s病,眼损伤和眼炎症有用的证据在“速激肽受体和速激肽受体拮抗剂”,J.Auton.Pharmacol.,13,23-93,1993中综述。
而且,神经激肽1受体拮抗剂被开发用于治疗多种与速激肽,尤其是P物质的过量或失衡有关的病症。与P物质有关的病症的例子包括中枢神经系统疾病如焦虑,抑郁和精神病(WO 95/16679,WO 95/18124和WO 95/23798)。
神经激肽-1受体拮抗剂还可用于治疗运动病和用于治疗诱发性呕吐。
另外,在New England Journal of Medicine,Vol.340,No.3,190-195,1999中已经描述了通过选择性的神经激肽-1受体拮抗剂减轻顺铂-引起的呕吐。
而且,US 5972938描述了通过施用速激肽受体,如NK-1受体拮抗剂来治疗精神免疫学疾病或身心失调的方法。
本发明的主题是式I化合物和其药用盐,上述化合物的制备,含有它们的医药和其生产,以及上述化合物在控制或预防疾病,尤其是前面所列出的疾病和失调中的用途或在生产相应医药中的用途。
本发明最优选的适应症是包括中枢神经系统疾病或呕吐的那些,例如通过施用NK-1受体拮抗剂治疗或预防某些抑郁型疾病。主要的抑郁发作已经被定义为至少二周的周期,大部分天数和几乎每天,要么有抑郁的心境,要么失去所有的兴趣或乐趣,或几乎所有的活力。
用于本说明书中的一般术语的下列定义不考虑所讨论的术语是单独出现还是以结合的形式出现。
本文所用的术语“低级烷基”指含有1-7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,叔丁基等等。
优选的低级烷基是有1-4个碳原子的基团。
术语“低级烷氧基”指其中烷基残基如上定义,并通过氧原子连接的基团。
术语“卤素”指氯,碘,氟和溴。
术语“环烷基”指含有3-6个碳原子的饱和碳环基。
术语“环状三级胺”指,例如,吡咯-1-基,咪唑-1-基,哌啶-1-基,哌嗪-1-基,吗啉-4-基,硫代吗啉-4-基,1-氧代硫代吗啉-4-基或1,1-二氧代硫代吗啉-4-基。
术语“5或6员杂环基”指,例如吡啶基,嘧啶基,噁二唑基,三唑基,四唑基,噻唑基,噻吩基,呋喃基,吡喃基,吡咯基,咪唑基,吡唑基,异噻唑基,哌嗪基或哌啶基。
术语“药用酸加成盐”包括与无机酸和有机酸,如盐酸,硝酸,硫酸,磷酸,柠檬酸,甲酸,富马酸,马来酸,醋酸,琥珀酸,酒石酸,甲磺酸,对甲苯磺酸等的盐。
举例性优选的是其中Y是-C(O)-,而R4是4-甲基哌嗪基的化合物,例如下列化合物:N-[2-苯甲酰基-4-(4-甲基哌嗪-1-基)苯基]-2-(3,5-二-三氟甲基-苯基)异丁酰胺,4-苯甲酰基-N-(3,5-二-三氟甲基-苄基)-N-甲基-6-(4-甲基哌嗪-1-基)烟酰胺和N-(3,5-二-三氟甲基-苄基)-4-(2-氯苯甲酰基)-N-甲基-6-(4-甲基哌嗪-1-基)烟酰胺。
更优选的是其中Y是-O-,而R4是氢,吗啉基或4-甲基哌嗪基的化合物。这类化合物的例子有:2-(3,5-二-三氟甲基-苯基)-N-甲基-N-(2-苯氧基苯基)异丁酰胺,2-(3,5-二-三氟甲基-苯基)-N-甲基-N-(2-o-甲苯氧基苯基)异丁酰胺,2-(3,5-二-三氟甲基-苯基)-N-[2-(2,4-二氯苯氧基)苯基]-N-甲基异丁酰胺,N-(3,5-二-三氟甲基-苄基)-N-甲基-6-吗啉-4-基-4-苯氧基烟酰胺,N-(3,5-二-三氟甲基-苄基)-4-(2-氯苯氧基)-N-甲基-6-吗啉-4-基烟酰胺,N-(3,5-二-三氟甲基-苄基)-4-(2-氯苯氧基)-N-甲基-6-(4-甲基哌嗪-1-基)烟酰胺,和N-(3,5-二-三氟甲基-苄基)-N-甲基-6-吗啉-4-基-4-o-甲苯氧基烟酰胺。
更优选的是其中Y是-N(CH3)-,而R4是氢的化合物,例如下列化合物:2-(3,5-二-三氟甲基-苯基)-N-甲基-N-[2-(甲基苯基氨基)苯基]丙酰胺,2-(3,5-二-三氟甲基-苯基)-N-甲基-N-[2-(甲基苯基氨基)苯基]异丁酰胺,2-(3,5-二-三氟甲基-苯基)-N-[2-(甲基苯基氨基)苯基]乙酰胺和2-(3,5-二-三氟甲基-苯基)-N-甲基-N-[2-(甲基苯基氨基)苯基]乙酰胺。
本发明的式I化合物和其药用盐可以通过本领域已知的方法制备,例如通过下述方法制备,该方法包括a)下式化合物与下式化合物反应给出下式化合物其中R1-R5,R,Y,Z和n具有上面给出的意义,或b)下式化合物与下式化合物反应给出下式化合物其中R1-R5,R,Z,Y和n具有上面给出的意义,或c)还原下式化合物给出下式化合物其中取代基的定义如上,或d)下式化合物与下式化合物反应给出下式化合物其中取代基的定义如上,或e)下式化合物与下式化合物反应给出下式化合物其中取代基的定义如上,或f)还原下式化合物给出下式化合物其中取代基的定义在上面给出,或g)下式化合物与下式化合物反应给出下式化合物其中取代基的定义在上面给出,或h)下式化合物与下式化合物反应给出下式化合物其中取代基的定义在上面给出,或i)下式化合物与下式化合物反应给出下式化合物其中取代基的定义在上面给出,或j)在上面给出的定义范围内修饰一个或多个取代基R1-R5或R,和如果需要,将所得的化合物转化为其药用酸加成盐。
根据方法变体a),式II化合物,例如3-氨基-4-苯甲酰基吡啶在冰浴中冷却,在DIPEA(N-乙基二异丙基胺)的二氯甲烷溶液存在下加入,例如2-(3,5-二-三氟甲基-苯基-2-甲基丙酰氯,然后将混合物在室温搅拌。纯化后以良好的产率给出所需的式I-1化合物。
方法变体b)描述了式IV化合物与式V化合物反应,给出式I-2的化合物。该反应以常规的方式进行,例如在溶剂如甲苯和三乙胺中进行。化合物被回流约1小时。
根据方法变体c),式I-2化合物被还原为式I-4化合物。该反应用还原剂如LiAlH4或BH3·THF,以常规方式进行。
方法变体d)描述了式VI化合物与式VII化合物反应,给出式I-2化合物。该反应通过式VI化合物用KHMDS(六甲基二硅氮化钾)使式VI化合物脱质子,随后加入式VII化合物而进行。合适的溶剂是四氢呋喃。反应在室温下进行。
根据方法变体e)制备式I-5化合物。该反应通过用氢化钠使式VIII化合物脱质子,随后加入式VII化合物而进行。该反应以常规方式进行。
制备式I化合物的另一方法在方法变体f)中描述。式I-1化合物以常规方式,例如用LiAlH4或BH3·THF还原为式I-3化合物。
在方法变体g)中,式IX化合物用DCC(N,N’-二环己基碳二亚胺)和DMAP(4-N,N-二甲基氨基吡啶)活化。随后加入式X化合物,给出式I-6化合物。
根据方法变体h),式IX化合物用CDI(1,1’-羰基二咪唑)活化,随后加入式V化合物,给出式I-2化合物。
方法变体i)描述了式I-1化合物的制备方法,其中式XII化合物用CDI活化,随后加入式II化合物,给出式I-13化合物。
盐的形成根据本领域技术人员熟悉的已知的方法,在室温下进行。不仅考虑与无机酸的盐,也考虑与有机酸的盐。盐酸盐,氢溴酸盐,硫酸盐,磷酸盐,硝酸盐,柠檬酸盐,醋酸盐,马来酸盐,琥珀酸盐,甲磺酸盐,对甲苯磺酸盐等是这类盐的例子。
下列路线1-7更详细地描述了制备式I化合物的方法。式IX,X,XI,II,III,XII,XIII,XV,XVII,XVIII,XX,XXII,XXIV和XXV的原料是已知化合物,或者可以根据本领域已知的方法制备。
在路线中使用如下缩写:DCC N,N’-二环己基碳二亚胺DMAP 4-(N,N-二甲基氨基)吡啶CDI 1,1’-羰基二咪唑KHMDS 六甲基二硅氮化钾DIPEA N-乙基二异丙基胺PivCl 新戊酰氯路线1取代基在上面给出。路线2取代基在上面给出。路线3取代基的定义在上面给出。路线4取代基的定义在上面给出。路线5取代基的定义在上面给出。路线6 取代基的定义在上面给出。路线 R,R1,R2,R3和R5具有上面给出的意义。
如前所述,式I化合物和其药用盐具有有价值的药理性质。已经发现,本发明化合物是神经激肽1(NK-1,P物质)受体拮抗剂。
该化合物根据下面给出的试验进行研究。
对于NK1受体试验化合物的亲和性以在用人NK1受体感染(用Semliki病毒表达体系)并用[3H]P物质放射标记的GHO细胞中的人NK1受体(最终浓度0.6nM)评价。结合试验在含有BSA(0.04%)亮抑蛋白酶肽(8mg/ml),MnCl2(3mM)和膦酰二肽(2mM)的HEPES缓冲液中进行。结合试验由250ml膜悬浮液(1.25×105个细胞/试验管),0.125ml替代剂的缓冲液和125ml[3H]P物质。替代曲线用至少7种浓度的化合物测定。试验管在室温下温育60分钟,然后管内物在真空下迅速用2×2ml洗涤的HEPES缓冲液(50mM,pH7.4)滤过用PEI(0.3%)预浸渍60分钟的GF/C滤纸。残留在滤纸上的放射活性通过闪烁计数测量。所用试验都在至少2个分开的实验重复三次进行。
对于优选的化合物,以pKi给出的NK-1受体的亲和性在7.50-9.00的范围内。这类化合物的例子有
N-(3,5-二-三氟甲基-苄基)-N-甲基-6-吗啉-4-基-4-苯氧基烟酰胺 | 7.86 |
N-(3,5-二-三氟甲基-苄基)-4-(2-氯苯氧基)-N-甲基-6-(4-甲基哌嗪-1-基)烟酰胺 | 8.42 |
N-(3,5-二-三氟甲基-苄基)-N-甲基-6-吗啉-4-基-4-o-甲苯氧基烟酰胺 | 8.56 |
N-(3,5-二-三氟甲基-苄基)-4-(2-氯苯氧基)-N-甲基-6-吗啉-4-基烟酰胺 | 8.76 |
式I化合物和其药用酸加成盐可以用作医药,例如以药物制剂的形式。药物制剂可以口服给药,例如以片剂,包衣片剂,糖丸,硬和软胶囊,溶液,乳液或悬浮液的形式。但是,给药也可以通过直肠进行,例如以栓剂形式给药,或者肠胃外给药,例如以注射溶液的形式给药。
式I化合物和其药用酸加成盐可以用药学上惰性的,用于生产片剂,包衣片剂,糖丸和硬胶囊的无机或有机赋形剂加工。乳糖,玉米淀粉或其衍生物,滑石,硬脂酸或其盐等可以被用作片剂,糖丸和硬胶囊的赋形剂。对于软胶囊的合适赋形剂是,例如植物油,蜡,脂肪,半固体或液体多醇等。
用于生产溶液和糖浆的合适赋形剂有,例如水,多醇,糖,转化糖,葡萄糖等。
用于注射溶液的合适赋形剂有,例如水,醇,多醇,甘油,植物油等。
用于栓剂的合适赋形剂有例如天然或硬化的油,蜡,脂肪,半液体或液体多醇等。
而且,药物制剂还可以含有防腐剂,增溶剂,稳定剂,润湿剂,乳化剂,甜味剂,着色剂,调味剂,改变渗透压的盐,缓冲剂,遮盖剂或抗氧化剂。它们也可以含有其它有治疗价值的物质。
剂量可以在宽的限制内变化,当然要与在各种情况下单个的需要相适应。一般说来,在口服的情况下,每人约10至1000mg的日剂量通式I化合物是合适的,尽管在需要时其上限可以被超过。
下列实施例举例说明本发明但不对其构成限制。所有温度都以摄氏度给出。
实施例1N-(4-苯甲酰基吡啶-3-基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺a)N-(4-苯甲酰基吡啶-3-基)-2-(3,5-二-三氟甲基-苯基)异丁酰胺
使397mg(2mmol)3-氨基-4-苯甲酰基吡啶和517mg(4mmol)N-乙基二异丙基胺在8ML二氯甲烷中的溶液在冰浴中冷却,滴加765mg(2.4mmol)2-(3,5-二-三氟甲基-苯基)-2-甲基丙酰氯在8ML二氯甲烷中的溶液。反应混合物被温热至室温并搅拌过夜。加入水(5ML),有机层被分出。水相用二氯甲烷萃取。合并的有机层被干燥(硫酸镁)并蒸发。残余物通过快速层析纯化,给出235mg(24%)标题化合物橙色油状物。MS m/e(%):481.3(M+H+,100)。b)N-(2-苯甲酰基-4-氯苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺
往96mg(0.2mmol)N-(4-苯甲酰基吡啶-3-基)-2-(3,5-二-三氟甲基-苯基)异丁酰胺在1.2ML二甲基甲酰胺的溶液中在0℃加入0.22ML 1M六甲基二硅氮化钾溶液。30分钟后,加入57mg甲基碘(0.4mmol),反应混合物在室温搅拌过夜。蒸发溶剂,往残余物中加入水和二氯甲烷分出有机层并用硫酸镁干燥。蒸发溶剂后,产物通过快速层析纯化,给出12mg(12%)标题化合物黄色油状物。MS m/e(%):495.2(M+H+,100)。
实施例2N-(2-苯甲酰基-4-氯苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺a)N-(2-苯甲酰基-4-氯苯基)-2-(3,5-二-三氟甲基-苯基)异丁酰胺
往233mg(1mmol)2-氨基-5-氯二苯酮在2ML 1,2-二氯乙烷中的溶液加入360mg(1.2mmol)2-(3,5-二-三氟甲基-苯基)-2-甲基丙酸,反应混合物在80℃摇动1小时。加入环己基碳二亚胺(194mg,1.2mmol),并在相同的温度下继续摇动过夜。蒸发溶剂,所得的残余物通过硅胶柱层析纯化,给出298mg(58%)标题化合物黄色油状物。MS m/e(%):514.2(M+H+,100)。b)N-(2-苯甲酰基-4-氯苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺
往154mg(0.3mmol)N-(2-苯甲酰基-4-氯苯基)-2-(3,5-二-三氟甲基-苯基)异丁酰胺在1ML二甲基甲酰胺的溶液中加入26mg(0.6mmol)氢化钠(55%矿物油悬浮液)。室温搅拌30分钟后,加入85mg甲基碘(0.6mmol),反应混合物在80℃搅拌过夜。减压蒸发溶剂,残余物通过快速层析纯化,给出51mg(32%)标题化合物白色晶体。M.p.89-91℃。MS m/e(%):528.1(M+H+,100)。
实施例3N-(2-苯甲酰基-5-氯苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺
根据上述用于制备N-(2-苯甲酰基-4-氯苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺的工艺,用2-氨基-4-氯二苯酮代替2-氨基-5-氯二苯酮,以类似的产率得到标题化合物黄色油状物。MS m/e(%):528.1(M+H+,100)。
实施例4N-(2-苯甲酰基-3-氯苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺
根据上述用于制备N-(2-苯甲酰基-4-氯苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺的工艺,用2-氨基-6-氯二苯酮代替2-氨基-5-氯二苯酮,以类似的产率得到标题化合物带黄色的油状物。MS m/e(%):528.1(M+H+,100)。
实施例52-(3,5-二-三氟甲基-苯基)-N-[2-(3-氯苯甲酰基)苯基]-N-甲基异丁酰胺
根据上述用于制备N-(2-苯甲酰基-4-氯苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺的工艺,用2-(3-氯苯甲酰基)苯胺代替2-氨基-5-氯二苯酮,以类似的产率得到标题化合物黄色油状物。MS m/e(%):528.1(M+H+,100)。
实施例6N-(2-苯甲酰基-6-甲氧基苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺
根据上述用于制备N-(2-苯甲酰基-4-氯苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺的工艺,用2-氨基-3-甲氧基二苯酮代替2-氨基-5-氯二苯酮,以类似的产率得到标题化合物黄色油状物。MS m/e(%):523.5(M+H+,100)。
实施例7N-(2-苯甲酰基-4-甲氧基苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺
根据上述用于制备N-(2-苯甲酰基-4-氯苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺的工艺,用2-氨基-5-甲氧基二苯酮代替2-氨基-5-氯二苯酮,以类似的产率得到标题化合物黄色油状物。MS m/e(%):523.5(M+H+,100)。
实施例8(RS)-2-(3,5-二-三氟甲基-苯基)-N-[4-氯-2-(2-氯苯基硫基)苯基]-N-甲基丙酰胺
往142mg(0.5mmol)1-氯-4-甲基氨基-3-(2-氯苯基硫基)苯在2ML 1,2-二氯乙烷中的溶液加入172mg(0.6mmol)2-(3,5-二-三氟甲基-苯基)-2-甲基丙酸,反应混合物在80℃摇动1小时。加入环己基碳二亚胺(97mg,0.6mmol),并在相同的温度下继续摇动过夜。蒸发溶剂,所得的残余物通过硅胶柱层析纯化,给出56mg(20%)标题化合物黄色油状物。MS m/e(%):551.9(M+H+,100),553.9(M+H+,90)。
实施例9(RS)-N-(2-苯甲酰基-4-氯苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基丙酰胺
根据上述用于制备(RS)-2-(3,5-二-三氟甲基-苯基)-N-[4-氯-2-(2-氯苯基硫基)苯基]-N-甲基异丁酰胺的工艺,用2-甲基氨基-5-氯二苯酮代替1-氯-4-甲基氨基-3-(2-氯苯基硫基)苯,以类似的产率获得标题化合物黄色油状物。MS m/e(%):514.2(M+H+,100)。
实施例10N-[2-苯甲酰基-4-(4-甲基哌嗪-1-基)苯基]-2-(3,5-二-三氟甲基-苯基)异丁酰胺盐酸盐(1∶1)a)2,2-二甲基-N-[4-(4-甲基哌嗪-1-基)苯基]丙酰胺
5.58g(29mmol)1-(4-氨基苯基)-4-甲基哌嗪和3.77g(29mmol)N-乙基二异丙基胺在30ML四氢呋喃中的溶液在冰浴中冷却,滴加3.518g(29mmol)新戊酰氯。悬浮液在室温搅拌18小时。加入水(30ML)和二氯甲烷(50ML),分出有机相。水相用二氯甲烷再萃取。合并的有机层被干燥(硫酸镁)并蒸发,给出白色固体。用己烷和乙酸乙酯混合物(4∶1)洗涤,给出6.69g(83%)白色晶状化合物。MS m/e(%):276.3(M+H+,100)。b)N-[2-苯甲酰基-4-(4-甲基哌嗪-1-基)苯基]-2,2-二甲基丙酰胺
将1.375g(5mmol)2,2-二甲基-N-[4-(4-甲基哌嗪-1-基)苯基]丙酰胺溶于25ML四氢呋喃中的溶液冷却至-70℃。在氩气中于此温度下慢慢加入7.8ML(12.5mmol)1.6M正丁基锂的己烷溶液。移走冷却浴,并将混合物在室温搅拌3小时。将反应混合物再冷却至-70℃,在-70℃慢慢加入1.234g N-甲氧基-N-甲基苯甲酰胺(7.2mmol)在5ML四氢呋喃中的溶液。10分钟后,移走冷却浴,在室温继续搅拌1小时。加入水50ML)淬灭反应,混合物用乙醚萃取(三次50ML)。有机层用硫酸镁干燥并蒸发,给出褐色油状物,通过快速层析纯化,用二氯甲烷/甲醇洗脱,给出315mg(17%)产物浅橙色固体。MS m/e(%):380.4(M+H+,100)。c)[2-氨基-5-(4-甲基哌嗪-1-基)苯基]苯基-甲酮
将0.3g(0.8mmol)N-[2-苯甲酰基-4-(4-甲基哌嗪-1-基)苯基]-2,2-二甲基丙酰胺在10ML 3N盐酸中的溶液在室温下搅拌20小时。反应混合物用乙酸乙酯萃取一次,水层用浓氢氧化钠溶液使其成碱性,并用二氯甲烷萃取四次。合并的有机层用硫酸镁干燥并蒸发,给出245mg(定量)产物浅黄色油状物。MS m/e(%):296.4(M+H+,100)。d)N-[2-苯甲酰基-4-(4-甲基哌嗪-1-基)苯基]-2-(3,5-二-三氟甲基-苯基)异丁酰胺盐酸盐
将200mg(0.68mmol)[2-氨基-5-(4-甲基哌嗪-1-基)苯基]苯基-甲酮和219mg(1.69mmol)N-乙基二异丙基胺在5ML二氯甲烷中的溶液在冰浴中冷却,滴加319mg(1.0mmol)2-(3,5-二-三氟甲基-苯基)-2-甲基丙酰氯在2ML二氯甲烷中的溶液。反应混合物被温热至室温,并搅拌3小时。加入水(5ML),分开各层。水相用二氯甲烷再萃取。合并的有机层被干燥(硫酸镁)并蒸发,给出50mg油状物。残余物溶于2ML乙酸乙酯,加入0.018ml 4.75N盐酸的乙醇溶液。加入1ML乙醚后,搅拌15分钟,滤出固体并干燥,给出24mg(6%)标题化合物白色固体。MS m/e(%):578.1(M+H+,100)。
实施例114-苯甲酰基-N-(3,5-二-三氟甲基-苄基)-N-甲基-6-(4-甲基哌嗪-1-基)烟酰胺盐酸盐(1∶1)a)2-氯-5-(4,4-二甲基-4,5-二氢-噁唑-2-基)吡啶盐酸盐
往10g(63.47mmol)2-氯吡啶-5-羧酸中加入60g(507mmol)亚硫酰氯,混合物被回流3小时。蒸出过量的亚硫酰氯,加入乙醚(50ML)并蒸发除去痕量的亚硫酰氯。残余物溶于30ML二氯甲烷,并在0℃滴加到11.88g(0.133mmol)2-氨基-2-甲基丙醇在30ML二氯甲烷中的溶液。反应混合物在室温搅拌2小时,并加入30ML水。分开各层,水相再用二氯甲烷萃取。合并的有机层用硫酸镁干燥并蒸发给出油状液体。在0℃往残余物中加入22.6g(190mmol)亚硫酰氯,混合物被搅拌30分钟。加入乙酸乙酯,混合物被搅拌30分钟,晶体用乙酸乙酯和乙醚洗涤,给出14g(89%)白色固体。MS m/e(%):210(M+H+,100)。b)1-[5-(4,4-二甲基-4,5-二氢-噁唑-2-基)吡啶-2-基]-4-甲基哌嗪
通过将8.0g(32mmol)溶于饱和碳酸氢钠溶液,并将碱萃取到二氯甲烷中而将2-氯-5-(4,4-二甲基-4,5-二氢-噁唑-2-基)吡啶盐酸盐转化为其游离碱。将溶剂蒸发,残余物溶于甲苯。加入11.35g(113mmol)N-甲基哌嗪之后,混合物被回流36小时。冷却至室温后,加入水(50ML)和乙酸乙酯(1 50ML),水层用乙酸乙酯(150ML)萃取。合并的有机层用1N盐酸萃取两次,酸性水层用28%氢氧化钠溶液使其成碱性,并用二氯甲烷萃取两次。有机层被干燥(硫酸镁)并蒸发。残余物从乙酸乙酯/己烷结晶,给出6.0g(67%)白色晶状化合物。MS m/e(%):274.1(M+H+,100)。c)[5-(4,4-二甲基-4,5-二氢-噁唑-2-基)-2-(4-甲基哌嗪-1-基)吡啶-4-基]苯基甲酮
将2,2,6,6-四甲基哌啶(0.932g,6.6mmol)放入三颈烧瓶。在氩气中加入10ML己烷,溶液被冷却至0℃,并慢慢加入正丁基锂(1.6M己烷溶液)。将黄色悬浮液搅拌10分钟后,加入N,N,N’,N’-四甲基乙二胺(767mg,6.6mmol)。此混合物在-78℃被滴加到1.65g(6mmol)1-[5-(4,4-二甲基-4,5-二氢-噁唑-2-基)吡啶-2-基]-4-甲基哌嗪在20ML己烷中的溶液。在此温度将黄色溶液搅拌30分钟,并在0℃搅拌45分钟后,在0℃慢慢加入1.19g N-甲氧基-N-甲基苯甲酰胺(7.2mmol)在2ML己烷/2ML四氢呋喃中的溶液。30分钟后,移走冷却浴并在室温继续搅拌过夜。加入水,混合物用乙酸乙酯萃取。有机层被干燥(硫酸镁)并蒸发,给出褐色油状物,通过快速层析用二氯甲烷/甲醇纯化,给出1.16g(51%)黄色固体。MS m/e(%):379.5(M+H+,100)。d)4-苯甲酰基-6-(4-甲基哌嗪-1-基)-烟酸2-氨基-2-甲基丙基酯
往1.13g(3mmol)[5-(4,4-二甲基-4,5-二氢-噁唑-2-基)-2-(4-甲基哌嗪-1-基)吡啶-4-基]苯基甲酮在30ML四氢呋喃中的溶液加入3ML 2N盐酸,反应混合物在50℃加热18小时。冷却至室温后,加入1N氢氧化钠溶液将pH调节至11,混合物用乙酸乙酯萃取。有机层被干燥(硫酸镁)并蒸发,给出1.18g(定量)产物黄色油状物。MS m/e(%):481.4(M+H+,100)。e)4-苯甲酰基-6-(4-甲基哌嗪-1-基)烟酸
往1.15g(2.9mmol)4-苯甲酰基-6-(4-甲基哌嗪-1-基)-烟酸2-氨基-2-甲基丙基酯在20ML四氢呋喃中的溶液在0℃滴加367mg(3.05mmol)新戊酰氯。在同样温度下将浅黄色悬浮液搅拌1小时后,加入1M盐酸。过量新戊酰氯用二氯甲烷萃取,水层用28%氢氧化钠溶液使其成碱性,并用二氯甲烷萃取两次。有机层被干燥(硫酸镁)并蒸发。残余物被溶于甲醇,在0℃慢慢加入1M氢氧化钠水溶液,混合物在65℃加热过夜。蒸发甲醇,水层被调节至pH5。蒸发溶剂,给出被氯化钠污染的产物,不经进一步纯化就用于下步。f)4-苯甲酰基-N-(3,5-二-三氟甲基-苄基)-N-甲基-6-(4-甲基哌嗪-1-基)烟酰胺盐酸盐(1∶1)
将上步的4-苯甲酰基-6-(4-甲基哌嗪-1-基)烟酸(1.5mmol)和3ML亚硫酰氯的混合物在110℃加热1小时。蒸发过量的亚硫酰氯,所得的褐色油状物再溶于乙醚并再次蒸发除去痕量的亚硫酰氯。残余物溶于2ML丙酮,加入1.16g(4.5mmol)(3,5-二-三氟甲基-苄基)甲基胺。混合物在室温搅拌1.5小时。蒸发溶剂,加入二氯甲烷和水,水层用氢氧化钠溶液(28%)使其成碱性。有机层被干燥(硫酸镁),蒸发并通过快速层析纯化,给出202mg油状物。此化合物溶于5ML乙醚,加入0.075ml 4.75N盐酸的乙醇溶液。搅拌15分钟后,将悬浮液蒸发至干,再悬浮于10ML乙醚,过滤并干燥给出190mg(21%)标题化合物白色固体。M.p.105℃,(分解)。MS m/e(%):565.2(M+H+,100)。
实施例12N-(3,5-二-三氟甲基-苄基)-4-(2-氯苯甲酰基)-N-甲基-6-(4-甲基哌嗪-1-基)烟酰胺盐酸盐(1∶1)
根据上述用于制备4-苯甲酰基-N-(3,5-二-三氟甲基-苄基)-N-甲基-6-(4-甲基哌嗪-1-基)烟酰胺盐酸盐(1∶1,在步骤c)用N-甲氧基-N-甲基2-氯苯甲酰胺代替N-甲氧基-N-甲基苯甲酰胺)的工艺,以类似的产率获得标题化合物白色晶体。M.p.145℃,(分解)。MS m/e(%):599.1(M+H+,100)。
实施例132-苯氧基苯甲酸3,5-二-三氟甲基-苄基酯
在0℃,往118mg(0.55mmol)2-苯氧基苯甲酸和122mg(0.50mmol)3,5-二-三氟甲基-苄基醇在1.5ML二氯甲烷中的溶液加入124mg(0.60mmol)1,3-二环己基碳二亚胺和7mg(0.06mmol)4-二甲基氨基吡啶在1ML二氯甲烷中的溶液。移走冰浴并在室温继续搅拌过夜。真空除去溶剂,残余物再溶于乙醚,过滤并蒸发。残余物通过快速层析纯化,给出70mg(32%)标题化合物白色晶体。MS m/e(%):440(M+,51),347(39),227(36),197(100)。
实施例142-苄基-N-(3,5-二-三氟甲基-苄基)苯甲酰胺
在0℃,往255mg(1.2mmol)2-苄基苯甲酸在1.5ML四氢呋喃中的溶液加入195mg(1.2mmol)1,1’-羰基二咪唑。在室温搅拌2.5小时后,加入243mg(1.0mmol)3,5-二-三氟甲基-苄基胺在0.5ML四氢呋喃中的溶液,并继续搅拌过夜。真空除去溶剂,残余物通过快速层析纯化,给出210mg(49%)标题化合物白色晶体。MS m/e(%):438(M+H+,100)。
实施例152-苄基-N-(3,5-二-三氟甲基-苄基)-N-甲基苯甲酰胺
在0℃,往100mg(0.23mmol)2-苄基-N-(3,5-二-三氟甲基-苄基)苯甲酰胺在1ML N,N-二甲基甲酰胺中的溶液加入50mg(0.25mmol)六甲基二硅氮化钾。在此温度继续搅拌1小时后,加入0.016ml(0.25mmol)甲基碘。在室温搅拌3小时后,加入乙酸乙酯。混合物用盐水洗涤,干燥(硫酸镁)并蒸发。真空蒸发溶剂,残余物通过快速层析纯化,给出90mg(87%)标题化合物无色油状物。MS m/e(%):452(M+H+,100)。
实施例16N-(3,5-二-三氟甲基-苄基)-N-甲基-2-(甲基苯基氨基)苯甲酰胺a)N-(3,5-二-三氟甲基-苄基)-2-苯基氨基苯甲酰胺
根据上述用于制备2-苄基-N-(3,5-二-三氟甲基-苄基)苯甲酰胺的工艺,以类似的产率获得标题化合物白色晶体。MS m/e(%):477(M+K+,24),461(M+Na+,40),439(M+H+,100)。b)2-苄基-N-(3,5-二-三氟甲基-苄基)-N-甲基苯甲酰胺
根据上述用于制备2-苄基-N-(3,5-二-三氟甲基-苄基)-N-甲基苯甲酰胺的工艺,以类似的产率获得标题化合物无色油状物。MS m/e(%):505(M+K+,12),489(M+Na+,19),467(M+H+,100)。
实施例17N-(2-苯磺酰基苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺a)N-(2-苯磺酰基苯基)-2-(3,5-二-三氟甲基-苯基)异丁酰胺
将233mg(1.0mmol)2-氨基苯基苯基砜和0.25ML(1.5mmol)N-乙基二异丙基胺在2ML二氯甲烷中的溶液在冰浴中冷却,并滴加350mg(1.1mmol)2-(3,5-二-三氟甲基-苯基)-2-甲基丙酰氯在1ML二氯甲烷中的溶液。反应混合物在室温搅拌过夜,蒸发,残余物通过快速层析纯化,给出490mg(95%)标题化合物浅黄色油状物。MS m/e(%):533(M+NH4 +,60),516(M+H+,100)。b)N-(2-苯磺酰基苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺
根据上述用于制备2-苄基-N-(3,5-二-三氟甲基-苄基)-N-甲基苯甲酰胺的工艺,以类似的产率获得标题化合物无色油状物。MS m/e(%):552(M+Na+,40),530(M+H+,100)。
实施例182-(3,5-二-三氟甲基-苯基)-N-甲基-N-(2-苯氧基苯基)-异丁酰胺
根据上述用于制备N-(2-苯磺酰基苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺的工艺,用2-苯氧基苯胺代替2-氨基苯基苯基砜,以类似的产率获得标题化合物无色油状物。MS m/e(%):482(M+H+,100)。实施例19N-(2-苄基苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基-异丁酰胺
根据上述用于制备N-(2-苯磺酰基苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺的工艺,用2-苄基苯胺代替2-氨基苯基苯基砜,以类似的产率获得标题化合物无色油状物。MS m/e(%):480(M+H+,100)。
实施例202-(3,5-二-三氟甲基-苯基)-N-甲基-N-(2-o-甲苯氧基苯基)-异丁酰胺
根据上述用于制备N-(2-苯磺酰基苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺的工艺,用2-(o-甲苯氧基)苯胺代替2-氨基苯基苯基砜,以类似的产率获得标题化合物浅黄色晶体。MS m/e(%):496(M+H+,100)。
实施例21N-(2-苯甲酰基苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基-异丁酰胺
根据上述用于制备N-(2-苯磺酰基苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺的工艺,用2-氨基二苯酮代替2-氨基苯基苯基砜,以类似的产率获得标题化合物浅黄色油状物。MS m/e(%):516(M+Na+,55),494(M+H+,100)。
实施例222-(3,5-二-三氟甲基-苯基)-N-[2-(2,4-二氯苯氧基)苯基]-N-甲基-异丁酰胺
根据上述用于制备N-(2-苯磺酰基苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺的工艺,用2-(2,4-二氯苯氧基)苯胺代替2-氨基苯基苯基砜,以类似的产率获得标题化合物无色泡沫。MS m/e(%):549(M+,4),530(21),388(100)。
实施例232-(3,5-二-三氟甲基-苯基)-N-(2-苯硫基苯基)-异丁酰胺
根据上述用于制备N-(2-苯磺酰基苯基)-2-(3,5-二-三氟甲基-苯基)-N-甲基异丁酰胺的工艺,用2-氨基苯基苯基硫醚代替2-氨基苯基苯基砜,以类似的产率获得标题化合物浅黄色油状物。步骤b)不进行。MS m/e(%):484(M+H+,100)。
实施例242-(3,5-二-三氟甲基-苯基)-N-(2-甲基苯基氨基)苯基]丙酰胺a) 2-(3,5-二-三氟甲基-苯基)-N-(2-苯基氨基苯基)乙酰胺
在0℃,往545mg(2.0mmol)3,5-二-三氟甲基-苯基乙酸在2ML四氢呋喃中的溶液加入325mg(2.0mmol)1,1’-羰基二咪唑。室温搅拌2.5小时后加入305mg(1.66mmol)2-氨基二苯基胺,并在60℃继续搅拌8小时。真空除去溶剂,残余物通过快速层析纯化,给出480mg(66%)标题化合物白色晶体。MS m/e(%):439(M+H+,35),142(100)。b)2-(3,5-二-三氟甲基-苯基)-N-甲基-N-[2-(甲基苯基氨基)苯基]丙酰胺
在0℃,往389mg(0.89mmol)2-(3,5-二-三氟甲基-苯基)-N-(2-苯基氨基苯基)乙酰胺在1ML N,N-二甲基甲酰胺的溶液加入560mg(2.66mmol)六甲基二硅氮化钾。在此温度继续搅拌1小时,加入510mg(2.66mmol)甲基碘。在室温搅拌3小时后,加入乙酸乙酯。混合物用盐水洗涤,干燥(硫酸镁)并蒸发。真空除去溶剂,残余物通过快速层析纯化,给出110mg(25%)标题化合物白色晶体。MS m/e(%):480(M+,76),239(100)。实施例252-(3,5-二-三氟甲基-苯基)-N-甲基-N-[2-(甲基苯基氨基)苯基]异丁酰胺
在0℃,往52mg(0.11mmol)2-(3,5-二-三氟甲基-苯基)-N-甲基-N-[2-(甲基苯基氨基)苯基]丙酰胺在0.5ML N,N-二甲基甲酰胺的溶液加入32mg(0.16mmol)六甲基二硅氮化钾。在此温度继续搅拌1小时,加入30mg(0.16mmol)甲基碘。在室温搅拌3小时后,加入乙酸乙酯。混合物用盐水洗涤,干燥(硫酸镁)并蒸发。真空除去溶剂,残余物通过快速层析纯化,给出54mg(定量%)标题化合物无色油状物。MS m/e(%):494(M+,87),195(100)。
实施例262-(3,5-二-三氟甲基-苯基)-N-[2-(甲基苯基氨基)苯基]乙酰胺
根据上述制备2-(3,5-二-三氟甲基-苯基)-N-甲基-N-[2-(甲基苯基氨基)苯基]丙酰胺的工艺,用N-甲基-N-苯基苯-1,2-二胺代替2-氨基二苯基胺,以类似的产率获得标题化合物白色晶体。不进行步骤b)。MS m/e(%):453(M+H+,100)。
实施例272-(3,5-二-三氟甲基-苯基)-N甲基-N-[2-(甲基苯基氨基)苯基]乙酰胺
根据上述制备2-(3,5-二-三氟甲基-苯基)-N-甲基-N-[2-(甲基苯基氨基)苯基]丙酰胺的工艺,用N,N’-二甲基-N-苯基苯-1,2-二胺代替2-氨基二苯基胺,以类似的产率获得标题化合物白色晶体。不进行步骤b)。MS m/e(%):467(M+H+,100)。
实施例28N-(3,5-二-三氟甲基-苄基)-N-甲基-6-吗啉-4-基-4-苯氧基烟酰胺a)6-氯-4-苯氧基烟酸乙酯
在氩气中于室温往196mg(约4mmol)氢化钠在矿物油中的悬浮液(约50%)在15ML N,N-二甲基甲酰胺溶液滴加385mg(4.09mmol)苯酚在10ML N,N-二甲基甲酰胺中的溶液。15分钟后,此溶液在室温经导管加入4,6-二氯烟酸乙酯在20ML N,N-二甲基甲酰胺溶液。2小时后,反应用20ML水淬灭。混合物用3×50ML乙酸乙酯萃取。合并的有机萃取液用硫酸钠干燥并浓缩。在50℃高真空干燥和快速柱层析后,得到800mg(70.4%)标题化合物白色固体。也分离出副产物130mg(11.4%)4-氯-6-苯氧基烟酸乙酯。MS m/e(%):277(M+,81),232([M-OEt]+,100)。b)6-吗啉-4-基-4-苯氧基烟酸乙酯
130mg(0.468mmol)6-氯-4-苯氧基烟酸乙酯,0.040ml(0.47mmol)吗啉和0.065ML(0.47mmol)三乙胺在7ML四氢呋喃中的溶液被搅拌回流40小时。冷却至室温后,将反应混合物过滤,用乙酸乙酯稀释,并用水和饱和氯化钠水溶液洗涤。有机层用硫酸钠干燥并浓缩。快速柱层析给出66mg(43%)标题化合物白色固体。MS m/e(%):329(M+H+,100)。c)6-吗啉-4-基-4-苯氧基烟酸
将66mg(0.20mmol)6-吗啉-4-基-4-苯氧基烟酸乙酯,2ml甲醇和2ML 1N氢氧化钠水溶液的混合物在室温搅拌1小时。反应混合物用水稀释,并用叔丁基-甲基醚洗涤。水层用浓盐酸酸化至pH4-5,并用3批二氯甲烷萃取。合并的有机层用饱和氯化钠水溶液洗涤,硫酸钠干燥。浓缩给出46mg(77%)标题化合物白色固体。MS m/e(%):301(M+H+,100)。d)N-(3,5-二-三氟甲基-苄基)-N-甲基-6-吗啉-4-基-4-苯氧基烟酰胺
将46mg(0.15mmol)6-吗啉-4-基-4-苯氧基烟酸,43mg(0.17mmol)3,5-二-三氟甲基-苄基)甲基胺,32mg(0.17mmol)1-(3-二氨基丙基)-3-乙基碳二亚胺盐酸盐和催化量的4-(N,N-二甲基氨基)吡啶在3ML二氯甲烷中的混合物在室温搅拌过夜。反应混合物用水稀释,用饱和氯化铵溶液调节至pH6,并用二氯甲烷萃取。合并的有机层用饱和氯化钠水溶液洗涤,硫酸钠干燥并浓缩。快速柱层析给出68mg(83%)标题化合物白色固体。MS m/e(%):540(M+H+,100)。
实施例29N-(3,5-二-三氟甲基-苄基)-4-(2-氯苯氧基)-N-甲基-6-吗啉-4-基烟酰胺
根据上述用于制备N-(3,5-二-三氟甲基-苄基)-N-甲基-6-吗啉-4-基-4-苯氧基烟酰胺(实施例28)的工艺,在步骤a)中用2-氯苯酚代替苯酚,以类似的产率获得标题化合物白色固体。MS m/e(%):574(M+H+,100)。
实施例30N-(3,5-二-三氟甲基-苄基)-4-(2-氯苯氧基)-N-甲基-6-(4-甲基哌嗪-1-基)烟酰胺
根据上述用于制备N-(3,5-二三氟甲基-苄基)-N-甲基-6-吗啉-4-基-4-苯氧基烟酰胺(实施例28)的工艺,在步骤a)中用2-氯苯酚代替苯酚,在步骤b)用1-甲基哌嗪代替吗啉,以类似的产率获得标题化合物白色固体。MS m/e(%):587(M+H+,100)。
实施例31N-(3,5-二-三氟甲基-苄基)-N-甲基-6-吗啉-4-基-4-o-甲苯氧基烟酰胺
根据上述用于制备N-(3,5-二-三氟甲基-苄基)-N-甲基-6-吗啉-4-基-4-苯氧基烟酰胺(实施例28)的工艺,在步骤a)中用o-甲苯酚代替苯酚,以类似的产率获得标题化合物白色固体。MS m/e(%):554(M+H+,100)。
实施例A以常规方法生产下列组合物的片剂:
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
总重:100
实施例B生产下列组合物的胶囊:
mg/胶囊活性物质 10乳糖 155玉米淀粉 30滑石 5
总重:200
活性物质,乳糖和玉米淀粉首先在混合器内混合,然后在细碎机内混合。混合物再回到混合器内,往其中加入滑石并充分混合。通过机器将混合物填充到硬胶囊内。
实施例C生产下列组合物的栓剂:
mg/栓剂活性物质 15栓剂基(mass) 1285
总重1300
将栓剂基在玻璃或钢容器中熔化,充分混合并冷却至45℃。往其中加入细粉状活性物质,并搅拌至完全分散。混合物被倒入适当大小的栓剂模内,使其冷却,然后从模中取出栓剂并以蜡纸或金属箔单个包装。
Claims (10)
2.根据权利要求1的化合物,其中Y是-C(O)-,而R4是4-甲基哌嗪-1-基。
3.根据权利要求2的化合物,它们是N-[2-苯甲酰基-4-(4-甲基哌嗪-1-基)苯基]-2-(3,5-二-三氟甲基-苯基)异丁酰胺,4-苯甲酰基-N-(3,5-二-三氟甲基-苄基)-N-甲基-6-(4-甲基哌嗪-1-基)烟酰胺或N-(3,5-二-三氟甲基-苄基)-4-(2-氯苯甲酰基)-N-甲基-6-(4-甲基哌嗪-1基)烟酰胺。
4.根据权利要求1的化合物,其中Y是-O-,而R4是氢,4-甲基哌嗪-1-基或吗啉-4-基。
5.根据权利要求4的化合物,它们是:2-(3,5-二-三氟甲基-苯基)-N-甲基-N-(2-苯氧基苯基)异丁酰胺,2-(3,5-二-三氟甲基-苯基)-N-甲基-N-(2-o-甲苯氧基苯基)异丁酰胺,2-(3,5-二-三氟甲基-苯基)-N-[2-(2,4-二氯苯氧基)苯基]-N-甲基异丁酰胺,N-(3,5-二-三氟甲基-苄基)-N-甲基-6-吗啉-4-基-4-苯氧基烟酰胺,N-(3,5-二-三氟甲基-苄基)-4-(2-氯苯氧基)-N-甲基-6-吗啉-4-基烟酰胺,N-(3,5-二-三氟甲基-苄基)-4-(2-氯苯氧基)-N-甲基-6-(4-甲基哌嗪-1-基)烟酰胺,或N-(3,5-二-三氟甲基-苄基)-N-甲基-6-吗啉-4-基-4-o-甲苯氧基烟酰胺。
6.根据权利要求1的化合物,其中Y是-N(CH3)-,而R4是氢。
7.根据权利要求6的化合物,它们是:2-(3,5-二-三氟甲基-苯基)-N-甲基-N-[2-(甲基苯基氨基)苯基]丙酰胺,2-(3,5-二-三氟甲基-苯基)-N-甲基-N-[2-(甲基苯基氨基)苯基]异丁酰胺,2-(3,5-二-三氟甲基-苯基)-N-[2-(甲基苯基氨基)苯基]乙酰胺或2-(3,5-二-三氟甲基-苯基)-N-甲基-N-[2-(甲基苯基氨基)苯基]乙酰胺。
8.用于治疗与NK-1受体拮抗剂有关的疾病且含有权利要求1所要求的一种或多种化合物和药用赋形剂的药物。
9.制备如权利要求1定义的式I化合物的方法,该方法包括a)下式化合物与下式化合物反应给出下式化合物其中R1-R5,R,Y,Z和n具有权利要求1中给出的意义,或b)下式化合物与下式化合物反应给出下式化合物其中R1-R5,R,Z,Y和n具有权利要求1给出的意义,或d)下式化合物与下式化合物反应给出下式化合物其中各取代基的定义在权利要求1中给出,或g)下式化合物与下式化合物反应给出下式化合物其中各取代基的定义在权利要求1中给出,或h)下式化合物与下式化合物反应给出下式化合物其中各取代基的定义在权利要求1中给出,或i)下式化合物与下式化合物反应给出下式化合物其中各取代基的定义在权利要求1中给出,或j)在上面给出的定义范围内修饰一个或多个取代基R1-R5或R,和非必要地,将所得的化合物转化为其药用酸加成盐。
10.权利要求1的式I化合物在制备用于治疗与NK-1受体有关疾病的含有式I化合物的药物中的用途。
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CN109678815B (zh) * | 2019-01-09 | 2022-11-29 | 中国药科大学 | N-苄基苯甲酰胺类衍生物及其制备方法与制药用途 |
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IL111960A (en) * | 1993-12-17 | 1999-12-22 | Merck & Co Inc | Morpholines and thiomorpholines their preparation and pharmaceutical compositions containing them |
ES2164758T3 (es) | 1993-12-29 | 2002-03-01 | Merck Sharp & Dohme | Derivados de morfolina sustituidos y su uso como agentes terapeuticos. |
TW385308B (en) | 1994-03-04 | 2000-03-21 | Merck & Co Inc | Prodrugs of morpholine tachykinin receptor antagonists |
WO1997031635A1 (en) * | 1996-03-01 | 1997-09-04 | Eli Lilly And Company | Methods of treating or preventing sleep apnea |
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US5972938A (en) | 1997-12-01 | 1999-10-26 | Merck & Co., Inc. | Method for treating or preventing psychoimmunological disorders |
EP1140067A1 (en) * | 1999-01-07 | 2001-10-10 | Warner-Lambert Company | Antiviral method using mek inhibitors |
DK1394150T3 (da) * | 1999-02-24 | 2011-03-21 | Hoffmann La Roche | 4-phenylpyridinderivater og deres anvendelse som NK-1-receptorantagonister |
US6291465B1 (en) * | 1999-03-09 | 2001-09-18 | Hoffmann-La Roche Inc. | Biphenyl derivatives |
ES2208205T3 (es) * | 1999-11-29 | 2004-06-16 | F. Hoffmann-La Roche Ag | 2-(3,5-bis-trifluorometil-fenil)-n-metil-n-(6-morfolin-4-il-4-otolil-piridin-3-il)-isobutiramida. |
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CN1293056C (zh) * | 2000-08-08 | 2007-01-03 | 弗·哈夫曼-拉罗切有限公司 | 作为神经激肽-1受体拮抗剂的4-苯基-吡啶衍生物 |
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