CN1190393A - 二芳基二胺衍生物及其作为δ-阿片样物质(拮抗)激动剂的用途 - Google Patents
二芳基二胺衍生物及其作为δ-阿片样物质(拮抗)激动剂的用途 Download PDFInfo
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- CN1190393A CN1190393A CN96195364A CN96195364A CN1190393A CN 1190393 A CN1190393 A CN 1190393A CN 96195364 A CN96195364 A CN 96195364A CN 96195364 A CN96195364 A CN 96195364A CN 1190393 A CN1190393 A CN 1190393A
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- Prior art keywords
- amino
- phenyl
- benzamide
- diethyl
- methoxy
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Abstract
本发明提供了一类具有式(Ⅰ)结构的二芳基二胺衍生物,其中R1和R2各自为氢,烷基,环烷基,环烯基,环烷基烷基,链烯基,炔基,芳基,芳烷基或呋喃-2或3-基烷基,或者一同形成可被氧间断的C3—7烷基环;R3和R4各自为氢,烷基,或者R4为氧,它与其所连接的碳原子形成C=O基团;R5为氢,羟基,烷氧基,巯基,烷硫基;R6为苯基,卤素,NH2或位于对位或间位的-C(Z)-R8基团,其中Z为氧或硫;R8为烷基,烷氧基或NR9R10,其中R9和R10为氢,烷基,环烷基,环烷基烷基,链烯基,芳基,芳烷基,或者R6为位于对位或间位的(a)基团,其中R11和R12为氢,烷基,环烷基,环烷基烷基,链烯基,芳基,芳烷基或任意取代的杂环,且Z的定义同上;以及R7为氢,烷基,或卤素。它们为有效的选择性δ阿片样物质激动剂和拮抗剂,并可用作止痛药和用于治疗通常能用δ阿片样物质受体激动剂和拮抗剂治疗的病症。
Description
本发明涉及新的二芳基二胺衍生物,它们的制备方法以及它们在医药方面的用途。
人们现已充分确认并有资料证明至少存在三种阿片样物质受体(μ,δ和κ),并且这三种受体似乎都存在于众多种属动物包括人的中枢和外周神经系统中(Lord J.A.H.等人,自然(Nature),1977,267,495)。
在动物模型中,这三种阿片样物质受体亚型的激活都能产生抗伤害感受作用。特别是,对肽类δ受体激动剂的研究表明,激活δ受体对啮齿动物和灵长目动物产生抗伤害感受作用,而对人则诱导临床止痛作用(D.E.Moulin等人,疼痛(Pain),1985,23,213)。这些资料存在暗示了δ拮抗剂具有较低的产生与μ和κ激活有关的常见副作用的倾向(Galligan等人,J.Pharm.Exp.Ther.,1984,229,641)。
先前已有文献描述了用作二苯并二氮杂合成中间体的取代二芳基二胺,其中所合成的二苯并二氮杂用作抗组胺和抗过敏剂[GB907646,Dr.A.Wonder A.G.;Hunziker等人,杂环化学学报(Helv.Chim.Acta),46,2337,(1963)]。欧洲专利508,334(Green Cross Corp.)公开了氧取代的二芳二胺,据说它们为TPA诱导的鼠耳水肿抑制剂。WO93/15062(The Wellcome Foundation Limited)公开了据说为所有三种阿片剂受体的激动剂的二苯基哌嗪衍生物。
我们现已发现一类新的二芳基二胺衍生物,它们为强有效的选择性δ阿片样物质受体激动剂和拮抗剂,因此它们具有下述强有效的治疗作用,如用作止痛药,防止器官和皮肤移植排斥的免疫抑制剂,抗过敏和消炎剂,脑细胞保护剂,治疗药物滥用和酗酒,胃炎,腹泻,心血管和呼吸疾病,咳嗽,精神病,癫痫的药剂,以及,更一般是用作δ阿片样激动剂和拮抗剂通常能治疗的病症的治疗剂。
本发明提供了式(I)化合物,或其溶剂化物或盐:其中:
R1和R2可以相同或不同,并且各自为氢,直链或支链C1-6烷基,C3-7环烷基,C3-7环烯基,C4-6环烷基烷基,C3-6链烯基,C3-5炔基,芳基,芳烷基或呋喃-2或3-基烷基,或者R1和R2一同形成可被氧间断的C3-7烷基环;
R3和R4可以相同或不同,并且各自为氢,直链或支链C1-6烷基,优选甲基,或R4为氧,它与其所连接的碳原子形成C=O基团;
R5为氢,羟基,C1-3烷氧基,优选甲氧基,巯基,烷硫基,优选甲硫基;
R6为苯基,卤素,优选溴,NH2或位于对位或间位的-C(Z)-R8基团,其中Z为氧或硫,R8为C1-8烷基,C1-8烷氧基或NR9R10,其中R9和R10可以相同或不同并为氢,直链或支链C1-6烷基,C3-7环烷基,C4-6环烷基烷基,C3-6链烯基,芳基,芳烷基,或者R6为位于对位或间位的
基团其中R11和R12可以相同或不同,并且为氢,直链或支链C1-6烷基,C3-7环烷基,C4-6环烷基烷基,C3-6链烯基,芳基,芳烷基或任意取代的杂环且Z的定义同上;和
R7为氢,直链或支链C1-8烷基,卤素,优选氯。
R1和R2的实例包括甲基,乙基,环丙基甲基,烯丙基或与N一起形成吡咯烷子基(pyrrolidino)。
R3和R4的实例包括氢,甲基,乙基,异丙基,=O。
R5的实例包括氢,羟基,甲氧基。
R6的实例包括COMe,CO-i-Pr,COOEt,CONH2,CONH-n-Pr,CON(Me)Et,CON(Me)i-Pr,CONEt2,CON(1-Pr)2,CONEt(i-Pr),CON(-CH2-)4,NHCOi-Pr,NH2,溴,苯基。
R7的实例包括氢和甲基。
第一组优选的式(I)化合物包括这样一些式(I)化合物,即其中R3和R4各自为氢,或C1-6烷基,优选甲基或乙基,且R1,R2,R5,R6和R7的定义同上。
第二组优选的式(I)化合物包括这样一些式(I)化合物,即其中R5为羟基或C1-6烷氧基,R1,R2,R6和R7的定义同上式(I),且R3和R4各自为氢或C1-6烷基。
特别优选的一组式(I)化合物为这样一些式(I)化合物,即其中R6为基团-C(Z)-R8,其中R8为C1-6烷基,OC1-4烷基或NR9R10,其中R9和R10的定义同上式(I),Z为氧,R1,R2和R7的定义同上式(I),R3和R4各自为氢或C1-6烷基,以及R5为羟基或C1-6烷氧基。
式(I)化合物或其盐或溶剂化物优选为可药用或基本纯净的形式。可药用形式特别是指它们具有可药用的纯度水平,所述水平不考虑常规药物添加剂如稀释剂或载体,并在正常剂量水平下不包括被认为有毒的物质。
基本纯净形式一般含有至少50%(排除常规药用添加剂),优选75%,较优选90%,且更优选95%式(I)化合物或其盐或溶剂化物。
一种优选的可药用形式为结晶形式,包括包含在药物组合物中的此种形式。对于盐和溶剂化物,其附加离子和溶剂部分也必须是无毒的。
式(I)化合物的可药用盐的实例包括与常规可药用酸形成的酸加成盐,这些酸例如有马来酸,盐酸,氢溴酸,磷酸,乙酸,富马酸,水杨酸,柠檬酸,乳酸,扁桃酸,酒石酸,琥珀酸,苯甲酸,抗坏血酸和甲磺酸。
本发明式(I)化合物可以多种立体异构形式存在,并且本发明包括所有这种形式以及它们的混合物(包括外消旋体)。
本发明还提供了制备式(I)化合物的方法。一般说来,这些化合物可以用下述一般反应流程中所述的方法制备,或者可采用易购得的原料,试剂,并使用常规合成方法对其进行修改而制备。如果需要本发明化合物的特定对映体,则可使用所希望原料的相应对映体,通过不涉及外消旋作用的反应合成,或者可通过手性合成制备,或通过用手性助剂衍生制备,在此方法中分离所产生的非对映体混合物并解离辅助基,得到需要的纯净对映体。另一方面,通过与合适的旋光性酸形成非对映体盐,继之分级结晶拆分,随后回收纯净对映体,可将式(I)化合物分离成其对映体形式。
通式(I)化合物可按照流程1中所述方法制得。通式(II)化合物可在CuI和碳酸钾存在下,以取代的N-乙酰苯胺和取代的溴苯衍生物为原料合成制得,如有机化学杂志(J.Org.Chem.),43,4975(1978)中所述。在NaH存在下,使用DMF作溶剂,用取代的α-溴代酯使双苯胺衍生物(II)烷基化,可以得到通式(III)化合物。这些化合物中的酯基可以用LiAlH4还原,此还原在THF溶剂中进行;或者,对于其中R6为含羰基的基团的化合物,另一方法是在t-BuOH/MeOH溶剂中用NaBH4还原,从而得到通式(IV)化合物。将该醇衍生物转化成其相应的甲磺酸酯,其后用合适的胺处理,得到通式(I)化合物及它们的区域异构体(regioismers),其中R3=R4。
流程1
另一方面,通式(I)化合物也可用下面流程2中所述方法合成。通式(III)酯(如流程1中所述制得)可在加压下用取代胺处理。相应的酰胺可用BH3·Me2S还原,从而得到其中R3为H的通式(I)化合物。
通式(I)化合物,其中R6为基团COR8,这里R8的定义同上,可以通式(IIb)和(IIc)化合物为原料制得,而这两种原料化合物本身又由式(IIa)化合物制得,如流程3中所述。酰胺(IIb)可通过使用DCC/HOBT为缩合剂,由合适的胺处理相应的羧酸(IIa)制得。酯(IIc)可在酸性介质中由相应的醇处理化合物(IIa)合成得到。
其中R4为=O的通式(I)化合物的制备见流程4中描述。在沸腾的甲苯中,用氯乙酰氯处理通式(II)化合物,并用合适的胺处理所得氯衍生物,得到通式(I)最终化合物。
其中R5为MeO基团的通式(I′)化合物可在二氯甲烷溶剂中用如BBr3,或者,在沸腾的CH3CN中用(CH3)3SiCl/NaI,脱甲基化,得到其中R5为OH的通式(I)其它化合物。参见流程5。
通式(I)化合物可以用NICl2/NaBH4除去通式(V)吩噻嗪化合物中的硫原子制得(其中通式(V)吩噻嗪化合物见EP0346238A1中描述)。参见流程6。
流程6
通过与合适的有机或无机酸反应,式(I)化合物可转化成其可药用的盐。
式(I)化合物的溶剂化物可通过用合适溶剂结晶或重结晶形成。例如,水合物可用水溶液,或含水有机溶剂的溶液结晶或重结晶形成。
同样,非药用的式(I)化合物的盐或溶剂化物也可在生产可药用盐或溶剂化物的过程中用作中间体。因此,这些盐或溶剂化物也构成了本发明的一部分。
一般说来,作为选择性δ受体配体的通式(I)化合物可用作止痛药,防止器官和皮肤移植排斥的免疫抑制剂,抗过敏和消炎剂,脑细胞保护剂,用于治疗药物滥用和酗酒,以减少胃分泌,治疗腹泻,心血管和呼吸疾病,咳嗽,精神病,癫痫以及其它神经失调症(以下称作“病症”)。特别是,式(I)化合物作为δ激动剂的活性在标准试验中表明,作为改善或消除疼痛的止痛剂,它们具有很强的治疗效力。
因此,本发明还提供了用作活性治疗物质的式(I)化合物,或其可药用盐或溶剂化物。
本发明进一步提供了包括式(I)化合物,或其可药用盐或溶剂化物,和可药用载体的药物组合物。
本发明还提供了式(I)化合物,或其可药用盐或溶剂化物在制备治疗上述病症的药物方面的应用。
这类药物,以及本发明的组合物,可通过混合本发明化合物和合适的载体而制得。其中可按常规方式含有稀释剂,结合剂,填料,崩解剂,调味剂,着色剂,润滑剂或防腐剂。
这些常规赋形剂可以用在治疗上述病症的已知药剂的组合物之制剂中。
优选本发明药物组合物为单位剂量形式和适合医学或兽医学领域使用的形式。例如,这些制剂可以是一种包装形式,带有节面或印刷说明书,以便作为药剂用于治疗这些病症。
本发明化合物的合适剂量范围取决于所使用的化合物和患者的症状。尤其取决于效力与吸收能力的关系以及给药次数和途径。
本发明化合物或组合物可配制成适合任何途径给药的形式,且优选为单位剂量形式或病人可自身给用的单剂量形式。优选组合物适于口服,直肠,局部,胃肠外,静脉内或肌内施用。制剂也可被设计成能缓慢释放活性成分的形式。
例如,本发明组合物可以为片剂,胶囊,小囊(sachets),小瓶,粉剂,粒剂,锭剂,再构粉剂,或液剂,例如溶液或悬浮液,或栓剂等形式。
本发明组合物,例如适合口服施用的组合物,可含有常规赋形剂如结合剂,例如,糖浆,阿拉伯胶,明胶,山梨糖醇,黄耆胶,或聚乙烯吡咯烷酮;填料,例如,乳糖,蔗糖,玉米淀粉,磷酸钙,山梨糖醇或甘氨酸;制片用润滑剂,例如硬脂酸镁;崩解剂,例如淀粉,聚乙烯吡咯烷酮,淀粉羟乙酸钠或微晶纤维素;或可药用的凝结剂(setting agent)如十二烷基硫酸钠。
固体组合物可利用常规的混合,填充,成片等方法制得。反复混合操作可使活性剂分散到使用大量填料的组合物的各处。当组合物为片剂,粉剂,或锭剂时,可使用适于配制固体组合物的任何载体,例如硬脂酸镁,淀粉,葡萄糖,乳糖,蔗糖,米粉和白垩。片剂可使用常规制药实践中公知的方法包衣,特别是肠溶包衣法。组合物还可以为含有化合物,如果需要,还含有载体或其它赋形剂的可食用胶囊形式。
液态口服用组合物可以为,例如,乳液,糖浆,或酏剂,或者以干性产物放置,使用前与水或其它合适赋形剂再配制。这类液态组合物可以含有常规添加剂如悬浮剂,例如山梨糖醇,糖浆,甲基纤维素,明胶,羟乙基纤维素,羧甲基纤维素,硬脂酸铝凝胶,氢化食用脂肪;乳化剂,例如卵磷脂,去水山梨糖醇一油酸酯,或阿拉伯胶;水或非水赋形剂,后者包括食用油,例如杏仁油,分级椰子油,油酯,例如甘油酯,或丙二醇,或乙醇,甘油,水或生理盐水;防腐剂,例如对-羟基苯甲酸甲酯或丙酯,或山梨酸;如果需要的话,还含有常规调味剂或着色剂。
本发明化合物也可经非口途径施用。按照常规制药方法,本发明组合物可配制成适合直肠给药的形式如栓剂。它们还可以配制成水或非水溶液的注射形式,可药用液体如无菌无热源水或非肠道可接受的油或液体混合物的悬浮液或乳液形式。液体可含有抑菌剂,抗氧剂或其它防腐剂,缓冲液或赋予溶液与血液等渗的溶质,增稠剂,悬浮剂或其它可药用添加剂。这种形式可以以单位剂量形式存在,如安瓿或可随意使用的注射装置,或者以多剂量形式如可从其中取出适当剂量的小瓶,或为可用于配制注射剂的固体形式或浓缩物。
本发明化合物还可经鼻或口途径吸入给药。这种给药可利用包括本发明化合物和合适载体(它们任选悬浮在烃类推进剂中)的喷雾制剂完成。
优选的喷雾制剂包括化合物粉碎颗粒以及表面活性剂,溶剂或防止悬浮颗粒沉降的分散剂。优选化合物的颗粒大小为约2至约10微米。
本发明化合物的其它施用方式包括使用皮肤斑制剂的透皮传送。优选的制剂包括分散在粘连于皮肤的压敏粘合剂中的本发明化合物,从而容许化合物从粘合剂中渗透穿过皮肤传送给患者。为保持恒定经皮吸收速率,可使用本领域中公知的压敏粘合剂如天然橡胶或硅酮。
如上所述,本发明的有效剂量取决于所用的特定化合物,患者的病症以及施用的次数和途径。单位剂量一般含有约20至1000mg,优选含有30至500mg,特别是50,100,150,200,250,300,350,400,450或500mg。组合物可每天给药一次或多次,例如2,3,或4次,并且对于70kg成人而言,总日剂量通常在100至3000mg范围内。另一方面,单位剂量将含有2至20mg活性成分,并且如果需要,可以多次施用以达到上述日剂量。
当本发明化合物按照本发明所述施用时,预计它们不存在有不可接受的毒性作用。
本发明还提供了治疗和/或预防哺乳动物,特别是人的上述病症的方法,包括对需要这种治疗和/或预防的哺乳动物施用有效量式(I)化合物或其可药用盐或溶剂化物。
本发明化合物作为选择性δ配体的活性物用下述放射性配体结合测定法测定。按Kosterlitz所述(Br.J.Pharmacol.,1981,73,939)制备小鼠脑膜。在40nM未标记的μ配体[D-Ala2,MePhe4,Gly-ol5]-脑啡肽(DAMGO)存在下,在其KD浓度(1.3nM)下测定优选的δ配体[3H]-[D-Ala2,D-Leu5]-脑啡肽(DADLE)的结合。μ配体[3H]-DAMGO(Eur.J.Pharmacol.,1989,166,213)以及κ配体[3H]-U69593(Excerpta Medica,1990,211)的结合均在0.5nM浓度下进行。在烯丙羟吗啡酮(10μM)存在下,测定所有氘化配体的非特异性结合。结合数据用抑制百分数表示并符合下述方程:f(x)=100·X/(IC50+X),其中X代表冷药物浓度值。所得IC50用于计算抑制常数(Ki)[按照Cheng和Prusoff公式(Biochem.Pharmacol.,1973,22,3099)]。
本发明化合物的δ激动/拮抗活性如下所述用小鼠输精管(MVD)生物检定法测定。
从CD-1小鼠中得到输精管并悬浮在37℃的无Mg2+克氏缓冲液内。用具有下述参数的脉冲序列电刺激组织:序列持续时间50ms,刺激持续时间2ms,刺激频率50Hz,最大电压60-70V,序列频率0.1Hz。渐增绘制每一化合物的浓度应答曲线。按照Tallarida和Murray所述(Manual of Pharmacological Calculations,Springer Verlag NY,1981),进行线性回归分析并测定IC50浓度。
本发明最有效化合物在0.5至200nM浓度范围内显示出对δ受体具有亲和性,并且其δ选择性为其它阿片样物质受体类型的10至1500倍。本发明化合物对于MVD制剂还显示出有效的δ激动或拮抗性质。选择性δ激动剂(由选择性δ拮抗剂纳郡朵尔拮抗)显示其IC50值在1至500nM范围内。例如,实施例5的化合物显示Kiδ=3.9nM,并且在MVD生物测定中显示IC50=7nM(30nMNTI引起剂量应答曲线10倍位移);实施例9的化合物显示Kiδ=3.9nM,Kiμ/Kiδ=148,Kiκ/Kiδ=153。
采用小鼠腹部紧窄感(MAC)(Proc.Soc.Exp.Biol.Med.,1957,95,729),小鼠尾抽动(MTF)(J.Pharm.Exp.Ther.,1941,72,74)和小鼠尾抽动温水(MTF-WW)(Life Sci.,1986,39,1795)试验评估本发明化合物的抗伤害感受活性。
下述制备实施例说明中间体的制备,而方法实施例则说明本发明化合物的制备。这些化合物概括在化学表4中,其分析数据则概括在表5内。制备1N,N-二乙基-4-[N-(3-甲氧基苯基)氨基]苯甲酰胺
将3.7g(2.3mmol)N-乙酰基-间-甲氧基苯胺,10.6g(41.4mmol)4-溴-N,N-二乙基苯甲酰胺和0.42g CuI一起加热到100℃;加入3g(22.3mmol)K2CO3,并加热所得混合物至250℃反应2小时。残留物溶于CH2Cl2并水洗,有机层用硫酸钠干燥并真空除去溶剂。将所得残留物溶于20ml无水乙醇中,并回流2小时。真空除去溶剂,残留物溶在水中,用乙酸乙酯提取水层。有机层用硫酸钠干燥并真空除去溶剂。所得残留物通过快速色谱纯化(乙酸乙酯/己烷6∶4),得到3g标题化合物。IR cm-1(净):3300,1595,1535。MS(EI)m/z:297.6(M-1).
表1
名称 | R1 | R2 | IR cm-1(净) | MS(EI)m/z |
4-溴-3′-甲氧基二苯胺 | H | Br | 3380,1580,1490 | |
3′-甲氧基-4-苯基二苯胺 | H | Ph | 3400,1600,1540 | 275.1 |
4-[N-(3-甲氧基苯基)氨基]苯甲酸 | H | COOH | 3380,1600,1590 | 243.0 |
N,N-二乙基-3-[N-(3-甲氧基苯基)氨基]苯甲酰胺 | CONEt2 | H | 3280,1600,1580 | 298.0 |
3′-甲氧基-4-硝基二苯基二胺 | H | NO2 | 3340,1580,1300 | 244.3 |
通式(II)化合物也可以按照下述方法制备:制备21-[4-[[N-(3-甲氧基苯基)]氨基]苯甲酰基]吡咯烷
氮气氛下,将2g(8.2mmol)4-[N-(3-甲氧基苯基)氨基苯甲酸,2.2g(16.4mmol)N-羟基苯并三唑和1ml(12.3mmol)吡咯烷溶于40mlTHF/CH3CN(7∶3)混合物中。冷却溶液至0℃并加入3.4g(16.4mmol)溶在20ml二氯甲烷中的二环己基碳化二亚胺。1小时内温热反应混合物至室温,再搅拌1小时,然后滤去沉淀并真空除去溶剂。残留物溶于水中并用乙酸乙酯提取,有机层用硫酸钠干燥并真空除去溶剂。所得粗制混合物通过快速色谱纯化(AcOEt),得到2.4g标题化合物。IR cm-1(KBr):3280,1600,1435;MS(EI)m/z:296.1.使用相同方法,制得N,N-二异丙基-4-[N-(3-甲氧基苯基)氨基]苯甲酰胺。IR cm-1(KBr):3280,1600,1340;MS(EI)m/z:326.1.制备3(±)-N,N-二乙基-4-[[N-(1-乙氧羰基乙基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺
氮气氛下,将2g(51.6mmol)60%NaH的矿物油悬浮液放入到100ml DMF中。冷却所得悬浮液至0℃,加入7.7g(25.8mmol)N,N-二乙基-4-[N-(3-甲氧基苯基)氨基]苯甲酰胺溶在50ml DMF的溶液。1小时后,加入8.4ml(64.5mmol)2-溴代丙酸乙酯的DMF(25ml)溶液。温热反应混合物至室温过夜,然后加入水,收集有机层,用硫酸钠干燥并真空除去溶剂。粗制反应混合物通过快速色谱纯化(AcOEt/己烷6∶4),得到3.5g标题化合物。IR cm-1(净):2980,1740,1610.MS(EI)m/z:398
表2
制备4(±)-N,N-二乙基-4-[[N-(1-羟基丙-2-基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺
名称 | R | R1 | R2 | IR cm-1(净) | MS(EI)m/z |
(±)-2-[N-(4-溴苯基)-N-(3-甲氧基苯基)氨基丙酸乙酯 | Me | H | Br | 2980,1740,1580 | 379(M+1) |
N-(4-溴苯基)-N-(3-甲氧基苯基)]氨基乙酸乙酯 | H | H | Br | 1760,1585,1495 | |
(±)-2-[N-(4-联苯基)-N-(3-甲氧基苯基)氨基丙酸乙酯 | Me | H | Ph | 1750,1615,1490 | 375.2 |
N,N-二乙基-4-[[N-乙氧羰基甲基-N-(3-甲氧基苯基)]氨基]苯甲酰胺 | H | H | CONEt2 | 1750,1620,1595 | 384.1 |
(±)-N,N-二乙基-4-[[N-(1-乙氧羰基丙基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺 | Et | H | CONEt2 | 2980,1740,1620 | 412.2 |
(±)-1-[4-[[N-(1-乙氧羰基乙基)-N-(3-甲氧基苯基)]氨基]苯甲酰基]吡咯烷 | Me | H | CON(CH2)4 | 1755,1615,1590 | 396.0 |
(±)-N,N-二异丙基-4-[[N-(1-乙氧羰基乙基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺 | Me | H | CON(i-Pr)2 | 2980,1740,1620 | 426.2 |
(±)-N,N-二乙基-3-[[N-(1-乙氧羰基乙基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺 | Me | CONEt2 | H | 2980,1740,1635 | 398.1 |
(±)-2-[N-(4-硝基苯基)-N-(3-甲氧基苯基)]氨基丙酸乙酯 | Me | H | NO2 | 2980,1740,1590 | 344.1 |
氮气氛下,将1.13g(2.8mmol)(±)-N,N-二乙基-4-[[N-(1-乙氧羰基乙基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺溶于14ml t-BuOH中并加入0.27g(7mmol)NaBH4。将反应混合物加热至回流,并在1小时内加入2.5ml MeOH。回流溶液2小时,然后加入水,真空除去溶剂,残留物溶于水中并用乙酸乙酯提取。有机层用硫酸钠干燥并真空除去溶剂。粗反应混合物用快速色谱纯化(AcOEt/己烷9∶1),得到0.5g标题化合物。IR cm-1(净):3350,2990,1600;MS(EI)m/z:356.1
表3
制备5(±)-2-[N-(4-氨基苯基)-N-(3-甲氧基苯基)氨基丙酸乙酯
名称 | R | R1 | R2 | IR | MS |
(±)-2-[N-(4-联苯基)-N-(3-甲氧基苯基)]氨基丙醇 | Me | H | p-Ph | 3380,2980,1600 | 333.1 |
N,N-二乙基-4-[[N-(2-羟乙基)-N-(3-甲氧基苯基)]氨基苯甲酰胺 | H | H | p-CONEt2 | 3400,2980,1600 | 342.1 |
(±)-N,N-二乙基-4-[[N-(1-羟基丁-2-基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺 | Et | H | p-CONEt2 | 3400,1595,1280 | 370.1 |
(±)-1-[4-[[N-(1-羟基丙-2-基)-N-(3-甲氧基苯基)]氨基]苯甲酰基]吡咯烷 | Me | H | p-CON(CH2)4 | 3380,1590,1430 | 354.0 |
(±)-N,N-二异丙基-4-[[N-(1-羟基丙-2-基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺 | Me | H | p-CON(i-Pr)2 | 3360,1600,1265 | 384.2 |
(±)-N,N-二乙基-3-[[N-(1-羟基丙-2-基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺 | Me | p-CONEt2 | H | 3400,1600,1490 | 356.2 |
将1.5g(4.3mmol)(±)-2-[N-(4-硝基苯基)-N-(3-甲氧基苯基)]氨基丙酸乙酯溶于50ml无水乙醇中;加入150mg 10%Pd/C,在帕尔装置中于40psi氢化所得混合物2小时。滤出晶体并真空除去溶剂,得到1.2g标题化合物。IR cm-1(净):3460,3360,1730;MS(EI)m/z:314.2.
将6.2g(16.4mmol)(±)-2-[N-(4-溴苯基)-N-(3-甲氧基苯基)]氨基丙酸乙酯和100ml吡咯烷放入中压装置中并加热至200℃过夜。然后真空除去吡咯烷,残留物溶于二氯甲烷中并用5%HCl洗涤。用硫酸钠干燥有机层并真空除去溶剂,得到6g标题化合物。IR cm-1(净):2985,1650,1610;MS(EI)m/z:402(M-1)
采用同样方法制得1-[2-[[N-(4-溴苯基)-N-(3-羟基苯基)]氨基]乙酰基]吡咯烷。IR cm-1(KBr):3180,1630,1590;MS(EI)m/z:374.1
采用同样方法制得1-[2-[[N-(4-氨基苯基)-N-(3-甲氧基苯基)]氨基]乙酰基]吡咯烷。IR cm-1(KBr):3440,3340,1630;MS(EI)m/z:339.1.制备7N,N-二乙基-4-[[N-氯乙酰基-N-(3-甲氧基苯基)氨基]苯甲酰胺
氮气氛下,将3.7g(12.4mmol)N,N-二乙基-4-[N-(3-甲氧基苯基)氨基]苯甲酰胺和1.2ml(14.9mmol)氯乙酰氯在40ml甲苯中加热回流2小时。真空除去溶剂,将残留物溶于水中并用乙酸乙酯提取。有机层用硫酸钠干燥并真空除去溶剂。粗制反应混合物通过快速色谱纯化(AcOEt/己烷8∶2),得到2.9g标题化合物。IR cm-1(净):2980,1695,1635;MS(EI)m/z:374.
采用同样方法制备N,N-二异丙基-4-[[N-氯乙酰基-N-(3-甲氧基苯基)]氨基]苯甲酰胺。IR cm-1(净):3280,1690,1620;
用方法A至l中所述的类似方法制备表4中所述的实施例化合物(其光谱数据概括在表5内),这些方法在一些特定实施例给予了完整描述。方法A(±)-N,N-二乙基-4-[[N-(3-甲氧基苯基)-N-(2-吡咯烷基-1-丁基)]氨基]苯甲酰胺盐酸盐-实施例39-和(±)-N,N-二乙基-4-[[N-(3-甲氧基苯基)-N-(1-吡咯烷基-2-丁基)]氨基]苯甲酰胺盐酸盐-实施例38-
氮气氛及10℃下,向1.0g(2.7mmol)(±)-N,N-二乙基-4-[[N-(1-羟基丁-2-基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺的二氯甲烷(10ml)溶液中加入0.6ml(4.3mmol)Et3N和0.3ml(4.3mmol)甲磺酰氯溶于4ml二氯甲烷的溶液。90分钟后,将反应混合物倾入水中,分离各层并将有机层用盐水洗涤,硫酸钠干燥并真空除去溶剂。残留物溶于50ml甲苯中,加入5ml吡咯烷并在90℃加热此溶液过夜。真空除去溶剂,用5%HCl调节残留物至酸性pH并用乙醚提取水层,然后用15%NaOH调节至pH14,再用乙酸乙酯提取。有机层用硫酸钠干燥并真空除去溶剂。残留物用快速色谱纯化[(i-Pr)2O/i-PrOH/浓NH4OH 98∶2∶0.5],在用Et2O/HCl酸化后,得到200mg具有高Rf值的产物,为(±)-N,N-二乙基-4-[[N-(3-甲氧基苯基)-N-(1-吡咯烷基-2-丁基)]氨基]苯甲酰胺盐酸盐,以及170mg具有低Rf值的产物,为(±)-N,N-二乙基-4-[[N-(3-甲氧基苯基)-N-(2-吡咯烷基-1-丁基)]氨基]苯甲酰胺盐酸盐。万法B(±)-N,N-二-乙基-4-[[N-(3-二甲氨基丙-2-基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺-实施例31-和(±)-N,N-二乙基-4-[[N-(2-二甲氨基丙-1-基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺-实施例30-
氮气氛及10℃下,向2.0g(5.6mmol)(±)-N,N-二乙基-4-[[N-(1-羟基丙-2-基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺的二氯甲烷(20ml)溶液中加入1.25ml(9.0mmol)Et3N和0.69ml(9.0mmol)甲磺酰氯/8ml二氯甲烷溶液。90分钟后,将反应混合物倾入水中,分离各层并将有机层用盐水洗涤,硫酸钠干燥并真空除去溶剂。残留物溶于30ml 33%二甲胺的乙醇溶液,将反应混合物放入中压装置中并在80℃加热过夜。真空除去溶剂,用5%HCl调节残留物至酸性pH,并用乙醚提取水相,然后用15%NaOH调节至pH14,再用乙酸乙酯提取。有机层用硫酸钠干燥并真空除去溶剂。反应粗产混合物用快速色谱纯化[CH2Cl2/MeOH/浓NH4OH94.5∶5∶0.5],得到790mg具有高Rf值的产物,为(±)-N,N-二乙基-4-[[N-(3-二甲氨基丙-2-基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺,以及645mg具有低Rf值的产物,为(±)-N,N-二乙基-4-[[N-(2-二甲氨基丙-1-基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺。方法C-实施例3-(±)-N-(4-溴苯基)-N-(3-甲氧基苯基)-α-甲基-1-吡咯烷子基乙胺柠檬酸盐
氮气氛下,回流2.6g(6.4mmol)(±)-1-[2-[[N-(4-溴苯基)-N-(3-甲氧基苯基)]氨基]丙酰基]吡咯烷的无水THF(80ml)溶液,然后缓慢加入4.2ml(41.6mmol)10M BH3·Me2S溶液。4小时后,冷却溶液至0℃并依次各加入15ml水,15ml 10%HCl和15ml 37%HCl。回流反应混合物4小时,然后冷却并真空除去挥发物。残留物溶于水中,用40%NaOH调节至pH14并用乙醚提取。有机层用硫酸钠干燥并真空除去溶剂。粗制反应混合物通过快速色谱纯化(CH2Cl2/MeOH/浓NH4OH 98∶2∶0.4),得到1.5g游离碱形式标题化合物。取150mg产物溶于MeOH,加入等摩尔量无水柠檬酸,真空除去溶剂并用乙醚研制所得固体,得到100mg标题化合物。方法D-实施例2-(±)-N-(4-溴苯基)-N-(3-羟基苯基)-α-甲基-1-吡咯烷子基乙胺盐酸盐
氮气氛下,将0.85ml(9mmol)三溴化硼溶于15ml无水CHCl3中。室温下向所得溶液内加入1.6g(1.5mmol)(±)-N-(4-溴苯基)-N-(3-甲氧基苯基)-α-甲基-1-吡咯烷子基乙胺的无水氯仿(7ml)溶液。2小时后,将所得溶液倾到含1.5ml浓NH4OH的15g碎冰上并搅拌20分钟。分离各层并将有机层用硫酸钠干燥,真空除去溶剂。粗反应混合物通过快速色谱纯化(CH2Cl2/MeOH/浓NH4OH 94∶5.5∶0.5),并将所得固体溶于MeOH,此溶液用Et2O/HCl调节至酸性pH,再真空除去溶剂。用乙醚研制所得固体产物,得到365mg标题化合物。方法E-实施例1-(-)-3-[N-(3-吡咯烷子基丙-2-基)苯基氨基]-N-丙基苯甲酰胺氢溴酸盐
室温下,向130mg(0.33mmol)(+)-N-丙基-10-(3-吡咯烷子基丙-2-基)吩噻嗪-2-甲酰胺(EP0346238A1)和1.1g(4.62mmol)NiCl2·6H2O在16ml比例相应为1∶2∶1的MeOH∶THF∶H2O混合物中的溶液内加入524mg(13.86mmol)NaBH4。3小时后,将反应混合物倾到硅藻土垫板上,真空除去溶剂并将残留物溶于水中,用二氯甲烷提取。有机相用硫酸钠干燥并真空除去溶剂。粗制反应混合物通过快速色谱纯化(AcOEt/MeOH/浓NH4OH 95∶5∶0.5)。将所得固体溶于丙酮中,并用24%HBr调节溶液至酸性pH,再真空除去溶剂。用(i-Pr)2O研制所得固体,得到50mg标题化合物。[α]25 D=-96(c=0.1,MeOH).方法F-实施例17-N,N-二乙基-4-[[N-(二甲氨基乙酰基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺柠檬酸盐
在中压装置内放入1.4g(3.9mmol)N,N-二乙基-4-[[N-氯乙酰基-N-(3-甲氧基苯基)]氨基}苯甲酰胺在30ml 33%二甲胺乙醇溶液内的溶液,于80℃下加热过夜。真空除去溶剂,用5%HCl调节残留物至酸性pH并将水相用乙醚提取,然后用15%NaOH调节至pH14,再用乙酸乙酯提取。有机层用硫酸钠干燥并真空除去溶剂。粗反应混合物通过快速色谱纯化(CH2Cl2/MeOH/浓NH4OH 90∶7∶0.7),得到1.7g游离碱形式标题化合物。取50mg产物溶于MeOH,加入等摩尔量无水柠檬酸并真空除去溶剂。用乙醚研制所得固体,得到30mg标题化合物。方法G-实施例43-(±)-N-[[4-[N-(3-甲氧基苯基)-N-[1-甲基-2-(1-吡咯烷基)乙基]]氨基]苯基]-2-甲基丙酰胺
向0.98g(3.0mmol)(±)-N-(4-氨基苯基)-N-(3-甲氧基苯基)-α-甲基-1-吡咯烷子基乙胺的无水二氯甲烷(25ml)溶液中加入1g(7.5mmol)K2CO3。冷却反应混合物至0℃,然后在氮气氛下加入溶在10ml无水二氯甲烷中的0.8g(7.5mmol)异丁酰氯。15小时后,于室温下加入水,分离各相并用硫酸钠干燥有机相,随后真空除去溶剂。所得残留物用快速色谱纯化(CH2Cl2/MeOH/浓NH4OH 94.5∶5∶0.5),得到1.0g标题化合物。方法H(-)-N,N-二乙基-4-[[N-(3-二甲氨基丙-2-基)-N-(3-羟基苯基)]氨基]苯甲酰胺三氟乙酸盐-实施例45-和(+)-N,N-二乙基-4-[[N-(3-二甲氨基丙-2-基)-N-(3-羟基苯基)]氨基]苯甲酰胺三氟乙酸盐-实施例46-
在手性固定相Chiradex(Merk)上进行HPLC拆分相应的外消旋物。柱:Lichrocart 250×21mm;洗脱剂:KH2PO4(75mM),TEA(0.2%),pH=4/MeCN=80/20方法I-实施例55-N,N-二乙基-4-[[N-(二乙基氨基乙酰基)-N-(3-羟基苯基)]氨基]苯甲酰胺盐酸盐
向2g(5.6mmol)N,N-二乙基-4-[[N-氯乙酰基-N-(3-甲氧基苯基)]氨基]苯甲酰胺的甲苯(20ml)溶液内加入2.7ml(25.8mmol)二乙胺,并将所形成的溶液于60℃加热15小时。真空除去溶剂,残留物溶于水中并用二氯甲烷提取,然后将有机层用硫酸钠干燥,再真空除去溶剂。所得残留物通过快速色谱纯化(CH2Cl2/MeOH/浓NH4OH 94.5∶5∶0.5),得到1.9g标题化合物。
表4
实施例 | 方法 | 名称 | R1 | R2 | R3 | R4 | R5 | R6 | R7 | 旋光性 |
1 | E | (-)-3-[N-(3-吡咯烷子基丙-2-基)苯基氨基]-N-丙基苯甲酰胺HBr | -(CH2)4- | H | Me | H | m-CONH-nPr | H | (-) | |
2 | D | (±)-N-(4-溴苯基)-N-(3-羟基苯基)-α-甲基-1-吡咯烷子基乙胺HCl | -(CH2)4- | H | Me | OH | p-Br | H | (±) | |
3 | C | (±)-N-(4-溴苯基)-N-(3-甲氧基苯基)-α-甲基-1-吡咯烷子基乙胺柠檬酸盐 | -(CH2)4- | H | Me | OMe | p-Br | H | (±) | |
4 | A | (±)-N,N-二乙基-4-[[N-(3-甲氧基苯基)-N-(3-吡咯烷子基丙-2-基)〕氨基]苯甲酰胺柠檬酸盐 | -(CH2)4- | H | Me | OMe | p-CONEt2 | H | (±) | |
5 | D | (±)-N,N-二乙基-4-[[N-(3-羟基苯基)-N-(3-吡咯烷子基丙-2-基)]氨基]苯甲酰胺柠檬酸盐 | -(CH2)4- | H | Me | OH | p-CONEt2 | H | (±) | |
6 | C | N-(4-溴苯基)-N-(3-羟基苯基)-1-吡咯烷子基乙胺 | -(CH2)4- | H | H | OH | p-Br | H | ||
7 | D | N,N-二乙基-4-[[N-(2-二甲氨基乙基)-N-(3-羟基苯基)]氨基]苯甲酰胺柠檬酸盐 | Me | Me | H | H | OH | p-CONEt2 | H | |
8 | D | (±)-N,N-二乙基-4-[[N-(2-二甲氨基丙-1-基)-N-(3-羟基苯基)]氨基]苯甲酰胺柠檬酸盐 | Me | Me | Me | H | OH | p-CONEt2 | H | (±) |
9 | D | (±)-N,N-二乙基-4-[[N-[(3-二甲氨基丙-2-基)-N-(3-羟基苯基)]氨基]苯甲酰胺草酸盐 | Me | Me | H | Me | OH | p-CONEt2 | H | (±) |
10 | D | N,N-二乙基-4-[[N-(3-羟基苯基)-N-(2-吡咯烷子基乙基)]氨基]苯甲酰胺柠檬酸盐 | -(CH2)4- | H | H | OH | p-CONEt2 | H | ||
11 | A | N,N-二乙基-4-[[N-(3-甲氧基苯基)-N-(2-吡咯烷子基乙基)]氨基]苯甲酰胺草酸盐 | -(CH2)4- | H | H | OMe | p-CONEt2 | H |
表4续
实施例 | 方法 | 名称 | R1 | R2 | R3 | R4 | R5 | R6 | R7 | 旋光性 |
12 | B | N,N-二乙基-4-[[N-(2-二甲氨基乙基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺柠檬酸盐 | Me | Me | H | H | OMe | p-CONEt2 | H | |
13 | D | (±)-N2-(4-联苯基)-N1,N1-二甲基-N2-(3-羟基苯基)-1,2-丙二胺柠檬酸盐 | Me | Me | H | Me | OH | p-Ph | H | (±) |
14 | D | (±)-N1-(4-联苯基)-N2,N2-二甲基-N1-(3-羟基苯基)-1,2-丙二胺柠檬酸盐 | Me | Me | Me | H | OH | p-Ph | H | (±) |
15 | B | (±)-N2-(4-联苯基)-N1,N1-二甲基-N2-(3-甲氧基苯基)-1,2-丙二胺柠檬酸盐 | Me | Me | H | Me | OMe | p-Ph | H | (±) |
16 | B | (±)-N1-(4-联苯基)-N2,N2-二甲基-N1-(3-甲氧基苯基)-1,2-丙二胺柠檬酸盐 | Me | Me | Me | H | OMe | p-Ph | H | (±) |
17 | F | N,N-二乙基-4-[[N-(二甲氨基乙酰基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺柠檬酸盐 | Me | Me | H | C=O | OMe | p-CONEt2 | H | (±) |
18 | B | (±)-1-[4-[[N-(3-二甲氨基丙-2-基)-N-(3-甲氧基苯基)]氨基]苯甲酰基]吡咯烷柠檬酸盐 | Me | Me | H | Me | OMe | p-CON(CH2)4 | H | (±) |
19 | B | (±)-1-[4-[[N-(2-二甲氨基丙-1-基)-N-(3-甲氧基苯基)]氨基]苯甲酰基]吡咯烷柠檬酸盐 | Me | Me | Me | H | OMe | p-CON(CH2)4 | H | (±) |
20 | D | (±)-1-[4-[[N-(3-二甲氨基丙-2-基)-N-(3-羟基苯基)]氨基]苯甲酰基]吡咯烷柠檬酸盐 | Me | Me | H | Me | OH | p-CON(CH2)4 | H | (±) |
21 | D | (±)-1-[4-[[N-(2-二甲氨基丙-1-基)-N-(3-羟基苯基)]氨基]苯甲酰基]吡咯烷柠檬酸盐 | Me | Me | Me | H | OH | p-CON(CH2)4 | H | (±) |
22 | D | (±)-N,N-二乙基-3-[[N-(3-二甲氨基丙-2-基)-N-(3-羟基苯基)]氨基]苯甲酰胺柠檬酸盐 | Me | Me | H | Me | OH | m-CONEt2 | H | (±) |
表4续
实施例 | 方法 | 名称 | R1 | R2 | R3 | R4 | R5 | R6 | R7 | 旋光性 |
23 | D | (±)-N,N-二乙基-3-[[N-(2-二甲氨基丙-1-基)-N-(3-羟基苯基)]氨基]苯甲酰胺柠檬酸盐 | Me | Me | Me | H | OH | m-CONEt2 | H | (±) |
24 | D | (±)-N,N-二异丙基-4-[[N-(3-二甲氨基丙-2-基)-N-(3-羟基苯基)氨基]苯甲酰胺柠檬酸盐 | Me | Me | H | Me | OH | p-CON(i-Pr)2 | H | (±) |
25 | D | (±)-N,N-二异丙基-4-[[N-(2-二甲氨基丙-1-基)-N-(3-羟基苯基)氨基]苯甲酰胺柠檬酸盐 | Me | Me | Me | H | OH | p-CON(i-Pr)2 | H | (±) |
26 | D | (±)-N,N-二乙基-3-[[N-(3-羟基苯基)-N-(3-吡咯烷子基丙-2-基)]氨基]苯甲酰胺柠檬酸盐 | -(CH2)4- | H | Me | OH | m-CONEt2 | H | (±) | |
27 | D | (±)-N,N-二乙基-3-[[N-(3-羟基苯基)-N-(2-吡咯烷子基丙-1-基)]氨基]苯甲酰胺柠檬酸盐 | -(CH2)4- | Me | H | OH | m-CONEt2 | H | (±) | |
28 | D | (±)-N,N-二乙基-4-[[N-(3-羟基苯基)-N-(1-吡咯烷基-2-丁基)]氨基]苯甲酰胺HCl | -(CH2)4- | H | Et | OH | p-CONEt2 | H | (±) | |
29 | D | (±)-N,N-二乙基-4-[[N-(3-羟基苯基)-N-(2-吡咯烷基-1-丁基)]氨基]苯甲酰胺HCl | -(CH2)4- | Et | H | OH | p-CONEt2 | H | (±) | |
30 | B | (±)-N,N-二乙基-4-[[N-(2-二甲氨基丙-1-基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺 | Me | Me | Me | H | OMe | p-CONEt2 | H | (±) |
31 | B | (±)-N,N-二乙基-4-[[N-(3-二甲氨基丙-2-基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺 | Me | Me | H | Me | OMe | p-CONEt2 | H | (±) |
32 | B | (±)-N,N-二乙基-3-[[N-(3-二甲氨基丙-2-基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺 | Me | Me | H | Me | OMe | m-CONEt2 | H | (±) |
33 | B | (±)-N,N-二乙基-3-[[N-(2-二甲氨基丙-1-基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺 | Me | Me | Me | H | OMe | m-CONEt2 | H | (±) |
表4续
实施例 | 方法 | 名称 | R1 | R2 | R3 | R4 | R5 | R6 | R7 | 旋光性 |
34 | B | (±)-N,N-二异丙基-4-[[N-(3-二甲氨基丙-2-基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺 | Me | Me | H | Me | OMe | p-CON(i-Pr)2 | H | (±) |
35 | B | (±)-N,N-二异丙基-4-[[N-(2-二甲氨基丙-1-基)-N-(3-甲氧基苯基)氨基]苯甲酰胺 | Me | Me | Me | H | OMe | p-CON(i-Pr)2 | H | (±) |
36 | A | (±)-N,N-二乙基-3-[[N-(3-甲氧基苯基)-N-(3-吡咯烷子基丙-2-基)]氨基]苯甲酰胺 | -(CH2)4- | H | Me | OMe | m-CONEt2 | H | (±) | |
37 | A | (±)-N,N-二乙基-3-[[N-(3-甲氧基苯基)-N-(2-吡咯烷子基丙-1-基)]氨基]苯甲酰胺 | -(CH2)4- | Me | H | OMe | m-CONEt2 | H | (±) | |
38 | A | (±)-N,N-二乙基-4-[[N-(3-甲氧基苯基)-N-(1-吡咯烷基-2-丁基)]氨基]苯甲酰胺HCl | -(CH2)4- | H | Et | OMe | p-CONEt2 | H | (±) | |
39 | A | (±)-N,N-二乙基-4-[[N-(3-甲氧基苯基)-N-(2-吡咯烷基-1-丁基)]氨基]苯甲酰胺HCl | -(CH2)4- | Et | H | OMe | p-CONEt2 | H | (±) | |
40 | D | (±)-4-[N-[1-(N-烯丙基-N-甲基)氨基-2-丙基]-N-(3-羟基苯基)氨基]-N,N-二乙基苯甲酰胺HCl | Me | 烯丙基 | H | Me | OH | p-CONEt2 | H | (±) |
41 | D | (±)-4-[N-[2-(N-烯丙基-N-甲基)氨基-1-丙基]-N-(3-羟基苯基)氨基]-N,N-二乙基苯甲酰胺HCl | Me | 烯丙基 | Me | H | OH | p-CONEt2 | H | (±) |
42 | D | N,N-二乙基-4-[[N-(二甲氨基乙酰基)-N-(3-羟基苯基)]氨基]苯甲酰胺HCl | Me | Me | H | C=O | OH | p-CONEt2 | H |
表4续
43 | G | (±)-N-[[4-[N-(3-甲氧基苯基)-N-[1-甲基-2-(1-吡咯烷基)乙基]]氨基]苯基]-2-甲基丙酰胺 | -(CH2)4- | H | Me | OMe | p-NHCOi-Pr | H | (±) | |
44 | D | (±)-N-[4-[N-(3-羟基苯基)-N-[1-甲基-2-(1-吡咯烷基)乙基]]氨基]苯基]-2-甲基丙酰胺柠檬酸盐 | -(CH2)4- | H | Me | OH | p-NHCOi-Pr | H | (±) | |
45 | H | (-)-N,N-二乙基-4-[[N-(3-二甲氨基丙-2-基)-N-(3-羟基苯基)氨基]苯甲酰胺三氟乙酸盐 | Me | Me | H | Me | OH | p-CONEt2 | H | [α]D 20=-68.1;c=0.1MeOH |
46 | H | (+)-N,N-二乙基-4-[[N-(3-二甲氨基丙-2-基)-N-(3-羟基苯基)氨基]苯甲酰胺三氟乙酸盐 | Me | Me | H | Me | OH | p-CONEt2 | H | [α]D 20=+60.5;c=0.1MeOH |
47 | D | N,N-二乙基-4-[[N-(二乙氨基乙酰基)-N-(3-羟基苯基)]氨基]苯甲酰胺HCl | Et | Et | H | C=O | OH | p-CONEt2 | H | |
48 | D | N,N-二乙基-4-[[N-(3-羟基苯基)-N-(吡咯烷-1-基乙酰基)]氨基]苯甲酰胺HCl | -(CH2)4- | H | C=O | OH | p-CONEt2 | H | ||
49 | D | N,N-二异丙基-4-[[N-(二甲氨基乙酰基)-N-(3-羟基苯基)]氨基]苯甲酰胺 | Me | Me | H | C=O | OH | p-CON(i-Pr)2 | H | |
50 | D | 4-[[N-[[(N-烯丙基-N-甲基)氨基]乙酰基]-N-(3-羟基苯基)]氨基]-N,N-二乙基苯甲酰胺HCl | Me | 烯丙基 | H | C=O | OH | p-CONEt2 | H | |
51 | D | N,N-二乙基-4-[[N-(3-羟基苯基)-N-(甲氨基乙酰基)]氨基]苯甲酰胺HCl | H | Me | H | C=O | OH | p-CONEt2 | H | |
52 | D | N,N-二异丙基-4-[[N-氨基乙酰基-N-(3-羟基苯基)]氨基]苯甲酰胺 | H | H | H | C=O | OH | p-CON(i-Pr)2 | H | |
53 | A | (±)-4-[N-[1-(N-烯丙基-N-甲基)氨基-2-丙基]-N-(3-甲氧基苯基)氨基]-N,N-二乙基苯甲酰胺 | Me | 烯丙基 | H | Me | OMe | p-CONEt2 | H | (±) |
表4续
54 | A | (±)-4-[N-[2-(N-烯丙基-N-甲基)氨基-1-丙基]-N-(3-甲氧基苯基)氨基]-N,N-二乙基苯甲酰胺 | Me | 烯丙基 | Me | H | OMe | p-CONEt2 | H | (±) |
55 | I | N,N-二乙基-4-[[N-(二乙氨基乙酰基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺 | Et | Et | H | C=O | OMe | p-CONEt2 | H | |
56 | I | N,N-二乙基-4-[[N-(3-甲氧基苯基)-N-(吡咯烷-1-基乙酰基)]氨基]苯甲酰胺 | -(CH2)4- | H | C=O | OMe | p-CONEt2 | H | ||
57 | F | N,N-二异丙基-4-[[N-(二甲氨基乙酰基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺 | Me | Me | H | C=O | OMe | p-CON(i-Pr)2 | H | |
58 | I | 4-[[N-[[(N-烯丙基-N-甲基)氨基]乙酰基]-N-(3-甲氧基苯基)]氨基]-N,N-二乙基苯甲酰胺 | Me | 烯丙基 | H | C=O | OMe | p-CONEt2 | H | |
59 | F | N,N-二乙基-4-[[N-(3-甲氧基苯基)-N-(甲氨基乙酰基)]氨基]苯甲酰胺 | H | Me | H | C=O | OMe | p-CONEt2 | H | |
60 | F | N,N-二异丙基-4-[[N-氨基乙酰基]-N-(3-甲氧基苯基)]氨基]苯甲酰胺 | H | H | H | C=O | OMe | p-CON(i-Pr)2 | H | |
61 | C | (±)-N-(4-氨基苯基)-N-(3-甲氧基苯基)-α-甲基-1-吡咯烷子基乙胺 | -(CH2)4- | H | Me | OMe | p-NH2 | H | (±) |
表5
实施例 | NMR | MS | IR cm-1(KBr) |
1 | (CDCl3):11.40(s br,1H);8.00(s br,1H);7.60(d,1H);7.37(dd,2H);7.25(dd,1H);7.18(dd,1H);7.08(d,2H);6.89(dbr,1H);5.25(m,1H);4.00-3.80(m,2H);3.60-3.40(m,1H);3.49(dt,2H);3.30-3.20(m,1H);2.30-2.00(m,4H);1.77(ddq,2H);1.41(d,3H);1.00(t,3H). | 365(M+.);281EI;源ee 200C;70V;200uA | 3420,2960,1640. |
2 | (CDCl3):10.58(s br,1H);8.30(s br,1H);7.36(d,2H);7.11(dd,1H);6.85(d,2H);6.70(s br,1H);6.63(d,1H);6.36(d,1H);4.84(ddq,1H);4.00-3.70(m,2H);3.36(dd,1H);3.11(dd,1H);3.00-2.70(m,2H);2.30-1.90(m,4H);1.40(d,3H). | 374-376(M+.),290-292,84EI;源 200C;70V;200uA | 2980,1585,1490. |
3 | (DMSO):11.00(s br,4H);7.41(d,2H);7.27(dd,1H);6.78(d,2H);6.72(d,1H);6.52(d,1H);6.50(s,1H);4.35(ddq,1H);3.72(s,3H);3.40-2.80(m,6H);2.60(ABq,4H);1.80(s br,4H);1.10(d,3H). | 388-390(M+.);304-306;84EI;源 200C;70V;200uA | 3440,1730,1580. |
4 | (DMSO):10.80(s br,4H);7.33(dd,1H);7.23(d,2H);6.82(d,1H);6.74(d,2H);6.63(d,1H);6.62(s,1H);4.50(ddq,1H);3.75(s,3H);3.30(q br,4H);3.10-2.70(m,6H);2.60(ABq,4H);1.82(s br,4H);1.15(d,3H);1.10(t,6H). | 409(M+.);325;84EI;源 200C;70V;200uA | 2960,1610,1430(游离碱). |
5 | (DMSO):10.80(s br,4H);9.45(s br,1H);7.22(d,2H);7.21(dd,1H);6.73(d,2H);6.66(dd,1H);6.52(d,1H);6.46(dd,1H);4.47(ddq,1H);3.32(q br,4H);3.10-2.80(m,6H);2.60(ABq,4H);1.84(s br,4H);1.16(d,3H);1.10(t,3H). | 395(M+.);311;211;84EI;源 200C;70V;200uA | 2980,1730,1600. |
6 | (DMSO):9.30(s,1H);7.36(d,2H);7.09(dd,1H);6.86(d,2H);647(d,1H);6.45(s,1H);6.42(d,1H);3.72(t,2H);2.60(t,2H);2.44(m,4H);1.65(m,4H) | 360-362(M+.);276-278;84EI;源 200C;70V;200uA | 1620,1570,1485. |
7 | (DMSO):11.00(s br,4H);9.45(s br,1H);7.24(d,2H);7.17(dd,1H);6.88(d,2H);6.58(d,1H);5.54(d,1H);6.52(s,1H);3.90(t,2H);3.32(q br,4H);2.92(t,2H);2.59(ABq,4H);2.55(s,6H);1.10(t,6H). | 355(M+.);297;197;58EI;源 200C;70V;200uA | 3420,1730,1600. |
8 | (DMSO):11.00(s br,4H);9.45(s br,1H);7.25(d,2H);7.17(dd,1H);6.90(d,2H);6.60(d,1H);6.55(d,1H);6.50(s,1H);3.92(dd,1H);3.72(dd,1H);3.40-3.20(m,5H);2.60(ABq,4H);1.10(d,3H);1.09(t,3H). | 369(M+.);298;72EI;源 200C;70V;200uA | 3400,1730,1600. |
9 | (DMSO):7.20(d,2H);7.20(dd,1H);6.70(d,2H);6.65(d,1H);6.51(d,1H);6.44(s,1H);4.55(ddq,1H);3.50(dd,1H);3.40(dd,1H);3.30(q br,4H);2.60(s,6H);1.01(d,3H);1.06(t,3H). | 369(M+.);311;211;58EI;源ee 200C;70V;200uA | 3200,1600,1450(游离碱). |
10 | (DMSO):11.00(s br,4H);9.45(s br,1H);7.25(d,2H);7.15(dd,1H);6.85(d,2H);6.60(d,1H);6.55(d,1H);6.50(s,1H);3.95(t,2H);3.40-3.00(m,10H);2.60(ABq,4H);1.85(m,4H);1.12(t,6H). | 381(M+.);297;84EI;源 200C;70V;200uA | 2980,1730,1600. |
11 | (DMSO):7.30(dd,1H);7.255(d,2H);6.90(d,2H);6.71(m,3H);4.03(t,2H);3.75(s,3H);3.40-3.10(m,10H);1.88(m,4H);1.10(t,6H). | 395(M+.);311;211;84EI;源 200C;70V;200uA | 2975,1730,1620. |
表5续
实施例 | NMR | MS | IR cm-1(KBr) |
12 | (DMSO):11.00(s br,4H);7.28(dd,1H);7.24(d,2H);7.90(d,2H);6.70(d,1H );6.70(d,1H);6.68(s,1H);3 93(t,2H);3.74(s,3H);3.34(d br,4H);2.91(t,2H);2.59(ABq,4H);2.52(s,6H);1.10(t,6H). | 369(M+.);311;211;58EI;源 200C;70V;200uA | 2980,1620,1600(游离碱). |
13 | (DMSO):11.00(s br,4H);9.34(s br,1H);7.62(d,2H);7.58(d,2H)7.42(dd,2H);7.30(dd,1H);7.14(dd,1H);6.71(d,2H);6.52(dd,1H);6.45(dd,1H);6.36(dd,1H);4,47(ddq,1H);2.80(m,1H);2.60(ABq,4H);2.55(s,6H);2.50(m,1H);1.12(d,3H). | 346(M+.);288;58EI;源 200C;70V;200uA | 3400,1720,1600. |
14 | (DMSO);11.00(s br,4H);9.35(s br,1H);7.62(d,2H);7.59(d,2H);7.43(dd,2H);7.30(dd,1H);7.14(dd,1H);7.07(d,2H);6.55(dd,1H);6.49(d,1H);6.48(d,1H);4.01(dd,1H);3.75(dd,1H);3.33(m,1H);2.60(s,6H);2.58(ABq,4H);1.19(d,3H) | 346(M+.);275;274;72EI;源 200C;70V;200uA | 3400,1720,1600. |
15 | (DMSO):11.00(s br,4H);7.66(d,2H);7.60(d,2H);7.43(dd,2H);7.31(dd,1H);7.25(dd,1H);6.94(d,2H);6.67(dd,1H);6.53(d,1H);6.51(s,1H);4.52(ddq,1H);3.70(s,3H);2.78(m,1H);2.60(ABq,4H);2.52(m,1H);2.51(s,6H);1.15(d,3H). | 360(M+.);302;58EI;源 200C;70V;200uA | 2985,1600,1490(游离碱). |
16 | (DMSO):11.00(s br,4H);7.63(d,2H);7.60(d,2H);7.43(dd,2H);7.31(dd,1H);7.24(dd,1H);7.09(d,2H);6.68-6.61(m,3H);4.02(dd,1H);3.79(dd,1H);3.72(s,3H);3.31(m,1H);2.59(s,6H);2.58(ABq,4H);1.18(d,3H). | 360(M+.);289;288;72EI;源 200C;70V;200uA | 2985,1600,1490(游离碱). |
17 | (DMSO,353K):7.42-7.31(m,5H);7.00-6.92(m,3H);3.80(s,3H);3.40-3.30(m,6H);2.68(ABq,4H);2.42(s,6H);1.10(t,6H). | 383(M+.);355;325;225;58EI;源 200C;70V;200uA | 1730,1690,1600. |
18 | (DMSO):1.100(s br,4H);7.40(d,2H);7.35(dd,1H);6.86(dd,1H);6.71-6.63(m,4H);4.51(m,1H);3.74(s,3H);3.43(m,4H);2.73(m,1H);2.62(ABq,4H);2.55(m,1H);2.50(s,3H);1.80(m,4H);1.11(d,3H). | 381(M+.);323;58EI;源 200C;70V;200uA | 2960,1600,1400(游离碱). |
19 | (DMSO):11.00(s br,4H);7.42(d,2H);7.31(dd,1H);6.89(d,2H);6.76(m,3H);4.01(dd,1H);3.81(dd,1H);3.74(s,3H);3.43(m,4H);3.38-3.22(m,1H);2.61(ABq,4H);2.60(s,6H);2.80(m,4H);1.15(d,3H). | 381(M+.);310;309;72EI;源 200C;70V;200uA | 2960,1600,1400(游离碱). |
20 | (DMSO):10.80(s br,4H);9.50(s br,1H);7.39(d,2H);7.23(dd,1H);6.69(dd,1H);6.68(d,2H);6.55(dd,1H);6.49(d,1H);4.50(ddq,1H);3.40(m,4H);2.75(m,1H);2.60(ABq,4H);2.55(m,1H);1.83(m,4H);1.10(d,3H). | 367(M+.);309;58EI;源 200C;70V;200uA | 2960,1600,1430(游离碱). |
21 | (CDCl3):7.33(d,2H);7.04(dd,1H);6.81(d,2H);6.66(dd,1H);6.54(dd,1H);6.44(dd,1H);4.20(dd,1H);3.65(dd,1H);3.55-3.35(m,5H);2.72(ABq,4H);1.90-1.75(m,4H);1.25(d,3H). | 367(M+.);296;295;72EI;源 200C;70V;200uA | 2960,1600,1440(游离碱). |
22 | (DMSO);10.80(s br,4H);9.40(s br,1H);7.30(dd,1H);7.14(dd,1H);6.92(dd,1H);6.85(d,1H);6.65(s br,1H);6.55(dd,1H);6.44(dd,1H);6.34(d,1H);4.46(ddq,1H);3.40-3.10(m,4H);2.75(dd,1H);2.61(ABq,4H);2.60(dd,1H);1.10(d,3H);1.00(m,6H). | 369(M+.);311;58EI;源 200C;70V;200uA | 3420,1730,1590. |
表5续
实施例 | NMR | MS | IR cm-1(KBr) |
23 | (DMSO);10.90(s br,4H);9.40(s br,1H);7.33(dd,1H);7.13(dd,1H);7.06(dd,1H);6.88(d,1H);6.81(s,1H);6.54(dd,1H);6.50(d,1H);6.45(s br,1H);3.99(dd,1H);3.74(dd,1H);3.40-3.10(m,5H);2.61(s,6H);2.60(ABq,4H);1.18(d,3H);1.15-0.90(m,6H). | 369(M+.);298;72EI;源 200C;70V;200uA | 3420,1730,1590. |
24 | (DMSO):10.85(s br,4H);9.42(s br,1H);7.20(dd,1H);7.14(d,2H);6.71(d,2H);6.64(dd,1H);6.50(dd,1H);6.44(dd,1H);4.46(ddq,1H);3.70(m,2H);2.73(dd,1H);2.61(ABq,4H);2.51(dd,1H);2.51(s,6H);1.26(d,12H);1.13(d,3H). | 397(M+.);339;297;211;58EI;源ee 200C;70V;200uA | 2960,1735,1595. |
25 | (DMSO):10.95(s br,4H);9.45(s br,1H):7.17(d,2H);7.16(dd,1H);6.90(d,2H);6.60(dd,1H);6.55(d,1H);6.53(s br,1H);3.96(dd,1H);3.80-3.65(m,3H);3.35-3.20(m,2H);2.59(ABq,4H);2.57(s,6H);1.27(d,12H);1.15(d,3H). | 397(M+.);325;197;72EI;源 200C;70V;200uA | 2960,1735,1595. |
26 | (DMSO):10.90(s hr,4H);9.40(s br,1H);7.32(dd,1H);7.16(dd,1H);6.93(dd.1H);6.87(d,1H);6.67(s br,1H);6.55(dd,1H);6.44(dd,1H);6.36(dd,1H);4.48(ddq,1H);3.50-2.80(m,10H);2.60(ABq,4H);1.85(m,4H);1.15(d,3H);1.05(m,6H). | 395(M+.);311;84EI;源 200C;70V;200UA | 2970,1595,1450(游离碱). |
27 | (DMSO):11.00(s br,4H);9.40(s br,1H);7.33(dd,1H);7.14(dd,1H);7.06(dd,1H);6.88(d,1H);6.83(s br,1H);6.54(d,1H);6.48(d,1H);6.46(s br,1H);4.09(dd,1H);3.76(dd,1H);3.50-3.00(m,9H);2.60(ABq,4H);1.85(m,4H);1.22(d,3H);1.00(m,6H). | 395(M+);298;297;98EI;源 200C;70V;200uA | 2970,1595,1450(游离碱). |
28 | (DMSO):10.08(s br,1H);9.55(s br,1H);7.23(d,2H);7.22(dd,1H);6.85(d,2H);6.66(dd,1H);6.60(dd,1H);6.54(dd,1H);4.55(dddd,1H);3.70-3.40(m,6H);3.40-3.25(m,4H);2.10-1.90(m,4H);1.75-1.50(m,2H);1.10(t,6H);0.99(t,3H). | 409(M+.);325;84EI;源 200C;70V;200uA | 3410,2970,1600. |
29 | (DMSO):10.40(s br,1H);9.52(s br,1H);7.26(d,2H);7.19(dd,1H);6.95(d,2H);6.64(dd,1H);6.58(dd,1H);6.56(d,1H);4.13(dd,1H);3.99(dd,1H);3.68-3.56(m,1H);3.54-3.41(m,1H);3.40-3.25(m,5H);3.25-3.10(m,2H);2.05-1.70(m,6H);1.10(t,6H);0.91(t,3H). | 409(M+.);297;197;112EI;源 180C;70V;200uA | 3180,2970,1600. |
30 | (CDCl3):7.35(m,3H),6.75-6.55(m,5H);4.3(m,1H);3.8(s,3H);3.4(m,4H);2.5-2.4(m,1H);2.35(s,6H);2.1(m,1H);1.2(t,9H). | 383(M+.);325EI;源 200C;70V;200uA | 2970,1620,1595. |
31 | (CDCl3):7.30-7.20(m,3H),6.90(m,2H);6.70-6.55(m,3H);3.85(m,1H);3.8(s,3H);3.75-3.45(m,5H);2.95(m,1H);2.25(s,6H);1.2(t,6H);1.0(d,3H). | 383(M+.);312EI;源 200C;70V;200uA | 2970,1620,1595. |
32 | - | - | 2980,1635,1595. |
33 | - | - | 2980,1635,1595. |
34 | - | - | 2990,1630,1600. |
35 | - | - | 2990,1630,1600. |
36 | - | - | 2960,1630,1580. |
37 | - | - | 2960,1630,1580. |
表5续
实施例 | NMR | MS | IR cm-1(KBr) |
38 | (DMSO):10.2(s br,1H);7.40-7.20(m,3H);6.90-6.70(m,5H);4.55(dddd,1H);3.85(s,3H);3.80-3.30(m,9H);2.10-1.60(m,7H);1.10(t,6H);0.95(t,3H). | 423(M+.);339;84.EI;源 200C;70V;200uA | 2980,1600,1490. |
39 | (DMSO):10.70(s br,1H);7.27(m,3H);7.05(m,2H);6.7(m,3H);4.50-4.00(m,6H);3.85(s,3H);3.80-3.30(m,9H);2.00-1.70(m,2H);1.10(t,6H);0.91(t,3H) | 423(M+.);311;211;112.EI;源 200C;70V;200uA | 2980,1600,1490. |
40 | (DMSO):10.20(s br,1H);9.50(s,1H);7.24(d,2H);7.22(dd,1H);6.80(m,2H);6.69(d,1H);6.56(dd,1H);6.49(d,1H);6.04-5.86(m,1H);5.47(m,2H);4.80-4.68(m,1H);3.90-3.70(m,2H);3.31(q br,4H);3.25-3.01(m,2H);2.82(s br,3H);1.23(d,3H);1.12(t,6H). | 395(M+.);311,211,84EI;TSQ 700;sorgente 180C;70V;200uA | 3410,2970,1600. |
41 | (DMSO):10.22 and 10.10(s br,1H);9.50(s br,1H);7.25(d,2H);7.19(dd,1H);6.99-6.92(m,2H);6.64(d,1H);6.58(d,1H);6.55(s,1H);5.98-5.82(m,1H);5.55-5.38(m,2H);4.20(dd,1H);4.00-3.77(m,2H);3.75-3.63(m,1H);3.60-3.50(m,1H);3.32(q br,4H);2.73 and 2.70(d,3H);1.35 and 1.27(d,3H);1.10(t,3H). | 395(M+.);298;297,197,98EI;TSQ 700;sorgente 180C;70V;200uA | 3180,2970,1600. |
42 | (DMSO-353K):10.05(s br,1H);9.72(s br,1H);7.44(ABq,1H);7.41(ABq,1H);7.28(dd,1H);6.90(d br,1H);6.87-6.83(m,2H);4.05(s,2H);3.35(q,4H);2.87(s,6H);1.11(t,3H). | 370(MH+)Cl;gas reagente isobutano;P4000mTorr;sorgente 150C; | 3400,1680,1605. |
43 | (CDCl3):7.49(d,2H);7.11(s br,1H);7.07(dd,1H);7.02(d,2H);6.36(d,1H);6.29(d,1H);6.28(s,1H);4.30-4.20(m,1H);3.72(s,3H);2.61-2.46(m,6H);2.35(dd,1H);1.75(m,4H);1.23(d,6H);1.19(d,3H). | 395(M+.);312;311;84EI;TSQ 700;sorgente 180C;70V;200uA | 3280,2960,1660. |
44 | (DMSO):9.85(s,1H);9.05(s br,1H);7.64(d,2H);7.00(d,2H);6.95(dd,1H);6.18(m,2H);6.02(dd,1H);4.38(dt,1H);3.15-2.80(m,6H);2.62(ABq,1H);2.59(m,1H);2.54(ABq,1H);1.86(m,4H);1.12(d,3H);1.11(d,6H). | 381(M+);297;84EI;SQ 700;sorgente 180C;70V;200uA | 3300,2960,1670. |
45 | (CDCl3+TFA):9.10(s br,1H);7.30(dd,1H);7.26(dd,2H);6.90(d,1H);6.80(d,2H);6.78(s,1H);6.62(d,1H);4.68(m,1H);3.71-3.45(m br,4H);3.33(m,1H);3.10(m,1H);3.00(d,6H);1.32(m,9H) | 369(M+);3HEI;TSQ 700;sorgente 180C;70V;200uA | |
46 | (CDCl3+TFA):9.10(s br,1H);7.30(dd,1H);7.26(dd,2H);6.90(d,1H);6.80(d,2H);6.78(s,1H);6.62(d,1H);4.68(m,1H);3.71-3.45(m br,4H);3.33(m,1H);3.10(m,1H);3.00(d,6H);1.32(m,9H). | 369(M+);311EI;TSQ 700;sorgente 180C;70V;200uA | |
47 | (DMSO):10.05(s br,1H):9.51(s br,1H);7.70-7.13(m,5H);7.05-6.70(m,3H);3.95(s,2H);3.49-3.14(m,8H);1.20(t,6H);1.10(s br,6H). | 398(MH+);86Cl;gas reagente isobutano;P4000mTorr;sorgente 150C; | 3400,1680,1600. |
48 | (DMSO):10.19(s br,1H);10.01(s br,1H);7.60-7.20(m,5H);7.00-6.70(m,3H);4.11(s,1H);3.60-3.00(m,8H);1.90(m,4H);1.10(m,6H). | 396(MH+);84Cl;gas reagente isobutano;P4000 mTorr;sorgente 150C; | 3450,1675,1605. |
49 | (CDCl3):7.27(s,4H);7.15(dd,1H);6.73(m,2H);6.66(d,1H);3.75(m br,2H);3.10(s,3H);2.32(s,6H);1.35(m br,12H); | 397(M+);369;58EI;TSQ 700;sorgente 180C;70V;200uA | 3400,1680,1600. |
表5续
50 | (CDCl3-作为基准):7.36(d,2H);7.28(d,2H);7.20(dd,1H);6.77(d,1H);6.72(m,2H);5.86-5.73(m,1H);5.21-5.12(m,2H);3.61-3.45(m br,2H);3.45-3.26(mbr,2H);3.20(s,2H);3.15(d,2H);2.37(s,3H);1.20(m br,6H). | 395(M+);325;84;41EI;TSQ 700;sorgente 180C;70V;200uA | 3400,1675,1600. |
51 | (CDCl3):7.40(m,4H);7.30(dd,1H);6.84(d,1H);6.73(d,1H);6.72(s,1H);3.70-3.10(m,6H);3.40(s,2H);2.51(s,3H);1.30(s br,6H) | 355(M+);284;212EI;TSQ 700;sorgente 180C;70V;200uA | 3450,1680,1610. |
52 | (CDCl3+TFA):7.48(s br,5H);7.35(m,5H);7.00(d,1H);6.88(d,1H);6.80(s,1H);3.91(s br,2H);3.75(m,2H);1.55(d,3H);1.22(d,3H) | 369(M+);312;269;212EI;TSQ 700;sorgente 180C;70V;200uA | 3400,1675,1600. |
53 | - | - | 2990,1630,1600. |
54 | - | - | 2980,1630,1590. |
55 | - | - | 2990,1680,1590. |
56 | - | - | 2990,1675,1600. |
57 | - | - | 2980,1675,1600. |
58 | - | - | 2990,1680,1600. |
59 | - | - | 2990,1675,1595. |
60 | - | - | 3000,1680,1600. |
61 | - | - | 3370,2960,1610 |
Claims (12)
1.式(I)化合物,或其溶剂化物或盐:
其中:
R1和R2可以相同或不同,并且各自为氢,直链或支链C1-6烷基,C3-7环烷基,C3-7环烯基,C4-6环烷基烷基,C3-6链烯基,C3-5炔基,芳基,芳烷基或呋喃-2或3-基烷基,或者R1和R2一同形成可被氧间断的C3-7烷基环;
R3和R4可以相同或不同,并且各自为氢,直链或支链C1-6烷基,或者R4为氧,它与其所连接的碳原子形成C=O基团;
R5为氢,羟基,C1-3烷氧基,巯基,烷硫基;
R6为苯基,卤素,NH2或位于对位或间位的-C(Z)-R8基团,其中Z为氧或硫;R8为C1-8烷基,C1-8烷氧基或NR9R10,其中R9和R10可以相同或不同,并且为氢,直链或支链C1-6烷基,C3-7环烷基,C4-6环烷基烷基,C3-6链烯基,芳基,芳烷基,或者R6为位于对位或间位的基团
其中R11和R12可以相同或不同,并且为氢,直链或支链C1-6烷基,C3-7环烷基,C4-6环烷基烷基,C3-6链烯基,芳基,芳烷基或任意取代的杂环,且Z的定义同上;和
R7为氢,直链或支链C1-8烷基,或卤素。
2.根据权利要求1的化合物,其中R1和R2各自为甲基,乙基,环丙基甲基,烯丙基,或者它们与N原子一起形成吡咯烷子基。
3.根据权利要求1或2的化合物,其中R3和R4各自为氢,甲基,乙基,异丙基或氧代。
4.根据权利要求1至3中任一权项的化合物,其中R5为氢,羟基或甲氧基。
5.根据权利要求1至4中任一权项的化合物,其中R6为COMe,CO-i-Pr,COOEt,CONH2,CONH-n-Pr,CON(Me)Et,CON(Me)i-Pr,CONEt2,CON(i-Pr)2,CONEt(i-Pr),CON(-CH2-)4,NHCOi-Pr,NH2,溴或苯基。
6.根据权利要求1至5中任一权项的化合物,其中R7为氢或甲基。
7.选自下面的化合物:
(-)-3-[N-(3-吡咯烷子基丙-2-基)苯基氨基]-N-丙基苯甲酰胺;
(±)-N-(4-溴苯基)-N-(3-羟基苯基)-α-甲基-1-吡咯烷子基乙胺;
(±)-N-(4-溴苯基)-N-(3-甲氧基苯基)-α-甲基-1-吡咯烷子基乙胺;
(±)-N,N-二乙基-4-[[N-(3-甲氧基苯基)-N-(3-吡咯烷子基丙-2-基)]氨基]苯甲酰胺;
(±)-N,N-二乙基-4-[[N-(3-羟基苯基)-N-(3-吡咯烷子基丙-2-基)]氨基]苯甲酰胺;
N-(4-溴苯基)-N-(3-羟基苯基)-1-吡咯烷子基乙胺;
N,N-二乙基-4-[[N-(2-二甲氨基乙基)-N-(3-羟基苯基)]氨基]苯甲酰胺;
(±)-N,N-二乙基-4-[[N-(2-二甲氨基丙-1-基)-N-(3-羟基苯基)]氨基]苯甲酰胺;
(±)-N,N-二乙基-4-[[N-(3-二甲氨基丙-2-基)-N-(3-羟基苯基)]氨基]苯甲酰胺;
N,N-二乙基-4-[[N-(3-羟基苯基)-N-(2-吡咯烷子基乙基)]氨基]苯甲酰胺;
N,N-二乙基-4-[[N-(3-甲氧基苯基)-N-(2-吡咯烷子基乙基)]氨基]苯甲酰胺;
N,N-二乙基-4-[[N-(2-二甲氨基乙基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺;
(±)-N2-(4-联苯基)-N1,N1-二甲基-N2-(3-羟基苯基)-1,2-丙二胺;
(±)-N1-(4-联苯基)-N2,N2-二甲基-N1-(3-羟基苯基)-1,2-丙二胺;
(±)-N2-(4-联苯基)-N1,N1-二甲基-N2-(3-甲氧基苯基)-1,2-丙二胺;
(±)-N1-(4-联苯基)-N2,N2-二甲基-N1-(3-甲氧基苯基)-1,2-丙二胺;
N,N-二乙基-4-[[N-(二甲氨基乙酰基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺;
(±)-1-[4-[[N-(3-二甲氨基丙-2-基)-N-(3-甲氧基苯基)氨基]苯甲酰基]吡咯烷;
(±)-1-[4-[[N-(2-二甲氨基丙-1-基)-N-(3-甲氧基苯基)氨基]苯甲酰基]吡咯烷;
(±)-1-[4-[[N-(3-二甲氨基丙-2-基)-N-(3-羟基苯基)氨基]苯甲酰基]吡咯烷;
(±)-1-[4-[[N-(2-二甲氨基丙-1-基)-N-(3-羟基苯基)氨基]苯甲酰基]吡咯烷;
(±)-N,N-二乙基-3-[[N-(3-二甲氨基丙-2-基)-N-(3-羟基苯基)]氨基]苯甲酰胺;
(±)-N,N-二乙基-3-[[N-(2-二甲氨基丙-1-基)-N-(3-羟基苯基)]氨基]苯甲酰胺;
(±)-N,N-二异丙基-4-[[N-(3-二甲氨基丙-2-基)-N-(3-羟基苯基)]氨基]苯甲酰胺;
(±)-N,N-二异丙基-4-[[N-(2-二甲氨基丙-1-基)-N-(3-羟基苯基)]氨基]苯甲酰胺;
(±)-N,N-二乙基-3-[[N-(3-羟基苯基)]-N-(3-吡咯烷子基丙-2-基)]氨基]苯甲酰胺;
(±)-N,N-二乙基-3-[[N-(3-羟基苯基)]-N-(2-吡咯烷子基丙-1-基)]氨基]苯甲酰胺;
(±)-N,N-二乙基-4-[[N-(3-羟基苯基)]-N-(1-吡咯烷基-2-丁基)]氨基]苯甲酰胺;
(±)-N,N-二乙基-4-[[N-(3-羟基苯基)]-N-(2-吡咯烷基-1-丁基)]氨基]苯甲酰胺;
(±)-N,N-二乙基-4-[[N-(2-二甲氨基丙-1-基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺;
(±)-N,N-二乙基-4-[[N-(3-二甲氨基丙-2-基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺;
(±)-N,N-二乙基-3-[[N-(3-二甲氨基丙-2-基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺;
(±)-N,N-二乙基-3-[[N-(2-二甲氨基丙-1-基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺;
(±)-N,N-二异丙基-4-[[N-(3-二甲氨基丙-2-基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺;
(±)-N,N--二异丙基-4-[[N-(2-二甲氨基丙-1-基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺;
(±)-N,N-二乙基-3-[[N-(3-甲氧基苯基)-N-(3-吡咯烷子基丙-2-基)]氨基]苯甲酰胺;
(±)-N,N-二乙基-3-[[N-(3-甲氧基苯基)-N-(2-吡咯烷子基丙-1-基)]氨基]苯甲酰胺;
(±)-N,N-二乙基-4-[[N-(3-甲氧基苯基)-N-(1-吡咯烷基-2-丁基)]氨基]苯甲酰胺;
(±)-N,N-二乙基-4-[[N-(3-甲氧基苯基)-N-(2-吡咯烷基-1-丁基)]氨基]苯甲酰胺;
(±)-4-[N-[1-(N-烯丙基-N-甲基)氨基-2-丙基]-N-(3-羟基苯基)氨基]-N,N-二乙基苯甲酰胺;
(±)-4-[N-[2-(N-烯丙基-N-甲基)氨基-1-丙基]-N-(3-羟基苯基)氨基]-N,N-二乙基苯甲酰胺;
N,N-二乙基-4-[[N-(二甲氨基乙酰基)-N-(3-羟基苯基)]氨基]苯甲酰胺;
(±)-N-[[4-[N-(3-甲氧基苯基)-N-[1-甲基-2-(1-吡咯烷基)乙基]]氨基]苯基]-2-甲基丙酰胺;
(±)-N-[[4-[N-(3-羟基苯基)-N-[1-甲基-2-(1-吡咯烷基)乙基]]氨基]苯基]-2-甲基丙酰胺;
(-)-N,N-二乙基-4-[[N-(3-二甲氨基丙-2-基)-N-(3-羟基苯基)]氨基]苯甲酰胺;
(+)-N,N-二乙基-4-[[N-(3-二甲氨基丙-2-基)-N-(3-羟基苯基)]氨基]苯甲酰胺;
N,N-二乙基-4-[[N-(二乙氨基乙酰基)-N-(3-羟基苯基)]氨基]苯甲酰胺;
N,N-二乙基-4-[[N-(3-羟基苯基)-N-(吡咯烷-1-基乙酰基)]氨基]苯甲酰胺;
N,N-二异丙基-4-[[N-(二甲氨基乙酰基)-N-(3-羟基苯基)]氨基]苯甲酰胺;
4-[[N-[[(N-烯丙基-N-甲基)氨基]乙酰基]-N-(3-羟基苯基)氨基]-N,N-二乙基苯甲酰胺;
N,N-二乙基-4-[[N-(3-羟基苯基)-N-(甲氨基乙酰基)]氨基]苯甲酰胺;
N,N-二异丙基-4-[[N-氨基乙酰基-N-(3-羟基苯基)]氨基]苯甲酰胺;
(±)-4-[N-[1-(N-烯丙基-N-甲基)氨基-2-丙基]-N-(3-甲氧基苯基)氨基]-N,N-二乙基苯甲酰胺;
(±)-4-[N-[2-(N-烯丙基-N-甲基)氨基-1-丙基]-N-(3-甲氧基苯基)氨基]-N,N-二乙基苯甲酰胺;
N,N-二乙基-4-[[N-(二乙氨基乙酰基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺;
N,N-二乙基-4-[[N-(3-甲氧基苯基)-N-(吡咯烷-1-基乙酰基)]氨基]苯甲酰胺;
N,N-二异丙基-4-[[N-(二甲氨基乙酰基)-N-(3-甲氧基苯基)]氨基]苯甲酰胺;
4-[[N-[[(N-烯丙基-N-甲基)氨基]乙酰基]-N-(3-甲氧基苯基)氨基]-N,N-二乙基苯甲酰胺;
N,N-二乙基-4-[[N-(3-甲氧基苯基)-N-(甲氨基乙酰基)]氨基]苯甲酰胺;
N,N-二异丙基-4-[[N-氨基乙酰基-N-(3-甲氧基苯基)]氨基]苯甲酰胺;
(±)-N-(4-氨基苯基)-N-(3-甲氧基苯基)-α-甲基-1-吡咯烷子基乙胺。
8.一种药物组合物,包括权利要求1至7中任一权项的化合物和可药用载体。
9.权利要求1至7中任一权项的化合物,其用作活性治疗物质。
10.根据权利要求1至7中任一权项的化合物,其用作止痛药,防止器官和皮肤移植排斥的免疫抑制剂,抗过敏和消炎剂,脑细胞保护剂,用于治疗药物滥用和酗酒,以减少胃分泌,用于治疗腹泻,心血管和呼吸疾病,咳嗽和呼吸受阻,精神病,癫痫发作以及其它神经失调症。
11.权利要求1至7中任一权项的化合物在制备具有下述用途的药物方面的应用:用作止痛药,防止器官和皮肤移植排斥的免疫抑制剂,抗过敏和消炎剂,脑细胞保护剂,用于治疗药物滥用和酗酒,以减少胃分泌,用于治疗腹泻,心血管和呼吸疾病,咳嗽和呼吸受阻,精神病,癫痫发作以及其它神经失调症。
12.治疗和/或预防哺乳动物,特别是人所患的权利要求11中所述病症的治疗方法,包括对需要这种治疗和/或预防的哺乳动物施用有效量权利要求1至7中任一权项的化合物。
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US7164021B2 (en) * | 2002-09-18 | 2007-01-16 | The Curators Of The University Of Missouri | Opiate analogs selective for the δ-opioid receptor |
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CA2578205A1 (en) * | 2004-08-25 | 2006-03-30 | The Regents Of The University Of Michigan | Partially acetylated dendrimers and related methods of use |
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US20090088376A1 (en) * | 2007-04-19 | 2009-04-02 | The Regents Of The University Of Michigan | Dendrimer based compositions and methods of using the same |
US8252834B2 (en) | 2008-03-12 | 2012-08-28 | The Regents Of The University Of Michigan | Dendrimer conjugates |
WO2010039861A2 (en) | 2008-09-30 | 2010-04-08 | The Regents Of The University Of Michigan | Dendrimer conjugates |
US9017644B2 (en) | 2008-11-07 | 2015-04-28 | The Regents Of The University Of Michigan | Methods of treating autoimmune disorders and/or inflammatory disorders |
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CH298886A (de) * | 1951-06-15 | 1954-05-31 | Ag Sandoz | Verfahren zur Herstellung eines grünen substantiven Farbstoffes der Anthrachinonreihe. |
US2739981A (en) * | 1952-08-26 | 1956-03-27 | American Home Prod | Diamines and salts thereof |
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US3042045A (en) * | 1958-07-02 | 1962-07-03 | David S Sheridan | Medico-surgical tubes having integral connectors formed in their ends |
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US4217452A (en) * | 1974-02-09 | 1980-08-12 | Akzona Incorporated | Synthesis for the preparation of tetracyclic compounds |
FR2376123A1 (fr) * | 1977-01-04 | 1978-07-28 | Esteve Intercional Sa Prod | Nouveaux derives de 4-tert.butyl-3'-chlorodiphenylamine a activite anti-histaminique, et leur procede de preparation |
FR2646847B1 (fr) * | 1989-05-12 | 1991-07-12 | Rhone Poulenc Sante | N-phenyl amides, leurs procedes de preparation et les medicaments les contenant |
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GB9202238D0 (en) * | 1992-02-03 | 1992-03-18 | Wellcome Found | Compounds |
-
1995
- 1995-05-19 IT ITMI951020A patent/IT1275433B/it active IP Right Grant
-
1996
- 1996-05-17 ZA ZA963939A patent/ZA963939B/xx unknown
- 1996-05-20 EP EP96916128A patent/EP0825991B1/en not_active Expired - Lifetime
- 1996-05-20 CN CN96195364A patent/CN1190393A/zh active Pending
- 1996-05-20 US US08/952,443 patent/US5922887A/en not_active Expired - Fee Related
- 1996-05-20 AU AU58998/96A patent/AU5899896A/en not_active Abandoned
- 1996-05-20 BR BR9608458A patent/BR9608458A/pt not_active Application Discontinuation
- 1996-05-20 JP JP53457496A patent/JP3205343B2/ja not_active Expired - Fee Related
- 1996-05-20 TR TR97/01388T patent/TR199701388T1/xx unknown
- 1996-05-20 PL PL96323385A patent/PL323385A1/xx unknown
- 1996-05-20 HU HU9802222A patent/HUP9802222A3/hu unknown
- 1996-05-20 WO PCT/EP1996/002152 patent/WO1996036620A1/en not_active Application Discontinuation
- 1996-05-20 DE DE69619512T patent/DE69619512T2/de not_active Expired - Fee Related
- 1996-05-20 ES ES96916128T patent/ES2171675T3/es not_active Expired - Lifetime
- 1996-05-20 KR KR1019970708252A patent/KR19990014907A/ko not_active Application Discontinuation
- 1996-05-20 CA CA002221380A patent/CA2221380A1/en not_active Abandoned
- 1996-05-20 AT AT96916128T patent/ATE213735T1/de not_active IP Right Cessation
- 1996-05-20 CZ CZ973652A patent/CZ365297A3/cs unknown
-
1997
- 1997-11-18 NO NO975294A patent/NO975294L/no unknown
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Publication number | Publication date |
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ITMI951020A1 (it) | 1996-11-19 |
PL323385A1 (en) | 1998-03-30 |
NO975294D0 (no) | 1997-11-18 |
KR19990014907A (ko) | 1999-02-25 |
ES2171675T3 (es) | 2002-09-16 |
AU5899896A (en) | 1996-11-29 |
BR9608458A (pt) | 1999-01-05 |
CA2221380A1 (en) | 1996-11-21 |
DE69619512T2 (de) | 2002-10-31 |
US5922887A (en) | 1999-07-13 |
ITMI951020A0 (it) | 1995-05-19 |
EP0825991B1 (en) | 2002-02-27 |
NO975294L (no) | 1997-11-18 |
JP3205343B2 (ja) | 2001-09-04 |
HUP9802222A2 (hu) | 1999-07-28 |
ATE213735T1 (de) | 2002-03-15 |
JPH11505237A (ja) | 1999-05-18 |
HUP9802222A3 (en) | 1999-09-28 |
IT1275433B (it) | 1997-08-07 |
DE69619512D1 (de) | 2002-04-04 |
CZ365297A3 (cs) | 1998-06-17 |
TR199701388T1 (xx) | 1998-03-21 |
WO1996036620A1 (en) | 1996-11-21 |
MX9708973A (es) | 1998-03-31 |
EP0825991A1 (en) | 1998-03-04 |
ZA963939B (en) | 1997-01-21 |
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