CN1541203A - 4-(苯基-(哌啶-4基)-氨基)-苯甲酰胺衍生物及其在治疗疼痛、焦虑症或胃肠病中的应用 - Google Patents
4-(苯基-(哌啶-4基)-氨基)-苯甲酰胺衍生物及其在治疗疼痛、焦虑症或胃肠病中的应用 Download PDFInfo
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- CN1541203A CN1541203A CNA028141733A CN02814173A CN1541203A CN 1541203 A CN1541203 A CN 1541203A CN A028141733 A CNA028141733 A CN A028141733A CN 02814173 A CN02814173 A CN 02814173A CN 1541203 A CN1541203 A CN 1541203A
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- compound
- phenyl
- piperidin
- benzyl
- amino
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- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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Abstract
本申请公开并要求保护通式(I)化合物[此处应插入化学式,参见文件副本],R1选自苯基、吡啶基、噻吩基、呋喃基、咪唑基、吡咯基、三唑基、噻唑基和吡啶-N-氧化物中任何一个基团;其中各R1苯环和R1杂芳族环可任选并独立被选自以下的1、2或3个取代基进一步取代:直链和支链C1-C6烷基、NO2、CF3、C1-C6烷氧基、氯、氟、溴和碘。苯环和杂芳族环上的取代可发生在所述环系的任何位置;本申请还公开并要求保护所述化合物的盐、包含所述新化合物的药用组合物及其在治疗尤其在治疗疼痛、焦虑症或功能性胃肠病方面的用途。
Description
发明领域
本发明涉及新化合物、其制备方法、用途以及包含新化合物的药用组合物。此新化合物用于治疗目的,尤其用于治疗疼痛、焦虑症和功能性胃肠病。
发明背景
δ受体被确认在许多身体机能如循环系统和疼痛系统中起作用。因而δ受体配体可能具有止痛药物和/或抗高血压药物的潜在用途。还证实δ受体配体有免疫调节活性。
目前充分鉴定了至少三种不同的阿片受体(μ、δ和κ),显然三种阿片受体存在于包括人类在内的许多物种的中枢系统和外周神经系统。当在各种动物模型中激活一种或多种上述受体时,可观察到痛觉缺失。
目前可应用的选择性阿片样物质δ配体本质上几乎无一例外地是肽,不适于经全身途径给药。一个非肽类δ激动剂的例子是SNC80(Bilsky E.J.等,Journal of Pharmacology and ExperimentalTherapeutics,273(1),pp.359-366(1995)。但是仍然需要选择性提高而副作用减少的选择性δ-激动剂。
因此,本发明要解决的问题是寻找与目前的μ激动剂相比,不仅止痛效果增强而且副作用减少以及提高全身性作用的新止痛药物。
已经鉴定和现有技术领域已有的止痛药物存在许多缺点,它们的药代动力学差,当全身途径给药时没有止痛作用。同时,有资料证明,现有技术中的优选δ激动剂化合物全身给药时表现出明显的惊厥作用。
现已发现某些化合物在多种特性上表现出惊人改善,即在δ-激动剂效力、体内效力、药代动力学、生物利用度、体外稳定性方面增强和/或毒性降低。
发明概述
本发明的新化合物用以下结构式I定义:
其中
R1选自以下任意一个基团:
(i)苯基;
(ii)吡啶基
(iii)噻吩基
(iv)呋喃基
(v)咪唑基
(vi)三唑基
(vii)吡咯基
(viii)噻唑基
(ix)吡啶基-N-氧化物
其中各R1苯环和R1杂芳族环可任选并独立地被选自以下的1、2或3个取代基进一步取代:直链和支链C1-C6烷基、NO2、CF3、C1-C6烷氧基、氯、氟、溴和碘。苯环和杂芳族环上的取代可发生在所述环系的任何位置。
当R1苯环和R1杂芳族环被取代时,优选的取代基选自CF3、甲基、碘、溴、氟和氯中任何一个基团。
本发明的另一个实施方案是这样的式I化合物,其中R1同上定义,各个R1苯环和R1杂芳族环可以独立被甲基进一步取代。
本发明的又一个实施方案是这样的式I化合物,其中R1为苯基、吡咯基、吡啶基、噻吩基或呋喃基,R1苯环或R1杂芳族环上任选含有1个或2个优选取代基。
本发明的再一个实施方案是这样的式I化合物,其中R1为苯基、吡咯基或吡啶基,R1苯环或R1杂芳族环上任选含有1个或2个优选取代基。
本发明的又一个实施方案是这样的式I化合物,其中R1为噻吩基或呋喃基,R1杂芳族环上任选含有1个或2个优选取代基。
式I化合物的盐和对映异构体,包括对映异构体的盐也属于本发明范围。
流程1的反应步骤
c(见下页)如下进行:用钯催化剂如三(二亚苄基丙酮)二钯(O)(Pd2(dba)3),在碱(例如叔丁醇钠)和膦配体(例如双-二苯基膦烷基-二甲基-9H-氧杂蒽(xantphos)存在下,使通式II中间体化合物
其中PG为氨基甲酸乙酯保护基团(例如Boc和CBZ),或为苄基或取代的苄基保护基团(例如2,4-二甲氧基苄基);与N,N-二异丙基-4-溴苯甲酰胺反应得到通式III化合物,
然后在标准条件下脱去保护,在碱性条件下水解,并用以下任意一组化合物烷基化得到通式I化合物(在腈官能团水解后):
i)通式为R1-CH2-X的化合物[其中R1同上定义,X为卤素,优选溴或氯]以及合适的碱,或者
ii)通式为R1-CHO的化合物[其中R1同上定义]以及合适的还原剂。
用于标准烷基化步骤i)的合适碱包括但不限于三乙胺和碳酸钾。
用于标准还原步骤ii)的合适还原剂包括但不限于氰基硼氢化钠和三乙酰氧基硼氢化钠。
流程1反应步骤
c也可按照流程3步骤
b(见下页)进行:用钯催化剂如Pd2(dba)3,在碱(例如叔丁醇钠)和膦配体(例如xantphos)存在下,使通式IV中间体化合物
其中PG为氨基甲酸乙酯保护基团(例如Boc和CBZ),或为苄基或取代的苄基保护基团(例如2,4-二甲氧基苄基);与3-溴苯甲腈反应得到以上通式III化合物。
本发明新化合物可用于治疗目的,尤其是用于治疗各种疼痛,例如慢性疼痛、神经性疼痛、急性疼痛、癌痛、类风湿性关节炎性疼痛、偏头痛、内脏痛等。但上列类型疼痛不应解释为对疼痛的完全列举。
本发明化合物可用作免疫调节剂,尤其可用于自身免疫疾病(如关节炎);皮肤移植、器官移植及类似的外科需要;胶原性疾病;各种变态反应;用作抗肿瘤药和抗病毒药。
本发明化合物可用于所述范例中存在或涉及阿片受体退变或功能障碍的疾病。包括在诊断技术和成像如正电子发射断层成像(PET)中应用同位素标记形式的本发明化合物。
本发明化合物可用于治疗腹泻、抑郁症、焦虑症和压力性疾病(例如创伤后压力症、恐慌症、广泛性焦虑症、社交恐惧症和强迫症)、尿失禁、各种精神疾病、咳嗽、肺水肿、各种胃肠病(例如便秘、功能性胃肠病如肠易激综合征和功能性消化不良)、帕金森氏病和其它运动障碍、创伤性脑损伤、中风、心肌梗塞后心脏保护、脊柱损伤和药物成瘾(包括酒精、尼古丁、阿片样物质和其它药物滥用)以及交感神经系统疾病如高血压。
本发明化合物可用作在全身麻醉和监控麻醉护理时使用的止痛药物。常常联合使用不同特性的药物,以达到维持麻醉状态(例如记忆缺失、痛觉缺失、肌肉松弛和镇静)所需的平衡作用。联合用药包括吸入麻醉剂、安眠药、抗焦虑药、神经肌肉阻滞剂和阿片样物质。
应用任何上式I化合物生产用于治疗上述任何疾病的药物也属于本发明的范围。
本发明再一方面是治疗患有任何上述疾病的患者的治疗方法,其中对需要这种治疗的患者给予有效量的上式I化合物。
本发明另一方面是通式II、III和IV的中间体,
其中PG为氨基甲酸乙酯保护基团如Boc和CBZ,或为苄基或取代的苄基保护基团如2,4-二甲氧基苄基。
本发明的再一方面是式X中间体,
其中R1同上式I中的定义。
在以下流程4描述的另一种合成途径中,以下流程1的步骤
b和
c,或流程3的步骤
a和
b用“一罐法”完成,其中不分离出通式II或IV中间体。采用此方案,最初的钯催化偶合反应按照流程1步骤
b(或流程3的步骤
a)的反应的相同方式进行。但是,反应完成后,并不分离出式II或IV中间体,而是加入第二种芳基溴和额外的碱(叔丁醇钠),使用步骤
c(流程1)或
b(流程3)中的温度条件,获得以上通式III的产物。
在另一种替代合成途径中,流程5中反应步骤
b(见下文)如下进行:用钯催化剂如三(二亚苄基丙酮)二钯(O)[Pd2(dba)3],在碱(例如叔丁醇钠)和膦配体(例如双-二苯基膦烷基-二甲基-9H-氧杂蒽(xantphos)存在下,使通式V中间体化合物
其中PG为氨基甲酸乙酯保护基团如Boc和CBZ,或为苄基或取代的苄基保护基团如2,4-二甲氧基苄基,与N,N-二异丙基-4-溴苯甲酰胺反应得到通式VI化合物,
然后脱去保护并通过上述方法烷基化(用通式R1-CHO化合物还原性烷基化,或者使用通式R1-CH2-X化合物直接烷基化),接着在标准条件下经由以下反应将酮缩醇官能团转化为伯酰胺:i)将酮缩醇水解为醛(VII),ii)接着将醛氧化为相应的羧酸(VIII),iii)然后用氯化铵将其酰胺化为伯酰胺得到通式I化合物。
可用于标准水解步骤(i)的合适水解条件包括但不限于含盐酸水溶液的四氢呋喃。
氧化步骤(ii)的合适条件包括但不限于:在过量2-甲基-2-丁烯存在下,在磷酸二氢钠水溶液和亚氯酸钠中于0℃下搅拌。
酰胺化步骤(iii)的合适条件包括但不限于:在偶合剂如苯并三唑-1-基氧基-三磷鎓六氟磷酸盐(下文称为Py-BOP)和1-羟基苯并三唑(HOBT)存在下,并在酸清除剂如二异丙基乙胺(DIPEA)存在下,用过量氯化铵处理。
制备方法
实施例
现在通过以下流程和实施例更详细地描述本发明,但不应理解为对本发明的限制。
流程1:合成中间体1(方法1)
中间体1:[(3-氰基-苯基)-哌啶-4-基-氨基]-N,N-二异丙基-苯甲酰胺(化
合物3)
i.N,N-二异丙基-4-溴苯甲酰胺
在0℃,向4-溴苯甲酰氯(10.0g)的无水二氯甲烷(60mL)溶液中缓慢加入二异丙基胺(19mL;3.0eq)。将反应物在氮气氛下搅拌过夜,逐步加温至室温。溶液用水洗涤两次,有机物用无水硫酸镁干燥,过滤,然后浓缩。残余物用快速色谱法提纯,用15%乙酸乙酯洗脱。获得接近定量产量的产物。
ii.4-(3-氰基-苯基氨基)-哌啶-1-甲酸叔丁酯(化合物1)
在装有4-氨基-哌啶-1-甲酸叔丁酯(5.0g;1.2eq)和3-溴苯甲腈(3.79g;1.0eq)的无水甲苯(80mL)溶液的干燥烧瓶中加入BINAP(390mg;0.03eq)、醋酸钯(94mg;0.02eq)和叔丁醇钠(2.8g;1.4eq)。将反应物加热至80℃,在氮气氛下搅拌24h。冷却溶液,用乙酸乙酯稀释,用水洗涤两次。有机物用无水硫酸镁干燥,过滤,然后浓缩。残余物用快速色谱法提纯,用100%己烷至含30%乙酸乙酯的己烷洗脱。获得无色油状物(5.12g;82%收率)。
iii.4-[(1-甲酸叔丁酯-哌啶-4-基)-(3-氰基-苯基)-氨基]-N,N-二异丙基-
苯甲酰胺(化合物2)
在装有胺(3.68g)的无水甲苯(60mL)溶液的干燥烧瓶中加入芳基溴(4.86g;1.4eq)、xantphos(424mg;0.06eq)、Pd2(dba)3(336mg;0.03eq)和叔丁醇钠(1.64g;1.4eq)。将反应物在氮气氛下加热至回流过夜。在20h后冷却反应物,用乙酸乙酯稀释,用水洗涤一次。有机物用无水硫酸镁干燥,过滤,然后浓缩。残余物用快速色谱法提纯,用100%己烷至含30%乙酸乙酯的己烷洗脱。获得黄色泡沫状产物(4.757g;77%收率)。
iv.[(3-氰基-苯基)-哌啶-4-基-氨基]-N,N-二异丙基-苯甲酰胺(化合物3)
化合物2(4.757g)的无水二氯甲烷(60mL)溶液中加入三氟乙酸(7.3mL;10.0eq),将反应物在室温、氮气氛下搅拌过夜。反应物用2N氢氧化钠洗涤一次,水溶液用二氯甲烷萃取一次。合并的有机物用无水硫酸镁干燥,过滤,然后浓缩。残余物用快速色谱法提纯,用含50%甲醇的二氯甲烷洗脱。获得无色泡沫状产物(3.01g;79%收率)。
流程2:合成中间体1(方法2)
i.3-(1-苄基-哌啶-4-基氨基)-苯甲腈(化合物4).
在装有无水甲苯(20mL)的干燥烧瓶中加入1-苄基-哌啶-4-基胺(1.60mL;1.0eq)、3-溴苯甲腈(1.43g;1.0eq)、BINAP(392mg;0.08eq)、Pd2(dba)3(288mg;0.04eq)和叔丁醇钠(1.06g;1.4eq)。将反应物在氮气氛下加热至80℃。在3.5h后冷却反应物,用乙酸乙酯稀释,用水洗涤,通过硅藻土过滤。分离出有机物,用无水硫酸镁干燥,过滤,然后浓缩。残余物用快速色谱法提纯,用含3%甲醇的二氯甲烷洗脱。获得橙色固体(2.193g;96%收率)。
ii.4-[(1-苄基-哌啶-4-基)-(3-氰基-苯基)-氨基]-N,N-二异丙基-苯甲酰胺
(化合物5)
在装有胺(1.383g)的无水甲苯(15mL)溶液的干燥烧瓶中加入芳基溴(1.89g;1.4eq)、xantphos(165mg;0.06eq)、Pd2(dba)3(131mg;0.03eq)和叔丁醇钠(639mg;1.4eq)。将反应物在氮气氛下加热至回流过夜。冷却溶液,用乙酸乙酯稀释,用水洗涤一次。分离出有机物,然后用无水硫酸镁干燥,过滤,浓缩。残余物用快速色谱法提纯,用含3%甲醇的二氯甲烷洗脱。获得橙色泡沫状产物(1.889g;80%收率)。
iii.[(3-氰基-苯基)-哌啶-4-基-氨基]-N,N-二异丙基-苯甲酰胺(化合物
3)
在0℃,向N-苄基(3.429g)的无水二氯乙烷(60mL)溶液中加入氯甲酸1-氯乙酯(860μl;1.15eq)。将反应物在0℃搅拌15min,加温至室温,然后加热至70℃。在90min后,冷却溶液,然后浓缩。将残余物溶于甲醇(60mL),加热至70℃。在1h后冷却溶液,然后浓缩。残余物用快速色谱法提纯,用含10%至40%甲醇的二氯甲烷洗脱。获得浅黄色固体(2.718g;97%收率).
流程3:合成实施例1:
1A:4-(1-苄基-哌啶-4-基氨基)-N,N-二异丙基-苯甲酰胺(化合物6)
在装有胺(3.0mol;1.2eq)的无水甲苯(45mL)溶液的干燥烧瓶中加入芳基溴(3.49g;1.0eq)、BINAP(230mg;0.03eq)、Pd(OAc)2(55mg;0.02eq)和叔丁醇钠(1.65g;1.4eq)。在氮气氛下将反应物加热至80℃,搅拌过夜。在17h后冷却溶液,用乙酸乙酯稀释。反应物用水洗涤两次,有机物用无水硫酸镁干燥,过滤,然后浓缩。残余物用快速色谱法提纯,用含5%甲醇的二氯甲烷洗脱。残余物在乙酸乙酯中煮沸,冷却悬浮液,过滤收集淡棕色固体。获得淡棕色固体(3.326g;69%收率)。
1B:4-[(1-苄基-哌啶-4-基)-(3-氰基-苯基)-氨基]-N,N-二异丙基-苯甲酰
胺(化合物5)
在装有胺(1.50g;1.0eq)和3-溴苯甲腈(973mg;1.4eq)的无水甲苯(25mL)溶液的干燥烧瓶中加入xantphos(176mg;0.08eq)、Pd2(dba)3(140mg;0.04eq)和叔丁醇钠(513mg;1.4eq)。将反应物加热至110℃,在氮气氛下搅拌过夜。在22h后冷却溶液,用乙酸乙酯稀释,用水洗涤,然后通过硅藻土过滤。分离出有机物,用无水硫酸镁干燥,过滤,然后浓缩。残余物用快速色谱法提纯,用含2%至4%甲醇的二氯甲烷洗脱。获得橙色泡沫状产物(1.65g;88%收率)。
1C:3-[(1-苄基-哌啶-4-基)-(4-二异丙基氨基甲酰基-苯基)-氨基]苯甲
酰胺(实施例1)
腈(1)(1.65g)的叔丁醇(45mL)溶液中加入氢氧化钾(468mg;2.5eq)。将反应物加热至回流。在1h后冷却溶液,用二氯甲烷稀释,用水洗涤一次。水层用2N盐酸中,用二氯甲烷萃取一次。合并的有机物用无水硫酸镁干燥,过滤,然后浓缩。残余物用快速色谱法提纯,用含5%甲醇的二氯甲烷洗脱。获得浅黄色泡沫状产物(1.605g;94%收率)。将产物悬浮于乙醚(30mL)中,加入二氯甲烷获得均匀溶液,然后加入1N HCl的乙醚(4.7mL;1.5eq)溶液。在1h后,浓缩悬浮液,高真空干燥。
流程4:化合物5的替代合成法:N,N-二异丙基-4-[[3-氰基苯基)[1-(苯
基甲基)-4-哌啶基]氨基]苯甲酰胺
NaOtBu,甲苯,110℃,76%
1.07g 3-溴苯甲腈(5.88mmol)的15ml无水甲苯溶液中加入1.2mL 4-氨基-N-苄基哌啶(5.89mmol)、293mg外消旋BINAP(0.47mmol)、215mg三(二亚苄基丙酮)二钯(O)(0.23mmol)和790mg叔丁醇钠(8.23mmol)。将反应物在氮气氛、80℃下加热4h。冷却反应物至室温,加入2.34g N,N-二异丙基-4-溴苯甲酰胺(8.24mmol)和790mg叔丁醇钠(8.23mmol),将反应物加热至回流。在20h后冷却溶液至室温,将反应物用乙酸乙酯(50ml)稀释,加入水(30ml),通过硅藻土过滤,然后分离出有机层,用硫酸镁干燥,过滤,然后浓缩。残余物通过快速色谱法提纯,用含2%二氯甲烷的甲醇至含5%甲醇的二氯甲烷洗脱。残余物再用快速色谱法提纯,用10%己烷∶90%乙酸乙酯洗脱得到橙色泡沫状产物(2.20g,4.45mmol;76%)。HPLC检测出产物纯度>94%(LUNA30-80%乙腈)。
(400MHz,CDCl3)δH,1.37(brs,12H,CH3);1.45-1.55(m,2H,CH2);1.91(d,J=13Hz,2H,CH2);2.12(t,J=12Hz,2H,NCH2);2.97(d,J=12Hz,2H,NCH2);3.51(s,2H,NCH2Ar);3.75(br s,2H,NCH);3.77-3.84(m,1H,NCH);6.82-6.84(m,1H,Ar-H);6.93-6.96(m,3H,Ar-H);7.10(d,J=7.5Hz,1H,Ar-H);7.22-7.36(m,8H,Ar-H)。
流程5:经由中间体10的替代合成法
中间体7:(1-苄基-哌啶-4-基)-(3-[1,3]二氧戊环-2-基-苯基)-胺
在装有2-(3-溴苯基)-1,3-二氧戊环(1.0eq)和胺(1.2eq)溶液的无水甲苯溶液的干燥烧瓶中加入BINAP(0.03eq)、醋酸钯(0.02eq)和叔丁醇钠(1.4eq)。将反应物在氮气氛下加热至80℃。在2h后将溶液冷却,用乙酸乙酯稀释,用水洗涤一次。有机物用无水硫酸镁干燥,过滤,然后浓缩。残余物用快速色谱法提纯,用含甲醇的二氯甲烷梯度洗脱。
中间体8:[(1-苄基-哌啶-4-基)-(3-[1,3]二氧戊环-2-基-苯基)-氨基]-N,N-
二异丙基-苯甲酰胺
在装有胺
7的无水甲苯(约6mL/mmol
7)溶液的干燥烧瓶中加入芳基溴(1.4eq)、xantphos(0.06eq)、Pd2(dba)3(0.03eq)和叔丁醇钠(1.4eq)。将反应物在氮气氛下加热至110℃。在约24h后将溶液冷却,用乙酸乙酯稀释,用水洗涤一次。有机物用无水硫酸镁干燥,过滤,然后浓缩。残余物用快速色谱法提纯,用含甲醇的二氯甲烷梯度洗脱。
中间体9:[(1-苄基-哌啶-4-基)-(3-甲酰基-苯基)-氨基]-N,N-二异丙基-
苯甲酰胺
缩醛
8的四氢呋喃溶液中加入2N HCl溶液(2.0eq)。在室温下16h后,加入二氯甲烷,水层用饱和碳酸氢钠水溶液中和。除去有机层,水层用二氯甲烷萃取两次。合并的有机萃取液用硫酸镁干燥,过滤,然后浓缩,残余物用快速色谱法提纯,用含甲醇的二氯甲烷梯度洗脱。
中间体10:3-[(1-苄基-哌啶-4-基]-(4-二异丙基氨基甲酰基-苯基)-氨基]-
苯甲酸
醛
9(1.0eq)的叔丁醇溶液中加入2-甲基-2-丁烯(10.0eq),将溶液冷却至0℃。加入磷酸二氢钠(9eq)和亚氯酸钠(9eq)的水溶液,将反应物在0℃搅拌30min。除去叔丁醇,反应混合物用二氯甲烷萃取5次。合并的有机萃取液用硫酸镁干燥,过滤,然后浓缩,残余物用快速色谱法提纯,用甲醇/二氯甲烷梯度洗脱。
实施例1:3-[(1-苄基-哌啶-4-基)-(4-二异丙基氨基甲酰基-苯基)-氨基]-
苯甲酰胺(替代合成法)
酸
10(1.0eq)的DMF溶液中加入pyBOP(1.5eq)、HOBt(1.5eq)、二异丙基乙胺(4.0eq)和氯化铵(2eq)。在室温下16-24h后,浓缩反应物。将残余物溶于乙酸乙酯,用水洗涤两次,用饱和碳酸氢钠溶液洗涤一次。有机层用硫酸镁干燥,过滤,然后浓缩,残余物用快速色谱法提纯,用含甲醇的二氯甲烷梯度洗脱。
另外的实施例经由下述常规步骤合成。
A.还原性胺化中间体3:
胺
1的无水四氢呋喃(THF)或1,2-二氯乙烷溶液中加入醛(1-1.5eq.),然后加入三乙酰氧基硼氢化钠(1-1.6eq.)。将反应物在室温、氮气氛下长时间(6-48h)搅拌以保证反应完全。然后将反应混合物用标准后续步骤以及标准提纯法处理。THF或1,2-二氯乙烷用量并非决定性的。优选相当于约1mL/30mg的用量。
以下合成实施例2的步骤2A为典型的例子。
B.水解中间体氰基化合物:
氰基中间体的叔丁醇溶液中加入经研磨的氢氧化钾(KOH)(2.5eq.),将所得混合物加热至回流约2h。然后冷却混合物至室温,将其用标准后续步骤和标准提纯法处理。叔丁醇用量并非决定性的。优选相当于约1mL/30mg的用量。
以下合成实施例2的步骤2B为典型的例子。
实施例2:
胺3(472mg)的无水四氢呋喃(15mL)溶液中加入2-吡啶甲醛(144μL;1.3eq)和三乙酰氧基硼氢化钠(347mg;1.4eq)。将反应物在室温、氮气氛下搅拌过夜。溶液用二氯甲烷稀释,用饱和碳酸氢钠洗涤。水溶液用二氯甲烷萃取一次,合并的有机物用无水硫酸镁干燥,过滤,然后浓缩。残余物用快速色谱法提纯,用含10%甲醇的二氯甲烷洗脱。获得无色泡沫状产物(542mg;94%收率)。
腈7(542mg)的叔丁醇(15mL)溶液中加入压碎的氢氧化钾(153mg;2.5eq),将反应物加热至回流。在90min后,冷却溶液,用水稀释,用二氯甲烷萃取一次。水溶液用2N盐酸中和,用二氯甲烷萃取一次。合并的有机物用无水硫酸镁干燥,过滤,然后浓缩。残余物用快速色谱法提纯,用含10%甲醇的二氯甲烷洗脱。获得无色泡沫状产物(420mg;75%收率)。将产物溶于乙醚和二氯甲烷的混合物中,然后加入1N HCl的乙醚(2.5mL;3.0eq)溶液。在1h后,浓缩悬浮液,高真空干燥固体。
其它实施例按类似方法制备。合成的实施例的分析数据在下表1中列出。
表1:各合成的实施例的分析数据
表1(续):各合成的实施例的分析数据
表1(续):各合成的实施例的分析数据
表1(续):各合成的实施例的分析数据
药用组合物
本发明的新化合物可口服、舌下、肌内、皮下、局部、鼻内、腹膜内、胸腔内、静脉内、硬膜外、鞘内、脑室内给药及注射入关节给药。
优选给药途径为口服、静脉内或肌内给药。
为具体患者确定最佳个体给药方案和剂量水平时,其剂量取决于给药途径、疾病严重性、患者的年龄和体重以及主治医师通常考虑的其它因素。
为了用本发明化合物制备药用组合物,药学上可接受的惰性载体既可为固体也可为液体。固体制剂包括粉剂、片剂、可分散颗粒剂、胶囊剂、扁囊剂和栓剂。
固体载体可以为能起稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂或片剂崩解剂作用的一种或多种物质;也可为包囊材料。
为粉剂时,载体为磨成细粉的固体,它可与磨成细粉的活性成分混合。为片剂时,活性成分与具有必要粘合性的载体按适当比例混合,并压制成需要的形状和规格。
为了制备栓剂组合物,首先熔解低熔点蜡如脂肪酸甘油酯和可可脂的混合物,并通过例如搅拌将活性成分分散于其中。然后将熔融的均匀混合物倾入常用规格模型中,使其冷却固化。
合适的载体有碳酸镁、硬脂酸镁、滑石粉、乳糖、糖、果胶、糊精、淀粉、西黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可脂等。
盐包括但不限于药学上可接受的盐。本发明范围的药学上可接受的盐的实例包括:乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、酒石酸氢盐、溴化物、乙酸钙、樟脑磺酸盐、碳酸盐、氯化物、柠檬酸盐、二盐酸盐、乙二胺四乙酸盐、乙二磺酸盐、丙酸酯十二烷基硫酸盐、乙磺酸盐、富马酸盐、glucaptate、葡萄糖酸盐、谷氨酸盐、乙醇酰阿散酸盐、己基间苯二酚盐、哈胺(hydrabamine)、氢溴酸盐、盐酸盐、羟基萘甲酸盐、羟乙磺酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、溴代甲烷、甲基硝酸盐、甲基硫酸盐、粘酸盐、萘磺酸盐、硝酸盐、双羟萘酸盐(扑酸盐)、泛酸盐、磷酸盐/二磷酸盐、聚半乳糖醛酸盐、水杨酸盐、硬脂酸盐、碱式乙酸盐、琥珀酸盐、硫酸盐、单宁酸盐、酒石酸盐、8-氯茶碱盐、三乙基碘和苯乍生。
本发明范围中药学上不可接受的盐的实例包括:氢碘酸盐、高氯酸盐、四氟硼酸盐。由于在物理和/或化学特性方面的优点(例如结晶性),药学上不可接受的盐也可能是有用的。
药学上可接受的盐优选为盐酸盐、硫酸盐和酒石酸氢盐。特别优选盐酸盐和硫酸盐。
术语组合物包括所述活性成分与作为载体的包囊材料的制剂,在包囊材料提供的胶囊中活性成分(与或不与其它载体一起)被所述载体所包围,由此使载体与活性成分结合。同样,扁囊剂也包括在术语组合物内。
片剂、粉剂、扁囊剂和胶囊剂可用作适于口服给药的固体剂型。
液体组合物包括溶液、悬浮液和乳液。适于胃肠外给药的液体制剂实例有所述活性化合物的无菌水溶液或水-丙二醇溶液。也可将液体组合物制成聚乙二醇水溶液。
通过将活性组分溶解于水中并根据需要加入适当的着色剂、调味剂、稳定剂和增稠剂,可制备口服给药的水溶液剂。通过将微细活性组分和粘性原料如天然合成树胶、树脂、甲基纤维素、羧甲基纤维素钠和药用制剂领域已知的其它悬浮剂分散于水中,可制备口服用药的水性悬浮液。
优选的药用组合物是单位剂型。为单位剂型时,所述组合物分成含适量活性组分的单位剂量。所述单位剂型可为有包装的制剂,包装中包含离散量的单位制剂,例如有包装的片剂、胶囊剂以及用小瓶或安瓿包装的粉剂。单位剂型也可为胶囊剂、扁囊剂或片剂本身,或者它可为适当数量的任何上述包装形式。
生物学评价
体外模型
细胞培养
A.在37℃、5%CO2下,在含有无钙DMEM、10%FBS、5%BCS、0.1%Pluronic F-68和600μg/ml遗传霉素的振摇瓶中,悬浮培养表达克隆的人μ、δ和κ受体和新霉素抗性的人293S细胞。
B.称量小鼠和大鼠的大脑重量,用冰冷的PBS(含有2.5mMEDTA,pH7.4)清洗。在冰冷的裂解缓冲液中(50mM Tris,pH7.0,2.5mMEDTA,临用前用0.5M苯甲磺酰氟的DMSO:乙醇母液加入至0.5mM)用polytron对大脑匀化15秒(小鼠)或30秒(大鼠)。
膜制备
沉淀细胞,将其重新悬浮于裂解缓冲液中(50mM Tris,pH7.0,2.5mM EDTA,临用前用0.1M PMSF的乙醇母液加入至0.1mM),在冰上温育15分钟,然后用polytron匀化30秒。在4℃下以1000g(最大)离心该悬浮液10分钟。将其上清液收集于冰上,重新悬浮沉淀后如上离心。将两次离心所得的上清液混合,以46,000g(最大)离心30分钟。将沉淀物重新悬浮于冷Tris缓冲液(50mM Tris/Cl,pH7.0)中,再离心。将最终的沉淀物重新悬浮于膜缓冲液(50mM Tris、0.32M蔗糖、pH7.0)中。聚丙烯管中的等份物(1ml)用干冰/乙醇冷冻并在-70℃贮存待用。用SDS通过改良的Lowry测定法检测蛋白浓度。
结合测定
于37℃解冻膜,并用冰冷却,通过25-号针头三次,稀释入结合缓冲液(50mM Tris、3mM MgCl2、1mg/ml BSA(Sigma A-7888),pH7.4,稀释液经0.22m滤纸过滤,并向其中加入5μg/ml抑肽酶、10μM苯丁抑制素、10μM diprotin A(无DTT)后在4℃贮存)。将100μl等份液加入冰冻的装有100μl适当放射性配体和100μl各种浓度的受试化合物的12×75mm聚丙烯管中。分别测定包含和不含10μM纳洛酮的总的结合(TB)和非特异性(NS)结合。将所述试管涡旋并于25℃温育60-75分钟,之后,快速真空-过滤内容物,以约12ml/管的冰冷洗涤缓冲液(50mMTris、pH7.0、3mMMgCl2)通过GF/B滤纸(Whatman)(在0.1%聚环乙亚胺中预浸渍至少2小时)洗涤。将滤纸在包含6-7ml闪烁液的微管中浸渍至少12小时后,用β计数器测量保留在滤纸上的放射性(dpm)。如果所述测定在96-位深孔板中进行,用96位PEI-浸渍的单滤纸(96-place PEI-soaked unifilters)过滤,将所述单滤纸用3×1ml洗涤缓冲液洗涤并于55℃烤箱中干燥2小时。加入50μl MS-20闪烁液/孔后,滤板用TopCount(Packard)计数。
功能分析
通过检测化合物受体复合物刺激GTP与偶合受体的G-蛋白结合的程度来测量本化合物的激动剂活性。在GTP结合分析中,GTP[γ]35S与受试化合物以及来自表达克隆的人阿片受体的HEK-293S细胞的细胞膜或来自于匀化的大鼠和小鼠大脑的细胞膜相混合。激动剂刺激GTP[γ]35S结合在这些膜上。各化合物的EC50值和Emax值根据剂量-反应曲线确定。δ拮抗剂纳屈吲哚引起的剂量反应曲线右移用来验证激动剂活性是通过δ受体介导的。
用于大鼠大脑GTP的方法
于37℃解冻大鼠大脑细胞膜,通过25-号钝针头三次,稀释入GTPγS结合液(50mM Hepes,20mM NaOH,100mM NaCl,1mMEDTA,5mM MgCl2,pH7.4,加入新的:1mM DTT,0.1%BSA)。将120μM GDP最后加入膜稀释液。各化合物的EC50和Emax用10点剂量-反应曲线评价,10点剂量-反应曲线是用每孔300μL含有适当量的膜蛋白(20μg/孔)以及100000-130000dpm GTPγ35S(0.11-0.14nM)获得的。检测不存在以及存在3μM SNC-80时的基础和最大刺激结合作用。
数据分析
特异性结合(SB)计算为TB-NS,存在各种受试化合物时的SB表示为对照SB的百分比。用分对数图或曲线拟合程序例如Ligand、GraphPad Prism、SigmaPlot或ReceptorFit计算在置换特异性结合放射性配体中各配体的IC50值和Hill系数(nH)。用Cheng-Prussoff方程计算Ki值。用至少三个置换曲线报告受试配体的IC50、Ki和nH的平均值±S.E.M。本发明化合物的生物学活性数据列于下表2中。
表2:生物学数据
Ex.# | HDELTA(nM) | 大鼠大脑(nM) | 小鼠大脑(nM) | ||||
IC50 | EC50 | %EMax | EC50 | %EMax | EC50 | %EMax | |
1-13 | 0.293-1.18 | 0.262-33.981 | 95.005-112.41 | 3.97-30.387 | 118.825-162.873 | 4.493-31.267 | 122-162.71 |
受体饱和实验
用浓度为0.2-5倍于估计Kδ的适当放射性配体(如果所需放射配体量适宜的话,可高达10倍)对细胞膜进行结合试验,从而测定放射性配体Kδ值。特异性放射性配体结合表示为pmole/mg膜蛋白。由各个试验的特异性结合(B)的放射性配体对nM游离(F)的放射性配体的单位点非线性拟合获得各实验的Kδ值和Bmax值。
用Von Frey试验测定机械性异常性疼痛
用Chaplan等(1994)介绍的方法在08:00至16:00进行试验。将大鼠置于Plexiglas笼的金属丝网底(可通过网底接触到大鼠爪)上,让其适应10-15分钟。试验区域为左后爪的足底中部,避开较不敏感的足垫部分。用一系列刚度呈对数递增(0.41、0.69、1.20、2.04、3.63、5.50、8.51和15.14克;Stoelting,Ill,USA)的8 Von Frey细丝接触其爪。从网状底板的下面,垂直于足底表面使用Von Frey细丝,对爪用足够的力使Von Frey细丝产生轻微弯曲并保持约6-8秒。如爪急剧缩回则为阳性反应。细丝一移开立即退缩也认为是阳性反应。走开是不明确的反应,需要重复刺激。
试验方案
FCA处理组在手术后第一天对大鼠进行试验。用Dixon(1980)的增减法确定50%缩回阈值。用2.04g(处于中等大小的细丝)细丝开始试验。无论刺激强度是增强或减弱,采用连续刺激方式。爪对最初选定的细丝刺激无回缩反应时,就逐渐增强刺激;若爪回缩,则选择更弱的刺激。应用这种方法计算最优阈值需要6个接近50%阈值的反应,当反应发生第一个变化时,例如首次超过阈值时,才开始计数这6个反应。如果阈值落在刺激范围之外,阀值分别指定为15.14(正常敏感度)或0.41(最大异常性疼痛)。按照常规(X=未缩回;O=缩回)对所得阳性和阴性反应特征制表,用以下公式内推出50%收缩阀值:
50%阈值(g)=10(Xf+kδ)/10,000
其中Xf=最后使用的Von Frey细丝值(对数单位);k=阳性/阴性反应特征的表格数值(Chaplan等(1994);而δ=刺激的平均差值(对数单位)。此处δ=0.224。
根据Chaplan等(1994),将Von Frey阈值转化为最大可能作用的百分比(%MPE)。下列方程用于计算%MPE:
受试化合物的给药
在Von Frey试验前将受试物质注射(皮下、腹膜内、静脉内或口服)给予大鼠,受试化合物给药与Von Frey试验时间间隔取决于受试化合物的性质。
扭体试验
小鼠腹膜内给予后,乙酸会引起腹部收缩。然后呈现典型的机体伸展。用了止痛药后,较少观察到所述运动,则该药选作潜在的良好侯选物。
只有出现下列情况才认为是完全典型的扭体反射:所述动物未运动;后背略微降低;双爪足底表面可观察到。在该测定时,口服给予1-100μmol/kg本发明化合物后,证实其明显抑制扭体反应。
(i)溶液制备
乙酸(AcOH):将120μl乙酸加入19.88ml的蒸馏水中以得到最终体积为20ml、最终浓度为0.6%的AcOH。再将该溶液混合(涡旋)以备注射用。
化合物(药物):根据标准方法制备各化合物并溶解于最适当的溶媒中。
(ii)溶液剂的给药
在试验前20、30或40分钟(根据化合物的种类及其特性),以10ml/kg(考虑小鼠平均体重)将所述化合物经口、腹膜内(i.p.)、皮下(s.c.)或静脉内(i.v.)给药。当所述化合物中枢性给药时:脑室内(i.c.v.)或鞘内(i.t.)给药,给药量为5μl。
临试验前以10ml/kg(考虑小鼠平均体重)AcOH在两侧腹膜内(i.p.)给药。
(iii)试验
观察所述动物(小鼠)20分钟,记录(扭体反射)发生次数,实验结束时进行数据整理。将小鼠放置在带接触衬垫的单个“鞋盒”状笼中。通常同时观察4只小鼠:一只为对照,三只分别给予三种剂量的药物。
关于焦虑症和焦虑症样的适应症,化合物效能已经在大鼠的geller-seifter冲突试验中证实。
关于功能性胃肠病适应症,化合物效能可以按照Coutinho SV等[American Journal of Physiology-Gastrointestinal & Liver Physiology。282(2):G307-16,2002年2月]介绍的评价方法用大鼠证实。
Claims (16)
2.权利要求1的化合物,其中各R1苯环和R1杂芳族环可独立被选自以下的1、2或3个取代基进一步取代:甲基、CF3、氯、氟、溴和碘。
3.权利要求1的化合物,其中各R1苯环和R1杂芳族环可独立被甲基进一步取代。
4.权利要求1的化合物,其中R1是苯基、吡咯基、吡啶基、噻吩基或呋喃基。
5.权利要求1的化合物,它选自以下任何一种化合物:
1 3-[(1-苄基-哌啶-4-基)-(4-二异丙基-氨基甲酰基-苯基)-氨基]-苯甲酰胺;
2 3-[(4-二异丙基-氨基甲酰基-苯基)-(1-吡啶-2-基甲基-哌啶-4-基)-氨基]-苯甲酰胺;
3 3-[(4-二异丙基-氨基甲酰基-苯基)-(1-噻吩-2-基甲基-哌啶-4-基)-氨基]-苯甲酰胺;
4 3-[(4-二异丙基-氨基甲酰基-苯基)-(1-噻唑-2-基-甲基-哌啶-4-基)-氨基]-苯甲酰胺;
5 3-[(4-二异丙基-氨基甲酰基-苯基)-(1-噻吩-3-基甲基-哌啶-4-基)-氨基]-苯甲酰胺;
6 3-[(4-二异丙基-氨基甲酰基-苯基)-(1-呋喃-2-基-甲基-哌啶-4-基)-氨基]-苯甲酰胺;
7 3-[(4-二异丙基-氨基甲酰基-苯基)-(1-呋喃-3-基-甲基-哌啶-4-基)-氨基]-苯甲酰胺;
8 3-[[1-(4-氯-苄基)-哌啶-4-基]-(4-二异丙基-氨基甲酰基-苯基)-氨基]-苯甲酰胺;
9 3-{(4-二异丙基-氨基甲酰基-苯基)-[1-(3H-咪唑-2-基-甲基)-哌啶-4-基]-氨基)-苯甲酰胺;
10 3-[[1-(4-氟-苄基)-哌啶-4-基]-(4-二异丙基-氨基甲酰基-苯基)-氨基]-苯甲酰胺;
11 3-[(4-二异丙基-氨基甲酰基-苯基)-(1-吡咯-2-基-甲基-哌啶-4-基)-氨基]-苯甲酰胺;
12 3-[[1-(4-甲基-苄基)-哌啶-4-基]-(4-二异丙基-氨基甲酰基-苯基)-氨基]-苯甲酰胺;或
13 3-[[1-(4-乙基-苄基)-哌啶-4-基]-(4-二异丙基-氨基甲酰基-苯基)-氨基]-苯甲酰胺。
6.任一项前述权利要求的化合物,它为其盐酸盐、二盐酸盐、硫酸盐、酒石酸盐、二三氟乙酸盐或柠檬酸盐的形式。
8.一种制备式I化合物的方法,该方法包括用钯催化剂如Pd2(dba)3,在碱如叔丁醇钠存在下,使通式IV化合物
其中PG为氨基甲酸乙酯保护基团如Boc和CBZ,或为苄基或取代的苄基保护基团如2,4-二甲氧基苄基;与3-溴苯甲腈反应得到通式III化合物,
然后在标准条件下脱去保护,在还原条件下用通式为R1-CHO的化合物烷基化得到通式I化合物。
9.用于治疗目的的权利要求1的化合物。
10.权利要求1的式I化合物在制备用于治疗疼痛、焦虑症或功能性胃肠病的药物中的应用。
11.一种药用组合物,该组合物包含作为活性成分的权利要求1的式I化合物以及药学上可接受的载体。
12.一种治疗疼痛的方法,该方法将有效量的权利要求1的式I化合物给予需要治疗疼痛的患者。
13.一种治疗功能性胃肠病的方法,该方法将有效量的权利要求1的式I化合物给予患有所述功能性胃肠病的患者。
14.一种治疗焦虑症的方法,该方法将有效量的权利要求1的式I化合物给予患有所述焦虑症的患者。
16.一种通式X化合物,
其中R1选自苯基、吡啶基、噻吩基、呋喃基、咪唑基、三唑基、吡咯基、噻唑基或吡啶基-N-氧化物中任意一个基团。
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CN103724366A (zh) * | 2014-01-21 | 2014-04-16 | 贵州威顿晶磷电子材料有限公司 | 一种对羧基苯硼酸的制备方法 |
CN103724366B (zh) * | 2014-01-21 | 2016-04-27 | 贵州威顿晶磷电子材料股份有限公司 | 一种对羧基苯硼酸的制备方法 |
CN107531670A (zh) * | 2014-12-19 | 2018-01-02 | 菲勒诺沃公司 | 二芳基亚甲基哌啶衍生物及其作为δ阿片受体激动剂的用途 |
CN107531670B (zh) * | 2014-12-19 | 2020-12-15 | 菲勒诺沃公司 | 二芳基亚甲基哌啶衍生物及其作为δ阿片受体激动剂的用途 |
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EP1395556A1 (en) | 2004-03-10 |
IL158630A0 (en) | 2004-05-12 |
CZ20033091A3 (cs) | 2004-07-14 |
EE200300535A (et) | 2004-02-16 |
WO2002094784A1 (en) | 2002-11-28 |
ZA200308641B (en) | 2005-02-07 |
SK13972003A3 (en) | 2004-10-05 |
IS7029A (is) | 2003-11-12 |
JP2005508290A (ja) | 2005-03-31 |
HUP0401324A2 (hu) | 2004-11-29 |
PL366770A1 (en) | 2005-02-07 |
CO5540318A2 (es) | 2005-07-29 |
US20040142965A1 (en) | 2004-07-22 |
MXPA03010442A (es) | 2004-03-09 |
AR033760A1 (es) | 2004-01-07 |
US7186733B2 (en) | 2007-03-06 |
BG108332A (bg) | 2004-12-30 |
NO20035114D0 (no) | 2003-11-17 |
BR0209675A (pt) | 2004-07-27 |
KR20040000470A (ko) | 2004-01-03 |
RU2003131965A (ru) | 2005-05-10 |
SE0101771D0 (sv) | 2001-05-18 |
CA2446316A1 (en) | 2002-11-28 |
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