CN1449396A - 由芳基烷基胺得到的氨基甲酸酯 - Google Patents
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Abstract
本发明涉及具有一般结构(I)的氨基甲酸酯,其中的R1、R2和R3是H、OH、SH、CN、F、Cl、Br、I、(C1~C4)-烷硫基、(C1~C4)-烷氧基、被一个或几个F基团取代的(C1~C4)-烷氧基、氨基甲酰胺、(C1~C4)-烷基和被一个或几个F或OH基团取代的(C1~C4)-烷基;R4表示取代的或未取代的环烷基或环芳基(杂烷基或者不是)。此奎宁环的胺也可以形成季铵盐或者处于氧化状态(N-氧化物)。氨基甲酸酯(I)是M3蕈毒碱受体的拮抗剂,有选择性地是M2受体的拮抗剂。因此,它们可以用于治疗尿失禁(特别是由于不稳定膀胱引起的尿失禁)、过敏性肠道综合症、呼吸道疾病(特别是慢性阻塞性肺部疾病、慢性支气管炎、哮喘、肺气肿和鼻炎)以及用于眼科手术。
Description
本发明涉及用做蕈毒碱受体拮抗剂的新型N-苯基-N-烷基氨基甲酸奎宁环酯型化合物,涉及这种化合物的制备方法,还涉及这种化合物在预防和治疗与呼吸道、消化道和泌尿***有关的疾病方面的应用。
现有技术背景
已知具有蕈毒碱受体拮抗效果的化合物会诱发支气管扩张、胃肠道动力性能抑制、胃酸分泌减少、口干、瞳孔扩大、心动过速以及泌尿膀胱收缩抑制。
从1983年到1993年,在蕈毒碱受体药理学的知识方面连续取得进展。在此时期内,克隆并表达出总共5个人类基因编码蕈毒碱受体亚型(m1、m2、m3、m4和m5),它们为5种功能受体(M1、M2、M3、M4和M5)进行了编码。虽然M5还没有完全被表征,但按照NC-IUPHARGuidelines(M.P.Caulfield等Pharmacol.Rev.1998,50,279~290)已经将其认为是一种功能受体。
M1受体是一种突触后神经受体,主要位于大脑和末梢副交感腺体中。在平滑心肌中,有大量M2受体存在。M3受体主要存在于外分泌腺体组织中,比如在唾腺中。M4受体在特殊物种中主要存在于大脑皮层、纹状体和某些周边位置。在肠道、膀胱和支气管的平滑肌中,M2和M3受体可以共存。然而,普遍接受的官能信息指出,M3受体在后三种组织中负责内源神经介质的收缩作用。因此,得到M3受体的选择性拮抗剂以避免由于其他蕈毒碱受体的阻断而产生的副作用似乎是有意义的。目前,其中的奥昔布宁(Nippon Shinyaku)和托特罗定(Pharmacia)都是商品化合物,它们都显示出对M2和M3受体的减小的选择性。然而,仍处于开发阶段的达非那新(Pfizer)和YM-905(Yamanouchi)都显示出M3的拮抗剂活性,对M2受体没有任何明显的亲和性。奥昔布宁托特罗定达非那新YM-905
下面是对某些具有氨基甲酸酯结构的化合物作为M3受体选择性拮抗剂的化合物提出权利要求的专利申请:JP 04/95071-A、WO95/06635-A、EP 747355-A和EP 801067-A。所有这些都叙述了与本发明所述不同的氨基甲酸酯,而本发明叙述了在结构上与它们所提出权利要求的最接近的化合物。
因此,应该理解,提供作为M3受体选择性拮抗剂的新型治疗药剂是有很大意义的。
本发明的概述
本发明的一个方面涉及到提供一种通式(I)的新型氨基甲酸酯及其立体异构体、立体异构体的混合物、其可药用的盐和可药用的溶剂化物:其中,R1、R2和R3是独立地选自H、OH、SH、CN、F、Cl、Br、I、氨基甲酰胺、(C1~C4)-烷硫基、(C1~C4)-烷氧基、被一个或多个F取代的(C1~C4)-烷氧基、(C1~C4)-烷基、被一个或多个F或OH取代的(C1~C4)-烷基,或者,R1和R2或者R2和R3可以形成一个选自-CH2-CH2-CH2-和-CH2-CH2-CH2-CH2-的二价基团。
在通式(I)的化合物中,R4是选自环丙基、环丁基、环戊基、环己基、环己烯基、降冰片烯基、双环[2.2.1]庚基、2-,3-噻吩基、2-,3-呋喃基、2-,3-,4-吡啶基、1-,2-萘基、1-,2-苯并二氧戊环基、1-,2-苯并二噁烷基、苯基和被一个或多个选自OH、SH、CN、F、Cl、Br、I的取代基取代的苯基、氨基甲酰胺基、羟基羰基、(C1~C4)-烷氧羰基、(C1~C4)-烷硫基、(C1~C4)-烷基、(C1~C4)-烷氧基、被一个或多个F或OH取代的(C1~C4)-烷基以及被一个或多个F取代的(C1~C4)-烷氧基的基团。
在一个特定的实施方案中,R4是苯基或被一个或多个选自OH、SH、CN、F、Cl、Br、I的取代基取代的苯基、氨基甲酰胺基、羟基羰基、(C1~C4)-烷氧羰基、(C1~C4)-烷硫基、(C1~C4)-烷基、(C1~C4)-烷氧基、被一个或多个F或OH取代的(C1~C4)-烷基和被一个或多个F取代的(C1~C4)-烷氧基。在另一个特定的实施方案中,R4是选自环丙基、环丁基、环戊基、环己基、环己烯基、降冰片烯基、双环[2.2.1]庚基、2-,3-噻吩基、2-,3-呋喃基、2-,3-,4-吡啶基、1-,2-萘基、1-,2-苯并二氧戊环基和1-,2-苯并二噁烷基。
奎宁环的氮原子可以处于被氧化的状态(N-氧化物)或者作为可药用的季烷基铵盐,其中具有1~4个碳原子的烷基链可以是直链,也可以是分支的。
特别优选的化合物是具有如下通式(I),其中奎宁环的碳原子3是(R)的化合物:
在通式(I)的化合物具有不对称碳的情况下,可以通过传统的方法把其外消旋混合物拆分为其对映体,比如用手性固定相进行的色谱分离或者用其非对映异构体盐的分级结晶的方法。此盐可以通过与对映体纯的酸之间的反应来制备。通过手性前体进行的对映体选择性合成也可以得到通式(I)的手性化合物。
本发明还涉及生理上可接受的通式(I)的氨基甲酸盐,特别是与无机酸,比如盐酸、氢溴酸、硝酸、硫酸和磷酸,以及和有机酸比如草酸、琥珀酸、富马酸、酒石酸和马来酸加合形成的盐。
本发明还涉及通式(I)的氨基甲酸酯的N-氧化物和这样的氨基甲酸酯与可药用的阴离子形成的季(C1~C4)-烷基铵盐。
可以通过在下面的示意图中表示的两种通用方法(即方法A和方法B)来制备通用结构(I)的化合物。原料芳基烷基胺(II)可商购,或者通过已知的方法合成,比如苯胺烷基化、还原胺化或酰苯胺还原。
按照方法A,首先在从0℃到溶剂回流的温度下,在惰性溶剂(比如二甲基甲酰胺、CH2Cl2、1,2-二氯乙烷、四氢呋喃或甲苯)中通过氯甲酸酯(比如氯甲酸甲酯、氯甲酸乙酯或氯甲酸4-硝基苯酯)进行芳基烷基胺(II)的酰基化。在某些情况下,建议使用相应的氯甲酸酯作为溶剂,或者使用碱,比如叔胺或碳酸钾来进行反应。然后使用碱,比如金属钠、氢化钠或甲氧基钠,通过氨基甲酸酯中间体(III)和3-奎宁醇之间的酯交换反应引入烷氧基链节。此反应可以在0℃到所用溶剂的回流温度下进行。
按照方法B,首先在溶剂的回流温度下,在惰性溶剂(比如二甲基甲酰胺、二氯甲烷、1,2-二氯乙烷)中,让3-奎宁醇(quinuclidol)与氯甲酸酯(比如氯甲酸三氯甲酯)反应,得到相应的氯甲酸奎宁醇酯的盐酸盐,然后,用氯甲酸奎宁醇酯将芳基烷基胺(II)进行酰基化。反应在20℃到溶剂的回流温度下,在惰性溶剂(比如二甲基甲酰胺、二氯甲烷、氯仿、1,2-二氯乙烷)中进行。
如同在所附的人类蕈毒碱受体结合测试方法中所说明的,本发明的化合物是对M2受体有选择性的M3受体拮抗剂。因此,它们可用来治疗尿失禁(特别是由于不稳定的膀胱所引起的尿失禁)、过敏性肠道综合症、和呼吸***的疾病(特别是慢性阻塞性肺部疾病、慢性支气管炎、哮喘、肺气肿和鼻炎)以及在涉及眼科的疾病中。
因此,本发明的另一方面是通式(I)的氨基甲酸酯在制备用于治疗以下疾病的药物方面的应用:尿失禁,特别是由于不稳定的膀胱所引起的尿失禁、过敏性肠道综合症、和呼吸***的疾病,特别是慢性阻塞性肺部疾病、慢性支气管炎、哮喘、肺气肿和鼻炎。再有,其在制备用于涉及眼科的疾病中的药物方面的应用也构成本发明此方面的一部分。
对人类M
2
和M
3
蕈毒碱受体的结合测试
下面的测试显示出通式(I)化合物的M3拮抗剂活性以及其对M2受体的选择性。列出了对于克隆的人类蕈毒碱M2和M3受体所得到的结果,并叙述了使用的方法。
使用用人类M2或M3受体(Receptor Biology)转染的CHO-K1细胞得到的膜。对于两种受体,实验程序概要如下:在有拮抗剂或无拮抗剂存在下,用[3H]-NMS(0.3~0.5nM)在25℃下培养膜(15~20μg)60min。培养在96孔的聚苯乙烯微量板上进行,pH值为7.4的PBS的总培养体积是0.2mL。在阿托品(5μM)存在下进行的平行实验确认没有特异性的结合。通过预先用0.3%的PEI培养的GF/C型玻璃纤维过滤试样。用50mM的Tris-HCl、0.9%的NaCl,在4℃和7.4的pH值下洗涤过滤器3~4次,然后在50℃下干燥45min。用液体闪烁计数器对过滤器结合的放射性进行定量。
为了计算出抑制常数(Kj),用非线性回归(GraphPad Prism)分析位移曲线。通过在与用拮抗剂进行实验的同样条件下得到的饱和曲线,对于每种受体得到[3H]-NMS的离解常数(KD)。在下面的表中显示出得到的结果,该结果以重复进行的两次独立实验的平均值表示。M2/M3比大于1表明了M3的选择性拮抗活性。
下面的非限定性实施例用来说明本发明。
实施例:
中间体1:氯甲酸-(R)-3-奎宁环酯,盐酸盐
在0℃和惰性气氛下,伴随着连续的搅拌,在8.7mL(74.8mmol)氯甲酸三氯甲酯在240mL二氯甲烷的溶液里滴加4.75g(37.4mmol)(R)-3-奎宁醇在240mL二氯甲烷中的溶液。然后,在室温下搅拌此混合物24hr,在减压下蒸出溶剂,得到8.46g(37.4mmol)相当于标题化合物的白色固体。IR(KBr,cm-1):3380,2650~2500,1776。
实施例1:N-苄基-N-苯基氨基甲酸3-奎宁环酯,盐酸盐
方法A
在5.1g(20mmol)N-苄基-N-苯基氨基甲酸乙酯(Dannley,L.J.Org.Chem.1957,22,268)和7.3g(60mmol)3-奎宁醇在120mL甲苯中的溶液里加入800mg(20mmol)氢化钠(60%的油分散液),将该混合物沸腾3hr。在此期间,要加入甲苯补充蒸出的体积。让反应的粗产物冷却下来,用250mL甲苯稀释,再用水洗涤,用无水硫酸钠干燥。然后,在减压下蒸出溶剂。在室温下用氯化氢饱和的甲醇处理得到的油状物,蒸出溶剂,用1∶1的乙酸乙酯/***混合物分解得到230mg(0.6mmol)相当于标题化合物的白色固体(熔点54℃)。
方法B
在750mg(2.58mmol)氯甲酸3-奎宁环酯在20mL 1,2-二氯乙烷的悬浮液里滴加395mg(2.15mmol)N-苯基苄胺在5mL的1,2-二氯乙烷中的溶液。一旦添加结束,将混合物回流3hr。让反应的粗产物冷却下来,并在减压下蒸出溶剂。用柱色谱(洗脱液:氯仿-甲醇10∶1)提纯残渣,得到720mg(1.95mmol)相当于标题化合物的吸湿性泡沫。IR(KBr,cm-1):3400~3200,2700~2300,1700cm-1。1H-RMN(δTMS,CDCl3,ppm):12.30(1H,s),7.20~6.90(10H,m),5.10(1H,m),4.83(2H,m),3.52(1H,m),3.18(4H,m),2.80(1H,m),2.34(1H,s),1.92(2H,m),1.60(2H,m)。
实施例2:N-苄基-N-苯基氨基甲酸(R)-3-奎宁环酯,盐酸盐
按照在实施例1中所述的方法,从390mg(1.5mmol)N-苄基-N-苯基氨基甲酸乙酯、587mg(4.6mmol)(R)-3-奎宁醇和61mg(1.5mmol)氢化钠开始得到标题化合物。用色谱柱(洗脱液:氯仿∶甲醇,5∶1)提纯得到的残渣。在室温下用氯化氢饱和的甲醇处理分离出的油状物,然后蒸出溶剂。然后用***分解得到的固体,在减压下于40℃下干燥,得到310mg(0.8mmol)相当于标题的盐酸盐的白色固体。熔点50℃。[α]25 D:-26.5(c=1.0,H2O)。IR(KBr,cm-1):2700~2300,1700,1H-RMN(δTMS,CDCl3,ppm):12.30(1H,s),7.20~6.90(10H,m),5.10(1H,m),4.83(2H,m),3.50(1H,m),3.18(4H,m),2.80(1H,m),2.35(1H,s),1.99(2H,m),1.61(2H,m)。
实施例3:(R)-3-(N-苄基-N-苯基氨基甲酰氧基)-1-甲基奎宁鎓
碘化物
将300mg(0.89mmol)N-苄基-N-苯基氨基甲酸(R)-3-奎宁环酯(实施例2)和60μL甲基碘(0.98mmol)在9mL丙酮中的溶液回流2hr。在室温下让反应粗产物冷却下来,并在减压下蒸出溶剂。用***分解得到的固体,在真空下于40℃干燥,得到480mg(0.89mmol)相当于标题化合物的吸湿性白色固体。IR(薄膜,cm-1):1690。
实施例4:N-苯基-N-苄基氨基甲酸-3-奎宁环酯,N-氧化物
将300mg(0.9mmol)N-苯基-N-苄基-氨基甲酸-3-奎宁环酯在20mL二氯甲烷中的悬浮液和95mg(1.1mmol)碳酸氢钠被冷却到0℃,然后加入567mg(1.1mmol)m-氯过氧苯甲酸(70%)。让反应混合物达到室温,同时搅拌1hr。然后用5%的硫代硫酸钠溶液洗涤有机层,用无水硫酸钠干燥,过滤并在减压下蒸出溶剂。使用氯仿∶甲醇为5∶1作为洗脱液将得到的残渣进行色谱柱提纯。得到289mg(0.82mmol)相当于标题化合物的无色油状物。IR(薄膜。cm-1):1702。
Claims (12)
1.如通式(I)的化合物,及其在奎宁环的氮上面的可药用(C1~C4)-烷基铵盐,及其在奎宁环氮上的N-氧化物,以及其立体异构体、立体异构体的混合物、可药用的盐及其可药用的溶剂化物:其中,R1、R2和R3是在其任何可能的位置与苯环相连的相同或不同的基团,它们选自H、OH、SH、CN、F、Cl、Br、I、(C1~C4)-烷硫基、(C1~C4)-烷氧基、被一个或多个F取代的(C1~C4)-烷氧基、氨基甲酰胺、(C1~C4)-烷基、被一个或多个F或OH取代的(C1~C4)-烷基,或者,R1和R2或者R2和R3可以形成一个选自-CH2-CH2-CH2-和-CH2-CH2-CH2-CH2-的二价基团;以及
R4是选自环丙基、环丁基、环戊基、环己基、环己烯基、降冰片烯基、双环[2.2.1]庚基、2-,3-噻吩基、2-,3-呋喃基、2-,3-,4-吡啶基、1-,2-萘基、1-,2-苯并二氧戊环基、1-,2-苯并二噁烷基、苯基和被一个或多个选自OH、SH、CN、F、Cl、Br、I的取代基取代的苯基、氨基甲酰胺基、羟基羰基、(C1~C4)-烷氧羰基、(C1~C4)-烷硫基、(C1~C4)-烷基、(C1~C4)-烷氧基、被一个或多个F或OH取代的(C1~C4)-烷基以及被一个或多个F取代的(C1~C4)-烷氧基的基团。
2.如权利要求1的化合物,其中R4是苯基或被一个或多个独立地选自OH、SH、CN、F、Cl、Br、I的取代基取代的苯基、氨基甲酰胺、羟基羰基、(C1~C4)-烷氧羰基、(C1~C4)-烷硫基、(C1~C4)-烷基、(C1~C4)-烷氧基、被一个或多个F或OH取代的(C1~C4)-烷基和被一个或多个F取代的(C1~C4)-烷氧基。
3.如权利要求1的化合物,其中R4选自环丙基、环丁基、环戊基、环己基、环己烯基、降冰片烯基、双环[2.2.1]庚基、2-,3-噻吩基、2-,3-呋喃基、2-,3-,4-吡啶基、1-,2-萘基、1-,2-苯并二氧戊环基、和1-,2-苯并二噁烷基。
4.如权利要求1~3中任意一项的化合物,其中奎宁环的氮形成可药用的(C1~C4)-烷基铵盐。
5.如权利要求1~3中任意一项的化合物,其中奎宁环的氮形成N-氧化物。
7.如权利要求1~6中任意一项的化合物在制造用于治疗尿失禁药物方面的应用。
8.如权利要求7的应用,其中的尿失禁是由于不稳定的膀胱引起的。
9.如权利要求1~6中任意一项的化合物在制造用于治疗过敏性肠道综合症药物方面的应用。
10.如权利要求1~6中任意一项的化合物在制造用于治疗呼吸***疾病的药物方面的应用。
11.如权利要求10的应用,其中该疾病选自慢性阻塞性肺部疾病、慢性支气管炎、哮喘、肺气肿和鼻炎。
12.如权利要求1~6中任意一项的化合物在制造用于治疗涉及眼科疾病的药物方面的应用。
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