CN1141921A - 色酮衍生物 - Google Patents
色酮衍生物 Download PDFInfo
- Publication number
- CN1141921A CN1141921A CN96106111A CN96106111A CN1141921A CN 1141921 A CN1141921 A CN 1141921A CN 96106111 A CN96106111 A CN 96106111A CN 96106111 A CN96106111 A CN 96106111A CN 1141921 A CN1141921 A CN 1141921A
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- China
- Prior art keywords
- formula
- compound
- substituted
- salt
- trifluoromethyl
- Prior art date
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Abstract
本发明涉及式(I)化合物,该化合物具有有用的药理特性,作为NK1拮抗剂和P物质拮抗剂特别有效。所述化合物按本身已知的方法制备。所述的式(I)化合物如下,式中环A和B的定义见说明书。
Description
本发明特别涉及这样一些式(I)化合物及其盐:式中环A未被取代或者被低级烷基、低级烷氧基、卤素、硝基或三氟甲基单取代,和环B未被取代或者被1-4个选自低级烷基、羟基、低级烷氧基、低级烷硫基、卤素、硝基、氰基和三氟甲基的取代基取代;本发明涉及这些化合物的制备方法,包含这些化合物的药用组合物,和这些化合物在治疗人或动物方面或制备药用组合物方面的用途。
由于本发明化合物含有至少两个光活性碳原子,因此它们可以立体异构体、立体异构体混合物以及(基本上)纯的非对映异构体形式存在。本发明还包括相应的立体异构体。式(I)化合物最好为式(Ia)所代表的非对映异构形式:
除非另行定义,本文上下文中所用的通用术语具有下述意义。
术语“低级”指各含1至至多7个碳原子最好是1至至多4个碳原子的相应的基团和化合物。
低级烷基一般是甲基,乙基,正丙基,异丙基,正丁基,异丁基,仲丁基,叔丁基或相应的戊基、己基或庚基,优选C1-C4烷基。
低级烷氧基一般是甲氧基,乙氧基,正丙氧基,异丙氧基,正丁氧基,异丁氧基,仲丁氧基,叔丁氧基或相应的戊氧基、己氧基或庚氧基,优选C1-C4烷氧基。
卤素一般是氟,氯或溴,但也可以是碘。优选氯。
式(I)化合物可以是盐、最好是药学上可接受的盐的形式。与哌啶环的碱性中心可形成酸加成盐。适宜的酸组分可以是例如强无机酸,一般是矿酸,例如硫酸、磷酸类例如正磷酸、氢卤酸例如盐酸,或强有机羧酸,一般是可被取代例如被卤素取代的低级链烷羧酸,例如乙酸或三氟乙酸,二元酸,可以是不饱和的,例如草酸、丙二酸、琥珀酸、马来酸、富马酸、邻苯二甲酸或对苯二甲酸,羟基羧酸,例如抗坏血酸、羟基乙酸、乳酸、苹果酸、酒石酸或柠檬酸,氨基酸,例如天冬氨酸或谷氨酸,或苯甲酸,或有机磺酸,一般是可被取代例如被卤素取代的低级链烷磺酸,通常是甲磺酸,或者是可被取代例如被低级烷基取代的芳基磺酸,通常是对甲苯磺酸。还包括不宜用于治疗用途但可以例如用于分离或纯化游离的式(I)化合物或其药学上可接受的盐的盐。仅仅药学上可接受的无毒的盐用于治疗用途,因此是优选的。
式(I)化合物(在下文中总是包括其药学上可接受的盐)具有有用的药理特性。特别是它们可用作神经激肽1拮抗剂(NK1拮抗剂),因此能够预防尤其是由于P物质的释放所引起的症状.
呼吸道具有含多种神经肽、特别是速激肽和CGRP(=降钙素基因相关肽)的感觉神经。感觉神经的激活导致肺内神经肽的局部释放。P物质和神经激肽A大部分被释放,这将触发称作神经原性炎的急性炎性反应。这个炎性反应主要通过NK1受体激活进行,尤其包括血管舒张,微脉管渗漏,炎性白细胞募集和粘液过量分泌。这些P物质的效果是典型的气喘症状。
式(I)化合物的药理作用尤其基于NK1受体的拮抗作用。式(I)化合物还能够抑制神经原性炎以及速激肽所致支气管收缩。
用不同的体外或体内试验法可证实式(I)化合物有益的作用。例如在对豚鼠的具有ED50值的体外NK1支气管痉挛试验中,大约0.03mg/kg的口服剂量是有效的,试验物质在静脉给与3.0μl/kg[Sar9,Met(O2)11]-P物质[=SarSP]之前2、4或24小时给与。用SarSP激发会导致豚鼠气管内的压力增高。本发明化合物显示出极好的口服活性以及不寻常的长效。
作为NK1受体的拮抗剂,式(I)化合物在治疗学上可用于预防、治疗或诊断许多疾病,例如上呼吸道和下呼吸道的疾病,例如支气管性气喘,变应性气喘,非变应性气喘,变应性过敏性和分泌过多性状况,例如慢性支气管炎和胰囊性纤维变性;各种病因的肺纤维变性;肺和支气管性循环的疾病,例如肺动脉高血压症,血管生成,转移;胃肠道的疾病,例如Crohn氏病,Hirsprung氏病,腹泻,吸收障碍性状况,炎性状况;中枢和外周神经系统的情感、创伤和炎性损害,例如抑郁症,焦虑症,偏头痛和其它形式的颅痛,中风,呕吐;血管例如颅血管的疾病;与不同组织例如皮肤和眼睛的微循环相关的疾病;免疫系统和网状组织细胞系统例如脾髓和淋巴组织的疾病;疼痛和其它在发病机制、病理学和病因学方面涉及神经肽、速激肽或其它相关物质的活性的疾病。
P物质是天然存在的速激肽家族的十一肽。它在哺乳动物体内产生并在药理学方面起神经肽的作用。P物质在多种疾病中起重要的作用,所述疾病有例如疼痛,偏头痛和中枢神经系统的一些疾病,例如焦虑症,呕吐,神经分裂症和抑郁症以及某些运动障碍,例如Parkinson氏病,但亦包括炎性疾病,例如类风湿性关节炎、虹膜炎和结膜炎,呼吸器官的疾病,例如气喘和慢性支气管炎,胃肠道的疾病,例如溃疡性结肠炎和Crohn氏病,和高血压。
在P物质拮抗剂领域的开发方面人们做了许多工作,寻找例如具有广谱活性以及增强的活性和增强的生物利用度并还具有增进的化学稳定性和结晶性的适宜的P物质拮抗剂,
多方面的药理试验表明,所述的新化合物及其盐能拮抗P物质达到特别可取的程度,因此特别适于治疗由P物质引起的症状。
该拮抗P物质的作用可例如按下面所述用业内人士公知的方法来检测。这样的作用不但在体外试验中而且在体内试验中被发现。在根据H.Bittiger,Ciba Foundation Symposium91(1982)196-199的放射性受体测定试验中,式(I)化合物例如能在意想不到的高程度上抑制3HP物质与牛视网膜结合,IC50值从大约5nM起。
由P物质诱发的人星形细胞瘤细胞中的磷酸肌醇(phosphoinositol)的形成例如也在体外试验中被拮抗,IC50值从大约1nM起。检测该抑制作用的适宜的模型是例如C.M.Lee等人在J.Neurochem.59(1992)406-414中所述的模型。
i.c.v.给与沙土鼠P物质甲酯能导致行为异常。该作用可在经口给与式(I)化合物时在体内被抑制。所用的试验方法是A.Vassout等人在Worchester,Mass.1990的“Substance P and Related Peptides:Cellularand Molecular Physiology”的会议上提出的方法。ED50值被证实为从大约0.1mg/kg p.o.起。这些数据证实式(I)化合物对于中枢神经系统的疾病的治疗具有极佳的适应性,
与迄今已知的NK1或P物质拮抗剂比较,该新化合物具有高得多的活性并具有例如对氧高得多的化学稳定性和增强的结晶性以及改进的口服生物利用度。
因此,由本发明提供的式(I)P物质拮抗剂极适于治疗上述的病理症状。
本发明特别涉及这样一些式(I)化合物及其药学上可接受的盐:式中环A未被取代或者被卤素单取代,和环B未被取代或者被1-2个选自低级烷基、羟基、低级烷氧基、低级烷硫基、卤素、硝基和氰基的取代基取代。
本发明主要涉及这样一些式(I)化合物及其药学上可接受的盐:式中环A未被取代或者被氯单取代,和环B未被取代或者被1-2个选自羟基、低级烷氧基、氯和溴的取代基取代。
本发明特别涉及这样一些式(I)化合物及其药学上可接受的盐:式中环A未被取代或者被氯单取代,和环B未被取代或者被氯或氟单取代。
要着重强调的几组式(I)化合物是:(a)环A未被取代或在4位被氯取代的式(I)化合物;(b)环A在4位被氯取代的式(I)化合物;(c)环B被氯或氟单取代的式(I)化合物;(d)环B未被取代的式(I)化合物。
本发明特别涉及在实施例中所描述的具体化合物及其盐、特别是其药学上可接受的盐。
式(I)化合物可用本身已知的方法来制备,一般按下述来制备:(a)使式(IIa)化合物与式(IIb)化合物或其盐反应,所述式(IIa)和(IIb)如下:式中环A和B的定义同式(I),式中Q1是可被醚化的羟基,例如羟基、低级烷氧基或未被取代的或被取代的苯氧基,或活性的酯化羟基,例如卤素、优选氯,或下式基团:或者(b)使式(IIIa)化合物与式(IIIb)化合物或其盐反应,所述式(IIIa)和(IIIb)如下:式中环A的定义同式(I),式中环B的定义同式(I),和Q1是可被醚化的羟基,例如羟基、低级烷氧基或未被取代的或被取代的苯氧基,或活性的酯化羟基,例如卤素、优选氯,或下式基团:并且,若期望,将一个式(I)化合物转化成另一个式(I)化合物和/或,若期望,将所得到的盐转化成游离的化合物或另一种盐和/或,若期望,将所得到的具有成盐性能的游离的式(I)化合物转化成盐和/或,若期望,将所得到的立体异构体或非对映异构体的混合物分离成单独的立体异构体和非对映异构体。
具有至少一个碱性中心的原料的盐例如式(IIa)或(IIIa)的盐是相应的酸加成盐,而含有酸性基团的原料的盐例如式(IIb)或(IIIb)的盐是与碱形成的盐。
在下面对所述方法的详细描述中,除另作说明外,环A和环B各自具有对式(I)所述的意义。
在上文和下文的变异法中所述的反应按本身已知的方法进行,一般是在下述条件下进行:在无溶剂或稀释剂存在下或常常是在适宜的溶剂或稀释剂或其混合物存在下,并根据需要在冷却、室温或加热的条件下,一般是在大约-80℃至反应介质的沸腾温度、最好是在大约-10℃-+200℃范围内的温度并且,若需要,在封闭的容器中,在压力下,在惰性气体气氛中和/或在无水条件下。变异法a)和b):用于制备各自的酰胺键的缩合反应可按本身已知的方法例如按例如下列文献中所述的标准操作来进行:“Houben-Weyl,Methoden der organischen Chemie”,第4版,第15/II卷,Georg ThiemeVerlag,Stuttgart1974,“The Peptides’’(E.Gross和J.Meienhofer编辑),第1和2卷,Academic Press,London and New York,1979/1980,或M.Bodanszky,“Principles of Peptide Synthesis”,Springer-Verlag,Berlin 1984。
缩合反应可在一种常规缩合剂存在下进行。常规缩合剂一般是碳化二亚胺类,例如二乙基碳化二亚胺,二丙基碳化二亚胺,N-乙基-N’-(3-二甲氨基丙基)碳化二亚胺,或者最好是二环己基碳化二亚胺,也可以是适宜的羰基化合物,一般是碳酰二咪唑,1,2-噁唑鎓化合物,一般是2-乙基-5-苯基-1,2-噁唑鎓-3’-磺酸酯和2-叔丁基-5-甲基异噁唑鎓高氯酸盐,或适宜的酰氨基化合物,一般是2-乙氧基-1-乙氧基羰基-1,2-二氢喹啉,也可以是活性磷酸衍生物,一般是二苯基磷酰基叠氮,二乙基磷酰氰化物,苯基-N-苯基磷酰氨基氯化物,二(2-氧代-3-噁唑烷基)次膦酰氯或六氟磷酸1-苯并三唑基氧基三(二甲氨基)鏻。
若需要,加入有机碱例如含有大基团的三低级烷基胺,例如乙基二异丙基胺,或杂环碱,一般是吡啶,4-二甲氨基吡啶,或最好是N-甲基吗啉。
酰卤例如与相应胺的缩合还可以在适宜的碱存在下不加适宜的偶联组分来进行。
缩合最好是在下列条件下进行:在惰性的极性非质子溶剂、优选无水溶剂或溶剂混合物中,在低温或高温、一般是大约-40℃-+100℃、优选大约-10℃-+50℃范围内的温度下,并可任选地在惰性气体气氛下例如在氮气下;所述溶剂一般是酰胺,例如甲酰胺或二甲基甲酰胺,卤代烃,例如二氯甲烷、四氯化碳或氯苯,酮,例如丙酮,环醚,例如四氢呋喃,酯,例如乙酸乙酯,或腈,例如乙腈,或它们的混合物。
活性酸衍生物还可以就地生成。
式(IIb)和(IIIb)原料是已知的,或可按本身已知的方法来制备。
式(IIIa)化合物可按本身已知的方法例如由式(IIIc)化合物出发来制备;所述式(IIIc)化合物如下:式中Q3是例如低级烷基或苯基低级烷基。该化合物一般通过与低级烷氧基卤代甲烷例如乙氧基氯甲烷在碱存在下被N-烷基化。将生成的式(IIId)化合物在强酸、一般是氯磺酸存在下用腈、一般是乙腈处理;所述式(IIId)化合物如下:式中Q4是例如低级烷基。在生成的式(IIIe)化合物中,-C(=O)-OQ3基团通过用强酸、一般是氢溴酸处理来去除;所述式(IIIe)化合物如下:
关于对映体纯化合物的制备,将可如此获得的式(IIIf)化合物中的仲氨基用光学活性化合物、一般是相应的O-酰化α-羟基羧酸或其活性衍生物例如O-乙酰基-(+)扁桃酰氯酰化,并将如此获得的非对映异构体混合物按本身已知的方法例如通过层析来分离;所述式(IIIf)化合物如下:在一般通过酸解例如用盐酸水解去除这两个N-酰基后得到式(IIIg)化合物:将式(IIIg)化合物的4-氨基按本身已知的方法、一般是通过与苯甲醛反应暂时保护起来。然后例如按变异法a)所述通过与式(IIb)化合物偶联引入3,5-双(三氟甲基)苯甲酰基基团,然后将该保护基团一般通过用酸例如盐酸处理去除,得到相应的式(IIIa)化合物。
式(IIa)化合物可按本身已知的方法来制备,一般是通过由式(IIIg)化合物出发,将其按例如变异法b)所述在偶联剂存在下与式(IIIb)化合物偶联,因此引入相应的酰基基团。于是得到相应的式(IIa)化合物。
得到的盐可按本身已知的方法转化成游离的化合物,一般是通过用碱或酸处理;所述碱有例如碱金属氢氧化物,金属碳酸盐或金属碳酸氢盐,或氨,或另一种本文开头所述的成盐碱,所述酸有无机酸,例如盐酸,或另一种本文开头所述的成盐酸。
得到的盐可按本身已知的方法转化成其它的盐;在酸加成盐的情况下,一般通过用适宜的金属盐例如另一种酸的钠盐、钡盐或银盐在所生成的无机盐不溶解因而能从反应平衡中被去除的适宜的溶剂中进行处理;而在碱盐的情况下,通过生成游离酸并重新成盐来转化。
式(I)化合物包括其盐还可以水合物的形式获得,或者还可以包含用于结晶的溶剂。
由于所述新化合物的游离形式与其盐的形式密切相关,本说明书全文涉及的游离化合物及其盐也同样适于相应的盐或游离的化合物。
由于所得到的非对映异构体和外消旋体混合物的组分的物理化学上的差异,可将其按本身已知的方法、一般是通过层析和/或分级结晶分离成纯的非对映异构体和外消旋物。
此外,可将所得到的外消旋物用已知的方法、一般是用下述方法分离成旋光对映体:使用微生物用光学活性溶剂重结晶,或例如根据存在于式(I)化合物中的酸性、碱性或可官能改性的基团使生成的非对映异构体混合物或外消旋物与光学活性辅助化合物、光学活性酸、碱或光学活性醇反应,成为非对映异构的盐和官能衍生物例如酯,将它们分离成非对映异构体,由此可按各自的常规方法释放出各自所需的对映体。适宜于该目的的碱、酸和醇一般是光学活性生物碱,例如马钱子碱,辛可宁或番木鳖碱,或D-或L-(1-苯基)乙胺,3-甲基哌啶,麻黄碱,苯丙胺和可通过合成获得的类似的碱,光学活性羧酸或磺酸,例如奎尼酸或D-或L-酒石酸,D-或L-二邻甲苯甲酰基酒石酸,D-或L-苹果酸,D-或L-扁桃酸,或D-或L-樟脑磺酸,或光学活性醇,例如冰片或D-或L-(1-苯基)乙醇。
本发明还涉及本发明方法的一些实施方案,其中将在该方法的任何阶段作为中间体可获得的化合物用作原料并进行其余的步骤,或者原料以盐的形式使用或者最好是在反应条件下生成。
本发明还涉及已被专门开发出用于制备所述新化合物、尤其是能制得在本文开头所述的作为特别优选的式(I)化合物的新的原料,涉及其制备方法及其作为中间体的用途。
式(I)新化合物可例如以药用组合物的形式来使用,所述药用组合物含有治疗有效量的所述活性成分,若合适,还含有无机的或有机的、固体的或液体的适于肠内用例如口服或不经肠用的药学上可接受的载体。因此,使用片剂或胶囊剂,所述片剂或胶囊剂含有所述活性成分以及稀释剂,一般是乳糖、葡萄糖、蔗糖、甘露醇、山梨醇、纤维素和/或润滑剂,例如硅藻土、滑石、硬脂酸或其盐,例如硬脂酸镁或硬脂酸钙,和/或聚乙二醇。片剂还可以含有粘合剂,特别是硅酸铝镁,淀粉,一般是玉米淀粉、小麦淀粉、稻米淀粉或木薯淀粉,明胶,西黄蓍胶,甲基纤维素,羧甲基纤维素钠和/或聚乙烯吡咯烷酮和,若需要,崩解剂,一般是淀粉、琼脂、海藻酸或其盐,例如海藻酸钠,和/或泡腾混合物,或吸收剂,着色剂,矫味剂和甜味剂。式(I)新化合物还可以以不经肠用组合物或灌注溶液的形式来使用。这样的溶液最好是例如在仅含有所述活性成分或还含有载体例如甘露醇的冻干组合物的情况下可在使用前制备的等渗的水溶液或悬浮液。所述药用组合物可被灭菌和/或可含有赋形剂,一般是防腐剂,稳定剂,润湿剂和/或乳化剂,增溶剂,调节渗透压用盐和/或缓冲剂。如此获得的,若需要,还含有其它药理活性物质的药用组合物按本身已知的方法,通过常规混合、制粒、包糖衣、溶解或冷冻干燥的方法来制备,所述药用组合物含有大约0.1%至100%、最好是大约1%至50%、冷冻干燥物至大约100%的活性成分。
本发明还涉及式(I)化合物、优选为药用组合物形式的式(I)化合物的用途。剂量可以取决于多种因素,例如施用方式,种类、年龄和/或个人状况。在口服情况下,日剂量在大约0.25-10mg/kg范围内,对于体重为大约70kg的温血动物,日剂量优选在大约20-500mg范围内。
下面将用下列实施例说明本发明,其中的温度均为摄氏度,压力均为毫巴。FD-MS=场解析质谱。实施例1:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯苄基)哌啶-4-基]-4-氧代-4H-1-苯并吡喃-2-甲酰胺
将3.77ml三乙胺和2.35g4-氧代-4H-1-苯并吡喃-2-甲酰氯(得自由例如Sigma提供的相应的羧酸与亚硫酰氯的反应)加至4.36g(2R,4S)-4-氨基-1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯苄基)哌啶的二氯甲烷(200ml)溶液中,并将混合物于20℃搅拌4小时。将反应混合物依次用1N盐酸水溶液、盐水和水洗涤,用硫酸镁干燥,并真空浓缩。将得到的泡沫状物用叔丁基甲基醚/己烷/二氯甲烷重结晶,得到标题化合物,为无色结晶,m.p.21l-212℃,[α]D 20=3.7±2.6(c=0.382,甲醇)。
起始化合物可如下制备:a)N-[1-(4-氯苄基)丁-3-烯基]-N-乙氧基甲基氨基甲酸甲酯:将10.0g氢化钠(80%,在矿物油中,333mmol)在无水四氢呋喃[THF]中的悬浮液在氩气下回流。用1小时的时间滴加60.5g(238mmol)[1-(4-氯苄基)丁-3-烯基]氨基甲酸甲酯[McCarty F J等人,J.Med.Chem.,1968,11(3),534]的无水THF(50ml)溶液。然后将混合物回流2小时直至无气体逸出。将混合物冷却至0℃,并滴加氯甲基乙基醚以使得反应温度不升至5℃以上。然后将混合物缓慢加热至25℃并搅拌12小时。在将过量的氢化钠小心用1ml水处理掉后加入较多的水。使相分离,并将水相用叔丁基甲基醚萃取。将合并的有机相用盐水洗涤,用硫酸钠干燥,并蒸发浓缩。将粗产物在0.1毫巴下蒸馏,其沸点范围为120-125℃。DC:乙酸乙酯/己烷(1∶6)Rf=0.34,FD-MS:M+=311(313)。b)(2R*,4S*)-4-乙酰基氨基-2-(4-氯苄基)哌啶-1-羧酸甲酯:将20.6(308mmol)氯磺酸加至-40℃的500ml乙腈中。将48.0g(154mmol)N-[1-(4-氯苄基)丁-3-烯基]-N-乙氧基甲基氨基甲酸甲酯的乙腈(50ml)溶液滴加至该混合物中以使得反应温度不升高至-10℃以上。然后在将反应混合物于-15℃搅拌20分钟后加入370ml 2N氢氧化钠溶液和100ml10%碳酸氢钠水溶液。使相分离,并将水相用甲苯萃取两次。将合并的有机相用硫酸钠干燥。将粗产物用甲苯结晶,得到标题化合物,为白色结晶。M.p.:169-170℃。DC:二氯甲烷/甲醇/浓氨水(90∶9∶1)Rf=0.42,FD-MS:M+=325。c)(2R*,4S*)N-[2-(4-氯苄基)哌啶-4-基]乙酰胺:将51.8ml33%的溴化氢乙酸溶液加至(2R*,4S*)-4-乙酰基氨基-2-(4-氯苄基)哌啶-1-羧酸甲酯(30.0g,92.3mmol)中。16小时后,向混合物中加入200ml水,然后用甲苯洗涤两次。将水相碱化,并用乙酸乙酯萃取两次。将有机相用钾干燥,并在旋转蒸发器上蒸发浓缩。标题化合物以盐酸盐的形式由乙醇/乙酸乙酯中结晶。M.p.:288-289℃。DC:二氯甲烷/甲醇/浓氨水(90∶9∶1)Rf=0.17,FD-MS:(M+1)+=267。d)(2’S,2R,4S)乙酸-2-[-4-乙酰基氨基-2-(4-氯苄基)哌啶-1-基]-2-氧代-1-苯基乙酯:将外消旋的N-[2-(4-氯苄基)哌啶-4-基]乙酰胺盐酸盐(20.5g,67.6mmol)于0℃在剧烈搅拌下加至34ml 2N氢氧化钠溶液、150ml10%碳酸氢钠水溶液和50ml二氯甲烷中。用1小时的时间滴加S(+)-O-乙酰基扁桃酰氯[Pracejus G,Ann.,1959,622,10](14.9g,70mmol)。然后将混合物于+4℃搅拌1小时。使相分离,将有机相用硫酸钠干燥,并在旋转蒸发器上蒸发浓缩。用二氯甲烷/叔丁基甲基醚结晶两次,以纯的非对映异构体形式分离出标题化合物。M.p.:209-211℃,DC:二氯甲烷/异丙醇(9∶1)Rf=0.65,FD-MS:M+=443。[α]D=+77.5°(c=1,二氯甲烷)。
母液主要含有非晶性非对映异构体(2’S,2S,4R)N-[2-(4-氯苄基)-1-(乙酰氧基苯基乙酰基)哌啶-4-基]乙酰胺,DC:二氯甲烷/异丙醇(9∶1)Rf=0.70。e)(2R,4S)-4-氨基-1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯苄基)哌啶:将(2’S,2R,4S)乙酸-2-[-4-乙酰基氨基-2-(4-氯苄基)哌啶-1-基]-2-氧代-1-苯基乙酯(37.4g,84.5mmol)在370ml 6N盐酸中回流2天。冷却后,将混合物用固体氢氧化钠碱化,并用二氯甲烷萃取。将合并的有机相用碳酸钾干燥,并在旋转蒸发器上蒸发浓缩。将几乎由纯的(2R,4S)-2-(4-氯苄基)哌啶-4-胺(19.0g 84.5mmol,100%)构成的残余物溶于8.5ml(84.5mmol)苯甲醛中,并在旋转蒸发器上与150ml甲苯一起浓缩两次。将油状残余物溶于180ml二氯甲烷和15.3ml(110mmol)三乙胺中,并冷却至10℃。用15分钟的时间滴加双(三氟甲基)苯甲酰氯(25.7g,92.9mmol),然后将混合物于25℃搅拌1小时。向反应混合物中加入250ml 1N盐酸,并在旋转蒸发器上减压去除二氯甲烷。加入己烷和乙醇直至获得两个均相。将有机相去除,并将混合物用己烷洗涤直至苯甲醛被完全除去。将混合物用氢氧化钠固体碱化,并用氢氧化钠反复萃取。将有机相用硫酸钠干燥,并在旋转蒸发器上浓缩。用叔丁基甲基醚/己烷结晶,得到标题化合物,为白色结晶。M.p.:79-81℃。DC:二氯甲烷/甲醇/浓氨水(90∶9∶1)Rf=0.21,FD-MS:(M+1)+=465。[α]D=-12.7°(c=1,二氯甲烷)。
按照实施例1中所述的通法还可以制得下列化合物;相应的原料(2R,4S)-4-氨基-1-(3,5-双(三氟甲基)苯甲酰基)-2-苄基哌啶的制备在EP-A-532456,实施例38f中有述:实施例1/1:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-苄基哌啶-4-基]-4-氧代-4H-1-苯并吡喃-2-甲酰胺,m.p.107-108°,[α]D 20=18.3±2.6(c=0.388,甲醇)。实施例1/2:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-苄基哌啶-4-基]-7-氯-4-氧代-4H-1-苯并吡喃-2-甲酰胺,m.p.224-226°,[α]D 20=21.5±2.5(c=0.40,甲醇)。实施例1/3:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-苄基哌啶-4-基]-7-甲氧基-4-氧代-4H-1-苯并吡喃-2-甲酰胺,m.p.190-192°,[α]D 20=25.7±2.3(c=0.44,甲醇)。实施例1/4:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-苄基哌啶-4-基]-7-甲硫基-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例1/5:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-苄基哌啶-4-基]-6-甲氧基-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例1/6:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-苄基哌啶-4-基]-6-氯-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例1/7:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-苄基哌啶-4-基]-6-溴-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例1/8:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-苄基哌啶-4-基]-6-氟-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例1/9:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-苄基哌啶-4-基]-6-甲基-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例1/10:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-苄基哌啶-4-基]-6-氰基-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例1/11:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-苄基哌啶-4-基]-6-硝基-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例1/12:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-苄基哌啶-4-基]-7-氟-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例1/13:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-苄基哌啶-4-基]-7-溴-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例1/14:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-苄基哌啶-4-基]-7-甲基-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例1/15:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-苄基哌啶-4-基]-7-硝基-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例1/16:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-苄基哌啶-4-基]-6,7-二甲氧基-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例2:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-苄基哌啶-4-基]-7-羟基-4-氧代-4H-1-苯并吡喃-2-甲酰胺
将0.127g(2R,4S)-4-氨基-1-(3,5-双(三氟甲基)苯甲酰基)-2-苄基哌啶的二氯甲烷(3.1ml)溶液溶于在2ml二氯甲烷/二甲基甲酰胺(1∶1)中的0.038g4-二甲氨基吡啶、0.059g N-(3-二甲氨基丙基)-N’-乙基碳化二亚胺盐酸盐和0.064g7-羟基-4-氧代-4H-1-苯并吡喃-2-羧酸中,并于20°搅拌24小时。将反应混合物蒸发浓缩,并将残余物在硅胶上用二氯甲烷和二氯甲烷/甲醇(19∶1)层析,得到标题化合物,为淡黄色粉末,m.p.为224-225°;[α]D 20=23.3±3.5(c=0.288,甲醇)。
按照实施例2中所述的通法还可以制得下列化合物:实施例2/1:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-苄基哌啶-4-基]-6-溴-7-羟基-4-氧代-4H-1-苯并吡喃-2-甲酰胺。M.p.:173-174°。实施例3:按照实施例1中所述的通法,由(2R,4S)-4-氨基-1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯苄基)哌啶[实施例1e)]出发,还可以制得下列化合物:实施例3/1:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯苄基)哌啶4-基]-7-氯-4-氧代-4H-1-苯并吡喃-2-甲酰胺。M.p.:218-220°,[α]D 20=31.5±2.0(c=0.50,甲醇)。实施例3/2:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯苄基)哌啶-4-基]-7-甲氧基-4-氧代-4H-1-苯并吡喃-2-甲酰胺。M.p.:198-200°,[α]D 20=29.7±2.2(c=0.45,甲醇)。实施例3/3:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯苄基)哌啶-4-基]-7-甲硫基-4-氧代-4H-1-苯并吡喃-2-甲酰胺。M.p.:137-140°,[α]D 20=20.8±2.8(c=0.355,甲醇)。实施例3/4:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯苄基)哌啶-4-基]-6-甲氧基-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例3/5:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯苄基)哌啶-4-基]-6-氯-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例3/6:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯苄基)哌啶-4-基]-6-溴-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例3/7:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯苄基)哌啶-4-基]-6-氟-4-氧代-4H-1-苯并吡喃-2-甲酰胺。M.p.:215-218°;Rf(乙酸乙酯/己烷4∶1)=0.58。作为原料所需的酰氯6-氟-4-氧代-4H-1-苯并吡喃-2-甲酰氯尤其在Chemical Abstracts:96:52132w或88:106066w中有述,并具有CAS登记号65843-87-0。实施例3/8:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯苄基)哌啶-4-基]-6-甲基-4-氧代-4H-1-苯并吡喃-2-甲酰胺。M.p.:240-241°;Rf(乙酸乙酯/己烷4∶1)=0.65。实施例3/9:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯苄基)哌啶-4-基]-6-氰基-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例3/10:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯苄基)哌啶-4-基]-6-硝基-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例3/11:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯苄基)哌啶-4-基]-7-氟-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例3/12:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯苄基)哌啶-4-基]-7-溴-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例3/13:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯苄基)哌啶-4-基]-7-甲基4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例3/14:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯苄基)哌啶-4-基]-7-硝基-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例3/15:(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯苄基)哌啶-4-基]-6,7-二甲氧基-4-氧代-4H-1-苯并吡喃-2-甲酰胺。实施例4:各含50mg活性成分的片剂可如下制备:
组成(10000片)
活性成分 500.0g
乳糖 500.0g
马铃薯淀粉 352.0g
明胶 8.0g
滑石粉 60.0g
硬脂酸镁 10.0g
二氧化硅(高度分散的) 20.0g
乙醇 适量
将活性成分与乳糖和292g马铃薯淀粉混合,然后将混合物用明胶的乙醇溶液润湿并过筛制粒。干燥后,将剩余的马铃薯淀粉、硬脂酸镁、滑石粉和二氧化硅混合,并压制成各重145.0mg并具有50.0mg活性成分含量的片剂。若期望,这些片剂可以具有分割刻痕以能较细致地调节剂量。实施例5:各含100mg活性成分的薄膜包衣片剂可如下制备:
组成(1000薄膜包衣片)
活性成分 100.0g
乳糖 100.0g
玉米淀粉 70.0g
滑石粉 8.5g
硬脂酸钙 1.5g
羟丙基甲基纤维素 2.36g
虫胶 0.64g
水 适量
二氯甲烷 适量
将活性成分、乳糖和40g玉米淀粉混合,然后将混合物用由15g玉米淀粉和水(在加热下)制成的糊状物润湿并制粒。将颗粒干燥,加入剩余的玉米淀粉、滑石粉和硬脂酸钙并与颗粒混合。将混合物压制成片(片重:280mg),然后将其用羟丙基甲基纤维素和虫胶的二氯甲烷溶液包衣。该包衣片的最后重量:283mg。实施例6:各含100mg活性成分的干填充胶囊可例如如下制备:
组成(1000粒胶囊)
活性成分 100.0g
乳糖 250.0g
微晶纤维素 30.0g
月桂基硫酸钠 2.0g
硬脂酸镁 8.0g
将月桂基硫酸钠通过过0.2mm筛目的筛加至冻干的活性成分中。将这两种组分紧密混合。随后先通过过0.6mm筛目的筛加入乳糖,然后通过过0.9mm筛目的筛加入微晶纤维素。将混合物再紧密混合10分钟。最后通过过0.8mm筛目的筛加入硬脂酸镁。再混合3分钟后,以每个胶囊390mg的量将如此获得的配制物填充至0号干填充胶囊中。实施例7:含有0.1%(重量)活性成分的含抛射剂的吸入悬浮液:
组成 %(重量)
活性成分,微粒化的 0.1
脱水山梨醇三油酸酯 0.5
抛射剂A(三氯三氟乙烷) 4.4
抛射剂B(二氯二氟甲烷和 15.0
1,2-二氯四氟乙烷) 80.0
使用一种常规的均化器在排阻湿气的条件下将活性成分悬浮在三氯三氟乙烷中,同时加入脱水山梨醇三油酸酯。然后将该悬浮液填充至装有计量阀的气溶胶容器中。将该容器密封,并在压力下填充抛射剂B。
Claims (14)
2.按照权利要求1的式(I)化合物及其药学上可接受的盐,其中环A未被取代或者被卤素单取代,和环B未被取代或者被1-2个选自低级烷基、羟基、低级烷氧基、低级烷硫基、卤素、硝基和氰基的取代基取代。
3.按照权利要求1的式(I)化合物及其药学上可接受的盐,其中环A未被取代或者被氯单取代,和环B未被取代或者被1-2个选自羟基、低级烷氧基、氯和溴的取代基取代。
4.按照权利要求1的式(I)化合物及其药学上可接受的盐,其中环A未被取代或者被氯单取代,和环B未被取代或者被氯或氟单取代。
6.按照权利要求1的(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯苄基)哌啶-4-基]-4-氧代-4H-1-苯并吡喃-2-甲酰胺及其药学上可接受的盐。
7.按照权利要求1的(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-苄基哌啶-4-基]-4-氧代-4H-1-苯并吡喃-2-甲酰胺及其药学上可接受的盐。
8.按照权利要求1的(2R,4S)-N-[1-(3,5-双(三氟甲基)苯甲酰基)-2-(4-氯苄基)哌啶-4-基]-6-氟-4-氧代-4H-1-苯并吡喃-2-甲酰胺及其药学上可接受的盐。
9.包含按照权利要求1至8之任一项的化合物和至少一种药学上可接受的载体的药用组合物。
10.用于治疗动物或人的按照权利要求1至8之任一项的化合物。
11.按照权利要求1至8之任一项的化合物在治疗对NK1受体的拮抗作用敏感的疾病方面的用途。
12.按照权利要求1至8之任一项的化合物在制备药用组合物方面的用途。
13.按照权利要求1至8之任一项的化合物在制备用于治疗对NK1受体的拮抗作用敏感的疾病的药用组合物方面的用途。
14.按照权利要求1的式(I)化合物的制备方法,包括:(a)使式(IIa)化合物与式(IIb)化合物或其盐反应,所述式(IIa)和(IIb)如下:式中环A和B的定义同式(I)式中Q1是可被醚化的羟基,例如羟基、低级烷氧基或未被取代的或被取代的苯氧基,或活性的酯化羟基,例如卤素、优选氯,或下式基团:或者(b)使式(IIIa)化合物与式(IIIb)化合物或其盐反应,所述式(IIIa)和(IIIb)如下:式中环A的定义同式(I),式中环B的定义同式(I),和Q1是可被醚化的羟基,例如羟基、低级烷氧基或未被取代的或被取代的苯氧基,或活性的酯化羟基,例如卤素、优选氯,或下式基团:并且,若期望,将一个式(I)化合物转化成另一个式(I)化合物和/或,若期望,将所得到的盐转化成游离的化合物或另一种盐和/或,若期望,将所得到的具有成盐性能的游离的式(I)化合物转化成盐和/或,若期望,将所得到的立体异构体或非对映异构体的混合物分离成单独的立体异构体和非对映异构体。
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EP (1) | EP0739892B1 (zh) |
JP (1) | JP3068458B2 (zh) |
KR (1) | KR100416674B1 (zh) |
CN (1) | CN1063176C (zh) |
AR (1) | AR001813A1 (zh) |
AT (1) | ATE224891T1 (zh) |
AU (1) | AU714523B2 (zh) |
BR (1) | BR9602025A (zh) |
CA (1) | CA2174707C (zh) |
DE (1) | DE59609707D1 (zh) |
DK (1) | DK0739892T3 (zh) |
ES (1) | ES2183923T3 (zh) |
HU (1) | HUP9601062A3 (zh) |
IL (1) | IL117989A (zh) |
NO (1) | NO309813B1 (zh) |
NZ (1) | NZ286422A (zh) |
PT (1) | PT739892E (zh) |
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CN1300163C (zh) * | 2004-06-23 | 2007-02-14 | 南京大学 | 3-羟基色原酮糖苷及其制法和用途 |
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JP2000511193A (ja) * | 1996-05-24 | 2000-08-29 | イーライ・リリー・アンド・カンパニー | 高血圧の処置法 |
TW426667B (en) * | 1997-11-19 | 2001-03-21 | Pfizer | Piperidinylaminomethyl trifluoromethyl cyclic ether compounds as substance P antagonists |
JP4510290B2 (ja) * | 1998-08-25 | 2010-07-21 | ノバルティス アーゲー | 慢性疲労症候群および/または線維筋痛の処置のためのサブスタンスpアンタゴニストの使用および慢性疲労症候群の処置のためのnk−1レセプターアンタゴニストの使用 |
EP1178984B1 (en) * | 1999-05-21 | 2003-03-19 | Pfizer Products Inc. | 1-trifluoromethyl-4-hydroxy-7-piperidinyl-aminomethylchroman derivatives |
GB0220953D0 (en) * | 2002-09-10 | 2002-10-23 | Novartis Ag | Organic compounds |
GB2394417A (en) * | 2002-10-24 | 2004-04-28 | Novartis Ag | Solid dispersion comprising a piperidine substance P antagonist and a carrier |
DE10256182A1 (de) * | 2002-12-02 | 2004-06-24 | Merck Patent Gmbh | 2-Oxadiazolchromonderivate |
DE10256174A1 (de) * | 2002-12-02 | 2004-06-09 | Merck Patent Gmbh | 2-Benzoylchromonderivate |
US20050209274A1 (en) * | 2004-02-26 | 2005-09-22 | Lynch John K | Antagonists of melanin concentrating hormone effects on the melanin concentrating hormone receptor |
AU2007238071B2 (en) * | 2006-04-18 | 2012-06-07 | Abbvie Inc. | Antagonists of the vanilloid receptor subtype 1 (VR1) and uses thereof |
GB0701365D0 (en) * | 2007-01-24 | 2007-03-07 | Glaxo Group Ltd | Novel pharmaceutical compositions |
UA105182C2 (ru) | 2008-07-03 | 2014-04-25 | Ньюрексон, Інк. | Бензоксазины, бензотиазины и родственные соединения, которые имеют ингибирующую nos активность |
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DE3117389A1 (de) * | 1981-05-02 | 1982-11-18 | Boehringer Mannheim Gmbh, 6800 Mannheim | Benzopyranylether, verfahren zu deren herstellung sowie diese verbindungen enthaltende arzneimittel |
MY110227A (en) * | 1991-08-12 | 1998-03-31 | Ciba Geigy Ag | 1-acylpiperindine compounds. |
WO1995011895A1 (en) * | 1993-10-26 | 1995-05-04 | Ciba-Geigy Ag | N-benzoyl-4-oxy/thio-2-substituted piperidines as substance-p receptor antagonists |
ATE212981T1 (de) * | 1994-09-30 | 2002-02-15 | Novartis Erfind Verwalt Gmbh | 1-acyl-4-aliphatische aminopiperidin verbindungen |
TW397825B (en) * | 1994-10-14 | 2000-07-11 | Novartis Ag | Aroyl-piperidine derivatives |
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HU9601062D0 (en) | 1996-06-28 |
KR100416674B1 (ko) | 2004-06-11 |
JP3068458B2 (ja) | 2000-07-24 |
IL117989A0 (en) | 1996-08-04 |
EP0739892A3 (de) | 1997-01-22 |
CA2174707C (en) | 2008-03-25 |
US5604247A (en) | 1997-02-18 |
DK0739892T3 (da) | 2003-01-20 |
HUP9601062A3 (en) | 1998-10-28 |
EP0739892B1 (de) | 2002-09-25 |
MX9601515A (es) | 1997-09-30 |
ZA963211B (en) | 1996-10-24 |
JPH093066A (ja) | 1997-01-07 |
NZ286422A (en) | 1998-01-26 |
AR001813A1 (es) | 1997-12-10 |
CA2174707A1 (en) | 1996-10-25 |
AU5080596A (en) | 1996-11-07 |
RU2156250C2 (ru) | 2000-09-20 |
NO309813B1 (no) | 2001-04-02 |
ATE224891T1 (de) | 2002-10-15 |
NO961616D0 (no) | 1996-04-23 |
TW475930B (en) | 2002-02-11 |
KR960037680A (ko) | 1996-11-19 |
PT739892E (pt) | 2003-01-31 |
DE59609707D1 (de) | 2002-10-31 |
HUP9601062A2 (en) | 1997-10-28 |
AU714523B2 (en) | 2000-01-06 |
ES2183923T3 (es) | 2003-04-01 |
IL117989A (en) | 2000-01-31 |
BR9602025A (pt) | 1998-10-06 |
NO961616L (no) | 1996-10-25 |
EP0739892A2 (de) | 1996-10-30 |
CN1063176C (zh) | 2001-03-14 |
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