CN1336924A - 作为5-ht重吸收抑制剂和5-ht1b/1d配体的酰胺和脲衍生物 - Google Patents
作为5-ht重吸收抑制剂和5-ht1b/1d配体的酰胺和脲衍生物 Download PDFInfo
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- CN1336924A CN1336924A CN98814399A CN98814399A CN1336924A CN 1336924 A CN1336924 A CN 1336924A CN 98814399 A CN98814399 A CN 98814399A CN 98814399 A CN98814399 A CN 98814399A CN 1336924 A CN1336924 A CN 1336924A
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Abstract
式I的酰胺和脲衍生物R1-(CH2)n-(Y)q-(Z)r-CO-NH-R2,其中R1、n、Y、q、Z、r和R2具有权利要求1中说明的意义,是有效的5-HT1B/1D拮抗剂,具有5-HT重摄取抑制作用,适于治疗和预防焦虑症、抑郁症、精神分裂症、强迫性思维、迟发性运动障碍、认知障碍、年龄有关的记忆障碍,正面影响强迫观念与行为疾病(OCD),并能治疗和控制大脑梗塞的后遗症,如中风和大脑局部缺血。
Description
本发明涉及式I的酰胺和脲衍生物及其生理上可接受的盐
R1-(CH2)n-(Y)q-(Z)r-CO-NH-R2 I其中R1 是3-吲哚基,它是非取代或被A、AO、OH、Hal、CN、NO2、
NH2、NHA、NA2、COA、CONH2、CONHA、CONA2、CH2OH、
CH2OA、CH2NH2、CH2NHA、CH2NA2、COOH和/或COOA单
环,它们也可以被部分脱氢,Z 是(CH2)n或(CH2)nNH-,q 是0或1,r 是0或1,R3 是A,R4 是AO,Hal是F、Cl、Br或I,A 是具有1-6个C原子的直链或支链烷基,条件是q和r不同时为0。
本发明目的是发现具有有用性质的新化合物,具体地讲,即那些可用于制备药物的化合物。
现已发现:由于式I化合物及其生理上可接受的酸加成盐对中枢神经系统有影响,它们具有有用的药理性质并具有较好的耐受力。这些化合物通过抑制5-羟色胺(5-HT)的重吸收并且对5-HT1B/1D受体具有强亲和作用,尤其可影响5-羟色胺能的传递。由于具有这些综合活性,这些化合物尤其可适用于作为抗抑郁剂和抗焦虑剂。
本发明化合物呈现5-HT-激动和拮抗性质,而且还显示出5-HT重吸收抑制作用。由于其体外呈现5-HT重吸收抑制作用,所以可用于突触小体的吸收的抑制(Wong等,Neuropsychopharmacology8(1993),22-33)。在体内,根据Waldmeier(European J.Pharmacol.46(1997),387-392)的方法,研究了在小鼠脑组织中的这种性质。如,可根据Peroutka等(Synapse 3(1983),61-66)和Hoyer等(EuropeanJPharmacol.118(1985),1-12)所述的方法, 测定对5-HT1B/1D受体的亲和作用,根据Choppin等(British Journa1 of Pharmacology114(1995),309-314)的方法,测定5-HT1B/1D-拮抗性质。
例如,在专利申请WO97/14689或WO97/41802中,说明了同样呈现5-HT1B/D[原文如此]拮抗[原文如此]作用的类似化合物。
因此,式I化合物适用于兽医学和人类医学中,用于治疗中枢神经系统功能紊乱以及炎症。它们可用于预防和控制脑梗塞(大脑卒中)后遗症,如中风和大脑局部缺血,用于治疗精神抑制药的锥体束外运动原副作用以及帕金森氏病,用于阿尔滋海默氏病的急性和症状治疗,以及用于治疗肌萎缩的晚期硬化。同样地,它们适用于作为治疗脑和脊髓外伤的治疗剂。但是,这些化合物尤其适合用作药用活性化合物,用作抗焦虑剂、抗抑郁剂、抗精神病药、精神抑制药、抗高血压药和/或阳性影响强迫观念与行为疾病(OCD)、焦虑症、恐慌病发作、精神病、厌食、妄想、旷野恐怖症、偏头痛、阿尔滋海默氏病、睡眠紊乱、迟发性运动障碍、认知障碍、年龄依赖性记忆障碍、饮食紊乱如食欲过盛、药物滥用和/或性功能障碍。
另外,它们适用于治疗内分泌紊乱如血乳酸过多,还可用于血管痉挛、高血压和胃肠道疾病。
它们还可用作制备其它药用活性化合物的中间体。
本发明涉及式I的酰胺和脲衍生物及其生理上可接受的酸加成盐。
本发明尤其涉及选自下列的式I化合物及其生理上可接受的盐:a)N-[2-(5-氟-3-吲哚基)乙基基]-N’-[4-甲氧基-3-(4-甲基-1-哌嗪基)苯基]脲;b)4-(5-氰基-3-吲哚基)-N-[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]哌啶-1-甲酰胺;c)4-(6-氟-3-吲哚基)-N-[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]哌啶-1-甲酰胺;d)3-{1-[4-甲氧基-3-(4-甲基-1-哌嗪基)苯基氨基羰基]-4-哌啶基}吲哚-5-甲酰胺;e)4-(5-氟-3-吲哚基)-N-[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]哌啶-1-甲酰胺;f)4-[2-(3-吲哚基)乙基]-N-[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]哌啶-1-甲酰胺;g)4-(3-吲哚基)-N-[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]哌啶-1-甲酰胺;h)4-(4-氟-3-吲哚基)-N-[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]哌啶-1-甲酰胺;j)4-(7-甲氧基吲哚-3-基)哌啶-1-甲酸[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]酰胺;j)4-[4-(5-氟-3-吲哚基)丁基]哌嗪-1-甲酸[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]酰胺;k)4-(5-氰基引哚-3-基)-3,6-二氢-2H-吡啶[缺漏]1-甲酸[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]酰胺;l)3-(5-氟吲哚-3-基)吡咯烷-1-甲酸[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]酰胺;m)4-(5-氟吲哚-3-基)环己烷甲酸[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]酰胺;n)N-[2-(5-羟基-3-吲哚基)乙基]-N’-[4-甲氧基-3-(4-甲基-1-哌嗪基)苯基]脲;o)N-{2-[4-(6-氟-3-吲哚基)哌啶-1-基]乙基}-N’-[4-甲氧基-3-(4-甲基-1-哌嗪基)苯基]脲;p)N-[4-(5-氰基-3-吲哚基)丁基]-N’-[4-甲氧基-3-(4-甲基-1-哌嗪基)苯基]脲;q)4-[4-(5-氰基-3-吲哚基)丁基]哌嗪-1-甲酸[4-甲氧基-3-(4-甲基-1-哌嗪基)苯基]酰胺;r)4-(5-氟吲哚-3-基)哌啶-1-甲酸(2,3-二氢-1’-甲基螺(苯并呋喃)-3,4-哌啶)酰胺;s)N-{2-[4-(6-氟-3-吲哚基)哌啶-1-基]乙基}-[2,3-二氢-1-甲基螺(苯并呋喃)-3,4-哌啶]脲。
因此本发明涉及式I化合物以及制备根据权利要求1的式I化合物的方法。
制备方法特征如下:a)使式II化合物
II H2N-R2其中R2具有权利要求1中指明的意义,与式III化合物反应
III R1-(CH2)n-(Y)q-(Z)r-CO-L其中L是Cl、Br、I、OH或另一种活性[原文如此]功能修饰的OH基
团或易于亲核取代的离去基团和R1、n、Y、q、Z和r具有权利要求1中指明的意义,或者b)使式II胺成分
II H2N-R2与式IV成分反应
IV R1-(CH2)n-(Y)q-(Z)r-H其中R1、R2、n、Y、q、Z和r具有权利要求1中说明的意义,同时加入偶合剂,如N,N’-羰基二咪唑、双光气、三光气或其它氯甲酸酯,和/或c)通过如形成OH基团而裂解OA基团和/或将CN、COOH或COOA基团衍生化,将基团R1、R3和/或R4中之一任选转化为另一个基团R1、R3和/或R4,和/或如将伯或仲N原子烷基化,和/或通过用酸或碱处理,将获得的式I的碱或酸转化为其一种盐。
同样本发明涉及含有式I化合物及其生理上可接受的盐的药物,其具有5-HT1B/D-拮抗[原文如此]和5-HT重吸收抑制作用。
本发明涉及式I化合物和其对映体和非对映体及其盐类。
对于所有出现2或多次的基团,如A或R3,条件是其意义都彼此独立。
基团A是烷基,具有1-6个,优选1、2、3或4个,特别优选1或2个碳原子。因此,烷基尤其是,如甲基、以及乙基、正丙基、异丙基、正丁基、仲丁基或叔丁基,以及戊基、1-、2-或3-甲基丁基、1,1-、1,2-或2,2-二甲基丙基、1-乙基丙基、己基、1-、2-、3-或4-甲基戊基、1,1-、1,2-、1,3-、2,2-、2,3-或3,3-二甲基丁基、1-或2-乙基丁基、1-乙基-1-甲基丙基、1-乙基-2-甲氧基丙基、1,1,2-或1,2,2-三甲基丙基。
OA优选是甲氧基、以及还可以是乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基。
NHA优选是甲氨基、还可以是乙氨基、异丙氨基、正丁氨基、异丁氨基、仲丁氨基或叔丁氨基。NA2优选是二甲氨基、还可以是N-乙基-N-甲氨基、二乙氨基、二正丙氨基、二异丙氨基或二正丁氨基。由此可得,CO-NHA优选是N-甲基氨基甲酰基或N-乙基氨基甲酰基;CO-NA2优选是N,N-二甲基氨基甲酰基或N,N-二乙基氨基甲酰基。
Hal优选是氟、氯、溴或碘,尤其是氟或氯。
n是0、1、2、3或4,尤其是0、2或4。
基团R3是各种情况下彼此独立的A,式(Ic)中的两个基团R3可能相同或不同。优选它们彼此相同,尤其优选都是甲基。
Y优选是1,4-亚哌嗪基或1,4-亚哌啶基环,它们还可以部分脱氢,优选1,4-取代的3,6-二氢-2H-吡啶环,还优选1,3-亚吡咯烷基或1,4-亚环己基环。
R1优选是2-或3-吲哚基,它是未取代的或被Hal、CN、A、AO、CONH2、CONHA、CONA2、COOH、COOA、CH2Ar、CH2OAr和/或CH2NA2单或双取代,尤其是单取代,特别优选3-吲哚基。所述吲哚基优选在5-位被取代,还可以在4、6-或7-位上被取代。
因此,R1特别优选是3-吲哚基、5-或6-甲基吲哚-3-基、5-或6-甲氧基吲哚-3-基、5-或6-羟基吲哚-3-基、4-、5-或6-氟吲哚-2-基、4-、5-或6-氟吲哚-3-基、5-或6-氰基吲哚-3-基、5-或6-氯吲哚-3-基、5-或6-羧基吲哚-3-基、5-或6-甲氧基羰基吲哚-3-基、5-或6-羟基吲哚-3-基、5-或6-羟甲基吲哚-3-基、5-或6-氨基甲基吲哚-2-基、5-或6-氨基甲基吲哚-3-基,以及还可以是5-或6-溴吲哚-3-基、5-或6-乙基吲哚-3-基、5-或6-异丙基吲哚-3-基、5-或6-二甲氨基吲哚-3-基或5-或6-乙氧基吲哚-3-基。
R2是(Ia)、(Ib)、(Ic)或(Id)。本文最优选的化合物是那些其中含有基团[原文如此](Ia)、(Ic)或(Id)作为R2的化合物。
m优选是1或2,更优选2。
Z是(CH2)n或(CH2)nNH-,n优选是2或4。
q和r各自是0或1,条件是q和r不同时为0。
在本发明中,对于所有在分子中出现2次或多次的基团,条件是它们可以相同或不同,即彼此独立。
因此,本发明尤其涉及那些式I化合物,其中至少一个以上提到的基团具有以上说明的优选意义。某些化合物的优选基团可用下式I1-I12表示,其与式I相符,其中未详细说明的基团与式I中说明的意义相同,但是其中:在I1中,R2是基团(Ia);在I2中,R2具有I1中说明的意义,R4是甲氧基,R3是甲基;在I3中,R2是基团(Id);在I4中,R2具有I3中说明的意义,R3是甲基;在I5中,R2是基团(Ib)或(Ic);在I6中,q=1且r=0;在I7中,R1是被CN、F、OA、CONH2或OH单取代的吲哚-3-基;在I8中,q=0且r=1;在I9中,q和r具有I6中表示的意义,Y是1,4-亚哌啶基环;在I10中,q和r具有I6中表示的意义,Y是1,4-亚环己基或1,4-亚
哌嗪基环;在I11中,q和r具有I8中表示的意义,n是2或4;在I12中,q=r=1。
另外,式I化合物及其制备的原料可通过本身已知的方法制备,如文献中说明的方法(如标准著作,如Houben-Weyl,Methoden derOrganischen Chemie[Methods of Organic Chemistry],Georg ThiemeVerlag,Stuttgart;Organic Reactions,John Wiley&Sons,Inc.,NewYock),即,在已知的、适于所述反应的反应条件下来制备。还可对这些用法进行改变,这些改变本身是已知的,在此不详细说明。
如果要求,即不从反应混合物中分离它们,而是直接进行下一步反应以生成式I化合物,用于所要求保护的方法的原料也可以这样一种方式在原位形成。另一方面,可分步进行该反应。
在式III化合物中,基团L优选Cl或Br;但也可以是I、OH或其它优选的活性[原文如此]官能修饰的OH基团,尤其是具有1-6个碳原子的烷基磺酰氧基(如,甲磺酰氧基)或具有6-10个碳原子的芳基磺酰氧基(如,苯磺酰氧基、对甲苯磺酰氧基、1-或2-萘磺酰氧基)或其它的三氯甲氧基、烷氧基,如甲氧基、乙氧基、丙氧基或丁氧基,以及还可以是苯氧基。
式I化合物可优选通过使式II化合物与式III化合物反应来制备。
一般地,式II和III的原料是已知的;未知的式II和III化合物可根据与已知化合物类似的方法容易地制备。
式III化合物也可从已知的化合物制备,例如还可通过亲电取代或者,在某些情况下,还可通过亲核芳族取代制备。
此处合适的原料通常是对应的吲哚-3-链烷酸(其可根据Japp-Klinngemann型Fischer吲哚合成类似方法制备,参考Bottcher等,J.Med.Chem.1992,35,4020-4026或Iyer等,J.Chem.Soc.Perkin TransII1973,872-878),如果要求,可将其进一步还原和取代。
可根据从文献中得知的使胺烷基化或酰基化的方法,进行式II化合物与式III化合物的反应。然而,在惰性溶剂存在下,使该化合物反应也是可能的。适合的溶剂是,如,烃,如苯、甲苯、二甲苯;酮,如丙酮、丁酮;醇,如甲醇、乙醇、异丙醇、N-丁醇[原文如此];醚,如四氢呋喃(THF)或二氧六环;酰胺,如二甲基甲酰胺(DMF)或N-甲基吡咯烷酮;腈,如乙腈,以及如果适合,还可以是这些溶剂彼此的混合物或者与水的混合物。可优选加入酸结合剂,如碱金属或碱土金属的氢氧化物、碳酸盐或碳酸氢盐或者加入碱金属或碱土金属的其它弱酸盐,优选钾、钠或钙,或者加入有机碱,如三乙胺、二甲基苯胺、吡啶或喹啉,或者过量的式II的哌嗪衍生物。根据所采用的条件,反应时间为数分钟至14日之间,反应温度在约0-150℃之间,一般在20-130℃之间。
在进行该反应之前,可能有必要通过引入适当的保护基,将烷基化或酰基化反应得到的氨基进一步保护。术语氨基保护基一般是已知的,主要涉及一些适于保扩氨基使免于化学反应的基团,但在分子中其它位置进行所要求的反应之后,该基团又易于除去。由于本领域技术熟练人员从大量的参考文献及教科书中熟知这样的保护基及其引入和除去,在此没有必要对其赘述。
另外,式I化合物可通过式II的胺与含有基团R1的式IV的成分反应制备。
一般地,各合成部分是已知的或者可如上所述,根据已知的方法制备。
例如,还可根据Clitherow,J.W.等在J.Med.Chem.1994,37(15),2253-2257中说明的方法,制备其中R2是基团Ia(哌嗪衍生物)的式II化合物。类似地,如WO96/31508公开了其中R2是Ib(哌啶衍生物)的式II化合物。
WO96/19477公开其中R2是Id的式II螺环化合物,WO95/26328公开其中R2是基团Ic的式II化合物。
然后在偶合剂,如N,N’-羰基二咪唑、二光气或三光气或其它氯甲酸酯的帮助下,使式[原文如此]II和IV化合物进行[原文如此]反应。可根据以上说明的酰化反应的常规条件进行该合成。该偶合反应优选在室温下、采用N,N-羰基二咪唑,用三乙胺和乙腈作为惰性溶剂进行。
另外,可能采用H2气体及催化作用的过渡金属,如阮內镍或Pd,进行某些还原反应。可能以该种方式,用H置换如Cl、Br、I、SH或(某些情况下的)OH。类似地,可通过在甲醇中,用Pd/H2催化氢化,将硝基转化为NH2。
另外,可将对应于式I的化合物(但含有一或多个溶剂可分解基团以代替一或多个H原子)进行溶剂分解,尤其是水解,生成式I化合物。
此外,还可通过本身已知的方法,将式I化合物转化为另一个式I化合物。
通过部分水解,将适当取代的式I化合物衍生化,可获得其中R1是被CONH2、CONHA或CONA2取代的吲哚基的式I化合物。还可以先将式I的氰基取代化合物水解成酸,然后用伯或仲胺将该酸酰胺化。该游离羧酸与胺的反应优选在肽合成条件下进行。该反应优选在脱水剂如碳化二亚胺如二环己基碳化二亚胺或N-(3-二甲氨基丙基)-N-乙基碳化二亚胺、以及丙基膦酸酐(参考Angew.Chem.92,129(1980))、二苯基磷酰叠氮化物或2-乙氧基-N-乙氧基羰基-1,2-二氢喹啉存在下,在惰性溶剂中,如,卤代烃如二氯甲烷、醚如THF或二氧六环、酰胺如DMF或二甲基乙酰胺、腈如乙腈中,在温度约-10至40°之间,优选在0-30°之间进行。代替酸或酰胺,在反应中还可使用这些物质的活性衍生物,如其中活性基团被保护基在中间阻断的物质。还可使用酸的活性酯形式,其可例如通过加入1-羟基苯并三唑或N-羟基琥珀酰亚胺,原位临时形成。
然而以可逆方式,用酰胺为原料,通过脱水制备腈是特别有利的,如通过三氯乙酰氯/Et3N[Synthesis(2),184(1985)]或采用POCl3(J.Org.Chem.26,1003(1961))制备。
可用酸将得到的式I碱转化为相关的酸加成盐。可生成生理上可接受的盐的酸适于该反应。因此,可采用无机酸,如硫酸、氢卤酸如盐酸或氢溴酸、磷酸如正磷酸、硝酸、氨基磺酸,以及有机酸,尤其是脂族、脂环族、芳脂族、芳族或杂环单或多元羧酸、磺酸或硫酸,如甲酸、乙酸、丙酸、新戊酸、二乙基乙酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、乳酸、酒石酸、苹果酸、苯甲酸、水杨酸、2-苯基丙酸、柠檬酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲或乙磺酸、乙烷二磺酸、2-羟基乙磺酸、苯磺酸、对甲苯磺酸、萘磺酸和萘二磺酸以及十二烷基硫酸。
如果要求,若分子中无其它酸性基团存在,通过用强碱,如氢氧化钠或氢氧化钾或者碳酸氢钠或碳酸钾处理,可从式I的盐中释放出式I的游离碱。在式I化合物具有游离酸基团的情况下,也可通过用碱处理形成盐。适当的碱是碱金属氢氧化物、碱土金属氢氧化物或者伯、仲或叔胺形式的有机碱。
本发明还涉及式I化合物和/或其生理上可接受的盐在制备药用制剂,尤其是在以非化学途径制备药物中的用途。从这一意义上说,可将式I化合物和/或其生理上可接受的盐与至少一种固体、液体和/或半液体赋形剂或辅助剂一起制成适当的剂量形式,如果适合,可与一或多种其它的活性化合物组合。
本发明还涉及组合物,尤其是药用制剂,其含有至少一种式I化合物和/或它的一种生理上可接受的盐。
这些制剂可用作人或兽医用药物。可能的赋形剂是有机或无机物质,它们适于肠道(如,口)或非肠道给药或者局部应用,开且不与新化合物反应,如,水、植物油、苄基醇、聚乙二醇、明胶、碳水化合物如乳糖或淀粉、硬脂酸镁、滑石粉和凡士林。片剂、包衣片、胶囊剂、糖浆剂、糖汁剂、滴剂或栓剂尤其适用于肠道给药,溶液剂(优选油性或水性溶液)以及混悬剂、乳剂或植入剂适用于非肠道给药,软膏剂、霜剂或粉末适用于局部应用。还可将新化合物冷冻干燥,使用得到的冷冻干燥品,如制成注射剂。
可将所述制剂灭菌,和/或这些制剂可含有辅助剂,如润滑剂、防腐剂、稳定剂和/或润湿剂、乳化剂、影响渗透压的盐、缓冲物质、着色剂、矫味剂和/或香料。如果需要,它们还可以含有一或多种其它的活性化合物,如一或多种维生素。
式I化合物及其生理上可接受的盐可用于人或动物体的治疗,并可用于控制疾病。它们适用于治疗中枢神经系统疾病,如紧张状态、抑郁、焦虑、精神分裂症、胃肠道疾病、恶心、迟发性运动障碍、帕全森氏病和/或精神病,以及高血压治疗中的副作用(如,用α-甲基多巴)。本发明化合物还可用于内分泌学和妇科学中,如治疗肢端巨大症、性腺机能减退、继发性经闭、经前综合征、不良的产后泌乳,并还可用于预防和治疗脑病(如偏头痛),尤其用于老年病学,类似于某些麦角生物碱。特别优选地,它们还可用作治疗剂,用于控制脑梗塞(脑中风)后遗症,如中风和大脑局部缺血,并可用于治疗脑和脊髓外伤。
但是,这些化合物尤其适合作为药用活性化合物,用作抗焦虑剂、抗抑郁剂、抗精神病药和/或正面影响强迫观念与行为疾病(OCD)、睡眠紊乱、迟发性运动障碍、认知障碍、年龄依赖性记忆障碍病、饮食紊乱如食欲过盛和/或性功能障碍。
在这种情况下,一般根据与已知制剂类似的方法给予本发明的物质,优选每剂量单位约0.1-500mg之间,尤其是5-300mg之间的剂量。日剂量优选在每kg体重约0.01-250mg之间,尤其是0.02-100mg/kg之间。
在这种情况下,一般优选以每剂量单位约1-500mg之间,尤其是5-100mg之间的剂量,给予本发明物质。日剂量优选在每kg体重约0.02-10mg之间。但是,对于每个具体患者的特定剂量依据各种因素而变化,例如与治疗有关的所用特定化合物的效力、年龄、体重、健康状况、性别、饮食、给药的次数和途径、排泄率、联合用药以及特定疾病的严重程度。优选口服给药。
本文中,所有温度用℃表示。在以下实施例中,“常规处理”是指:如果必要,除去溶剂,如果必要,加入水,如果必要,根据终产物的组成,将混合物调节至pH2-10之间,用乙酸乙酯或二氯甲烷提取,分离有机相,经硫酸钠干燥,过滤,浓缩,残留物经硅胶层析和/或经结晶纯化。
实施例1
室温下,将4-甲氧基-3-(4-甲基哌嗪-1-基)苯胺二盐酸盐(2.65g;9mmol)、三乙胺(4.5ml;31.5mmol)和N,N’-羰基二咪唑(1.6g;10mmol)的125ml乙腈溶液搅拌3小时。向该混合液中加入2.0g(9mmol)的5-氟-3-哌啶-4-基-1H-吲哚和1.3ml(9mmol)三乙胺的125ml乙腈混悬液,室温下,再搅拌12小时。经常规处理后,将残留物溶于丙酮中,用1N HCl沉淀盐酸盐。用乙醇/乙醚重结晶,得到4-(5-氟-1H-吲哚-3-基)哌啶-1-甲酸[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]酰胺盐酸盐
m.p.231°.
类似地制备下列化合物:4-(3-吲哚基)-N-[4-甲氧基-3-(4-甲基-1-哌嗪基)苯基]哌啶-1-甲酰胺二盐酸盐,mp.204°;4-(5-氟-1H-吲哚-3-基)哌啶-1-甲酸[4-甲氧基-3-(N,N’-二甲氨基乙氧基)苯基]酰胺;4-(5-氟-1H-吲哚-3-基)哌啶-1-甲酸[4-甲氧基-3-(4-甲基哌啶-1-基)苯基]酰胺盐酸盐;4-(5-氰基-3-吲哚基)-N-[4-甲氧基-3-(4-甲基-1-哌嗪基)苯基]哌啶[缺漏]1-甲酰胺,m.p.194-195°;4-(6-氟-3-引哚基)-N-[4-甲氧基-3-(4-甲基-1-哌嗪基)苯基]哌啶[缺漏]1-甲酰胺,m.p.135-137°;3-{1-[4-甲氧基-3-(4-甲基-1-哌嗪基)苯基氨基-羰基]-4-哌啶基}吲哚-5-甲酰胺,m.p.176-178°;4-(4-氟-3-吲哚基)-N-[4-甲氧基-3-(4-甲基-1-哌嗪基)苯基]哌啶[缺漏]1-甲酰胺二盐酸盐,m.p>205°(分解);4-(4-氟-3-吲哚基)-N-[4-甲氧基-3-(4-甲基-1-哌啶基)苯基]哌啶[缺漏]1-甲酰胺二盐酸盐;4-(7-甲氧基-1H-吲哚-3-基)哌啶-1-甲酸[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]酰胺,m.p.219-222°;4-[2-(3-吲哚基)乙基]-N-[4-甲氧基-3-(4-甲基-1-哌嗪基)苯基]哌啶[缺漏]1-甲酰胺,m.p.200-202°;4-[2-(3-吲哚基)乙基]-N-[4-甲氧基-3-(N,N’-二甲氨基乙氧基)苯基]哌啶-1-甲酰胺;4-[2-(3-吲哚基)乙基]-N-[4-甲氧基-3-(4-甲基-1-哌啶基)苯基]哌啶[缺漏]1-甲酰胺;4-(5-氰基-3-吲哚基)-3,6-二氢-2H-吡啶-1-甲酸[4-甲氧基-3-(4-甲基-1-哌嗪基)苯基]酰胺,m.p.223-225°;4-[4-(5-氟吲哚-3-基)丁基]哌嗪-1-甲酸[4-甲氧基-3-(4-甲基-1-哌嗪基)苯基]酰胺二盐酸盐,m.p.>220°(分解);3-(5-氟吲哚-3-基)吡咯烷-1-甲酸[4-甲氧基-3-(4-甲基-1-哌啶基)苯基]酰胺,m.p.210-213°;4-(5-氟吲哚-3-基)哌啶-1-甲酸(2,3-二氢-1’-甲基螺(苯并呋喃)-3,4-哌啶)酰胺;4-[4-(5-氰基-3-吲哚基)丁基]哌嗪-1-甲酸[4-甲氧基-3-(4-甲基-1-哌嗪基)苯基]酰胺;4-[4-(5-氰基-3-吲哚基)丁基]哌嗪-1-甲酸[4-甲氧基-3-(4-甲基-1-哌啶基)苯基]酰胺;4-(5-氰基-1H-吲哚-3-基)哌啶-1-甲酸[4-甲氧基-3-(N,N’-二甲氨基乙氧基)苯基]酰胺;4-(3-吲哚基)哌啶-1-甲酸[4-甲氧基-3-(N,N’-二甲氨基乙氧基)苯基]酰胺;4-[4-(5-氟-1H-吲哚-3-基)丁基]哌嗪-1-甲酸[4-甲氧基-3-(N,N’-二甲氨基乙氧基)苯基]酰胺;4-[4-(5-氰基-1H-吲哚-3-基)丁基]哌嗪-1-甲酸[4-甲氧基-3-(N,N’-二甲氨基乙氧基)苯基]酰胺;4-(5-氰基-1H-吲哚-3-基)哌啶-1-甲酸(2,3-二氢-1’-甲基螺(苯并呋喃)-3,4-哌啶)酰胺;4-(3-吲哚基)哌啶-1-甲酸(2,3-二氢-1’-甲基螺(苯并呋喃)-3,4-哌啶)酰胺;4-[4-(5-氟-1H-吲哚-3-基)丁基]哌啶-1-甲酸(2,3-二氢-1’-甲基螺(苯并呋喃)-3,4-哌啶)酰胺;4-[4-(5-氰基-1H-吲哚-3-基)丁基]哌啶-1-甲酸(2,3-二氢-1’-甲基螺(苯并呋喃)-3,4-哌啶)酰胺;4-[3-(1H-吲哚-3-基)丙基]哌啶-1-甲酸(2,3-二氢-1’-甲基螺(苯并呋喃)-3,4-哌啶)酰胺。
实施例2
按类似于实施例1的方法,使1.17g(4mmol)4-甲氧基-3-(4-甲基哌嗪-]-基)苯胺二盐酸盐、2.0ml(14mmol)三乙胺和714mg(4.4mmol)的N,N’-羰基二咪唑的35ml乙腈溶液与859mg(4mmol)的5-氟色胺盐酸盐和1.1ml(8mmol)三乙胺的35ml乙腈混悬液反应,然后用乙酸乙酯/石油醚重结晶,得到N-[2-(5-氟-3-吲哚基)乙基]-N’-[4-甲氧基-3-(4-甲基-1-哌嗪基)苯基]脲
m.p.98°,
类似地制备下列化合物:N-[2-(5-羟基-3-吲哚基)乙基]-N’-[4-甲氧基-3-(4-甲基-1-哌嗪基)苯基]脲;N-[4-(5-氰基-3-吲哚基)丁基]-N’-[4-甲氧基-3-(4-甲基-1-哌嗪基)苯基]脲;N-[2-(5-氟-3-吲哚基)乙基]-N’-[4-甲氧基-3-(4-甲基-1-哌啶基)苯基]脲;N-[2-(5-氟-3-吲哚基)乙基]-N’-[4-甲氧基-3-(N,N’-4-二甲氨基乙氧基)苯基]脲;N-{2-[4-(6-氟-3-吲哚基)哌啶-1-基]乙基}-N’-[1’-甲基哌啶-3,4’-螺-2,3-二氢苯并呋喃-5-基]脲;N-{2-[4-(6-氟-3-吲哚基)哌啶-1-基]乙基}-N’-[4-甲氧基-3-(4-甲基-1-哌嗪基)苯基]脲,m.p.189-192[缺漏];N-{2-[4-(6-氟-3-吲哚基)哌啶-1-基]乙基}-N’-[4-甲氧基-3-(4-甲基-1-哌啶基)苯基]脲;N-{2-[4-(6-氟-3-吲哚基)哌啶-1-基]乙基}-N’-[4-甲氧基-3-(N,N’-4-二甲氨基乙氧基)苯基]脲。实施例3
将173μl(1.2mmol)三乙胺和230mg(1.2mmol)的1-乙基-3-(3-二甲氨基丙基)-碳化二亚胺盐酸盐加入到314mg(1.2mmol)的4-(5-氟-1 H-吲哚-3-基)环己烷甲酸和265mg(1.2mmol)的4-甲氧基-3-(4-甲基哌嗪-1-基)苯胺的40ml二氯甲烷混合液中。先在0℃下,将混合液搅拌1小时,然后在室温下搅拌12小时。浓缩反应混合液,将残留物溶于乙酸乙酯中,将混合液用水、5%柠檬酸和饱和碳酸氢钠溶液洗涤,干燥,蒸发。经柱层析分离后,得到4-(5-氟-1H-吲哚-3-基)环己烷甲酸(cyclohexanoic acid)[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]酰胺。
类似地制备下列化合物:4-(5-氰基-1H-吲哚-3-基)环己烷甲酸[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]酰胺,4-(6-氟-1H-吲哚-3-基)环已烷甲酸[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]酰胺,4-(5-氟-1H-吲哚-3-基)环己烷甲酸[4-甲氧基-3-(4-甲基哌啶-1-基)苯基]酰胺,4-(5-氰基-1H-吲哚-3-基)环己烷甲酸[4-甲氧基-3-(4-甲基哌啶-1-基)苯基]酰胺,4-(6-氟-1H-吲哚-3-基)环己烷甲酸[4-甲氧基-3-(4-甲基哌啶-1-基)苯基]酰胺,4-(5-氟-1H-吲哚-3-基)环已烷甲酸[4-甲氧基-3-(N,N’-二甲氨基乙氧基)苯基]酰胺,2-[4-(5-氟-1H-吲哚-3-基)哌啶-1-基]-N-[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]乙酰胺,2-[4-(5-氟-1H-吲哚-3-基)哌啶-1-基]-N-[3-(2-二甲氨基乙氧基)-4-甲氧基-3-苯基]乙酰胺,2-[4-(1H-吲哚-3-基)哌啶-1-基]-N-[4-甲氧基-3-(4-甲基哌嗪-1-
基)苯基]乙酰胺,10 2-[4-(1H-吲哚-3-基)哌啶-1-基]-N-[3-(2-二甲氨基乙氧基)-4-甲
氧基-3-苯基]乙酰胺。
下列实施例涉及药用制剂:
实施例A:瓶装注射剂
用2N盐酸,将100g式I活性化合物和5g磷酸氢二钠的3L双蒸水溶液调节至pH6.5,无菌过滤,分装于注射小瓶中,冷冻干燥,无菌密封。每只注射小瓶含5mg活性化合物。
实施例B:栓剂
将20g式I活性化合物的混合物与100g大豆卵磷脂和1400g可可脂融合,倒入模中,冷却。每粒栓剂含20mg活性化合物。
实施例C:溶液剂
制备1g式I活性化合物、9.38g NaH2PO4×2H2O、28.48g NaH2PO4×12H2O和0.1g苯扎氯铵的940ml双蒸水溶液。将溶液调节至pH6.8,配成1L,辐射灭菌。该溶液可以滴眼液的形式使用。
实施例D:软膏剂
无菌条件下,将500mg式I活性化合物与99.5g凡士林混合。
实施例E:片剂
按常规方法,将1kg式I活性化合物、4kg乳糖、1.2kg马铃薯淀粉、0.2kg滑石粉和0.1kg硬脂酸镁混合物压制成片,每片含10mg活性化合物。实施例F:包衣片剂
按类似于实施例E的方法,压制成片,然后按常规方法,用蔗糖、马铃薯淀粉、黄耆胶和着色剂包衣。
实施例G:胶囊剂
按常规方法,将2kg式I活性化合物分装于硬明胶胶囊中,每粒胶囊含20mg活性化合物。
实施例H:安瓿剂
无菌条件下,将1kg式I活性化合物的60L双蒸水溶液分装于安瓿中,冷冻干燥,无菌密封。每只安瓿含10mg活性化合物。
Claims (8)
1.式I化合物及其生理上可接受的盐
R1-(CH2)n-(Y)q-(Z)r-CO-NH-R2 I其中R1 是3-吲哚基,它是未取代的或被A、AO、OH、Hal、CN、NO2、
NH2、NHA、NA2、COA、CONH2、CONHA、CONA2、CH2OH、
CH2OA、CH2NH2、CH2NHA、CH2NA2、COOH和/或COOA单
或双取代,R2 是m 是1或2,n 是0、1、2、3或4,Y 是1,4-亚环己基、1,3-亚吡咯烷基、1,4-亚哌嗪基或1,4-亚哌啶基
环,它们也可以被部分脱氢,Z 是(CH2)n或(CH2)nNH-,q 是0或1,r 是0或1,R3 是A,R4 是AO,Hal 是F、Cl、Br或I,A 是具有1-6个C原子的直链或支链烷基,条件是q和r不同时为0。
2.制备权利要求1的式I化合物的方法,其特征在于a)使式II化合物
II H2N-R2其中R2具有权利要求1中指出的意义,与式III化合物反应
III R1-(CH2)n-(Y)q-(Z)r-CO-L其中L是Cl、Br、I、OH或另一个活性[sic]功能修饰的OH基团或易于亲核取代的离去基团,R1、n、Y、q、Z和r具有权利要求1中指出的意义,或者b)使式II胺成分
II H2N-R2与式IV成分反应
IV R1-(CH2)n-(Y)q-(Z)r-H其中R1、R2、n、Y、q、Z和r具有已指明的意义,同时加入偶合剂,如N,N’-羰基二咪唑、二光气、三光气或其它氯甲酸酯,和/或c)通过如形成OH基团而裂解OA基团和/或使CN、COOH或COOA基团衍生化,将基团R1、R3和/或R4中的一个任选转化为另一个基团R1、R3和/或R4,和/或例如将伯或仲N原子烷基化,和/或通过用酸或碱处理,将获得的式I的碱或酸转化为它的一种盐。
3.制备药物制剂的方法,其特征在于,将式I化合物和/或其生理上可接受的一种盐与至少一种固体、液体或半液体赋形剂或辅助剂,如果合适的话,再与一或多种其它的活性化合物组合在一起制成合适的剂型。
4.作为具有5-HT重摄取抑制作用的5-HT1B/D拮抗剂的 1的式I化合物和/或其生理上可接受的盐。
5.作为抗抑郁剂和抗焦虑剂的权利要求1的式I化合物和/或其生理上可接受的盐。
6.药用制剂,其特征在于,该制剂含有至少一种通式I的化合物和/或它的一种生理上可接受的盐。
7.权利要求1的式I化合物或其生理上可接受的盐在制备药物中的用途。
8.权利要求1的式I化合物或其生理上可接受的盐在控制疾病中的用途。
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DE19756036A DE19756036A1 (de) | 1997-12-17 | 1997-12-17 | Amid- und Harnstoffderivate |
PCT/EP1998/008457 WO2000037456A1 (de) | 1997-12-17 | 1998-12-22 | Amid- und harnstoffderivate als 5-ht-reuptake-inhibitoren und als 5-ht1b/1d-liganden |
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US (1) | US6509340B1 (zh) |
EP (1) | EP1140898B1 (zh) |
JP (1) | JP2002533333A (zh) |
CN (1) | CN1336924A (zh) |
AT (1) | ATE222903T1 (zh) |
AU (1) | AU753335B2 (zh) |
BR (1) | BR9816121A (zh) |
CA (1) | CA2355861A1 (zh) |
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DE (2) | DE19756036A1 (zh) |
DK (1) | DK1140898T3 (zh) |
ES (1) | ES2182401T3 (zh) |
HU (1) | HUP0104878A3 (zh) |
NO (1) | NO20013086L (zh) |
PT (1) | PT1140898E (zh) |
SI (1) | SI1140898T1 (zh) |
SK (1) | SK9232001A3 (zh) |
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CN100448849C (zh) * | 2006-02-02 | 2009-01-07 | 深圳市天和医药科技开发有限公司 | 一种4位-酰基取代-2-甲基哌嗪化合物的制备方法 |
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DE10252650A1 (de) * | 2002-11-11 | 2004-05-27 | Grünenthal GmbH | Cyclohexyl-Harnstoff-Derivate |
DE10337184A1 (de) | 2003-08-13 | 2005-03-10 | Gruenenthal Gmbh | Substituierte 3-Pyrrolidin-Indol-Derivate |
MXPA06007172A (es) | 2003-12-23 | 2006-08-23 | Lundbeck & Co As H | Derivados de 2-(1h-indolilsulfanil)-bencilamina como ssri. |
GB0400895D0 (en) * | 2004-01-15 | 2004-02-18 | Smithkline Beecham Corp | Chemical compounds |
PE20060373A1 (es) | 2004-06-24 | 2006-04-29 | Smithkline Beecham Corp | Derivados 3-piperidinil-7-carboxamida-indazol como inhibidores de la actividad cinasa de ikk2 |
AR052308A1 (es) * | 2004-07-16 | 2007-03-14 | Lundbeck & Co As H | Derivados de 2-(1h-indolilsulfanil)-arilamina y una composicion farmaceutica que contiene al compuesto |
US7629473B2 (en) * | 2005-06-17 | 2009-12-08 | H. Lundbeck A/S | 2-(1H-indolylsulfanyl)-aryl amine derivatives |
AR054393A1 (es) * | 2005-06-17 | 2007-06-20 | Lundbeck & Co As H | Derivados de benzo(b)furano y benzo(b)tiofeno, composiciones farmaceuticas que los contienen y su uso en la fabricacion de un medicamento para el tratamiento de enfermedades mediadas por la inhibicion de la reabsorcion de neurotransmisores de amina biogenicos. |
US8063071B2 (en) * | 2007-10-31 | 2011-11-22 | GlaxoSmithKline, LLC | Chemical compounds |
PE20081889A1 (es) | 2007-03-23 | 2009-03-05 | Smithkline Beecham Corp | Indol carboxamidas como inhibidores de ikk2 |
AU2008310883A1 (en) * | 2007-10-09 | 2009-04-16 | Hamann, Mark T | Method to use compositions having antidepressant anxiolytic and other neurological activity and compositions of matter |
JP2012520257A (ja) | 2009-03-10 | 2012-09-06 | グラクソ グループ リミテッド | Ikk2阻害剤としてのインドール誘導体 |
CA2785284A1 (en) * | 2009-12-25 | 2011-06-30 | Tomoyuki Kamino | Novel aryl urea derivative |
WO2013085954A1 (en) * | 2011-12-06 | 2013-06-13 | Janssen Pharmaceutica Nv | Substituted piperidinyl-carboxamide derivatives useful as scd 1 inhibitors |
WO2013085957A1 (en) | 2011-12-06 | 2013-06-13 | Janssen Pharmaceutica Nv | Substituted piperidinyl-pyridazinyl derivatives useful as scd 1 inhibitors |
UY36390A (es) * | 2014-11-05 | 2016-06-01 | Flexus Biosciences Inc | Compuestos moduladores de la enzima indolamina 2,3-dioxigenasa (ido), sus métodos de síntesis y composiciones farmacéuticas que los contienen |
EP3215141A4 (en) | 2014-11-05 | 2018-06-06 | Flexus Biosciences, Inc. | Immunoregulatory agents |
CA3103711A1 (en) * | 2018-07-12 | 2020-01-16 | UCB Biopharma SRL | Spirocyclic indane analogues as il-17 modulators |
WO2020183011A1 (en) | 2019-03-14 | 2020-09-17 | Institut Curie | Htr1d inhibitors and uses thereof in the treatment of cancer |
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FR2740134B1 (fr) | 1995-10-18 | 1998-01-09 | Pf Medicament | Derives d'amines cycliques d'aryl-piperazines, leur preparation et les compositions pharmaceutiques les contenant |
DE19615232A1 (de) * | 1996-04-18 | 1997-10-23 | Merck Patent Gmbh | Neue Carbamoylderivate und deren Verwendung als 5-HT ¶1¶¶A¶-Antagonisten |
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EP1140898B1 (de) | 2002-08-28 |
AU2514099A (en) | 2000-07-12 |
EP1140898A1 (de) | 2001-10-10 |
CA2355861A1 (en) | 2000-06-29 |
ZA9811467B (en) | 1999-06-14 |
SI1140898T1 (en) | 2003-02-28 |
PT1140898E (pt) | 2003-01-31 |
US6509340B1 (en) | 2003-01-21 |
HUP0104878A2 (hu) | 2002-04-29 |
JP2002533333A (ja) | 2002-10-08 |
SK9232001A3 (en) | 2001-12-03 |
NO20013086D0 (no) | 2001-06-21 |
DE19756036A1 (de) | 1999-06-24 |
DK1140898T3 (da) | 2002-11-25 |
BR9816121A (pt) | 2001-11-13 |
WO2000037456A1 (de) | 2000-06-29 |
ES2182401T3 (es) | 2003-03-01 |
AU753335B2 (en) | 2002-10-17 |
CZ20012270A3 (cs) | 2001-12-12 |
ATE222903T1 (de) | 2002-09-15 |
DE59805363D1 (de) | 2002-10-02 |
HUP0104878A3 (en) | 2003-01-28 |
NO20013086L (no) | 2001-08-21 |
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