CN1037513C - 嘧啶类化合物和其药用盐的制备方法 - Google Patents
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Abstract
本文介绍2,6-二-、2,4,6-、2,5,6-三-或2,4,5,6-四-取代的嘧啶和2,6-二-取代的吡啶,这些化合物用来治疗神经疾病。
Description
本发明涉及新的嘧啶或其药物上可接受的盐,含有上述化合物作为活性成分的新颖治疗剂,用于治疗动物末稍和中枢神经系统神经性疾病。
日本特许公报№.23,394/1971介绍了由下式表示的氨基嘧啶类化合物:式中A表示具有多至16个碳原子的亚烷基,或由氨基或C2-5酰氨基取代的低级亚烷基,M表示H、Na、K、NH4、Mg、Ca或有机碱铵盐,n是等于M原子价的数值,该化合物具有重要的治疗活性,尤其在精神病领域内,可作为抗忧郁剂和精神兴奋剂。
日本特许公报№.22044/1976介绍了2-异丙氨基嘧啶的二氯-低级脂羧酸盐,例如2-异丙氨基嘧啶二氯乙酸盐可用作神经疾病治疗剂。
日本公开特许公报№.100477/1977(特许公报№.28548/1984)介绍了2-异丙氨基嘧啶磷酸盐可用作神经疾病治疗剂。
日本特许公报№.157575/1979公开了以高产量生产2-氯密啶的方法。在该特许公报的操作实例中介绍了得率为69%的2-氯嘧啶的制备方法。
日本公开特许公报№.393/1980介绍了以高产量生产2-异丙氨基嘧啶的方法。在该公报的操作实例中介绍了得率为60%的2-异丙氨基嘧啶的制备方法。
日本公开特许公报№.145670/1980介绍了由下式表示的2-异丙氨基卤代嘧啶:式中A4 1、A5 1和A6 1各自为H或卤原子,其中至少1个是卤原子,该化合物可用来治疗各种神经疾病和肌营养不良症。
日本公开特许公报№.145,671/1980介绍了制备2-异丙氨基嘧啶的羟基衍生物的方法。
据日本公开特许公报№.151,571/1980介绍,2-异丙氨基-5-卤代嘧啶在治疗神经疾病中是极有效的。
日本公开特许公报№.10177/1981公开了用异丙胺氨解2-甲磺酰嘧啶,基本上以定量收率生产2-异丙氨基嘧啶的方法。
日本公开特许公报№.26880/1981公开了制备2-异丙氨基嘧啶的方法,该方法包括双(异丙基胍)硫酸盐与1,1,3,3-四乙氧基丙烷反应。
日本公开特许公报№.90,013/1981公开了用于肌营养不良、肌病、肌僵直和/或神经肌肉传递机能不良的治疗剂,它包括作为活性成分的嘧啶的取代衍生物或其治疗上可接受的盐或其代谢产物。然而,它仅仅公开了各种盐,例如2-异丙氨基嘧啶作为活性成分的正磷酸盐。
本发明人以前提供过治疗神经疾病的新颖治疗剂,它包括具体的2-哌嗪子基嘧啶衍生物或其药物上可接受的盐(国际公开№·WO87/04928)。
本发明的目的之一是提供新颖的嘧啶类化合物和其药物上可接受的盐。
本发明的目的之二是提供神经疾病和脊柱损伤的治疗剂,它包括上述新颖化合物。
本发明的目的之三是提供一种新颖的具有使神经细胞再生和恢复作用的神经疾病治疗剂。
本发明的目的之四是提供一种新颖的神经疾病治疗剂,可医治末稍神经、脑脊髓损伤等疾病。
本发明的目的之五是提供一种新颖的神经疾病治疗剂,可医治不同于精神病的中枢神经疾病,其中主要包括化学传递质操作系统或代谢系统的异常。
本发明的目的之六是提供一种新颖的大脑疾病的治疗剂,它具有促进和恢复意识和记忆的作用。
本发明的目的之七是提供一种新颖的神经疾病或大脑疾病的治疗剂,它包括众多极好和有效的化合物,均具有适于治疗神经疾病或大脑疾病的药理作用,几乎不带副作用,例如不会引起肝病。
本发明的其它目的和优点以下文阐述将更显而易见。
本发明首先提供由式(1)表示的嘧啶类化合物或其药物上可接受的盐,式(1)如下:式中R1表示氢原子或低级烷基;
X表示下述基团:式中R2表示氢原子,低级烷基,苯基,苄基或α-(对氯苯基)苄基,R3相当于1个或至少2个相同或不同取代基该取代基取代相同或不同亚甲基上的1个或至少2个氢原子,并表示低级烷基,羟基,由硝基任意取代的苯基,苄基,苯酰氧基,苯酰氨基,低级烷基氨基,二-低级烷基氨基,HO(C6H5)2C-基团,哌啶子基,羟基(低级烷基),C6H5SO2O-基团,由卤素任意取代的苯甲酰基,低级烷基磺酰酰胺基或低级烷氧基羰基,n是4、5、6或7,R4表示氢原子,低级烷基或苄基,R5表示低级烷基,低级酰基,2-糠酰基,苄基,由苯甲酰任意取代的4-哌啶基、
基团或由卤素或硝基任意取代的苯甲酰基,
Y表示下述基团:式中R9表示氢原子,低级烷基,低级烷氧基,低级烷硫基,或二-低级烷基氨基,R6表示氢原子,低级烷基,苯基,苄基,低级烷氧基或2-(N,N-二-甲氨基)乙基,R7表示低级烷基,低级酰基,环己基羰基,2-糠酰基,低级烷氧基羰基,肉桂酰基,苄基,苄基羰基,甲苯磺酰基,苯氧乙酰基,二-低级烷基氦基甲酰基,2-噻嗯基,下述各式基团:4-低级烷基哌嗪基、或由卤素、硝基、低级烷基、低级烷氧基、氨基、苯甲酰氨基或苯基任意取代的苯甲酰,前提是当R6为氢原子时,R7为苯甲酰,R8相当于置换亚甲基上氢原子的取代基,并表示氢原子,低级烷基,苯基或苄基,m是4,5、6或7;
Z表示氢原子,卤素原子,低级烷基或低级烷氧基羰基;前提是仅当Z是低级烷氧基羰基时,Y表示-CH2R9;仅当R5表示低级烷基,低级酰基,2-糠酰,苄基,苯乙基或由卤素或硝基任意取代的苯甲酰时,R4表示氢原子,Y表示CH2R9和Z表示低级烷氧基羰基;仅当X是
和R4是低级烷基时,Y可为:
在式(1)中,R1是氢原子或低级烷基。该低级烷基可以是直链或支链,并且最好具有1至4个碳原子。实例包括甲基,乙基,正丙基,异丙基,正丁基,仲丁基,异丁基和叔丁基。
在式(I)中,X表示下述基团:
在上述基团中,R2表示氢原子,低级烷基,苯基,苄基或α-(对氯苯基)苄基。该低级烷基的实例如同R1所列举的。
R3相当于置换亚甲基上氢原子的取代基,并表示低级烷基,羟基,由硝基任意取代的苯基,苄基,苯酰氧基,苯酰氨基,低级烷基氨基,二-低级烷基氨基,HO(C6H5)2C-基团,哌啶子基,羟基(低级烷基),C6H5SO2O-基团,由卤素任意取代的苯甲酰基,低级烷基磺酰酰胺基或低级烷氧基羰基,n是4、5、6或7。低级烷基的实例如同R1所列举的。
R4表示氢原子,低级烷基或苄基,R5表示低级烷基,低级酰基,2-糠酰基,苄基,由苯甲酰任意取代的4-哌啶基、苯乙基、基团或由卤素或硝基任意取代的苯甲酰基。
用于R4和R5的低级烷基实例与R5的相同。
用于R5的低级酰基的烷基部分可以是直链或支链的。
具有2至6个碳原子的酰基是优选的,其实例包括乙酰基,丙酰基,丁酰基,异丁酰基,戊酰基,异戊酰基和己酰基。
R5表示氢原子,低级烷基,低级烷氧基,低级烷硫基,或二-低级烷基氨基,
R6表示氢原子,低级烷基,苯基,苄基,低级烷氧基或2-(N,N-二甲氨基)乙基,
R7表示低级烷基,低级酰基,环己基羰基,2-糠酰基,低级烷氧基羰基,肉桂酰基,苄基,苄基羰基,甲苯磺酰,苯氧乙酰基,二-低级烷基氨基甲酰基,2-噻嗯基,下述各式基团:4-低级烷基哌嗪基,或由卤素、低级烷氧基、硝基、氨基、苯甲酰氨基或苯基任意取代的苯甲酰,
用于R9、R6和R7的低级烷基的实例可如同R1所列举的。
用于R7的低级酰基的实例可如同上述R6所列举的。
用作苯甲酰基R7的取代基卤素和低级烷氧基的实例是氟,氯,溴和碘,以及具有1至4个碳原子的烷氧基,例如,甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,异丁氧基和仲丁氧基。当R6是氢原子时,R7是苯甲酰基。
此外,在式(1)中,Z表示氢原子,卤原子,低级烷氧基羰基或低级烷基。
卤原子的实例是氟,氯,溴和碘。低级烷基的实例可与R1所列举的相同。
本发明还提供了一种由式(2)表示的化合物或其药物上可接受的盐,式(2)如下:式中A1表示=CH-或-N=;A2是=CH-,-N=,或;A3表示=CH-或-N=;R11表示低级烷基;R12表示由卤素、低级烷基或低级烷氧基任意取代的苯基,2-呋喃基或2-噻嗯基;前提是当A1是-N=时,A2是,当A1和A2是=CH-时,A是=CH-,当A2是-N=时,A1和A3是=CH-,
在式(2)中,R11是低级烷基,R12表示由卤素、低级烷基或低级烷氧基任意取代的苯基,2-呋喃基或2-噻嗯基。
用于R11和R12的低级烷基实例可与R1所列举的相同。
根据本发明的另一方面,还提供了由式(3)所示新的化合物,它具有相同药效。一种式(3)所示嘧啶或其药物上可接受的盐,式(3)如下:式中A表示下式基团:或
R21表示式(a)或式(b)基团:或
式中R23表示氢原子,低级烷基,低级烷氧基或苯基,R24表示氢原子,低级烷基,环己基,苯基,4-卤代苯基,对联苯基,2-吡啶基或2-苯硫基,前提是R23和R24不能同时为氢原子,式(b)是9-勿基或三苯甲基;
R22表示低级烷基;以及1是0或1。
式(a)中R23是氢原子,低级烷基,低级烷氧基或苯基,和R24表示氢原子,低级烷基,环己基,苯基,4-卤代苯基,对联苯基,2-吡啶基或2-苯硫基,R23和R24不能同时为氢原子。
R23和R24中的低级烷基互不相关,为直链或支链烷基,优选者含1至4个碳原子。其实例是甲基,乙基,丙基,异丙基,丁基,仲丁基和异丁基。
R23的低级烷氧基可为直链或支链,优选者含1至4个碳原子。其实例包括甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,仲丁氧基,异丁氧基和叔丁氧基,R24的4-卤代苯基实例是4-氟苯基,4-氯苯基或4-溴苯基。
在式(3)中,R22是低级烷基,其实例如同R23所给出的。1是0或1。
由本发明提供的式(1)、(2)和(3)的实例详列如下。(104) (100)的对甲苯磺酸盐(112) (108)的对甲苯磺酸盐(120) (116)的对甲苯磺酸盐(128) (124)的对甲苯磺酸盐(136) (132)的对甲苯磺酸盐(138) (137)的对甲苯磺酸盐(144) (140)的对甲苯磺酸盐(150) (149)的对甲苯磺酸盐(152) (148)的对甲苯磺酸盐(146) (145)的对甲苯磺酸盐(I47-1) (147)的对甲苯磺酸盐(154) (153)的对甲苯磺酸盐(154-2) (154-1)的对甲苯磺酸盐(160) (156)的对甲苯磺酸盐(165) (164)的硫酸盐(166) (164)的磷酸盐(167) (164)的马来酸盐(169) (164)的萘磺酸盐(171) (164)的柠檬酸盐(171-1) (164)的酒石酸盐(171-1-1) (164)的富马酸盐(168) (164)的对甲苯磺酸盐(170) (164)的盐酸盐(170-2) (170-1)的对甲苯磺酸盐(171-3) (171-2)的对甲苯磺酸盐(171-5) (171-4)的对甲苯磺酸盐(171-7) (171-6)的对甲苯磺酸盐(171-9) (171-8)的对甲苯磺酸盐(171-11) (171-10)的对甲苯磺酸盐(171-13) (171-12)的对甲苯磺酸盐(176) (172)的对甲苯磺酸盐(184) (180)的对甲苯磺酸盐(192) (188)的对甲苯磺酸盐(200) (196)的对甲苯磺酸盐(208) (204)的对甲苯磺酸盐(216) (212)的对甲苯磺酸盐(224) (220)的对甲苯磺酸盐(232) (228)的对甲苯磺酸盐(240) (236)的对甲苯磺酸盐(242) (241)的对甲苯磺酸盐(248) (244)的对甲苯磺酸盐(256) (252)的对甲苯磺酸盐(264) (260)的对甲苯磺酸盐(272) (268)的对甲苯磺酸盐(280) (276)的对甲苯磺酸盐(288) (284)的对甲苯磺酸盐(296) (292)的对甲苯磺酸盐(298) (297)的对甲苯磺酸盐(304) (300)的对甲苯磺酸盐(306) (305)的对甲苯磺酸盐(307-1) (307)的对甲苯磺酸盐(312) (308)的对甲苯磺酸盐(320) (316)的对甲苯磺酸盐(328) (324)的对甲苯磺酸盐(336) (332)的对甲苯磺酸盐(344) (340)的对甲苯磺酸盐(352) (348)的对甲苯磺酸盐(360) (356)的对甲苯磺酸盐(368) (364)的对甲苯磺酸盐(376) (372)的对甲苯磺酸盐(384) (380)的对甲苯磺酸盐(392) (388)的对甲苯磺酸盐(400) (396)的对甲苯磺酸盐(408) (404)的对甲苯磺酸盐(416) (412)的对甲苯磺酸盐(424) (420)的对甲苯磺酸盐(432) (428)的对甲苯磺酸盐(604) (600)的对甲苯磺酸盐(612) (608)的对甲苯磺酸盐(620) (616)的对甲苯磺酸盐(628) (624)的对甲苯磺酸盐(636) (632)的对甲苯磺酸盐(644) (640)的对甲苯磺酸盐(652) (648)的对甲苯磺酸盐(660) (656)的对甲苯磺酸盐(662) (661)的盐酸盐(668) (664)的对甲苯磺酸盐(676) (672)的对甲苯磺酸盐(684) (680)的对甲苯磺酸盐(692) (688)的对甲苯磺酸盐(700) (696)的对甲苯磺酸盐(804) (800)的马来酸盐(812) (808)的马来酸盐 (828) (824)的马来酸盐(2004) (2000)的对甲苯磺酸盐(2012) (2008)的对甲苯磺酸盐(2020) (2016)的对甲苯磺酸盐(2022-1) (2022)的对甲苯磺酸盐(2023-1) (2O23)的对甲苯磺酸盐(2028) (2024)的对甲苯磺酸盐(2036) (2032)的二对甲苯磺酸盐(2044) (2040)的对甲苯磺酸盐(2052) (2048)的二盐酸盐(2060) (2056)的盐酸盐(2070) (2064)的盐酸盐(2076) (2074)的盐酸盐(2084) (2080)的盐酸盐(2092) (2088)的盐酸盐(2100) (2096)的盐酸盐(2108) (2104)的盐酸盐(2116) (2112)的对甲苯磺酸盐(2124) (2120)的对甲苯磺酸盐(2132) (2128)的对甲苯磺酸盐(2140) (2136)的二对甲苯磺酸盐(2148) (2144)的二盐酸盐(2156) (2152)的盐酸盐(2164) (2160)的二盐酸盐(2174) (2170)的对甲苯磺酸盐(2182) (2178)的对甲苯磺酸盐(2188) (2184)的对甲苯磺酸盐(2194) (2192)的甲苯磺酸盐(2202) (2198)的对甲苯磺酸盐(2210) (2206的对甲苯磺酸盐(2218) (2214)的对甲苯磺酸盐(2226) (2222)的盐酸盐(2234) (2230)的二对甲苯磺酸盐(2242) (2238)的对甲苯磺酸盐(2250) (2246)的对甲苯磺酸盐(2260) (2254)的对甲苯磺酸盐(2270) (2264)的对甲苯磺酸盐(2278) (2274)的对甲苯磺酸盐(2286) (2282)的对甲苯磺酸盐(2294) (2290)的对甲苯磺酸盐(2302) (2298)的对甲苯磺酸盐(2310) (2306)的对甲苯磺酸盐(2318) (2314)的对甲苯磺酸盐(2326) (2322)的对甲苯磺酸盐(2334) (2330)的对甲苯磺酸盐(2342) (2338)的二盐酸盐(2350) (2346)的盐酸盐(3104) (3100)的盐酸盐(3112) (3108)的对甲苯磺酸盐(3128) (3124)的盐酸盐(3136) (3132)的盐酸盐(3144) (3140)的盐酸盐(3152) (3148)的对甲苯磺酸盐(3176) (3172)的对甲苯磺酸盐(3184) (3180)的对甲苯磺酸盐(3192) (3188)的对甲苯磺酸盐(3200) (3200)的盐酸盐(3404) (3400)的对甲苯磺酸盐(3412) (3408)的盐酸盐(3420) (3416)的盐酸盐
采用巳知方法,尤其在日本公开特许公报NOS.140568/1986和87627/1986中介绍的方法,或按巳知方法(例如还原消去保护基)处理由这些方法获得的中间体,制备式(1)、(2)和(3)的化合物。下文给出实施例1至9,详细介绍这些化合物的制备方法。
例如,可用下述反应路线1制备式中Y是-NR6R7,R6不是氢原子的式(I)化合物。
反应路线2用J.Chem.Soc,1965,P755-761中介绍的方法,以作为原料可制备反应路线1和2中式(II)和(III)的起始化合物。如需要,在碱性化合物的存在下,于20至150℃、溶剂(例如甲苯,二噁烷,吡啶或水)中可方便地实施反应路线1和2的反应。该碱性化合物可以是适宜的有机碱(例如三乙胺,吡啶和4-二甲氨基吡啶)和无机碱(例如碳酸钠和碳酸钾)。
按下述反应路线3可制备式中Y是CH2R9,R9是氢或低级烷基和Z是低级烷氧基羰基的式(1)化合物。
具体来说,在温度20至100℃下,于反应介质如水、甲醇、乙醇、THF和DMF中,使化合物(IV)与(V)反应,得到式中Y=R10,Z=COOR13的式(I)化合物。
按反应路线4可制备式中Y是CH2R9,R9不是氢和低级烷基,Z是低级烷氧基羰基的通式(I)化合物。
反应路线4
除所用X代替苄基哌嗪外,采用与日本公开特许公报№.65873/1986〔制备方法7〕中介绍的相同制备方法,可以制备化合物(VI)。在惰性溶剂如甲苯或四氢呋喃存在或无溶剂存在下,于有机碱如吡啶或三乙胺中,或于无机碱如碳酸钾,碳酸钠,氢氧化钾,氢氧化钠,氢化钾或氢化钠中,使化合物(VI)与R9H反应,得到式中Y是CH2R9,Z是COOR10的式(I)化合物。
采用与通式(1)化合物的相同合成方法,可以合成通式(2)的化合物。
采用示于下述路线5和6的方法,可以制备通式(3)的化合物。
用J·A·C·S·,71,2731(1949)中介绍的方法,可制备原料(VII)。在温度20至150℃、最好为20至100℃下,任意地在碱性化合物存在下,于溶剂如乙腈或二甲基甲酰胺中或无溶剂下,化合物(VII)与N-甲酰-哌嗪反应,生成化合物(VIII)。无机碱如碳酸钠或碳酸钾,或者有机碱如三乙胺或吡啶可用作碱性化合物。然后,在酸或碱存在下,水解化合物(III),得到化合物(TV)。在温度0至150℃、最好为20至100℃下,于溶剂如水、甲醇或Z醇中实施水解。
采用巳知方法,尤其在日本公开特许公报NOS.140568/1986和87627/1986中介绍的方法,或按巳知方法(例如保护基的还原消去)处理由这些方法获得的中间体,根据路线5,从化合物(TV)或(X)制备式(3)化合物。下文给出的实施例7至9详细说明式(3)化合物的制备方法。
本发明人的研究说明:式(1)、(2)和(3)化合物可用作神经疾病的治疗剂。
通常以药用组合物形式使用式(1)、(2)和(3)的化合物,通过各种途径给药(例如口服、皮下、肌内、静脉内、鼻内、皮肤渗透和通过直肠)。
本发明还包括含通式(1)、(2)或(3)化合物或其药物上可接受盐的药用制剂。该药物可接受盐包括如酸成盐和季铵(或胺)盐。
化合物(1)、(2)和(3)在药物上可接受盐的实例包括由能形成含阴离子药物上可接受无毒酸成盐的酸所形成的盐,例如,盐酸盐,氢溴酸盐,硫酸盐,亚硫酸氢盐,磷酸盐,酸式磷酸盐,乙酸盐,马来酸盐,富马酸盐,琥珀酸盐,乳酸盐,酒石酸盐,苯甲酸盐,柠檬酸盐,葡糖酸盐,葡聚糖酸盐,甲磺酸盐,对甲苯磺酸盐和萘磺酸盐或它们的水合物,以及季铵(或胺)盐或其水合物。
本发明组合物可配制成片剂,胶囊,粉剂,粒剂,锭剂,糯米纸扁囊剂,酏剂,乳剂,溶液,糖浆,混悬剂,气雾剂,油膏,无菌注射剂,模制泥敷剂,胶带,软、硬明胶胶囊,栓剂和无菌填充粉剂。药物上可接受载体的实例包括乳糖,葡萄糖,蔗糖,山梨醇,甘露醇,玉米淀粉,结晶纤维素,阿拉伯胶,磷酸钙,藻酸盐,硅酸钙,微晶纤维素,聚乙烯吡咯烷酮,黄蓍胶,明胶,糖浆,甲基纤维素,羧甲基纤维素,羟基苯甲酸甲酯,羟基苯甲酸丙酯,滑石粉,硬脂酸镁,惰性聚合物,水和矿物油。
固体和液体组合物均可含上述的填充剂,粘合剂,润滑剂,湿润剂,崩解剂,乳化剂,混悬剂,防腐剂,增甜剂和调味剂。应将本发明组合物配制成给患者给药后,使该活性化合物迅速、连续或缓慢释放的组合物。
在口服给药情况下,将式(1)、(2)或(3)化合物与载体或稀释剂混合,形成片剂,胶囊等。在非肠道给药情况下,活性成分溶于10%葡萄糖水溶液、等渗盐水、无菌水等液体中,并装入小瓶或安瓿中,用以静脉滴注或注射,或者肌肉注射。在介质中还可合适地包含溶解助剂,局部麻醉剂,防腐剂和缓冲剂。为提高稳定性,在装入小瓶或安瓿后,可冻干本发明组合物。非肠道给药的另一实例是作为油膏或泥敷剂通过皮肤施用本发明组合物。若是这样,模制泥敷剂或胶带是合适的。
本发明组合物每单元剂型含活性成分0.1至2000mg,优选为0.5至1000mg。
式(1)、(2)或(3)化合物的有效剂量范围很宽,例如,施用的化合物量通常每天为0.03mg/kg至100mg/kg。实际施用该化合物的量由医生根据所用化合物的种类,患者年令,体重,反应情况等,以及给药途径而定。
因此,上述剂量范围不限制本发明范围。适宜的给药次数每天为1至6次,通常为1至4次。
式(1)、(2)或(3)化合物本身对末稍神经系统和中枢神经系统是有效的治疗剂。如有需要,可以与至少一种其它等效药物一起给药。这种附加药的实例是神经节甙脂,甲钴胺和异丙胺嘧啶。
本发明化合物(1),(2)和(3)的制剂及它们的生物活性将通过下述一系列实施例B和实施例给以详细说明。然而应理解,这不限制本发明范围。下述每个实施例表明本发明组合物使用以上所述化合物之一或其它药用活性化合物之一,均包括在通式(1)、(2)和(3)内。对照实施例1
4-甲氨基-2-(4-苯基哌啶子基)嘧啶(化合物№.1024):
将甲胺(0.25摩尔,20ml 40%甲醇溶液)以保持溶液温度为5℃的速率加到17.0g(0.11摩尔)2,4-二氯嘧啶的150ml二氯甲烷溶液中,此后,该溶液于室温搅拌12小时,减压浓缩反应混合物,用二氯甲烷提取,该二氯甲烷层用无水硫酸钠干燥,减压浓缩,得到14.0g(纯度80%)2-氯-4-甲氨基嘧啶。
将200ml正丁醇加到3.0g(0.02摩尔)2-氯-4-甲氨基嘧啶和8.4g(0.05摩尔)4-苯基哌啶混合物中,在130℃下加热1小时。减压浓缩该反应混合物,用二氯甲烷提取,该二氯甲烷层用无水硫酸钠干燥,减压浓缩。残留物经硅胶柱层析纯化,得到4.0g(得率71%)油状所期化合物。
1H-NMR谱(CDCl3,δppm):1H-NMR(CDCl3,δppm):
1.4-2.0(5H,m),2.93(3H,d,J=5.2Hz),
2.6-3.1(2H,m),4.60(1H,m),4.92(2H,br.d,
J=12.6Hz),5.67(1H,d,J=7.2Hz),7.28(5H,s),
化合物(中间体)的性质列于表1
表1
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3 溶液:δppm) |
1000 | 51 | 油 | 2.90(3H,d,J=5.2Hz),3.13(6H,s),4.66(1H,m),5.63(1H,d,J=5.2Hz),7.88(1H,d,J=5.2Hz) |
1004 | 29 | 油 | 0.92(6H,m),1.0-1.8(8H,m),2.88(3H,d,J=5.2Hz),3.51(4H,m),4.55(1H,m),5.56(1H,d,J=5.2Hz),7.84(1H,d,J=5.2Hz) |
1008 | 68 | 油 | 1.92(4H,m),2.88(3H,d,J=5.2Hz),3.52(4H,m),4.76(1H,m),5.63(1H,d,J=5.2Hz),7.88(1H,d,J=5.2Hz) |
1012 | 95 | 油 | 1.62(6H,br,s),2.92(3H,d,J=5.4Hz),3.72(4H,br,s),4.60(1H,m),5.64(1H,d,J=6.0Hz),7.90(1H,d,J=6.0Hz) |
1016 | 72 | 油 | 0.95(3H,d,J=5.2Hz),0.9-1.8(5H,m),2.6-3.0(2H,m),2.90(3H,d,J=5.2Hz),4.69(2H,br,d,J=12.6Hz),4.70(1H,m),5.64(1H,d,J=5.2Hz),7.89(1H,d,J=5.2Hz) |
1020 | 62 | 油 | 0.9(9H,s),1.0-1.9(5H,m),2.5-3.0(2H,m),2.90(3H,d,J=5.2Hz),4.6(1H,m),4.80(2H,br,d,J=12.6Hz),5.64(1H,d,J=5.2Hz),7.9(1H,d,J=5.2Hz) |
表1(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液:δppm) |
1028 | 63 | 油 | 1.0-2.0(5H,m),2.5 4(2H,d,J=5.2Hz),2.4-3.0(2H,m),2.87(3H,d,J=5.2Hz),4.65(2H,m),4.72(2H,br,d,J=12.6Hz),5.62(1H,d,J=5.2Hz),7.0-7.4(5H,m),7.88(1H,d,J=5.2Hz) |
1032 | 66 | 96-98 | 1.7-2.2(2H,m),2.8(2H,t,J=7.2Hz)2.89(3H,d,J=5.2Hz),4.02(2H,t,J=7.2Hz),4.70(1H,m),5.82(1H,d,J=5.2Hz),6.8-7.3(3H,m),7.82(1H,d,J=7.2Hz),7.99(1H,d,J=5.2Hz) |
1036 | 77 | 油 | 2.92(5H,m),4.02(2H,t,J=5.2Hz),4.7(1H,m),4.89(2H,s),5.67(1H,d,J=7.2Hz),7.18(4H,m),7.94(1H,d,J=7.2Hz) |
1040 | 60 | 油 | 2.89(3H,d,J=5.2Hz),3.73(8H,s),4.70(1H,m),5.69(1H,d,J=5.2Hz),7.88(1H,d,J=5.2Hz) |
1048 | 56 | 油 | 2.32(3H,s),2.43(4H,m),2.88(3H,d,J=5.2Hz),3.78(4H,m),4.72(1H,m), 5.65(1H,d,J=5.2Hz),7.86(1H,d,J=5.2Hz) |
1052 | 56 | 120-122 | 2.91(3H,d,J=4Hz),3.24(4H,m),3.95(4H,m),4.60(1H,m),5.70(1H,d,J=5.4Hz),6.8-7.4(5H,m),7.92(1H,d,J=5.4Hz) |
表1(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
1056 | 68 | 油 | 2.48(4H,m),2.87(3H,d,J=5.2Hz),3.53(2H,s),3.77(4H,m),4.60(1H,m),5.64(1H,d,J=5.2Hz),7.32(5H,m),7.87(1H,d,J=5.2Hz) |
1060 | 80 | 油 | 2.42(4H,m),2.85(3H,d,J=5.6Hz),3.76(4H,m),4.24(1H,s),4.56(1H,m),5.65(1H,d,J=5.6Hz),7.0-7.5(9H,m),7.88(1H,d,J=5.6Hz) |
1064 | 61 | 油 | 1.4-2.2(4H,m),2.5-3.1(3H,m),4.62(2H,br,s),4.88(2H,br,d,J=12.6Hz),5.72(1H,d,J=5.2Hz),7.25(5H,m),7.94(1H,d,J=5.2Hz) |
1068 | 58 | 油 | 1.24(3H,t,J=7.2Hz),1.4-2.0(4H,m),2.5-3.1(3H,m),3.1-3.5(2H,m),4.58(1H,m),4.90(2H,br,d,J=12.6Hz),5.65(1H,d,J=5.2Hz),7.0-7.5(5H,m),7.92(1H,d,J=5.2Hz) |
1072 | 75 | 油 | 0.97(3H,t,J=7.2Hz),1.4-2.1(6H,m),2.5-3.1(3H,m),3.24(2H,q,J=7.2Hz),4.68(1H,br,s),4.88(2H,br,d,J=12.6Hz),5.65(1H,d,J=5.2Hz),7.27(5H,m),7.90(1H,d,J=5.2Hz) |
1076 | 57 | 油 | 1.4-2.0(4H,m),2.5-3.1(3H,m),4.52(2H,d,J=5.2Hz),4.90(2H,br,d,J=12.6Hz), |
表1(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
1076 | 57 | 油 | 4.91(1H,m),5.68(1H,d,J=5.2Hz),7.0-7.5(10H,m),7.92(1H,d,J=5.2Hz) |
1080 | 36 | 油 | 1.4-2.0(4H,m),2.27(6H,s),2.50(2H,m),2.5-3.2(3H,m),3.36(2H,m),3.46(2H,s),4.90(2H,br,d,J=12.6Hz),5.24(1H,m),5.67(1H,d,J=5.2Hz),7.27(5H,m),7.88(1H,d,J=5.2Hz) |
1084 | 50 | 91-93 | 1.60(6H,br,s),2.23(3H,s),2.88(3H,d,J=5.2Hz),3.75(4H,br,s),4.50(1H,m),5.54(1H,s) |
1088 | 57 | 油 | 1.5-2.0(4H,m),2.23(3H,s),2.6-3.0(3H,m),2.90(3H,d,J=5.2Hz),4.51(1H,m),4.96(2H,br,d,J=12.6Hz),5.57(1H,s),7.28(5H,s) |
1092 | 21 | 油 | 1.60(6H,br,s),1.88(3H,s),3.0(3H,d,J=5.2Hz),3.75(4H,br,s),4.2(1H,br,s),7.65(1H,s) |
1096 | 75 | 油 | 1.4-2.0(4H,m),1.92(3H,s),2.5-3.1(3H,m),3.0 2(3H,d,J=5.2Hz),4.40(1H,m),4.90(2H,br,d,J=12.6Hz),7.28(5H,m),7.68(1H,s) |
1100 | 81 | 油 | 1.8-2.1(5H,m),2.79(2H,t,J=7.2Hz),2.99(3H,d,J=5.2Hz), |
表1(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
1100 | 81 | 油 | 4.03(2H,t,J=7.2Hz),4.42(1H,m),6.8-7.2(3H,m),7.7-8.0(2H,m) |
1104 | 48 | 121-124 | 1.4-2.1(4H,m),2.5-3.1(3H,m),3.02(3H,d,J=4.0Hz),4.85(1H,m),4.88(2H,br,d,J=12.6Hz),7.28(5H,m),7.75(1H,d,J=4.0Hz) |
1112 | 24 | 117-118 | 0.96(3H,d,J=5.2Hz),0.9-1.8(5H,m),2.6-3.0(2H,m),2.96(3H,d,J=5.2Hz),4.32(2H,br,d,J=12.6Hz),4.80(1H,m),5.88(1H,d,J=5.2Hz),7.87(1H,d,J=5.2Hz) |
1116 | 16 | 179-180 | 0.89(9H,s),1.0-1.9(5H,m),2.5-3.0(2H,m),2.95(3H,d,J=5.2Hz),4.45(2H,br,d,J=12.6Hz),4.75(1H,m),5.89(1H,d,J=5.2Hz),7.88(1H,d,J=5.2Hz) |
1120 | 18 | 148-154 | 1.4-2.1(5H,m),2.97(3H,d,J=5.2Hz),2.6-3.1(2H,m),4.53(2H,br,d,J=12.6Hz),5.95(1H,d,J=7.2Hz),7.28(5H,s),7.88(1H,d,J=7.2Hz) |
1124 | 20 | 175-176 | 1.8-2.1(2H,m),2.76(2H,t,J=7.2Hz),2.99(3H,d,J=5.2Hz),3.96(2H,t,J=7.2Hz),4.9(1H,m),6.32(1H,d,J=5.2Hz),6.9-7.5(4H,m),7.88(1H,d,J=5.2Hz) |
表1(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
1128 | 19 | 123-126 | 2.90(5H,m),3.83(2H,t,J=5.2Hz),4.72(2H,s),4.90(1H,m),5.92(1H,d,J=7.2Hz),7.19(4H,s),7.92(1H,d,J=7.2Hz) |
1132 | 17 | - | 2.47(4H,m),2.92(3H,d,J=5.2Hz),3.52(2H,s),3.59(4H,m),4.75(1H,m),5.84(1H,d,J=5.2Hz),7.31(5H,m),7.85(1H,d,J=5.2Hz) |
1136 | 17 | 158-160 | 1.24(3H,t,J=7.2Hz),1.5-2.1(4H,m),2.5-3.2(3H,m),3.2-3.6(2H,m),4.52(2H,br,d,J=12.6Hz),4.70(1H,m),5.92(1H,d,J=5.2Hz),7.0-7.5(5H,m),7.89(1H,d,J=5.2Hz) |
1140 | 18 | 134-136 | 0.98(3H,t,J=7.2Hz),1.4-2.1(6H,m),2.6-3.1(3H,m),3.35(2H,q,J=7.2Hz),4.53(2H,br,d,J=12.6Hz),4.80(1H,br,s),5.93(1H,d,J=5.2Hz),7.29(5H,m),7.90(1H,d,J=5.2Hz) |
1144 | 13 | 158-160 | 1.2(3H,s),1.27(3H,s),1.4-2.0(4H,m),2.2-3.1(3H,m),3.9-4.3(1H,m),4.52(2H,br,d,J=12.6Hz),4.65(1H,m),5.9(1H,d,J=5.2Hz),7.0-7.5(5H,m),7.89(1H,d,J=5.2Hz) |
1148 | 21 | 148-149 | 1.3-2.05(4H,m),2.5-3.1(3H,m),4.50(2H,br,d,J=12.6Hz),4.60(2H,br,d,J=5.2Hz), |
表1(续)
对照实施例2
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
1148 | 21 | 148-149 | 5.35(1H,m),5.95(1H,d,J=5.2Hz),7.0-7.5(10H,m),7.88(1H,d,J=5.2Hz) |
1152 | 31 | 84-85 | 1.65(6H,br,s),2.22(3H,s),2.95(3H,d,J=5.2Hz),3.57(4H,br,s),4.75(1H,m),5.77(1H,s) |
1156 | 10 | 198-199 | 1.5-2.0(4H,m),2.23(3H,s),2.6-3.1(3H,m),2.96(3H,d,J=5.2Hz),4.4-4.8(3H,m),5.83(1H,s),7.26(5H,m) |
1160 | 83 | 162-165 | 2.03(3H,s),3.12(3H,d,J=5.2Hz),4.90(1H,m),7.2-7.5(3H,m),7.85(3H,m),8.12(1H,s),8.6(1H,s) |
4-甲氨基-2-(4-苯基哌啶子基)嘧啶马来酸盐(化合物№.1026):
将0.43g(3.73毫摩尔)马来酸的10ml甲醇溶液加到1.0g(3.73毫摩尔)4-甲氨基-2-(4-苯基哌啶子基)嘧啶的10ml甲醇溶液中,该混合物在室温下搅拌1小时,减压浓缩该混合溶液,用水洗涤,得到1.25g(得率87%)所期产物。
M.p.:163-166℃.
1H-NMR(CDCl3,δppm):
1.6-2.2(4H,m),2.6-3.3(5H,m),3.04(3H,d,
J=5.2Hz),4.74(1H,br,d,J=12.6Hz),
6.30(1H,d,J=7.2Hz),7.30(5H,m),
7.71(1H,d,J=7.2Hz),8.40(1H,m).
用类似方法制得下列化合物。
(1014):(1012)的马来酸盐
(1026):(1024)的马来酸盐
(1034):(1032)的马来酸盐
(1038):(1036)的马来酸盐
(1086):(1084)的马来酸盐
(1090):(1088)的马来酸盐
(1094):(1092)的马来酸盐
(1098):(1096)的马来酸盐
(1102):(1100)的马来酸盐
(1110):(1108)的马来酸盐
(1122):(1120)的马来酸盐
(1130) (1128)的马来酸盐
(1158):(1156)的马来酸盐
(1162):(1160)的马来酸盐
这些化合物的数据列于表2。
表2
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
1014 | 89 | 164-165 | 1.70(6H,br,s),3.02(3H,d,J=3.8Hz),3.76(4H,br,s),6.35(2H,s),7.65(1H,m),8.32(1H,m),12.50(1H,m) |
1034 | 94 | 42-46 | 1.9-2.3(2H,m),2.79(2H,t,J=7.2Hz),3.01(3H,d,J=5.2Hz),4.0(2H,t,J=7.2Hz),6.22(2H,s),6.46(1H,d,J=5.2Hz),7.20(3H,m),7.50(1H,m),7.76(1H,d,J=5.2Hz),8.80(1H,m) |
1038 | 77 | 149-151 | 2.9-3.2(5H,m),4.0(2H,t,J=7.2Hz),4.92(2H,s),6.32(1H,d,J=7.2Hz),6.36(2H,s),7.25(4H,s),7.75(1H,d,J=7.2Hz),8.40(1H,m) |
1086 | 99 | 155-157 | 1.68(6H,br,s),2.28(3H,s),3.0(3H,d,J=5.2Hz),3.80(4H,br,s),6.0(1H,s),6.33(2H,s),8.15(1H,m),11.7(1H,m) |
1090 | 91 | 151-154 | 1.5-2.2(4H,m),2.29(3H,s),2.6-3.3(6H,m),4.81(2H,br,d,J=12.6Hz),6.02(1H,s),6.32(2H,s),7.28(5H,br,s),8.15(1H,m),12.2(1H,m) |
1094 | 91 | 150-152 | 1.70(6H,br,s),2.04(3H,s),3.08(3H,d,J=5.2Hz),3.76(4H,br,s),6.33(2H,s),7.15(1H,m),7.59(1H,s) |
表2(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
1098 | 92 | 163-165 | 1.6-2.2(4H,m),2.03(3H,s),2.6-3.3(3H,m),3.09(3H,d,J=5.2Hz),4.71(2H,br,d,J=12.6Hz),6.33(2H,s),7.0-7.4(5H,m),7.60(1H,s) |
1102 | 81 | 145-150 | 1.8-2.3(5H,m),2.80(2H,t,J=5.2Hz),3.08(3H,d,J=5.2Hz),4.0(2H,t,J=5.2Hz),6.25(2H,s),7.1-7.6(4H,m),7.70(1H,s) |
1110 | 91 | 187-188 | 1.74(6H,br,s),2.32(3H,s),2.96(3H,d,J=5.2Hz),3.5(2H,br,s),3.95(2H,br,s),5.83(1H,s),6.33(2H,s),9.10(1H,m),13.8(1H,m) |
1122 | 92 | 155-158 | 1.6-2.2(4H,m),3.0(3H,d,J=5.2Hz)2.7-3.5(3H,m),4.10(1H,br,d,J=12.6Hz),5.25(1H,br,d,J=12.6Hz),6.12(1H,d,J=7.2Hz),6.33(2H,s),7.30(5H,m),7.50(1H,d,J=7.2Hz),9.0(1H,br,s) |
1130 | 87 | 179-180 | 2.9-3.2(5H,d,J=5.2Hz),3.79(1H,t,J=5.2Hz),4.16(1H,t,J=5.2Hz),4.70(1H,s),5.20(1H,s),6.15(1H,br,d,J=7.2Hz),6.30(2H,s),7.27(4H,s),7.52(1H,d,J=7.2Hz),9.1(1H,m) |
表2(续)
对照实施例3
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
1158 | 95 | 173-175 | 1.6-2.2(4H,m),2.32(3H,s),2.6-3.5(6H,m),4.1(1H,m),5.2(1H,m),5.88(1H,s),6.34(2H,s),7.30(5H,br,s),9.20(1H,m),13.9(1H,m) |
1162 | 74 | 179-180 | 2.11(3H,s),3.11(3H,d,J=7.2Hz),6.32(2H,s),6.50(1H,m),7.2-8.0(6H,m),8.20(1H,s),8.84(1H,s) |
1-二苯甲基哌嗪:
将11.2g(98毫摩尔)1-甲酰哌嗪加到10g(49毫摩尔)氯二苯甲烷中,该溶液在室温下搅拌48小时,用水和二氯甲烷提取该混合物,用无水硫酸镁干燥有机层,减压蒸发溶剂,残留物经硅胶柱层析纯化,得到的8.9g(31.9毫摩尔)甲酰化合物溶于100ml乙醇,加入6.5g(64毫摩尔)浓盐酸,该溶液回流1小时,然后,减压蒸发溶剂,残留物用K2CO3/水/CH2Cl2提取。有机层用无水硫酸镁干燥,减压蒸发溶剂,得到6.8g(得率55%)所期产物。
M.p.:93-95℃.
1H-NMR(CDCl3,δppm):
2.33(4H,m),2.87(4H,m),4.19(1H,s),
7.1-7.5(10H,m).实施例1
4-(N-甲基苯氨基)-2-(4-苯基哌啶子基)嘧啶(化合物№.164):
室温下,在30分钟内将5.2g(0.037摩尔)苯甲酰氯的50ml四氢呋喃溶液加到9.0g(0.034摩尔)4-甲氨基-2-(4-苯基哌啶子基)嘧啶的90ml四氢呋喃和5ml三乙胺溶液中,加完后2小时,加入1ml吡啶,然后,将该混合物搅拌2天,用二氯甲烷提取反应混合物,该二氯甲烷层用无水硫酸钠干燥,减压浓缩,残留物经硅胶柱层析纯化,得到8.8g(得率70%)油状所期产物。1H-NMR(CDCl3,δppm):
1.4-2.0(4H,m),2.5-3.0(3H,m),3.55(3H,s),
4.62(2H,br,d,J=12.6Hz),6.14(1H,d,J=7.2Hz),
7.1-7.6(10H,m),8.06(1H,d,J=7.2Hz).用上述相同方法制备的化合物的数据列于表3。
表3(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
100 | 48 | 油 | 3.0(6H,s),3.52(3H,s),6.04(1H,d,J=5.2Hz),7.1-7.5(5H,m),7.98(1H,d,J=5.2Hz) |
108 | 30 | 油 | 0.93(6H,m),1.0-1.7(8H,m),3.2-3.65(4H,m),3.50(3H,s),6.04(1H,d,J=5.2Hz),7.1-7.6(5H,m),7.96(1H,d,J=5.2Hz) |
116 | 41 | 油 | 1.92(4H,m),3.38(4H,m),3.53(3H,m),6.0(1H,d,J=5.2Hz),7.2-7.5(5H,m),7.96(1H,d,J=5.2Hz) |
124 | 63 | 油 | 1.67(6H,br,s),2.35(3H,s),3.38(3H,s),3.78(4H,m),6.52(1H,d,J=6.0Hz),8.25(1H,d,J=6.0Hz) |
132 | 55 | 油 | 1.55(6H,m),3.53(3H,s),3.56(4H,m),6.08(1H,d,J=5.2Hz),7.40(5H,m),8.04(1H,d,J=5.2Hz) |
140 | 71 | 油 | 1.92(3H,d,J=5.2Hz),0.8-1.8(5H,m),2.7(2H,m),3.52(3H,s),4.44(2H,br,d,J=12.6Hz),6.08(1H,d,J=5.2Hz),7.40(5H,m),8.04(1H,d,J=5.2Hz) |
148 | 34 | 油 | 0.88(9H,s),1.0-1.8(5H,m),2.63(2H,m),3.53(3H,s),4.55(2H,br,d,J=12.6Hz),6.08(1H,d,J=5.2Hz),7.2-7.7(5H,m),8.05(1H,d,J=5.2Hz) |
表3(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
156 | 71 | 油 | 1.4-2.0(4H,m),2.5-3.2(3H,m),4.91(2H,br,d,J=12.6Hz),7.0-7.7(7H,m),7.90(2H,m),8.32(2H,m) |
172 | 20 | 油 | 1.33(3H,t,J=7.2Hz),1.4-2.0(4H,m),2.5-3.0(3H,m),4.13(2H,q,J=7.2Hz),4.64(2H,br,d,J=12.6Hz),6.01(1H,d,J=5.2Hz),7.0-7.7(10H,m,),8.04(1H,d,J=5.2Hz) |
180 | 37 | 油 | 0.98(3H,t,J=7.2Hz),1.3-2.0(6H,m),2.5-3.01(3H,m),4.03(2H,t,J=7.2Hz),4.63(2H,br,d,J=12.6Hz),6.0(1H,d,J=5.2Hz),7.1-7.6(10H,m),8.04(1H,d,J=5.2Hz) |
188 | 59 | 油 | 1.2-2.0(4H,m),2.5-3.0(3H,m),4.60(2H,br,d,J=12.6Hz),5.28(2H,s),5.95(1H,d,J=5.2Hz),7.0-7.70(15H,m),7.96(1H,d,J=5.2Hz) |
196 | 60 | 油 | 1.2-2.0(4H,m),2.56(6H,s),2.5-3.10(5H,m),4.36(2H,t,J=8Hz),4.67(2H,br,d,J=12.6Hz),6.0(1H,d,J=5.6Hz),7.0-7.6(10H,m),8.0(1H,d,J=5.6Hz) |
204 | 28 | 油 | 1.5-2.1(4H,m),2.35(3H,s),2.6-3.2(3H,m),3.40(3H,s),4.90(2H,br,d,J=12.6Hz),6.60(1H,d,J=12.6Hz),7.28(5H,m),8.28(1H,d,J=7.2Hz) |
表3(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
212 | 34 | 88-94 | 1.16(6H,d,J=7.2Hz),1.4-2.1(4H,m),2.6-3.3(4H,m),3.36(3H,s),4.88(2H,br,d,J=12.6Hz),6.51(1H,d,J=5.2Hz),7.24(5H,m),8.24(1H,d,J=5.2Hz) |
220 | 45 | 油 | 1.25(9H,s),1.5-2.0(4H,m),2.6-3.2(3H,m),3.29(3H,s),4.91(2H,br,d,J=12.6Hz),6.50(1H,d,J=5.2Hz),7.26(5H,m),8.26(1H,d,J=5.2Hz) |
228 | 35 | 油 | 1.0-2.1(14H,m),2.6-3.2(4H,m),3.36(3H,s),4.90(2H,br,d,J=12.6Hz),6.50(1H,d,J=5.2Hz),7.25(5H,m),8.25(1H,d,J=5.2Hz) |
236 | 66 | 油 | 1.3-2.0(4H,m),2.5-3.0(3H,m),3.52(3H,s),4.60(2H,br,d,J=12.6Hz),6.11(1H,d,J=5.2Hz),7.1-7.5(9H,m),8.10(1H,d,J=5.2Hz) |
244 | 33 | 油 | 1.2-2.0(4H,m),2.5-3.0(3H,m),3.51(3H,s),4.56(2H,br,d,J=12.6Hz),6.15(1H,d,J=5.2Hz),7.0-7.5(9H,m),8.10(1H,d,J=5.2Hz) |
260 | 41 | 油 | 1.2-1.9(4H,m),2.4-2.9(3H,m),3.56(3H,s),4.49(2H,br,d,J=12.6Hz),6.16(1H,d,J=3.6Hz),7.0-7.5(5H,m),7.6(2H,d,J=9.5Hz),8.16(1H,d,J=3.6Hz),8.20(2H,d,J=9.5Hz) |
表3(续)
化合物No. | 得率(%)- | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
268 | 27 | 油 | 1.4-2.0(4H,m),2.5-3.0(3H,m),3.55(3H,s),3.79(3H,s),4.72(2H,br,d,J=12.6Hz),6.07(1H,d,J=5.2Hz),6.81(2H,m),7.1-7.6(7H,m),8.05(1H,d,J=5.2Hz) |
276 | 57 | 油 | 1.4-2.0(4H,m),2.5-3.1(3H,m),3.53(3H,s),3.79(6H,s),3.84(3H,s),4.70(2H,br,d,J=12.6Hz),6.13(1H,d,J=5.2Hz),6.70(2H,s),7.22(5H,m),8.05(1H,d,J=5.2Hz) |
292 | 44 | 油 | 1.5-2.0(4H,m),2.6-3.1(3H,m),3.55(3H,s),4.77(2H,br,d,J=12.6Hz),6.24(1H,d,J=5.2Hz),6.44(1H,dd,J=3.2,2.0Hz),7.0(1H,dd,J=3.0,1.0Hz),7.1-7.5(6H,m),8.16(1H,d,J=5.2Hz) |
300 | 84 | 油 | 0.5-2.0(5H,m),2.2-2.6(4H,m),3.59(3H,s),3.76(2H,br,d,J=12.6Hz),6.06(1H,d,J=5.2Hz),7.0-7.6(10H,m),8.0(1H,d,J=5.2Hz) |
308 | 35 | 油 | 2.37(3H,s),2.95(2H,t,J=5.2Hz),3.41(3H,s),4.05(2H,t,J=5.2Hz),4.92(2H,s),6.64(1H,d,J=5.2Hz),7.22(4H,s),8.32(1H,d,J=5.2Hz) |
表3(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
316 | 96 | 油 | 1.85-2.20(2H,m),2.33(3H,s),2.80(2H,t,J=5.2Hz),3.40(3H,s),4.04(2H,t,J=5.2Hz),6.93(1H,d,J=5.2Hz),6.95-7.30(3H,m),7.72(1H,dd,J=7.2,2.0Hz),8.34(1H,d,J=5.2Hz) |
324 | 79 | 油 | 1.6-2.1(2H,m),2.76(2H,t,J=5.2Hz),3.52(3H,s),3.80(2H,t,J=5.2Hz),6.39(1H,d,J=5.2Hz),6.9-7.7(9H,m),8.15(1H,d,J=5.2Hz) |
332 | 42 | 油 | 3.52(3H,s),3.59(8H,m),6.18(1H,d,J=5.2Hz),7.36(5H,m),8.04(1H,d,J=5.2Hz) |
340 | 33 | 油 | 2.18(1H,s),2.79(4H,m),3.51(3H,s),3.56(4H,m),6.12(1H,d,J=5.2Hz),7.35(5H,m),8.02(1H,d,J=5.2Hz) |
348 | 19 | 油 | 2.31(3H,s),2.36(4H,m),3.52(3H,s),3,60(4H,m),6.12(1H,d,J=5.2Hz),7.1-7.5(5H,m),8.01(1H,d,J=5.2Hz) |
356 | 72 | 油 | 3.10(4H,m),3.56(3H,s),3.76(4H,m),6.20(1H,d,J=5.4Hz),6.90(3H,m),7.1-7.6(7H,m),8.09(1H,d,J=5.4Hz) |
364 | 52 | 油 | 2.36(4H,m),3.4-3.8(9H,m),6.11(1H,d,J=5.2Hz),7.1-7.6(10H,m),8.01(1H,d,J=5.2Hz) |
表3(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
372 | 50 | 58-62 | 2.32(4H,m),3.49(3H,s),3.62(4H,m),4.23(1H,s),6.13(1H,d,J=5.2Hz),7.0-7.6(14H,m),8.02(1H,d,J=5.2Hz) |
380 | 63 | 油 | 1.65(6H,br,s),2.29(3H,s),2.35(3H,s),3.34(3H,s),3.77(4H,m),6.32(1H,s) |
388 | 64 | 油 | 1.5-2.11(4H,m),2.32(3H,s),2.37(3H,s),2.6-3.1(3H,m),3.36(3H,s),4.92(2H,br,d,J=12.6Hz),6.40(1H,s),7.28(5H,br,s) |
396 | 52 | 油 | 1.3-2.0(4H,m),2.22(3H,s),2.5-3.0(3H,m),3.53(3H,s),4.64(2H,br,d,J=12.6Hz),6.05(1H,s),7.1-7.6(10H,m) |
404 | 49 | 油 | 1.3-1.8(6H,m),1.89(3H,s),3.40(3H,s),3.63(4H,m),7.1-7.5(5H,m),8.0(1H,s) |
412 | 28 | 油 | 1.5-2.1(4H,m),2.0(3H,s),2.08(3H,s),2.6-3.2(3H,m),3.20(3H,s),4.85(2H,br,d,J=12.6Hz),7.27(5H,m),8.26(1H,s) |
420 | 54 | 油 | 1.4-1.9(4H,m),1.94(3H,s),2.5-3.05(3H,m),3.42(3H,s),4.71(2H,br,d,J=12.6Hz),7.0-7.6(10H,m),8.05(1H,s) |
表3(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
428 | 55 | 油 | 1.3-2.1(4H,m),2.5-3.0(3H,m),3.51(3H,d,J=0.5Hz),4.60(1H,br,d,J=12.6Hz),7.0-7.6(10H,m),8.0(1H,d,J=2Hz) |
600 | 67 | 油 | 1.2-1.7(6H,m),3.12(4H,m),3.61(3H,s),6.09(1H,d,J=7.2Hz),7.1-7.5(5H,m),8.0(1H,d,J=7.2Hz) |
608 | 57 | 油 | 0.5-1.0(2H,m),0.87(3H,d,J=5.2Hz),1.3-1.7(3H,m),2.3-2.7(2H,m),3.61(3H,s),3.5-3.9(2H,br,d,J=12.6Hz),6.10(1H,d,J=7.2Hz),7.1-7.5(5H,m),8.0(1H,d,J=7.2Hz) |
616 | 55 | 143-145 | 0.84(9H,s),0.9-1.6(5H,m),2.44(2H,m),3.61(3H,s),3.87(2H,br,d,J=12.6Hz).6.10(1H,d,J=5.2Hz),7.2-7.5(5H,m),8.0(1H,d,J=5.2Hz) |
624 | 67 | 油 | 1.0-1.9(4H,m),2.4-2.9(3H,m),3.64(3H,s),3.95(2H,br,d,J=12.6Hz),6.16(1H,d,J=5.2Hz),7.0-7.55(10H,m),8.07(1H,d,J=5.2Hz) |
632 | 67 | 油 | 1.35(3H,t,J=7.2Hz),1.0-1.9(4H,m),2.4-2.9(3H,m),3.97(2H,br,d,J=12.6Hz),4.22(2H,q,J=7.2Hz),6.15(1H,d,J=7.2Hz),7.0-7.6(10H,m),8.05(1H,d,J=7.2Hz) |
表3(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
640 | 52 | 油 | 0.99(3H,t,J=7.2Hz),1.0-2.0(6H,m),2.4-2.9(3H,m),3.99(2H,br,d,J=12.9Hz),4.0-4.3(2H,m),6.15(1H,d,J=7.2Hz),7.0-7.6(10H,m),8.04(1H,d,J=7.2Hz) |
648 | 63 | 油 | 1.0-2.0(4H,m),1.46(3H,s),1.54(3H,s),2.5-3.0(3H,m),4.15(2H,br,d,J=12.6Hz),5.13(1H,m),6.19(1H,d,J=7.2Hz),7.0-7.6(10H,m),8.04(1H,d,J=7.2Hz) |
658 | 88 | 油 | 1.0-1.85(4H,m),2.4-2.80(3H,m),3.95(2H,br,d,J=12.6Hz),5.38(2H,s),6.10(1H,d,J=5.2Hz),7.0-7.60(15H,m),7.98(1H,d,J=5.2Hz) |
664 | 71 | 160-162 | 1.0-2.0(4H,m),2.4-2.9(3H,m),3.62(3H,s),3.99(2H,br,d,J=12.6Hz),6.16(1H,d,J=5.2Hz),7.0-7.5(9H,m),8.05(1H,d,J=5.2Hz) |
672 | 60 | 153-154 | 1.0-2.0(4H,m),2.5-2.9(3H,m),3.65(3H,s),4.0(2H,br,d,J=12.6Hz),6.20(1H,d,J=7.2Hz),7.0-7.5(5H,m),7.56(2H,d,J=10.8Hz),8.01(1H,d,J=7.2Hz),8.14(2H,d,J=10.8Hz) |
表3(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
680 | 59 | 油 | 1.4-2.0(4H,m),2.5-3.0(3H,m),3.56(3H,s),4.22(2H,br,d,J=12.6Hz),6.25(1H,d,J=5.2Hz),6.36(1H,dd,J=4.0,1.0Hz),6.88(1H,d,J=4.0Hz),7.0-7.5(6H,m),8.08(1H,d,J=5.2Hz) |
688 | 41 | 油 | 0.8-1.8(5H,m),2.3-2.8(4H,m),3.51(3H,s),4.45(2H,br,d,J=12.6Hz),6.07(1H,d,J=5.2Hz),7.0-7.6(10H,m),8.02(1H,d,J=5.2Hz) |
696 | 69 | 99-101 | 2.0(2H,m),2.48(3H,s),2.79(2H,t,J=5.2Hz),3.48(3H,s),3.97(2H,t,J=5.2Hz),6.80(1H,d,J=5.2Hz),7.0-7.5(4H,m),8.13(1H,d,J=5.2Hz) |
252 | 38 | 油 | 1.3-2.0(4H,m),2.4-3.0(3H,m),3.47(3H,s),4.59(2H,br,d,J=12.6Hz),6.47(1H,d,J=5.2Hz),7.0-7.6(9H,m),8.13(1H,d,J=5.2Hz) |
284 | 38 | 136-138 | 1.2-2.0(4H,m),2.4-3.0(3H,m),3.53(3H,s),4.59(2H,br,d,J=12.6Hz),6.15(1H,d,J=5.2Hz),6.95-7.60(14H,m),8.05(2H,d,J=5.2Hz) |
表3(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
137 | 95 | 油 | 0.88(3H,d,J=7Hz),1.1-2.8(7H,m),3.50(3H,s),4.28(2H,m),6.03(1H,d,J=5Hz),7.34(5H,m),7.99(1H,d,J=5Hz) |
145 | 38 | 油 | 0.7-2.8(12H,m),3.49(3H,s),4.40(2H,m),6.02(1H,d,J=5Hz),7.32(5H,m),7.96(1H,d,J=5Hz) |
147 | 96 | 油 | 0.88(6H,d,J=7Hz),1.0-2.9(8H,m),3.50(3H,s),4.47(2H,m),6.04(1H,d,J=5Hz),7.34(5H,m),8.00(1H,d,J=5Hz) |
153 | 38 | 油 | 1.04(3H,d,J=7Hz),1.54(6H,m),2.76(1H,m),3.49(3H,s),4.28(1H,m),4.70(1H,m),6.02(1H,d,J=5Hz),7.32(5H,m),7.98(1H,d,J=5Hz), |
171-2 | 56 | 126-129 | 1.2-2.0(4H,m),2.32(3H,s),2.5-3.0(3H,m),3.52(3H,s),4.65(2H,br,d,J=12.6Hz),6.08(1H,d,J=5.2Hz),6.98-7.42(9H,m),8.01(1H,d,J=5.2Hz) |
2000 | 95 | 油 | 0.87(6H,d,J=7Hz),1.1-3.4(6H,m),3.50(3H,s),4.36(2H,m),6.06(1H,d,J=5Hz),7.36(5H,m),8.02(1H,d,J=5Hz) |
2008 | 50 | 油 | 1.4-2.0(4H,m),2.38(3H,s),2.5-3.1(3H,m),3.44(3H,s),4.75(2H,br,d,J=12.6Hz),6.80(1H,d,J=5.2Hz),7.0-7.4(7H,m),7.66(2H,d,J=7.2Hz),8.09(1H,d,J=5.2Hz) |
表3(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
2048 | 37 | 油 | 8.00(1H,d,J=5Hz),7.2-7.5(5H,m),6.12(1H,d,J=5Hz),4.4-4.7(2H,m),3.50(3H,s),1.1-3.0(17H,m) |
2056 | 89 | 油 | 8.00(1H,d,J=5Hz),7.2-7.5(5H,m),6.08(1H,d,J=5Hz),3.7-4.3(4H,m),3.50(3H,s),2.9-3.3(2H,m),1.0-2.0(4H,m) |
2064 | 47 | 油 | 8.00(1H,d,J=5Hz),7.2-7.6(5H,m),6.18(1H,d,J=5Hz),4.2-4.5(2H,m),3.60(3H,s),1.0-4.0(12H,m) |
2074 | 35 | 油 | 8.12(2H,d,J=7Hz),7.88(1H,d,J=5Hz),7.35(1H,d,J=7Hz),6.22(1H,d,J=5Hz),7.2-7.6(5H,m),4.8-5.0(2H,m),3.64(3H,s),2.7-3.1(2H,m),1.1-2.0(5H,m) |
2080 | 16 | 油 | 8.02(1H,d,J=7Hz),7.2-7.6(5H,m),6.29(1H,d,J=7Hz),4.0-4.6(2H,m),2.49(3H,s),0.8-3.2(14H,m) |
2088 | 38 | 油 | 8.03(1H,d,J=7Hz),7.2-7.5(5H,m),6.28(1H,d,J=7Hz),3.47(3H,s),3.08(3H,s),1.6-3.8(10H,m) |
表3(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
2096 | 36 | 油 | 8.03(1H,d,J=5Hz),7.2-7.6(5H,m),6.58(1H,d,J=5Hz),4.5-4.8(2H,m),4.18(2H,q,J=7Hz),1.50(3H,s),1.5-3.0(7H,m),1.30(3H,t,J=2Hz) |
2112 | 95 | 油 | 0.96(6H,s),1.26(4H,m),3.48(3H,s),3.50(4H,m),6.02(1H,d,J=5Hz),7.32(5H,m),7.98(1H,d,J=5Hz) |
2120 | 44 | 油 | 0.85(3H,t,J=7Hz),1.47(4H,m),2.79(2H,m),3.1-3.7(6H,m),6.08(1H,d,J=5Hz),7.30(10H,m),8.04(1H,d,J=5Hz) |
2128 | 28 | 油 | 1.4-2.1(4H,m),2.5-3.1(3H,m),3.54(3H,s),4.73(2H,br,d,J=12.6Hz),6.24(1H,d,J=5.4Hz),6.92(1H,dd,J=5.4,3.6Hz),7.0-7.5(7H,m),8.08(1H,d,J=5.4Hz) |
2136 | 93 | 油 | 1.3-2.0(4H,m),2.45-3.0(3H,m),3.52(3H,s),4.48(2H,br,d,J=12.6Hz),6.13(1H,d,J=5.4Hz),7.0-7.4(6H,m),7.75(1H,m),8.10(1H,d,J=5.4Hz),8.54(2H,m) |
2144 | 53 | 油 | 8.00(1H,d,J=7Hz),7.2-7.5(5H,m),6.13(1H,d,J=7Hz),4.3-4.5(2H,m),2.0-3.8(7H,m),3.10(6H,s),3.36(3H,s),11.8-18.6(2H,br) |
表3(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
2152 | 40 | 油 | 8.00(1H,d,J=7Hz),7.2-7.5(5H,m),6.38(1H,d,J=7Hz),3.38(3H,s),4.0-4.8(2H,m),0.8-2.04(14H,m) |
2160 | 45 | 油 | 8.00(1H,d,J=5Hz),7.2-7.6(5H,m),6.10(1H,d,J=5Hz),4.1-4.4(2H,m),3.58(3H,s),1.0-3.5(10H,m) |
2170 | 42 | 油 | 1.2-3.1(7H,m),3.51(3H,s),3.89(1H,m),4.40(2H,m),6.19(1H,d,J=5Hz),7.2-7.9(10H,m),8.01(1H,d,J=5Hz) |
2178 | 85 | 油 | 1.5-3.1(6H,m),3.51(3H,s),3.90(1H,m),4.74(2H,m),6.02(1H,d,J=5Hz),6.50(2H,d,J=8Hz),7.24(7H,m),7.96(1H,d,J=8Hz) |
2184 | 56 | 油 | (CDCl3-CD30D)1.2-3.3(7H,m),3.50(3H,s),4.46(2H,m),6.20(1H,d,J=5Hz),7.36(5H,m),8.01(1H,d,J=5Hz) |
2192 | 50 | 油 | 1.4-3.3(6H,m),3.56(3H,s),4.2-4.7(3H,m),6.60(1H,d,J=7Hz),7.1-7.9(14H,m),7.96(1H,d,J=7Hz) |
表3(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
2198 | 42 | 油 | (CDCl3-CD3OD)1.4-3.3(7H,m),3.53(3H,s),4.42(2H,m),6.72(1H,d,J=7Hz),7.3-7.9(10H,m),7.98(1H,d,J=7Hz) |
2206 | 45 | 油 | 1.61(6H,br,s),1.4-2.1(4H,m),2.55-3.15(3H,m),3.22(3H,s),3.40(4H,br,s),4.87(2H,br,d,J=12.6Hz),5.97(1H,d,J=5.2Hz),7.24(5H,m),8.0(1H,d,J=5.2Hz) |
2214 | 26 | 131-132 | 1.5-2.2(4H,m),2.5-3.3(3H,m),3.40(3H,s),4.80(2H,br,d,J=12.6Hz),6.16(1H,d,J=5.2Hz),6.89-7.65(10H,m),8.20(1H,d,J=5.2Hz),12.23(1H,br,s) |
2222 | 60 | 46-49 | 7.9-8.1(3H,m),7.2-7.6(8H,m),6.10(1H,d,J=5Hz),5.0-5.2(1H,m),3.8-4.1(2H,m),3.50(3H,s),1.8-2.0(6H,m) |
2230 | 97 | 油 | 1.26-2.10(4H,m),2.30(3H,s),2.39(4H,m),2.5-3.20(3H,m),3.21(3H,s),3.47(4H,m),4.85(2H,br,d,J=12.6Hz),5.96(1H,d,J=5.2Hz),7.20(5H,m),8.0(1H,d,J=5.2Hz) |
表3(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
2238 | 69 | 油 | 1.35(3H,t,J=7.2Hz),1.4-2.15(4H,m),2.55-3.20(3H,m),3.44(3H,s),4.25(2H,q,J=7.2Hz),4.86(2H,br,d,J=12.6Hz),7.23(6H,m),8.12(1H,d,J=5.2Hz) |
2246 | 13 | 油 | 1.2-3.4(7H,m),3.56(3H,s),3.92(2H,s),4.74(2H,m),6.50(1H,d,J=7Hz),7.18(10H,m),8.18(1H,d,J=7Hz) |
2254 | 45 | 油 | 0.94(3H,t,J=7Hz),1.52(6H,m),2.02(2H,m),2.79(4H,m),3.50(3H,s),4.50(2H,m),5.04(2H,m),6.09(1H,d,J=7Hz),7.36(5H,m),7.98(1H,d,J=7Hz) |
2264 | 90 | 油 | 1.1-1.6(4H,m),2.4-2.9(3H,m),3.46(3H,s),4.50(2H,m),6.06(1H,d,J=5Hz),7.28(15H,m),7.94(1H,d,J=5Hz) |
2274 | 62 | 112-115 | 1.35-2.10(4H,m),2.50-3.10(3H,m),3.0(3H,s),4.74(2H,s),4.88(2H,br,d,J=12.6Hz),5.79(1H,d,J=5.2Hz),7.22(10H,m),7.90(1H,d,J=5.2Hz) |
2282 | 67 | 油 | 1.45-2.15(4H,m),2.55-3.20(3H,m),3.40(3H,s),4.82(2H,br,d,J=12.6Hz),5.05(2H,s),6.37(1H,d,J=5.2Hz),6.70-7.10(3H,m),7.10-7.45(7H,m),8.25(1H,d,J=5.2Hz) |
表3(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
2290 | 42 | 油 | 1.4-2.1(4H,m),2.96(6H,s),2.58-3.20(3H,m),3.20(3H,s),4.85(2H,br,d,J=12.6Hz),5.92(1H,d,J=5.2Hz),7.22(5H,m),8.02(1H,d,J=5.2Hz) |
2298 | 56 | 油 | 1.15(6H,m),1.4-2.1(4H,m),2.5-3.2(3H,m),3.18(3H,s),3.35(4H,m),4.88(2H,br,d,J=12.6Hz),5.90(1H,d,J=5.2Hz),7.22(5H,m),7.98(1H,d,J=5.2Hz) |
2306 | 75 | 油 | 1.76(4H,m),2.92(2H,m),3.36(1H,m),3.51(3H,s),4.52(2H,m),6.52(1H,d,J=7Hz),7.39(7H,m),7.86(2H,d,J=7Hz),8.02(1H,d,J=7Hz) |
2314 | 26 | 油 | 1.2-2.0(4H,m),2.1-2.9(3H,m),3.90(3H,s),4.32(2H,m),6.70(1H,d,J=7Hz),7.0-7.7(10H,m),8.23(1H,d,J=7Hz) |
2322 | 77 | 油 | 1.4-2.1(4H,m),2.5-3.4(3H,m),3.24(3H,s),3.57(8H,m),4.88(2H,br,d,J=12.6Hz),6.0(1H,d,J=5.4Hz),7.23(5H,m),8.04(1H,d,J=5.4Hz) |
2330 | 59 | 119-121 | 1.4-2.1(4H,m),2.6-3.2(3H,m),3.61(3H,s),4.89(2H,br,d,J=12.6Hz),7.0-7.5(11H),8.16(1H,d,J=5.4Hz) |
表3(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
2338 | 23 | 油 | 8.02(1H,d,J=7Hz),7.2-7.6(5H,m),6.38(1H,d,J=7Hz),3.36(3H,s),1.0-3.5(13H,m) |
2346 | 54 | 油 | 8.00(1H,d,J=7Hz),7.2-7.9(10H,m),6.48(1H,d,J=7Hz),4.2-4.5(2H,m),3.38(3H,s),1.4-3.8(7H,m) |
2016 | 50 | 油 | 1.4-2.0(4H,m),2.5-3.0(3H,m),3.53(3H,s),4.21(2H,br,d,J=12.6Hz),6.12(1H,d,J=7.2Hz),6.35(1H,d,J=7.2Hz),7.0-7.4(11H,m) |
2024 | 36 | 油 | 1.4-2.0(4H,m),2.5-3.1(3H,m),3.54(3H,s),4.25(2H,br,d,J=12.6Hz),7.0-7.6(10H,m),7.41(1H,s).7.79(1H,s) |
2032 | 69 | 7682 | 1.2-2.0(8H,m),2.4-3.9(6H,m),3.56(3H,s),4.50(2H,m),7.0-7.52(15H,m) |
2040 | 28 | 油 | 1.4-2.1(4H,m),2.5-3.2(3H,m),3.50(3H,s),4.38(2H,br,d,J=12.6Hz),6.32(1H,d,d,J=3.6,2.0Hz),6.71(1H,d,d,J=3.0,1.0Hz),7.24(6H,m),7.58(1H,s),7.93(1H,s) |
表3(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
154-1 | 61 | 油 | 1.4-2.2(4H,m),2.6-3.2(3H,m),3.36(3H,s),3.43(3H,s),4.43(2H,s),4.84(2H,br,d,J=12.6Hz),6.44(1H,d,J=5.2Hz),7.22(5H,m),8.22(1H,d,J=5.2Hz) |
171-4 | 64 | 油 | 1.37(3H,t,J=7.2Hz),1.4-2.1(4H,m),2.5-3.05(3H,m),3.52(3H,s),3.98(2H,q,J=7.2Hz),4.69(2H,br,d,J=12.6Hz),6.03(1H,d,J=5.2Hz),6.76(2H,m),7.0-7.6(7H,m),8.0(1H,d,J=5.2Hz) |
297 | 60 | 油 | 1.80(4H,m),2.90(3H,m),4.92(2H,m),6.64(1H,d,J=5Hz),7.20(5H,m),7.80(4H,m),8.39(1H,d,J=5Hz) |
305 | 90 | 油 | 1.76(4H,m),2.90(2H,m),3.40(1H,m),3.51(3H,s),4.49(2H,m),6.11(1H,d,J=5Hz),7.40(8H,m),7.92(2H,m),8.01(1H,d,J=5Hz) |
307 | 19 | 油 | 8.01(1H,d,J=7Hz),7.2-7.6(5H,m),6.10(1H,d,J=7Hz),4.2-4.4(2H,m),1.2-3.8(10H,m),3.35(3H,s) |
241 | 69 | 油 | 1.1-2.1(4H,m),2.5-3.0(3H,m),3.50(3H,s),4.60(2H,br,d,J=12.6Hz),6.04(1H,d,J=5.2Hz),6.8-7.7(9H,m),8.04(1H,d,J=5.2Hz) |
表3(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
2022 | 84 | 油 | 1.4-2.0(4H,m),2.45-3.0(3H,m),3.52(3H,s),4.20(2H,br,d,J=12.6Hz),6.10(1H,d,J=7.2Hz),6.35(1H,d,J=7.2Hz),7.0-7.4(10H,m) |
2023 | 85 | 112-114 | 1.3-2.1(4H,m),2.5-3.2(3H,m),3.47(3H,s),4.35(2H,br,d,J=12.6Hz),6.31(1H,d,J=7.2Hz),6.50(1H,d,J=7.2Hz),6.65-7.6(9H,m,J=7.2Hz) |
149 | 87 | 103-105 | 0.5-1.8(5H,m),0.88(3H,d,J=5.2Hz),2.3-2.8(2H,m),4.15(2H,br,d,J=12.6Hz),6.06(1H,d,J=5.2Hz),7.1-7.8(10H,m),8.08(1H,d,J=5.2Hz) |
171-8 | 79 | 油 | 1.2-2.0(4H,m),2.4-3.0(3H,m),3.52(3H,s),4.51(2H,br,d,J=12.6Hz),6.32(1H,d,J=5.2Hz),6.76-7.65(9H,m),8.1(1H,d,J=5.2Hz) |
171-10 | 62 | 油 | 1.2-2.1(4H,m),2.5-3.0(3H,m),3.49(3H,s),4.53(2H,br,d,J=12.6Hz),6.36(1H,d,J=5.2Hz),7.0-7.5(8H,m),8.12(1H,d,J=5.2Hz) |
171-1 | 26 | 油 | 1.3-2.1(4H,m),2.5-3.0(3H,m),3.47(3H,s),4.85(2H,d,J=12.6Hz),6.35(1H,d,J=5.2Hz),6.90(1H,d,J=15.4Hz),7.0-7.6(10H,m),7.65(1H,d,J=15.4Hz),8.20(1H,d,J=5.2Hz) |
表3(续)
实施例2
化合物 | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
171-6 | 41 | 油 | 1.4-2.0(4H,m),2.34(3H,s),2.5-3.0(3H,m),3.46(3H,s),4.64(2H,br,d,J=12.6Hz),6.32(1H,d,J=5.2Hz),7.0-7.4(9H,m),8.04(1H,d,J=5.2Hz) |
171-12 | 71 | 113-116 | 1.1-2.1(4H,m),2.4-3.0(3H,m),3.49(3H,s),4.51(2H,br,d,J=12.6Hz),6.1(1H,d,J=5.2Hz),7.0-7.7(8H,m),8.1(1H,d,J=5.2Hz) |
4-(N-甲基苯氨基)-2-(4-苯基哌啶子基)嘧啶对甲苯磺酸盐(化合物№.168).
室温下,将3.0g(0.022摩尔)对甲苯磺酸-水化物的300ml乙酸乙酯溶液缓慢地加到6.0g(0.022摩尔)4-(N-甲基苯氨基)-2-(4-苯基哌啶子基)嘧啶的100ml乙酸乙酯溶液中,-经加入就形成混悬液。加完后,该混悬液搅拌10分钟,过滤分离得到的固体,用乙酸乙酯和醚洗涤,干燥,得到6.8g(得率83%)所期化合物。
M.p.:180-182℃.
1H-NMR(CDCl3,δppm):
1.4-2.1(4H,m),2.35(3H,s),2.6-3.3(3H,m),
3.56(3H,s),4.55(2H,br.d,J=12.6Hz),
6.60(1H,d,J=7.2Hz),7.0-7.9(14H,m),
8.36(1H,d,J=7.2Hz).
用上述相同方法制得下列化合物,有关数据列于表4。
表4
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
104 | 100 | 54-58 | 2.33(3H,s),2.8-3.5(6H,m),3.50(3H,s),6.64(1H,d,J=7.2Hz)7.13(2H,d,J=7.2Hz),7.50(5H,m,),7.75(2H,d,J=7.2Hz)8.24(1H,d,J=7.2Hz) |
112 | 100 | 油 | 0.90(6H,m),1.0-1.8(8H,m),2.35(3H,s),3.2-3.7(4H,m),3.5(3H,s),6.58(1H,d,J=7.2Hz),7.13(2H,d,J=7.2Hz),7.3-7.7(5H,m),7.76(2H,d,J=7.2Hz)8.36(1H,d,J=7.2Hz) |
120 | 82 | 125-126 | 2.0(4H,m),2.35(3H,s),3.44(2H,m),3.52(3H,s),3.72(2H,m),6.56(1H,d,J=7.2Hz),7.15(2H,d,J=7.2Hz),7.2-7.7(5H,m),7.78(2H,d,J=7.2Hz),8.22(1H,d,J=7.2Hz) |
128 | 90 | 149-150 | 1.72(6H,br,s),2.37(3H,s),2.48(3H,s),3.50(3H,s),3.84(4H,br,s),7.18(2H,d,J=7.5Hz),7.44(1H,d,J=7.2Hz),7.81(2H,d,J=7.5Hz),8.38(1H,d,J=7.2Hz) |
136 | 79 | 48-52 | 1.63(6H,br,s),2.36(3H,s),3.52(3H,s),3.64(4H,br,s),6.56(1H,d,J=7.2Hz),7.16(2H,d,J=7.2Hz),7.55(5H,m),7.79(2H,d,J=7.2Hz),8.30(1H,d,J=7.2Hz) |
144 | 90 | 49-51 | 0.94(3H,d,J=5.2Hz),0.8-1.90(5H,m),2.36(3H,s), |
表4(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
144 | 90 | 49-51 | 2.8-3.2(2H,m),3.52(3H,s),4.32(2H,br,d,J=12.6Hz),6.6(1H,d,J=7.2Hz),7.16(2H,d,J=7.2Hz),7.3-7.7(5H,m),7.8(2H,d,J=7.2Hz),8.3(1H,d,J=7.2Hz) |
152 | 72 | 52-56 | 0.85(9H,s),1.0-2.0(5H,m),2.36(3H,s),2.5-3.2(2H,m),3.52(3H,s),4.44(2H,br,d,J=12.6Hz),6.58(1H,d,J=7.2Hz),7.16(2H,d,J=7.2Hz),7.3-7.7(5H,m),7.8(2H,d,J=7.2Hz)8.28(1H,d,J=7.2Hz) |
160 | 80 | 206-207 | 1.3-2.1(4H,m),2.32(3H,s),2.5-3.3(3H,m),4.76(2H,br,d,J=12.6Hz),7.0-8.4(16H,m) |
176 | 75 | 68-72 | 1.36(3H,t,J=7.2Hz),1.4-2.1(4H,m),2.33(3H,s),2.5-3.3(3H,m),4.12(2H,q,J=7.2Hz),4.42(2H,br,d,J=12.6Hz),6.34(1H,d,J=7.2Hz),7.0-7.9(12H,m),8.32(1H,d,J=7.2Hz) |
184 | 85 | 53-57 | 1.0(3H,t,J=7.2Hz),1.4-2.1(6H,m)2.35(3H,s),2.5-3.3(3H,m),4.04(2H,m),4.42(2H,br,d,J=12.6Hz),6.28(1H,d,J=7.2Hz),7.0-7.7(14H,m),8.35(1H,d,J=7.2Hz) |
表4(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
192 | 80 | 59-62 | 1.2-2.0(4H,m),2.31(3H,s),2.5-3.2(3H,m),4.3 4(2H,m),5.28(2H,s),6.33(1H,d,J=7.2Hz),7.0-7.8(19H,m),8.25(1H,d,J=7.2Hz) |
200 | 79 | 98-105 | 1.4-2.0(4H,m),2.32(6H,s),2.5-3.2(3H,m),2.92(3H,s),2.98(3H,s),2.98(3H,s),3.50(2H,m),4.40(2H,br,d,J=12.6Hz),4.60(2H,m),6.40(1H,d,J=5.2Hz),7.0-7.8(18H,m),8.10(1H,d,J=5.2Hz),10.80(1H,m) |
208 | 90 | 172-174 | 1.6-2.2(4H,m),2.35(3H,s),2.48(3H,s),2.6-3.5(3H,m),3.52(3H,s),4.77(2H,br,d,J=12.6Hz),7.1-7.9(10H,m),8.42(1H,d,J=7.2Hz) |
216 | 86 | 154-156 | 1.24(6H,d,J=7.0Hz),1.4-2.2(4H,m),2.32(3H,s),2.6-3.4(4H,m),3.51(3H,s),4.75(2H,br,d,J=12.6Hz),7.12(2H,d,J=7.2Hz),7.20(5H,m),7.36(1H,d,J=7.2Hz),7.76(2H,d,J=7.2Hz),8.34(1H,d,J=7.2Hz) |
224 | 86 | 158-160 | 1.40(9H,s),1.5-2.2(4H,m),2.34(3H,s),2.6-3.3(3H,m),3.38(3H,s),4.76(2H,br,d,J=12.6Hz),6.56(1H,d,J=7.2Hz),7.0-7.4(7H,m),7.82(2H,d,J=7.2Hz)8.30(1H,d,J=7.2Hz) |
表4(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
232 | 100 | 49-52 | 1.0-2.3(14H,m),2.33(3H,s),2.6-3.5(4H,m),3.48(3H,s),4.75(2H,br,d,J=12.6Hz),7.12(2H,d,J=7.2Hz),7.0-7.5(6H,m),7.76(2H,d,J=7.2Hz),8.32(1H,d,J=7.2Hz) |
240 | 77 | 132-134 | 1.4-2.1(4H,m),2.36(3H,s),2.6-3.3(3H,m),3.55(3H,s),4.52(2H,br,d,J=12.6Hz),6.67(1H,d,J=7.2Hz),7.16(2H,d,J=7.2Hz),7.0-7.7(9H,m),7.81(2H,d,J=7.2Hz),8.44(1H,d,J=7.2Hz) |
248 | 84 | 168-170 | 1.2-2.1(4H,m),2.32(3H,s),2.5-3.4(3H,m),3.51(3H,s),4.48(2H,br,d,J=12.6Hz),6.69(1H,d,J=7.2Hz),7.12(2H,d,J=7.2Hz),7.0-7.65(9H,m),7.76(2H,d,J=7.2Hz),8.40(1H,d,J=7.2Hz) |
264 | 95 | 189-190 | 1.2-2.0(4H,m),2.34(3H,s),2.5-3.3(3H,m),3.55(3H,s),4.40(2H,br,d,J=12.6Hz),6.85(1H,d,J=7.2Hz),7.0-7.5(7H,m),7.77(4H,d,J=7.2Hz),8.31(2H,d,J=7.2Hz),8.52(1H,d,J=7.2Hz) |
272 | 84 | 56-60 | 1.4-2.0(4H,m),2.33(3H,s),2.6-3.25(3H,m),3.54(3H,s),3.84(3H,s),4.65(2H,br,d,J=12.6Hz), |
表4(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
272 | 84 | 56-60 | 6.38(1H,d,J=7.2Hz),6.92(2H,d,J=8.5Hz),7.23(7H,m),7.59(2H,d,J=8.5Hz),7.80(2H,d,J=7.2Hz),8.22(1H,d,J=7.2Hz) |
280 | 91 | 174-76 | 1.4-2.2(4H,m),2.32(3H,s),2.5-3.4(3H,m),3.51(3H,s),3.86(6H,s),3.91(3H,s),4.65(2H,br,d,J=12.6Hz),6.69(1H,d,J=7.2Hz),6.85(2H,s),7.0-7.4(7H,m),7.76(2H,s),8.30(1H,d,J=7.2Hz) |
296 | 91 | 174-78 | 1.4-2.2(4H,m),2.35(3H,s),2.6-3.3(3H,m),3.58(3H,s),4.69(2H,br,d,J=12.6Hz),6.55(1H,d,J=7.2Hz),6.60(1H,m),7.0-7.5(8H,m),7.56(1H,m),7.8(2H,d,J=7.2Hz),8.36(1H,d,J=7.2Hz) |
304 | 100 | 54-58 | 0.8-2.0(5H,m),2.33(3H,s),2.51(2H,d,J=7.2Hz),2.6-3.2(2H,m),3.49(3H,s),4.35(2H,br,d,J=12.6Hz),6.57(1H,d,J=7.2Hz),7.0-7.9(14H,m),8.28(1H,d,J=7.2Hz), |
312 | 78 | 182-184 | 2.37(3H,s),2.51(3H,s),3.01(2H,t,J=5.2Hz),3.57(3H,s),4.04(2H,t,J=5.2Hz),4.95(2H,s),7.20(2H,d,J=7.2Hz),7.25(4H,s),7.54(1H,d,J=7.2Hz),7.94(2H,d,J=7.2Hz),8.40(1H,d,J=7.2Hz) |
表4(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
320 | 81 | 49-51 | 1.9-2.3(2H,m),2.36(3H,s),2.40(3H,s),2.72(2H,t,J=5.2Hz),3.38(3H,s),4.04(2H,t,J=5.2Hz),7.20(5H,m),7.50(1H,m),7.76(3H,m),8.53(1H,d,J=5.2Hz) |
328 | 75 | 136-138 | 2.04(2H,q,J=5.2Hz),2.38(3H,s),2.73(2H,t,J=5.2Hz),3.48(3H,s),3.99(2H,t,J=5.2Hz),6.88(1H,d,J=7.2Hz),7.20(5H,m),7.50(6H,m),7.80(2H,d,J=7.2Hz),8.50(1H,d,J=7.2Hz) |
336 | 100 | 58-62 | 2.36(3H,s),3.52(3H,s),3.68(8H,brs),6.69(1H,d,J=7.0Hz)7.15(2H,d,J=7.2Hz),7.52(5H,m),7.75(2H,d,J=7.2Hz),8.28(1H,d,J=7.0Hz) |
344 | 100 | 164-168 | 2.39(3H,s),3.10(4H,m),3.48(3H,s),3.83(4H,m),6.28(1H,d,J=5.2Hz),7.20(2H,d,J=7.2Hz),7.35(5H,m),7.73(2H,d,J=7.2Hz),8.05(1H,d,J=5.2Hz), |
352 | 100 | 58-60 | 2.36(3H,s),2.83(3H,s),2.98(4H,m),3.49(3H,s),3.90(4H,m),6.33(1H,d,J=5.2Hz),7.15(2H,d,J=7.2Hz),7.0-7.5(5H,m),7.75(2H,d,J=7.2Hz),8.06(1H,d,J=5.2Hz) |
360 | 100 | 52-56 | 2.34(3H,s),3.32(4H,br,s),3.49(3H,s),4.0(4H,br,s),6.68(1H,d,J=7.2Hz), |
表4(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
360 | 100 | 52-56 | 7.0-7.8(14H,m),8.22(1H,d,J=7.2Hz) |
368 | 82 | 66-72 | 2.38(3H,s),3.05(4H,m),3.46(3H,s),4.0(4H,m),4.25(2H,s),6.32(1H,d,J=5.2Hz),7.17(2H,d,J=7.2Hz),7.40(10H,m),7.79(2H,d,J=7.2Hz),8.05(1H,d,J=5.2Hz) |
376 | 91 | 120-125 | 2.36(3H,s),2.94(4H,m),3.44(3H,s),4.0(4H,m),5.0(1H,m)6.40(1H,d,J=5.2Hz),7.0-7.9(18H,m),8.05(1H,d,J=5.2Hz) |
384 | 80 | 157-158 | 1.67(6H,br,s),2.31(3H,s),2.46(3H,s),2.71(3H,s),3.48(3H,s),3.76(4H,m),6.33(1H,s),7.14(2H,d,J=7.2Hz),7.80(2H,d,J=7.2Hz) |
392 | 85 | 159-161 | 1.6-2.2(4H,m),2.34(3H,s),2.48(3H,s),2.71(3H,s),2.7-3.4(3H,m),3.50(3H,s),4.87(2H,br,d,J=12.6Hz),7.14(2H,d,J=7.2Hz),7.30(6H,m),7.80(2H,d,J=7.2Hz) |
400 | 94 | 60-65 | 1.4-2.1(4H,m),2.32(3H,s),2.64(3H,s),2.6-3.3(3H,m),3.52(3H,s),4.64(2H,br,d,J=12.6Hz),6.51(1H,s),7.15(2H,d,J=7.2Hz),7.0-7.7(10H,m),7.80(2H,d,J=7.2Hz) |
表4(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
408 | 83 | 50-55 | 1.64(6H,br,s),2.04(3H,d,J=1.0Hz),2.39(3H,s),3.48(3H,s),3.70(4H,br,s),7.20(2H,d,J=7.2Hz),7.52(5H,m),7.80(2H,d,J=7.2Hz),8.33(1H,s) |
416 | 80 | 58-62 | 1.6-2.2(4H,m),2.09(3H,m),2.29(3H,s),2.35(3H,s),2.6-3.5(3H,m),3.36(3H,s),4.79(2H,br,d,J=12.6Hz),7.18(2H,d,J=7.2Hz),7.30(5H,m),7.84(2H,d,J=7.2Hz),8.46(1H,s), |
424 | 94 | 68-72 | 1.4-2.2(4H,m),2.06(3H,s),2.35(3H,s),2.6-3.4(3H,m),3.49(3H,s),4.62(2H,br,d,J=12.6Hz),7.0-7.7(12H,m),7.81(2H,d,J=8.5Hz),8.37(1H,s) |
432 | 80 | 146-148 | 1.3-2.2(4H,m),2.36(3H,s),2.5-3.4(3H,m),3.58(3H,d,J=1.0Hz),4.56(2H,br,d,J=12.6Hz),7.0-7.9(14H,m),8.44(1H,d,J=5.2Hz) |
604 | 100 | 44-48 | 1.2-1.8(6H,m),2.36(3H,s),3.28(4H,m),3.64(3H,s),6.50(1H,dd,J=7.2,1.5Hz),7.20(2H,d,J=7.2Hz),7.2-7.6(5H,m),7.85(2H,d,J=7.2Hz)8.39(1H,d,J=7.2Hz) |
表4(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
612 | 100 | 44-48 | 0.5-1.1(2H,m),0.89(3H,d,J=5.2Hz),1.4-1.8(3H,m),2.36(3H,s),2.3-2.9(2H,m),3.64(3H,s),3.85(2H,br,d,J=12.6Hz),6.53(1H,d,J=7.2Hz),7.19(2H,d,J=7.2Hz),7.2-7.6(5H,m),7.84(2H,d,J=7.2Hz),8.36(1H,d,J=7.2Hz) |
620 | 84 | 106-110 | 0.82(9H,s),0.9-1.8(5H,m),2.0-3.0(2H,m),2.36(3H,s),3.61(3H,s),4.0(2H,br,d,J=12.6Hz),6.72(1H,d,J=7.2Hz),7.18(2H,d,J=7.2Hz),7.2-7.6(5H,m),7.84(2H,d,J=7.2Hz),8.42(1H,d,J=7.2Hz) |
628 | 84 | 160-161 | 1.0-2.0(4H,m),2.35(3H,s),2.4-3.2(3H,m),3.64(3H,s),4.05(2H,br,d,J=12.6Hz),6.72(1H,d,J=7.2Hz),7.0-7.6(12H,m),7.84(2H,d,J=7.2Hz),8.49(1H,d,J=7.2Hz) |
636 | 83 | 143-147 | 1.30(3H,t,J=7.2Hz),1.0-2.0(4H,m),2.35(3H,s),2.4-3.3(3H,m),4.10(2H,br,d,J=12.6Hz),4.17(2H,q,J=7.2Hz),6.80(1H,d,J=7.2Hz)7.0-7.6(12H,m),7.84(2H,d,J=7.2Hz),8.48(1H,d,J=7.2Hz) |
表4(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
644 | 96 | 178-180 | 0.95(3H,t,J=7.2Hz),1.4-2.1(6H,m),2.37(3H,s),2.5-3.3(3H,m),3.9-4.3(4H,m),6.67(1H,d,J=7.2Hz),7.0-8.0(14H,m),8.55(1H,d,J=7.2Hz) |
652 | 87 | 66-68 | 1.0-2.0(4H,m),1.44(3H,s),1.52(3H,s),2.36(3H,s),2.5-3.3(3H,m),3.9-4.5(2H,m),4.76(1H,m),6.78(1H,d,J=7.2Hz),7.0-7.7(12H,m),7.83(2H,d,J=7.2Hz),8.39(1H,d,J=7.2Hz) |
660 | 91 | 116-120 | 1.2-2.0(4H,m),2.33(3H,s),2.4-3.2(3H,m),4.04(2H,br,d,J=12.6Hz),5.36(2H,s),6.56(1H,d,J=7.2Hz),6.9-7.9(19H,m),8.38(1H,d,J=7.2Hz) |
668 | 82 | 173-175 | 0.9-2.0(4H,m),2.35(3H,s),2.4-3.3(3H,m),3.6(3H,s),4.12(2H,br,d,J=12.6Hz),6.82(1H,d,J=7.2Hz)7.0-7.9(13H,m),8.45(1H,d,J=7.2Hz) |
676 | 79 | 199-200 | 1.0-2.0(4H,m),2.36(3H,s),2.5-3.2(3H,m),3.64(3H,s),4.14(2H,br,d,J=12.6Hz),6.80(1H,d,J=7.2Hz)6.95-7.50(7H,m),7.76(4H,m),8.20(2H,d,J=7.2Hz),8.46(1H,d,J=7.2Hz) |
表4(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
684 | 86 | 60-66 | 1.3-2.1(4H,m),2.33(3H,s),2.5-3.3(3H,m),3.60(3H,s),4.30(2H,br,d,J=12.6Hz),6.48(1H,dd,J=4.0,1.0Hz),6.87(1H,d,J=7.2Hz)7.0-7.5(9H,m),7.82(2H,d,J=7.2Hz),8.52(1H,d,J=7.2Hz) |
692 | 100 | 56-60 | 0.3-1.9(5H,m),2.33(3H,s),2.44(2H,d,J=7.2Hz),2.2-3.1(2H,m),3.57(3H,s),3.89(2H,br,d,J=12.6Hz),6.64(1H,d,J=7.2Hz),6.9-7.9(14H,m),8.40(1H,d,J=7.2Hz) |
700 | 96 | 136-138 | 2.5(2H,q,J=5.2Hz),2.32(3H,s),2.51(3H,s),2.79(2H,t,J=5.2Hz),3.58(3H,s),4.04(2H,t,J=5.2Hz),6.95(1H,d,J=7.2Hz),7.11(2H,d,J=7.0Hz),7.30(4H,s),7.78(2H,d,J=7.2Hz),8.58(1H,d,J=7.2Hz) |
256 | 100 | 65-70 | 1.2-2.2(4H,m),2.34(3H,s),2.5-3.4(3H,m),3.46(3H,s),4.5(2H,br,d,J=12.6Hz),6.9-7.6(12H,m),7.78(2H,d,J=7.2Hz),8.40(1H,d,J=7.2Hz) |
288 | 100 | 80-85 | 1.2-2.0(4H,m),2.32(3H,s),2.5-3.3(3H,m),3.55(3H,s),4.47(2H,br,d,J=12.6Hz),6.62(1H,d,J=7.2Hz)6.9-7.9(18H,m),8.33(1H,d,J=7.2Hz) |
表4(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
138 | 66 | 121-123 | 0.88(3H,d,J=7Hz),1.1-3.1(10H,m)3.49(3H,s),4.20(2H,m),6.54(1H,d,J=7Hz),7.12(2H,d,J=7Hz),7.48(5H,m),7.74(2H,d,J=7Hz),8.26(1H,d,J=7Hz) |
146 | 93 | 98-102 | 0.85(3H,t,J=7Hz),1.0-3.2(15H,m)3.47(3H,s),4.26(2H,m),6.58(1H,d,J=7Hz),7.10(2H,d,J=7Hz),7.48(5H,m),7.72(2H,d,J=7Hz),8.18(1H,d,J=7Hz) |
147-1 | 44 | 98-100 | 0.85(6H,d,J=7Hz),1.0-3.2(11H,m)3.48(3H,s),4.37(2H,m),6.50(1H,d,J=7Hz),7.10(2H,d,J=7Hz),7.48(5H,m),7.74(2H,d,J=7Hz),8.24(1H,d,J=7Hz) |
154 | 68 | 52-55 | 1.16(3H,d,J=7Hz),1.60(5H,m),2.34(3H,s),2.5-3.3(2H,m),3.50(3H,s),4.18(1H,m),4.52(1H,m),6.50(1H,d,J=7Hz),7.12(2H,d,J=7Hz),7.48(5H,m),7.76(2H,d,J=7Hz)8.28(1H,d,J=7Hz) |
171-3 | 81 | 128-129 | 1.3-2.2(4H,m),2.33(3H,s),2.40(3H,s),2.5-3.4(3H,m),3.52(3H,s),4.58(2H,br,d,J=12.6Hz),6.48(1H,d,J=7.2Hz),7.0-7.9(13H,m),8.28(1H,d,J=7.2Hz),13.0-15.0(1H,m) |
表4(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
2004 | 64 | 167-169 | 0.89(6H,d,J=7Hz),1.3-2.7(9H,m),3.50(3H,s),4.26(2H,m),6.52(1H,d,J=7Hz),7.12(2H,d,J=7Hz),7.48(5H,m),7.76(2H,d,J=7Hz),8.28(1H,d,J=7Hz) |
2012 | 83 | 186-187 | 1.4-2.2(4H,m),2.33(3H,s),2.44(3H,s),2.5-3.4(3H,m),3.55(3H,s),4.65(2H,br,d,J=12.6Hz),7.0-7.5(11H,m),7.70(4H,m),8.35(1H,d,J=7.2Hz) |
2020 | 100 | 54-60 | 1.7-2.2(4H,m),2.34(3H,s),2.5-3.3(3H,m),3.4-3.7(2H,m),3.55(3H,s),6.9-7.9(17H,m),8.35(1H,m) |
2028 | 100 | 60-70 | 2.4-3.1(4H,m),2.35(3H,s),2.5-3.2(3H,m),3.50(3H,s),4.24(2H,br,d,J=12.6Hz),7.0-7.5(12H,m),7.75(2H,m),8.04(2H,m) |
2036 | 100 | 54-58 | 1.4-2.1(8H,m),2.32(6H,m),2.2-3.3(6H,m),3.55(3H,s),4.50(4H,m),6.95-7.8(23H,m),9.1(2H,m) |
2044 | 100 | 62-72 | 1.4-2.2(4H,m),2.35(3H,s),2.5-3.4(3H,m),3.59(3H,s),4.36(2H,br,d,J=12.6Hz),6.48(1H,dd,J=3.6,2.0Hz),7.0-7.6(9H,m),7.76(2H,d,J=7.2Hz),7.97(1H,s),8.15(1H,s),10.92(1H,m) |
表4(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
2116 | 78 | 138-140 | 0.96(6H,s),1.36(4H,m),2.33(3H,s),3.48(3H,s),3.60(4H,m),6.50(1H,d,J=7Hz),7.12(2H,d,J=7Hz),7.48(5H,m),7.74(2H,d,J=7Hz),8.24(1H,d,J=7Hz) |
2124 | 61 | 145-147 | 0.91(3H,t,J=7Hz),1.60(2H,m),2.34(3H,s),2.7-4.0(9H,m),6.54(1H,d,J=7Hz),7.0-7.6(12H,m)7.76(2H,d,J=7Hz),8.37(1H,d,J=7Hz) |
2132 | 61 | 175-178 | 1.4-2.2(4H,m),2.32(3H,s),2.6-3.4(3H,m),3.59(3H,s),4.68(2H,br,d,J=12.6Hz),6.63(1H,d,J=7.2Hz)7.0-7.4(8H,m),7.45-7.90(4H,m),8.28(1H,d,J=7.2Hz),12-14(1H,m) |
2140 | 100 | 82-88 | 1.1-2.0(4H,m),2.31(6H,s),2.4-3.2(3H,m),3.5(3H,s),4.18(2H,br,d,J=12.6Hz),6.81(1H,d,J=7.2Hz),6.9-7.4(9H,m),7.55-8.0(5H,m),8.2-8.6(2H,m),8.85(1H,d,J=5.2Hz),9.10(1H,s),9.62(2H,m) |
2174 | 62 | 94-100 | 1.2-3.3(10H,m),3.47(3H,s),4.34(2H,m),6.55(1H,d,J=7Hz),6.9-7.9(14H,m),8.08(1H,d,J=7Hz) |
2182 | 78 | >300 | 1.5-2.1(4H,m),2.32(3H,s),2.4-3.2(2H,m),3.48(3H,s),4.07-4.7(3H,m),6.46(1H,d,J=7Hz)6.72(2H,d,J=7Hz),7.18(7H,m), |
表4(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
2182 | 78 | >300 | 7.48(2H,d,J=7Hz),7.68(2H,d,J=7Hz),7.88(1H,d,J=7Hz) |
2188 | 60 | 151-156 | 1.4-3.2(10H,m),3.41(3H,s),4.40(2H,m),6.50(1H,d,J=7Hz),7.08(2H,d,J=7Hz),7.42(5H,m),7.66(2H,d,J=7Hz),7.88(1H,d,J=7Hz) |
2194 | 39 | 106-109 | 1.4-3.3(10H,m),3.45(3H,s),4.52(2H,m),6.50(1H,d,J=7Hz),7.0-8.1(19H,m) |
2202 | 52 | 203-207 | 1.5-3.4(10H,m),3.46(3H,s),4.44(2H,m),6.60(1H,d,J=7Hz),7.10(2H,d,J=7Hz),7.2-7.9(13H,m) |
2210 | 100 | 62-66 | 1.3-2.2(10H,m),2.31(3H,s),2.5-3.6(7H,m),3.25(3H,s),4.72(2H,br,d,J=12.6Hz),6.10(1H,d,J=7.2Hz),7.0-7.4(7H,m),7.75(2H,d,J=7.2Hz),8.16(1H,d,J=7.2Hz) |
2218 | 89 | 186-187 | 1.4-2.2(4H,m),2.31(3H,s),2.6-3.4(3H,m),3.49(3H,s),4.63(2H,br,d,J=12.6Hz),6.76(1H,d,J=7.2Hz),6.9-7.8(14H,m),7.95(1H,d,J=7.2Hz),10.20(1H,s) |
2234 | 94 | 95-102 | 1.45-2.15(4H,m),2.32(6H,s),2.5-3.2(3H,m),2.80(3H,s),3.23(3H,s),3.35(4H,m), |
表4(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
2234 | 94 | 95-102 | 3.80(4H,m),4.60(2H,br,d,J=12.6Hz),6.62(1H,d,J=7.2Hz),6.96-7.45(9H,m),7.76(4H,d,J=7.2Hz),8.23(1H,d,J=7.2Hz) |
2242 | 76 | 116-117 | 1.40(3H,t,J=7.2Hz),1.4-2.2(4H,m),2.34(3H,s),2.6-3.5(3H,m),3.48(3H,s),4.35(2H,q,J=7.2Hz),4.76(2H,br,d,J=12.6Hz),7.0-7.4(7H,m),7.6(1H,d,J=7.2Hz),7.78(2H,d,J=7.2Hz),8.35(1H,d,J=7.2Hz),14.0(1H,br,m) |
2250 | 30 | 192-196 | 1.50-3.40(10H,m),3.50(5H,s),4.05(2H,s),4.70(2H,m),7.10(2H,d,J=7Hz),7.23(10H,m),7.48(1H,d,J=7Hz),7.76(2H,d,J=7Hz),8.35(1H,d,J=7Hz) |
2260 | 45 | 166-173 | 0.85(3H,t,J=7Hz),1.1-2.2(8H,m),2.33(3H,s),2.82(4H,m),3.46(3H,s),5.10(1H,m),6.28(1H,d,J=7Hz),7.10(2H,d,J=7Hz),7.36(5H,m),7.66(2H,d,J=7Hz),7.96(1H,d,J=7Hz),8.76(2H,m) |
2270 | 50 | 168-169 | 1.52(4H,m),2.30(3H,s),2.4-3.2(3H,m),3.42(3H,s),4.40(2H,m),6.46(1H,d,J=7Hz),7.04(2H,d,J=7Hz),7.36(15H,m),7.66(2H,d,J=7Hz),8.21(1H,d,J=7Hz) |
表4(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
2278 | 86 | 163-164 | 1.4-2.2(4H,m),2.35(3H,s),2.5-3.4(6H,m),4.5-5.0(4H,m),6.10(1H,d,J=7.2Hz),7.0-7.5(12H,m),7.80(2H,d,J=7.2Hz),8.15(1H,m),13.15(1H,m) |
2286 | 90 | 204-207(分解) | 1.4-2.15(4H,m),2.33(3H,s),2.5-3.3(3H,m),3.48(3H,s),4.70(2H,br,d,J=12.6Hz),5.05(2H,s),6.7-7.5(13H,m),7.68(2H,m),8.35(1H,m) |
2294 | 100 | 48-52 | 1.4-2.15(4H,m),2.32(3H,s),2.6-3.2(3H,m),3.0(6H,s),3.26(3H,s),4.73(2H,br,d,J=12.6Hz),6.10(1H,d,J=7.2Hz),7.0-7.4(7H,m),7.76(2H,d,J=7.2Hz),8.18(1H,d,J=7.2Hz) |
2302 | 71 | 50-55 | 1.21(6H,t,J=7.2Hz),1.5-2.2(4H,m),2.32(3H,s),2.5-3.7(10H,m),4.70(2H,br,d,J=12.6Hz),6.08(1H,m),6.9-7.5(7H,m),7.76(2H,d,J=7.2Hz),8.18(1H,m),13.33(1H,m) |
2310 | 60 | 174-176 | 1.88(4H,m),2.32(3H,s),3.40(3H,m),3.51(3H,s),4.32(2H,m),6.60(1H,d,J=7Hz),7.10(2H,d,J=7Hz),7.40(2H,d,J=7Hz),7.50(5H,m),7.74(2H,d,J=7Hz),7.84(2H,d,J=7Hz),8.24(1H,d,J=7Hz) |
表4(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
2318 | 67 | 80-85 | 1.4-2.1(4H,m),2.6-3.4(3H,m),3.92(3H,s),7.0(1H,d,J=7Hz),7.18(2H,d,J=7Hz),7.1-7.8(10H,m)7.78(2H,d,J=7Hz),8.50(2H,d,J=7Hz) |
2322 | 92 | 192-194 | 1.4-2.2(4H,m),2.32(3H,s),2.5-3.4(3H,m),3.29(3H,s),3.58(8H,m),4.69(2H,br,d,J=12.6Hz),6.20(1H,d,J=7.2Hz),6.95-7.42(7H,m),7.74(2H,d,J=7.2Hz),8.23(1H,d,J=7.2Hz) |
2330 | 78 | 160-162 | 1.4-2.2(4H,m),2.32(3H,s),2.6-3.6(3H,m),3.69(3H,s),4.79(2H,br,d,J=12.6Hz),7.0-7.9(15H,m),8.40(1H,d,J=7.2Hz) |
154-2 | 86 | 191-193 | 1.4-2.2(4H,m),2.32(3H,s),2.5-3.4(3H,m),3.44(3H,s),3.47(3H,s),4.4(2H,s),4.70(2H,br,d,J=12.6Hz),7.0-7.4(6H,m),7.75(2H,d,J=7.2Hz),8.40(1H,d,J=7.2Hz) |
171-5 | 74 | 172-173 | 1.41(3H,t,J=7.2Hz),1.4-2.2(4H,m),2.32(3H,s),2.5-3.4(3H,m),3.52(3H,s),4.05(2H,q,J=7.2Hz),4.60(2H,br,d,J=12.6Hz),6.40(1H,d,J=7.2Hz),6.89(2H,d,J=7.2Hz),7.0-7.5(7H,m),7.56(2H,d,J=7.2Hz), |
表4(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
171-5 | 74 | 172-173 | 7.75(2H,d,J=7.2Hz),8.22(1H,d,J=7.2Hz) |
298 | 70 | 217-218 | 1.6-2.2(4H,m),2.35(3H,s),2.7-3.5(3H,m),4.90(2H,m),7.22(8H,m),7.88(6H,m),8.75(1H,d,J=7Hz) |
306 | 70 | 108-110 | 1.88(4H,m),2.31(3H,s),3.42(3H,m),3.51(3H,s),4.30(2H,m),6.58(1H,d,J=7Hz),7.10(2H,d,J=7Hz),7.50(8H,m),7.72(2H,d,J=7Hz),7.88(2H,m),8.24(1H,d,J=7Hz) |
242 | 93 | 119-122 | 1.3-2.2(4H,m),2.33(3H,s),2.5-3.4(3H,m),3.52(3H,s),4.55(2H,br,d,J=12.6Hz),6.59(1H,d,J=7.2Hz),7.0-7.5(9H,m),7.5-8.0(4H,m),8.35(1H,d,J=7.2Hz) |
2022-1 | 46 | 118-121 | 1.75-2.90(4H,m),2.35(3H,s),2.95-3.40(3H,m),3.55(3H,s),3.68(2H,br,d,J=12.6Hz),6.9-8.0(16H,m),8.70(1H,br,s) |
2023-1 | 100 | 57-64 | 1.8-3.0(4H,m),2.38(3H,s),3.1-4.0(5H,m),3.59(3H,s),6.70-8.0(15H,m) |
150 | 100 | 48-58 | 0.5-1.8(5H,m),0.87(3H,d,J=5.2Hz),2.35(3H,s),2.4-3.2(2H,m),3.4-4.5(2H,m),6.22(1H,d,J=7.2Hz),7.0-7.9(14H,m),8.28(1H,d,J=7.2Hz) |
表4(续)
实施例3
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
171-9 | 88 | 137-139 | 1.2-2.2(4H,m),2.32(3H,s),2,5-3.4(3H,m),3.51(3H,s),4.44(2H,br,d,J=12.6Hz),6.84(1H,d,J=7.2Hz),6.9-7.9(14H,m),8.40(1H,d,J=7.2Hz) |
170-11 | 100 | 75-80 | 1.3-2.2(4H,m),2.32(3H,s),2.5-3.5(3H,m),3.45(3H,s),4.48(2H,br,d,J=12.6Hz),6.95-7.5(11H,m),7.72(2H,d,J=7.2Hz),8.44(1H,d,J=7.2Hz) |
170-2 | 88 | 147-148 | 1.4-2.1(4H,m),2.33(3H,s),2.5-3.5(3H,m),3.55(3H,s),4.72(2H,br,d,J=12.6Hz),6.8-8.0(17H,m),8.40(1H,d,J=7.2Hz) |
171-7 | 95 | 70-76 | 1.3-2.1(4H,m),2.32(3H,s),2.36(3H,s),2.5-3.3(3H,m),3.44(3H,s),4.56(2H,br,d,J=12.6Hz),6.80(1H,d,J=7.2Hz),9.0-9.6(11H,m),7.73(2H,d,J=7.2Hz),8.30(1H,d,J=7.2Hz) |
171-13 | 97 | 154-158 | 1.2-2.1(4H,m),2.3(3H,s),2.5-3.3(3H,m),3.48(3H,s),4.4(2H,br,d,J=12.6Hz),6.7(1H,d,J=7.2Hz),7.0-7.9(12H,m),8.39(1H,d,J=7.2Hz) |
4-(N-甲基苯氨基)-2-(4-苯基哌啶子基)嘧啶盐酸盐(化合物№.170):
将0.27g(0.0027摩尔)浓盐酸的2ml CH3OH溶液缓慢加到1.0g(0.0027摩尔)4-(N-甲基苯氨基)-2-(4-苯基哌啶子基)嘧啶的10ml氯防溶液中,加完后,减压浓缩该混合物,得到1.1g(得率100%)所期产物。
M.p.:80-84℃.
1H-NMR(CDCl3,δppm)
1.4-22(4H,m),2.6-3.4(3H,m),3.56(3H,s),
2.2(2H,m),6.69(1H,d,J=7.2Hz),
7.0-7.7(10H,m),8.1(1H,d,J=7.2Hz).
用上述相同方法制得下列化合物,有关数据列于表5。
表5
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
662 | 46 | 241-243 | 10.9(1H,br),8.03(1H,d,J=5Hz),7.2-7.8(10H,m),6.28(1H,d,J=5Hz),4.63(2H,s),3.50(3H,s),3.0-3.4(1H,m),1.48(6H,d,J=7Hz) |
2052 | 86 | 96-99 | 12.9(2H,br),8.03(1H,d,J=5Hz),7.2-7.6(5H,m),6.36(1H,d,J=5Hz),4.5-4.8(2H,m),3.56(3H,s),1.1-3.3(17H,m) |
2060 | 93 | 185-189 | 7.98(1H,d,J=7Hz),7.3-7.7(5H,m),6.64(1H,d,J=7Hz),3.6-4.4(6H,m),3.62(3H,s),1.4-2.2(4H,m) |
2070 | 93 | 77-80 | 8.03(1H,d,J=5Hz),7.2-7.6(5H,m),6.36(1H,d,J=5Hz),4.0-4.7(2H,m),3.63(3H,s),1.0-4.0(12H, m) |
2076 | 86 | 237-239 | 12.5(1H,br),8.53(1H,d,J=5Hz),8.12(9H,d,J=7Hz),7.32(2H,d,J=7Hz),6.43(1H,d,J=5Hz),7.2-7.7(5H,m),4.8-5.0(2H,m),3.53(3H,s),1.1-3.4(7H,m) |
2084 | 90 | 60-63 | 12.3(1H,br),8.70(1H,d,J=7Hz),7.2-7.6(5H,m),6.37(1H,d,J=7Hz),4.0-4.8(2H,m),2.63(3H,s),0.8-3.5(14H,m) |
表5(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
2092 | 86 | 183-186 | 8.06(1H,d,J=7Hz),7.2-7.6(5H,m),6.38(1H,d,J=7Hz),3.60(3H,s),3.10(3H,s),1.8-4.0(10H,m) |
2100 | 90 | 213-215 | 8.70(1H,d,J=5Hz),7.3-7.6(5H,m),6.48(1H,d,J=5Hz),4.4-4.8(2H,m),4,20(2H,q,J=7Hz),3.58(3H,s),1.32(3H,t,J=7Hz),1.5-3.4(7H,m) |
2108 | 93 | 89-91 | 10.5(1H,br),8.07(1H,d,J=5Hz),7.0-7.6(15H,m),6.18(1H,d,J=5Hz),4.68(4H,s),3.44(3H,s) |
2148 | 94 | 218-221 | 8.05(1H,d,J=7Hz),7.2-7.5(5H,m),6.40(1H,d,J=7Hz),4.3-4.5(2H,m),2.3-4.0(7H,m),3.30(5.6H),3.58(3H,s) |
2156 | 89 | 57-60 | 14.0(1H,br),8.04(1H,d,J=7Hz),7.3-7.6(5H,m),6.56(1H,d,J=7Hz),3.50(3H,s),4.0-4.8(2H,m),1.0-2.4(14H,m) |
2164 | 96 | 140-142 | 8.03(1H,d,J=5Hz),7.2-7.6(5H,m),6.40(1H,d,J=5Hz),4.2-4.5(2H,m),3.63(3H,s),1.0-3.8(10H,m) |
表5(续)
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
2226 | 86 | 187-189 | 7.9-8.1(3H,m),7.2-7.7(8H,m),6.66(1H,d,J=7Hz),5.1-5.4(1H,m),3.6-4.3(4H,m),3.55(3H,s),1.7-2.2(4H,m) |
2342 | 94 | 135-138 | 12.0-12.8(1H,br),8.03(1H,d,J=7Hz),7.2-7.6(5H,m),6.50(1H,d,J=7Hz),3.53(3H,s),1.0-3.7(13H,m) |
2350 | 88 | 153-157 | 12.8(1H,br),8.03(1H,d,J=7Hz),7.2-7.9(10H,m),6.60(1H,d,J=7Hz),4.3-4.6(2H,m),3.50(3H,s),1.5-4.0(7H,m) |
307-1 | 94 | 259-261 | 8.07(1H,d,J=7Hz),7.2-7.6(5H,m),6.38(1H,d,J=7Hz),4.2-4.4(2H,m),3.50(3H,s),1.4-4.0(10H,m) |
除了采用硫酸、磷酸等代替盐酸以外,用实施例3的相同方法制得下列化合物。
表6
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
165 | 84 | 151-154 | 1.0-2.0(4H,m)2.5-3.2(3H,m),3.45(3H,s),4.24(2H,br,d,J=12.6Hz),6.67(1H,d,J=7.2Hz),6.73(1H,d,J=7.2Jz),7.0-7.6(10H,m),8.15(1H,d,J=7.2Hz) |
166 | 67 | 108-113 | 1.2-2.0(4H,m),2.5-3.0(3H,m),3.51(3H,s),4.58(2H,br,d,J=12.6Hz),6.15(1H,d,J=5.4Hz),7.0-7.55(10H,m),8.02(1H,d,J=5.4Hz),11.0(1H,m) |
167 | 37 | 94-96 | 1.3-2.2(4H,m),2.6-3.2(3H,m),3.52(3H,s)4.54(2H,br,d,J=12.6Hz),6.32(2H,s),6.49(1H,d,J=7.2Hz)7.0-7.7(10H,m),8.15(1H,d,J=7.2Hz),8.93(2H,br,s) |
169 | 32 | 132-136 | 1.3-2.2(4H,m),2.55-3.3(3H,m),3.49(3H,s),4.49(2H,br,d,J=12-6Hz),6.58(1H,d,J=7.2Hz),6.8-8.5(19H,m) |
171 | 45 | 108-112 | 1.0-1.9(4H,m),2.4-2.9(6H,m),3.0-3.6(3H,m),3.40(3H,s),4.36(2H,br,d,J=12.6Hz),6.42(1H,d,J=5.4Hz),7.0-7.4(5H,m),7.35(5H,s),8.15(1H,d,J=5.4Hz),12-13(2H,m) |
表6(续)
实施例4
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
171-1 | 49 | 133-135 | 1.0-1.8(4H,m),2.4-2.9(3H,m),3.0-3.5(3H,m),3.40(3H,s),4.30(2H,s,),4.38(2H,br,d,J=12.6Hz),6.42(1H,d,J=5.4Hz),7.0-7.4(5H,m),7.35(5H,s),8.15(1H,d,J=5.4Hz),12-13(1H,m) |
171-1-1 | 90 | 124-127 | 1.2-2.0(4H,m),2.5-3.0(3H,m),3.48(3H,s),4.55(2H,br,d,J=12.6Hz),6.17(1H,d,J=5.4Hz),6.69(2H,s),6.9-7.5(10H,m),8.02(1H,d,J=5.4Hz) |
2-异丙氨基-4-甲基-5-甲氧基羰基嘧啶(化合物№.800)的制备:
将18.2g(0.12摩尔)1-脒基异丙胺硫酸盐加到13.0g(0.12摩尔)叔丁醇钾的200ml甲醇溶液中,该混合物于室温搅拌30分钟,然后,在0℃下,30分钟内加入18.5g(0.12摩尔)2-甲氧基亚甲基乙酰乙酸乙酯,该混合物搅拌3小时,蒸发溶剂,残留物用醚提取,硅胶柱层析纯化,得到10.6g(得率44%)黄色固体所期产物。
M.p.:118-119℃.
1H-NMR(CDCl3,δppm)
1.26(6H,d,J=7Hz),2.66(3H,s),3.87(3H,s),
4.25(1H,sex,J=7Hz),5.40(1H,br,s),
8.80(1H,s).实施例5
2-哌啶子基-4-甲氧基甲基-5-甲氧基羰基嘧啶(化合物№.820)的制备:
在室温下,将氢化钠(0.19g,7.8毫摩尔)加到50ml甲醇中,再加入2.1g(7.8毫摩尔)2-哌啶子基-4-氯甲基-5-甲氧基羰基嘧啶。该混合物搅拌3小时,蒸发溶剂后,将水加到残留物中,用乙酸乙酯提取该混合物,乙酸乙酯层用无水硫酸钠干燥,减压浓缩,残留物经硅胶层析纯化得到0.90g(得率44%)白色固体所期产物。M.p:89-92℃.1H-NMR(CDCl3,δppm):
1.70(6H,m),3.54(3H,s),3.86(3H,s),
3.92(4H,m),4.83(2H,s),8.82(1H,s).用上述相同方法制得下列化合物。
表7
实施例6
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
808 | 53 | oil | 1.35(3H,t,J=7Hz),1.66(6H,m)2.44(3H,s),3.90(2H,s),3.92(4H,m),4.30(2H,q,J=7Hz)8.80(1H,s) |
816 | 35 | oil | 1.40(3H,t,J=7Hz),1.70(6H,m)2.21(3H,s),3.92(4H,m),4.06(2H,s),4.36(2H,q,J=7Hz)8.91(1H,s) |
824 | 90 | oil | 1.22(6H,d,J=8Hz),1.33(3H,t,J=8Hz),2.36(6H,s)3.84(2H,s),5.5(1H,br,s),8.78(1H,s) |
2-异丙氨基-4-甲基-5-甲氧基羰基嘧啶马来酸盐(化合物№.804)的制备:
将2.48g(11.9毫摩尔)2-异丙氨基-4-甲基-5-甲氧基羰基嘧啶和1.38g(11.9毫摩尔)马来酸溶于2Oml乙醇和20ml氯仿混合物中,该溶液搅拌3小时,蒸去溶剂并加入醚,于0℃结晶,得到3.21g(得率83%)淡黄色晶体所期产物。
M.p.:75-79℃.
1H-NMR(CDCl3,δppm):
1.33(6H,d,J=7Hz),2.85(3H,s),
3.95(3H,s),4.36(1H,sex,J=7Hz),
6.40(2H,s),9.08(1H,br,s).
用上述相同方法制得下列化合物。
表8
实施例7
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
812 | 74 | 115.5-118.5 | 1.40(3H,t,J=7Hz),1.68(6H,m),3.08(3H,s),3.92(4H,m),4.34(2H,q,J=7Hz),4.72(2H,s),6.32(2H,s),8.90(1H,s) |
828 | 67 | 111-121 | 1.30(6H,d,J=8Hz),1.40(3H,t,J=8Hz),3.07(6H,s),4.34(2H,q,J=8Hz),4.66(2H,s),6.32(2H,s),8.92(1H,s) |
2-(4-二苯甲基哌嗪子基)-5,6-二氢-7-甲基-6-氧(7H)吡咯并(2,3-d)嘧啶(化合物№3124)的制备:
将1.9g(7.5毫摩尔)1-二苯甲基-哌嗪和1.7g(7.5毫摩尔)(2-甲基-硫代-4-羟基嘧啶-5-基)乙酸乙酯加到60ml戊醇中,该混合物于170℃搅拌20小时。然后,减压蒸发溶剂,将10ml磷酰氯加到残留物中,在100℃下反应2小时,此后,该混合物渐渐地加到碳酸钾水溶液中,用二氯甲烷提取,该有机层用无水硫酸镁干燥,减压蒸发溶剂,将该残留物、15ml乙醇和40%甲胺的甲醇溶液放进压力容器中,在140℃下反应10小时。然后,蒸发溶剂,残留物经硅胶柱层析纯化,得到0.9g(得率30%)所期产物。
M.p:75-80℃.
1H-NMR(CaCl3,ppm):
2.43(4H,m),3.13(3H,s),3.37(2H,s),
3.80(4H,m),4.23(1H,s),7.08-7.52(10H,m),
7.82(1H,s).
用上述相同方法制得下列化合物,有关数据列于表9。
表9
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
3100 | 78 | 210-213 | 2.47(4H,m),3.17(3H,s),3.39(2H,s),3.50(2H,s),3.82(4H,m),7.28(4H,m),7.88(1H,s) |
3108 | 56 | 82-86 | 0.74(3H,d,J=7Hz),1.02(3H,d,J=7Hz),2.38(4H,m),3.13(3H,s),3.35(2H,s),3.74(4H,m),4.10(1H,m),7.20(5H,m),7.80(1H,s) |
3132 | 38 | 80-85 | 2.42(4H,m),3.15(3H,s),3.38(2H,s),3.81(4H,m),4.24(1H,s),6.8-7.5(9H,m),7.85(1H,s) |
3140 | 54 | 105-110 | 2.43(4H,m),3.15(3H,s),3.39(2H,s),3.82(4H,m),4.24(1H,s),7.32(9H,m),7.88(1H,s) |
3148 | 35 | - | 2.29(3H,s),2.43(4H,m),3.14(3H,s),3.38(2H,s),3.80(4H,m),4.21(1H,s),6.9-7.5(9H,m),7.84(1H,s) |
3172 | 26 | - | 2.41(4H,m),3.14(3H,s),3.36(2H,s),3.80(4H,m),4.22(1H,s),7.28(8H,m),7.84(1H,s) |
3180 | 12 | 91-94 | 2.40(4H,m),3.14(3H,s),3.37(2H,s),3.80(4H,m),4.23(1H,s),6.8-7.4(8H,m),7.83(1H,s) |
3188 | 44 | 170-175 | 2.50(4H,m),3.16(3H,s),3.40(2H,s),3.84(4H,m),4.44(1H,s),7.1-7.6(8H,m),7.84(1H,s),8.49(1H,m) |
表9(续)
实施例8
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
3196 | 51 | 179-181 | 2.66(4H,m),3.12(3H,s),3.36(2H,s),3.76(4H,m),4.88(1H,s),7.28(4H,m),7.70(4H,m),7.84(1H,s) |
3300 | 49 | 263-267(分解) | 2.36(4H,m),3.13(3H,s),3.36(2H,s),3.92(4H,m),7.1-7.6(15H,m),7.82(1H,s) |
3400 | 40 | 2.78(3H,s),3.18(3H,s),3.26(4H,m),3.40(2H,s),3.94(4H,m),7.87(1H,s) | |
3408 | 68 | 1.1-2.0(12H,m),3.18(3H,s),3.32(4H,m),4.20(2H,m),7.84(1H,s) | |
3416 | 61 | 1.2-2.4(12H,m),3.18(3H,s),3.3-3.8(4H,m),7.86(1H,s) |
2-(4-二苯甲基哌嗪子基)-5,6-二氢-7-甲基-6-氧(7H)吡咯并〔2,3-d〕嘧啶盐酸盐(化合物№.3128)的制备:
将浓盐酸(0.23g;2.2毫摩尔)加到2-(4-二苯甲基哌嗪子基)-5,6-二氢-7-甲基-6-氧(7H)吡咯并〔2,3-d〕嘧啶的氯化乙醇/亚甲基溶液中,该溶液在室温下搅拌1小时,然后,减压蒸发溶剂,残留物用醚洗涤,得到0.88g(得率90%)所期产物。
Mp.:217-222℃.
1H-NMR(CDCl3,δppm):
3.18(3H,s),3.20(4H,m),3.52(2H,s),
4.40(4H,m),5.20(1H,s),7.2-7.9(1H,m).
用上述相同方法制得下列化合物,有关数据列于表10。
表10
实施例9
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
3104 | 82 | >300 | (CDCl3-CD3OD)3.20(3H,s),3.30(4H,m),3.48(2H,s),4.32(2H,s),4.54(4H,m),7.52(4H,m),7.93(1H,s) |
3136 | 80 | 238-243(分解) | (CDCl3-CD3OD)3.20(3H,s),3.24(4H,m),3.50(2H,s),3.8-4.6(4H,m),5.10(1H,s),7.0-8.0(10H,m) |
3144 | 93 | 238-245(分解) | 3.20(3H,s),3.29(4H,m),3.57(2H,s),4.58(4H,m),5.26(1H,s),7.40(5H,m),7.90(5H,m) |
3200 | 73 | 244-245(分解) | 3.12(3H,s),3.14(4H,m),3.40(2H,s),4.56(4H,m),5.45(1H,s),7.17-8.27(9H,m) |
3412 | 70 | 250-252(分解) | 1.2-2.2(12H,m),3.26(3H,s),3.52(4H,m),4.50(2H,m),8.00(1H,s) |
3420 | 70 | 256-257(分解) | 1.2-2.5(12H,m),3.25(3H,s),3.3-4.2(4H,m),7.99(1H,s) |
2-{4-〔α-(4-甲苯基)苄基〕哌嗪子基}-5,6-二氢-7-甲基-6-氧(7H)吡咯并-〔2,3-d〕嘧啶对甲苯磺酸盐(化合物№.3152)的制备:
将0.13g(0.75毫摩尔)对甲苯磺酸的乙酸乙酯/甲醇溶液加到0.31g(0.75毫摩尔)2-{4-〔α-(4-甲苯基)苄基〕哌嗪子基}-5,6-二氢-7-甲基-6-氧(7H)吡咯并〔2,3-d〕嘧啶的乙酸乙酯/甲醇溶液中,该混合物于室温搅拌1小时。然后,减压蒸发溶剂,残留物用己烷洗涤,得到0.36g(得率81%)所期化合物。
M.P.:150-155℃.
1H-NMR(CDCl3,αppm):
2.28(3H,s),2.34(3H,s),3.00(4H,m),
3.11(3H,s),3.39(2H,s),4.14(4H,m),
4.73(1H,s),7.0-7.8(13H,m),7.93(1H,s).
用上述相同方法制得下列化合物,有关数据列于表11。
表11
实施例1B
化合物No. | 得率(%) | 熔点(℃) | 1H-NHR(CDCl3溶液,δppm) |
3112 | 92 | - | 0.86(3H,d,J=7Hz),1.16(3H,d,J=7Hz),2.35(3H,s),3.12(7H,m),3.39(2H,s),4.20(5H,m),7.14(2H,d,J=7Hz),7.35(5H,m),7.76(2H,d,J=7Hz),7.87(1H,s) |
3176 | 90 | 145-150 | 2.34(3H,s),2.83(4H,m),3.13(3H,s),3.43(2H,s),4.06(4H,m),4.72(1H,s),7.0-7.5(10H,m),7.66(2H,d,J=7Hz),8.03(1H,s) |
3184 | 91 | 124-130 | 2.34(3H,s),2.74(4H,m),3.14(3H,s),3.43(2H,s),4.04(4H,m),4.56(1H,s),6.8-7.8(12H,m),8.01(1H,s) |
3192 | 100 | 135-140 | 2.35(3H,s),3.0-3.4(4H,m),3.16(3H,s),3.44(2H,s),4.18(4H,m),5.34(1H,s),7.0-7.8(8H,m),7.11(2H,d,J=7Hz),7.74(2H,d,J=7Hz),7.96(1H,s),8.60(1H,m) |
3404 | 70 | 220-223(分解) | (CDCl3-CD3OD)2.38(3H,s),2.86(3H,s),3.27(3H,s),3.38(4H,m),3.60(2H,s),4.03(4H,m),7.16(2H,d,J=7Hz),7.64(2H,d,J=7Hz),8.02(1H,s) |
用下述方法制备每片含10mg活性成分的片剂。
每片
活性成分 10mg
玉米淀粉 55mg
结晶纤维素 35mg
聚乙烯吡咯烷酮(10%水溶液) 5mg
羧甲基纤维素钙 10mg
硬脂酸镁 4mg
滑石粉 1mg
总计 120mg
将活性成分、玉米淀粉和结晶纤维素通过80目筛子并充分混合,该混合物与聚乙烯吡咯烷酮溶液一起研磨,通过18目筛子。得到的颗粒在50至60℃干燥,再通过18目筛子以调节其粒度。将巳通过80目筛子的羧甲基纤维素钙、硬脂酸镁和滑石粉加到这些颗粒中,用制片机混合制片,得到片重为120mg的片剂。实施例2B
用下述方法制备每片含200mg活性成分的片剂。
每片
活性成分 200mg
玉米淀粉 50mg
结晶纤维素 42mg
硅酐 7mg
硬脂酸镁 1mg
总计 300mg
将上述各成分通过80目筛子并充分混合,得到的混合物模压成片重为300mg的片剂。实施例3B
用下述方法制备每颗含100mg活性成分的胶囊。
每颗
活性成分 100mg
玉米淀粉 40mg
乳 糖 5mg
硬脂酸镁 5mg
总计 150mg
混合上述各成分,通过80目筛子并充分混合。得到的混合粉充进胶囊,得到颗重为150mg的胶囊。实施例4B
用下述方法制备每瓶含5mg活性成分的注射制剂。
每瓶
活性成分 5mg
甘露糖醇 50mg
当开始注射前,将这些化合物溶于1ml蒸馏水中施药。实施例5B
按下述处方配制每安瓿含50mg活性成分的注射制剂。
每安瓿
活性成分 50mg
氯化钠 18mg
注射用蒸馏水 适量
总计 2ml实施例6B
用下述方法制备每张含17.5mg活性成分的粘性膏药。
将10份聚(丙烯酸铵)溶于60份水中,2份甘油二环氧甘油醚加热溶于10份水中。此外,将10份聚乙二醇(400)、10份水和1份活性成分搅拌成溶液。在搅拌聚(丙烯酸铵)水溶液时,加入甘油二环氧甘油醚水溶液和含活性成分的溶液、聚乙二醇和水,并进行混合,得到的溶液用作水凝胶涂复在柔韧的塑料膜上,使活性成分为0.5mg/cm2,用防粘纸复盖其表面,按尺寸35cm2切成粘性膏药。实施例7B
按下述方法制备含10mg活性成分的粘性膏药。
用100份聚(丙烯酸钠)、100份甘油、150份水、0.2份三环氧丙基聚氨酯、100份乙醇、25份肉豆蔻酸异丙酯、25份丙二醇和15份活性成分制成水性溶胶,然后涂复在由人造丝非织物和聚乙烯膜组成的非织物合成膜上,厚度达100微米,制成含药物的粘性层,含在该层中的释放助剂(肉豆蔻酸异丙酯和丙二醇)的量约为30%(重量),然后,该粘性层在25℃交联24小时,将防粘膜粘合到粘性层表面。然后,把整张膜切成每张面积为35cm2的膏药。
体内试验式(1)、(2)或(3)化合物对神经系统细胞的生物活性。受试细胞是小鼠的成神经细胞瘤细胞系神经-2a(Dainipponpharmaceutical Co,Ltd.)、NS-20Y等(巳指定为神经系细胞)。在指数为5%二氧化碳气体存在下,于37℃恒温箱中使上述神经细胞生长,然后,与本发明化合物一起培养一定的时间。结果表明:本发明化合物的促神经细胞生长及促神经突生成和生长的作用明显地高于对照组,并等于或高于作为对照药物的异丙胺嘧啶(在日本特许公报№.28548/1984中介绍了这种化合物)。
还试验本发明化合物对鼠的PC-12嗜铬细胞瘤细胞系的生物活性。当将NGF加到PC-12细胞时,神经突生长。当在此时加入本发明化合物后,显示NGF粘附于PC-12细胞并且细胞摄取NGF量增加,神经突的生长也随之增加。
当试验了本发明化合物对NGF粘合于兔子上颈神经节的影响时,发现这些化合物能促进NGF的粘合。
将坐骨神经受损的鼠制作为末稍神经疾病模型,试验本发明化合物对它的影响,清楚可见,本发明化合物具有促进趾间距离复原和使比目鱼肌重量达正常值的作用。
制备大鼠和小鼠中枢神经疾病模型,试验本发明化合物的药理作用。具体地说,注射很少量6-羟基多巴胺,用化学方法破坏鼠脑的黑质多巴胺细胞,以诱发运动原失调。两周后,将胎鼠脑多巴胺细胞移植进该鼠脑尾状核的受损侧,借以改善运动原失调的状况。具体来说,从移植当天开始,每天腹膜内注射本发明化合物,持续两周,测试本发明化合物对改善运动原失调和对移植细胞生长的作用。试验表明:本发明化合物具有促使运动原疾病改善的作用。
经汞中毒使大鼠和小鼠神经的神经受损,并进行本发明化合物的活性试验。发现:本发明化合物具有缓解该病情并使之恢复至正常的促进作用;对化学物质诱发神经疾病具有治疗作用:具有改善和恢复知觉与记忆的作用。
这样,很显然,本发明化合物可以作为缓解或治疗哺乳动物各种神经科疾病(例如末稍和中枢神经疾病)的有效药剂,还可用作改善知觉和记忆的药剂。
各种类型的神经病包括:例如,由于运动原、感觉或他觉屈由阻滞引起的和酒精诱发或药物诱发、糖尿病性和代谢性的各种末稍神经疾病,或自发末稍神经疾病,它包括创伤、炎性或免疫神经根损伤引起的神经疾病,这些均可引证为这种神经疾病。更具体的实例包括面神经麻痹,坐骨神经麻痹,脊柱肌肉萎缩,肌肉营养不良,重症肌无力,多发性硬化,肌萎缩性侧索硬化,急性播散脑脊髓炎,急性热病性多神经炎,种痘后的脑脊髓炎,亚急性脊髓视神经病,痴呆,阿尔茨海默综合症,颅损伤后的病症,大脑局部缺血,脑梗死或脑出血的后遗症,脑脊髓损伤和风湿病。这些实例并非限定的。
通过毒性试验,得出本发明化合物仅具有弱毒性和轻的副作用,可用作安全、有效的药物。试验实施例1
用下述方法测试本发明化合物对成神经细胞瘤细胞的影响。
把在含10%FCS的Dulbe∝o改进的Eagle培养基〔DMEM,含100单位/ml青霉素G钠和100微克/ml硫酸链霉素〕中以积数生长的小鼠神经2a细胞接种在48井的板中,使细胞数为1000细胞/井,在37℃含5%二氧化碳气体的空气恒温器中,于每井0.25ml培养液中培养1天。然后,将4%戊二醛水溶液以相同量作为介质(0.25ml)加入其中,留下培养液在室温静置2小时,使细胞固定,用水洗涤后,加入0.05%亚甲蓝水溶液,使细胞染色。在显微镜下,用目测计数含赘疣化神经突的细胞数(至少具有1个神经突的细胞长度至少是细咆直径的2倍),计算这些细胞占全部细咆的比例。用5个或更多目测区(至少为2%全井面积)观察该井,连续从井中心标记处向左和向右计数,计数结果超过200个细胞。至多用6种不同浓度使用1种药物化合物,每种浓度进行三次计数,其结果表示为平均数±S.D.,列于表12。
同样地,把小鼠成神经细胞瘤细胞NS-20Y置于涂复多乌氨酸的盘中培养,测试化合物的作用。从培养开始24和48小时后得到的结果示于表13。
表12
对神经-2a的活性
RunNo. | 化合物 | 具有神经突(其长度是每一细胞直径的两倍)的细胞数/细胞总数,%(化合物的浓度) |
1 | 1034 | 3.9±2.8(0.03mM),7.6±2.1(0.1mM),11.3±1.6(0.3mM) |
312 | 4.5±0.4(0.03mM),9.7±0.9(0.1mM) | |
异丙胺嘧啶 | 26.7±7.7(10mM) | |
对照组 | 1.8±0.8 | |
2 | 128 | 9.9±0.6(0.3mM),9.1±0.7(0.5mM),19.8±2.8(1mM),14.3±2.4(2mM) |
208 | 7.2±2.3(0.5mM),10.6±1.5(1mM),11.1±1.2(2mM),8.0±4.0(3mM) | |
168 | 23.8±2(0.05mM),35.7±0.8(0.1mM),24.4±6.9(0.2mM),14.6±4.3(0.3mM) | |
异丙胺嘧啶 | 28.5±5.4(10mM) | |
对照组 | 1.4±0.2 | |
3 | 384 | 10.4±2.5(0.3mM),10.8±7.2(1mM) |
392 | 14.6±6.0(0.1mM),30.9±5.7(0.3mM),23.8±4.2(1mM),11.1±9.7(3mM) | |
700 | 5.9±1.4(0.1mM),6.4±1.4(0.3mM) |
表12(续)
对神经-2a的活性
RunNo. | 化合物 | 具有神经突(其长度是每一细胞直径的两倍)的细胞数/细胞总数,%(化合物的浓度) |
3 | 异丙胺嘧啶 | 30.8±2.9(10mM) |
对照组 | 3.2±1.6 | |
4 | 416 | 13.2±1.3(0.1mM),10.8±1.5(0.3mM) |
320 | 7.2±0.2(0.1mMO,8.5±1.1(0.3mM) | |
328 | 6.6±0.5(0.01mM),10.2±8.2(0.03mM),28.0±6.8(0.1mM),10.6±3.4(0.3mM) | |
400 | 11.4±4.3(0.3mM),16.0±2.7(1mM) | |
异丙胺嘧啶 | 30.7±5.9(10mM) | |
对照组 | 2.9±1.9 | |
5 | 136 | 11.6±6.3(0.1mM),12.1±2.9(0.3mM) |
628 | 10.2±1.3(0.03mM),13.4±3.2(0.1mM),12.6±3.2(0.3mM),10.0±3.9(1mM) | |
144 | 13.7±7.8(0.1mM),33.8±8.6(0.3mM) | |
408 | 9.1±1.8(0.1mM),9.6±3.9(0.3mM), | |
异丙胺嘧啶 | 23.8±4.0(10mM) | |
对照组 | 1.8±0.8 |
表12(续)
对神经-2a的活性
RunNo. | 化合物 | 具有神经突(其长度是每一细胞直径的两倍)的细胞数/细胞总数,%(化合物的浓度) |
6 | 264 | 5.2±3.1(0.1mM),8.7±1.6(0.3mM),15.2±3.2(1mM),7.2±1.8(3mM) |
424 | 4.5±1.4(0.03mM),7.6±1.3(0.1mM) | |
异丙胺嘧啶 | 27.3±4.4(10mM) | |
对照组 | 2.1±0.5 | |
7 | 360 | 6.5±0.7(0.03mM),10.0±0.7(0.1mM) |
272 | 4.8±1.3(0.03mM),30.9±2.8(0.1mM),15.9±0.5(0.3mM),17.0±4.3(1mM) | |
676 | 4.2±2.1(1.0mM),6.0±1.1(0.3mM) | |
异丙胺嘧啶 | 27.3±4.4(10mM) | |
对照组 | 1.8±0.5 | |
8 | 240 | 19.8±5.7(0.03mM),38.7±4.5(0.1mM),33.2±0.9(0.3mM),30.9±5.9(1mM) |
296 | 44.4±5.5(0.1mM),22.4±3.0(0.3mM) | |
170 | 33.5±2.4(0.1mM),31.0±4.6(0.3mM) | |
224 | 4.6±1.7(0.03mM),5.5±1.5(0.1mM) |
表12(续)
对神经-2a的活性
RunNo. | 化合物 | 具有神经突(其长度是每一细胞直径的两倍)的细胞数/细胞总数,%(化合物的浓度) |
8 | 432 | 2.9±1.0(0.1mM),3.6±1.7(0.3mM) |
604 | 18.7±4.1(0.1mM),24.6±2.9(0.3mM) | |
612 | 13.8±1.5(0.01mM),19.1±3.0(0.03mM),19.4±3.9(0.1mM),22.4±2.4(0.3mM) | |
异丙胺嘧啶 | 21.1±0.6(10mM) | |
对照组 | 1.7±1.3 | |
9 | 636 | 12.1±3.4(0.03mM),8.9±5.2(0.1mM) |
176 | 5.3±1.9(0.03mM),3.2±3.1(0.1mM) | |
184 | 18.8±4.7(0.1mM),16.0±2.4(0.3mM) | |
644 | 26.1±7.3(0.03mM),14.7±7.3(0.1mM) | |
620 | 4.7±0.4(0.01mM),4.0±1.3(0.03mM) | |
652 | 6.1±0.6(0.03mM),12.5±2.8(0.1mM) | |
152 | 6.2±2.3(0.03mM),33.8±4.7(0.1mM) | |
异丙胺嘧啶 | 27.5±0.8(10mM) | |
对照组 | 1.4±0.7 |
表12(续)
对神经-2a的活性
RunNo. | 化合物 | 具有神经突(其长度是每一细胞直径的两倍)的细胞数/细胞总数,%(化合物的浓度) |
10 | 376 | 13.6±1.2(0.03mM),14.7±1.5(0.1mM),17.2±1.4(0.3mM),16.4±3.0(1mM) |
200 | 4.2±1.6(0.01mM),7.6±1.6(0.03mM) | |
192 | 12.1±1.5(0.3mM),14.6±1.0(1mM) | |
异丙胺嘧啶 | 27.8±2.5(10mM) | |
对照组 | 3.0±0.8 | |
11 | 660 | 13.5±1.3(0.03mM),9.1±3.7(0.1mM) |
304 | 38.1±1.6(0.1mM),15.3±6.3(0.3mM) | |
异丙胺嘧啶 | 30.7±3.8(10mM) | |
对照组 | 2.6±0.5 | |
12 | 692 | 5.8±0.9(0.03mM),11.1±2.9(0.1mM) |
160 | 11.3±6.3(0.1mM),6.7±4.3(0.3mM) | |
异丙胺嘧啶 | 23.9±1.8(10mM) | |
对照组 | 1.5±1.5 | |
13 | 668 | 5.6±0.8(0.01mM),4.8±0.4(0.03mM), |
表12(续)
对神经-2a的活性
RunNo. | 化合物 | 具有神经突(其长度是每一细胞直径的两倍)的细胞数/细胞总数,%(化合物的浓度) |
13 | 668 | 5.2±0.7(0.1mM),4.1±2.5(0.3mM) |
684 | 3.8±0.5(0.01mM),5.8±2.0(0.03mM),16.4±2.8(0.1mM) | |
280 | 4.5±1.2(0.03mM),17.2±1.3(0.1mM),13.4±3.5(0.3mM),17.4±2.6(1mM) | |
异丙胺嘧啶 | 15.8±2.2(3mM) | |
对照组 | 2.9±1.0 | |
14 | 368 | 3.5±0.5(0.03mM),9.0±1.8(0.1mM) |
344 | 3.6±0.7(0.01mM),4.0±1.7(0.03mM),4.7±1.8(0.1mM),4.5±2.1(0.3mM) | |
异丙胺嘧啶 | 16.8±3.4(3mM) | |
对照组 | 2.6±0.6 | |
15 | 336 | 5.8±2.4(0.1mM),6.3±2.8(0.3mM) |
120 | 4.9±1.0(0.1mM),7.5±4.1(0.3mM) | |
232 | 3.9±1.8(0.03mM),18.7±5.2(0.1mM) | |
248 | 4.3±0.4(0.03mM),25.4±3.0(0.1mM),21.5±5.7(0.3mM),17.4±4.5(1mM) |
表12(续)
对神经-2a的活性
RunNo. | 化合物 | 具有神经突(其长度是每一细胞直径的两倍)的细胞数/细胞总数,%(化合物的浓度) |
15 | 异丙胺嘧啶 | 19.4±3.1(3mM) |
对照组 | 3.2±1.2 | |
16 | 812 | 3.5±0.5(0.1mM),3.4±0.5(0.3mM) |
816 | 4.7±2.1(0.03mM),4.0±0.3(0.1mM) | |
820 | 8.4±1.1(1mM),8.8±2.3(3mM) | |
800 | 11.4±1.2(0.3mM),25.7±1.9(1mM),22.3±0.7(3mM),16.9±0.8(10mM) | |
828 | 7.3±1.6(0.3mM),6.1±2.0(1mM) | |
异丙胺嘧啶 | 27.0±3.8(10mM) | |
对照组 | 2.3±0.4 | |
17 | 1014 | 4.7±0.7(0.1mM),7.6±1.5(0.3mM) |
1122 | 4.2±2.1(0.01mM),10.2±3.8(0.03mM) | |
1026 | 3.5±0.5(0.03mM),5.6±2.2(0.1mM) | |
1130 | 1.8±0.5(0.03mM),2.0±0.3(0.1mM) | |
1038 | 2.2±0.4(0.03mM),2.9±0.3(0.1mM) |
表12(续)
对神经-2a的活性
RunNo. | 化合物 | 具有神经突(其长度是每一细胞直径的两倍)的细胞数/细胞总数,%(化合物的浓度) |
17 | 异丙胺嘧啶 | 27.4±2.4(10mM) |
对照组 | 1.8±1.3 | |
18 | 112 | 4.8±0.1(0.03mM),18.6±5.2(0.1mM),2.6±0.6(0.3mM),7.6±4.9(1mM) |
216 | 3.7±0.4(0.01mM),6.3±2.4(0.03mM),26.6±5.6(0.1mM) | |
异丙胺嘧啶 | 23.3±2.9(10mM) | |
对照组 | 2.3±0.6 | |
19 | 104 | 2.5±0.8(0.03mM),4.1±1.5(0.1mM),7.7±3.8(0.3mM),3.6±1.4(1mM) |
352 | 3.2±1.9(0.1mM),9.9±1.6(0.3mM) | |
异丙胺嘧啶 | 22.6±0.5(10mM) | |
对照组 | 1.8±1.4 | |
20 | 288 | 1.4±0.1(0.03mM),3.3±0.9(0.1mM),3.8±1.9(0.3mM),5.1±2.7(1mM) |
256 | 4.5±0.6(0.03mM),17.9±6.3(0.1mM),21.6±4.9(0.3mM),16.6±2.5(1mM) | |
异丙胺嘧啶 | 19.4±3.1(10mM) |
表12(续)
对神经-2a的活性
RunNo. | 化合物 | 具有神经突(其长度是每一细胞直径的两倍)的细胞数/细胞总数,%(化合物的浓度) |
20 | 对照组 | 2.2±1.0 |
21 | 1086 | 1.9±1.8(0.03mM),3.1±1.3(0.1mM),8.7±0.8(0.3mM),17.4±1.1(1mM) |
1110 | 3.4±1.1(0.01mM),4.4±0.3(0.03mM),6.3±4.4(0.1mM),16.5±2.1(0.3mM) | |
异丙胺嘧啶 | 30.2±3.5(10mM) | |
对照组 | 2.6±1.0 | |
22 | 1090 | 3.7±1.0(0.01mM),5.7±0.6(0.03mM),12.2±2.5(0.1mM),10.3±0.9(0.3mM) |
1158 | 9.9±1.4(0.03mM),18.4±3.0(0.1mM),22.1±6.7(0.3mM),19.1±2.7(1mM) | |
异丙胺嘧啶 | 26.7±3.3(10mM) | |
对照组 | 2.4±1.6 | |
23 | 804 | 9.4±1.3(0.3mM),13.0±2.1(0.5mM),26.1±6.8(1mM),18.8±3.1(2mM) |
异丙胺嘧啶 | 28.5±5.4(10mM) | |
对照组 | 1.4±0.2 | |
24 | 1094 | 5.4±1.9(0.1mM),16.9±1.2(0.3mM), |
表12(续)
对神经-2a的活性
RunNo. | 化合物 | 具有神经突(其长度是每一细胞直径的两倍)的细胞数/细胞总数,%(化合物的浓度) |
24 | 1094 | 10.9±1.1(1mM) |
1098 | 5.3±1.4(0.01mM),10.2±0.9(0.03mM),5.7±2.0(0.1mM) | |
异丙胺嘧啶 | 15.7±4.1(3mM) | |
对照组 | 1.2±1.1 | |
25 | 1162 | 4.7±3.0(0.03mM),5.9±1.9(0.1mM) |
1102 | 11.9±0.7(0.1mM),10.1±3.0(0.3mM) | |
异丙胺嘧啶 | 26.7±7.7(10mM) | |
对照组 | 1.8±0.8 | |
26 | 138 | 6.3±1.8(0.03mM),12.6±4.1(0.1mM) |
2004 | 6.6±2.2(0.03mM),30.2±6.4(0.1mM) | |
171.3 | 28.8±3.1(0.1mM),19.5±7.0(0.3mM) | |
2052 | 4.6±2.1(0.01mm),3.7±0.4(0.03mM) | |
2060 | 3.6±0.1(0.03mM),7.6±0.7(1mM) | |
2070 | 5.6±3.9(0.1mM),11.7±3.1(0.3mM) |
表12(续)
对神经-2a的活性
RunNo. | 化合物 | 具有神经突(其长度是每一细胞直径的两倍)的细胞数/细胞总数,%(化合物的浓度) |
26 | 2076 | 4.8±1.4(0.01mM),1.9±1.3(0.03mM) |
异丙胺嘧啶 | 31.4±5.5(10mM) | |
对照组 | 2.5±0.2 | |
27 | 2084 | 11.1±2.2(0.03mM),17.6±6.6(0.1mM) |
2092 | 23.9±0.4(0.1mM),11.0±3.9(1mM) | |
2100 | 4.4±0.8(0.03mM),4.7±1.4(0.1mM) | |
2108 | 4.8±2.0(0.03mM),13.5±0.1(1mM) | |
146 | 8.7±2.0(0.03mM),40.0±6.1(0.1mM) | |
147.1 | 6.6±0.4(0.03mM),30.5±6.1(0.1mM) | |
2116 | 34.2±3.8(0.1mM),8.2±3.6(0.3mM) | |
2124 | 12.5±5.3(0.03mM),31.7±7.0(0.1mM) | |
异丙胺嘧啶 | 31.4±5.5(10mM) | |
对照组 | 2.5±0.2 | |
28 | 165 | 41.0±0.7(0.1mM),12.4±1.8(0.3mM) |
表12(续)
对神经-2a的活性
RunNo. | 化合物 | 具有神经突(其长度是每一细胞直径的两倍)的细胞数细胞总数,%(化合物的浓度) |
28 | 166 | 36.8±7.1(0.1mM),13.4±4.0(0.3mM) |
167 | 22.5±3.4(0.1mM),9.3±2.3(0.3mM) | |
169 | 34.1±5.7(0.1mM),16.6±5.2(0.3mM) | |
171 | 37.1±1.9(0.1mM),8.8±2.6(0.3mM) | |
171.1 | 36.4±7.8(0.1mM),15.2±3.1(0.3mM) | |
171.11 | 36.8±7.1(0.1mM),14.3±3.0(0.3mM) | |
异丙胺嘧啶 | 21.0±2.3(10mM) | |
对照组 | 2.5±0.2 | |
29 | 2132 | 32.6±4.4(0.1mM),31.7±5.0(0.3mM) |
2140 | 5.4±3.9(0.03mM),17.0±1.2(0.1mM) | |
2148 | 4.5±1.3(0.03mM),4.2±1.2(0.1mM) | |
2156 | 8.6±1.0(0.03mM),19.6±5.3(0.1mM) | |
307-1 | 3.6±0.4(0.03mM),9.0±2.5(0.3mM) | |
2164 | 4.6±1.1(0.1mM),11.7±0.7(1mM) |
表12(续)
对神经-2a的活性
RunNo. | 化合物 | 具有神经突(其长度是每一细胞直径的两倍)的细胞数/细胞总数,%(化合物的浓度) |
29 | 异丙胺嘧啶 | 21.0±2.3(10mM) |
对照组 | 3.1±1.2 | |
30 | 154 | 5.2±1.5(0.03mM),16.2±1.1(0.1mM) |
2174 | 2.5±1.0(0.01mM) | |
2182 | 8.0±3.2(0.03mM),2.7±0.9(0.1mM) | |
2188 | 2.4±0.9(0.1mM),3.8±1.1(0.3mm) | |
2194 | 9.5±3.5(0.1mM),7.6±2.8(0.3mM) | |
2202 | 2.2±2.0(0.1mM) | |
2210 | 9.5±2.0(0.03mM),9.5±1.9(0.1mM) | |
异丙胺嘧啶 | 19.4±2.4(10mM) | |
对照组 | 1.7±0.9 | |
31 | 2218 | 9.7±1.8(0.03mM),11.4±6.1(0.1mM) |
662 | 3.1±1.6(0.1mM),2.6±0.9(0.3mM) | |
2226 | 6.4±3.3(0.03mM),15.4±3.9(0.1mM) |
表12(续)
对神经-2a的活性
RunNo. | 化合物 | 具有神经突(其长度是每一细胞直径的两倍)的细胞数/细胞总数,%(化合物的浓度) |
31 | 2234 | 5.1±3.2(0.03mM),5.7±2.8(0.1mM) |
2242 | 3.3±0.9(0.03mM),24.8±2.9(0.1mM) | |
2250 | 10.9±3.9(0.1mM),19.2±1.0(0.3mM) | |
异丙胺嘧啶 | 19.4±2.4(10mM) | |
对照组 | 1.7±0.9 | |
32 | 2260 | 2.2±0.3(0.03mM),2.3±0.5(0.1mM) |
2270 | 14.7±5.1(0.03mM),19.9±4.2(0.1mM)21.3±3.5(0.3mM),15.2±1.5(1mM) | |
2278 | 13.9±6.3(0.03mM),12.5±1.3(0.1mM) | |
2286 | 9.7±5.4(0.03mM),8.4±0.8(0.1mM) | |
2294 | 3.7±0.9(0.03mM),8.1±1.6(0.1mM) | |
2302 | 8.0±2.7(0.03mM),8.2±4.7(0.1mM) | |
异丙胺嘧啶 | 19.4±2.4(10mM) | |
对照组 | 1.7±0.9 | |
33 | 2012 | 6.6±1.2(0.03mM),6.6±3.1(0.3mM) |
表12(续)
对神经-2a的活性
RunNo. | 化合物 | 具有神经突(其长度是每一细胞直径的两倍)的细胞数/细胞总数,%(化合物的浓度) |
33 | 2020 | 4.6±1.1(0.03mM),33.8±9.6(0.1mM),30.5±9.5(0.3mM),15.1±5.0(1mM) |
2028 | 4.0±0.8(0.03mM),12.5±1.2(0.1mM) | |
2036 | 3.9±0.8(0.03mM),5.4±1.1(0.1mM) | |
2044 | 3.7±0.7(0.01mM),10.3±4.7(0.1mM) | |
异丙胺嘧啶 | 19.5±3.6(10mM) | |
对照组 | 2.7±0.6 | |
34 | 2310 | 8.3±1.8(0.1mM),12.1±3.6(0.3mM) |
2318 | 7.7±1.4(0.03mM),35.1±1.3(0.1mM),18.6±5.2(0.3mM),8.8±1.3(1mM) | |
2326 | 4.6±1.4(0.03mM),8.3±2.6(0.1mM) | |
2334 | 13.2±0.2(0.03mM),16.7±0.8(0.1mM) | |
2342 | 5.9±2.1(0.03mM),11.4±1.4(0.1mM) | |
2350 | 5.9±1.5(0.3mM),8.3±2.0(1mM) | |
154.2 | 3.9±0.6(0.03mM),8.9±2.4(0.1mM) |
表12(续)
对神经-2a的活性
RunNo. | 化合物 | 具有神经突(其长度是每一细胞直径的两倍)的细胞数/细胞总数,%(化合物的浓度) |
34 | 171.5 | 7.2±1.1(0.01mM),28.4±2.2(0.1mM),32.7±0.6(0.3mM),14.0±4.1(1mM) |
异丙胺嘧啶 | 16.1±0.6(10mM) | |
对照组 | 3.3±0.6 | |
35 | 3104 | 2.8±0.8(0.03mM),4.0±2.2(0.1mM),7.2±2.8(0.3mM),6.1±1.6(1mM) |
异丙胺嘧啶 | 16.8±3.4(3mM) | |
对照组 | 2.6±0.6 | |
36 | 3144 | 20.8±4.7(0.03mM),34.1±3.8(0.1mM),44.5±9.7(0.3mM),32.2±1.6(1mM) |
异丙胺嘧啶 | 30.8±2.9(10mM) | |
对照组 | 3.2±1.6 | |
37 | 3200 | 3.6±0.5(0.03mM) |
异丙胺嘧啶 | 23.3±2.9(10mM) | |
对照组 | 2.3±0.6 | |
38 | 3300 | 6.1±1.2(0.3mM),7.8±1.0(1mM) |
表12(续)
对神经-2a的活性
RunNo. | 化合物 | 具有神经突(其长度是每一细胞直径的两倍)的细胞数/细胞总数,%(化合物的浓度) |
38 | 3200 | 2.7±0.7(0.01mM),2.5±2.3(0.03mM) |
异丙胺嘧啶 | 19.4±3.1(3mM) | |
对照组 | 3.2±1.2 | |
39 | 3136 | 5.8±0.6(0.01mM),13.8±4.8(0.03mM),20.9±5.3(0.1mM),7.1±3.0(0.3mM) |
异丙胺嘧啶 | 22.6±0.5(10mM) | |
对照组 | 1.8±1.4 | |
40 | 3128 | 14.2±1.9(0.1mM),11.9±4.5(0.3mM) |
3112 | 6.3±0.4(0.03mM),6.2±3.4(0.1mM) | |
3152 | 11.4±3.1(0.03mM),6.8±4.2(0.1mM) | |
3176 | 7.3±3.3(0.03mM),23.1±4.8(0.1mM),21.2±4.9(0.3mM),14.6±5.0(1mM) | |
3184 | 3.7±1.1(0.03mM),13.9±2.3(0.1mM),18.4±1.9(0.3mM),17.0±2.1(1mM) | |
3192 | 9.7±1.1(0.1mM),3.7±3.2(0.3mM) | |
异丙胺嘧啶 | 19.4±3.1(10mM) |
表12(续)
对神经-2a的活性
RunNo. | 化合物 | 具有神经突(其长度是每一细胞直径的两倍)的细胞数/细胞总数,%(化合物的浓度) |
40 | 对照组 | 2.2±1.0 |
41 | 3404 | 3.3±1.3(0.03mM),3.4±1.4(0.3mM) |
3412 | 2.9±0.9(0.03mM),20.6±8.2(0.1mM) | |
3420 | 4.2±1.9(0.03mM),8.7±2.3(0.1mM) | |
异丙胺嘧啶 | 19.4±2.4(10mM) | |
对照组 | 1.7±0.9 | |
42 | 298 | 2.7±1.7(0.1mM),6.1±5.6(0.3mM) |
306 | 7.7±0.5(0.03mM),2.8±0.8(0.1mM) | |
242 | 17.0±2.3(0.1mM),12.8±6.3(0.3mM)9.4±3.9(1mM) | |
150 | 9.3±1.9(0.03mM),13.6±1.2(0.1mM)6.6±3.0(0.3mM) | |
171-9 | 24.4±6.6(0.1mM),7.1±2.9(0.3mM) | |
异丙胺嘧啶 | 12.1±1.6(3mM) | |
对照组 | 2.4±0.4 |
表12(续)
对神经-2a的活性
RunNo. | 化合物 | 具有神经突(其长度是每一细胞直径的两倍)的细胞数/细胞总数,%(化合物的浓度) | |
43 | 171-11170-2171-7 | 5.9±0.9(0.03mM),22.1±2.3(0.1mM)29.2±1.5(0.3mM),31.7±5.9(1mM) | |
14.7±1.1(0.1mM),5.6±2.1(0.3mM)13.9±3.0(1mM) | |||
8.5±1.0(0.03mM),6.7±3.1(0.1mM) | |||
171-12 | 13.3±1.1(0.1mM),10.7±4.2(0.3mM)12.7±0.9(1mM) | ||
异丙胺嘧啶 | 14.9±1.9(10mM) | ||
对照组 | 2.5±1.0 | ||
44 | 2022-1 | 23.1±4.8(0.1mM),18.1±2.8(0.3mM)19.8±2.1(1mM) | |
2023-1 | 8.3±2.1(0.1mM),7.0±0.5(0.3mM) | ||
异丙胺嘧啶 | 20.1±3.0(10mM) | ||
对照组 | 3.2±0.9 |
表13
对NS-20Y细胞的活性
化合物 | 出现神经突的细胞数/细胞包总数(化合物的浓度) |
24小时 48小时 | |
112 | 4/51(0.025mM) 9/50(0.025mM)4/49(0.01mM) |
对照组 | 0/51 1/51 |
120 | 23/50(0.5mM) 4/50(0.5mM) |
对照组 | 1/49 0/50 |
144 | 37/50(0.1mM) 31/50(0.1mM)8/52(0.05mM) |
对照组 | 0/50 1/506/50(0.025mM) |
152 | 3/50(0.05mM) 2/50(0.025mM) |
对照组 | 0/50 0/50 |
160 | 10/53(0.5mM) 2/50(0.5mM) |
对照组 | 0/50 0/50 |
168 | 26/50(0.1mM) 20/55(0.1mM)12/50(0.25mM) |
对照组 | 3/50 2/50 |
208 | 27/53(0.1mM) 28/50(0.1mM)17/51(0.25mM) |
对照组 | 1/50 0/52 |
表13(续)
对NS-20Y细咆的活性
化合物 | 出现神经突的细胞数/细胞总数(化合物的浓度) |
24小时 48小时 | |
128 | 23/55(1.0mM) 31/50(0.3mM)4/49(0.3mM) 21/50(0.5mM) |
对照组 | 3/50 4/50 |
216 | 3/49(0.025mM) 24/50(0.025mM)20/50(0.05mM) |
对照组 | 0/51 1/50 |
232 | 2/50(0.025mM) 2/49(0.01mM) |
对照组 | 0/51 0/50 |
240 | 4/50(0.2mM) 3/50(0.2mM) |
对照组 | 0/50 0/50 |
248 | 3/49(0.1mM) 2/50(0.05mM) |
对照组 | 0/49 0/50 |
256 | 5/51(0.2mM) 2/48(0.05mM) |
对照组 | 0/51 0/50 |
272 | 33/50(0.1mM) 17/50(0.1mM)24/50(0.2mM) |
对照组 | 0/50 0/51 |
280 | 3/50(0.2mM) 8/53(0.1mM) |
对照组 | 0/50 1/53 |
表13(续)
对NS-20Y细咆的活性
化合物 | 出现神经突的细胞数/细胞总数(化合物的浓度) |
24小时 48小时 | |
288 | 2/52(0.1mM) 2/50(0.1mM) |
对照组 | 0/50 0/50 |
296 | 9/49(0.1mM) 2/50(0.1mM) |
对照组 | 0/50 0/48 |
304 | 40/50(0.1mM) 3/50(0.01mM) |
对照组 | 0/50 0/51 |
328 | 32/50(0.1mM) 8/50(0.025mM)12/51(0.1mM) |
对照组 | 0/51 0/50 |
336 | 3/54(0.2mM) 2/50(0.5mM) |
对照组 | 0/52 0/50 |
344 | 3/51(0.2mM) 2/49(0.5mM) |
对照组 | 0/50 0/51 |
368 | 14/50(0.1mM) 8/51(0.05mM)5/50(0.1mM) |
对照组 | 0/50 0/50 |
376 | 2/50(0.2mM) 2/50(0.1mM) |
对照组 | 0/50 0/50 |
表13(续)
对NS-20Y细胞的活性
化合物 | 出现神经突的细胞数/细胞总数(化合物的浓度) |
24小时 48小时 | |
392 | 8/50(0.1mM) 6/51(0.05mM)3/43(0.1mM) |
对照组 | 0/52 0/50 |
612 | 2/50(0.1mM) 2/50(0.1mM) |
对照组 | 0/50 1/51 |
668 | 2/50(0.1mM) 2/50(0.05mM) |
对照组 | 0/50 0/50 |
684 | 2.50(0.1mM) 2/50(0.05mM) |
对照组 | 0/53 0/50 |
1094 | 7/48(0.4mM) 2/50(0. mM)4/54(0.1mM) |
对照组 | 2/50 1/50 |
1026 | 31/50(0.1mM) 2/50(0.02mM)4/50(0.02mM) |
对照组 | 2/50 1/50 |
1086 | 4/50(0.4mM) 2/50(0.02mM) |
对照组 | 2/50 1/50 |
1090 | 21/50(0.1mM) 3/50(0.1mM)4/50(0.02mM) |
对照组 | 1/50 1/50 |
表13(续)
对NS-20Y细胞的活性
化合物 | 出现神经突的细胞数/细胞总数(化合物的浓度) |
24/小时 48/小时 | |
1014 | 9/50(0.4mM) 6/50(0.4mM)3/50(0.1mM) |
对照组 | 2/50 2/50 |
384 | 8/50(0.4mM) 3/50(0.4mM) |
对照组 | 2/50 1/50 |
416 | 11/50(0.4mM) 2/50(0.1mM)7/50(0.1mM) |
对照组 | 1/50 0/50 |
320 | 8/50(0.1mM) 6/50(0.1mM) |
对照组 | 2/50 1/50 |
400 | 30/53(0.4mM) 3/48(0.4mM)9/50(0.1mM) 3/50(0.1mM) |
对照组 | 2/50 1/50 |
136 | 42/50(0.4mM) 15/50(0.4mM)9/50(0.1mM) |
对照组 | 3/50 1/50 |
264 | 8/48(0.4mM) 4/50(0.4mM) |
对照组 | 2/50 1/50 |
424 | 16/50(0.4mM) 3/50(0.4mM) |
对照组 | 3/52 1/50 |
表13(续)
对NS-20Y细胞的活性
化合物 | 出现神经突的细胞数/细胞总数(化合物的浓度) |
24小时 48小时 | |
360 | 18/50(0.1mM) 4/50(0.1mM)8/50(0.02mM) |
对照组 | 3/50 1/50 |
224 | 6/50(0.02mM) 3/50(0.02mM) |
对照组 | 1/50 1/50 |
432 | 7/50(0.4mM) 4/50(0.4mM)7/50(0.02mM) |
对照组 | 2/50 2/50 |
200 | 4/50(0.02mM) 2/50(0.02mM) |
对照组 | 2/50 1/50 |
192 | 23/50(0.4mM) 4/50(0.4mM) |
对照组 | 2/50 1/50 |
176 | 8/50(0.1mM) 2/50(0.02mM) |
对照组 | 1/50 0/50 |
184 | 8/50(0.02mM) 3/50(0.02mM)5/48(0.1mM) |
对照组 | 1/52 1/50 |
628 | 9/50(0.1mM) 3/50(0.1mM) |
对照组 | 3/50 1/50 |
表13(续)
对NS-20Y细胞的活性
化合物 | 出现神经突的细胞数/细胞总数(化合物的浓度) |
24小时 48/小时 | |
700 | 6/50(0.4mM) 4/50(0.1mM)4/53(0.1mM) |
对照组 | 2/50 1/50 |
660 | 5/50(0.1mM) 4/50(0.1mM) |
对照组 | 2/50 1/50 |
604 | 7/50(0.4mM) 2/50(0.02mM)6/50(0.02mM) |
对照组 | 2/50 1/50 |
804 | 8/55(0.25mM) 25/51(0.5mM)7/50(0.5mM) 8/50(0.25mM) |
对照组 | 4/50 0/50 |
168 | 26/50(0.1mM) 20/55(0.1mM)12/50(0.25mM) |
对照组 | 3/50 2/50 |
208 | 27/53(0.1mM) 28/50(0.1mM)17/51(0.25mM) |
对照组 | 1/50 0/52 |
820 | 5/53(0.5mM) 5/55(0.25mM)4/50(0.1mM) 4/50(0.1mM) |
对照组 | 3/50 0/50 |
表13
对NS-20Y细咆的活性
化合物 | 出现神经突的细胞数/细胞总数(化合物的浓度) |
24小时 48小时 | |
828 | 10/58(0.3mM) 6/50(0.3mM)5/59(0.5mM) 5/51(0.5mM) |
对照组 | 2/50 2/51 |
812 | 11/50(1.0mM) 9/50(0.3mM)9/50(0.5mM) 5/51(0.5mM) |
对照组 | 2/53 2/50 |
3192 | 6/50(0.02mM) 4/50(0.02mM) |
对照组 | 1/50 0/50 |
242 | 6/50(0.4mM) 11/50(0.2mM)4/50(0.2mMM) 6/50(0.1mM) |
对照组 | 0/50 0/50 |
2022-1 | 12/50(0.2mM) 2/50(0.1mM)5/50(0.4mM) |
对照组 | 0/50 0/50 |
2023-1 | 2/50(0.1mM) 2/50(0.2mM) |
对照组 | 0/50 0/50 |
171-9 | 7/45(0.4mM) 2/50(0.02mM) |
对照组 | 0/50 0/50 |
171-11 | 5/50(0.3mM) 2/50(0.1mM) |
表13(续)
对NS-20Y细咆的活性
试验实施例2
化合物 | 出现神经突的细胞数/细胞总数(化合物的浓度) |
24小时 48小时 | |
对照组 | 0/50 9/50 |
170-2 | 3/50(0.1mM) 2/50(0.1mM) |
对照组 | 0/50 0/50 |
171-7 | 4/50(0.1mM) 2/50(0.1mM) |
对照组 | 0/50 0/50 |
对坐骨神经受损鼠的疗效
用下述方法试验本发明化合物对坐骨神经受损作为末稍神经疾病模型鼠的疗效,所用方法:(1)坐骨神经受损后爪的动作的变化,(2)以末稍神经退化和再生过程指数表示肌重改变。
在试验中,采用Wistar雄性鼠(6周令),每组7只。使用类似于Yamatsn等人的方法〔参见Kiyomi Yamatsu,TakenoriKaneko,Akifumi Kitahara和Isao Ohkawa,Journal ofJapanese Pharmacological Society",72,259-268(1976)〕和Hasegawa等人的方法〔参见 Kazuo Hasegawa,NaojiMikuni和Yutaka Sakai,Journal of JapanesePharmacological Society,74,721-734(1978)〕损伤它们的坐骨神经。具体来说,用戊巴比妥(40mg/kg,ip)使之感觉缺损,暴露股的左侧坐骨神经,用止血钳把暴露在具体部位的坐骨神经损伤30秒钟,受损后,立即缝合该手术部位,此后,以每周一次剂量100μg/kg腹膜内注射现有的长春新碱,以延缓末稍神经的再生。
选择本发明化合物作为试验药物,腹膜内给药每天一次,以受损当天开始直至第30天。而对照组的鼠,仅给以0.9%盐水。
(1)带有受损神经后爪的功能变化
抽搐紧张是由电刺激或类似的运动神经产生受支配肌收缩所伴随的短暂紧张,与通常介绍的趾间距离一样被认为是神经和肌肉的反射功能的变化。
这样,30天后,用水合氯醛(400mg/kg,i.p.)使之麻醉,用Kern等人的方法〔J.Neurosci.Methods,19,259(1987)〕测量鼠的抽搐紧张。具体来说,刮去鼠后爪的毛,涂复Cardiocream(Nihon Denko K.K.产品),然后,用皮带夹子将电极系于鼠后爪皮肤上,阴极系于肱骨大结节的后部,阳极系于阳极电极朝后1cm和朝其背面1cm的部位。将大鼠固定在阳极电极背面,受试后爪垂直地固定。一条约长20cm丝线,其一端系于受试后爪第三趾传出关节处,另一端系于张力换能器,第三趾肌曲的等张挛缩记录在多种波动描记器上。在电压为100V,频率为2Hz矩形波连续持续时间1毫秒下产生电刺激,静力为15至30g,在15秒钟内10刺激重复3次,收缩力表示为张力(g)。由两爪测量值计算受损神经爪的收缩力的复原率(%,左/右),结果列于表14和15。
表14抽搐紧张
*1,平均值±S.D.,*2,P<0.05,*3,P<0.01
化合物 | 剂量(mg/kg) | 病例数 | 抽搐紧张*1左/右(%) |
盐水168168296 | -103030 | 7788 | 33.3±7.048.4±11.8*251.2±13.6*348.1±9.4*2 |
表15抽搐紧张
化合物 | 剂量(mg/kg) | 病例数 | 抽搐紧张左/右(%) | |
第18天 | 第23天 | |||
生理盐水3144 | -30 | 78 | 44.2±17.654.5±17.1 | 49.8±14.857.9±15.5 |
与对照组相比试验化合物明显地提高了抽搐紧张的复原率(属于电生理学指标),并改善了症状。
测量足趾间的距离,因为这是一种在功能上显示神经退化和再生的良好指标,随着这段时间可测量其变化值。
用类似于Hasegawa的方法〔Hasegawa,K.,Experientia,34,750-751(1978)〕,测量后爪第一和第五足趾之间的距离。
计算所测距离与正常后爪足趾间距离的比率,并以百分比(%)表示。受损神经的后爪趾间距比受损后立即治疗正常的后爪少50%。给药组的鼠趾间距离开始复原12至16天后,从约第17天至最后(第26天),与对照组相比,明显地存在加速复原的趋向。
一个实例示于表16。
表16
对坐骨神经受损鼠的疗效
化合物 | 剂量(mg/kg,i.p.) | 趾间距的复原 | |
第18天 | 第23天 | ||
生理盐水3144 | 1ml/kg30 | 67.6±16.172.7±14.0 | 76.5±20.283.8±12.2 |
(2)肌重变化
众所周知,切除神经或神经疾病是引起肌肉萎缩的原因(肌肉是受神经控制的),再次恢复神经对肌肉的控制可逐渐治愈肌肉萎缩。为此,可定量地选择某一肌重变化作为指标,手术后30天,在麻醉下切除受坐骨神经控制的两只爪的趾伸缩肌,称重,计算受损侧对正常侧的趾伸缩肌重量比率,以百分比(%)表示。结果示于表17。
表17
化合物 | 剂量(mg/kg) | 病例数 | 趾伸缩肌重量*1左/右(%) |
盐水16816896 | -103030 | 7788 | 48.8±6.452.1±5.459.4±11.8*256.9±9.7*2 |
*1平均值±S.D.,*2,P<0.05
结果表明,与对照组相比,这些试验化合物明显地增加了趾伸缩肌的重量%。
因此,这些试验化合物可用作末稍神经疾病的缓解和治疗剂。试验实施例3
试验对改善运动原失调的促进作用,运动原失调归因于胎脑细胞移植引起鼠脑细胞损伤:
注射很少量6-羟基多巴胺,使4周令雌性Wister(体重100g)左脑黑质多巴胺神经细胞受损,这些鼠表现出在受损侧相对方向自发旋转趋势,该现象持续几天,但是,此后未看到明显的反常动作。对黑质多巴胺神经细胞受损的鼠施给甲基苯丙胺(5mg/kg,i.p),它们开始朝受损侧旋转运动。
从给药破坏两周后,切取14至17天令胎鼠脑含多巴胺细胞的胼胝体体干部分(即,在腹侧的黑质和tagmentum),精细地切割,用胰蛋白酶处理。然后,将提取的组织在37℃保温30分钟,该组织经滴管吸取形成混悬液,在受损侧尾状核的两个部点中的每一位点移入5μ1混悬液(总计10μl,约为10’细胞)。
从移植之日起,施给本发明化合物№.168,剂量为156mg/kg(i.p.),共计4天,然后,施用混悬液7天,从第11天起10天内的剂量为50mg/kg(i.p.)。以剂量153mg/kg施给本发明化合物№.296,然后,按同一进程给以50mg/kg。
按同一进程还给以化合物№.3144,剂量为135mg/kg,然后给以45mg/kg。
在移植和给药前的1周和2周和移植,给药后的2(或3)、4、6和8周,测试由施以甲基苯丙胺诱发的旋转运动。施以甲基苯丙胺后,以10分钟为间隔,计算第一个一分钟旋转运动次数,平均六次所计旋转总次数,得出旋转运动的平均数。
结果列于表18。
该结果表明这些试验化合物可用作中枢神经疾病的缓解和治疗剂。
表18
试验实施例4
化合物 | -1W 3W 4W 6W 8W |
168 | 13.3±7.8 9.1±5.6* 4.5±4.5 1.5±3.9 0.8±2.1 |
296 | 13.2±4.1 8.4±5.0* 3.1±3.4 0.9±2.3 1.0±1.5 |
3144 | 14.1±4.7 7.7±4.7* 4.0±5.6 0.2±2.2 1.1±4.1 |
生理盐水 | 16.7±9.1 11.2±9.6* 5.3±8.3 2.8±5.4 2.2±6.0 |
改善因汞中毒诱发 神经疾病鼠的识别和记忆能力,以及复原作用:
在1周内,先使7周令Balbc种雄鼠识别成T型曲径3次,它们立刻从开始点跑向安全区。然后,给Balbc种雄鼠(7周令)口服氯化甲基汞(缩写为MMC)6天,剂量为6mg/kg/天,对一组对照组鼠给以盐水,剂量为0.1ml/10g/天。紧接着服用MMC的一天开始,在腹膜内施给本发明化合物10天,在给药后第6天(即,开始试验后第12天),恢复对T型曲经的识别,并看到鼠的跑动行为。在恢复后第10和第11天(试验开始后第21和第22天),计算可在T型曲经受试的鼠数,作为分母,计算在5秒钟内从10次足迹跑动中至少8次跑到安全区的鼠数,并作为分子,因MMC中毒而死亡,受试鼠数减少,测量鼠跑到安全区所需时间(秒钟),计算平均值±标准差(SE)。
结果证明本发明化合物具有改善鼠的识别和记忆作用及其复原作用。试验实施例5
按下述方法测试本发明化合物的急性毒性。
把5周令ddy种雄鼠作为试验动物,每组4-6只。每一种化合物均为腹膜内(i.p.)给药,给药后24小时,评定该化合物的毒性。结果列于表19。
表19
对鼠的急性毒性
化合物 | 测定的LD50(mg/kg,i.p.) |
12813614415216820839232840824029627217060464430436037642424821610901158612184192280232 | >1000>1000>1000>1000>1000>1000500-1000>1000500-1000>1000>1000>1000>1000<500>1000>1000>1000500-1000>1000>1000>1000500-1000<250500-1000>1000500-1000500-1000>1000 |
表19(续)
化合物d | 测定的LD50(mg/kg,i.p.) |
1121201601762643123203523684006286606848041041382004146154147.116921162124171.325628821322140 | >1000>1000>1000>1000500-1000>1000>1000500-1000500-1000500-1000500-1000500-1000500-1000500-1000500-1000>1000>1000>1000>1000>1000>1000500-1000>1000>1000>1000500-1000>1000>1000 |
表19(续)
化合物 | 测定LD50(mg/kg,i.p.) |
2020202820442070208420922156216421822210221822422250227022782302231823262342154.2171.5231023503104 | 500-1000500-1000500-1000>1000>1000>1000>1000>1000500-1000500-1000500-1000500-1000500-1000>1000500-1000500-1000500-1000500-1000500-1000500-1000>1000500-1000500-1000>1000 |
3122,3144,3176,3184,3192,34123420 | 500-1000 |
表19(续)
化合物 | 测定的 LD50(mg/kg,i.p.) |
23182334171-9171-11170-2170-122022-1 | >1000>1000500-1000>1000500-1000>1000>1000 |
本发明提供的式(1)、(2)和(3)的化合物具有对患神经疾病大鼠和小鼠的神经细胞增生、神经突形成和生长的促进作用,神经再生作用和运动原功能复原作用,可适用于缓解和治疗神经病科疾病,例如末稍神经或中枢神经疾病和痴呆病。预期还可适用于由涉及知觉和感觉功能及自主功能的神经组织和细胞引起的神经病科疾病的复原、缓解和治疗。
业巳发现本发明化合物的生物活性等于或高于如示于试验实施例1-4和表12-19对照组的甲乙基嘧啶胺磷酸盐和钴宾酰胺的生物活性,本发明化合物的毒性一般较弱,如试验实施例5所示。这样,本发明化物被认为是具高活性、极安全、很有效的弱毒性药物。
Claims (3)
1.制备式(I)表示的嘧啶类化合物或其药物上可接受的盐的方法,式(I)如下:式中R1表示氢原子或低级烷基;
R3相当于氢,低级烷基,羟基,由硝基任意取代的苯基,苄基、苯酰氧基,苯酰氨基,低级烷基氨基,二-低级烷基氨基,HO(C6H5)2C-基团,哌啶子基,羟基(低级烷基),C6H5SO2O-基团,由卤素任意取代的苯甲酰基,低级烷基磺酰胺或低级烷氧基羰基,n是4、5、6或7,
R6表示氢原子,低级烷基,苯基,苄基,低级烷氧基或2-(N,N-二甲氨基)乙基,
4-低级烷基哌嗪基或由卤素、硝基、低级烷基、低级烷氧基、氨基、苯甲酰氨基或苯基任意取代的苯甲酰基,前提是当R6为氢原子时,R7苯甲酰,
Z表示氢原子,卤素原子,低级烷基或低级烷氧基羰基;
该方法包括:
a)使式(II)的化合物与式R7Cl(其中R7如上所限定)的化合物在碱性化合物存在下在20-150℃在溶剂甲苯、二噁烷、吡啶或水中反应,其中X,Z,R1和R6如上所限定,只是R6不是氢,得到Y是-NR6R7且R6不是氢的式(I)化合物,或
b)使式(III)的化合物与式R5Cl(其中R5如上所限定)的化合物在碱性化合物存在下在20-150℃在溶剂(例如甲苯、二烷、吡啶或水)中反应,其中Y、Z、R1和R4如上所限定,得到X是-NR4R5的式(I)化合物
如果需要,可利用常规方法将上述方法(a)或(b)制得的式I化合物转化成其盐。
2.如权利要求1的方法,其中,方法a)和b)中的碱性化合物选自有机碱例如三乙胺、吡啶或4-二甲氨基吡啶和无机碱侧如碳酸钠或碳酸钾。
3.如权利要求1或2的方法,其中,药物可接受的盐可选自盐酸盐,氢溴酸盐,亚硫酸氨盐,磷酸盐,酸式磷酸盐,乙酸盐,马来酸盐,富马酸盐,琥珀酸盐,乳酸盐,酒石酸盐,苯甲酸盐,柠檬酸盐,葡聚糖酸盐,甲磺酸盐,对甲苯磺酸盐,萘磺酸盐和季铵盐。
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US9271967B2 (en) | 2010-11-08 | 2016-03-01 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors |
CA2814998C (en) | 2010-11-08 | 2019-10-29 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors |
EP2928891B1 (en) * | 2012-12-04 | 2019-02-20 | Rigel Pharmaceuticals, Inc. | Protein kinase c inhibitors and uses thereof |
CN104370897A (zh) * | 2013-01-24 | 2015-02-25 | 韩冰 | 一类蛋白酶抑制剂及其制备方法和用途 |
CN104370888A (zh) * | 2013-01-24 | 2015-02-25 | 韩冰 | 一类具有神经保护作用的化合物及其制备方法和用途 |
JO3368B1 (ar) | 2013-06-04 | 2019-03-13 | Janssen Pharmaceutica Nv | مركبات 6، 7- ثاني هيدرو بيرازولو [5،1-a] بيرازين- 4 (5 يد)- اون واستخدامها بصفة منظمات تفارغية سلبية لمستقبلات ميجلور 2 |
JO3367B1 (ar) | 2013-09-06 | 2019-03-13 | Janssen Pharmaceutica Nv | مركبات 2،1، 4- ثلاثي زولو [3،4-a] بيريدين واستخدامها بصفة منظمات تفارغية موجبة لمستقبلات ميجلور 2 |
SI3096790T1 (sl) | 2014-01-21 | 2019-11-29 | Janssen Pharmaceutica Nv | Kombinacije, ki vsebujejo pozitivne aleostrične modulatorje ali ortosterične agoniste metabotropnega glutamatergičnega receptorja podtipa 2 in njihova uporaba |
ME03518B (me) | 2014-01-21 | 2020-04-20 | Janssen Pharmaceutica Nv | Kombinacije koje obuhvataju pozitivne alosterične modulatore ili ortosterične agoniste metabotropnog glutamatergičnog receptora podtipa 2 i njihova primjena |
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GB1259685A (en) * | 1969-04-03 | 1972-01-12 | Soc D Etudes Prod Chimique | Amino-pyrimidine derivatives |
US3984414A (en) * | 1971-10-09 | 1976-10-05 | Societe D'etudes De Produits Chimiques | Dichloroacetate salt of 2-isopropylamino pyrimidine |
JPS5122044A (ja) * | 1974-08-19 | 1976-02-21 | Nissin Electric Co Ltd | Kyorikeidensochi |
GB1525995A (en) * | 1976-02-18 | 1978-09-27 | Soc D Etudes Prod Chimique | Aminopyrimidine salt |
JPS54157575A (en) * | 1978-05-31 | 1979-12-12 | Expansia Sa | Manufacture of 22chloropyrimidine |
IL57352A0 (en) * | 1978-06-16 | 1979-09-30 | Expansia Sa | Preparation of 2-isopropylamino-pyrimidine |
IN153791B (zh) * | 1979-03-10 | 1984-08-18 | Soc D Etudes Prod Chimique | |
BE882593A (fr) * | 1979-04-30 | 1980-07-31 | Soc D Etudes Prod Chimique | Preparation des derives hydroxyles de l'isopropyalmino-pyrimidine |
BE882836A (fr) * | 1979-05-15 | 1980-08-18 | Soc D Etudes Prod Chimique | Nouveaux derives halogenes de l'isopropylamino pyrimidine, leur preparation et leur utilisaton therapeutique |
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-
1989
- 1989-12-22 HU HU896762A patent/HU206337B/hu not_active IP Right Cessation
- 1989-12-27 AT AT89313595T patent/ATE136542T1/de not_active IP Right Cessation
- 1989-12-27 EP EP89313595A patent/EP0379806B1/en not_active Expired - Lifetime
- 1989-12-27 EP EP94105018A patent/EP0612746A1/en not_active Withdrawn
- 1989-12-27 DE DE68926232T patent/DE68926232T2/de not_active Expired - Fee Related
- 1989-12-28 AU AU47329/89A patent/AU629595B2/en not_active Ceased
- 1989-12-29 US US07/459,376 patent/US5147876A/en not_active Expired - Fee Related
- 1989-12-29 CA CA002006944A patent/CA2006944A1/en not_active Abandoned
- 1989-12-29 CN CN89109731A patent/CN1037513C/zh not_active Expired - Fee Related
- 1989-12-29 KR KR1019890020122A patent/KR920003129B1/ko not_active IP Right Cessation
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1993
- 1993-10-21 CN CN93119388A patent/CN1090846A/zh active Pending
Also Published As
Publication number | Publication date |
---|---|
EP0612746A1 (en) | 1994-08-31 |
CN1090846A (zh) | 1994-08-17 |
ATE136542T1 (de) | 1996-04-15 |
HUT52769A (en) | 1990-08-28 |
CA2006944A1 (en) | 1990-06-29 |
AU629595B2 (en) | 1992-10-08 |
KR920003129B1 (ko) | 1992-04-20 |
EP0379806A3 (en) | 1991-05-29 |
CN1045390A (zh) | 1990-09-19 |
EP0379806B1 (en) | 1996-04-10 |
DE68926232D1 (de) | 1996-05-15 |
HU896762D0 (en) | 1990-03-28 |
HU206337B (en) | 1992-10-28 |
KR900009625A (ko) | 1990-07-05 |
US5147876A (en) | 1992-09-15 |
EP0379806A2 (en) | 1990-08-01 |
DE68926232T2 (de) | 1996-10-17 |
AU4732989A (en) | 1990-07-05 |
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