CN1045957C - 三环苯并吖庚因,它们的应用和制备 - Google Patents

三环苯并吖庚因,它们的应用和制备 Download PDF

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CN1045957C
CN1045957C CN94191882A CN94191882A CN1045957C CN 1045957 C CN1045957 C CN 1045957C CN 94191882 A CN94191882 A CN 94191882A CN 94191882 A CN94191882 A CN 94191882A CN 1045957 C CN1045957 C CN 1045957C
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R·霍韦格
E·B·尼尔森
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Abstract

通式(Ⅰ)的三环苯并吖庚因或其药学上可接受的盐,其中A与α-和β-标记的碳原子一起是一个环戊烯、环已烯、呋喃、二氢呋喃、吡喃、二氢吡喃、噻吩、__唑、吡咯、吡咯啉、四氢吡啶或间二氧杂环戊烯环,R1是H或烷基,R2和R3各自独立地是H、烷氧基、卤素、硝基、氰基或羟基,或者R2和R3一起可以形成一个呋喃、二氢呋喃、环戊烯或间二氧杂环戊烯环,R4是H、烷氧基、硝基、氰基、羟基或卤素,该化合物可用于治疗中枢神经系统的某些病症,例如精神病、疼痛、压抑、睡眠失调、运动障碍、帕金森病、中风等。

Description

三环苯并吖庚因,它们的应用和制备
本发明涉及新的三环苯并吖庚因及其药学上可接受的酸加成盐,它们的制备方法,含有它们的药物组合物,以及它们在治疗与多巴胺受体系统机能障碍有关的中框神经系统的某些疾病(例如精神病、疼痛、压抑、睡眠失调、运动障碍、帕金森病、中风)中的应用。
在过去10年中对于苯并吖庚因作了深入细致的药学研究。苯并吖庚因的药学性质在很大程度上取决于取代基。已知有各种具有抑制精神、抗攻击性、抗帕金森病和血管作用的取代的苯并吖庚因。
各种有关化合物是先有技术中已知的。
在美国专利4,255,445中介绍了在苯并吖庚因骨架的第4位上有一个羟基或甲氧基,第2、3位上有一个缩合的甲基取代的二氢呋喃环的三环苯并吖庚因。该化合物具有周边多巴胺能活性,尤其是肾血管舒张活性,但不能显示出中央多巴胺能活性。
现已发现,一组新的不同结构的三环苯并吖庚因化合物,尤其是在第4位上未被取代的本发明化合物,令人惊奇地显示出很强的抗多巴胺能作用,从而使它们可作为精神药物使用。
根据本发明,提供了通式Ⅰ的三环苯并吖庚因或其药学上可接受的盐
Figure C9419188200081
其中A与标有α和β的碳原子一起是一个环戊烯、环己烯、呋喃、二氢呋喃、吡喃、二氢吡喃、噻吩、噁唑、吡咯、吡咯咻、四氢吡啶或间二氧杂环戊烯环,
R1是氢或C1-5烷基,R2和R3独立地为氢、C1-6烷氧基、卤素、硝基、氰基或羟基,或者R2与R3一起可以构成一个呋喃、二氢呋喃、环戊烯或间二氧杂环戊烯环,
R4是氢、C1-6烷氧基、硝基、氰基、羟基或卤素。
通式Ⅰ的具体化合物有:6-(苯并呋喃-7-基)-8-甲基-7,8,9,10-四氢-6H-呋喃并[2,3-g][3]苯并吖庚因,
6-(2,3-二氢苯并呋喃-7-基)-8-甲基-2,3,7,8,9,10-六氢-6H-呋喃并[2,3-g][3]苯并吖庚因,
5-(苯并呋喃-7-基)-3-甲基-1,2,3,4,5,8,9,10-八氢化茚并[4,5-d]吖庚因,
6-(苯并呋喃-7-基)-8-甲基-7,8,9,10-四氢-6H-噻吩并[2,3-g][3]苯并吖庚因,
1-(2,3-二氢苯并呋喃-7-基)-6,7-亚甲二氧基-3-甲基-2,3,4,5-四氢-1H-3-苯并吖庚因,
3-甲基-5-苯基-1,2,3,4,5,8,9,10-八氢化茚并[4,5-d]吖庚因,
3-甲基-5-苯基-2,3,4,5,8,9,10,11-八氢-1H-萘并[1,2-d]吖庚因,
8-甲基-6-苯基-7,8,9,10-四氢-6H-噁唑并[4,5-g][3]苯并吖庚因。
通式Ⅰ化合物可以以对映体混合物的形式存在,它可以拆解成单个的纯对映体。这种拆解可以方便地从通式Ⅰ化合物与旋光性酸的盐的各种溶剂中利用分级结晶或者文献中已知的其它方法(例如手性柱状色谱法)来进行。因此,本发明包括所有的异构体,不管是拆解的还是它们的混合物。
本发明的特别有价值的实施方案是通式Ⅰ的苯并吖庚因的药学上可接受的无毒的酸加成盐。这些盐包括由无机和有机酸(例如盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙酸、乳酸、马来酸、邻苯二甲酸和酒石酸)衍生得到的那些。
这些盐可以用本领域技术人员所熟悉的方法制备。
本发明还提供了含有本发明化合物的药物组合物。剂量配方中最好含0.1mg到约1000mg的活性化合物用于口服。用于抗精神病作用的典型剂量在每天0.5-10mg/kg之间变化,分2或3剂口服用药。
本发明还涉及制备上述化合物的方法。这些方法包括:
a)使通式Ⅳ的2-芳基乙胺与通式Ⅲ的环氧化物在50-110℃的温度下加热反应,形成通式Ⅱ化合物,
Figure C9419188200101
其中R1是氢或低级烷基,A的定义同上,其中R2、R3和R4的定义如上,
Figure C9419188200103
其中A、R1、R2、R3和R4的定义同上;然后使通式Ⅱ的氨基醇与诸如三氟乙酸、硫酸、甲磺酸、多磷酸或它们的混合物或者其它的酸或脱水介质等试剂反应,发生分子内成环作用,从而将通式Ⅱ化合物转化成所要的通式Ⅰ苯并吖庚因:
Figure C9419188200111
b)使通式Ⅴ的2-芳基乙胺与通式Ⅲ的环氧化物在50-110℃的温度间加热反应,形成通式Ⅵ化合物,
Figure C9419188200112
其中R1是氢或低级烷基,R5和R6各自独立地是羟基、巯基、氨基、羧基,或者R5和R6各自独立地代表能用本领域技术人员熟悉的标准步骤转化成羟基、巯基、氨基或羧基的取代基,
Figure C9419188200113
其中R2、R3和R4的定义同上,其中R1、R2、R3、R4、R5和R6的定义同上,随后使通式Ⅵ的氨基醇与诸如三氟乙酸、硫酸、甲磺酸、多磷酸或其混合物或者其它的酸或脱水介质等试剂反应,发生分子内成环作用,转化成通式Ⅶ的苯并吖庚因:
Figure C9419188200122
上述的成环作用最好是在-10℃至+20℃之间的温度于硫酸(1-20%)和三氟乙酸的混合物中进行。
通式Ⅶ的苯并吖庚因在形成上面定义的基团A的环加成反应中转化成所要的通式Ⅰ的缩合苯并吖庚因。
这种环加成反应可以通过其中的R5和R6是羟基的通式Ⅶ苯并吖庚因与二卤甲烷及一种碱在溶剂(例如DMF)中反应来进行,结果形成其中的A是亚甲二氧基的通式Ⅰ的苯并吖庚因。
在合成通式Ⅰ化合物中使用的起始物是本领域技术人员熟悉的。
例如,利用本领域技术人员已知的分几步的标准方法,例如从相应的芳基醛出发,可以合成通式Ⅳ化合物其中的A的定义如上。
本发明的化合物因其药理活性而有用。特别是,本发明的化合物预测有抑制精神活动的活性。于是,用文献方法(Life Science,第37卷,P.1971,1985年,P.Andersen等)试验了通式Ⅰ化合物与小鼠纹状体的组织匀浆中的多巴胺D1受体的结合,结果列在表1。IC50是试验化合物对多巴胺D1受体的亲合性。
                     表1
            试验化合物   IC50(nM)
                         多巴胺D1受体
            实施例1      1 2
本发明的化合物与常规的辅助剂、载体或稀释剂一起,需要时采用它的药学上可接受的酸加成盐的形式,可以做成药物组合物及其单位剂量的形式,在这些形式中可以作为固体(例如片剂或填充的胶囊)或液体(例如溶液、悬浮液、乳状液、酏剂或填充它们的胶囊)用于口服,以栓剂的形式直肠给药;或者以灭菌的可注射溶液的形式用于非肠道(包括皮下)给药。这些药物组合物及其单位剂量形式可以含有常规比例的常用组分,加或不加另外的活性化合物或成分,而且这种单位剂量形式可以含有任何对中枢神经系统疾病有减缓效果的合适数量的活性组分,其数量与预期使用的日剂量范围相当。每片含0.1-1000mg,或者更具体地,每片含0.5-10mg活性组分的片剂是有代表性的合适的单位剂量形式。
因此,本发明的化合物可以按照植物制剂配药学按常规方法用于配制药物制剂,例如供哺乳动物(包括人)口服或非肠道用药。
常用的赋形剂是适合非肠道用药或口服而又与活性化合物无不利反应的药学上可接受的有机或无机载体物质。
这类载体的实例是水、盐溶液、醇、聚乙二醇、多羟基乙氧基化蓖麻油、糖浆、花生油、橄榄油、明胶、乳糖、石膏粉、蔗糖、琼脂、果胶、阿拉伯树胶、直链淀粉、硬脂酸镁、滑石粉、硅胶、硬脂酸、脂肪酸单甘油酯和双甘油酯、季戊四醇脂肪酸酯、羟甲基纤维素和聚乙烯吡咯烷酮。
这些药物制剂可以作灭菌处理,如果需要,与对于活性化合物无不利影响的辅助剂(例如润滑剂、防腐剂、稳定剂、润湿剂、乳化剂、调节渗透压的盐、缓冲剂和/或着色剂等)混合。
对于非肠道用药,特别合适的是可注射的溶液或悬浮液,最好是含有溶在多羟基乙氧基化蓖麻油中的活性化合物的水溶液。
安瓿制剂是方便的单位剂量形式。
对于口服制剂,特别合适的是有滑石和/或碳水化合物载体或粘合剂或类似物质的片剂、糖锭剂或胶囊,载体最好是乳糖和/或玉米淀粉和/或土豆淀粉。当可以使用增甜的赋形剂时,可以使用糖浆、酏剂或类似物质。一般来说,就大致的范围而言,本发明化合物以每单位剂量含0.05-100mg的形式配制在药学上可接受的载体之中。
一种可以用常规的压片技术制备的典型的片剂中含有:
活性化合物           1.0mg
乳糖                 67.8mg,欧洲药典
Avicel            31.4mg
AmberliteIRP 88   1.0mg
硬脂酸镁             0.25mg,欧洲药典
以下实施例说明了本发明新化合物的制备:
                      实施例16-(苯并呋喃-7-基)-8-甲基-7,8,9,10-四氢-6H-呋喃并[2,3-g][3]苯并吖庚因
A.7-羧甲基苯并呋喃用已知方法由7-氯甲基苯关呋喃借助腈并随后水解制备,得到白色晶体粉末,熔点:115-118℃。1H-NMR,在CDCl3中[δ,ppm]:3.98(s,2H);6.78(d,1H);7.20(m,2H);7.55(dd,1H);7.65(d,1H).
B.苯并呋喃-7-基-N-甲基乙酰胺
向9.9g(0.056mol)7-羧甲基苯并呋喃在50ml甲苯中的溶液里加入6.1ml(0.084mol)亚硫酰二氯。将混合物回流,直到停止放出气体(45分钟)。减压除掉溶剂,残余物用甲苯溶出。将粗制的酰基氯溶在80ml丙酮中,于激烈搅拌下慢慢加到冰冷的40%甲基胺水溶液中。所形成的黄色溶液减压浓缩直到开始结晶。该滤出产物,用水洗,干燥。产率:9.06g(85%),为灰白色粉状化合物。熔点:138-142℃。1H-NMR,在CDCl3中[δ,ppm]:2.75(d,3H);3.85(s,2H);5.6(宽s,1H);6.8(d,1H);7.25(m,2H);7.55(dd,1H);7.67(d,1H).
C.2-(苯并呋喃-7-基)乙基-N-甲胺
将8.70g苯并呋喃-7-基-N-甲基乙酰胺和5.21g(0.138mol)硼氢化钠溶在100ml二噁烷中。向冰冷的上述溶液中逐滴加入乙酸。然后将反应混合物缓慢温热,回流1小时。在冷却到室温之后,加入25ml 6N HCl,将该混合物温热回流5分钟。将混合物冷却,pH调节到10,用二氯甲烷萃取该混合物。用水和盐水洗有机层,在硫酸钠上干燥,减压浓缩。将剩余的油蒸馏(沸点:111-114℃/1mmHg)。得到3.7g(46%)无色油状化合物。1H-NMR,在CDCl3中[δ,ppm]:1.17(宽s,1H);2.45(s,3H);3.05(m,4H);6.77(d,1H);7.15(m,2H);7.45(dd,1H);7.63(d,1H).
D.2-[[2-(苯并呋喃-7-基)乙基]甲氨基]-1-(苯并呋喃-7-基)乙醇
将1.0g(0.0057mol)2-(苯并呋喃-7-基)乙基-N-甲胺和1.39g(0.0085mol)7-环氧乙基苯并呋喃溶在5ml乙腈中,回流24小时。将该溶剂减压蒸发,残余物再溶于甲苯中。用150ml1N HCl萃取此溶液。将该水溶液调节至碱性pH,用甲苯萃取。有机相用水和盐水洗,用硫酸钠干燥,减压浓缩。得到浅黄色浆状标题化合物。产量:1.87g(97%)。1H-NMR,在CDCl3中[δ,ppm]:2.50(s,3H);2.65-3.25(m,6H);3.95(宽s,1H);5.23(dd,1H);6.77(d,1H);6.78(d,1H);7.05-7.30(m,3H);7.47-7.55(m,3H);7.62(d,1H);7.63(d,1H).
E.6-(苯并呋喃-7-基)-8-甲基-7,8,9,10-四氢-6H-呋喃并[2,3-g][3]-苯并吖庚因
将1.70g(0.005mol)2-[[2-(苯并呋喃-7-基)乙基]甲氨基]-1-(苯并呋喃-7-基)乙醇溶在5ml三氯乙酸中,冷却到10℃。在激烈搅拌下向该溶液中加入0.3ml浓硫酸,将反应混合物在室温保持90分钟。将该溶液减压浓缩至20ml,倒在50ml4N氢氧化钠与冰的混合物上。随后用甲苯萃取,用水洗该甲苯溶液,浓缩后得到油状的粗制品,将其在硅胶上用柱状色谱法纯化,用二氯甲烷/甲醇/吡啶(96∶4∶1)作为洗脱液。得到无定形粉末状的纯产物。将它溶在乙醚中,加入HCl在乙醚中的溶液以沉淀出盐酸盐,得到480mg(27%)的白色晶体粉末。熔点:259-261℃。1H-NMR,在CDCl3中[δ,ppm]:2.85(d,3H);3.00(m,1H);3.65-4.10(m,5H);5.59(d,1H);6.35(d,1H);6.74(d,1H);6.85(d,1H);7.20-7.35(m,3H);7.53-7.70(m,3H);13.40(宽s,1H).
                    实施例26-(2,3-二氢苯并呋喃-7-基)-8-甲基-2,3,7,8,9,10-六氢-6 H-呋喃并[2,3-g][3]苯并吖庚因
将0.40g(0.0011mol)6-(苯并呋喃-7-基)-8-甲基-7,8,9,10-四氢-6H-呋喃并[2,3-g][3]苯并吖庚因溶在30ml乙醇中,加入0.12g钯催化剂(10%碳),在一个与气体量管连接的烧瓶中于略微过高的压力下进行氢化。16小时后,样品的NMR谱表明已完全转化成标题化合物。滤出该催化剂,溶液减压浓缩。残余物再溶于二氯甲烷中,溶液依次用1N NaOH、水和盐水洗。减压浓缩得到浅黄色浆体。将它再溶于乙腈中,逐滴加入浓盐酸沉淀出盐酸盐(浅黄色晶体,熔点:280-283℃)。1H-NMR,游离碱在CDCl3中[δ,ppm]:2.30(dd,1H);2.38(s,3H);2.80-3.30(m,9H);4.40-4.60(m,5H);6.22(d,1H);6.75-6.92(m,3H);7.10(d,1H).
                    实施例35-(苯并呋喃-7-基)-3-甲基-1,2,3,4,5,8,9,10-八氢化茚并[4,5-d]吖庚因
A.2-(2,3-二氢化茚-4-基)乙基-N-甲胺
此胺用类似于2-(苯并呋喃-7-基)乙基-N-甲胺(实施例1C)的方法合成1H-NMR,在CDCl3中[δ,ppm]:2.08(五重峰,2H);2.33(s,3H);2.55-2.85(m,4H);2.90(m,4H);6.90-7.20(m,3H).
B.2-[[2-(2,3-二氢化茚-4-基)乙基]甲氨基]-1-(苯并呋喃-7-基)乙醇按类似于实施例1D的方法合成1H-NMR,在CDCl3中[δ,ppm]:2.08(五重峰,2H);2.50(s,3H);2.60-3.00(m,10H);4.02(宽s,1H);5.25(dd,1H);6.77(d,1H);6.90-7.30(m,4H);7.47(d,1H);7.52(dd,1H);7.62(d,1H).
C.5-(苯并呋喃-7-基)-3-甲基-1,2,3,4,5,8,9,10-八氢化茚并[4,5-d]吖庚因按类似于实施例1E的方法由2-{[2-(2,3-二氢化茚-4-基)乙基]甲氨基}-1-(苯并呋喃-7-基)乙醇合成,作为盐酸盐分离:白色晶体粉末。熔点:146-148℃。1H-NMR,游离碱在CDCl3中[δ,ppm]:2.07(五重峰,2H);2.38(s,3H);2.8-3.25(m,10H);4.85(dd,1H);6.35(d,1H);6.77(d,1H);6.85(d,1H);7.06(d,1H);7.22(t,1H);7.52(d,1H);7.55(d,1H).
                    实施例46-(苯并呋喃-7-基)-8-甲基-7,8,9,10-四氢-6H-噻吩并[2,3-g][3]苯并吖庚因
A.2-(苯并[b]噻吩-7-基)乙基-N-甲胺按类似于实施例1C的方法合成1H-NMR,在CDCl3中[δ,ppm]:1.40(宽s,1H);2.40(s,3H);3.02(m,4H);7.15(d,1H);7.30(m,3H);7.67(d,1H).
B.2-[[2-(苯并[b]噻吩-7-基)乙基]甲氨基]-1-(苯并呋喃-7-基)乙醇按类似于实施例1D的方法合成1H-NMR,在CDCl3中[δ,ppm]:2.55(s,3H);2.65-3.2(m,6H);5.24(dd,1H);6.75(d,1H);7.1-7.75(m,9H).
C.6-(苯并呋喃-7-基)-8-甲基-7,8,9,10-四氢-6H-噻吩并[2,3-g][3]苯并吖庚因按类似于实施例1E的方法由2-[[2-(苯并[b]噻吩-7-基)乙基]甲氨基]-1-(苯并呋喃-7-基)乙醇合成,作为盐酸盐分离:白色晶体,熔点178-184℃。1H-NMR,在d6-DMSO中[δ,ppm]:2.87(d,3H);3.20-4.10(m,6H);5.40(d,1H);6.33(d,1H);7.06(d,1H);7.27(d,1H);7.39(t,1H);7.43(d,1H);7.55(d,1H);7.44(d,1H);7.80(d,1H),7.98(d,1H);11.4(宽s,1H).
                    实施例51-(2,3-二氢苯并呋喃-7-基)-6,7-亚甲二氧基-3-甲基-2,3,4,5-四氢-1H-3-苯并吖庚因
A.2,3-二甲氧苯乙基-N-甲胺按类似于先前所述的苯乙基胺的方法合成1H-NMR,在CDCl3中[δ,ppm]:1.15(宽s,1H);2.45(s,3H);2.83(s,4H);3.83(s,3H);3.87(s,3H);6.80(m,2H);7.0(dd,1H).
B.2-[[2-(2,3-二甲氧苯基)乙基]甲氨基]-1-(苯并呋喃-7-基)乙醇按类似于先前所述的2-氨基乙醇的方法合成1H-NMR,在CDCl3中[δ,ppm]:2.48(s,3H);2.65-2.90(m,6H);3.85(s,6H);5.24(dd,1H);6.72-6.85(m,3H);7.00(t,1H);7.25(m,1H);7.40-7.55(m,2H);7.60(d,1H).
C.1-(苯并呋喃-7-基)-6,7-二甲氧基-3-甲基-2,3,4,5-四氢-1H-3-苯并吖庚因,按类似于实施例1E的方法由2-[[2-(2,3-二甲氧苯基)乙基]甲氨基]-1-(苯并呋喃-7-基)乙醇合成,为无色油状物。(盐酸盐的熔点:135℃)。1H-NMR,在CDCl3中[δ,ppm]:2.35(m,1H);2.40(s,3H);2.95-3.30(m,4H);3.47(dd,1H);3.78(s,3H);3.82(s,3H);4.84(d,1H);6.26(d,1H);6.52(d,1H);6.75(d,1H);7.08(d,1H);7.24(t,1H);7.54(d,1H);7.56(d,1H).
D.1-(苯并呋喃-7-基)-6,7-二羟基-3-甲基-2,3,4,5-四氢-1H-3-苯并吖庚因
将1.10g(0.0033mol)1-(苯并呋喃-7-基)-6,7-二甲氧基-3-甲基-2,3,4,5-四氢-1H-3-苯并吖庚因溶解在25ml干燥的二氯甲烷中。将该溶液冷却到-60℃,缓慢加入0.93g(0.0098mol)三溴化硼。反应混合物在-60℃搅拌15分钟,温热至0℃,搅拌1小时。减压蒸发得到褐色残余物,将其再溶于二氯甲烷中。将溶液在冰浴中搅拌,逐滴加入5ml甲醇。将该溶液再次减压浓缩,残余物溶在6N HCl中,回流30分钟。然后用2N NaOH溶液将pH调节到8,用乙酸乙酯萃取该产物。有机层用水和盐水洗,减压浓缩。得到灰白色粉末状的1-(苯并呋喃-7-基)-6,7-二羟基-3-甲基-2,3,4,5-四氢-1H-3-苯并吖庚因。1H-NMR,在CDCl3中[δ,ppm]:2.05(m,1H);2.08(s,3H);2.55-2.90(m,4H);3.10(dd,1H);4.45(t,1H);5.57(d,1H);6.14(d,1H);6.48(d,1H);6.74(d,1H);6.90(t,1H);7.22(d,1H);7.30(d,1H).
E.1-(2,3-二氢苯并呋喃-7-基)-6,7-二羟基-3-甲基-2,3,4,5-四氢-1H-3-苯并吖庚因
将0.5g(0.0016mol)1-(苯并呋喃-7-基)-6,7-二羟基-3-甲基-2,3,4,5-四氢-1H-3-苯并吖庚因溶在25ml乙醇和2ml乙酸的混合物中。加入0.2g催化剂(10%Pd/C),使该混合物在50磅/平方英寸的压力下于Parr装置中加氢。24小时后滤出催化剂,将该溶液减压浓缩。残余物再溶于二氯甲烷中,该溶液依次用NaHCO3溶液、水和盐水洗。减压蒸发,得到灰白色泡沫状的1-(2,3-二氢苯并呋喃-7-基)-6,7-二羟基-3-甲基-2,3,4,5-四氢-1H-3-苯并吖庚因。1H-NMR,在CDCl3中[δ,ppm]:2.38(s和m,4H);2.80-3.42(m,7H);4.45(t和m,3H);6.00(d,1H);6.40(d,1H);6.80(m,2H);7.09 (m,1H).
F.1-(2,3-二氢苯并呋喃-7-基)-6,7-亚甲二氧基-3-甲基-2,3,4,5-四氢-1H-3-苯并吖庚因
将0.27g(0.00087mol)1-(2,3-二氢苯并呋喃-7-基)-6,7-二羟基-3-甲基-2,3,4,5-四氢-1H-3-苯并吖庚因溶在1ml二甲基甲酰胺中。加入0.66g氟化铯,将混合物在室温搅拌1小时。然后加入0.1ml二氯甲烷,混合物在一支有螺旋盖的小瓶中热至110℃1小时。冷却后,用乙醚萃取该混合物。醚溶液用水洗,在无水硫酸钠上干燥,减压浓缩。粗产品用制备型薄层色谱纯化。用气态HCl处理它的乙醚溶液,得到盐酸盐形式的1-(2,3-二氢苯并呋喃-7-基)-6,7-亚甲二氧基-3-甲基-2,3,4,5-四氢-1H-3-苯并吖庚因(白色晶体粉末)。1H-NMR,在CDCl3中[δ,ppm]:2.84(d,3H);2.93(dd,1H);3.10-3.90(m,7H);4.53(t,2H);4.98(d,1H);5.95(s,2H);6.08(d,1H);6.53(d,1H);6.87(t,1H);7.00(d,1H);7.20(d,1H).
                    实施例63-甲基-5-苯基-1,2,3,4,5,8,9,10-八氢化茚并[4,5-d]吖庚因
A.2-[[2-(2,3-二氢化茚-4-基)乙基]甲氨基]-1-苯乙醇,按与实施例1D类似的方法由2-(2,3-二氢化茚-4-基)乙基-N-甲胺和苯基环氧乙烷合成1H-NMR,在CDCl3中[δ,ppm]:2.00-2.15(m,2H);2.92(t,4H);3.02(s,3H);3.11-3.36(m,6H);5.37(d,1H);6.97-7.17(m,3H);7.28-7.39(m,5H).
B.3-甲基-5-苯基-1,2,3,4,5,8,9,10-八氢化茚并[4,5-d]吖庚因,按与实施例1E类似的方法合成,作为盐酸盐分离,白色晶体,熔点:238-240℃。1H-NMR,在CDCl3中[δ,ppm]:2.02-2.16(m,2H);2.76-3.00(m,8H);3.11-3.33(m,2H);5.08(d,1H);6.35(d,1H);6.92(d,1H);7.19-7.45(m,5H);13.27(宽s,1H).
                    实施例73-甲基-5-苯基-2,3,4,5,8,9,10,11-八氢-1H-萘并[1,2-d]吖庚因
A.2-(1,2,3,4-四氢萘-5-基)乙基-N-甲胺
此胺用已知方法(例如实施例1中所述方法)合成,以盐酸盐的形式分离。1H-NMR,在d6-DMSO中[δ,ppm]:1.67-1.75(m,4H);2.48-2.78(m,7H);2.86-3.05(m,4H);6.93-7.09(m,3H);9.19(宽s,2H).
B.2-[[2-(1,2,3,4-四氢萘-5-基)乙基]甲氨基]-1-苯基乙醇,按照与实施例1D相类似的方法由7A和苯基环氧乙烷合成。1H-NMR,在CDCl3中[δ,ppm]:1.73-1.86(m,4H);2.45(s,3H);2.51-2.81(m,11H);3.98(宽s,1H);4.68(t,1H);6.90-7.06(m,3H);7.23-7.36(m,5H).
C.3-甲基-5-苯基-2,3,4,5,8,9,10,11-八氢-1H-萘[1,2-d]吖庚因,按照与实施例1E类似的方法由7B合成。此化合物以盐酸盐的形式分离,白色晶体,熔点:247-250℃。1H-NMR,在d6-DMSO中[δ,ppm]:1.67-1.76(m,4H);2.65-2.78(m,7H);3.29-3.78(m,6H);4.87(d,1H);6.13(d,1H);6.78(d,1H);7.18-7.48(m,5H);11.63(宽s,1H).
                    实施例88-甲基-6-苯基-7,8,9,10-四氢-6H-噁唑并[4,5-g][3]吖庚因
A.2-(3-甲氧基-2-硝基苯基)乙胺,按照标准方法由3-甲氧基-2-硝基苯甲醛合成。此化合物以盐酸盐的形式分离。无色晶体,熔点:200-203℃。1H-NMR,游离碱在CDCl3中[δ,ppm]:1.55(宽s,2H);2.70(t,2H);2.98(t,2H);3.90(s,3H);6.88(d,2H);7.36(t,1H).
B.2-[2-(3-甲氧基-2-硝基苯基)乙氨基]-1-苯基乙醇,按照与实施例1D相类似的方法由2-(3-甲氧基-2-硝基苯基)乙胺和苯基环氧乙烷制备。白色晶体粉末,熔点99-101℃。1H-NHR,在CDCl3中[δ,ppm]:1.50(宽s,1H);2.65-2.80(m,3H);2.85-2.98(m,3H);3.50(宽s,1H);3.89(s,3H);4.67(dd,1H);6.87(d,1H);6.90(d,1H);7.23-7.40(m,6H).
C.7-甲氧基-6-硝基-1-苯基-2,3,4,5-四氢-1H-3-苯并吖庚因
将2.25g(0.0071mol)2-[2-(3-甲氧基-2-硝基苯基)乙氨基]-1-苯基乙醇悬浮在20ml正庚烷中。在激烈搅拌下将17.5g多磷酸加到上述混合物中,加热回流2小时。加入100ml水,用4N NaOH中和冷却的混合物。将庚烷分离,水相用二氯甲烷萃取。合并的有机相用水和饱和盐水洗。蒸发后得到粗产品,将其在硅胶上用柱状色谱纯化,用正庚烷/四氢呋喃(1∶2)作为洗脱液。得到浅黄色浆状的纯化合物。1H-NMR,在CDCl3中[δ,ppm]:1.95(宽s,1H);2.70-2.78(m,2H);2.93-3.03(m,2H);3.33(dd,1H);3.50(dd,1H);3.84(s,3H);4.29(dd,1H);6.73(d,1H);6.89(d,1H);7.13(d,2H);7.22-7.42(m,3H).
D.7-甲氧基-3-甲基-6-硝基-1-苯基-2,3,4,5-四氢-1H-3-苯并吖庚因
将0.40g(0.00134mol)7-甲氧基-6-硝基-1-苯基-2,3,4,5-四氢-1H-3-苯并吖庚因溶在5ml甲酸和4ml 35%甲醛水溶液的混合物中。将此混合物加热回流2.5小时,然后减压蒸发。残余物分配在二氯甲烷和饱和的NaHCO3溶液之中,有机层用水洗二次,用盐水洗一次,用Na2SO4干燥,减压浓缩,得到浅黄色油状化合物。1H-NMR,在CDCl3中[δ,ppm]:2.39(s,3H);2.30-2.45(m,1H);2.67-3.15(m,5H);3.82(s,3H);4.34(d,1H);6.68(s,2H);7.13-7.43(m,5H).
E.7-羟基-3-甲基-6-硝基-1-苯基-2,3,4,5-四氢-1H-3-苯并吖庚因
将0.40g(0.00128mol)7-甲氧基-3甲基-6-硝基-1-苯基-2,3,4,5-四氢-1H-3-苯并吖庚因溶在6ml干燥的二氯甲烷中。将该溶液冷却到-20℃,逐滴加入1.5ml三溴化硼。将反应混合物在-20℃搅拌15分中,室温搅拌2.5小时。然后将该混合物减压浓缩,残余物中小心地加入甲醇进行水解。加入10ml水,将该溶液加热回流0.5小时。冷却后的溶液中加入NaHCO3溶液将pH调节到8.5,用二氯甲烷萃取。将溶剂蒸发,得到黄色粉末状化合物。1H-NMR,在CDCl3中[δ,ppm]:2.43(s,3H);2.52(dd,1H);2.75-3.25(m,5H);4.39(dd,1H);6.56(s,2H);7.05-7.40(m,6H).
F.6-氨基-7-羟基-3-甲基-1-苯基-2,3,4,5-四氢-1H-3-苯并吖庚因
将0.16g(0.00053mol)7-羟基-3-甲基-6-硝基-1-苯基-2,3,4,5-四氢-1H-3-苯并吖庚因溶在15ml乙醇中。加入0.05g 10%Pd/C催化剂,在量管装置中进行氢化2小时。滤出催化剂,溶液减压浓缩。得到浅褐色粉末的化合物。1H-NMR,在CDCl3中[δ,ppm]:2.95(s,3H);3.05-3.40(m,6H);3.20(宽s,2H);4.58(d,1H);6.52(d,1H);7.15-7.45(m,7H).
G.8-甲基-6-苯基-7,8,9,10-四氢-6H-噁唑并[4,5-g][3]苯并吖庚因
将0.12g(0.00043mol)6-氨基-7-羟基-3-甲基-1-苯基-2,3,4,5-四氢-1H-3-苯并吖庚因和0.80g 1,3,5-三嗪溶在12ml甲苯中,加热回流16小时。薄层色谱指示反应完全和形成单个产物。将该反应混合物减压浓缩,用甲苯提取几次。得到浅褐色泡沫状的化合物。1H-NMR,在CDCl3中[δ,ppm]:2.43(s,3H);2.53(m,1H);2.42(m,1H);3.00-3.15(m,2H);3.37(ddd,1H);3.55(ddd,1H);6.75(d,1H);7.15-7.40(m,6H);8.06(s,1H).

Claims (7)

1.通式Ⅰ的三环的2,3,4,5-四氢-1H-3-苯并吖庚因或其药学上可接受的盐
Figure C9419188200021
其中A与标记α-和β-的碳原子一起是一个环戊烯、环己烯、呋喃、二氢呋喃、吡喃、二氢吡喃、噻吩、噁唑、吡咯、吡咯啉、四氢吡啶或间二氧杂环戊烯环,
R1是氢或R1-6烷基,R2和R3各自独立地是氢、C1-6烷氧基、卤素、硝基、氰基或羟基,或者R2和R3一起可以构成呋喃、二氢呋喃、环戊烯或间二氧杂环戊烯环,
R4是氢、C1-6烷氧基、硝基、氰基、羟基或卤素。
2.根据权利要求1的化合物,其中R1是甲基。
3.根据权利要求1的化合物,它是
6-(苯并呋喃-7-基)-8-甲基-7,8,9,10-四氢-6H-呋喃并[2,3-g][3]苯并吖庚因,
6-(2,3-二氢苯并呋喃-7-基)-8-甲基-2,3,7,8,9,10-六氢-6H-呋喃并[2,3-g][3]苯并吖庚因,
5-(苯并呋喃-7-基)-3-甲基-1,2,3,4,5,8,9,10-八氢化茚并[4,5-d]吖庚因,
6-(苯并呋喃-7-基)-8-甲基-7,8,9,10-四氢-6H-噻吩并[2,3-g][3]苯并吖庚因,
1-(2,3-二氢苯并呋喃-7-基)-6,7-亚甲二氧基-3-甲基-2,3,4,5-四氢-1H-3-苯并吖庚因,
3-甲基-5-苯基-1,2,3,4,5,8,9,10-八氢化茚并[4,5-d]吖庚因,
3-甲基-5-苯基-2,3,4,5,8,9,10,11-八氢-1H-萘[1,2-d]吖庚因,
8-甲基-6-苯基-7,8,9,10-四氢-6H-噁唑并[4,5-g][3]苯并吖庚因。
4.一种药物组合物,其中含有权利要求1或2或3的一种化合物或其药学上可接受的酸加成盐以及一种药学上可接受的载体或稀释剂。
5.根据权利要求4的一种药物组合物,其形式为含0.1-100mg活性化合物的口服剂量形式。
6.权利要求1或2或3的化合物在制造用于治疗与中枢神经系统失调有关的疾病药物组合物中的应用。
7.一种制备权利要求1的化合物的方法,其特征在于,
a)使通式Ⅳ的2-芳基乙胺与通式Ⅲ的环氧化物在50-110℃的温度加热反应,形成通式Ⅱ化合物
Figure C9419188200041
其中R1是氢或低级烷基,A的定义如上,
Figure C9419188200042
其中R2、R3和R4的定义同上,其中A、R1、R2、R3和R4的定义同上;随后再将通式Ⅱ的氨基醇与一种酸性试剂或脱水剂反应,进行分子内环化,将通式Ⅱ化合物转化成所要的通式Ⅰ的吖庚因,或
Figure C9419188200051
b)使通式Ⅴ化合物与通式Ⅲ的环氧化物在50-110℃的温度加热反应,形成通式Ⅵ化合物,
Figure C9419188200052
其中R1是氢或低级烷基,R5和R6各自独立地为羟基、巯基、氨基、羧基,或者R5和R6各自独立地代表能用本领域技术人员熟知的标准方法转化成羟基、巯基、氨基或羧基的取代基,其中R2、R3和R4的定义同上,
Figure C9419188200061
其中R1、R2、R3、R4、R5和R6的定义如上;
再将通式Ⅵ的氨基醇与一种酸性试剂或脱水剂反应,进行分子内成环作用,转化成通式Ⅶ的苯并吖庚因:
Figure C9419188200062
随后通过与二卤甲烷和碱在溶剂中反应,将通式Ⅶ的苯并吖庚因转化成通式Ⅰ的化合物。
CN94191882A 1993-03-10 1994-02-18 三环苯并吖庚因,它们的应用和制备 Expired - Fee Related CN1045957C (zh)

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