CN1269790A - 经取代的1,2,3,4,5,6-六氢-2,6-亚甲基-3-苯并吖辛因-10-醇,其制法及作为药物组合的用途 - Google Patents
经取代的1,2,3,4,5,6-六氢-2,6-亚甲基-3-苯并吖辛因-10-醇,其制法及作为药物组合的用途 Download PDFInfo
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- CN1269790A CN1269790A CN98809015A CN98809015A CN1269790A CN 1269790 A CN1269790 A CN 1269790A CN 98809015 A CN98809015 A CN 98809015A CN 98809015 A CN98809015 A CN 98809015A CN 1269790 A CN1269790 A CN 1269790A
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- Prior art keywords
- methyl
- hydrogen
- reaction
- acid
- benzomorphane
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- 239000000203 mixture Substances 0.000 claims description 46
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
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Abstract
本申请是关于新颖通式1的经取代的1,2,3,4,5,6-六氢-2,6-亚甲基-3-苯并吖辛因-10-醇,其制法及其作为药物组合物的用途。
Description
X指单键,-O-,C1-C4-亚烷基,有1至8个碳原子的亚烷基桥,它可以是支链或直链,且在桥的任何位置可有一或二个氧原子,优选是O-C1-C3-亚烷基或-O-CH2-CH2-O-,-O-CH2-CH2-NH;
R1是氢,甲基,乙基,苯基;
R2是氢,甲基;
R3是氢,氟,氯,溴,羟基,甲基,甲氧基;
R4是氢,甲基,乙基;
R5是氢,甲基,乙基;
R6是氢,甲基,乙基;
R8是氢,C1-C4-烷基;
Z是氧,NH,硫;
R9是氢,甲基,氟,氯,溴,甲氧基;
R10是氢,甲基,氟,氯,溴,甲氧基;视需要它呈个别旋光异构体的形式,个别对映体或外消旋物混合物形式,以及是自由态碱或与药理上可接受的酸所形成的酸加成盐的形式,如与卤素氢酸--例如盐酸或氢溴酸--或相应的有机酸--例如富马酸或二乙醇酸,所形成的酸加成盐。
优选的通式I化合物是:其中上述定义R4及R5或者同时都是甲基或者各自分别为氢或甲基,其中至少取代基中的一个是甲基;优选的通式I化合物是,其中
X是氧;
R1是氢,甲基或乙基;
R2是氢,
R3是氢,
R4是氢或甲基;
R5是氢或甲基;
R6是甲基;
R7是视需要以R9及R10取代的苯基,而R9及R10可相同或不同;
R8指氢;
R9及R10分别是氢,甲基,氟或甲氧基。特佳的通式I化合物是,其中上述定义的R4及R5或者同时都是甲基或者各自分别是氢或甲基,至少取代其中的一个是甲基;最佳的是下述化合物;(-)-(1R,2″S)-2-(2″-苄基氧基)丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷和(-)-(1R,2″S)-2-[2″-(2,6-二氟苄基)氧基]丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷它是自由态碱的形式,或是与药理上可接受的酸所形成的相应的酸加成盐。
除非另有说明,一般定义为下述含义:C1-C4-烷基或C1-C8-烷基一般分别指支链的或直链的、有1至4个或1至8个碳原子的烃基,必要时可以一或多个卤素--优选是氟--取代,它彼此可相同或不同。作为实例可例举下述烃基基团:甲基,乙基,丙基,1-甲基乙基(异丙基),正-丁基,1-甲基丙基,2-甲基丙基,1,1-二甲基乙基,戊基,1-甲基丁基,2-甲基丁基,3-甲基丁基,1,1-二甲基丙基,1,2-二甲基丙基,2,2-二甲基丙基,1-乙基丙基,己基,1-甲基戊基,2-甲基戊基,3-甲基戊基,4-甲基戊基,1,1-二甲基丁基,1,2-二甲基丁基,1,3-二甲基丁基,2,2-二甲基丁基,2,3-二甲基丁基,3,3-二甲基丁基,1-乙基丁基,2-乙基丁基,1,1,2-三甲基丙基,1,2,2-三甲基丙基,1-乙基-1-甲基丙基和1-乙基-2-甲基丙基。除非另有说明,优选的是有1至4个碳原子的低级烷基,如甲基,乙基,丙基,异丙基,正-丁基,1-甲基丙基,2-甲基丙基或1,1-二甲基乙基。相应地,亚烷基是支链或直链的、有1至8个碳原子的二价烃桥,可视需要它以一或多个卤素--优选是氟--取代,彼此可相同或不同。烷氧基一般是以氧原子键合的直链或支链的烃基基团--优选是有1至4个碳原子的低级烷氧基。尤其是甲氧基。制备方法
本发明化合物可用现有技术已知的方法[WO97/06146]制备。本发明主题是关于对映体纯的化合物以及其外消旋物。
关键化合物是降苯并吗吩烷2a至5a,在结构图中作为相应的(-)-对照体表示。结构图1:R=H的(-)-2a的合成公开于德国申请案195 28 472中。
化合物3可以类似于化合物2方法制备。起始化合物是合成2时作为中间体的哌啶酮6,例如,它和乙基三苯基鏻盐反应,而不是和对应的甲基衍生物反应--这由现有技术中已知的(参考流程2)。流程2:化合物4是类似于WO97/06146所述方法,用2-甲氧基苄基氰(11)和2-溴丙酸(12)制备。例如,在第一步骤中,以2-甲氧基苄基氰(11)和2-溴丙酸乙酯(12)反应制得对应的取代的3-氨基-2-甲基丁酸酯衍生物(13)(由于由所需最终产物观点看,其部分酯构造不一定是醇成分,因而也可使用任何其他的C1-C8-烷基酯或苄基酯):
为要进行这种Reformatsky反应的转化,将烷基卤代硅烷,优选是三烷基氯硅烷,尤其是三甲基氯硅烷,和锌粉置于所择反应条件呈惰性的溶剂,优选是醚或卤代烃,尤其是二氯甲烷内。在将这混合物以极性-惰性-溶剂,优选是环醚,最佳是四氢呋喃稀释后,将反应混合物加热,优选是在回流温度加热,再和通式3的2-溴丙酸乙酯及邻-甲氧基苄基氰混合并再加热,优选是在回流温度加热。然后冷却并过滤出锌粉后,再将反应混合物和能使亚氨基官能基还原的所择还原剂,优选是复合碱金属硼氢化物,最佳是氰基硼氢化钠混合,然后与醇,优选是直链或支链的C1-C4-醇,最佳是乙醇混合。然后加碱性反应的混合物的水溶液,优选是氨溶液,最佳是浓氨溶液,然后分离反应混合物的有机相。经干燥并真空蒸发后,将残余物溶于惰性溶剂,优选是脂肪族或芳香烃类,最佳是甲苯内,用酸的水溶液,优选是无机酸,最佳是2N盐酸进行萃取。最后用碱性反应的化合物的水溶液,优选是氨溶液,最佳是浓氨溶液使水相变碱性,再以有机的与水不混溶的萃取剂,优选是卤代烃,最佳是二氯甲烷萃取。将这样制得的萃取物干燥,然后浓缩,并分离出通式4的3-氨基-2-甲基丁酸酯衍生物。
在第二反应步骤中,以所制得的3-氨基-2-甲基丁酸乙基酯衍生物13和丙烯酸乙酯反应(从所需最终产物观点而言,酯构造中的醇部分并非必要,因而可使用任何其他C1-C8-烷基酯或甚至苄基酯)以制得对应的3-(2-乙氧基羰基乙基)-氨基-2-甲基丁酸乙酯衍生物14:
为要进行此迈克尔加成反应,将3-氨基-2-甲基丁酸乙酯衍生物13和丙烯酸乙酯溶于反应条件下呈惰性的介质中,优选是直链或支链的C1-C4-醇,最佳是乙醇内,并加热,优选是在回流温度加热。待反应后,真空除去溶剂,并分离所得的3-(2-乙氧基羰基乙基)氨基-2-甲基丁酸乙酯衍生物14。
为要进行这迪克曼的酯缩合的环化步骤,将3-(2-乙氧基羰基乙基)氨基-2-甲基丁酸酯衍生物14溶于环化条件呈惰性的溶剂,优选是脂肪族或芳香族烃类,最佳是甲苯内,并在有碱性反应化合物,优选是直链或支链的C1-C4-醇的碱金属醇化物,最佳是叔-丁醇钾的存在下加热至回流温度,并在该温度下蒸馏除去挥发的反应混合物的成分,例如在共沸范围内除去。在该反应结束后,将反应混合物水解,并与酸性反应的化合物的水溶液混合,优选是与无机酸水溶液,最佳是浓盐酸水溶液混合。然后加入一种在反应条件下呈惰性的、和水不混溶的萃取剂,优选是二烷基醚,最佳是二乙醚,并与碱性反应化合物的水溶液混合,优选是与氨的水溶液,最佳是浓氨溶液混合。待分离有机相及水相的萃取液后,合并有机萃取物,用水洗,干燥,真空蒸发,分离所得哌啶酮酯。
或者是,上述迪克曼缩合反应也可用四氯化钛在卤代烃类,优选是二氯甲烷内进行反应[M.N.Deshmukh等人,Synth.Comun.25(1995)177]。
将该哌啶酮酯在极性含水溶剂或溶剂混合物,优选的由直链或支链的C1-C4-醇与水的混合物,最佳是乙醇/水混合物中,与碱性或酸性反应化合物,优选是碱金属氢氧化物或无机酸,最佳是氢氧化钠,或者,如果使用无机酸,例如在盐酸或硫酸的存在下加热,优选是在回流温度加热。待皂化完成后,真空除去反应介质,将残余物溶于适于形成盐的溶剂中,优选是在极性有机溶剂,最佳是丙酮内中,沉淀出相应的酸加成酸。
于下一个步骤中,以溴化甲基三苯基鏻进行维悌希反应,生成相应的4-亚甲基-哌啶衍生物16,此衍生物可以酸加成盐的形式,优选是氢化卤盐的形式,最佳是盐酸盐的形式,分离出。为要进行维悌希反应,将酸加成盐形式,例如盐酸盐形式,的3-甲基哌啶酮衍生物15溶于水中,与碱性反应的化合物,优选是其水溶液混合,最佳是加入浓氨水溶液。
水相用有机的不与水混溶的溶剂,优选是卤代烷,最佳是二氯甲烷萃取。干燥并真空蒸发后,将残余物溶于在维悌希反应中呈惰性反应介质中,优选是环形醚,最佳是四氢呋喃内,与产生亚甲基的维悌希试剂,优选是甲基三苯基鏻卤素化物,最佳是溴化甲基三苯基鏻,在有碱性反应化合物,优选是碱金属烷醇化物,最佳是叔-丁醇钾的存在下,视所加入的加成物而定,于0-80℃,优选是20-60℃,最佳是约40℃进行反应。在该反应完成后,将反应混合物与水混合并用与水不混溶的有机溶剂,优选是卤代烷,最佳是二氯甲烷混合,并分离有机相。待水相萃取并将合并的萃取物干燥后,除去萃取剂,将残余物溶于适于生成酸加成盐的溶剂内,优选是溶于支链或直链的C1-C4-醇,最佳是异丙醇内,与适宜的酸优选是无机酸,如氢卤酸,最佳是浓盐酸混合,分离出结晶的维悌希产物16的酸加成盐。
由上一步骤,例如,以卤化氢分离出的哌啶衍生物16时,先转化成相应的自由态的碱,例如将该哌啶衍生物溶于水内,再与碱性反应的化合物混合,优选是与碱性反应化合物的水溶液,最佳是与浓氨溶液混合,用有机溶剂,优选是用卤代烷,最佳是二氯甲烷,萃取自由态的哌啶。将萃取物干燥并蒸馏掉萃取剂后,将该自由态碱溶于有机溶剂,如,例如烃类内,优选是溶于烷基芳香族化合物,最佳是甲苯内,与甲酰化剂反应,优选是与烷基甲酸酯,尤其是与正-丁基甲酸酯反应,分离反应产物17。
于下一环化反应中,在有相应的活性路易斯酸,如,例如,无机盐酸,特别是氢溴酸,的存在下,优选是用磺酸或用卤化铝(III),如三氯化铝,在最后第八反应步骤中合成18的苯并吗吩烷骨架。
以下的反应步骤导致甲酰基的裂解,制成对应的4′-甲氧基-5,9-二甲基-6,7-苯并吗吩烷(19)。
这里,将甲酰基苯并吗吩烷18溶于极性溶剂,优选是烷醇,最佳是正-丙醇内,与酸性反应的化合物,优选是无机酸水溶液,最佳是浓盐酸混合,然后加热。待裂解甲酰基后,将反应混合物蒸发,与水混合,并用与水不混溶的溶剂萃取,优选是用羧酸酯,最佳是醋酸乙酯萃取。将纯化的水相用浓氨溶液碱化,再用有机溶剂萃取,优选是用卤代烃类,最佳是用二氯甲烷萃取。待合并的有机萃取物干燥并浓缩后,可分离相应的(-)-4′-甲氧基-5,9-二甲基-6,7-苯并吗吩烷(19)。
在这步骤中,如果尚未完成立体异构物的分离。则该分离可用已描述的方法或现有技术已知的分离旋光异构体方法分离。
于下述步骤中,可将这样制得的(-)-4′-甲氧基-5,9-二甲基-6,7-苯并吗吩烷(19)在酸性条件下,优选是用无机酸,例如用盐酸,最佳是用氢溴酸进行醚裂解,生成相应的自由态的酚部分结构。
醚的裂解是在酸性条件下进行;现已证明优选是用无机酸。并已证明最佳是用氢溴酸。该皂化所生成的皂化产物例如是其氢溴酸盐的形式。
N-取代基的引入是通过关键化合物2a至5a与酰化剂反应,以生成中间体25,然后再将其还原,或者以烷基化剂直接将关键化合物2a至5a烷基化,或通过与醛反应制得26然后再还原。流程5是以关键化合物(-)-2a举例表示该方法。流程5:
现已证实由于糖尿病性低血糖、缺氧(Hypoxie)、组织缺氧(anoxia)以及心肌缺血所导致的细胞损伤及由于突触活性的增加所致的部分功能缺损。一系列实验表明这类糖尿病性低血糖及缺氧的情况会使受影响的细胞发生大量的去极化。而这种去极化转而引起细胞内的钙发生病理性升高,并进一步引起神经组织内释出过多的兴奋氨基酸。在此一联串变化中压力依赖性的钠通道有关键性的作用。由于该阻断可防止细胞的去极化,从而经由压力相关的钙通道减少钙流,并通过NDMA受体通道使神经组织内的钙流降低。此外,钠离子流进入细胞的减少,防止钙/钠交换不进行相反方向移动,而将钙带入细胞内。于神经组织中,还阻碍减少的钠离子流进入细胞,这样,谷氨酸盐输送体以相反方向操作并释放谷氨酸盐[C.P.Taylor and B.S.Meldrum,TIPS16(1995)309;J.Urenjak and T.P.Obrenovitch Am.Soc.Phar,Exp.Ther.48(1996)21]。
令人惊奇的是,现已发现本发明通式I化合物,和现有技术的化合物[EP-B-0 521422]不同,它没有NMDA受体亲合性(Ki[3H]MK801:>10000nM)。相反地,现已发现本发明化合物为压力相关的钠通道的阻断剂。这种化合物以高亲合性竞争性地或非竞争性地排除蟾蜍毒素(BTX)在钠通道上的结合位点。这类物质在钠通道被阻断时呈现“使用-依赖性”(use-depen-dency),即这类物质结合于钠通道时,钠通道必须首先活化。只有重复刺激钠通道才能使钠通道达到最大阻断。因此,这类物质较易结合于多次活化的钠通道上。结果是,这类物质能在体内的病理性地过度刺激的区域发挥活性。
BTX对钠通道的结合可作为试验体系以测定钠通道阻断效果[S.W.Postma&W.A.Catteral,Mol.Pharmacol.25,219-224(1984)],如斑夹实验(patch-clamp experiments)一样,表示本发明化合物以“使用依赖性”方式阻断电刺激的钠通道[W.A.Catteral,Trends Pharmacol.Sci.,8,57-65(1987)]。
另外,本发明化合物显示,通过阻断由藜芦定诱导谷氨酸盐的释放,具有神经保护效果[S.Villlauneva,P.Frenz,Y.Dragnic,G.Orrego,BrainRes.461,377-380(1988)]。藜芦定是一种毒素,它能使钠通道持久性地开放。这就导致钠流进细胞的增加。基于上述得出,钠流的增加在神经组织内导致谷氨酸盐释放的增加。谷氨酸盐释放的增加可用本发明化合物拮抗。
本发明物质的抗惊厥的性质可通过对鼠最大电休克所导致的痉挛的保护效果表示[M.A.Rogawski&R.J.Porter,Pharmacol.Rev.42,223-286(1990)]--神经保护性质是通过鼠-MCAO模型的保护效果表示[U.Pschorn&A.J.Carter,J.Stroke,Cerebrovascular diseases,6,93-99(1996)]。
另外还有用于治疗循环性精神病(燥郁疾病)的钠通道阻断剂的报告[J.A.Calabrese,C.Bowden,M.J.Woyshville:Psycho-pharmacology:The fourthgeneration of Progress(Eds.:D.E.Bloom&J.Kupfer)1099-1111,Raven PressLtd.New York]。这结果证明,通式I的1,2,3,4,5,6-六氢-2,6-亚甲基-3-苯并吖辛因-10-醇可用于治疗因过度刺激所导致的机能障碍。这种疾病包括心率失常,痉挛,心及脑缺血,以及各种原因的神经变性疾病。例如下述疾病:癫痫持续状态,低血糖,缺氧,组织缺氧,脑外伤,脑水肿,脑中风,产期窒息,肌萎缩性侧索硬化,享廷顿舞蹈病,爱尔茨海默病,帕金森病,循环性精神病,低血压,心肌梗塞,心率失常,心绞痛,痛,动脉麻醉及局部麻醉。
下述化合物已证明在这方面特别有效:(-)-2(1R2,″S)-2-(2″-苄基氧基)丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷和(-)-2(1R,2″S)-2-(2,6-二氟苄基)氧基)丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷。
本发明化合物可由现有技术的已知化合物用包括下述实例所述方法制备。
特别是,本发明关于包括制备通式5的降苯并吗吩烷的方法,其特点在于
b)将该四氢吡啶衍生物22重排制得N-苄基苯并吗吩烷23
其中
a)将其中R30是C1-C4-烷基的通式32的苄基氰,和其中R40是C1-C8-烷基或苄基的通式33的卤代羧酸酯,在有烷基卤代硅烷,优选是三烷基氯硅烷,最好是三甲基氯硅烷,及锌粉的存在下在惰性溶剂,优选是醚,或在卤代烃类,最好是在二氯甲烷中,并在有对亚氨基有选择性还原反应的还原剂,优选是在有碱金属硼氢化物衍生物的存在下,特别是在有氰基硼氢化钠的存在下进行Reformatsky反应,并分离生成的通式34的羧酸酯衍生物
c)将这样制得的通式35的羧酸二酯衍生物在惰性溶剂,优选是在脂肪族或芳族烃类,特别是甲苯中,在有碱性反应化合物的存在下,优选是在有碱金属烷醇化物,特别是支链或直链C1-C4-烷醇,最佳是在有叔-丁醇钾的存在下进行迪克曼酯缩合反应,并分离生成的通式36的哌啶酮衍生物
d)在酸或碱条件下将哌啶酮衍生物36皂化及脱羧基化,优选是在有碱金属氢氧化物或无机酸的存在下,尤其是在有氢氧化钠的存在下在极性溶剂或溶剂混合物中,优选是在直链或支链C1-C4-烷醇和水的混合物中,最好是在乙醇/水混合物中加热,制得相应的通式37哌啶酮酯衍生物,然后分离,并视需要用酸制成相应的酸加成盐,然后分离
e)如有必要,将这样制得的立体异构体混合物溶于对对映体分离呈惰性的反应介质内,视需要在释放对映体的自由态碱之后,和一种适于和对映体混合物的立体异构物生成盐的有机酸的适宜的立体异构物混合,这样用旋光性酸分离出加成盐形式的所需立体异构物
f)在分离出对映体纯的酸加成盐后,将这样制得的纯立体异构体38′或38″或异构体混合物38在惰性溶剂中与产生CH2=或CH3-CH=基团的维悌希试剂进行维悌希反应,优选是使用乙基三苯基鏻卤素化物或用甲基三苯基鏻卤素化物,最好是用溴化甲基三苯基鏻或溴化乙基三苯基鏻,在有碱性反应化合物的存在下,优选是在有碱金属烷醇化物存在下,尤其是在有叔-丁醇钾存在下,在惰性反应介质内,优选是在环形醚中,最好是在四氢呋喃中进行维悌希反应,并视需要以酸加成盐的形式分离出反应产物39或相应的立体异构物
g)视需要先由其酸加成盐释出由Wittig反应制得的烯39后,将39的自由态碱溶于有机溶剂内,优选是溶于卤代烃类中,最好是溶于二氯甲烷中,于哌啶氮上用甲酰化剂行甲酰化,优选是用正-丁基甲酸酯,然后分离出40的反应产物或相应的立体异构体
h)将这样制得的甲酰基化合物40,或相应的立体异构物,与无机酸或与路易士酸反应,优选是氯化铝(III),溶于惰性溶剂内,优选是在卤代烃类内,最好是在二氯甲烷内,然后分离由此反应产生的41的环化产物
i)将环化反应生成的苯并吗吩烷衍生物溶于极性溶剂,优选是C1-C4-烷醇,最好是正-丙醇内,并与酸性反应的化合物反应,优选是与无机酸水溶液反应,最好是和浓盐酸反应,然后视需要以其酸加成盐的形式分离出42的去甲酰化的降苯并吗吩烷
和YC(O)R′化合物反应,其中Y是仲氨基氮可取代的离去基,优选是卤素如氯,溴,碘,或有机磺酸盐,优选是三氟甲烷磺酸盐,R′是-CR1R2XR7,然后将羰基化合物还原成化合物(-)-2xx(如上述)或者,
1)视需要,在亲电子取代的架构内引入取代基R3
本专业技术人员会从本说明中了解到不同的其他制法的具体实施例。要特别指出的是,这些实施例及其相关的说明书只供说明目的,而不能被认为是限定本发明。
此外,有关德国专利申请No19740110.4的内容,本申请要求其优先权,是明显相关的。实施例实施例1:3-氨基-4-(2-甲氧基苯基)-2-甲基丁酸乙酯(13)
将1.5升无水二氯甲烷内的150克锌在氮气下与15毫升三甲基氯硅烷混合,在室温搅拌30分钟。然后加900毫升无水四氢呋喃(THF),并加热至42℃。于该混合物中滴加在100毫升THF中的147克(1.0摩尔)2-甲氧基苄基氰(11)和362克(2.0摩尔)2-溴丙酸乙酯的混合物,然后将该混合物加热回流2小时。使其冷却,倾析过量的锌,冷至5℃后和70克(1.8摩尔)硼氢化钠混合。然后滴加250毫升乙醇(有气体产生)。使该混合物于5℃反应3小时,缓慢加入1升2N的盐酸,分离各相,水相用每次200毫升二氯甲烷萃取二次。真空除去合并的有机相的溶剂,残余物与冰及甲苯混合,以浓氨水使成碱性。分离各相,水相再用每次800毫升甲苯萃取二次。将合并的有机相在硫酸镁上干燥,真空除去溶剂。制得149克(61%)油体。实施例2:3-(2-乙氧基羰基乙基)氨基-4-(2-甲氧基苯基)-2-甲基丁酸乙酯(14)
将148克(0.6摩尔)3-氨基-4-(2-甲氧基苯基)-2-甲基丁酸乙酯(13)和119克(1.2摩尔)丙烯酸乙酯的250毫升无水乙醇,加热回流6小时。将该混合物真空蒸发浓缩。残余物再溶于300毫升甲苯内,再真空蒸发一次。分离出210克(100%)所需产物,呈油体。实施例3:2-(2-甲氧基苯基)甲基-3-甲基-4-哌啶酮(15)
将210克(0.6摩尔)3-(2-乙氧基羰基乙基)氨基-4-(2-甲氧基苯基)-2-甲基丁酸乙酯(14)溶于3升甲苯内,首先蒸馏除去约100毫升溶剂/水混合物。将该混合物冷至约70℃,与80克(0.7摩尔)叔-丁醇钾混合,加热至105℃30分钟,同时蒸去生成的乙醇。然后使混合物冷却,真空除去溶剂。残余物与400毫升乙醇和200毫升40%的氢氧化钠溶液混合,加热回流3小时。真空除去醇,水相用每次400毫升乙醚(醚)萃取三次。将合并的有机相于硫酸镁上干燥,真空除去溶剂。制得109克(78%)油体。实施例4:(+)-4-亚乙基-2-(2-甲氧基苯基)甲基-3,3-二甲基-哌啶((+)-7)
将74.2克(200毫摩尔)溴化乙基-三苯基鏻悬浮于200毫升无水四氢呋喃中,在氮气下与80毫升2.5N的正-丁基锂的己烷溶液混合。将该混合物在30℃下搅拌30分钟,然后与23克(93毫摩尔)哌啶酮(+)-6在100毫升THF中的溶液混合。使该混合物在室温下反应12小时,加100毫升水,真空除去THF。残余物用每次200毫升醋酸乙酯萃取三次,合并的有机萃取物再用50毫升水洗,在硫酸镁上干燥,真空除去溶剂。残余物于闪柱(300毫升硅胶;4升环己烷/醋酸乙酯3∶1)上纯化。分离出所需产物,呈油体,产额17.4克(72%)。
以类似实施例4的方法制得以下产物:2-(2-甲氧基苯基)甲基-3-甲基-4-亚甲基-哌啶(16)
使用在200毫升无水THF内的20.1克(56毫摩尔)溴化甲基-三苯基鏻,6.3克(56毫摩尔)叔-丁醇钾及11克2-(2-甲氧基苯基)甲基-3-甲基-4-哌啶酮(15)。产物用丙酮结晶,为草酸盐。产额:13.1克(87%);熔点:145℃。实施例5:(+)4-亚乙基-N-甲酰基-2-(2-甲氧基苯基)甲基-3,3-二甲基-哌啶((+)-8)
将3.5克(12.6毫摩尔)(+)-4-亚乙基-2-(2-甲氧基苯基)甲基-3,3-二甲基-哌啶(7)与20毫升正-丁基甲酸酯于80℃搅拌4小时。然后将混合物真空蒸发。剩余3.6克(100%)所需产物,呈油体形式。
以类似实施例5方法制得以下产物:N-甲酰基-2-(2-甲氧基苯基)甲基-3-甲基-4-亚甲基-哌啶(17)
使用8克(34毫摩尔)2-(2-甲氧基苯基)甲基-3-甲基-4-亚甲基-哌啶(16)作为碱和30毫升正-丁基甲酸酯。产额:9.1克(100%),呈油体。实施例6:N-苄基-2-(2-甲氧基苯基)甲基-4-甲基-亚哌-3-啶(piperi-d-dene)(22)
将6.0克(250毫摩尔)镁片及少许碘置于150毫升醚中。在其中滴加在50毫升醚中的31.32克(200毫摩尔)2-甲氧基苄基氯,致使该混合物轻轻沸腾。任其反应1小时。将这样制得的格利雅试剂在氮气下迅速滴加到冷却至-10℃的在100毫升醚中的52.8克(200毫摩尔)N-苄基-4-甲基-吡啶鎓溴化物使之反应2.5小时。然后将该整个反应化合物加入到200毫升10%的氯化铵溶液内。分离出有机相,水相再用每次100毫升醚萃取二次。将合并的有机相在硫酸镁上干燥,真空除去溶剂。为避免氧化,用氮气冲洗这旋转蒸发器。将残余物立即溶于250毫升甲醇中,并加入9.5克(250毫摩尔)硼氢化钠和20毫升2N的氢氧化钠溶液。将该混合物在室温下搅拌过夜,真空蒸发。水性残余物用每次150毫升醚萃取二次,合并的有机相进行真空蒸发浓缩。将残余物溶于酯酸乙酯内,用每次150毫升2N的盐酸萃取5次。然后将合并的水相用氢氧化钠溶液变成碱性,再用每次200毫升醋酸乙酯萃取二次。将合并的有机相在硫酸镁(MgSO4)上干燥,真空蒸发掉溶剂。将残余物于200毫升硅胶上过滤纯化(淋洗剂:醚)。制得31克(51%)所需产物,呈油体。实施例7:(-)-5-乙基-2-甲酰基-4′-甲氧基-9,9-二甲基-6,7-苯并吗吩烷((-)-9)
将3.6克(12.6毫摩尔)(+)-4-亚乙基-N-甲酰基-2-(2-甲氧基苯基)甲基-3,3-二甲基哌啶(8)与35毫升甲磺酸混合,于80℃搅拌3小时。使该反应混合物冷却,并倒在50克冰上,用氨水中和,每次用100毫升醋酸乙酯萃取二次。合并的有机萃取物再用50毫升水洗涤,于MgSO4上干燥,真空除去溶剂。残余物于闪柱(50毫升硅胶;750毫升环己烷/醋酸乙酯3∶1)上纯化。分离出所需产物,呈油体,产额2.1克(58%)。
以类似于实施例7方法制得以下产物:N-甲酰基-4′-甲氧基-5,9-二甲基-6,7-苯并吗吩烷(18)
使用5.0克(19毫摩尔)N-甲酰基-2-(2-甲氧基苯基)甲基-3-甲基-4-亚甲基-哌啶(17)和30毫升甲磺酸。制得4.8克(96%)所需产物(油体),为90%α-差向异构体及10%β差向异构体的混合物。N-苄基-4′-甲氧基-9-甲基-6,7-苯并吗吩烷-草酸盐(23OX)
使用31克(100毫摩尔)N-苄基-2-(2-甲氧基苯基)甲基-4-甲基-亚哌-3-啶(22)和100毫升甲磺酸。残余物溶于100毫升甲醇内,并和60克活性碳进行短暂沸腾,趁热在硅胶上抽吸过滤。真空除去溶剂,将残余物溶于醚中,用草酸沉淀出草酸盐。制得30克(75%);熔点:152℃(MK1-11)。实施例8:4′-甲氧基-9-甲基-6,7-苯并吗吩烷草酸盐(240X)
将30克(75毫摩尔)N-苄基-4′-甲氧基-9-甲基-6,7-苯并吗吩烷-草酸盐(23OX)溶于600毫升甲醇内,于60℃以5巴氢压在3克Pd/活性碳(10%)上氢化。将混合物冷至5℃,吸滤沉淀的产物。制得17克(56%),熔点250℃(MK1-15)。实施例9:(-)-5-乙基-4′-甲氧基-9,9-二甲基-6,7-苯并吗吩烷((-)-10)
将2.0克(6.9毫摩尔)(-)-5-乙基-2-甲酰基-4′-甲氧基-9,9-二甲基-6,7-苯并吗吩烷(9)溶于30毫升正-丙醇中,与10毫升浓盐酸于微波炉内以300瓦加热2小时。然后真空除去溶剂,将残余物与15毫升冰水混合,用20毫升醋酸乙酯萃取二次(然后除去)。水相用浓氨水中和,用每次20毫升醋酸乙酯萃取三次。将合并的有机萃取物在MgSO4上干燥,真空除去溶剂。将残余物溶于丙酮内,用乙醚化盐酸沉淀出盐酸盐。产额:1.7克(82%),熔点:>250℃,[α]D 25=(-)43.0°(c=1,于甲醇内)。
以类似于实施例9方法制备以下化合物:4′-甲氧基-5,9-二甲基-6,7-苯并吗吩烷(19)
使用4.8克(18毫摩尔)N-甲酰基-4′-甲氧基-5,9-二甲基-6,7-苯并吗吩烷(18),50毫升正-丙醇及50毫升浓盐酸。将混合物回流8小时。产额2.9克(57%)。用草酸转化样品,成为相应的草酸盐(HB),其熔点为229℃。实施例10:(-)-(1R,9α)-4′-甲氧基-5,9-二甲基-6,7-苯并吗吩烷((-))-19)
将9.5克(41毫摩尔)4′-甲氧基-5,9-二甲基-6,7-苯并吗吩烷(19)溶于80毫升乙醇中,和6.2克(41毫摩尔)R-(+)-酒石酸混合。吸滤沉淀的结晶,用甲醇重结晶二次。产额2.6克(17%),熔点,236℃,ee>98%(以NMR谱使用自由态碱通过加入位移试剂而测定)。将酒石酸盐溶于水内,用碳酸钾放出碱,并用50毫升醋酸乙酯萃取二次。将合并的有机萃取物于MgSO4上干燥,真空除去溶剂。制得1.6克自由态碱。实施例11:(-)-(1R,9α)-4′-羟基-5,9-二甲基-6,7-苯并吗吩烷-氢溴酸盐((-)-4aBr)
将1.5克(6.5毫摩尔)(-)-4′-甲氧基-5,9-二甲基-6,7-苯并吗吩烷((-)-19)与15毫升48%的氢溴酸加热回流2小时。然后将混合物真空蒸发浓缩,将残余物用THF煮解。制得1.5克(78%)所需产物,为氢溴酸盐(无定形沉淀物)。
以类似于实施例11方法制备下述化合物:4′-羟基-9-甲基-6,7-苯并吗吩烷-氢溴酸盐(5aBr)
先将9.5克(31毫摩尔)4′-甲氧基-9-甲基-6,7-苯并吗吩烷-草酸盐(240X)溶于少量水中,用7克碳酸钾转化成自由态碱。用200毫升醋酸乙酯萃取三次,由合并的有机相除去溶剂。然后加30毫升48%的氢溴酸。制得6.1克(70%)所需氢溴酸盐;熔点227℃。实施例12:(-)-(1R,9α,2″S)-2-(2″-苄基氧基)丙基-4′-羟基-5,9-二甲基-6,7-苯并吗吩烷-盐酸盐((-)-4bCl)
将0.75克(2.5毫摩尔)(-)-4′-羟基-5,9-二甲基-6,7-苯并吗吩烷-氢溴酸盐((-)4aBr)悬浮于15毫升二氯甲烷内,与3毫升N-甲基吗啉混合。30分钟后将该混合物冷至-5℃,缓慢地滴加1.1克(5.5毫摩尔)(-)-S-2-苄基氧基丙酰氯于10毫升二氯甲烷中的溶液。将该混合物于-5℃再搅30分钟,与20毫升2N的盐酸混合,分离出有机相。将有机相在MgSO4上干燥,真空除去溶剂,将残余物溶于40毫升THF中。于该溶液中加入0.5克(13毫摩尔)LiAlH4,此时温度升至35℃。使该混合物反应30分钟,然后加入0.4毫升水及0.2毫升5N的氢氧化钠溶液,分离出无机沉淀物。沉淀物用100毫升THF洗涤,将合并的有机相真空蒸发浓缩。将残余物溶于100毫升乙醚内,于MgSO4上干燥,以乙醚化盐酸沉淀出盐酸盐。分离出结晶,并用丙酮洗涤。产额:0.6克(55%),熔点:227℃,[α]D 25=(-)13.3°(c=1,在甲醇中)。
以类似于实施例12方法制得下述产物:(-)-(1R,9α,2″R)-2-(2″苄基氧基)丙基-4′-羟基-5,9-二甲基-6,7-苯并吗吩烷-盐酸盐((-)-4cCl)
加入0.75克(2.5毫摩尔)-4′-羟基-5,9-二甲基-6,7-苯并吗吩烷-氢溴酸盐((-)-4aBr)和1.1克(5.5毫摩尔)(+)-R-2-苄基氧基丙酰氯。产额:0.7克(65%),熔点:217℃,[α]D 25=(-)76.1°(c=1,在甲醇中)。(-)-(1R,9α)-4′-羟基-5,9-二甲基-2-[2-(2-苯氧基)乙氧基]乙基-6,7-苯并吗吩烷-盐酸盐((-)-4cCl)
加入0.75克(2.5毫摩尔)(-)-4′-羟基-5,9-二甲基-6,7-苯并吗吩烷-氢溴酸盐((-)-4aBr)和1.1克(5.5毫摩尔)苯氧基乙氧基乙酰氯。产额:0.2克(20%),无定形粉末。(-)-(1R,2″R)-2-(2″-苄基氧基)丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2bCl)
加入1.6克(6.9毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和2.3克(11.6毫摩尔)(-)-S-2-苄基氧基丙酰氯。产额:2.1克(73%),熔点:254℃,[α]D 25=(-)20.7°(c=1,在甲醇内)。(+)-(1S,2″R)-2-(2″-苄基氧基)丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((+)-2bCl)
加入1.5克(6.5毫摩尔)(+)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((+)-2a)和1.5克(7.6毫摩尔)(+)-R-2-苄基氧基丙酰氯。产额:1.4克(52%),熔点:256℃,[α]D 25=(+)20.3°(c=1,在甲醇内)。(-)-(1R,2″R)-2-(2″-苄基氧基)丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2cCl)
加入1.6克(6.9毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和1.5克(7.6毫摩尔)(+)-R-2-苄基氧基丙酰氯。产额:1.7克(59%),熔点:245℃,[α]D 25=(-)96.5°(c=1,在甲醇内)。(+)-(1S,2″S)-2-(2″-苄基氧基)丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((+)-2cCl)
加入1.6克(6.9毫摩尔)(+)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((+)-2a)和2.3克(11.6毫摩尔)(-)-S-2-苄基氧基丙酰氯。产额:2.0克(70%),熔点:245℃,[α]D 25=(+)97.8°(c=1,在甲醇内)。(-)-(1R,2″S)-2-(2″-(2--氟苄基)氧基)丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2dCl)
加入0.8克(3.4毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和1.4克(6.5毫摩尔)(-)-S-2-(2′-氟苄基)氧基丙酰氯。产额:0.9克(61%),熔点:212℃,[α]D 25=(-)24.7°(c=1,在甲醇内)。(-)-(1R,2″R)-2-(2″-(2-氟苄基)氧基)丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2eCl)
加入0.5克(2.3毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和0.6克(3.0毫摩尔)(+)-R-2-(2′-氟苄基)氧基丙酰氯。产额:0.7克(70%),熔点:145℃,[α]D 25=(-)88.4°(c=1,在甲醇内)。(-)-(1R,2″S)-2-(2″-(4--氟苄基)氧基)丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2fCl)
加入0.8克(3.4毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和1.4克(6.5毫摩尔)(-)-S-2-(4′-氟苄基)氧基丙酰氯。产额:1.0克(68%),熔点:250℃,[α]D 25=(-)21.9°(c=1,在甲醇内)。(-)-(1R,2″R)-2-(2″-(4-氟苄基)氧基)丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2gCl)
加入0.5克(2.3毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和0.6克(3.0毫摩尔)(+)-R-2-(4′-氟苄基)氧基丙酰氯。产额:0.6克(58%),熔点:128℃,[α]D 25=(-)95.4°(c=1,在甲醇内)。(-)-(1R,2″S)-2-(2″-(2-,6-二氟苄基)氧基)丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2hCl)
加入1.5克(6.5毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和2.4克(10.2毫摩尔)(-)-S-2-(2′,6′-二氟苄基)氧基丙酰氯。产额:2.0克(68%),熔点:245℃,[α]D 25=(-)272.3°(c=1,在甲醇内)。(-)-(1R,2″R)-2-(2″-(2,6-二氯苄基)氧基)丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2iCl)
加入2.3克(10毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和3.2克(12毫摩尔)(-)-S-2-(2′,6′-二氯苄基)氧基丙酰氯。产额:2.8克(58%),熔点:260℃,[α]D 25=(-)14.1°(c=1,在甲醇内)。(-)-(1R,2″S)-2-(2″-(2--甲基苄基)氧基)丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2jCl)
加入0.8克(3.4毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和1.4克(6.5毫摩尔)(-)-S-2-(2′-甲基苄基)氧基丙酰氯。产额:0.8克(55%),熔点:249℃,[α]D 25=(-)10.9°(c=1,在甲醇内)。(-)-(1R,2″S)-2-(2″-(2″环己基甲氧基)丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2kCl)
加入1.9克(8.2毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和2.0克(10毫摩尔)(-)-S-2-(2′-环己基甲氧基)丙酰氯。产额:1.8克(52%),熔点:249℃,[α]D 25=(-)24.6°(c=1,在甲醇内)。(-)-(1R,2″R)-2-(2″-环己基甲氧基)丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2lCl)
加入1.9克(8.2毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和2.0克(10毫摩尔)(+)-R-2-(2′-环己基甲氧基)丙酰氯。产额:1.7克(49%),熔点:140℃,[α]D 25=(-)92.2°(c=1,在甲醇内)。(-)-(1R)-4′-羟基-2-(5″-苯氧基)戊基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2mCl)
加入3.0克(13毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和3.2克(15毫摩尔)5-苯氧基戊酰氯。产额:2.4克(44%),熔点:149℃,[α]D 25=(-)74.6°(c=1,在甲醇内)。(-)-(1R)-4′-羟基-2-(2″-(2-苯基)乙氧基)乙基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2nCl)
加入2.0克(8.7毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和2.2克(11毫摩尔)2-苯基乙氧基乙酰氯。产额:1.7克(48%),熔点:204℃,[α]D 25=(-)72.4°(c=1,在甲醇内)。(-)-(1R)-4′-羟基-2-(4″-苯氧基)丁基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2oCl)
加入1.0克(4.3毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和1.2克(6毫摩尔)4-苯氧基丁酰氯。产额:0.7克(39%),熔点:250℃,[α]D 25=(-)82.8°(c=1,在甲醇内)。(-)-(1R)-2-(2″-苄基氧基)乙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2pCl)
加入2.3克(10毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和4.3克(22毫摩尔)2-苄基氧基乙酰氯。产额:2.5克(62%),熔点:253℃,[α]D 25=(-)78.1°(c=1,在甲醇内)。(-)-(1R)-2-(2-(2,6-二氟苄基氧基)乙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2qCl)
加入1.2克(5毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和1.1克(5毫摩尔)2-(2′,6′-二氟苄基氧基乙酰氯)。产额:1.5克(68%),熔点: 246℃,[α]D 25=(-)71.0°(c=1,在甲醇内)。(-)-(1R)-2-(3″-(2,6-二氟苯基)丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2rCl)
加入1.9克(8.2毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和1.7克(8.3毫摩尔)3-(2′,6′-二氟苯基丙酰氯。产额:1.6克(46%),熔点:>250℃,[α]D 25=(-)68.6°(c=1,在甲醇内)。实施例13:(+)-(1R,2″S)-2-(2″-苄基氧基)丙基-4′-羟基-5-甲基-6,7-苯并吗吩烷-盐酸盐((+)-5bCl)和(1S,2″S)-2-(2″-苄基氧基)丙基-4-羟基-5-甲基-6,7-苯并吗吩烷-盐酸盐((+)-5cCl)
将5.1克(17毫摩尔)4′-羟基-9-甲基-6,7-苯并吗吩烷-氢溴酸盐(5aBr)和1.7克(17毫摩尔)N-甲基吗啉溶在20毫升DMF内,并冷至-5℃。在其中缓慢地滴加在-5℃制备的由3.5克(19毫摩尔)(-)-S-2-苄基氧基丙酸,1.8克(19毫摩尔)氯甲酸甲酯和2.0克(19毫摩尔)N-甲基吗啉在20毫升二氯甲烷中的溶液。使该混合物于室温下反应1小时,真空除去大部分溶剂,将残余物溶于60毫升二氯甲烷内,用20毫升2N的盐酸萃取二次,用30毫升水萃取一次。将有机相在MgSO4上干燥,真空除去溶剂。加入少许醚后,结晶出产物(熔点:110℃),吸滤,并溶于80毫升THF中。在该溶液中加入0.8克(21毫摩尔)LiAlH4,这时温度升到35℃。使该混合物反应1小时,和25毫升水及25毫升40%的酒石酸钠溶液混合。分离出有机相,用100毫升乙醚萃取二次,将合并的有机相真空干燥。残余物溶于100毫升乙醚中,在硫酸镁上干燥,用乙醚化盐酸沉淀出盐酸盐。分离结晶,并用异丙醇重结晶。制得1.1克(17%)(+)5bCl,熔点246℃,[α]D 25=(+)11.8°(c=1,在甲醇中)。将母液蒸发浓缩,释出碱并进行色层分析(300克硅胶;醋酸乙酯/环己烷1∶3)。再用乙醚化盐酸沉淀出盐酸盐。制得0.3克(5%)(+)-5cCl,熔点241℃,[α]D 25=(+)52.4°(c=1,在甲醇内)。
以类似于实施例13方法制备下述产物:(+)-(1R,2″S)-2-[2″-(2′,6-二氟苄基氧基)]丙基-4′-羟基-5-甲基-6,7-苯并吗吩烷-盐酸盐((+)-5dCl)及(+)-(1S,2″S)-2-(2″-(2′,6-二氟苄基氧基))丙基-4′-羟基-5-甲基-6,7-苯并吗吩烷-盐酸盐((+)-5eCl)
加入4.0克(14毫摩尔)4′-羟基-5-甲基-6,7-苯并吗吩烷-氢溴酸盐(5aBr)和3.0克(14毫摩尔)(+)-R-2-(2′,6′-二氟苄基氧基)丙酸。制得0.3克(5%)(+)-5dCl,熔点:122℃,[α]D 25=(+)20.9°(c=1,在甲醇内)和1.8克(30%)(+)-5dCl和(+)-5eCl的混合物,熔点194℃,[α]D 25=(+)42.2°(c=1,在甲醇内)。实施例14:(-)-(1R)-4′-羟基-5,9,9-三甲基-2-[2″-(2-苯氧基)乙氧基]乙基-6,7-苯并吗吩烷-盐酸盐((-)-2uCl)
将1.5克(6.5毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和1.5克(7.5毫摩尔)2-(2-苯氧基)乙氧基-乙基氯溶于20毫升DMF内,加入催化量的KI和1克碳酸钾。该混合物在130℃搅拌5小时,然后真空除去溶剂。将残余物溶于100毫升水内,用100毫升醋酸乙酯萃取三次,合并的有机萃取物再用50毫升水洗涤,在MgSO4上干燥,真空除去溶剂。将残余物溶于40毫升醚内,用醚化的盐酸沉淀出盐酸盐。产额:1.4克(50%),熔点:190℃,[α]D 25=(-)81.1°(c=1,在甲醇内)。
以类似于实施例14方法制备下述产物:(+)-(1S)-4′-羟基-5,9,9-三甲基-2-[2″-(2-苯氧基)乙氧基]乙基-6,7-苯并吗吩烷-盐酸盐((-)-2vCl)
加入1.5克(6.5毫摩尔)(+)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((+)-2a)和1.5克(7.5毫摩尔)2-(2-苯氧基)乙氧基)-乙基氯。产额:1.8克(64%),熔点:190℃,[α]D 25=(+)81.0°(c=1,在甲醇内)。(-)-(1R,2″S)-2-[2″-(2-氰基苄基)氧基]丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2WCl)
加入0.8克(3.4毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((+)-2a)和1.0克(3.7毫摩尔)2-(2′-氰基苄基)氧基丙基S-甲磺酸酯。产额:0.2克(13%),熔点:234℃。(-)-(1R)-2-[2″-(2-2-环己基氧基)乙氧基]乙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2xCl)
加入1.0克(4.3毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((+)-2a)和1.1克(5.4毫摩尔)2-(2′-环己基氧基)乙氧基)乙基氯。产额:0.7克(37%),熔点:204℃,[α]D 25=(-)71.1°(c=1,在甲醇内)。(-)-(1R)-2-[2″-(2-(2,6-二氟苯氧基)乙氧基]乙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2yCl)
加入2.3克(1 0毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((+)-2a)和2.8克(12毫摩尔)2-(2′-(2,6-二氟苯氧基)乙氧基)乙基氯。产额:2.3克(49%),熔点:183℃,[α]D 25=(-)73.3°(c=1,在甲醇内)。(-)-(1R)-2-[2″-(2,6-二氟苯氧基)乙基]-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2zCl)
加入1.2克(5毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和1.4克(9.8毫摩尔)2-(2,6-二氟苯氧基)乙基氯。产额:0.3克(14%),熔点:241℃。(-)-(1R)-2-(2″-环己基氧基)乙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2aaCl)
加入1.2克(5毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和1.1克(6.8毫摩尔)2-环己基氧基-乙基氯。产额:0.8克(41%),熔点:>250℃,[α]D 25=(-)71.1°(c=1,在甲醇内)。(-)-(1R)-2-[2″-(2-叔丁基氧基)乙氧基]乙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2acCl)
加入1.5克(6.4毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和1.4克(7.7毫摩尔)2-(2′-叔-丁基氧基)乙氧基)乙基氯。产额:0.8克(30%),熔点:209℃,[α]D 25=(-)72.4°(c=1,在甲醇内)。实施例15:(-)-(1R)-5-乙基-4′-羟基-9,9-二甲基-2-(2-(2-苯氧基)乙氧基)乙基-6,7-苯并吗吩烷-盐酸盐(3bCl):
将1.0克(3.4毫摩尔)(-)-5-乙基-4′-甲氧基-9,9-二甲基-6,7-苯并吗吩烷(10)和20毫升48%氢溴酸加热回流2小时。然后将该混合物真空蒸发浓缩,残余物溶于20毫升乙醇中,再蒸发浓缩。然后溶于20毫升DMF内,加入在10毫升DMF中的800毫克(4.0毫摩尔)2-(2-苯氧基)乙氧基-乙基氯,催化量的KI及1克碳酸钾。将该混合物在80℃搅拌4小时,真空除去溶剂。将残余物溶于100毫升水中,用100毫升醋酸乙酯萃取三次,并将合并的有机萃取物用50毫升水洗涤一次,在MgSO4上干燥,真空除去溶剂。将残余物溶于40毫升乙醚中,用乙醚化盐酸沉淀出盐酸盐。产额:1.0克(66%),熔点:90℃(分解)。实施例16:(-)-(1R)-4′-羟基-2-(2″-苯基乙基)-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2adCl)
将1.0克(4.3毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和1.0克(8.3毫摩尔)苯基乙醛溶于20毫升甲醇内,和分子筛混合,在室温下搅拌3小时。然后滤去分子筛,滤液与0.6克(9.5毫摩尔)氰基硼氢钠和1.2毫升冰醋酸混合。使该混合物静置约12小时,和20毫升4N的盐酸混合,真空蒸发。残余物和少量丙酮混合,吸滤结晶。产额:0.9克(56%),熔点:250℃,[α]D 25=(-)80.04°(c=1,在甲醇内)。
以类似于实施例16方法制备下述产物:(-)-(1R)-4′-羟基-2-(2″-苯基丙基)-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2aeCl)
加入1.0(4.3毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a),1.2克(8.9毫摩尔)3-苯基丙醛和0.6克(9.5毫摩尔)氰基硼氢钠。产额:0.8克(48%),熔点:>250℃,[α]D 25=(-)75.1°(c=1,在甲醇内)。实施例17:(-)-(1R)-4′-羟基-2-[2″-(2-苯氨基)-乙氧基-5,9,9-三甲基-6,7-苯并吗吩烷-二盐酸盐((-)-2aeCl2)
将1.3克(5.6毫摩尔)(-)-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷((-)-2a)和1.7克(5.6毫摩尔)2-(N-苯基-2″-叔-丁氧基羰基氨基)-乙氧基乙基氯溶于50毫升DMF中,加入催化量的KI及1克碳酸钾。该混合物在110℃下搅拌7小时,然后真空除去溶剂。将残余物溶于100毫升水中,用100毫升醋酸乙酯萃取三次,合并的有机萃取物用50毫升水洗涤一次,在MgSO4上干燥,真空除去溶剂。残余物于闪柱中(120毫升硅胶,醋酸乙酯/环己烷1∶1)纯化,并用50毫升浓盐酸在室温下搅拌30分钟。接着用150毫升冰水稀释,用50毫升醋酸乙酯萃取一次(倒出有机相),用浓氨水使成碱性。用100毫升醋酸乙酯萃取三次,合并的有机萃取物在MgSO4上干燥,真空除去溶剂。残余物溶于10毫升乙醇内,用乙醚化的盐酸沉淀出盐酸盐。产额:0.7克(27%),熔点:112℃,[α]D 25=(-)75.8°(c=1,在甲醇内)。实施例19:(-)-(1R,2″S)-2-(2″-苄基氧基)丙基-3′-氯-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2agCl)和(-)-(1R,2″S)-2-(2″-苄基氧基)丙基-1′-氯-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2ahCl)
将3克(7.3毫摩尔)(-)-(1R,2″S)-2-(2″-苄基氧基)丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷-盐酸盐((-)-2bCl)和1.0克(7.3毫摩尔)N-氯丁二酰亚胺悬浮在70毫升冰醋酸中,在室温下搅拌24小时,这时间悬浮液变成溶液。然后将该混合物真空蒸发浓缩,残余物与100毫升冰冷却的2N的氢氧化钠溶液混合,用100毫升醋酸乙酯萃取三次,合并的有机相在MgSO4上干燥,真空除去溶剂。残余物在硅胶上进行色层分析(180克硅胶;环己烷/醋酸乙酯5∶1)。将适宜馏分蒸发浓缩,将残余物溶于15毫升丙酮内,用乙醚化的盐酸沉淀出盐酸盐。制得0.4克(12%)(-)-2agCl,熔点:204℃,[α]D 25=(-)21.5°(c=1,在甲醇内)和0.6克(18%)(-)-2ahCl,熔点258℃,[α]D 25=(-)4.6°(c=1,在甲醇内)。
下面为使用活性成分的药物制剂的一些实例:片剂:通式I活性成分 20毫克硬脂酸镁 1毫克乳糖 190毫克注射用溶液:通式I活性成分 0.3毫克氯化钠 0.8克氯苄烷铵 0.01毫克注射用水 加至100毫升
类似于上述的溶液可适用于以喷雾剂方式经鼻给药,或与能产生优选是2至6微米的微粒气溶胶的喷雾装置结合施用,以经肺给药。供输液用溶液
将含有活性成分为2毫克/毫升的5%重量的木糖醇溶液用醋酸钠缓冲剂调整至pH4。
基于药物制剂的总重量,这类输液溶液可含0.001至20%重量范围的通式I活性物质,优选是0.001至10%重量,最佳是0.01至5%重量。供吸入的胶囊
将通式I活性物质以微粉化的形式(微粒基本上为2至6微米)装入硬明胶胶囊内,视需要加入微粉化的载剂如乳糖。以惯用的供粉末吸入的装置进行吸入使用。每一胶囊中含有,例如,0.2至20毫克的活性物质和0至40毫克的乳糖。供吸入的气雾剂通式I活性物质 1份大豆卵磷脂 0.2份推进剂气体混合物加至 100份
Claims (13)
其中
X是单键,-O-,C1-C4-亚烷基,有1至8个碳原子的亚烷基桥,它可以是支链或直链的,且于桥的任何位点可有一或二个氧原子,优选是C1-C3-亚烷基-O-或-O-CH2-CH2-O-,-O-CH2-CH2-NH;
R1是氢,甲基,乙基,苯基;
R2是氢,甲基;
R3是氢,氟,氯,溴,羟基,甲基,甲氧基;
R4是氢,甲基,乙基;
R5是氢,甲基,乙基;
R6是氢,甲基,乙基;
R7是叔-丁基,环己基,视需要可被R9及R10取代的苯基,
R9及R10可相同或不同;
R8是氢、C1-C4-烷基;
Z是氧,NH,硫;
R9是氢,甲基,氟,氯,溴,甲氧基;
R10是氢,甲基,氟,氯,溴,甲氧基;
视需要它呈个别旋光异构体的形式,个别对映体或外消旋物的混合物形式,以及是自由态碱或与药理上可接受的酸所形成的酸加成盐的形式。
2.根据权利要求1的通式I化合物,其中
X是氧;
R1是氢,甲基或乙基;
R2是氢,
R3是氢,
R4是氢或甲基;
R5是氢或甲基;
R6是甲基;
R7是苯基,视需要可以R9及R10取代,它可相同或不同;
R8是氢;
R9及R10彼此分别是氢,甲基,氟或甲氧基;
视需要,它呈个别旋光异构物的形式,个别对映体或外消旋物的混合物形式,以及是自由态碱或与药理上可接受的酸所形成的酸加成盐的形式。
3.自由态碱形式或与药理上可接受的酸所形成的酸加成盐的形式的(-)-(R,2″S)-2-(2″-苄基氧基)丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷。
4.自由态碱形式或与药理上可接受的酸所形成的酸加成盐的形式的(-)-(1R,2″S)-2-[2″-(2,6-二氟苄基)氧基]丙基-4′-羟基-5,9,9-三甲基-6,7-苯并吗吩烷。
6.一种制备通式I的降苯并吗吩烷的方法
其中
X是单键,-O-,C1-C4-亚烷基,有1至8个碳原子的亚烷基桥,它可以是支链或直链的,并在桥的任何位点可有一或二个氧原子,优选的是C1-C3-亚烷基-O-或-O-CH2-CH2-O-,-O-CH2-CH2-NH;
R1是氢,甲基,乙基,苯基;
R2是氢,甲基;
R3是氢,氟,氯,溴,羟基,甲基,甲氧基;
R4是氢,甲基,乙基;
R5是氢,甲基,乙基;
R6是氢,甲基,乙基;
R8指氢,C1-C4-烷基;
Z是氧,NH,硫;
R9是氢,甲基,氟,氯,溴,甲氧基;
R10是氢,甲基,氟,氯,溴,甲氧基;
其特征在于
a)将其中R30是C1-C4-烷基的通式32的苄基氰,和其中R40是C1-C8-烷基或苄基的通式33的卤羧酸酯,在有烷基卤代硅烷,优选是三烷基氯硅烷,最好是三甲基氯硅烷,和锌粉的存在下在惰性溶剂,优选是醚,或在卤代烃,最佳是二氯甲烷中,并在有对亚氨基有选择性还原反应的还原剂,优选是在有碱金属硼氢化物衍生物的存在下,特别是在有氰基硼氢钠存在下进行Reformatsky反应,并分离所生成的通式34的羧酸酯衍生物
c)将这样制得的通式35羧酸二酯衍生物在惰性溶剂,优选是脂肪族或芳香族烃,特优是甲苯中,在有碱性反应化合物存在下,优选是在有碱金属醇盐,特别是支链或直链的C1-C4-烷醇,最佳是在有叔-丁醇化钾存在下进行迪克曼的酯缩合反应,并分离生成的通式36的哌啶酮衍生物
d)在酸或碱的条件下将哌啶酮衍生物36皂化及脱羧基化,优选是在有碱金属氢氧化物或无机酸的存在下,特别是在有氢氧化钠的存在下在极性溶剂或溶剂混合物内,优选是在直链或支链C1-C4-烷醇和水的混合物内,特别是在乙醇/水混合物中加热,制得相应的通式37哌啶酮酯衍生物,然后分离,并视需要用酸制成对应的酸加成盐,然后分离
e)如有必要,将这样制得的立体异构体混合物溶于对对映体分离呈惰性的反应介质内,视需要在释放对映体的自由态碱之后,和一种适于和对映体混合物中的一种立体异构体生成盐的有机酸的适宜的立体异构物混合,以其与旋光性酸加成盐形式分离出所需立体异构物
f)在分离出对映体纯酸加成盐后,将这样制得的纯立体异构体38′或38″或异构体混合物38在惰性溶剂中和产生CH2=或CH3-CH=基团的维悌希试剂进行维悌希反应,优选是使用乙基三苯基鏻卤素化物或用甲基三苯基鏻卤素化物,尤其是用溴化甲基三苯基鏻或溴化乙基三苯基鏻,在有碱性反应化合物存在下,优选是在有碱金属醇化物的存在下,尤其是在有叔-丁醇钾的存在下,于惰性反应介质内,优选是在环形醚内,尤其是在四氢呋喃中进行维悌希反应,并视需要以酸加成盐的形式分离出反应产物39或对应的立体异构物
g)视需要先由其酸加成盐释出由维悌希反应制得的烯39后,将39的自由态碱溶于有机溶剂内,优选是溶于卤代烃内,尤其是溶于二氯甲烷内,用甲酰化剂优选是用正-丁基甲酸酯在哌啶氮上进行甲酰化,然后分离出40的反应产物或对应的立体异构体
i)将环化反应生成的苯并吗吩烷衍生物溶于极性溶剂,优选是C1-C4-烷醇,尤其是正-丙醇内,与酸性反应的化合物反应,优选是与无机酸水溶液反应,尤其是和浓盐酸反应,然后视需要以其酸加成盐的形式分离出42的去甲酰化的降苯并吗吩烷
或者
或者
1)视需要在亲电子取代的构架内引入取代基R3
7.一种药物制剂,其特征在于,它含有权利要求1至4中之一的化合物或其酸加成盐以及惯用的佐剂和载剂。
8.根据权利要求7的药物制剂,其特征在于,它调配成供输液用的溶液。
9.根据权利要求8的药物制剂,其特征在于,其活性物质含量,以药物制剂总量计,为0.001至20%重量。
10.根据权利要求9的药物制剂,其特征在于,其活性物质含量,以药物制剂总量计,为0.001至10%重量。
11.根据权利要求10的药物制剂,其特征在于,其活性物质含量,以药物制剂总量计,为0.01至5%重量。
12.根据权利要求1至4中之一的化合物的用途,它用作药物组合物。
13.根据权利要求1至4中之一的化合物的用途,它用于制备的药物组合物是用于治疗各种原因的脑缺血,神经变性疾病,癫痫持续状态,低血糖,缺氧,组织缺氧,脑外伤,脑水肿,脑中风,产期窒息,肌萎缩性侧索硬化,享廷顿舞蹈病,爱尔茨海默病,帕金森病,二极性疾病,循环性精神病,动脉性低血压,心肌梗塞,心率疾病,心绞痛,痛,动脉麻醉及局部麻醉。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE19740110A DE19740110A1 (de) | 1997-09-12 | 1997-09-12 | Substituierte 1,2,3,4,5,6-Hexahydro-2,6-methano-3-benzazocin-10-ole, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
DE19740110.4 | 1997-09-12 |
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Publication Number | Publication Date |
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CN1269790A true CN1269790A (zh) | 2000-10-11 |
CN1166640C CN1166640C (zh) | 2004-09-15 |
Family
ID=7842134
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CNB988090155A Expired - Fee Related CN1166640C (zh) | 1997-09-12 | 1998-09-09 | 经取代的1,2,3,4,5,6-六氢-2,6-亚甲基-3-苯并吖辛因-10-醇,其制法及作为药物组合物的用途 |
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US (1) | US6455538B1 (zh) |
EP (1) | EP1015433B1 (zh) |
JP (1) | JP3827528B2 (zh) |
KR (1) | KR100601008B1 (zh) |
CN (1) | CN1166640C (zh) |
AR (1) | AR017095A1 (zh) |
AT (1) | ATE267811T1 (zh) |
AU (1) | AU751036B2 (zh) |
BG (1) | BG64418B1 (zh) |
BR (1) | BR9812443A (zh) |
CA (1) | CA2302347C (zh) |
CO (1) | CO5011117A1 (zh) |
CZ (1) | CZ296909B6 (zh) |
DE (2) | DE19740110A1 (zh) |
DK (1) | DK1015433T3 (zh) |
EE (1) | EE04398B1 (zh) |
ES (1) | ES2222612T3 (zh) |
HR (1) | HRP980502B1 (zh) |
HU (1) | HUP0004588A3 (zh) |
ID (1) | ID24173A (zh) |
IL (1) | IL134572A (zh) |
MY (1) | MY120550A (zh) |
NO (1) | NO315650B1 (zh) |
NZ (1) | NZ503710A (zh) |
PE (1) | PE122899A1 (zh) |
PL (1) | PL198486B1 (zh) |
PT (1) | PT1015433E (zh) |
RS (1) | RS49888B (zh) |
RU (1) | RU2218334C2 (zh) |
SA (1) | SA98190765B1 (zh) |
SK (1) | SK284670B6 (zh) |
TR (1) | TR200000697T2 (zh) |
TW (1) | TW505645B (zh) |
UA (1) | UA61973C2 (zh) |
UY (2) | UY25175A1 (zh) |
WO (1) | WO1999014199A1 (zh) |
YU (1) | YU12000A (zh) |
ZA (1) | ZA988285B (zh) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19826365A1 (de) * | 1998-06-12 | 1999-12-16 | Gruenenthal Gmbh | Verwendung von Benzomorphanderivaten als Analgetikum |
US6355652B1 (en) | 1999-11-27 | 2002-03-12 | Boehringer Ingelheim Pharma Kg | Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and their use as pharmaceutical compositions |
DE19957156A1 (de) * | 1999-11-27 | 2001-05-31 | Boehringer Ingelheim Pharma | Substituierte 1,2,3,4,5,6-Hexahydro-2,6-methano-3-benzazocine und ihre Verwendung als Arzneimittel |
US6683089B2 (en) | 2002-02-02 | 2004-01-27 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | N-allyoxyethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine-10-ols |
DE10204276A1 (de) * | 2002-02-02 | 2003-08-07 | Boehringer Ingelheim Pharma | N-Allyloxyethyl-1,2,3,4,5,6-Hexahydro-2,6-methano-3-benzazocine und ihre Verwendung als Arzneimittel |
US20040019075A1 (en) * | 2002-05-29 | 2004-01-29 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New formulation for the parenteral application of crobenetine |
DE10223783A1 (de) * | 2002-05-29 | 2003-12-11 | Boehringer Ingelheim Pharma | Neue Formulierung zur parenteralen Applikation eines Na-Kanal-Blockers |
US6828311B2 (en) | 2002-05-29 | 2004-12-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Formulation for the parenteral application of a sodium channel blocker |
US20030235576A1 (en) * | 2002-06-15 | 2003-12-25 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New drug combinations for the treatment of ischaemic conditions |
DE10226814A1 (de) * | 2002-06-15 | 2004-01-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Arzneimittelkombinationen zur Behandlung ischämischer Zustände |
RS54522B1 (en) | 2005-12-22 | 2016-06-30 | Newron Pharmaceuticals S.P.A. | 2-Phenylethylamino Derivatives as Modulators of Calcium and (or Sodium) Channels |
CN101687773B (zh) | 2007-06-15 | 2014-07-30 | 纽朗制药有限公司 | 取代的2-[2-(苯基)乙氨基]烷酰胺衍生物及其作为钠和/或钙通道调节剂的应用 |
EA022973B1 (ru) | 2011-06-27 | 2016-03-31 | Ньюрон Фармасьютикалс С.П.А. | Фторированные арилалкиламинокарбоксамидные производные |
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DE2828039A1 (de) * | 1978-06-26 | 1980-01-10 | Boehringer Sohn Ingelheim | 2-(2-alkoxyethyl)-2'-hydroxy-6,7-benzomorphane deren saeureadditionssalze diese enthaltende arzneimittel und verfahren zu deren herstellung |
US4208523A (en) | 1978-11-30 | 1980-06-17 | Sterling Drug Inc. | 11-Lower-alkyl-, 11-phenyl-lower-alkyl- and 11-cyclo-lower-alkyl-lower-alkyl-hexahydro-2,6-methano-3-benzazocines |
DE4121821A1 (de) * | 1991-07-02 | 1993-01-14 | Boehringer Ingelheim Kg | Neue benzomorphane und ihre verwendung als arzneimittel |
US5607941A (en) * | 1992-06-26 | 1997-03-04 | Boehringer Ingelheim Kg | Useful for treating neurodegenerative diseases |
DE19528472A1 (de) * | 1995-08-03 | 1997-02-06 | Boehringer Ingelheim Kg | Neues Verfahren zur Herstellung von Norbenzomorphan einer Zwischenstufe bei Herstellung von pharmazeutisch wertvollen Benzomorphanderivaten, insbesondere von (-)-(1R,5S,S"R)-3'-Hydroxy-2-(2-methoxypropyl-)-5,9,9-trimethyl-6,7 benzomorphan |
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