CN86102479A - (一)-1β-乙基-1α-羟甲基-1,2,3,4,6,12,12bα -八氢吲哚基〔2,3-2〕喹嗪的制备方法 - Google Patents
(一)-1β-乙基-1α-羟甲基-1,2,3,4,6,12,12bα -八氢吲哚基〔2,3-2〕喹嗪的制备方法 Download PDFInfo
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- CN86102479A CN86102479A CN86102479.6A CN86102479A CN86102479A CN 86102479 A CN86102479 A CN 86102479A CN 86102479 A CN86102479 A CN 86102479A CN 86102479 A CN86102479 A CN 86102479A
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- ethyl
- compound
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- quinolizine
- alpha
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Abstract
本发明涉及通式Ⅰ及其酸加成盐和用拆开相应的外消旋化合物及随后任意水解和/或成盐途径提供制备通式Ⅰ化合物及其酸加成盐的方法。通式Ⅰ化合物有显著的外周血管扩张和抗缺氧的活性。
Description
根据本发明的另一方面,提供了制备通式(I)化合物及其酸加成盐的方法,此方法包括:将具有通式(IIa)的1α-乙基-1β-酰氧基甲基-1,2,3,4,6,7,12,12bβ一八氢吲哚基〔2,3-a〕喹嗪衍生物和具有通式(IIb)的1β-乙基-1α-酰氧基甲基-1,2,3,4,6,7,12,12bα一八氢吲哚基〔2,3-a〕喹嗪衍生物
(其中,R1为氢;烷基部分含1-6个碳原子的烷基羰基;被任意取代的芳基羰基或烷基部分含1-6个碳原子的芳烷基羰基)的1∶1混合物拆开,并任意地将得到的新的具有旋光活性的通式(III)的(-)-1β-乙基-1α-酰氧基甲基-1,2,3,4,6,7,12,12bα-八氢吲哚基〔2,3-a〕喹嗪衍生物
(其中,R2为烷基部分含1-6个碳原子的烷基羰基,被任意地取代的芳基或其烷基部分含1-6个碳原子的芳烷基羰基)进行水解,如果需要的话,用酸处理得到的新的具有通式(I)的(-)-1β-乙基-1α-羟甲基-1,2,3,4,6,7,12,12bα-八氢吲哚基〔2,3-a〕喹嗪。
在上面通式中,烷基R1和R2可以表示任何含有1-6个碳原子的直链或支链烷基,例如甲基,乙基,正-丙基,异丙基,正-丁基,异丁基,叔-丁基,正-戊基,异戊基等。芳基R1和R2可以表示单环或多环的(稠合的或非稠合的)芳香烃基,例如苯基,二苯基或萘基等。“芳烷基”一词是指上述定义的芳基和烷基的任何组合。
通式(I)化合物显示了优良的药物活性,特别是心血管、尤其是外周血管扩张及抗缺氧活性。
在匈牙利专利说明书NO.170,495(英国专利说明书NO.1,499,546)中公开了1,1-双取代的八氢吲哚基〔2,3-a〕喹嗪。这种化合物可以在1位上被取代,其中,取代基与本发明的化合物的取代基一致。然而,在这些化合物中,在1-位上的取代基和12b-氢的构型没有确定,进一步说,尽管在说明书和权利要求中旋光活性的化合物和拆开方法也给予一般的公开,但明确公开的化合物都是外消旋体。
已知的外消旋化合物具有血管扩张性质,在外周和大脑循环系统中都能观察到这种活性,即所述化合物的血管扩张活性没有选择性。与此形成鲜明对照的是,本发明的化合物具有选择性的外周血管扩张活性。已知的化合物与本发明的化合物进一步的区别是,前者没有抗缺氧活性,而本发明的化合物在具有外周血管扩张活性的同时还具有抗缺氧活性。
根据Helv,Chim.Acta,
60,1801(1977),外消旋反式1-乙基-1-羟甲基-1,2,3,4,6,7,12,12b-八氢吲哚基〔2,3-a〕喹嗪是通过将在长春蔓胺合成中作为中间体得到的、在1位上含有醛基的相应外消旋反式化合物还原来制备的。然而,在上述文献中没有提到所得到的化合物的拆开,也未提及相应的旋光活性的化合物或它们可能具备的任何药物活性。
根据在Caz.Chim.Italiana
111,257(1981)中所描述的方法,外消旋反式1-乙基-1-羟甲基-1,2,3,4,6,7,12,12b-八氢吲哚基〔2,3-a〕喹嗪是通过在二异丙基乙胺的存在下,将1-乙基-六氢吲哚基〔2,3-a〕喹嗪鎓高氯酸盐与甲醛水溶液在乙腈中加热来制备的。此文献中也提到了外消旋化合物。但此文献中没有公开相应的旋光活性的衍生物、所得到的化合物的拆开、及此化合物或其衍生物的任何药物活性。
出人意外地发现,在先有技术中没有明确公开并且从未制备过的、具有旋光活性的通式为(I)的、反式(-)-1β-乙基-1α-羟甲基-1,2,3,4,6,7,12,12bα-八氢吲哚基〔2,3-a〕喹嗪具有优良的选择性的外周血管扩张活性。这一点与相应的外消旋化合物相反,相应外消旋化合物表现出无选择性的、一般的血管扩张活性。此外,两者的基本区别在于本发明得到的具有旋光活性的化合物在很低的剂量下(例如,0.03毫克/公斤静脉注射剂量)即显示出它的选择性的外周血管扩张活性,而相应的外消旋化合物在大约高出2个数量级的剂量下(例如,1毫克/公斤静脉注射剂量)才显效。本发明化合物的一个更大的、出乎意料的优点是它的附加的抗缺氧活性。这种活性与选择性的外周血管扩张活性相结合,在治疗中提供了新的可能性。而相应的外消旋化合物根本不具有抗缺氧活性。
在本发明的方法中作为原料的通式(IIa)和(IIb)外消旋化合物是按照匈牙利专利说明书NO.170,495(英国专利说明书NO.1,499,546)中公开的方法制备的。
通式(IIa)和(IIb)化合物的拆开可以用已知的方法进行。例如,根据一个较好的实施方案,用一种旋光活性的酸进行拆开,较好的为D-酒石酸,二苯甲酰基-D-酒石酸,莰烯-磺酸等。
拆开一般都是在适当选择的惰性有机溶剂中进行的,如脂肪酮(例如丙酮),脂肪醇,或在这些溶剂与水的混合物中进行。
将同有旋光活性的酸形成的酸加成盐分离为一对相应的非对映异构盐,如果需要的话,从左旋的盐可以游离出(deliberated)通式为(III)的反式化合物的相应碱。碱的游离(deliberation)最好是通过将盐溶解或悬浮在水中或与水不混溶的有机溶剂与水的混合物中进行,有机溶剂可为任意卤代的脂肪烃或芳香烃,直链的或环状的醚如二氯甲烷,氯仿,乙醚,甲苯等;用无机碱使溶液或悬浮液碱化,无机碱可为碱金属碳酸盐,如碳酸钾或碳酸钠,氨等,如果需要的话,用上述任一与水不混溶的有机溶剂萃取通式(III)的左旋反式碱。可以通过蒸发,将通式(III)的左旋反式碱从其与水不混溶的有机溶剂的溶液中分离出来。如果需要的话,可以通过从适当的溶剂中重结晶来进一步提纯新得到的反式通式(III)化合物,适当的溶剂可为含有1-6个碳原子的脂肪醇,如甲醇。
通式(III)的左旋反式化合物的水解最好是在碱性介质中进行。合适的碱包括碱金属醇盐,如甲醇钠等。水解最好是在惰性有机溶剂中完成。更好是在含1-6个碳原子的脂肪醇(如甲醇)中进行。另一方面,水解可以与无机碱在水/醇介质中进行。水解温度一般为60-100℃,最好是在惰性有机溶剂中加热使反应混合物沸腾。水解反应可在短时间内完成。
如果需要的话,可用已知方法与酸反应使根据上述方法制备的式(I)化合物转化为它的酸加成盐。这样的酸包括:无机酸类如氢卤酸(例如:氢氯酸和氢溴酸),硫酸,磷酸和高卤酸(如高氯酸等);有机羧酸类如甲酸,乙酸,丙酸,羟基乙酸,马来酸,羟基马来酸,富马酸,琥珀酸,酒石酸,抗坏血酸,柠檬酸,苹果酸,水杨酸,乳酸,肉桂酸,苯甲酸,苯乙酸,对-氨基苯甲酸,对-羟基苯甲酸,对-氨基-水杨酸等;烷基磺酸类如甲基磺酸,乙基磺酸等;环脂磺酸类如环己基磺酸,萘基磺酸,对氨基苯磺酸(sulfanylicacid)等;氨基酸类如天冬氨酸,谷氨酸,N-乙酰基-天冬氨酸,N-乙酰基-戊二酸等。
盐的形成可以在惰性有机溶剂如含有1-6个碳原子的脂肪醇中进行。将通式(I)化合物溶解在溶剂中,将选择好的酸或其与上述同样的溶剂配制的溶液加入式(I)化合物的溶液中,直到略显酸性(PH值:5-6)。随后,将酸加成盐分离出来,并可以采用如过滤的方法将其分出。
如果需要的话,可以将本发明化合物进一步提纯,例如通过重结晶。
通过(I)化合物的血管扩张活性是在麻醉的狗身上试验的。在动物的股动脉和内颈动脉上放置电磁流计(Hellige),在血管床中的血流量以毫升/分计量。用Statham压力传感器测量动脉平均压力,该传感器与一导入动脉的聚乙烯套管相接。每分钟的脉搏数由测量血压的动脉脉搏成份而定,后者用频率计测量。所有测量的参数连续地记录在多通道的多种波动描记器上。
为了比较,除本发明通式(I)化合物外,也试验了相应的右旋反式化合物和已知的相应消旋反式化合物。
在使用的剂量内,本发明的新的左旋反式化合物对脉膊数和颈动脉血流没有影响。所有三种化合物具有过渡的、轻微的、低血压活性。在已知的外消旋化合物情况下,血压约降低20%,(+)-异构体为6%,本发明的(-)异构体为7-10%。发现本发明的新的左旋反式化合物具有明显的提高股动脉血压的活性。为了作比较,对结构上不同的五氧费林(pentoxyfilline)(一种广泛使用的外周血管扩张剂)也进行了试验。结果列于表1。
将每种化合物进行了更多的动物试验。将个别的结果进行平均。表中列出了动物数(n),测量参数的平均值及其变化的百分率。
测定了静脉内给药(静脉注射)的起始基本值和最大变化。
表1
在静脉注射情况下试验化合物对股动脉中血流量的影响。
化合物 | 剂量毫克/公斤 | n | 血流量(毫升/公斤) | % | 活性持续时间(分) | |
基本 | 最大变化 | |||||
外消旋体(+)(-)五氧费林 | 1.00.031.00.030.010.032.0 | 5242675 | 306042.56240.242.349.6 | 146.67554.5626399.660.6 | +144+25+280+57+135+22 | 15.613.702.39.61.5 |
表1中的结果表明,本发明的新的反式(-)-立体异构体的外周血管扩张活性比五氧费林(Pentoxyfilline)更好。此外,与相应的消旋化合物和(+)-异构体比较,出乎意料地发现,本发明的(-)-立体异构体的外周血管扩张活性比相应的(+)-立体异构体高100倍,而比相应的外消旋化合物高30倍。
尽管在极端的情况下,可发生这种情况,即两种可能的立体异构体之一可能与相应的外消旋化合物具有基本相同的活性,而另一异构体就根本无效,即两种立体异构中只有一种具有活性,但本发明则不是这样。我们的试验结果已完全出乎意料地表明,本发明的左旋反式立体异构体的外周血管扩张活性比相应的外消旋化合物高出大约30倍。
进一步说,根据表1中列出的结果可明显看出,当已知的外消旋反式化合物与新的右旋反式化合物在1.0毫克/公斤剂量下均最有效时,本发明的新的左旋反式化合物的最有效剂量却仅为0.03毫克/公斤。根据表中公开的数据,当在这样小(0.03毫克/公斤)的剂量下给药时,相应的右旋反式立体异构体根本就无效,而已知的外消旋反式化合物的作用比本发明的(-)-化合物弱6倍左右。此外,这种外消旋化合物这样低的活性也仅能持续1分钟,而本发明的(-)反式化合物的活性持续时间大约可延长10倍,即10分钟左右。
用在标准大气的缺氧条件下清醒的小鼠进行本发明的新的左旋反式化合物的抗缺氧活性实验。将五只雄性小鼠放进3升的、不断吹入含96%氮气和4%氧气的混合气的玻璃圆筒中。分别测量每只小鼠放入玻璃圆筒到它们死之为止的时间间隔,其最大值为15分钟。
如果动物的存活时间比未经处理的动物死亡时间(6.2分钟)延长两倍,即从实验开始后存活了12.4分钟,即认为小鼠受到了保护。在将小鼠放入玻璃圆筒之前30分钟,将参考物质以50毫克/公斤的剂量给20只小鼠腹腔给药。而本发明的通式(I)的(-)反式异构体的给药剂量为25毫克/公斤。将直至动物死亡所需的时间平均化。将用药物处理过的动物死亡时间与未处理过的动物死亡的平均对照时间差值百分数计算出来,即为存活时间的变化。作为最重要的活性特征参数,受到保护的小鼠的数目,即那些在放入缺氧介质后12.4分钟仍然存活的小鼠数目,也列于表中。
一方面,将本发明的新的左旋反式化合物的抗缺氧活性与相应的外消旋反式化合物及相应的右旋反式立体异构体的活性比较。另一方面,也同其它在英国专利说明书NO.1,499,546中公开的外消旋反式化合物进行了比较研究。后一比较试验的目地在于确定是否其它结构近似的化合物其左旋反式异构体也比其相应的消旋体及右旋化合物其有明显的、较高的活性及本质上不同的活性。
这个试验的结果列于表2。
表2
试验化合物使小鼠在缺氧介质中存活时间和保护作用。
相对于平均对照 受到保护的
化合物
存活时间的变化(%) 小鼠百分数(%)已知的(±)-1-羟甲基衍生物〔英
+25 10国专利说明书NO.1,499,546,通式(II)*R1为氢原子〕
*术语“通式(II)”是指通式(IIa)化合物与通式(IIb)化合物的1∶1混合物。**剂量为25毫克/公斤
新的(+)-1-羟甲基 +15 10衍生物 |
新的(-)-1-羟甲基衍+75 70生物〔通式(I)**〕 |
已知的(±)-1-酰氧基甲基衍生物〔英国专+4 5利说明书No.1,499,546,通式(II)R1为甲基 |
新的(+)-1-酰氧+3 0基衍生物 |
新的(-)-1-酰氧基甲基衍生物〔通式(III) +31 10R2为甲基〕 |
已知的(±)-1-丙酰氧基甲基衍生物〔英国专利说明-11 0书No.1,499,546,通式(II)*R1为乙基〕 |
新的(+)-1-丙酰氧基+38 20甲基衍生物 |
新的(-)-1-丙酰氧基甲基衍生物〔通式(III) -6 0R2为乙基〕 |
列于表2中的结果表明,本发明的新的(-)反式立体异构体具有显著的抗缺氧活性,也就是说,即使在小剂量情况下,它也能显著地增强身体组织和器官对缺氧的忍受性。而相应的(+)反式异构体及相应的外消旋反式化合物实际上缺乏这种活性。对于治疗指征来说,抗缺氧活性是非常优越的,这是因为在一些疾病情况下伴随有血管收缩,使组织和器官中的供血大量减少,从而发生缺氧使组织坏死。因此,血管扩张作用与增强细胞对缺氧的抵抗力结合起来在治疗上是很有利的。
已知的外消旋和右旋反式化合物甚至在较大剂量下也不具有抗缺氧活性。10%保护的频率不具有统计学上的显著意义,因为未经处理的小鼠也可能证明在这个比例数上得到保护。
从试验可进一步看出,当与相应的外消旋体及右旋反式化合物比较时,在结构近似的有关化合物中,只有本发明的新的左旋反式异构体具有这一重要的和新的活性。不论在英国专利说明书No.1,499,546中公开的外消旋反式1-酰氧基甲基或1-丙酰氧基甲基衍生物,或者通过将上述化合物拆开得到的相应的具有旋光活性的通式(III)左旋化合物,或者相应的右旋化合物都不具有任何显著的抗缺氧活性。
通式(I)新的左旋反式化合物可用于治疗中,首先是在那些伴随有血管收缩的疾病的治疗中。希望的治疗剂量是:肠胃外给药时为0.01-1.0毫克/公斤体重,口服时为0.5-5.0毫克/公斤体重。
为了治疗的目的,可以将通式(I)新的化合物及其生理上可接受的盐配制在一起。因此,本发明还涉及到药剂组合物。这种组合物包括作为活性组分的通式(I)化合物或其生理上可接受的酸加成盐,与药物载体和/或赋形剂相结合。常规的用于此目的的并适于肠胃给外药的载体以及其它添加剂都可使用。作为载体,固态或液态化合物 如水、明胶、乳糖、淀粉、果胶、硬脂酸镁、硬脂酸、滑石粉;植物油如花生油、橄榄油等,都是可以使用的。可以将化合物按常规药剂配方制成各种剂型,如固态剂型(球形的和角形的丸剂,糖衣丸,胶囊剂如硬明胶胶囊剂)或液态剂型(可注射的油的或水的溶液或悬浮液)。固态载体的量可在较宽的范围内变化,但较好的为25毫克到1克之间。组合物中还可随意地包含传统的药用添加剂,如防腐剂,湿润剂,调整渗透压的盐,缓冲剂,调味剂和香味物质。
本发明组合物可随意地包含通式(1)化合物与其它已知的活性组分。根据给药途径来选择单位剂量。药剂组合物可用常规的技术来制备,包括将活性组分过筛,混合,制成颗粒,压制或溶解。然后将得到的配方进行常规的附加处理,如消毒。
借助于下述不具限制意义的实施例,对本发明进行详细的说明。
实施例1
(+)-1β-酰氧基甲基-1α-乙基-1,2,3,4,6,7,12,12bβ-八氢吲哚基〔2,3-a〕喹嗪和(-)-1α-酰氧基甲基-1β-乙基-1,2,3,4,6,7,12,12bα-八氢吲哚基〔2,3-a〕喹嗪
将溶于25毫升无水丙酮中的1.1319克(7.54毫摩尔)D-酒石酸溶液加入到热的溶于25毫升无水丙酮中的1.3619克(7.54毫摩尔)(±)-1-酰氧基甲基-1-乙基-1,2,3,4,6,7,12,12b-八氢吲哚基〔2,3-a〕喹嗪(英国专利说明书No.1,499,546)的溶液中。混合物在室温下静置24-28小时。将折出的结晶过滤出来,用最少量的丙酮洗涤后得到2.00克相应的酒石酸盐。将此盐溶解于50毫升的蒸馏水中,在冰-水冷却条件下用5%碳酸钠水溶液将其PH值调至8。用二氯甲烷分三次(每次20毫升)萃取此碱性溶液。用无水硫酸镁干燥合并的有机溶液,然后在真空中蒸发。将剩留油在甲醇中结晶,得到1.20克(97.4%)右旋的标题化合物,为一结晶物质。
熔点:122-123℃
〔α〕D=+38.7°(C=1,二氯甲烷)
将经过拆开的毋液在真空中蒸发得到1.65克固体泡沫状物。基本仿照上述步骤,产物从甲醇中结晶,得到1.00克(81.2%)左旋的标题化合物。
熔点:122-123℃
〔α〕D=-37.5°(C=1,二氯甲烷)
实施例2
(+)-1α-乙基-1β-羟甲基-1,2,3,4,6,7,12,12bβ-八氢吲哚基〔2,3-a〕喹嗪和(-)-1β-乙基-1α-羟甲基-1,2,3,4,6,7,12,12bα-八氢吲哚基〔2,3-a〕喹嗪
(a)将根据实施例1中的方法制备的1.95克(5.97毫摩尔)的(+)-1β-酰氧基甲基-1α-乙基-1,2,3,4,6,7,12,12bβ-八氢吲哚基〔2,3-a〕喹嗪溶解在100毫升的热甲醇中,随后加入0.05克(0.92毫摩尔)甲醇钠,将混合物回流30分钟。将反应混合物冷却至室温,然后倾入300毫升蒸馏水中,将析出的白色结晶过滤出来并用冷水洗涤。
得到1.65克(97.6%)右旋的标题化合物,为一白色结晶物质。
熔点:220-221℃
〔α〕D=+110.4°(C=1,二甲基甲酰胺)
(b)基本仿照(a)中所描述的步骤,但采用根据实施例1制备的(-)-1α-酰氧基甲基-1β-乙基-1,2,3,4,6,7,12,12bα-八氢吲哚基〔2,3-a〕喹嗪作原料。得到1.60克(94.2%)左旋的标题化合物,为一结晶物质。
熔点:220-221℃
〔α〕D=-108.0°(C=1,二甲基甲酰胺)
左旋标题化合物的氢溴酸盐是从10倍于此化合物体积的热丙酮48%的氢溴酸水溶液中制得的。
熔点:280-282℃
从甲醇中结晶后的熔点:285-287℃
Claims (5)
1.制备具有旋光活性的、通式(I)反式(-)-1β-乙基-1α-羟甲基-1,2,3,4,6,7,12,12bα-八氢吲哚基〔2,3-a〕喹嗪及其酸加成盐的方法,此方法包括将具有通式(IIa)的1α-乙基-1β-酰氧基甲基-1,2,3,4,6,7,12,12 bβ-八氢吲哚基〔2,3-a〕喹嗪衍生物与具有通式(IIb)的1β-乙基-1α-酰氧基甲基-1,2,3,4,6,7,12,12bα-八氢吲哚基〔2,3-a〕喹嗪衍生物(其中R1为氢;烷基部分含1-6个碳原子的烷基羰基;被任意取代的芳基羰基或烷基部分含1-6个碳原子的芳烷基羰基)的1,1混合物拆开,并将得到的具有通式(III)的新的旋光活性的(-)-1β-乙基-1α-酰氧基甲基-1,2,3,4,6,7,12,12bα-八氢吲哚基〔2,3-a〕喹嗪衍生物
(其中,R2为烷基部分含1-6个碳原子的烷基羰基;被任意取代的芳基或烷基部分含1-6个碳原子的芳烷基羰基)水解,如果需要的话,用酸处理得到的新的(-)-1β-乙基-1α-羟甲基-1,2,3,4,6,7,12,12bα-八氢吲哚基〔2,3-a〕喹嗪。
2.如权利要求1中所要求的方法,此方法包括用D-酒石酸进行拆开。
3.如权利要求1中所要求的方法,此方法包括在碱性条件下进行水解。
4.具有外周血管扩张活性的药剂组合物的制备方法,此方法包括将具有通式(I)的(-)-1β-乙基-1α-羟甲基-1,2,3,4,6,7,12,12bα-八氢吲哚基〔2,3-a〕喹嗪或其生理上可接受的酸加成盐与药物载体和/或赋形剂混合。
5.具有抗缺氧活性的药剂组合物的制备方法,此方法包括将具有通式(I)的(-)-1β-乙基-1α-羟甲基-1,2,3,4,6,7,12,12bα-八氢吲哚基〔2,3-a〕喹嗪或其生理上可接受的酸加成盐与药物载体和/或赋形剂混合。
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HU1519/85 | 1985-04-19 | ||
HU851519A HU194221B (en) | 1985-04-19 | 1985-04-19 | Process for preparing novel octahydro-indolo/2,3-a/quinoline derivative and pharmaceutical comprising this compound |
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US (1) | US4806545A (zh) |
JP (1) | JPH072637B2 (zh) |
CN (1) | CN1023560C (zh) |
AR (1) | AR240699A1 (zh) |
AT (1) | AT390954B (zh) |
AU (1) | AU591896B2 (zh) |
BE (1) | BE904588A (zh) |
BG (1) | BG60433B2 (zh) |
CA (1) | CA1299574C (zh) |
CH (1) | CH668262A5 (zh) |
CS (1) | CS274276B2 (zh) |
DD (1) | DD244556A5 (zh) |
DE (1) | DE3613180C2 (zh) |
DK (1) | DK159780C (zh) |
EG (1) | EG18059A (zh) |
ES (1) | ES8706152A1 (zh) |
FI (1) | FI83870C (zh) |
FR (1) | FR2580649B1 (zh) |
GB (1) | GB2174701B (zh) |
GR (1) | GR861027B (zh) |
HU (1) | HU194221B (zh) |
IE (1) | IE59199B1 (zh) |
IL (1) | IL78538A (zh) |
IN (1) | IN162810B (zh) |
IT (1) | IT1204306B (zh) |
LU (1) | LU86397A1 (zh) |
NL (1) | NL8600976A (zh) |
NO (1) | NO167143C (zh) |
NZ (1) | NZ215879A (zh) |
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HU191454B (en) * | 1984-10-05 | 1987-02-27 | Richter Gedeon Vegyeszeti Gyar Rt.,Hu | Process for producing amides of oktahydro-indolo/2,3-a/quinolyzin-1-yl-alkanecarboxylic acids and pharmaceutically acceptable acid additional salts thereof |
HU195214B (en) * | 1985-04-19 | 1988-04-28 | Richter Gedeon Vegyeszet | Process for producing 12b-substituted-1-(hydroxymethyl)-octahydro-indolo /2,3-a/ quinolizine derivatives and pharmaceutical preparations comprising these compounds |
HU194220B (en) * | 1985-04-19 | 1988-01-28 | Richter Gedeon Vegyeszet | Process for production of derivatives of 1,12 b disubstituated-octahydro-indolo /2,3-a/ quinolisine and medical compounds containing thereof |
HU207070B (en) * | 1990-10-31 | 1993-03-01 | Richter Gedeon Vegyeszet | Process for producing 1beta-ethyl-1alpha-hydroxymethyl-1,2,3,4,6,712,12balpha-octahydroindolo(2,3-a) quinolizine |
DE19821039A1 (de) * | 1998-05-11 | 1999-11-18 | Bayer Ag | Verfahren zur Herstellung von (S,S)-Benzyl-2,8-diazabicyclo[4.3.0]nonan |
IL164203A0 (en) * | 2002-04-03 | 2005-12-18 | Orion Corp | Polycyclic compounds as potent alpah2-adrenoceptorantagonists |
WO2003094917A1 (fr) * | 2002-05-13 | 2003-11-20 | Takata Seiyaku Co., Ltd. | Composition medicinale contenant du vintoperol destinee a une administration transdermique |
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GB1499546A (en) * | 1974-05-07 | 1978-02-01 | Richter Gedeon Vegyeszet | Indolo-quinolizidine derivatives and a process for the preparation thereof |
HU170495B (zh) * | 1974-05-07 | 1977-06-28 | ||
HU195214B (en) * | 1985-04-19 | 1988-04-28 | Richter Gedeon Vegyeszet | Process for producing 12b-substituted-1-(hydroxymethyl)-octahydro-indolo /2,3-a/ quinolizine derivatives and pharmaceutical preparations comprising these compounds |
HU194220B (en) * | 1985-04-19 | 1988-01-28 | Richter Gedeon Vegyeszet | Process for production of derivatives of 1,12 b disubstituated-octahydro-indolo /2,3-a/ quinolisine and medical compounds containing thereof |
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