BETA-AMINO KETONES - SYNTHESIS AND SOME BIOLOGICAL-ACTIVITIES IN MICE OF 3,3-DIALKYL-1,2,3,4-TETRAHYDRO-4-QUINOLINONES AND RELATED MANNICH-BASES
BETA-AMINO KETONES - SYNTHESIS AND SOME BIOLOGICAL-ACTIVITIES IN MICE OF 3,3-DIALKYL-1,2,3,4-TETRAHYDRO-4-QUINOLINONES AND RELATED MANNICH-BASES
复制标题
DOI：
10.1021/jm00254a008
复制
发表时间：
1974-01-01
影响因子：
7.3
通讯作者：
BAUER, L
中科院分区：
文献类型：
--
作者：
DARUWALA, AB;GEARIEN, JE;BAUER, L
一系列Mannich碱，基于-烷基-d-二甲氨基丙基苯环骨架，以及密切相关的环状类似物，即。合成了3-烷基取代的L-甲基-L，2，3，4-四氢-4-喹啉酮类化合物。在小鼠身上对它们进行了镇痛和抗惊厥活性的筛选。此外，还用增强戊巴比妥钠睡眠时间的方法测试了一些化合物的镇静活性。一系列开链/3-氨基酮和与L密切相关的2，3，4-四氢-4-喹诺酮类化合物已被报道具有镇痛作用。该系列中的几个成员表现出了足够的生物活性，证明有必要对一些相关化合物进行进一步研究(表I)。曼尼奇基地。从先前研究d-二甲氨基苯丙酮，ArCOC、C、NMeQ的镇痛活性的研究中，出现了先导化合物5(表I)。在这个特殊的结构中，活性的亚甲基质子被两个甲基取代。人们寻求对这类分子进行结构修饰，并启动了一个项目来合成一些Mannich碱。这项研究的第一阶段是准备I类化合物(表I)。目的是检测当C6H5COCHRCH2NMe2中酮的侧翼只有一个烷基时生物活性的变化，并评估将R中的烷基链从CH3延长到n-CSH？的影响。这些曼尼希碱基具有可同化的体系-COCHR-。通过合成不可能发生烯醇化的第二类Mannich碱，验证了烯醇形式可能是活性物种的可能性。这些化合物显示了良好的止痛活性，并计划开发一系列对位取代的衍生物，如表I中的第二类。本系列中的对位取代基被设计成在脂亲性和电子性方面有所不同(类型II，表I)。为了确定酮功能是否对这些生物活性是必要的，用NaBH*将其中几个Mannich碱还原为相应的氨基醇(类型，表I)。这些醇至少与抗惊厥药一样有效，如果不是比相应的酮II更有效的话。
A series of Mannich bases, based on the-alkyl-d-dimethylaminopropiophenong skeleton, and closely related cyclic analogs, viz. 3-alkyl-substituted l-methyl-l, 2, 3, 4-tetrahydro-4-quinolinones, was synthesized. They were screened in mice for analgetic and anticonvulsant activities. In addition, a number of these compounds were tested for seda-tive properties through the method involving sodium pentobarbital sleeping time potentiation.A series of open-chain/3-amino ketones and closely re-lated l, 2, 3, 4-tetrahydro-4-quinolinones was previously re-ported to have analgetic properties1 (Haffner tail-pinch method2). Sufficient biological activity was exhibited by several members in the series to warrant further investigation of a number of related compounds (Table I). Mannich Bases. From prior studies which investigated d-dimethylaminopropiophenones, ArCOC^ C^ NMeQ, for analgetic activity, there emerged the lead compound 5 (Table I). In this particular structure, the active methy-lene protons were replaced by two methyl groups. Struc-tural modification of this type ofmolecule was sought and a project initiated to synthesize a number of Mannich bases. The first phase of this study was to prepare com-pounds of type I (Table I). The aim was to detect changes in biological activity when only one alkyl group flanks the ketone in C6H5COCHRCH2NMe2 and assess the affect of lengthening the alkyl chain in R from CH3to n-CsH?. These Mannich bases possess an enolizable system,-COCHR-. The possibilitythat the enol form may be the active species was tested by synthesizing type II Mannich bases in which enolization is impossible. These showed good analgetic activity and a series of para-substituted derivatives, type II in Table I, was planned. The para substituent in this series was designed to vary in lipophil-ic and electronic character (type II, Table I). To ascertain if the ketone function was essential to these biological activities, several of these Mannich bases were reduced with NaBH* to the corresponding amino alcohol (type, Table I). These alcohols were at least as effective as anticonvulsants, if not more so, than the cor-responding ketones, type II.