SYNTHESIS OF PHARMACOLOGICALLY ACTIVE NITROGEN ANALOGS OF TETRAHYDROCANNABINOLS
SYNTHESIS OF PHARMACOLOGICALLY ACTIVE NITROGEN ANALOGS OF TETRAHYDROCANNABINOLS
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DOI：
10.1021/jo00924a021
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发表时间：
1974-01-01
影响因子：
3.6
通讯作者：
CASTAGNOLI, N
中科院分区：
文献类型：
--
作者：
CUSHMAN, M;CASTAGNOLI, N
The synthesis of a nitrogen analog of A1, 6)-trans-tetrahydrocannabinol, a psychoactive component of Canna-bis sativa L, is described. The condensation of 2, 6-dimethoxy-4-n-amylbenzylidenemethylamine (9) with glutar-ic anhydridein refluxing xylene provided trons-l-methyl-5-carboxy-6-(2, 6-dimethoxy-4-n-amylphenyl)-2-piperi-done (11). Subsequent transformations yielded the desired tricyclic system 27 in which theC-2 methylene of All6,-trons-tetrahydrocannabinol is replaced by an (V-methyl moiety. Configurational and conformational as-signments of the intermediates were made by nmr spectroscopy. The diastereomeric mixture of amines 4 and 5 5 obtained on catalytic reduction of 27 possesses both antidepressant and anticonvulsant activity.Two psychoactive constituents of Cannabis have been shown, 1-trans-tetrahydrocannabinol (A1-THC, l) 2 and 1 (61-irons-tetrahydrocannabinol (1 6,-THC, 2). 3 We re-cently reported the synthesis of a series of model nitrogen analogs of the THC’s, including 3.4 Since a phenolic group and an alkyl side chain have been demonstrated to be structural requirementsfor pharmacologic activity, 5’6 our model compounds did not appearto be promising candi-dates for biologic evaluation. We now wish to report the successful extension of our studies to the preparation of the nitrogen analog of 1 (6!-, compound 27. Catalytic reduction of 27 gave a diastereomeric mixture of amines 4 and 5. Preliminary pharmacologic tests7 indicate that this mixture possesses both antidepressant (modified dopa test in mice; marked activity at 5 mg/kg) and anticonvulsant (audiogenic seizure in mice; 60% protection at 30 mg/kg) activity.
