Collection of Czechoslovak Chemical Communications - digital archive 

Abstract

Reaction of nitrile IVa with the Grignard’s reagent 1-methyl-4-piperidylmagnesium chloride gave carbinol XIb as product. Carbinols XIa and XIb were dehydrated and hydrolysed with dilute hydrochloric acid to give hydrochlorides of the tricyclic amino acids Vb and Vc. Isomeric compounds with a carboxyl group in position 9 of the tricyclic skeleton were obtained either by hydrolysis of the formely prepared nitrile VIIb (compound VIIIb) or on reaction of bromoketone VIa with 1-methyl-4-piperidylmagnesium chloride, nucleophilic substitution of the bromine atom by the cyano group at the stage of carbinol XIIIb, and subsequent dehydration and hydrolysis of the cyano group, to give amino acid VIIIc. In the first case the synthesis of thiophene analogues XVIIIb and XVIIIc started from ketone XVa, which was brominated with bromine in acetic acid into position 2 of the tricyclic skeleton, followed by Grignard’s reaction with 3-dimethylaminopropylmagnesium chloride in tetrahydrofuran and hydrolysis to bromo derivative XVIb. In the second case derivative XVIc was obtained directly by bromination of hydrochloride XVc. Basic bromo derivatives XVIb and XVIc were reacted with butyllithium in tetrahydrofuran at –60°C to afford corresponding organometallic reagents which, when reacted with solid carbon dioxide, afforded the required amino acids XVIIIb and XVIIIc. Further, some other tricyclic nitriles were synthesized as potential intermediates. The prepared tricyclic amino acids Vb, Vc, VIIIb, VIIIc, XVIIIb and XVIIIc were tested both on animals and in assays of biochemical pharmacology. Some of them displayed considerable antihistaminic activity. The most interesting compound of this series, hydrochloride Vc (VUFB-17689) is a strong antihistaminic with distinctly suppressed sedative effects and it was therefore selected for a more detailed pharmacological testing.