Potential antihistaminics: Tricyclic carboxylic acids derived from 6,11-dihydrodibenzo[b,e]thiepine and 4,9-dihydrothieno[2,3-c]-2-benzothiepine

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Title:Potential antihistaminics: Tricyclic carboxylic acids derived from 6,11-dihydrodibenzo[b,e]thiepine and 4,9-dihydrothieno[2,3-c]-2-benzothiepine
Creators:
Šindelář, Karel
Holoubek, Jiří
Svátek, Emil
Metyš, Jan
Blehová, Hana
Polívka, Zdeněk
Journal or Publication Title:
Collection of Czechoslovak Chemical Communications, 56, 11, pp. 2482-2493

Abstract

Reaction of nitrile <i>IVa</i> with the Grignard’s reagent 1-methyl-4-piperidylmagnesium chloride gave carbinol <i>XIb</i> as product. Carbinols <i>XIa</i> and <i>XIb</i> were dehydrated and hydrolysed with dilute hydrochloric acid to give hydrochlorides of the tricyclic amino acids <i>Vb</i> and <i>Vc</i>. Isomeric compounds with a carboxyl group in position 9 of the tricyclic skeleton were obtained either by hydrolysis of the formely prepared nitrile <i>VIIb</i> (compound <i>VIIIb</i>) or on reaction of bromoketone <i>VIa</i> with 1-methyl-4-piperidylmagnesium chloride, nucleophilic substitution of the bromine atom by the cyano group at the stage of carbinol <i>XIIIb</i>, and subsequent dehydration and hydrolysis of the cyano group, to give amino acid <i>VIIIc</i>. In the first case the synthesis of thiophene analogues <i>XVIIIb</i> and <i>XVIIIc</i> started from ketone <i>XVa</i>, 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 <i>XVIb</i>. In the second case derivative <i>XVIc</i> was obtained directly by bromination of hydrochloride <i>XVc</i>. Basic bromo derivatives <i>XVIb</i> and <i>XVIc</i> 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 <i>XVIIIb</i> and <i>XVIIIc</i>. Further, some other tricyclic nitriles were synthesized as potential intermediates. The prepared tricyclic amino acids <i>Vb, Vc, VIIIb, VIIIc, XVIIIb</i> and <i>XVIIIc</i> 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 <i>Vc</i> (VUFB-17689) is a strong antihistaminic with distinctly suppressed sedative effects and it was therefore selected for a more detailed pharmacological testing.

Title:Potential antihistaminics: Tricyclic carboxylic acids derived from 6,11-dihydrodibenzo[b,e]thiepine and 4,9-dihydrothieno[2,3-c]-2-benzothiepine
Creators:
Šindelář, Karel
Holoubek, Jiří
Svátek, Emil
Metyš, Jan
Blehová, Hana
Polívka, Zdeněk
Divisions:Life and Chemical Sciences > Institute of Organic Chemistry and Biochemistry > Collection of Czechoslovak Chemical Communications
Journal or Publication Title:Collection of Czechoslovak Chemical Communications
Volume:56
Number:11
Page Range:pp. 2482-2493
ISSN:0010-0765
E-ISSN:1212-6950
Publisher:Institute of Organic Chemistry and Biochemistry
Related URLs:
URLURL Type
http://dx.doi.org/10.1135/cccc19912482UNSPECIFIED
ID Code:5179
Item Type:Article
Deposited On:22 Feb 2010 11:32
Last Modified:22 Feb 2010 10:32

Citation

Šindelář, Karel; Holoubek, Jiří; Svátek, Emil; Metyš, Jan; Blehová, Hana; Polívka, Zdeněk (1991) Potential antihistaminics: Tricyclic carboxylic acids derived from 6,11-dihydrodibenzo[b,e]thiepine and 4,9-dihydrothieno[2,3-c]-2-benzothiepine. Collection of Czechoslovak Chemical Communications, 56 (11). pp. 2482-2493. ISSN 0010-0765

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