Patent GB-1500744-A (GB)
Title: 2,3-dihydro-1-benzothiepin-4-carboxamides process for their manufacture and pharmaceutical preparations containing them
IPC: C07D337/08
Filed: 1975-09-24
Abstract: 1500744 2,3 - Dihydro - 1 - benzothiepin derivatives CIBA-GEIGY AG 24 Sept 1975 [26 Sept 1974 9 June 1975] 39094/75 Heading C2C Compounds of the general formula where Ph is 1,2-phenylene optionally substituted by one or more of C 1-7  alkyl, alkoxy, alkylthio, halo, -CF 3 , -CN or -NO 2 , X is -OH (or a keto tautomer), C 1-7  alkoxy, alkanoyloxy, di - (C 1-7  alkyl)amino or C 2-7  alkyleneimino, Am is -NH 2 , mono- or di-(C 1-7  alkyl or hydroxyalkyl)amino, C 2-7  alkyleneimino, monoaza-, oxa- or thia-alkyleneimino, cycloalkylamino, C 6 H 5 -NH- or C 6 H 5 -N(alkyl)-, the benzene ring of which may be substituted as for Ph, or is Hc-amino or Hc-N(alkyl)- wherein, He is furyl, thienyl, pyrryl, 1,2- or 1,3-oxazolyl or -thiazolyl, pyrazolyl, imidazolyl, pyridyl, pyridazinyl, pyrimidyl or pyrazinyl or alkyl derivatives thereof, "alk" is C 1-7  alkylene separating the S and C atoms by two carbon atoms and n is 0, 1 or 2, are prepared by (1) reacting a compound of formula where Y is C 1-7  alkoxy with the amine H-Am usually at up to 200‹ C. in an aromatic hydrocarbon solvent and in equivalent amounts, or by (ii) reacting a compound in which X is di-C 1-7  alkyl amino, C 2-7  alkyleneimino or -OY where Y is an alkali metal with an isocyanate Am<SP>11</SP> = CO where Am<SP>11</SP>H is a primary or secondary amino group as for Am at up to 100‹ C. in a polar solvent such as THF or diethylether. The thus - obtained compounds may be converted into other Formula I compounds and salts thereof: the enol ethers (X = alkoxy) and enamines may be hydrolysed to enols which may be salified with bases (particularly 2-aminopyridine, pyrrolidine and morpholine) or alkali metals (particularly sodium); the salts may be acylated to enol esters; enols may be reacted with dialkylamines or alkyleneimines (pyrrolidine, piperidine) to provide enamines of Formula I; enols with n=O may be oxidized to the 1-oxide by sodium periodate or to the 1,1-dioxides by H 2 O 2  or per-acids. The compounds and their salts have pharmaceutical properties and may be made up into compositions, especially as tablets. 7 - Chloro - 5 - dimethylamino - 2,3 - dihydro - -1 - benzothiepin-1,1-dioxide is prepared by reacting the corresponding 5-hydroxy compound with (CH 3 ) 2 NH in the presence of TiCl 4 . The 5- hydroxy compound is obtained by oxidation of 7 - Cl - 5 - OH - 2,3 - dihydro - 1 - benzothiepin with H 2 O 2  in acetic acid and is itself converted to the 5-pyrrolidino or -piperidino derivative by reaction with pyrrolidine or piperidine respectively. The 7-unsubstituted-5-pyrrolidino compound is similarly prepared. The compounds 7 - chloro - 5 - pyrrolidino - 2,3 - dihydro - 1 - benzothiepin - 1,1 - dioxide - 4 - carboxymethyl is prepared by reaction of the non-carboxylated compound with COCl 2  to produce a solution of the 4-acid chloride which is then reacted with methanol/(C 2 H 5 ) 3 N, and is subsequently converted to the 5-hydroxy-4-methyl ester by HCl/ methanol. The 7-unsubstituted analogue of the latter is also prepared. 7 - Chloro - 5 - hydroxy - 2,3 - dihydro - 1- benzothiepin-1-oxide is prepared by oxidation of the corresponding 1-benzothiepin with sodium metaperiodate and is converted to the 5- pyrrolidino derivative.