Patent GB-1297313-A (GB)
IPC: C07D513/04
Filed: 1970-08-10
Abstract: 1297313 1 - [4 - (Thieno[2,3-b][1,5]benzothiazepin - 4 - yl) -1 - piperazinyl - alkyl] - 3 - alkyl- 2-imidazolidinones CIBA-GEIGY AG 10 Aug 1970 [11 Aug 1969] 38403/70 Heading C2C Novel 1 - [4 - (thieno[2,3-b][1,5]benzothiazepin - 4 - yl) - 1 - piperazinyl - alkyl] - 3 - alkyl- 2-imidazolidinones of the general formula wherein R is a C 1-4  alkyl group, n is 2 or 3 and Y is a hydrogen or chlorine atom, and pharmaceutically acceptable acid addition salts thereof are prepared (a) by reaction of an N-thieno- [2,3-b][1,5]benzothiazepin- 4 - yl - piperazine of the general formula or an alkali metal derivative thereof with a reactive ester of a 1-hydroxyalkyl-3-alkyl-2- midazolidinone of the general formula, (b) when n is 2, by reaction of an N-thieno[2,3-b]- [1,5] - benzothiazepin - 4 - yl - piperazine of the second general formula above or an alkali metal derivative thereof with a 1-alkyl-3,3-bis-(2- haloethyl)-urea of the general formula wherein Z is a halogen atom, or an alkali metal derivative thereof; and (c) by reaction of a thieno[2,3-b][1,5]benzothiazepine of the general formula wherein Q is a reactive esterified hydroxy group or an optionally activated alkoxy or alkylthio group, with a 1 -piperazinoalkyl-3-alkyl-2-imidazolidinone of the general formula or an alkali metal derivative thereof; followed potionally by salification of the product. N - Thieno[2,3-b][1,5]benzothiazepin - 4 - ylpiperazines of the second general formula above are prepared by reaction of the corresponding 4 chloro or 4 - methylthio - thieno[2,3-b][1,5]- benzothiazepine with ethyl 1-piperazinecarboxylate and hydrolysis and decarboxylation of the resulting 4 - (thieno[2,3-b][1,5]benzothiazepin - 4 - yl) - piperazine - 1 - carboxylic acid ethyl ester. 1 - (3 - Chloropropyl) - 3 - butyl - 2 - imidazolidinone is prepared by heating 1-butyl-1-(2- chloroethyl) - 3 - (3 - chloropropyl) - urea. 1 - (2- Chloroethyl) - 3 - ethyl - 2 - imidazolidinone is prepared by refluxing 1 -ethyl-3,3-bis-(2-chloroethyl)-urea in the presence of sodium hydride. 2,4 - Dichlorothieno[2,3-b][1,5]benzothiazepine is prepared by condensation of 2-chloro-5-mercaptothiophene with 1-chloro-2-nitrobenzene in the presence of sodium hydroxide, reduction of the resulting 2-(o-nitrophenylthio)-5-chlorothiophene with iron and hydrochloric acid, reaction of the 2 - (o - aminophenylthio) - 5 - chlorothiophene so obtained with phosgene, cyclization of the resulting 2-(o-isocyanatophenylthio)-5-chlorothiophene with aluminium chloride and reaction of the 2-chlorothieno[2,3-b][1,5]benzothiazepin- 4(5H)-one thus produced with phosphorus pentachloride. 4 - Methylthiothieno[2,3-b][1,5]- benzothiazepine is prepared by reaction of o-(2- thienylthio) aniline with thiophosgene, cyclization of the resulting o-(2-thienylthio)-phenyl isothiocyanate with aluminium trichloride and reaction of the thieno[2,3-b][1,5]benzothiazepin- 4(5H)-thione so obtained with methyl iodide in the presence of potassium carbonate; and the 2-chloro derivative thereof is prepared analogously. 1 - [3 - Piperazinopropyl) - 3 - butyl - 2- imidazolidone is prepared by reaction of 1-(3- chloropropyl) - 3 - butyl - 2 - imidazolidinone with ethyl N - piperazine - carboxylate and hydrolysis and decarboxylation of the resulting 1 - [3 - (4 - ethoxycarbonyl - 1 - piperazinyl)- propyl] - 3 - butyl - 2 - imidazolidinone. 1-Alkyl- 3,3-bis-(2-chloroethyl)-ureas are prepared by reaction of diethanolamine with an alkyl isocyanate and treatment of the resulting 1-alkyl- 3,3 - bis - (2 - hydroxyethyl) - urea with thionyl chloride. 1 - Butyl - 1 - (2 - chloroethyl) - 3 - (3- chloropropyl)-urea is prepared by reaction of 1 - butyl - 1 - (2 - hydroxyethyl) - 3 - (3 - chloropropyl)-urea with thionyl chloride Pharmaceutical compositions having central nervous system depressant, adrenolytic and serotonin-antagonistic activity comprise, as active ingredient, a 1-[4-thieno[2,3-b][1,5]- benzothiazepin - 4 - yl) - 1 - piperazinyl-alkyl]- 3 - alkyl - 2 - imidazolidinone of the first general formula above or a pharmaceutically acceptable acid addition salt thereof, together with an inert carrier, and may be administered orally, rectally or parenterally.