Patent GB-1067471-A (GB)
Title: Thioxanthenesulfonamides and preparation thereof
IPC: A61K31/38
Filed: 1963-09-20
Abstract: The invention comprises I compounds of the formula <FORM:1067471/C2/1> and acid addition salts thereof, wherein R is hydrogen or together with R1 forms a single bond, R1 is hydrogen, C1- 4 alkyl or with R form a single bond, R2 is hydrogen or C1- 4 alkyl, R3 and R4 are each hydrogen or C1- 4 alkyl or together with the nitrogen atom form a pyrrolidino, piperidino, morpholino or 4-lower alkyl piperazino group and A is a dialkylamino, 4-alkylpiperazinyl, 4 - hydroxyalkylpiperazinyl, 4 - acyloxyalkylpiperazinyl, 4 - carbamoylalkylpiperazinyl, 4 - (mono- or di - alkyl) carbamoylalkylpiperazinyl, 4 - alkoxyalkylpiperazinyl, 4 - aryloxyalkylpiperazinyl, 4-hydroxyalkoxyalkylpiperazinyl, 4 - acylalkylpiperazinyl, 4 - aroylalkylpiperazinyl, 4 - carbalkoxypiperazinyl, 4 - carbamoylpiperazinyl, 4 - (mono- or di - alkyl) carbamoylpiperazinyl, 4 - acylpiperazinyl, 4 - aroyl piperazinyl, 4-alkylsulphonylpiperazinyl or 4 - dialkylsulphamoylpiperazinyl group wherein the alkyl and acyl groups have 1-4 carbon atoms; II the process for the preparation of 9-propylidene compounds of the above formula, i.e. compounds wherein R and R1 form a single bond by dehydrating the corresponding 9-hydroxy-9-propyl- or the 9-a -hydroxypropyl compounds and III the compounds 9-[3-(4-methyl-1-piperazinyl) - 1 - hydroxypropyl] - 2 - dimethylsulphamoylthioxanthene and 9 - (3 - dimethylamino - 2 - methylpropyl) - 2 - dimethylsulphamylthioxanthene - 9 - ol. Preferably, the group in the 9-position is a 4-methyl-, hydroxyethyl-, hydroxypropyl-, dimethylsulphamoyl- or methylsulphonyl-, piperazinopropyl or piperazinopropylidene group and R3 and R4 are hydrogen or lower alkyl, e.g. methyl.  Compounds wherein R3 and R4 are hydrogen atoms or C1- 4 alkyl groups and which have a 4-methyl-, 4 - b  - hydroxyethyl-, 4 - g  - hydroxypropyl-, 4 - dimethylsulphamoyl- or 4 - methylsulphonyl-, piperazinopropyl group in the 9-position are made by sulphonating thioxanthene with chlorosulphonic acid, converting the resulting 2-sulphonic acid (Na salt) to the sulphochloride with thionyl chloride, reacting with ammonia or an amine HNR3R4 to give the sulphonamide, forming the lithium derivative by reaction with n-butyl lithium which is then reacted with 1-chloro-3-bromopropane to give a 9-g -chloropropyl derivative and reacting with the appropriate piperazine compound:compounds wherein R3 and R4 are hydrogen atoms or C1- 4 alkyl groups and which have a 4-methyl-4 - b  - hydroxyethyl-, 4 - g - hydroxypropyl-, 4 - dimethylsulphamoyl- or 4 - methylsulphonyl - piperazinopropylidene group in the 9-position are made by converting a 2-sulphamoylthioxanthene to a 9-acetyl-2-sulphamoylthioxanthene by treatment with butyl lithium followed by methyl acetate, reacting with formaldehyde and dimethylamine hydrochloride to give 9 - (3 - dimethylaminopropionyl) - 2 - sulphamoyl - thioxanthene hydrochloride, converting to the corresponding 9-[3-(4-substituted-piperazino) - propanoyl] - derivative by reaction with the appropriately substituted piperazine, reducing to the 9-(1-hydroxy-3-piperazino) propyl compound with NaBH4 and dehydrating, e.g. with pyridine and POCl3 to form the 9-(3-piperazinopropylidene). Compounds having an unsaturated side chain in the 9-position may also be made by treating the appropriate 2-sulphamoylthioxanthene-9-one with a Grignard reagent A.CH2.CHR2.CH2MgCl and dehydrating the resulting 9-hydroxy-9-aminopropyl - 2 - sulphamoylthioxanthene; reacting a 2 - sulphamoyl - thioxanthene - 9 - one with a Grignard reagent of the formula R5.O.CH2.CHR2CH2MgHal wherein R5 is an acid-sensitive group, e.g. 2-tetrahydropyranyl, benzyl or isoamyl, replacing the group OR5 in the resulting 2-sulphamyl-9-hydroxythioxanthyl (9) propyl ether by a halogen atom by reaction with a hydrohalic acid, with simultaneous dehydration and reacting the resulting 9-(3-halopropylidene)-thioxanthene with an amine AH; reacting a 2-sulphamoyl-thioxanthene-9-one with allyl magnesium bromide, dehydrating the 9-hydroxy-9-allyl-thioxanthene compound obtained to give the corresponding 9-allylidene derivative and adding an amine AH or reacting a 2-sulphamoyl-9-alkanone with a propyne derivative HC­C-CH2A and reducing and dehydrating the resulting 9 - hydroxy - 9 - (3 - aminopropyn - (1) - yl) compound. Alternative methods for preparing compounds having an aminopropyl group in the side chain comprise reacting a 2-sulphamoyl-thioxanthene with an ester of an aminoalcohol of the formula Y.CHR1.CHR2.CH2A, wherein Y is an acid residue, e.g. a halogen atom in the presence of an alkali-metal or a suitable derivative thereof; heating a 2-sulphamoyl-9-aminopropylthioxanthene 9-carboxylic acid to eliminate CO2 or reacting an ester of a 3-(2-sulphamoyl - thioxanthene - 9) - propanol - (1) with an amine AH.  The products may be converted into their salts with organic and inorganic acids.  Pharmaceutical preparations for the treatment of excited mental states and having antiemetic activity, comprise the above sulphonamides of the invention or their salts, in liquid or solid dosage forms such as tablets, capsules or solutions, together with conventional pharmaceutical excipients.