Patent GB-1138163-A (GB)
Title: Benzothiophene derivatives having anti-fertility properties
Inventor: CRENSHAW RONNIE RAY
IPC: C07D333/56
Filed: 1966-05-20
Abstract: 1,138,163. Benzothiophene derivatives. BRISTOL-MYERS CO. 20 May, 1966 [21 May, 1965], No. 22678/66. Heading C2C. Novel benzothiophene derivatives of the formula wherein R<SP>1</SP> and R<SP>2</SP> are the same or different and are each a hydrogen atom, a chloro, bromo, iodo, fluoro, trifluoromethyl, hydroxy, C 1-8  alkyl, C 1-8  alkoxy, amino, di-C 1-8 -alkylamino or C 1-8  alkanoylamido radical, and R<SP>3</SP> is a C 1-8  alkyl group or a group of the formula -CnH 2 n-NR<SP>4</SP>R<SP>5</SP> wherein n is an integer from 1 to 6 and R<SP>4</SP> and R<SP>5</SP> are the same or different and each is a C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, phenyl or phenyl-C 1-8 -alkyl group, or a cycloalkyl group having from 3 to 7 carbon atoms, or when taken together with the adjacent nitrogen atom are pyrrolidino, C 1-8  - alkylpyrrolidino, di - C 1-8 - alkylpyrrolidino, piperidino, C 1-8  - alkylpiperidino, di - C 1-8  - alkylpiperidino, morpholino, C 1-8  - alkylmorpholino, di - C 1-8  - alkylmorpholino, tetrahydropyridino, C 1-8 -alkyltetrahydropyridino, di - C 1-8  - alkyltetrahydropyridino, N<SP>1</SP> - C 1-8  - alkylpiperazino, N<SP>1</SP>-C 1-8  - alkyl - C 1-8 - alkylpiperazino, N<SP>1</SP> - C 1-8  - alkyl - di - C 1-8 - alkylpiperazino, hexamethyleneimino, C 1-8 - alkylhexamethyleneimino, or a di-C 1-8 -alkylhexamethyleneimino group; and their S-dioxides and any pharmaceutically acceptable addition salts are obtained by (1) reacting 2-halobenzoyl chlorides R 1 HalC 6 H 3 COHal, where Hal represents chlorine, bromine or iodine, with benzene compounds C 6 H 5 OR<SP>3</SP> and either reacting the halogen-substituted benzophenones produced with α-toluene thiols R<SP>2</SP>C 6 H 4 -CH 2 SH, to give a 2-benzylthiobenzophenones which are then cyclized with strong bases to give the above benzothiophene derivatives or reacting the halogen-substituted benzophenones with the α- toluene thiols and strong bases to give the benzothiophene compounds directly, (2) reacting aromatic thiols R<SP>1</SP>C 6 H 4 SH dissolved in solutions of sodium in alcohol with α-haloketones R<SP>3</SP>OC 6 H 4 .CO.CH.Hal.C 6 H 4 R<SP>2</SP> to produce α-(arylthio) benzyl ketones which are then cyclized to the above benzothiophene compounds, or (3) when R<SP>3</SP> is a C 1-8  alkyl group, reacting the corresponding compounds in which R<SP>3</SP> is a hydrogen atom with alkylating agents, these compounds being obtainable by method (1) or (2), and if desired reacting the products with oxidizing agents, e.g. hydrogen peroxide, or acids to give the corresponding S-dioxides or addition salts respectively. Certain of the above benzothiophene compounds may be obtained from other compounds within the above definition, e.g. compounds in which R<SP>3</SP> is CnH 2 nNR<SP>4</SP>R<SP>5</SP> or R<SP>1</SP> or R<SP>2</SP> is a C 1-8  alkoxy group may be obtained by reacting the corresponding hydroxy compounds with Cl-CnH 2 nNR<SP>4</SP>R<SP>5</SP> or an alkylating agent, and amino compounds may be obtained by reduction of the corresponding nitro compounds and may be converted into the corresponding alkonoylamido or chloro, bromo, iodo or fluoro compounds by reaction with acid anhydrides or via the diazonium salts respectively. Similar interconversions may also be made at previous stages in the synthens, e.g. hydroxy substituted halo-benzophenones may be obtained by reacting the corresponding methoxy compound with BBr 3  or HBr. Pharmaceutical compositions useful as antifertility agents contain the above benzothiophene derivatives as active ingredients. The compositions are in a form suitable for oral administration.