Patent GB-1120735-A (GB)
Title: Improvements in or relating to thieno-benzothiazine derivatives
Inventor: RENZ JANY
IPC: A61K31/54
Filed: 1965-09-30
Abstract: <FORM:1120735/C2/1> <FORM:1120735/C2/2> <FORM:1120735/C2/3> <FORM:1120735/C2/4> <FORM:1120735/C2/5> <FORM:1120735/C2/6> <FORM:1120735/C2/7> <FORM:1120735/C2/8> <FORM:1120735/C2/9> <FORM:1120735/C2/100> an <FORM:1120735/C2/111> Novel compounds of Formula I, wherein (i) R1 is H, Cl, Br, C1- 4 alkoxy, C1- 4 alkylthio, C1- 4 alkylsulphinyl, C2- 4 aliphatic acyl CF3 or CN, R2 is H, each of R3 and R4 is H or CH3 and each of R5 and R6 is C1- 4 alkyl, or R5 and R6 together with the nitrogen atom form a piperidino radical which may be substituted in the 4-position by a hydroxy group, or a 1-piperazinyl radical which may be substituted on the second nitrogen atom by a C1- 4 alkyl or 2-hydroxyethyl radical, or (ii) R5 is C1- 4 alkyl, R3 together with R6 forms a trimethylene chain, and R1, R2 and R4 are as defined in (i) above, or (iii) R4 together with R6 forms a trimethylene or tetramethylene chain, and R1, R2 and R3 are as defined in (i) above, and R5 as in (ii) above, and their acid addition salts, are prepared by reacting a compound of Formula II with a compound of Formula III, in which Hal is Cl, Br or I, in the presence of an inert organic solvent and an acid binding agent, and optionally salifying the product.  Compounds of Formula Ia, in which R13, R14, R15 and R16 have the same meanings as R3, R4, R5 and R6, respectively, in (i) above, and their salts, are also prepared by reacting a compound of Formula IV, in which Hal1 is Cl or Br, with a compound of Formula V, and optionally salifying the product.  Compounds of Formula II are prepared by condensing an appropriate 2-amino-thiophenol, preferably in the form of an alkali metal salt, with 3-bromo-2-nitro-thiophene and heating the resulting sulphide of Formula VI, preferably after acylation of the primary amino group to form the corresponding acylamino compound, in a suspension of potassium or sodium carbonate in dimethyl formamide in the presence of copper.  Compounds of Formula IV are prepared by reacting a compound of Formula II with 1-chloro-3-bromopropane or 1-bromo-3-iodopropane optionally substituted by one or two methyl groups, in the presence of an alkaline condensation agent and an inert organic solvent.  4- or 5-R1-2-amino-thiophenols are prepared by reacting a 2-bromo-, 2-chloro- or 2-iodonitrobenzene, which may be correspondingly substituted in the 4- or 5-position, with an alkali metal sulphide and powdered sulphur to produce a 2,21-dinitro-diphenyl-disulphide, which may be substituted in the 4,41- or 5,51-position reducing this compound to the corresponding 2,21-diamino compound, splitting the disulphide linkage in alcoholic solution with a strong alkali metal base, and liberating the required thiophenol derivative from the resulting alkali metal salt. Compounds of Formula VII, in which R11 is C1- 4 alkylsulphinyl, are prepared by oxidizing a compound of Formula VIII, in which R111 is C1- 4 alkylthio and R17 is C1- 4 aliphatic acyl or benzoyl, with hydrogen peroxide in boiling alcoholic solution and saponifying the resulting compound of Formula IX by alkaline hydrolysis.  Compounds of Formula X, in which R17 is C1- 4 aliphatic acyl or benzoyl are prepared by brominating a compound of Formula XI.  3 - [1 - (2 - Hydroxyethyl) - piperazinyl - 4]- 1 - chloropropane is prepared by reacting 1-(2-hydroxyethyl)-piperazine with 1-chloro-3-bromo-propane. Pharmaceutical compositions having sedative, neuroleptic, antidepressant and antihistaminic properties, for enteral or parenteral administration, comprise a compound of the invention together with a carrier.