Patent GB-829433-A (GB)
Title: Phenothiazine derivatives
Filed: 1956-12-05
Abstract: The invention comprises compounds of the general formula <FORM:0829433/IV (b)/1> and salts thereof, wherein Y and Y1 are halogen or hydrogen atoms, lower alkyl or lower alkoxy groups (containing 1-4 carbon atoms), A is a lower alkylene chain (containing 2-5 carbon atoms), n is 1 or 2 and R is H2, (H) (OH), (H) (Cl), (H) (Br), O, (H) (OAcyl) (Acyl representing a carboxylic acyl group of molecular weight less than 250) or a single hydrogen atom in which case the elements of water or of a hydrogen halide have been split out from an adjacent carbon atom to form an imino cycloalkene and the preparation thereof by reacting a phenothiazine with a 1,5-iminocycloalkane or -alkene in the presence of an acid acceptor, either the phenothiazine or the 1,5-iminocycloalkane or -alkene bearing, attached to nitrogen, a halo-lower-alkyl group, and if desired, reacting the free base product with an acid or ester of an acid to produce an acid addition or a quaternary ammonium salt, or forming a quaternary ammonium salt in a single step by reacting a 10-phenothiazinyl lower-alkyl halide with an N-lower alkyl-1,5-iminocycloalkane. The invention also includes the S-, and N,S-oxides of the phenothiazinyliminocycloalkane or alkene compounds and the preparation thereof by hydrogen peroxideacetone oxidation of the intermediate 10-phenathiazinyl-lower-alkyl halides followed by condensation with the appropriate 1,5-iminocycycloalkane or -alkene, or by hydrogen peroxide oxidation of the N-[(10-phenothiazinyl)-lower - alkyl] - 1,5 - iminocycloalkanes or alkenes.  The various groups R, in the above formula are readily interconvertible, (OH) may be esterified to (OAcyl), or oxidized to (O), saponification and reduction of the respective products giving (OH); reaction with a thionyl halide converts (OH) to (X), where (X) is a halogen atom, and dehydration of an alkane where R is (OH) or dehydrohalogenation where R is (X) gives an alkene; hydrogenation of the alkene yields the alkane, R is (H2). Examples are given of the preparation, by the processes of the invention of compounds of the general formula wherein n is 1 or 2, A a straight or branch chained alkylene radical of 2 to 5 carbon atoms, Y and Y1 are both hydrogen, chlorine, methyl or methoxy, or hydrogen and chlorine, hydrogen and bromine, or hydrogen and methyl, and R is (H) (OH), (O), (H2), (H) (Cl), (H) (Br), (H) (Acetoxy) or (H) (the ring being a cycloalkene) together with hydrochlorides, methyl chlorides and methyl iodides of certain of the bases.  Examples are also given of compounds of the general formula wherein A is a straight chain alkylene group of 2-4 carbon atoms, n is 1 and Y and Y1 either both hydrogen or hydrogen and chlorine and R is (H) (acetoxy, propionoxy, butyryloxy, @b-carboxy propionoxy, cinnamoyloxy, acyloyloxy, crotonoyloxy, trimethoxybenzoyloxy, benzoyloxy, phenylacetoxy, N,N-dimethylcarbamoyloxy, or p-nitrobenzoyloxy) by esterification of the corresponding compounds where R is (H) (OH).  8 - (3 - [10 - (2 - Chlorophenothiazinyl)] propyl)-3-bromotropane (Y, Y1 are H, Cl; n=1; R is (H) (Br)) may be dehydrohalogenated by heating with a base to give 8-(3-[10-(2-chlorophenothiazinyl)] propyl) - nortropidine which may be reduced catalytically to give 8-(3-[10-(2 - chlorophenothiazinyl)] propyl) - nortropane (R is (H2)). 8-(3-[10-(2-Chlorophenothiazinyl - 5 - oxide) propyl]) - 3 - hydroxy - nortropane and -pesudo-nortropane are prepared oxidation of the corresponding phenothiazyl propyl chloride to give 10-(3-chloropropyl)-2-chlorophenothiazine - 5 - oxide and condensing this with nortropine or nor-pseudo-tropine.  8 - (3 - [10 - (2 - Chlorophenothiazinyl - 5 - oxide)] propyl) - 3 - hydroxy - nortropane - 8 - oxide is prepared by oxidation of the corresponding base.  5 - Chloropentyl - p - toluenesulphonate is prepared from p-toluene sulphonyl chloride, tetrahydrofuran and zinc chloride and 10-(5-chloropentyl) phenothiazine by reacting the above product with phenothiazine in the presence of lithium and n-butyl bromide.ALSO:Pharmaceutical compositions for oral or parenteral use comprise tablets, capsules or sterile solutions, containing compounds of the general formula <FORM:0829433/VI/1> and the S-oxides and the N,S-oxides, and a non-toxic acid addition salts or quaternary ammonium salts thereof, wherein Y and Y1 are halogen or hydrogen atoms, lower alkyl or lower alkoxy groups (C1-4), A is a lower alkylene chain (C2-5), n is 1 or 2 and R is H2, (H) (OH), (H) (Cl), (H) (Br), O, (H) (OAcyl) (Acyl being a carboxylic acyl group of molecular weight below 250) or a single hydrogen atom in which case the elements of water or of a hydrogen halide have been split out from an adjacent carbon atom to form an iminocycloalkene.