Patent GB-894913-A (GB)
Title: Substituted aralkyl phenothiazinylalkyl piperazines
IPC: C07D417/06
Filed: 1959-05-13
Abstract: The invention comprises compounds of the general formula <FORM:0894913/IV (b)/1> (wherein Y represents a hydrogen or chlorine atom or a methyl, trifluoromethyl, methoxy, trifluoromethoxy, acetyl, trifluoroacetyl, methylmercapto, trifluoromethylmercapto, methylsulphonyl, trifluoromethylsulphonyl or cyano group, A represents a C2-4 alkylene chain separating the two attached nitrogen atoms by at least 2 carbon atoms, R1, R2, R3 and R4 represent hydrogen atoms or methyl or ethyl groups, B represents a C1-4 alkylene or C3 or C4 alkenylen chain, and Z represents an amino, mono- or dimethylamino, acylamino, nitro, methoxy or methylmercapto group) and their non-toxic acid addition salts, and the preparation thereof by the methods of the examples, which may be summarized as follows: (a) (when Z is other than NH2) reacting a compound of the general formula <FORM:0894913/IV (b)/2> with a compound of the general formula <FORM:0894913/IV (b)/3> (wherein X represents a chlorine, bromine or iodine atom and W has the meanings given for Z, other than NH2); (b) (when Z=NH2) reducing the corresponding compounds in which Z = NO2; (c) (when Z is acylamino) treating the compounds in which Z = NH2 with an acyl halide in an inert organic solvent; (d) treating the free bases with inorganic or organic acids to form salts.  The products, which can be resolved into optically active isomers have a variety of medicinal uses. 10-Piperazinoalkylphenothiazines of the second general formula above are prepared by reacting an appropriate phenothiazine compound with an o -haloalkylpiperazine in which the second nitrogen atom carries a substituent (e.g. benzyl, formyl, carbobenzoxy, carbomethoxy or carbethoxy) which is easily removable and is subsequently removed or by reacting a 10-(o -ester-alkyl)-phenothiazine with an N-monosubstituted piperazine in which the substituent is an easily removable group and is subsequently removed.  2-Y-Phenthiazines, in which Y is CF3CO-, CF3O- or CF3SO2-, are prepared by cyclization, by the action of anhydrous potassium carbonate in the presence of copper bronze powder, of the corresponding 2-bromo-21-amino-41-Y-diphenyl sulphides, themselves prepared by reduction with stannous chloride of the corresponding 21-nitro compounds obtained by condensing o-bromothiophenol with, respectively, 4 - chloro - 3 - nitro - a , a , a  - trifluoroaceto - phenone, 3 - nitro - 4 - chlorophenyl trifluoro - methyl ether, and 3-nitro-4-chlorophenyl trifluoromethyl sulphone.  4 - Chloro - 3 - nitro - a , a , a  - trifluoroaceto - phenone is prepared by nitrating 4-chloro-a ,a ,a -trifluoroacetophenone, obtained by the action of trifluoroacetyl chloride on chlorobenzene in the presence of aluminium chloride.  3 - Nitro - 4 - chlorophenyl trifluoromethyl ether is prepared by the Sandmeyer reaction from 3-nitro-4-aminophenyl trifluoromethyl ether obtained by nitration of 4-aminophenyl trifluoromethyl ether.  3 - Nitro - 4 - chlorophenyl trifluoromethyl sulphone is prepared by oxidizing 3-nitro-4-chlorophenyl trifluoromethyl sulphide with chromic anhydride in sulphuric acid. 2-Trifluoromethylmercaptophenthiazine is prepared by chlorinating 3-bromophenyl methyl sulphide to form 3-bromophenyl trichloromethyl sulphide, heating this with antimony trifluoride to produce 3-bromophenyl trifluoromethyl sulphide, condensing this with acetanilide in the presence of anhydrous potassium carbonate and copper bronze powder and hydrolysing the product to 3-trifluoromethylmercaptodiphenylamine and heating this with sulphur in the presence of iodine.  N - Carbethoxy - N1 - (3- chloropropyl) - 2, 5 - dimethylpiperazine is prepared by reacting N-carbethoxy-2,5-dimethylpiperazine with 1-bromo-3-chloropropane.  N - Carbethoxy - N1 - (3 - chloro - 2 - methyl - propyl)-piperazine is prepared by reacting N-carbethoxypiperazine with 1-bromo-3-chloro-2-methylpropane.  p-Acetamidocinnamyl bromide is prepared by treating pnitrocinnamyl alcohol with PBr3, reducing the resulting bromide and acetylating the resulting p-aminocinnamyl bromide.  3-Chloro-1-(p-methylaminophenyl)-butene-1 is prepared by Meerwein-Ponndorf reduction of p-nitrostyryl methyl ketone, converting the resulting nitroalcohol to its chloride with SOCl2, reducing the nitro group, and alkylating the amino group with methyl iodide and potassium carbonate.  3 - (p - Butyramidophenyl) - 1 - chloropropane is prepared by acylating the free amino compound with butyryl chloride.  p-Methylaminophenethyl bromide is prepared by alkylating p-aminophenylethyl bromide with methyl iodide.  2 - Chloro - 1 - (p - methoxyphenyl) - propane is prepared by addition of HCl to p-allylphenol to give 2-chloro-1-(p-hydroxyphenyl)-propane, and treating the sodium salt of this with dimethyl sulphate. Specifications 716,205, 724,217, 799,919, 802,726, 805,887, 813,861, 819,886, 851,886, 851,887, 851,951 and 851,952 are referred to. Reference has been directed by the Comptroller to Specifications 716,206, 780,193, 802,725, 805,886 and 868,959.