Patent GB-898073-A (GB)
Title: Improvements in or relating to sulfonyl substituted phenoxazines
Filed: 1960-05-30
Abstract: The invention comprises substituted phenoxazines of the general formula <FORM:0898073/IV (b)/1> wherein R represents a lower alkyl, dilower alkylamino or trifluoromethyl radical, A represents an alkylene chain having 1 to 4 carbon atoms there being 2 to 4 carbon atoms separating the nitrogen atom of the phenoxazine ring and the proximal nitrogen atom of B, B represents a dilower alkylamino, N-pyrrolidinyl, N-piperidinyl, C-(N-lower alkyl)-piperidinyl, N-piperazinyl, N1-lower alkyl-N-piperazinyl, N1-formyl-N-piperazinyl, N1 - carbethoxy - N - piperazinyl, N1 - hydroxyethyl - N - piperazinyl, N1 - acetoxy - ethyl - N - piperazinyl, N1 - hydroxyethoxyehtyl - N - piperazinyl or N1 - hydroxy - ethoxyethoxy - ethyl-N-piperazinyl radical (lower alkyl groups have 1 to 4 carbon atoms), and the non-toxic acid addition salts thereof (including salts derived from 8-halo-theophyllines, such as 8-chlorotheophylline), and the preparation thereof by alkylating the required sulphonylphenoxazines with reactive aminoalkyl esters, and when the formed 10-(aminoalkyl)-sulphonylphenoxazine derivatives have a piperazinyl group containing an N-protective group removing said N-protective group and further N-alkylating the resulting piperazinyl moiety.  The -SO2R group in the compounds of the above general formula is preferably in the 2-position of the ring.  In the above process the reactive aminoalkyl ester may be a halide or an arylsulphonate, and the process may be carried out in the presence of an acid-binding agent, e.g. an alkali metal amide.  When the reactive amino alkyl ester is a o -haloalkyl-piperazine having the free nitrogen of the piperazinyl moiety protected by an N-protecting group such as a benzyl, carbobenzoxy, carbethoxy or formyl group, the protecting group is removed in the final product by mild hydrolysis. Following removal of the N-protecting group, the piperazine moiety in the final product may be N-alkylated, e.g. by reaction with a reactive ester such as alkyl halide or a halo substituted alcohol or by reaction with an alkylene oxide.  When the final product contains an N1-hydroxyalkyl-N-piperazinyl alkyl radical, the hydroxy group may be subjected to further reaction such as with an acyl halide to form an acyloxy group, or thionyl chloride to form an N-chloroalkyl compound which is then reacted with a suitable alcohol to form an ether link.  3-Methylsulphonyl-phenoxazine is prepared by reacting hydrogen peroxide and 3-chloro-4-nitrophenyl methyl sulphide to form 3-chloro-4-nitrophenyl methyl sulphone, condensing this sulphone with o-bromophenol to form 21-bromo - 5 - methylsulphonyl - 2 - nitrodiphenyl ether, reducing this ether with stannous chloride to form 2-amino-21-bromo-5-methylsulphonyl-diphenyl ether, and heating this compound with formic acid and then with copper-bronze powder. 1-Methylsulphonyl-phenoxazine is prepared by diazotising 3-chloro-2-nitroaniline and then reacting the product with potassium ethyl xanthate to form 3-chloro-2-nitrothiophenol, reacting the thiophenol with methyl iodide to form 3-chloro-2-nitrophenol methyl sulphide, oxidising the sulphide with hydrogen peroxide to form 3-chloro-2-nitrophenol methyl sulphone, treating the sulphone with o-bromophenol to form 21-bromo-3-methyl-sulphonyl-2-nitrodiphenyl ether, reducing the ether with stannous chloride to form 2-amino - 21 - bromo - 3 - methyl - sulphonyl - di - phenyl ether, and heating this compound with formic acid and then with copper-bronze powder. 4-Methylsulphonyl-phenoxazine is prepared by diazotising 2-chloro-3-nitroaniline and then treating the product with potassium ethyl xanthate to form 2-chloro-3-nitrophenol, treating this compound with methyl iodide to form 2-chloro-3-nitrophenyl methyl sulphide, treating the sulphide with hydrogen peroxide to form 2-chloro-3-nitrophenyl methyl sulphone, reacting the sulphone with o-bromophenol to form 21-bromo-6-methyl-sulphonyl-2-nitro-diphenyl ether, reducing this compound with stannous chloride to form 2-amino - 21 - bromo - 6 - methylsulphonyldiphenyl ether, and treating this compound with formic acid and then with copper-bronze powder.  N, N - Diethyl - 2 - phenoxazinyl - sulphon - amide is prepared by reacting diethylamine and 3 - chloro - 3 - nitrobenzenesulphonyl chloride to form 4-chloro-N,N-diethyl-3-nitrobenzenesulphonamide, reacting the sulphonamide with o-bromophenol to form 4-(21-bromophenoxy)-N,N-diethyl-3-nitrobenzene-sulphonamide, reducing this sulphonamide with stannous chloride and hydrochloric acid to form 3 - amino - 4 - (21 - bromo - phenoxy) - N, N - diethylbenzenesulphonamide, and heating this compound with formic acid and then with copper-bronze powder.  10 - [31 - (N - chloroethylpiperazinyl) - propyl] - 2 - trifluoromethylsulphonylphenoxazine dihydro - chloride is prepared by treating the corresponding 31 - (N - hydroxyethylpiperazinyl) compound with thionyl chloride. Specification 897,157 is referred to.