Dihydro- and tetrahydro- iminothiazines

#This invention is concerned with the derivatives of dihydro- and tetrahydro-iminothiazines which by virtue of their ability to inhibit indoleamine-N-methyl transferase are useful in the treatment of certain mental aberrations in man, such as schizophrenia.

#This invention also relates to processes for the preparation of the imines of this invention; to pharmaceutical compositions comprising the imines; and to a method of treating mental aberrations, such as schizophrenia, comprising the administration of the imines and compositions thereof. The imines may be depicted by the generic structure: ##STR1## wherein X--Y is --CH.sub.2 --S-- or --S--CH.sub.2 --.

#N,N-dimethylindoleamines such as dimethylserotonin and dimethyltryptamine are psychotomimetic agents and are believed to be produced in excessive amounts by individuals with certain mental aberrations, most commonly classified as schizophrenia. Indoleamine-N-methyl transferase is an enzyme which catalyzes methylation steps in the biosynthesis of these compounds. Accordingly, it is believed by those skilled in the art that inhibitors of this enzyme will be of therapeutic value in management of the body chemistry of patients having mental aberrations such as schizophrenia and thus result in alleviating some of the symptoms of the disease. Thus it is an object of the present invention to provide the above-described imines and their pharmaceutically acceptable acid addition salts; to provide processes for the preparation of such compounds; pharmaceutical compositions comprising such compounds; and to provide methods of treatment comprising administering such compounds and compositions, when indicated for the treatment/management of mental aberrations such as schizophrenia.

#A solution of 0.945 g. of 5,6-dihydro-2-methyl-thio-4H-1,3-thiazine was dissolved in 10 ml. of methylene chloride at room temperature and 0.460 g. of trimethyloxonium fluoroborate was added. After two hours the methylene chloride was evaporated to dryness and the residue of methyl-5,6-dihydro-2-methylthio-4H-1,3-thiazinium fluoroborate was dissolved in ethanol. Ammonia was bubbled into the solution for 1/2 hour, the ethanol was evaporated to dryness, and the residue was partitioned between chloroform and aqueous sodium hydroxide solution. The chloroform phase was evaporated to dryness, and the residue was dissolved in isopropanol and the solution was acidified with aqueous hydrobromic acid. Ether was added to incipient cloudiness, and the mixture was stored in the freezer until precipitation was complete. The solids were collected and dried to give 0.740 g. of 2-imino-3-methyltetrahydro-1,3-thiazine hydrobromide, m.p. 168.degree.-171.degree. C.

#Employing the procedure substantially as described in Example 1, but substituting for the trimethyloxonium fluoroborate used therein, an equimolecular amount of triethyloxonium fluoroborate, there is produced the intermediate ethyl 5,6-dihydro-2-methylthio-4H-1,3-thiazinium fluoroborate and 3-ethyl-2-imino-tetrahydro-1,3-thiazine hydrobromide, m.p. 194.degree.-195.degree. C.

#A mixture of 5 g. of trimethyloxonium fluoroborate and 5 g. of 3-ethoxy-5,6-dihydro-2H-1,4-thiazine in 75 ml. of methylene chloride was stirred at room temperature for 3 hours after slight warming to cause solution. The solvent was evaporated and the residue of methyl 3-ethoxy-5,6-dihydro-2H-1,4-thiazinium fluoroborate was treated with 50 ml. of concentrated ammonium hydroxide and evaporated to a heavy oil. The oil was dissolved in 50 ml. of 0.5 M hydrochloric acid, washed well with chloroform and made strongly basic with sodium carbonate and then 20% sodium hydroxide solution. The mixture was thoroughly extracted with chloroform and the combined extracts were evaporated to 1.5 g. of oil. The oil (1.2 g.) was dissolved in isopropanol and treated with 1.1 g. of fumaric acid to give 1.1 g. of crystalline 3-imino-4-methyl-tetrahydro-1,4-thiazine fumarate, m.p. 111.degree.-113.degree. C.