3,320,314 United States Patent Office Patented May 16, 1967 2 3,320,314 125 C. Agitation may be employed during the reaction, CHLOROBENZYL SULFAMDES but none is required. William J. Houlihan, Mountain Lakes, N.J., assignor to The tertiary amine medium provides a solvent system Sandoz Inc., Hanover, N.J. in which the reaction takes place. Contemplated tertiary No Drawing. Filled June 15, 1964, Ser. No. 375,288 5 amines include, for example, tri(lower) alkylamines, e.g. 6 Claims. (C. 260-556) triethylamine; (lower) alkyl pyrroles, e.g. N-propyl-pyr This application is a continuation-in-part of application role; pyridine; (lower) alkyl pyridines, e.g. 3-ethyl pyri Ser. No. 339,354, filed on Jan. 22, 1964, and now aban dine; (lower) alkoxy pyridines, e.g. 2,5-dimethoxypyri doned. dine; quinoline; (lower) alkyl quinolines, e.g. 8-ethyl O quinoline; N-(lower) alkyl morpholine, e.g. N-methyl This invention is directed to two groups of benzyl sulf morpholine; and N,N'-di(lower) alkyl piperazine, e.g. amides having one or more chlorine substituents on the N-methyl,N'-ethyl-piperazine. sole aromatic ring. These groups are, respectively, of For the preparation of Compounds II wherein R6 is a the formulae hydrogen atom similar reaction conditions are employed; R1 a primary benzyl amine (V) is substituted for the sec ondary benzyl amine (III), and the reaction medium is an R2- ceN seNH aqueous ethanolic medium: R R3- -H 20 R1 R4 (I) and R2- ot NH R1 -- (IV) - (II) -- NH3 R3 -Rs R' ce ise 25 R2- N NEI k (B) R6 R3 -R5 (V) RA (II) 30 wherein In both reaction (A) and reaction (B) each of R, R, R is either lower alkyl having two or more carbon atoms R, R3, R, R5 and R6 has its above-ascribed meaning. e.g. ethyl, propyl and isopropyl; cyclopropyl; allyl; Compounds III and V are prepared from known starting cy-methallyi; (3-methallyl or 6,6-dimethallyl; materials according to standard art-recognized procedures. each of The temperature at which reactions (A) and (B) are conducted is usually the reflux temperature of the system. R, R2, R3, R4 and R5 is either a hydrogen atom (-H); Compounds I and I are useful as anticonvulsants and lower alkyl, e.g. methyl, ethyl, propyl, isopropyl and mild tranquilizers which may be administered either oral butyl; lower alkoxy, e.g. methoxy, ethoxy, propoxy, ly or parenterally. Oral dosage forms include tablets isopropoxy and butoxy; a fluorine atom (-F); or a 40 and capsules having standard fillers and other compound chlorine atom (-CI); at least one of R, R, R8 and ing constituents. The average daily dose may vary within Ré being a chlorine atom; and the range of from 50 milligrams to 300 milligrams. R8 is either a hydrogen atom (-H) or methyl. The following examples illustrate the invention, all tem In Formula II, in addition, at least one of R, R, R, peratures being in degrees centigrade, the parts and per R4 and R5 must be a hydrogen atom, but both R and R centages being by weight unless otherwise stated, and the can be other than hydrogen in the same molecule. In relationship between parts by weight and parts by volume Formula I there must be at least one hydrogen atom ortho being the same as that between the kilogram and the liter. to the benzyl methylene group. An object of this invention is to obtain low-cost com 50 EXAMPLE 1. pounds which have CNS (central nervous system) activity with little or no direct peripheral effects. A further ob N-methyl-N-2,4-dichloro benzylsulfanide ject is to obtain CNS depressants which possess moderate to marked anticonvulsant activity. These and further objects are accomplished by com 55 pounds of both of the above-defined groups. C- -Cl CH The preparation of Compounds I and the Compounds N-SO2NIH II wherein R6 is methyl is accomplished by heating at a N/ temperature within the range of from about 50° to 250 C. and in a tertiary amine (a) secondary benzyl amine 60 (III) and (b) sulfamide (IV): In a flask equipped with a stirrer and a condenser at R1 tached to a bubble detector dissolve 19.0 parts (0.10 CH2 mole) of N-methyl-2,4-dichloro benzylamine and 9.6 R2- / NH H.N. 65 parts (0.10 mole) of sulfamide in 100 parts by volume of | -- SO2 -}. (I) -- NH3 pyridine. Stir and reflux the resulting solution until gas R-l. 1-H HN sing is no longer detected in the bubble detector. Remove the solvent (pyridine) in vacuo on a rotary evaporator. R4 (A) Crystallize the viscous residue from methanol-water. (III) (IV) 70 There are thus obtained 18.2 parts of N-methyl-N-2,4-di A reaction temperature in excess of 50° C. is recom chlorobenzylsulfamide, melting point (M.P.) 113 to mended, and a preferred range is from about 55 to about 115. 3,320,314 3. 4 In similar manner by separately replacing the N-meth In similar manner by separately replacing the N-meth yl-N-2,4-dichlorobenzylamine by an equivalent amount of yl-3,4-dichloro-benzylamine by an equivalent amount of each of each of: N-cyclopropyl-N-o-chlorobenzylamine, N-methyl-N-chlorobenzylamine, N-cyclopropyl-N-m-chlorobenzylamine, N-methyl-N-p-chlorobenzylamine, N-cyclopropyl-N-p-chlorobenzylamine, N-methyl-N-2,3-dichlorobenzylamine, N-cyclopropyl-N-2,3-dichlorobenzylamine, N-methyl-N-2,5-dichlorobenzylamine, N-cyclopropyl-N-2,4-dichlorobenzylamine, N-methyl-N-3,5-dichlorobenzylamine, N-cyclopropyl-N-2,5-dichlorobenzylamine, N-methyl-N-2,3,4-trichlorobenzylamine, O N-cyclopropyl-N-3,4-dichlorobenzylamine, N-methyl-N-2,3,5-trichlorobenzylamine, N-cyclopropyl-N-3,5-dichlorobenzylamine, N-methyl-N-2,4,5-trichlorobenzylamine, N-cyclopropyl-N-2,3,4-trichlorobenzylamine, N-methyl-N-3,4,5-trichlorobenzylamine and N-cyclopropyl-N-2,3,5-trichlorobenzylamine, N-methyl-N-2,3,4,5-tetrachlorobenzylamine, N-cyclopropyl-N-2,4,5-trichlorobenzylamine, each of the corresponding Compounds I is obtained. 5 N-cyclopropyl-N-3,4,5-trichlorobenzylamine and N-cyclopropyl-N-2,3,4,5-tetrachlorobenzylamine, EXAMPLE 2. each of the corresponding Compounds I is obtained. N-methyl-N-o-chlorobenzyl sulfamide EXAMPLE 4 20 N-2,4-dichlorobenzyl sulfamide Cl (H, N-SO2NE Cl- Cl / H CH2 N-SO-NH2 25 N/ In a flask equipped with a stirrer and a condenser at tached to a bubble detector dissolve 12.5 parts (0.08 In a flask equipped with a stirrer, condenser and drop mole) of N-methyl-o-chlorobenzylamine and 5.8 parts ping funnel place 150 parts by volume of water, 4.8 parts (0.06 mole) of sulfamide in 100 parts by volume of (0.05 mole) of sulfamide and 8.8 parts (0.05 mole) of pyridine. Stir and reflux the resulting solution until gas 30 2,4-dichlorobenzylamine. Stir and bring the mixture to sing is no longer detected in the bubble detector. Remove reflux. Then add dropwise ethanol until a clear solution the solvent (pyridine) in vacuo on a rotary evaporator. results. Continue stirring and refluxing for 10 hours. Crystallize the viscous residue from methanol-Water. Cool to room temperature (20) and filter off the crys There are thus obtained 7.1 parts of N-methyl-N-o-chlo talline product. Crystallize from methanol-water. There robenzylsulfamide, M.P. 112 to 113. are thus obtained 6.1 parts of N-2,4-dichlorobenzylsulf In similar manner by separately replacing the N-meth amide, melting point 129 to 130. yl-o-chlorobenzylamine by an equivalent amount of each In similar manner by separately replacing the 2,4-di of: chlorobenzylamine by an equivalent amount of each of: N-o-methallyl-N-(3-chloro-2-fluoro-4-isopropyl)- 2-chloro-4,5-difluorobenzylamine, 40 2-butyl-3-chlorobenzylamine, N-6-methallyl-N-(4-chloro-3-fluoro-2-methoxy)-benzylamine, 4-chloro-2-methoxybenzylamine, N-6,6-dimethallyl-N-(2,3-dichloro-5-isopropoxy)-benzylamine, 2,3-dichlorobenzylamine,2,4-dichloro-3-ethoxy-5-fluorobenzylamine, - 2,5-dichloro-3-fluorobenzylamine, and N-methyl-N-(2-chloro-3,5-difluoro)-benzylamine,benzylamine, 2,6-dichloro-4-propoxybenzylamine, N-ethyl-N-(2,4-dichloro-3-methoxy)-benzylamine, N-propyl-N-(2,5-dichloro-4-fluoro)-benzylamine, each of the corresponding Compounds II is obtained. N-isopropyl-N-(5-butyl-3,4-dichloro)-benzylamine, EXAMPLE 5 N-allyl-N-3,4-dichlorobenzylamine, N-2-chlorobenzylsulfamide N-propyl-N-2,3,5-trichlorobenzylamine, 50 N-isopropyl-N-(3-methyl-2,4,5-trichloro)-benzylamine, Cl N-ethyl-N-3,4,5-trichlorobenzylamine and E. N-propyl-N-2,3,4,5-tetrachlorobenzylamine, N-SO-NH2 each of the corresponding Compounds I is obtained. 55 In a flask equipped with a stirrer, condenser and drop EXAMPLE 3 ping funnel place 14.1 parts (0.10 mole) of 2-chloro N-methyl-N-3,4-dichlorobenzylsulfamide benzylamine, 9.6 parts (0.10 mole) of sulfamide and 300 parts by volume of water. Stir and bring the mix Cl ture to reflux. Then add dropwise ethanol until a clear 60 Solution results. Continue stirring and refluxing for 10 hours. Cool to room temperature and filter off the crys Cl- SO-NE talline product. Crystallize from ethanol. There are N thus obtained 11.7 parts of N-2-chlorobenzylsulfamide, N/bH, melting point 95 to 96. 65 In similar manner, by separately replacing the 2-chlo In a flask equipped with a stirrer and a condenser at robenzylamine by an equivalent amount of each of: tached to a bubble detector dissolve 15.0 parts (0.08 2,3,4-trichlorobenzylamine, mole) of N-methyl-3,4-dichlorobenzylamine and 7.5 parts 2,3,5-trichlorobenzylamine, (0.08 mole) of sulfamide in 100 parts by volume of pyri 5-isopropoxy-2,3,6-trichlorobenzylamine, dine.