3,336,308 United States Patent Office Patented Aug. 15, 1967 1. 2 3,336,308 at room temperature. Two mols or a small excess there NOVEL AMNO HALO-BENZYLAMINES over of the halogenation agent, such as chlorine or bro Johannes Keck, Biberach (Riss), Germany, assignor to mine, are used per mol of amino benzylamine. The Boehringer Ingelheim G.m.b.H., Ingelheim am Rhine, hydrochloric or hydrobromic acid salts initially formed Germany, a corporation of Germany thereby may either be isolated directly and may be purified No Drawing. Filed June 4, 1965, Ser. No. 461,492 by recrystallization, or the compounds may be purified Claims priority, application Germany, Oct. 14, 1963, in known fashion by way of their free bases and may then T 24,890; Apr. 9, 1965, T 28,358 be transformed into any other desired acid addition . 10 Claims. (C. 260-247.5) Method B-Reaction of a (3,5-dihalo-diacylamino This application is a continuation-in-part application 10 benzyl) halide of the formula of my copending applications Ser. No. 237,714 filed Nov. 14, 1962 and Ser. No. 403,339, filed Oct. 12, 1964, now abandoned. X >- CH-Hal The invention relates to novel amino-halo-benzylamines 5 (Ac).2N having a formula selected from the group consisting of X wherein X has the above definition, Hal is a halogen and NH R Ac is any desired acyl radical with an of the formula 20 N R R1 H-NC and - R1 25. wherein R and R1 have the above definition and subse quently splitting off the acyl radicals. This reaction is performed in the presence of an agent II which ties up or neutralizes the hydrogen halide split off 30 by the reaction. An inorganic or tertiary organic or wherein G is a halogen selected from the group consisting also an excess of the amine of Formula IV may be used of chlorine and bromine, R is selected from the group for this purpose, an excess of at least one mol of amine consisting of hydrogen, lower alkyl, hydroxy lower alkyl, being used per mol of (3,5-dihalo-diacylamino-benzyl)- halo lower alkyl, lower alkenyl, cyclo alkyl, aralkyl and halide. The reaction is advantageously performed in the aryl, R1 and R2 are selected from the group consisting of 35 presence of an inert organic solvent, such as , ben lower alkyl, lower alkenyl, cycloalkyl, aralkyl, hydroxy Zene, toluene, etc., and at elevated temperatures, preferably lower alkyl, halo lower alkyl, pyridyllower alkyl, and aryl, at the of the particular solvent employed. In and R and R1, and R1 and R2 when taken together with the event that an excess of the amine IV or a tertiary the nitrogen atom form a heterocyclic selected from the organic base is employed as the agent to tie up the group consisting of pyrrolidino, lower alkyl pyrrollidino, 40 hydrogen halide split off by the reaction, these agents may piperidino, lower alkyl piperidino, piperazino, lower alkyl simultaneously serve as the solvent for the reactants. piperazino, hexamethylene imino, lower alkyl hexamethyl The deacylation is effected according to known method, ene imino, and Ri and R2 together with the nitrogen atom preferably by heating the acylated compound with a dilute also form a heterocyclic selected from the group consist mineral acid or a dilute inorganic base. ing of lower alkyl morpholino and morpholino, and R3 45 Method C.-Reduction of (halo-nitro-benzyl) amine and R4 are different and are selected from the group of the formula consisting of hydrogen and -NH2 and their non-toxic, pharmacologically acceptable acid addition salts. Lower alkyl means alkyl having 1 to 7 carbon atoms. The inven- . NO2 i R tion also relates to novel compositions and method of 50 -CBI-N increasing secretion of the trachea-bronchial, an of y R1 Suppressing coughs. The compounds of the invention may be prepared by and methods which are well known in principle for the synthe X sis of other halogenated-amino-benzylamines. The follow 55 Ri ing processes have been found to be especially advan ? -CH-N- tageous but the compounds may also be prepared by other known analogous methods. No, YT- Ra Method A.-Chlorination or bromination of amino 60 wherein R, R1, R2 and X have the above definitions. benzylamines of the formula The reaction is performed according to known meth ods, preferably by catalytic reduction, for instance, with hydrogen in the presence of precious metal catalysts, Such as platinum or palladium, advantageously in a 65 solvent, such as methanol, ethanol, tetrahydrofuran or dioxan; or by reduction with hydrazine hydrate , preferably in a solvent such as methanol; or by reduction with nascent hydrogen which is formed from wherein R1,R2 R3 and R4 have the above definitions. iron, zinc or tin and a mineral acid, for example. How The reaction is performed in the presence of an inert 70 ever, the reduction may also be performed by any other organic solvent, preferably in the presence of a halogenated known process for transformation of aromatic nitro hydrocarbon or glacial acetic acid, and advantageously compounds into aromatic amino compounds. 3,336,308 e 4. ed tion had been added, the phase was shaken Method D.-By reduction of an amino-halo-benzamide with 100 cc. of 2 N sodium hydroxide. The chloroform of the formula phase was then separated, dried over sodium sulfate and evaporated. The oily residue was identified to be N-(2-amino-3,5-dibromobenzyl)-diethylamine of the for R1 mula N NE N Ra C2Es X Br CH-N and 10 X C2H5 R. R3- - -N br R This compound was dissolved in 50 cc. of ethanol, and R4 5 then was introduced into the Solu tion, whereby the hydrochloride of the free base was ob wherein R, R, R2, R, R and X have the above defini tained. The hydrochloride had a of 214 tions. 214.5 C. The best yields are obtained by reducing the said 20 EXAMPLE 2 benzamides with a complex metal halide, preferably Preparation of N-(4-amino-3,5-dibromobenzyl) - diethyl lithium aluminum hydride. The reduction is carried out amine hydrobromide in an inert anhydrous organic solvent, preferably abso lute ether, and at moderately elevated temperatures, A solution of 39.5 gm. of bromine in 150 cc. of glacial most advantageously at the boiling point of the solvent. 25 acetic acid was slowly added dropwise to a solution of The reduced product can be isolated from the reaction 12.6 gm. of N-(4-aminobenzyl)-diethylamine in 150 cc. mixture in customary fashion. of glacial acetic acid, accompanied by stirring. The glacial The starting materials for the above methods are known acetic acid was decanted from the precipitate, and the from the literature or may be prepared by methods de precipitate was recrystallized from ethanol. It was identi Scribed in the literature. For example, the diacylamino 30 fied to be N-(4-amino-3,5-dibromo-benzyl)-diethylamine halo-benzyl halides may be prepared by reacting 2-diacyl hydrobromide of the formula amino-halotoluene with N-bromosuccinimide or with halogen under ultraviolet light. The nitro-halo-benzyl C.H. may be prepared by reacting a nitro-halo-benzyl BT CH-N HBr halide with an appropriate amine. The amino-halo-benz C2H5 amides may be prepared by a halo-nitrobenzoyl halide HN with a secondary amine and reducing the nitro group of the intermediate to an amino group. Br The free bases of the invention may be transformed having a melting point of 218 C. (decomposition). by known methods into their non-toxic, pharmacological 40 ly acceptable acid addition salts, for instance, by react EXAMPLE 3 ing an alcoholic solution of the particular acid with the Preparation of N-(2-amino-3,5-dibromobenzyl)-disobu free base. Examples of suitable acids are inorganic acids tylamine hydrobromide Such as , hydrobromic acid, sulfuric acid, phosphoric acid and organic acids such as lactic A solution of 8.5 gm. of bromine in 30 cc. of glacial acid, citric acid, tartaric acid, maleic acid, 8-chloro 45 acetic acid was added dropwise to a solution of 6.09 gm. theophylline, etc. The said addition salts are of 2-aminobenzyl-diisobutylamine in 150 cc. of glacial soluble. acetic acid, accompanied by stirring. The glacial acetic The novel compounds of the invention possess useful acid was decanted from the precipitate formed thereby, pharmacodynamic properties in warm-blooded animals. and the precipitate was recrystallized from ethyl acetate. More particularly, they exhibit an excellent secretolytic It was identified to be N-(2-amino-3,5-dibromobenzyl)- activity (increase bronchial secretions) with extremely diisobutylamine hydrobromide of the formula low toxicity and cough-Suppressing, monoaminooxidase NE iso-C4H9 inhibiting and antipyretic activities. / The dosage unit of the compound of the invention is Br CH-N HBr from 1 to 100 mg. depending upon the desired activity. Thus, the effective individual dose for increasing bron iso-C4H9 chial Secretion is from 0.5 to 10 mg., preferably 2 to 4.0 mg, while the effective antitussive dose is 10 to 100 mg., Br preferably 25 to 50 mg. The compounds can be ad ministered perorally or parenterally in the form of tablets, 60 having a melting point of 165-167 C. coated pills, syrups, aerosols, solutions, suspensions, Sup EXAMPLE 4 positories, etc. Preparation of N-(2-amino-3,5-dibromobenzyl) - dialyl In the following examples there are described several amine hydrochloride preferred embodiments to illustrate the invention. How 65 ever, it should be understood that the invention is not A mixture of 24.7 gm. of 2-diacetylamino-3,5-dibromo intended to be limited to the specific embodiments. benzyl bromide, 11.8 gm. of diallylamine, and 300 cc. of ethanol was refluxed for 24 hours. Thereafter, the alcohol EXAMPLE 1. was distilled off and the residue was dissolved in 1 liter Preparation of N-(2-amino-3,5-dibromobenzyl)- of hot 3 N hydrochloric acid and the solution was refluxed diethylamine hydrochloride 70 for 12 hours. Subsequently, the solution was made alka A solution of 11.6 gm. of bromine in 50 cc. of chloro line with 10 N sodium hydroxide, and the alkaline solu form was added dropwise to a solution of 6.4 gm. of tion was shaken three times with 300 cc. portions of chlo 2-aminobenzyl diethylamine in 50 cc. of chloroform, roform. The chlorfoorm extract solutions were combined, accompanied by stirring. After all of the bromine solu 75 dried over sodium sulfate and then the chloroform was 3,336,308 5 6 evaporated. The residue was identified to be N-(2-amino solution, the hydrochloride of N-(2-amino-3,5-dibromo 3,5-dibromobenzyl)-diallylamine of the formula benzyl)-N-methyl-cyclohexylamine precipitated out. It NH had a melting point of 232-235 C. (decomposition). CH-CH=CH2 - The p-toluene sulfonate (C2H2BrNOS) had a melt BT CH-N ing point of 218-219 C. (decomposition). The perchlorate (C14H2BrCNO) had a melting CH-CH=CH point of 132.5-134° C. The phosphate (C14H2Br2NOP) had a melting point B of 137-138.5° C. The residue was dissolved in a small amount of ethanol, O The hydrobromide (CHBr3N2) had a melting point and then gaseous hydrogen chloride was introduced into of 227.5-228 C. (decomposition). the solution, whereby a precipitate formed. This precipi The oxalate (C18H22Br2N2O4) had a melting point of tate was separated by vacuum filtration and was dissolved 182-183° C. in about one liter of ethyl acetate. Upon concentration The nitrate (C4HaBr2N3O3) had a melting point of of the solution to about 300 cc., N-(2-amino-3,5-dibromo 15 135-136 C. benzyl)-diallylamine hydrochloride crystallized out. It The sulfate (CHBr2N2SO4 CHOH) had a melting had a melting point of 109-113 C. point of 108-109 C. EXAMPLE 5 EXAMPLE 7 Preparation of N-(4-amino-3,5-dibronobenzyl)-diallyl 20 Preparation of N-(4-amino-3,5-dibromo-benzyl)-N- amine hydrochloride methylbenzylamine hydrobromide A mixture of 20.3 gm. of 4-diacetylamino-3,5-dibromo A solution of 31.6 gm. of bromine in 30 cc. of glacial acetic acid was added dropwise to a solution of 18.0 gm. benzyl bromide, 6.9 gm. of diallylamine and 300 cc. of of N - (4 - amino-benzyl)-N-methyl-benzylamine, accom anhydrous ethanol was refluxed for 20 hours. Thereafter, 25 panied by stirring. The precipitate formed thereby was the ethanol was distilled off and the oily residue was dis separated from the glacial acetic acid by decanting, and solved in one liter of hot 3 N hydrochloric acid. The the precipitate was recrystallized from ethanol. It was resulting solution was refluxed for 10 hours. Subsequently, identified to be N-(4-amino-3,5-dibromo-benzyl)-N-meth the reaction solution was made alkaline with 10 N sodium ylbenzylamino hydrobromide of the formula hydroxide and was shaken three times with 700 cc. por 30 tions of chloroform. The chlorofrom extract solutions CH3 were combined, dried over sodium sulfate and concen Br CH-N Br trated. The partly oily and partly solid residue was taken up in absolute ethanol and the solution was filtered until HN YcH-C-H. clear. It was found to be a solution of N-(4-amino-3,5- 35 dibromobenzyl)-diallylamine of the formula br CH-CH-CH having a melting point of 202-206 C. BI CE-N EXAMPLE 8 CH-CH=CH 40 Preparation of N-(2-amino-3,5-dibromobenzyl)- HN pyrrollidine hydrochloride br 17.0 gm. of N-(o-aminobenzyl)pyrrollidine were dis in ethanol. Thereafter, the solution was concentrated to solved in 500 cc. of chloroform, and the resulting solution about 50 cc. and hydrogen chloride was introduced. After was admixed in small portions at room temperature, ac a short period of time the hydrochloride of N-(4-amino 45 companied by stirring, with a solution of 34.0 gm. of 3,5-dibromobenzyl)-diallylamine crystallized out. It had bromine in 500 cc. of chloroform (which corresponds to a ratio of 2.2 mols of bromine per mol of N-(o-amino a melting point of 191-195 C. benzyl)-pyrrolidine). The reaction product, which initially EXAMPLE 6 separated out as an oil was allowed to stand for about Preparation of N-(2-amino-3,5-dibromobenzyl)-N-meth 50 half an hour while repeatedly stirring and scraping the yl-cyclohexylamine sides of the container with a glass rod, whereupon crys tallization set in gradually. The yellow crystals were sep A solution of 29.3 gm. of bromine in 50 cc. of glacial arated by vacuum filtration and were washed with a small acetic acid was slowly added dropwise to a solution of amount of chloroform. The crystals were thereafter dis 15.9 gm. of N-(2-aminobenzyl)-N-methyl-cyclohexyla 55 solved in hot water, the resulting solution was made mine, acocmpanied by stirring. The glacial acetic acid alkaline to a pH of 11 with concentrated , and was decanted from the precipitate formed during the the alkaline solution was shaken four times with 250 cc. addition of the bromine solution, and the precipitate was portions of chloroform. The chloroform extract solutions thereafter shaken with 200 cc. of 2 N sodium hydroxide were combined, dried with soda, filtered and the chloro and 600 cc. of chloroform until all of the solids went into 60 form was distilled off in vacuo. A brownish oil remained solution. The chloroform phase was allowed to separate as a residue, which was identified to be N-(2-amino-3,5- from the aqueous phase. The chloroform phase was de dibromobenzyl)-pyrrolidine of the formula canted, evaporated to dryness and the residue was dis solved in absolute ether. The resulting solution was found NH to be a solution of N-(2-amino-3,5-dibromobenzyl)-N- 65 Br -CH-N methyl-cyclohexylamine of the formula Y NH

Br N CE-N\ D Br N 70 C3 This residue was dissolved in 44 cc. of absolute ethanol and the solution was heated to a temperature of 40-50 C. The clear solution was then admixed with 35 cc. of Br aqueous 10% hydrochloric acid. The mixture was allowed in ethanol. Upon introducing hydrogen chloride into this 75 to stand at 0° C. for several hours, whereupon the hydro 3,336,308 7 8 chloride of N-(2-amino-3,5-dibromobenzyl)-pyrrolidine was prepared from bromine and N-(2-aminobenzyl)-diso crystallized out in the form of colorless, fine crystals, propylamine. which were separated by vacuum filtration and washed Its hydrochloride had a melting point of 159-160° C. with ether. The hydrochloride had a melting point of EXAMPLE 13 219-220 C. Using a procedure analogous to that described in Ex EXAMPLE 9 ample 3, N-(2-amino-3,5-dibromobenzyl)-dipentylamine Preparation of N-(2-amino-3,5-dibromobenzyl)- piperidine hydrochloride hydrobromide of the formula NH (CH2)4-CH3 A solution of 16.3 gm. of bromine in 100 cc. of chloro O form was added dropwise to a solution of 9.67 gm. of Br- -CH-N ..HBr N-(2-aminobenzyl)-piperidine in 150 cc. of chloroform, accompanied by stirring. The resulting reaction mixture YoCH)-CH, was shaken with 200 cc. of 2 N sodium hydroxide, the chloroform phase was separated, and the aqueous phase Br was again shaken with chloroform. The combined chloro was prepared from bromine and N-(2-aminobenzyl)-di form phases were dried over sodium sulfate and evapo pentylamine. The product had a melting point of 111 rated. The residue was identified to be N-(2-amino-3,5- 113 C. dibromobenzyl)-piperidine of the formula EXAMPLE 1.4 NH Using a procedure analogous to that described in Ex Br CH-N X ample 4, N-(2-amino-3,5-dibromobenzyl)-dicyclohexyl N amine of the formula 2 5 ." A D Br Br -CH-N The residue was dissolved in about 100 cc. of ethanol, the solution was admixed with 15 cc. of concentrated hy \{r) drochloric acid and the acid solution was allowed to stand. N-(2-amino-3,5-dibromobenzyl)-piperidine hydro 30 Br chloride crystallized out in the form of leaflets having a was prepared from 2-diacetylamino-3,5-dibromobenzyl melting point of 244-245 C. bromide and dicyclohexylamine. Its hydrobromide had a melting point of 308-312 C. EXAMPLE 10 (decomposition). Using a procedure analogous to that described in Ex EXAMPLE 1.5 ample 1, N-(2-amino-3,5-dibromobenzyl)-dimethylamine Using a procedure analogous to that described in Ex of the formula ample 9, N-(2-amino-3,5-dibromobenzyl)-3-methyl-pi NH CH3 peridine of the formula / 40 NH Br CH-N CH3 Br- CH-N X

CH3 Br was prepared from bromine and N-(2-aminobenzyl)-di BT methylamine. was prepared from bromine and N-(2-aminobenzyl)-3- Its hydrochloride had a melting point of 235-237 C. methyl-piperidine. Its hydrochloride had a melting point EXAMPLE 11 of 209-215 C. Using a procedure analogous to that described in Ex EXAMPLE 16 ample 1, N-(2-amino - 3,5 - dibromobenzyl)-di-n-propyl Using a procedure analogous to that described in Ex ample 3, N-(2-amino - 3,5 - dibromobenzyl)-N-methyl amine of the formula benzylamine hydrobromide of the formula CH-CH-CH3 NH NH, 7 Br CE-N Br CH-CH-CH

Br 60 r was prepared from N-(2-aminobenzyl)-di-n-propylamine was prepared from bromine and N-(2-aminobenzyl)-N- and bromine. methyl-benzylamine. The product had a melting point of Its hydrochloride had a melting point of 153-156° C. 218.5-219 C. (decomposition). EXAMPLE 12 65 EXAMPLE 17 Using a procedure analogous to that described in Ex Using a procedure analogous to that described in Ex ample 1, N-(2-amino-3,5-dibromobenzyl)-diisopropyl ample 3, N-(2-amino-3,5-dibromobenzyl)-N-ethylbenzyl amine of the formula amine hydrobromide of the formula NH2 NE CH(CH3)2 CHs Br CI-N CH-N CH(CEI), YoH-( ) BI 3,336,308 9 10 was prepared from bromine and N-(2-aminobenzyl)-N- was prepared from bromine and N-(4-aminobenzyl)-di ethylbenzylamine. The product had a melting point of isobutylamine. 179-182 C. Its hydrochloride had a melting point of 141-144 C. EXAMPLE 18 EXAMPLE 23 5 Using a procedure analogous to that described in Ex Using a procedure analogous to that described in Ex ample 3, N-(2-amino-3,5-dibromobenzyl)-dibenzylamine ample 6, N-(4-amino-3,5-dibromobenzyl)-N-methylcy hydrobromide of the formula clohexylamine of the formula N CH3 10 / Br CH-N CH-( > EB B CH-N YouCH ( ) EIN

r Br was prepared from bromine and N-(2-aminobenzyl)-di was prepared from bromine and N-(4-aminobenzyl)-N- benzylamine. The product had a melting point of 192 methylcyclohexylamine. 196° C. Its hydrochloride had a melting point of 232-235 C. EXAMPLE 19 EXAMPLE 24 . Using a procedure analogous to that described in Ex 20 Using a procedure analogous to that described in Ex ample 4, N-(2-amino-3,5-dibromobenzyl)-N-ethylphenyl ample 5, N-(4-amino-3,5-dibromobenzyl)-pyrrolidine of amine of the formula the formula

NE 2 CH5 Br -CE-N / Br -CH-N HN "r

Br was prepared from (4-diacetylamino-3,5-dibromobenzyl)- r 30 bromide and pyrrolidine. was prepared from 2-diacetylamino-3,5-dibromobenzyl Its hydrochloride had a melting point of 200-205 C. bromide and ethyl-phenylamine. Its hydrochloride had a melting point of 123-130' C. EXAMPLE 25 Using a procedure analogous to that described in Ex EXAMPLE 2.0 35 ample 9, N-(4-amino-3,5-dibromobenzyl)piperidine of Using a procedure analogous to that described in Ex the formula ample 1, N-(4-amino-3,5-dibromobenzyl)-dimethylamine of the formula BT CH-N X 40 o s HN Br --CH-NN CH Br IN was prepared from N-(4-aminobenzyl)-piperidine and br bromine. 45 . Its hydrobromide had a melting point of 224-226 C. was prepared from bromine and N-(4-aminobenzyl)-di (decomposition). methylamine. EXAMPLE 26 Its hydrochloride had a melting point of 252-256° C. Using a procedure analogous to that described in Ex EXAMPLE 21 ample 2, N-(4-amino-3,5-dibromobenzyl)-N-ethylbenzyl Using a procedure analogous to that described in Ex 50 amine hydrobromide of the formula ample 2, N-(4-amino-3,5-dibromobenzyl)-di-n-propyl amine hydrobromide of the formula C2H5 CE-N EB n-C3H7 55 CE-N HN Yoh-( ) n-C3H7 Br was prepared from bromine and N-(4-aminobenzyl)-N- br 60 ethylbenzylamine. The product had a melting point of was prepared from bromine and N-(4-aminobenzyl)-di 198-203 C, n-propylamine. The product had a melting point of 227 EXAMPLE 27 C. (decomposition). Using a procedure analogous to that described in Ex EXAMPLE 22 ample 1, N-(4-amino-3,5-dibromobenzyl)-dibenzylamine 65 of the formula Using a procedure analogous to that described in Ex ample 1, N - (4 - amino - 3,5 - dibromobenzyl) - diiso / butylamine of the formula BT -CH-N CH-( > 70 HN Br. CH-N so-cal, iso-CEg HN r was prepared from bromine and N-(4-aminobenzyl)-di B 75 benzylamine. 3,336,308 12 Its hydrochloride had a melting point of 233-235 C. amino-toluene E. Lellmann and C. Klotz, Annalen 231, (decomposition). 308-326 (1886) and 30 cc. of acetic acid anhydride was EXAMPLE 28 refluxed for 2 hours. Thereafter, the excess acetic acid anhydride was distilled off and the residue was recrystal Using a procedure analogous to that described in Ex lized from petroleum ether. It was identified to be 3,5-di ample 4, N-(4-amino-3,5-dibromobenzyl)-N-ethylphenyl chloro-4-diacetylamino-toluene having a melting point of amine of the formula 59-60° C. (b) Preparation of 3,5-dichloro-4-diacetylaminobenzyl / Br -CH-N bromide.-A mixture of 30gm. of 3,6-dichloro-4-diacetyl IO amino-toluene, 21 gm. of N-bromosuccinimide, 3 gm. of HN N( ) dibenzoylperoxide and 450 cc. of carbon tetrachloride (dried over phosphorus pentoxide) was refluxed until Br the undissolved matter, which initially collected at the was prepared from (4-diacetylamino-3,5-dibromobenzyl)- bottom of the flask, floated on the surface of the solvent 15 (after about 8 hours refluxing). The reaction mixture bromide and ethyl-phenylamine. was allowed to cool, was filtered, and the filtrate was evap Its hydrochloride had a melting point of 211-215 C. orated until an oily residue remained. The residue was EXAMPLE 29 recrystallized from ethanol. It was identified to be (3,5- Preparation of N-(2-amino-3,5-dichlorobenzyl)piperidine dichloro-4-diacetylaminobenzyl)-bromide having a melt ing point of 106-123° C. (a) Preparation of 3,5-dichloro-2-diacetylaminotolu 20 (c) Preparation of N-(3,5-dichloro-4-aminobenzyl)-N- ene.-A mixture of 19 gm. of 3,5-dichloro-2-acetamino methyl-cyclohexylamine.-A mixture of 13.5gm. of (3,5- toluene A. Claus and E. Stapelberg, Annalen 274, 285 dichloro-4-diacetylaminobenzyl)-bromide, 9 gm. of N 304 (1893) and 250 cc. of acetic acid anhydride was re methyl-cyclohexylamine and 250 cc. of absolute ethanol fluxed for 2 hours. Thereafter, the excess acetic acid an 25 was refluxed for 6 hours. Thereafter, the solvent was dis hydride was distilled off and the solid residue was re tilled off and the oily residue was boiled for 16 hours crystallized from ethanol. It was identified to be 3,5-di with 3 N hydrochloric acid. Subsequently, the acid solu chloro-2-diacetylamino-toluene having a melting point of tion was made alkaline (pH 10) with approximately 10 N 84-86 C. sodium hydroxide. An oily precipitate formed, which (b) Preparation of (3,5 - dichloro - 2 - diacetylamino 30 crystallized upon standing. The crystallizate was separated benzyl)-bromide.-A mixture of 15.1 gm. of 3,5-dichloro by vacuum filtration and was recrystallized from ethanol. 2-diacetylamino-toluene, 11.0gm. of N-bromosuccinimide, It was identified to be N-(3,5-dichloro-4-aminobenzyl)- 0.5gm. of dibenzoylperoxide and 250 cc. of carbon tetra N-methyl-cyclohexylamine of the formula chloride was refluxed until the undissolved matter, which initially collected at the bottom of the flask, floated at the CH surface of the solvent (after about 10 hours of refluxing). / The reaction mixture was allowed to cool, was filtered, and the filtrate was evaporated to dryness. The solid Cl- CH-N\{ n > residue was recrystallized from ethanol. It was identified HN to be (3,5-dichloro-2-diacetylaminobenzyl)-bromide hav Cl ing a melting point of 122-125 C. 40 (c) Preparation of N-(2-amino-3,5-dichlorobenzyl)- having a melting point at 62-64 C. piperidine.-A mixture of 9.5 gm. of (3,5-dichloro-2-di acetylaminobenzyl)-bromide, 5 gm. of piperidine and 250 EXAMPLE 31 cc. of ethanol was refluxed for 18 hours. After distilling Using a procedure analogous to that described in Ex off the solvent, the reaction product was dissolved in 1 45 ample 29, N - (2-amino-3,5-dichlorobenzyl)-N-methyl liter of 3 N hydrochloric acid, and the solution was again cyclohexylamine of the formula refluxed for 18 hours. Thereafter, the reaction solution NH was made alkaline (pH 10) with 10 N sodium hydroxide, CH3 and the alkaline solution was exhaustively extracted with / chloroform. The combined chloroform extract solutions 50 C were dried over sodium sulfate and were then concen trated until an oily residue remained. The oily residue was identified to be N-(2-amino-3,5-dichlorobenzyl)- piperidine of the formula Cl 55 NH was prepared from (3,5-dichloro-2-diacetylaminobenzyl)- bromide and N-methyl-cyclohexylamine. C- -CH-N X Its hydrochloride had a melting point of 224-225 C. (decomposition). 60 EXAMPLE 32 Using a procedure analogous to that described in Ex b ample 29, N - (2 - amino-3,5-dichlorobenzyl)-diisobutyl It was dissolved in 50 cc. of absolute ethanol, and gaseous hydrogen chloride was introduced into solution, where amine of the formula upon a crystalline precipitate formed, which was identi 65 NH fied to be the hydrochloric acid addition salt of N-(2- iso-C4H9 amino-3,5-dichlorobenzyl)-piperidine. After recrystalliza / tion from ethanol, the melting point of the hydrochloride C CH-N was 234-235 C. (decomposition). iso-CEg EXAMPLE 30 70 Preparation of N-(4-amino-3,5-dichlorobenzyl)-N- Cl methyl-cyclohexylamine was prepared from 3,5-dichloro-2-diacetylaminobenzyl (a) Preparation of 3,5-dichloro-4-diacetylamino-tol bromide and diisobutylamine. uene.-A mixture of 10 gm. of 3,5-dichloro-4-acetyl 75 Its hydrochloride had a melting point of 142-148 C. 3,336,308 13 14 EXAMPLE 33 due, which was identified to be N-(2-amino-3,5-dibromo Using a procedure analogous to that described in Ex benzyl)-isobutylamine of the formula ample 30, N-(3,5-dichloro-4-aminobenzyl)-diethylamine of the formula NH CE; Cl CH-N

0 Cl

was prepared from 3,5-dichloro-4-diacetylaminobenzyl This product was dissolved in 15 cc. of absolute ethanol, bromide and diethylamine. Its sulfate had a melting point 5 and gaseous hydrogen chloride was introduced into the of 132-134' C. solution until saturation. The precipitate formed thereby EXAMPLE 34 was separated by vacuum filtration, washed with ethyl Using a procedure analogous to that described in Ex ... acetate, dried and recrystallized from 25 cc. of absolute ethanol. It was identified to be the hydrochloride of N ample 30, N - (3,5 - dichloro-4-aminobenzyl)-dibenzyl 20 (2-amino - 3,5 - dibromobenzyl)-isobutylamine having a amine of the formula melting point of 211-213 C. (decomposition). EXAMPLE 36 Preparation of N-(3,5-dibromo-4-aminobenzyl)-cyclo Cl 25 hexylamine (a) Preparation of N-(4-aminobenzyl)-cyclohexyl HN amine-2.38 gm. of N-(4-nitro-benzylidene)-cyclohexyl amine (F. G. Baddar, J.C.S. London 1950, 136-139) 30 were dissolved in 60 cc. of freshly distilled methanol, the resulting solution was introduced into a duck-shaped hy was prepared from 3,5-dichloro-4-diacetylaminobenzyl drogen vessel and was there hydrogenated with hydrogen bromide and dibenzylamine. in the presence of platinum as a catalyst. The reaction Its hydrochloride had a melting point of 237.5-238 C. mixture absorbed 4 mols of hydrogen. After completion (decomposition). 35 of the hydrogenation, the catalyst was filtered off and the EXAMPLE 35 solvent was distilled out of the filtrate. An oil remained Preparation of N-(2-amino-3,5-dibromobenzyl)-iso as a residue, which was identified to be N-(4-amino butylamine benzyl)-cyclohexylamine. This product was used in the subsequent step without further purification. (a) Preparation of N-(2-nitro-benzylidene)-isobutyl 40 (b) Preparation of N-(3,5-dibromo-4-aminobenzyl)- amine.-A solution of 1.51 gm. of 2-nitro- cyclohexylamine.-2.19 gm. of the raw N-(4-amino and 0.73 gm. of isobutylamine in ethanol was refluxed for benzyl)-cyclohexylamine obtained in step (a) were dis 5 hours. Thereafter, the solvent was distilled off, leaving solved in 50 cc. of glacial acetic acid, and the resulting an oily residue which was identified to be raw N-(2-nitro solution was admixed with 1.85gm. of sodium acetate. To benzylidene)-isobutylamine. This raw product was used 45 this mixture a solution of 3.6 gm. of bromine in 15 cc. of without further purification in the Subsequent step. glacial acetic acid was slowly added dropwise at room tem (b) Preparation of N - (2 - aminobenzyl) - isobutyl perature, accompanied by thorough stirring. After com amine-2 gm. of the raw N-(2-nitrobenzylidene)-iso pletion of the reaction, the glacial acetic acid was distilled butylamine obtained in step (a) were dissolved in 30 cc. off, the light brown residue was admixed with 150 cc. of of freshly distilled methanol, and the resulting solution 50 chloroform and 150 cc. of 2 N sodium hydroxide, and the was introduced into a duck-shaped hydrogenation vessel mixture was shaken. The aqueous phase was separated and was there catalytically hydrogenated with hydrogen from the chloroform phase and was again shaken twice in the presence of platinum as a catalyst. The reaction with 150 cc. portions of chloroform. The chloroform mixture absorbed 4 mols of hydrogen. After the hydro phases were combined, dried over sodium sulfate, filtered, genation had gone to completion, the reaction mixture was 55 and the solvent was distilled off. 2.92 gm. of a brown oil filtered to separate the catalyst, and the solvent was dis remained behind, which was identified to be N-(3,5-di tilled out of the filtrate. 1.7 gm. of N-(2-aminobenzyl)- bromo-4-aminobenzyl)cyclohexylamine of the formula isobutylamine remained as a residue. (c) Preparation of N-(2-amino-3,5-dibromobenzyl)- isobutylamine.-1.7 gm. of N-(2-aminobenzyl)-isobutyl 60 amine (obtained in step (b)) were dissolved in 40 cc. of glacial acetic acid, and the resulting solution was admixed Br -CH-NH-( ) with 1.64 gm. of sodium acetate. Thereafter, a solution of HN 3.2 gm. of bromine in 10 cc. of glacial acetic acid was slowly added dropwise thereto at room temperature ac br companied by thorough stirring. After the reaction had 65 gone to completion, the glacial acetic acid was distilled off, the residue was admixed with 60 cc. of chloroform This product was dissolved in 15 cc. of absolute ethanol, and 60 cc. of 2 N sodium hydroxide, and the resulting and gaseous hydrogen chloride was introduced into this mixture was shaken. The aqueous phase was separated 70 solution until Saturation. A precipitate formed which was from the chloroform phase and was again shaken twice separated by vacuum filtration, dried and recrystallized with 60 cc. portions of chloroform. The chloroform ex from absolute ethanol. It was identified to be the hydro tract solutions were combined, dried over sodium sulfate, chloride of N-(3,5-dibromo-4-aminobenzyl)-cyclohexyl filtered, and the solvent was distilled out of the filtrate. amine having a melting point of 259-262° C. (decom 2.56 gm. of a brown, viscous oil were obtained as a resi 75 position). 3,336,308 15 16 EXAMPLE 37 EXAMPLE 41 Using a procedure analogous to that described in Ex Preparation of N,N-diamyl-(2-amino-4-bromo-benzyl)- ample 35, N-(3,5-dibromo-2-aminobenzyl)-cyclohexyl amine amine of the formula A solution of 27 gm, of N,N-diamyl-(2-nitro-4-bromo benzyl)-amine in 200 cc. of methanol was admixed with NIH about 2 gm. of Raney nickel, and to the resulting mixture a solution of 10.6 gm. of 80% hydrazine hydrate in 50 Br cc. of methanol was slowly added dropwise, accompanied -CH-NH-CH > by stirring. The reaction mixture was then stirred for a 10 short period of time at about 60° C. The Raney nickel catalyst was separated by vacuum filtration through in br fusorial earth, and the filtrate was evaporated in an as was prepared from N-(2-aminobenzyl)-cyclohexylamine pirator pump vacuum. The oily residue was then distilled and bromine. in a high vacuum. The fraction passing over between 150 Its hydrochloride had a melting point of 247-248 C. 15 and 154 C. at 0.13 mm. Hg was identified to be N,N- (decomposition). diamyl-(2-amino-4-bromo-benzyl)-amine of the formula EXAMPLE 38 Using a procedure analogous to that described in Ex ample 35, N-(3,5-dibromo-4-aminobenzyl)-isobutylamine 20 of the formula Br -NH2 Br CH-NH-iso-CH HN 25 Its dihydrochloride, obtained by dissolving the free base in absolute ethanol and saturating the resulting solution BI with hydrogen chloride gas and adding a small amount of was prepared from N-(4-aminobenzyl)-isobutylamine ether, had a melting point of 128-132 C. and bromine. 30 EXAMPLE 42 Its hydrochloride had a melting point of 180-183° C. Preparation of N-(2-amino-4-bromo-benzyl)-3-methyl EXAMPLE 39 piperidine Using a procedure analogous to that described in Ex 33 gm. of N-(2-nitro-4-bromo-benzyl)-3-methyl-piper ample 1, N-(4-amino-3,5-dibromobenzyl)-dicyclopentyl idine were dissolved in 200 cc. of methanol, about 2 gm. amine of the formula 35 of Raney nickel were added, and the mixture was ad mixed dropwise, while stirring, with a solution of 13.1 gm. of 80% hydrazine hydrate in 50 cc. of methanol. The reaction mixture was then stirred for some time at about Br 60° C. The Raney nickel catalyst was separated by vac 40 uum filtration through infusorial earth, and the filtrate was evaporated in an aspirator pump vacuum. The oily residue was distilled in a high vacuum. The fraction pass Br ing over between 136 and 142° C. at 0.02 mm. Hg was was prepared from bromine and N-(4-aminobenzyl)-di identified to be N-(2-amino-4-bromo-benzyl)-3-methyl cyclopentylamine. 45 piperidine of the formula Its hydrochloride had a melting point of 189-197 C. (decomposition). - EXAMPLE 40 CH-N Preparation of N,N-diisopropyl-(2-amino-4-bromo benzyl)-amine 50 Br -NF E3 A solution of 44 gm. of N,N-diisopropyl-(2-nitro-4- bromobenzyl)-amine in 200 cc. of methanol was admixed with about 2 gm. of Raney nickel. To the resulting mix Its dihydrochloride, obtained by dissolving the free base ture a solution of 19 gm. of 80% hydrazine hydrate in 55 in absolute ethanol and saturating the resulting solution 50 cc. of methanol was slowly added dropwise accom with hydrogen chloride gas, had a melting point of 227 panied by stirring. Thereafter, the reaction mixture was 228 C. (decomposition). stirred for a short period of time at about 60° C. The EXAMPLE 43 Raney nickel catalyst was then separated by vacuum filtra Preparation of N-cyclohexyl-N-methyl-(2-amino-4-bromo tion through infusorial earth, and the filtrate was evap 60 orated under an aspirator pump vacuum. The oily residue benzyl)-amine was distilled twice in a high vacuum. The fraction passing About 2 gm. of Raney nickel were added to a solution over between 105 and 120° C. at 0.03 mm. Hg was iden of 24 gm. of N-cyclohexyl-N-methyl-(2-nitro-4-bromo tified to be N,N-diisopropyl-(2-amino-4-bromo-benzyl)- benzyl)-amine in 200 cc. of methanol, and the resulting amine of the formula 65 mixture was admixed dropwise, while stirring, with a solution of 10.6 gm. of 80% hydrazine hydrate in 50 cc. CH-N(CHCH3CH3) of methanol. The reaction mixture was then stirred for a short period of time at 60 C. The Raney nickel catalyst Br- -NE was separated by vacuum filtration through infusorial 70 earth, and the filtrate was evaporated in an aspirator pump The product thus obtained was dissolved in absolute eth vacuum. The initially oily residue, which gradually crys anol, and the resulting solution was saturated with hy tallized, was distilled in a high vacuum. The fraction pass drogen chloride gas, yielding the dihydrochloride of N,N- ing over between 140 and 144° C. at 0.18 mm. Hg crystal diisopropyl-(2-amino-4-bromo-benzyl)-amine which had lized and was recrystallized from ethanol, whereupon it a melting point of 182-187° C. (decomposition). 75 had a melting point of 78-81. C. It was identified to be 3,336,308 17 18 N - cyclohexyl - N - methyl-(2-amino-4-bromo-benzyl)- amine. Its dihydrochloride had a melting point of 196 amine of the formula 199 C. (decomposition). EXAMPLE 48 on 4 "D Using a procedure analogous to that described in Ex CBIs ample 40, N,N-di-n-propyl-(2-amino-4-bromo-benzyl)- Br -NE amine was prepared from N,N-di-n-propyl-(2-nitro-4-bro mo-benzyl)-amine. Its dihydrochloride had a melting point EXAMPLE 44 of 177-183° C. Preparation of N-allyl-N-cyclohexyl-(2-amino-4-bromo 0 EXAMPLE 49 Using a procedure analogous to that described in Ex benzyl)-amine ample 41, N,N-di-n-butyl-(2-amino-4-bromo-benzyl)- 500 cc. of concentrated hydrochloric acid were added amine was prepared from N,N-di-n-butyl-(2-nitro-4-bro to a mixture of 26.5 gm. of N-allyl-N-cyclohexyl-(2-nitro mobenzyl)-amine. Its dihydrochloride had a melting point 4-bromo-benzyl)-amine and 82 gm. of stannous chloride, 5 of 140-145 C. and the mixture was heated for 2 hours at 90-95 C. EXAMPLE 50 Thereafter, the reaction mixture was diluted with 750 cc. of water, the aqueous solution was extracted three Using a procedure analogous to that described in Ex times with 300 cc. portions of ether, and the acid aqueous ample 41, N,N- diisobutyl - (2-amino-4-bromo-benzyl)- phase was made alkaline with 10 N sodium hydroxide. The 20 amine was prepared from N,N-diisobutyl-(2-nitro-4-bro resulting alkaline solution was thoroughly extracted with mo-benzyl)-amine. Its dihydrochloride had a melting point chloroform, and the chloroform phase was separated, of 182-184 C. (decomposition). dried over sodium sulfate and evaporated in an aspirator EXAMPLE 51. pump vacuum. The oily residue was distilled in a high Using a procedure analogous to that described in Ex vacuum. The fraction passing over between 144 and 150 25 ample 42, N-(2-amino-4-bromo-benzyl)-piperidine was C. at 0.01 mm. Hg was identified to be N-allyl-N-cyclo prepared from N-(2-nitro-4-bromo-benzyl)-piperidine. Its hexyl-(2-amino-4-bromo-benzyl)-amine of the formula dihydrochloride had a melting point of 212-214 C. EXAMPLE 52 --CD 30 Using a procedure analogous to that described in Ex CH-CH=CH ample 42, N-(2-amino-4-bromo-benzyl)-2-methyl-piperi Br- -NE dine was prepared from N-(2-nitro-4-bromo-benzyl)-2- methyl-piperidine. The free base had a melting point of 72-78° C. Its dihydrochloride, obtained by dissolving the free base 35 in ethanol and acidifying the resulting solution with con EXAMPLE 53 centrated hydrochloric acid, had a melting point of 192 Using a procedure analogous to that described in Exam 195 C. (decomposition). ple 42, N-(2-amino-4-bromo-benzyl)-4-methyl-piperidine EXAMPLE 45 was prepared from N-(2-nitro-4-bromo-benzyl)-4-methyl 40 piperidine. Its dihydrochloride had a melting point of 208 Preparation of N-(2-brono-4-amino-benzyl)-piperidine 210 C. (decomposition). From 2 to 3 gm. of Raney nickel were added to a solu tion of 25.5 gm. of N-(2-bromo-4-nitro-benzyl)-piperi EXAMPLE 54 dine in 300 cc. of methanol, and the resulting mixture was Using a procedure analogous to that described in Ex admixed dropwise, while stirring, with a solution of 8.6 ample 43, N-(2-amino-4-bromo-benzyl)-2-ethyl-piperidine gm. of 80% hydrazine hydrate in 50 cc. of methanol. 45 was prepared from N-(2-nitro-4-bromo-benzyl)-2-ethyl After the endothermic reaction had gone to completion, piperidine. Its dihydrochloride had a melting point of the reaction mixture was stirred at room temperature for 198-201° C. (decomposition). some time, whereupon the Raney nickel catalyst was sepa EXAMPLE 55 rated by vacuum filtration through infusorial earth, and 50 Using a procedure analogous to that described in Ex the filtrate was evaporated in an aspirator vacuum. The ample 43, N-ethyl- N - cyclohexyl-(2-amino-4-bromo oily residue was identified to be N-(2-bromo-4-amino benzyl)-amine was prepared from N-ethyl-N-cyclohexyl benzyl)-piperidine of the formula (2-nitro-4-bromo-benzyl)-amine. Its dihydrochloride had C H-K 55 a melting point of 193-198 C. (decomposition). EXAMPLE 56 EN -Br Using a procedure analogous to that described in Ex ample 42, N-(2-amino-4-bromo-benzyl)-morpholine of It was dissolved in a small amount of ethanol and the the formula resulting solution was saturated with hydrogen chloride. 60 The hydrochloride thus obtained was recrystallized from a mixture of ethanol and , whereupon it had a -CE-N O melting point of 205-206 C. Y-1 EXAMPLE 46 Br -NH 65 Using a procedure analogous to that described in Ex ample 40, N,N-dimethyl - (2 - amino-4-bromo-benzyl)- amine was prepared from N,N-dimethyl-(2-nitro-4-bromo was prepared from N-(2-nitro-4-bromo-benzyl)-morpho benzyl)-amine. Its dihydrochloride had a melting point of line. The free base had a melting point of 96-99 C. 207-209 C. (decomposition). 70 EXAMPLE 57 Using a procedure analogous to that described in Ex EXAMPLE 47 ample 45, N,N-diethyl-(2-bromo-4-amino-benzyl)-amine Using a procedure analogous to that described in Ex was prepared from N,N-diethyl-(2-bromo-4-nitro-benzyl)- ample 40, N,N-diethyl-(2-amino-4-bromo-benzyl)-amine amine. Its hydrochloride had a melting point of 152 was prepared from N,N-diethyl-(2-nitro-4-bromo-benzyl)- 75 154 C. 3,336,308 9 20 mixture was refluxed for one hour and then cooled, the EXAMPLE 58 precipitated N-methyl-cyclohexylammonium bromide was Using a procedure analogous to that described in Ex separated by vacuum filtration, and the filtrate was evapo ample 45, N,N- di-n-propyl-(2-bromo-4-amino-benzyl)- rated in an aspirator vacuum. The residue was dissolved amine was prepared from N,N-di-n-propyl-(2-bromo-4- in 580 cc. of ethanol, 320 cc. of concentrated hydro nitro-benzyl)-amine. Its hydrochloride had a melting point chloric acid were added, and the acid solution was re of 154-157 C. fluxed for 16 hours. After completion of the acid hydroly EXAMPLE 59 sis the reaction solution was concentrated to about 50 cc., Using a procedure analogous to that described in Ex whereby the dihydrochloride of N-cyclohexyl-N-methyl ample 45, N-(2-bromo-4-amino-benzyl)-morpholine Was 10 (2-amino-5-bromo-benzyl)-amine of the formula prepared from N-(2-bromo-4-nitro-benzyl)-morpholine. CH3 The free base had a melting point of 100-101° C. / EXAMPLE 60 Br- \{ X 2HC Using a procedure analogous to that described in Ex -NH2 ample 45, N-(2-bromo-4-amino-benzyl)-2-methyl-piperi dine was prepared from N-(2-bromo-4-nitro-benzyl)-2- precipitated out. The precipitate was separated and re methyl-piperidine. Its hydrochloride had a melting point crystallized from absolute ethanol, whereupon it had a of 179-180 C. melting point of 195-198° C. (decomposition). EXAMPLE 61 20 EXAMPLE 65 Using a procedure analogous to that described in Ex Using a procedure analogous to that described in Ex ample 45, N-(2-bromo-4-amino-benzyl)-2-ethyl-piperidine ample 64, N,N-diethyl-(2 - amino - 5 - bromo-benzyl)- was prepared from N-(2-bromo-4-nitro-benzyl)-2-ethyl amine was prepared from 2-diacetylamino-5-bromo-ben piperidine. Its hydrochloride had a melting point of 174 zybromide and diethylamine. Its dihydrochloride had a 176 C. EXAMPLE 62 melting point of 200-204 C. (decomposition). Using a procedure analogous to that described in Ex EXAMPLE 66 ample 45, N - cyclohexyl-N-methyl-(2-bromo-4-amino Using a procedure analogous to that described in Ex benzyl)-amine was prepared from N-cyclohexyl-N-meth ample 64, N,N-di-n-propyl-(2-amino-5-bromo-benzyl)- yl-(2-bromo-4-nitro-benzyl)-amine. Its hydrochloride had 30 amine was prepared from 2-diacetylamino-5-bromo-ben a melting point of 178-181 C. (decomposition). zybromide and di-n-propylamine. Its dihydrochloride had EXAMPLE 63 a melting point of 183-186 C. (decomposition). Preparation of N-cyclohexyl-N-methyl-(2-chloro-4- EXAMPLE 67 amino-benzyl)-amine 3 5 Using a procedure analogous to that described in EX ample 64, N-(2-amino-5-bromo-benzyl)-piperidine was A solution of 30 gm. of N-cyclohexyl-N-methyl-(2- prepared from 2-diacetylamino-5-bromo - benzylbromide chloro-4-amino-benzamide) in 400 cc. of absolute tetra hydrofuran was added dropwise over a period of one hour, and piperidine. Its dihydrochloride had a melting point accompanied by stirring, to a boiling mixture consisting of 40 of 203-207 C. (decomposition). 11.4 gm. of lithium aluminum hydride and 300 cc. of EXAMPLE 68 absolute tetrahydrofuran. After all of the benzamide solu Preparation of N,N-diisopropyl-(2-amino-5-bromo tion had been added, the reaction mixture was refluxed benzyl)-amine for a few hours and then the excess lithium aluminum hydride was decomposed with ethyl acetate, Water and 39.4 gm. of diisopropylamine were added to a solution aqueous 10% sodium hydroxide. The inorganic precipitate of 64.5 gm. of 5-bromo-2-diacetylamino-benzybromide formed thereby was separated, and the aqueous phase in 0.9 i. of carbon tetrachloride and the reaction mixture was extracted with chloroform. The extract solution and was held at reflux for one hour and then cooled. The the previously separated organic phase were combined, precipitated diisopropyl ammonium bromide was suction drie. Sver sodium clfate and concentrated by evapora 50 filtered, and the filtrate was concentrated under water-jet tion. The oily residue was identified to oe raw N-cyclo vacuum. The remaining residue was dissolved in 520 cc. hexyl-N-methyl-(2-chloro-4-amino-benzyl)-amine of the of ethanol and after 280 cc. of concentrated hydrochloric formula acid had been added, it was held at reflux over a period CH of 20 hours. After saponification, the solution was con / 55 centrated to about 80 cc. and the N,N-diisopropyl-(2- -CH-N amnio-5-bromobenzyl)-amine crystallized therefrom as the dihydrochloride. Upon recrystallization from absolute HN - C ethanol, the compound had a melting point of 183-188 C. With decomposition. The oily substance was dissolved in 100 cc. of ethanol, and the resulting solution was saturated with hydrogen 60 EXAMPLE 69 chloride gas. Thereafter, 80 cc. of ether and 120 cc. of Preparation of N,N-dipropyl-(2-amino-6-chloro ethyl acetate were added, whereby a precipitate formed benzyl)-amine which was recrystallized from a mixture of ethanol and A Solution of 7.6 gm. of N,N-dipropyl-(6-chloro-2- ethyl acetate acidified with hydrochloric acid. The prod 65 nitro-benzyl)-amine in 50 cc. of methanol was admixed uct was the dihydrochloride of N-cyclohexyl-N-methyl with about 0.5gm. of Raney nickel. While stirring, a solu (2-chloro-4-amino-benzyl)-amine with a melting point of tion of 3.8 gm. of 80% hydrazine hydrate in 10 cc. of 188-194° C. (decomposition). methanol was added dropwise to this mixture. The reac EXAMPLE 64 tion mixture was then stirred for a while longer at a tem 70 perature of about 60° C. and then the Raney nickel was Preparation of N-cyclohexyl-N-methyl-(2-amino-5- removed by suction filtration through Celite 545. The bromo-benzyl)-amine filtrate was concentrated under water-jet vacuum and the 17.1 gm. of N-methyl-cyclohexylamine were added to oily residue was dissolved in absolute ethanol and satu a solution of 25.8 gm. of 2-diacetylamino-5-bromo-benzyl rated with hydrochloric acid gas. The resulting N,N-di bromide in 0.5 liter of carbon tetrachloride. The reaction 75 propyl-(2-amino-6-chlorobenzyl)-amine dihydrochloride 3,336,308 21 22 after recrystallization from absolute ethanol had a melting EXAMPLE 75 point of 185-190° C. with decomposition. Preparation of N,N-dibutyl-(2-amino-5-bromo-benzyl)- EXAMPLE 70 annine Preparation of N-cyclohexyl-N-methyl-(2-amino-5- Using the procedure of Example 68, 5-bromo-2-di bromo-benzyl)-amine acetylaminobenzyl-bromide was reacted with dibutylamine 6.3 gm. of N-cyclohexyl-N-methyl-2-amino-5-bromo to obtain N,N-dibutyl-(2-amino-5-bromo-benzyl)-amine benzamide were dissolved in 150 cc. of absolute tetra dihydrochloride having a melting point of 183-188 C. hydrofuran and this solution was slowly added dropwise (decomposition). with stirring to a suspension of 1.9 gm. of lithium alu 0. EXAMPLE 76 minum hydride in 50 cc. of tetrahydrofuran. Next, the reaction mixture was heated at reflux for 3 hours after Preparation of N,N-disobutyl-(2-amino-5-bromo which the excess lithium aluminum hydride was decom benzyl)-amine posed with a solution of ethyl acetate, water and 15% Using the procedure of Example 68, 5-bromo-2-di sodium hydroxide. The organic solution was decanted and 5 acetylaminobenzyl-bromide was reacted with diisobutyl the residue was extracted with chloroform. The organic amine to obtain N,N-diisobutyl-(2-amino-5-bromo-ben phases were combined, dried over sodium sulfate and con zyl)-amine dihydrochloride having a melting point of centrated under vacuum. The residue was dissolved in 147-153 C. absolute ethanol and the solution was saturated with hy EXAMPLE 77 drochloric acid gas and N-cyclohexyl-N-methyl-(2-amino 20 5 - bromo-benzyl) - amine dihydrochloride crystallized Preparation of N,N-diamyl-(2-amino-5-bromo-benzyl)- therefrom. The product was recrystallized from absolute amine ethanol to obtain a product having a melting point of Using the procedure of Example 68, 5-bromo-2-di 195-198 C. with decomposition. acetylaminobenzyl-bromide was reacted with diamylamine EXAMPLE 71 25 to obtain N,N-diamyl-(2-amino-5-bromo-benzyl)-amine dihydrochloride having a melting point of 163-169 C. Preparation of N-(2-amino-5-bromo-benzyl)-hexa (decomposition). methyleneimine EXAMPLE 78 While stirring, 48 gm. of bromine in 60 cc. of glacial acetic acid were added dropwise to a solution of 24.8 gm. 30 Preparation of N,N-disoamyl-(2-amino-5-bromo-benzyl)- of N-(2-acetyl-amino-benzyl)-hexamethyleneimine in 250 anine cc. of glacial acetic acid which had been heated in presence Using the procedure of Example 68, 5-bromo-2-di of iron powder to 80 C. After concentration of the solu acetylaminobenzyl-bromide was reacted with diisoamyl tion, N-(2-acetyl-amino-5-bromo-benzyl)-hexamethylene amine to obtain N,N-diisoamyl-(2-amino-5-bromo-ben immonium bromide precipitated and was then dissolved Zyl)-amine hydrochloride having a melting point of 167 in 300 cc. of ethanol and 160 cc. of concentrated hydro 170° C. (decomposition). chloric acid and saponified by refluxing for 20 hours. Then the solution was partially concentrated, made alkaline with EXAMPLE 79 concentrated ammonia and exhaustively extracted with Preparation of N,N-dihexyl-(2-amino-5-bromo-benzyl)- chloroform. The organic phase was dried over sodium 40 sulfate and concentrated. After purification by prismatic amine chromatography through aluminum oxide, N-(2-amino Using the procedure of Example 68, 5-bromo-2-di 5-bromo-benzyl)-hexamethyleneimine in neutral condi acetylaminobenzyl-bromide was reacted with dihexyla tion was precipitated from ethyl acetate with hydrochloric mine to obtain N,N-dihexyl-(2-amino-5-bromo-benzyl)- acid gas as dihydrochloride and, finally, recrystallized 45 amine hydrochloride having a melting point of 136.5- from absolute ethanol. The melting point was 188-192 138 C. (decomposition). C. with decomposition. EXAMPLE 80 EXAMPLE 72 Preparation of N,N-dimethyl-(2-amino-5-bromo Preparation of N-6-hydroxyethyl-N-methyl-(2-amino-5- benzyl)-amine 50 bromo-benzyl)-amine Using the procedure of Example 68, 5-bromo-2-di Using the procedure of Example 68, 5-bromo-2-di acetylaminobenzyl-bromide was reacted with dimethyl acetylaminobenzyl-bromide was reacted with N-methyl amine to obtain N,N-dimethyl-(2-amino-5-bromo-ben 6-hydroethylamine to obtain N-6-hydroxyethyl-N-methyl zyl)-amine dihydrochloride having a melting point of 55 (2-amino-5-bromo-benzyl)-amine having a melting point 193-198° C. with decomposition. of 63.5-64.5 C. EXAMPLE 81 EXAMPLE 73 Preparation of N-ethyl-N-cyclohexyl-(2-amino-5-bromo Preparation of N,N-diethyl-(2-amino-5-bromo-benzyl)- benzyl)-amine amine 60 Using the procedure of Example 68, 5-bromo-2-di Using the procedure of Example 68, 5-bromo-2-di acetylaminobenzyl-bromide was reacted with diethylamine acetylaminobenzyl-bromide was reacted with N-ethyl to obtain N,N-diethyl-(2-amino-5-bromo-benzyl)-amine cyclohexylamine to obtain N-ethyl- N - cyclohexyl-(2- dihydrochloride having a melting point of 200-204 C. amino-5-bromo-benzyl)-amine dihydrochloride having a (decomposition). 65 melting point of 179-182 C. (decomposition). EXAMPLE 74 EXAMPLE 82 Preparation of N,N-dipropyl- (2-amino-5-bromo-benzyl )- Preparation of N,N-dicyclohexyl-(2-amino-5-bromo amine benzyl)-amine 70 Using the procedure of Example 68, 5-bromo-2-di Using the procedure of Example 68, 5-bromo-2-di acetylaminobenzyl-bromide was reacted with dipropyl acetylaminobenzyl-bromide was reacted with dicyclohex amine to obtain N,N-dipropyl-(2-amino-5-bromo-benzyl)- ylamine to obtain N,N-dicyclohexyl-(2-amino-5-bromo amine dihydrochloride having a melting point of 183 benzyl)-amine dihydrochloride having a melting point of 186° C. (decomposition). 75 304-307 C. (decomposition). 3,336,308 23 24 EXAMPLE 83 EXAMPLE 91 Preparation of N,N-diallyl-(2-amino-5-bromo-benzyl)- Preparation of N-(2-amino-5-bromo-benzyl)- annine 3'-methyl-piperidine Using the procedure of Example 68, 5-bromo-2-diace Using the procedure of Example 68, 5-bromo-2-di 5 tylaminobenzyl-bromide was reacted with 3-methyl-piper acetylaminobenzyl-bromide was reacted with diallyl idine to obtain N-(2-amino-5-bromo-benzyl)-3-methyl amine to obtain N,N-diallyl-(2-amino-5-bromo-benzyl)- piperidine dihydrochloride having a melting point of 205 amine dihydrochloride having a melting poinnt of 160 209 C. (decomposition). 162 C. (decomposition). 0 EXAMPLE 92 EXAMPLE 84 Preparation of N-(2-amino-5-bromo-benzyl)- Preparation of N-allyl-N-cyclohexyl-(2-amino-5-benzyl)- 4'-methyl-piperidine amine Using the procedure of Example 68, 5-bromo-2-diace Using the procedure of Example 68, 5-bromo-2-di 15 tylaminobenzyl-bromide was reacted with 4-methyl-piper acetylaminobenzyl-bromide was reacted with N-allyl idine to obtain N-(2-amino-5-bromo-benzyl)-4'-methyl cyclohexylamine to obtain N- allyl - N - cyclohexyl-(2- piperidine hydrochloride having a melting point of 211 amino-5-bromo-benzyl)-amine dihydrochloride having a 213 C. (decomposition). melting point of 178-180° C. (decomposition). EXAMPLE 93 Preparation of N-(2-amino-5-bromo-benzyl)- EXAMPLE 85 2'-ethyl-piperidine Preparation of N-benzyl-N-methyl-(2-amino-5-bromo Using the procedure of Example 68, 5-bromo-2-diace benzyl)-amine tylaminobenzyl-bromide was reacted with 2-ethyl-piperi Using the procedure of Example 68, 5-bromo-2-di 25 dine to obtain N-(2-amino-5-bromo-benzyl)-2'-ethyl-pi acetylaminobenzyl-bromide was reacted with N-methyl peridine dihydrochloride having a melting point of 193 benzylamine to obtain N-benzyl-N-methyl-(2-amino-5- 198 C. (decomposition). bromo-benzyl)-amine dihydrochloride having a melting EXAMPLE 94. point of 191-196° C. (decomposition). 30 Preparation of N-(2-amino-5-bromo-benzyl)- EXAMPLE 86 N'-methyl- Preparation of N-ethyl-N-benzyl-(2-amino-5-bromo Using the procedure of Example 68, 5-bromo-2-diace benzyl)-amine tylaminobenzyl-bromide was reacted with N-methyl-piper 35 azine to obtain N-(2-amino-5-bromo-benzyl)-N'-methyl Using the procedure of Example 68, 5-bromo-2-di piperazine trihydrochloride having a melting point of 220 actylaminobenzyl-bromide was reacted with N-ethylben zylamine to obtain N-ethyl-N-benzyl-(2-amino-5-bromo 228 C. (decomposition). benzyl)-amine having a melting point of 57-58 C. EXAMPLE 95 Preparation of N-methyl-N-2'-picolyl-(2-amino EXAMPLE 87 40 5-bromo-benzyl)-amine Preparation of N,N-dibenzyl-(2-amino-5-bromo-benzyl)- Using the procedure of Example 68, 5-bromo-2-diace annine tylaminobenzyl-bromide was reacted with N-methyl-2- Using the procedure of Example 68, 5-bromo-2-di picolylamine to obtain N-methyl-N-2'-picolyl-(2-amino-5- acetylaminobenzyl-bromide was reacted with dibenzyl bromo-benzyl)-amine trihydrochloride having a melting amine to obtain N,N-dibenzyl-(2-amino-5-bromo-benzyl)- point of 174-177 C. (decomposition). amine dihydrochloride having a melting point of 225 EXAMPLE 96 230 C. (decomposition). Preparation of N-methyl-N-phenyl-(2-amino EXAMPLE 88 6-chloro-benzyl)amine Using the procedure of Example 68, 6-chloro-2-diace Preparation of N-(2-amino-5-bromo-benzyl)-pyrrollidine tylaminobenzyl-bromide was reacted with N-methyl-ani Using the procedure of Example 68, 5-bromo-2-di line to obtain N-methyl-N-phenyl-(2-amino-6-chloro-ben acetylaminobenzyl-bromide was reacted with pyrrolidine Zyl)-amine dihydrochloride in form of a noncrystallisable to obtain N-(2-amino-5-bromobenzyl)-pyrrolidine dihy 5 5 substance. drochloride having a melting point of 194-200° C. (de EXAMPLE 97 composition). Preparation of N,N-diisopropyl-(2-amino EXAMPLE 89 6-chloro-benzyl)-amine Preparation of N-(2-amino-5-bromo-benzyl)-piperidine 60 Using the procedure of Example 68, 6-chloro-2-diace Using the procedure of Example 68, 5-bromo-2-diace tylaminobenzyl-bromide was reacted with diisopropyl tylaminobenzyl-bromide was reacted with piperidine to amine to obtain N,N-diisopropyl-(2-amino-6-chloro-ben obtain N-(2-amino-5-bromo-benzyl)-amine dihydrochlo zyl)-amine dihydrochloride having a melting point of ride having a melting point of 203-207 C. (decomposi 198-203 C. (decomposition). tion). EXAMPLE 90 EXAMPLE 98 Preparation of N-(2-amino-5-bromo-benzyl)- Preparation of N,N-dibutyl-(2-amino-6- 2'-methyl-piperidine chloro-benzyl)-amine Using the procedure of Example 68, 5-bromo-2-diace Using the procedure of Example 68, 6-chloro-2-diace tylaminobenzyl-bromide was reacted with 2-methyl-piper tylaminobenzyl-bromide was reacted with dibutylamine to idine to obtain N-(2-amino-5-bromo-benzyl)-2'-methyl obtain N,N-dibutyl-(2-amino-6-chloro-benzyl)-amine di piperidine dihydrochloride having a melting point 197 hydrochloride having a melting point of 174-178 C. 200° C. (decomposition). 75 (decomposition). 3,336,308 25 26 EXAMPLE 99 EXAMPLE 107 Preparation of N,N-disobutyl-(2-amino Preparation of N,N-dibutyl-(2-amino-3-chloro 6-chloro-benzyl)-amine benzyl)-amine Using the procedure of Example 68, 6-chloro-2-diace 5 Using the procedure of Example 68, 3-chloro-2-diacetyl tylaminobenzyl-bromide was reacted with diisobutylamine aminobenzyl-bromide was reacted with dibutylamine to to obtain N,N-diisobutyl-(2-amino-6- chloro-benzyl)- obtain N,N-dibutyl-(2-amino-3-chloro-benzyl)-amine di amine dihydrochloride having a melting point of 156 hydrochloride having a melting point of 158-167 C. 159 C. (decomposition). EXAMPLE 108 EXAMPLE 100 O Preparation of N,N-diisobutyl-(2-amino-3-chloro Preparation of N,N-diamyl-(2-amino-6- s benzyl)-amine chloro-benzyl)-amine . Using the procedure of Example 68, 3-chloro-2-diacetyl Using the procedure of Example 68, 6-chloro-2-diace 5 aminobenzyl-bromide was reacted with diisobutylamine to tylaminobenzyl-bromide was reacted with diamylamine obtain N,N-diisobutyl-(2-amino-3-chloro-benzyl) - amine to obtain N,N-diamyl-(2-amino-6-chloro-benzyl)-amine dihydrochloride having a melting point of 167-174 C. dihydrochloride having a melting point of 152-158 C. EXAMPLE 109 (decomposition). Preparation of N,N-diamyl-(2-amino-3-chloro EXAMPLE 101 20 benzyl)-amine Preparation of N-cyclohexyl-N-methyl-(2-amino Using the procedure of Example 68, 3-chloro-2-diacetyl 6-chloro-benzyl)-amine aminobenzyl-bromide was reacted with diamylamine to Using the procedure of Example 68, 6-chloro-2-diace obtain N,N-diamyl-(2-amino-3-chloro-benzyl)-amine di tylaminobenzyl-bromide was reacted with N-methyl-cyclo 25 hydrochloride having a melting point of 144-150° C. hexylamine to obtain N-cyclohexyl-N-methyl-(2-amino-6- chloro-benzyl)-amine dihydrochloride having a melting EXAMPLE 110 point of 200–210° C. (decomposition). - - Preparation of N-cyclohexyl-N-methyl-(2-amino-3- EXAMPLE 102 30 chlorobenzyl)-amine Using the procedure of Example 68, 3-chloro-2-diacetyl Preparation of N-ethyl-N-cyclohexyl-(2-amino aminobenzyl-bromide was reacted with N-methyl-cyclo 6-chloro-benzyl)-amine hexylamine to obtain N-cyclohexyl-N-methyl-(2-amino-3- Using the procedure of Example 68, 6-chloro-2-diace chloro-benzyl)-amine dihydrochloride having a melting tylaminobenzyl-bromide was reacted with N-ethyl-cyclo 35 point of 165-173° C. (decomposition). hexylamine to obtain N-ethyl-N-cyclohexyl-(2-amino-6- chloro-benzyl)-amine dihydrochloride having a melting EXAMPLE 111 point of 176-180° C. (decomposition). Preparation of N-ethyl-N-cyclohexyl-(2-amino-3- EXAMPLE 103 40 chlorobenzyl)-amine Using the procedure of Example 68,3-chloro-2-diacetyl Preparation of N-(2-amino-6-chloro-benzyl)-piperidine aminobenzyl-bromide was reacted with N-ethyl-cyclo Using the procedure of Example 68, 6-chloro-2-diacetyl hexylamine to obtain N-ethyl-N-cyclohexyl-(2-amino-3- aminobenzyl-bromide was reacted with piperidine to chloro-benzyl)-amine hydrochloride having a melting obtain N-(2-amino-6-chloro-benzyl)-piperidine dihydro 45 point of 177-179° C. (decomposition). chloride having a melting point of 205-208 C. (decom position). EXAMPLE 112 EXAMPLE 104 Preparation of N-(2-amino-3-chloro-benzyl)-2'- Preparation of N-(2-amino-6-chloro-benzyl)-hexa 50 m methyl-piperidine methylenimine Using the procedure of Example 68, 3-chloro-2-diacetyl Using the procedure of Example 68, 6-chloro-2-diacetyl aminobenzyl-bromide was reacted with 2-methyl-piperi aminobenzyl-bromide was reacted with hexamethylen dine to obtain N-(2-amino-3-chloro-benzyl)-2'-methyl to obtain N-(2-amino-6-chloro-benzyl)-hexamethyl piperidine hydrochloride having a melting point of 225 enimine dihydrochloride 193-197 C. (decomposition). 55 226 C. (decomposition). EXAMPLE 105 EXAMPLE 113 Preparation of N,N-dipropyl-(2-amino-3-chloro Preparation of N-benzyl-N-methyl-(2-amino-3-chloro benzyl)-amine 60 benzyl)-amine Using the procedure of Example 68, 3-chloro-2-diacetyl Using the procedure of Example 68, 3-chloro-2-diacetyl aminobenzyl-bromide was reacted with N-methyl-benzyl aminobenzyl-bromide was reacted with dipropylamine to amine to obtain N-benzyl-N-methyl-(2-amino-3-chloro obtain N,N-dipropyl-(2-amino-3-chloro-benzyl) - amine benzyl)-amine hydrochloride having a melting point of dihydrochloride having a melting point of 172-180 C. 65 193-194° C. (decomposition). EXAMPLE 106 EXAMPLE 114 Preparation of N,N-diisopropyl-(2-amino-3-chloro benzyl)-amine Preparation of N,N-diisopropyl-(2-amino-5-chloro 70 - benzyl)-amine Using the procedure of Example 68, 3-chloro-2-diacetyl Using the procedure of Example 70, 2-amino-5-chloro aminobenzyl-bromide was reacted with diisopropylamine N,N-diisopropyl-benzamide was reacted with lithium to obtain N,N-diisopropyl-(2-amino-3-chloro-benzyl)- aluminum hydride to obtain N,N-diisopropyl-(2-amino-5- amine hydrochloride having a melting point of 181 chloro-benzyl)amine dihydrochloride having a melting 186 C. 75 point of 178-183° C. (decomposition). 3,336,308 27 28 Compounding procedure.-The distilled water is heated EXAMPLE 1.15 to 80° C. and then the polyvinyl pyrrolidone and the Drops. The drop solution is compounded from the active ingredient are dissolved therein that order, accom following ingredients: panied by stirring. The resulting solution is cooled, diluted Parts with additional distilled water to the desired volume and N-(2-amino - 3,5 - dibromo - benzyl-N-methyl filtered until free from suspended matter. The solution cyclohexylamine hydrochloride ------0.33 is then filled into white 1 cc. ampules which are sterilized p-Hydroxy- methyl ester ------0.07 for 20 minutes at 100° C. p-Hydroxy-benzoic acid propyl ester ------0.03 Polyvinyl pyrrolidone ------5.0 EXAMPLE 120 Distilled Water ------95.57 O Syrup. The syrup is compounded from the following ingredients: Total ------101.00 Parts Compounding procedure.- The distilled water is heated N-(2-amino - 3,5 - dibromo-benzyl)-N-methyl to 80° C. and then the p-hydroxy-benzoic acid esters, 5 cyclohexylamine hydrochloride ------0.04 the polyvinyl pyrrollidone and the active ingredient are Sodium benzoate ------0.2 dissolved therein in that order. The resulting solution is Ammonium chloride ------0.7 cooled and is filtered until free from suspended matter. Saccharin Sodium ------0.2 20 drops of this solution (about 1.2 cc.) contain 4.0 mgm. Sugar ------65.0 of N-(2-amino-3,5-dibromo-benzyl) - N - methyl-cyclo 20 Blue Food Coloring No. 2 ------0.002 hexylamine hydrochloride. Red Food Coloring No. 2 ------0.007 Yellow Food Coloring No. 2 ------0.024 EXAMPLE 116 Raspberry flavoring ------0.4 Tablets. The tablets are compounded from the fol Menthol ------"w we an a rom a m - a - H -- are m. 0.015 lowing ingredients: 25 Ethanol ------4.0 Parts Distilled water ------54,412 N-(2-amino - 3.5 - dibromo - benzyl)-N-methyl cyclohexylamine hydrochloride ------2.0 Total ------125.000 Lactose ------60.0 Compounding procedure.-The sugar and the active Potato starch, dry ------43.0 30 ingredient are dissolved in 45.412 parts of the distilled Soluble starch ------4.0 water accompanied by heating. The resulting solution is Magnesium stearate ------1.0 cooled (Solution A). The sodium benzoate, the am monium chloride, the saccharin sodium and the food Total ------110.0 colorings are dissolved in the remaining amount of dis Compounding procedure.-The active ingredient and 35 tilled water (Solution B). The menthol is dissolved in the lactose are thoroughly blended with each other and the ethanol (Solution C). Solution B is first stirred into the mixture is admixed with the potato starch, and this Solution A, and then Solution C is added. Finally, the mixture is granulated by moistening it with an aqueous raspberry flavoring is added and the resulting syrup is 20% solution of the soluble starch, and passing the filtered until free from suspended matter. 10 cc. of the moistened mixture through a 1 mm. mesh screen. The 40 syrup containing 4 mgm. of the active ingredient. moist granulate is then dried at 40 C., again passed The dosage unit compositions comprising the com through the screen, and finally admixed with the mag pounds of the present invention as active ingredients nesium stearate. The resulting mixture is then pressed into may also contain other active ingredients. The following tablets weighing 110 mgm. each. examples illustrate such compositions comprising addi 45 tional active ingredients besides the compounds of the EXAMPLE 117 present invention. Coated pills.- The tablets obtained in the preceding EXAMPLE 121 example are provided with a thin shell consisting essen Tablets.-The tablets are compounded from the fol tially of sugar and talcum in the customary manner. The lowing ingredients: coated pills thus obtained are then polished with bees Parts wax. Each coated pill weighs about 170 mgm. and con N-(2-amino-3,5-dibromo-benzyl)-N-methyl-cyclo tains 4.0 mgm. of the active ingredient. hexylamine hydrochloride ------4.0 EXAMPLE 1.18 1 - (p - chlorophenyl)-2,3-dimethyl - 4 - dimethyl amino - butanol - (2) hydrochloride ------40.0 Gelation capsules.--The contents of the capsules are 55 1 - (3,5-dihydroxyphenyl) - 2 - isopropyl - amino compounded from the following ingredients: ethane sulfate ------10.0 Parts Silicic acid, pressed.------61.0 N-(2-amino - 3,5 - dibromo - benzyl)-N-methyl Lactose ------50.0 cyclohexylamine hydrochloride ------4.0 Corn starch, dry------50.0 Lactose ------96.0 60 Tartaric acid ------2.0 Silicic acid, unpressed.------2.0 Total ------100.0 Magnesium stearate ------1.0 Compounding procedure.-The active ingredient is Total ------220.0 thoroughly blended with the lactose, and the mixture is 65 filled into gelatin capsules of sufficient size to hold 100 Compounding procedure.-The active ingredients, the mgm. of the mixture, pressed silicic acid, the lactose and the corn starch are admixed with each other, and the resulting mixture is EXAMPLE 119 granulated by moistening it with a 1.5% solution of the Hypodermic solution.--The hypodermic solution is tartaric acid in ethanol and passing the moist mix through compounded from the following ingredients: 70 a 1 mm. mesh screen. The moist granulate is dried at N-(2-amino - 3,5 - dibromo - benzyl)-N-methyl 40 C. and is again passed through the screen. The re cyclohexylamine hydrochloride ------parts-- 2.0 Sulting dry granulate is admixed with the unpressed silicic Polyvinyl pyrrolidone ------do. 30.0 acid and with the magnesium stearate and the resulting Distilled water, q.S.ad ------parts by volume-- 1000 75 mix is pressed into tablets weighing 220 mgm. each. 3,336,308 29 30 EXAMPLE 122 Compounding procedure.-The distilled water is heated Syrup.-The syrup is compounded from the following to 80 C. and then the hydroxy-benzoic acid ester, the ingredients: tartaric acid and the benzylamine compound are succes Parts sively dissolved therein. The solution is then cooled and N - (2 - amino - 3,5 - dibromo - benzyl) - N filtered. One ml. (about 15 drops) of the solution con methyl - cyclohexylamine hydrochloride---- 0.02 tains 2 mgm. of the active ingredient. 1 - (p - chlorophenyl) - 2,3 - dimethyl - 4 - di methylamino - butanol - (2) hydrochloride.- : 0.4 EXAMPLE 125 1 - (3,5-dihydroxyphenyl) - 2 - isopropyl - ami noethane sulfate ------0.1 0. Syrup.-The syrup is compounded from the following Sodium benzoate ------0.2 ingredients: Ammonium chloride ------0.7 Parts Saccharin Sodium ------0.2 N,N - diamyl (2-amino-4-bromobenzyl)-amine Sugar ------a mau ------am u m n um - - m 65.0 dihydrochloride ------0.5 Blue Food Coloring No. 2.------0.002 15 Sodium benzoate ------0.2 Red Food Coloring No. 2.------0.007 Ammonium chloride ------0.7 Yellow Food Coloring No. 2.------0.024 Saccharin Sodium ------0.2 Eucalyptus-menthol flavoring ------0.1 Sugar ------65.0 Menthol ------0.015 20 Certified food colors ------0.033 Ethanol ------4.0 Raspberry flavoring ------0.4 Distilled water ------54.232 Menthol ------0.015 Ethanol ------4.0 Total ------125,000 Distilled water ------53.952 Compounding procedure.-The sugar and the ben 25 Zylamine active ingredient are dissolved in 45.232 Total ------125.00 parts of distilled water, accompanied by heating. The resulting solution is cooled (Solution A). The so Compounding procedure.-The sugar and the benzyl dium benzoate, the ammonium chloride, the sac amine compound are dissolved in 45.952 parts of warm charin sodium and the food colorings are dissolved 30 distilled water, and the resulting solution is allowed to in the remaining amount of distilled water (Solution B). cool (Solution A). The sodium benzoate, the ammonium The menthol and the eucalyptus-menthol flavoring are chloride, the saccharin sodium and the food colors are dissolved in the ethanol (Solution C). First Solution B dissolved in the remaining amount of distilled water and then Solution C are stirred into Solution A. The (Solution B). The menthol is dissolved in the ethanol resulting syrup is filtered until free from suspended mat 35 (Solution C). First Solution B and then Solution C are ter. 10 cc. of the syrup contained 2 mgm. of N-(2-amino 3,5-dibromo-benzyl)-N-methyl-cyclohexylamine hydro stirred into Solution A. Finally, the raspberry flavoring is chloride, 40 mgm. of 1-(p-chlorophenyl)-2,3-dimethyl-4- added to the combined solution, and the finished syrup dimethylaminobutanol-(2)-hydrochloride and 10 mgm. of is filtered until free from suspended particles. 10 cc. of 40 Syrup contain 50 mgm. of the active ingredient. The syrup 1-(3,5-dihydroxyphenyl)-2-isopropylaminoethane sulfate. is an effective cough syrup adapted for peroral administra tion. EXAMPLE 123 Hypodermic solution.-The solution is compounded EXAMPLE 126 from the following ingredients: 45 Tablets-The tablet composition is compounded from N,N-diethyl-(2-amino-4-bromobenzyl)-amine di the following ingredients: hydrochloride ------parts-- 4.0 Parts Tartaric acid ------do---- 2.0 N - (2-bromo-4-amino-benzyl)-morpholine hydro Dextrose ------do---- 95.0 chloride ------4.0 Distilled water, q.s.ad. ------parts by volume. 2000.0 50 Lactose ------79.0 Potato starch ------34.5 Compounding procedure.-About 90% of the required Gelatin ------2.0 amount of water is heated to 80 C., and the tartaric acid and benzylamine compounds are dissolved therein. Magnesium stearate ------0.5 The solution is cooled to room temperature, the dextrose 55 is dissolved therein, and the solution is diluted to the Total ------120.0 required volume with distilled water. The finished solu Compounding procedure.-The benzylamine compound tion is then filtered until free from suspended particles is intimately admixed with the lactose and with the potato under substantially aseptic conditions. The filtered solu Starch, and the resulting mixture is moistened with an tion is filled into 2 cc. ampules, which are sterilized for 60 aqueous 10% solution of the gelatin. The moist mixture 20 minutes at 120° C. and sealed. Each ampule contains is forced through a 1 mm.-mesh screen, and the moist 4.0 mgm. of the active ingredient. granulate thus obtained is dried at 40° C. The dry gran EXAMPLE 124 ulate is again passed through the screen and is subse 65 quently intimately admixed with the magnesium stearate. Drops.--The drop solution is compounded from the The mixture is finally pressed into 120 mgm. tablets. Each following ingredients: tablet contains 4 mgm. of the active ingredient. Parts N,N- diethyl-(2-amino-4-bromobenzyl)-amine di EXAMPLE 127 hydrochloride ------0.2 70 Tartaric acid ------0.1 Coated pills. The tablets obtained in the preceding p-Hydroxy-benzoic acid methyl ester ------0.1 example are coated with a thin shell consisting essentially Distilled water ------99.6 of sugar and talcum. The coated tablets are then polished with beeswax. Each coated pill weighs approximately 200 Total ------100,0 75 mgm. and also contains 4 mgm. of the active ingredient. 3,336,308 31 32 wherein X is a halogen selected from the group consisting EXAMPLE 128 of chlorine and bromine, R is selected from the group con Aerosol.-The aerosol composition is compounded sisting of hydrogen, lower alkyl, hydroxy lower alkyl, from the following ingredients: lower alkenyl, cycloalkyl of 5 to 6 carbon atoms, phenyl Parts lower alkyl, phenyl R1 and R2 are selected from the group N - (2-bromo-4-amino-benzyl)-morpholine hydro consisting of lower alkyl, lower alkenyl, hydroxy lower chloride ------300.0 alkyl, cycloalkyl of 5 to 6 carbon atoms, phenyl lower Sorbitan trioleate ------135.0 alkyl, phenyl and pyridyl lower alkyl, and R and R1 and Isopropyl myristate ------75.0 R1 and R2 when taken together with the nitrogen atom Trifluoro-trichloro-ethane ------75.0 form a heterocyclic selected from the group consisting of Propellant gas mixture of monofluoro-trichloro 10 pyrrolidino, lower alkyl pyrrolidino, piperidino, lower methane, difluoro-dichloro-methane and tetra alkly piperidino, piperazino, lower alkyl piperazino, hexa fluoro-dichloro-ethane in weight ratio 23:54:23, methylenimino, lower alkyl hexamethylenimino, and R. 9.S. ad ------10,500 and R4 are different and are selected from the group con Compounding procedure.-The micronized benzyl 15 sisting of hydrogen and -NH2 and their non-toxic, phar amine compound (max. particle size 5u is triturated and macologically acceptable acid addition salts. homogenized with a mixture of the isopropyl myristate 2. N - (2-amino-3,5-dibromo-benzyl)-N-methylcyclo and the sorbitan trioleate. The resulting suspension is hexylamine. cooled and is admixed by stirring with the trifluoro-tri 3. N - (2 - amino - 3,5-dibromo-benzyl)-diisobutyl chloro-ethane. 585 mgm. portions of the resulting sus 20 amine. pension are filled into aerosol containers. Thereafter, 4. N - (2 - amino - 3,5 - dibromo-benzyl)-dicyclo enough of the deep-cooled, liquid propellant gas mixture hexylamine. is added to each container to make 10.5 gm., whereupon 5. N - (2 - amino - 3,5 - dibromo-benzyl) - dimethyl the containers are sealed with a valve which meters out 70 amine. mgm. of the contents each time it is actuated. Each con 25 6. N - (4 - amino-3,5-dibromo-benzyl)-N-methylcyclo tainer holds 150 individual doses of the aerosol mixture, hexylamine. and each dose contains 2 mgm. of the active ingredient. 7. N - (2 - amino - 3,5 - dibromo-benzyl)-cyclohexyl Various modifications of the compositions of the inven amine. tion may be made without departing from the spirit or 8. N,N-diethyl-N-(2-amino-4-bromo-benzyl)-amine. scope thereof and it is to be understood that the invention 30 9. N,N-diamyl-N-(2-amino-4-bromo-benzyl)-amine. is to be limited only as defined in the appended claims. 10. N-(2-bromo-4-amino-benzyl)-morpholine. I claim: 1. An amino-halo-benzylamine of the formula selected References Cited from the group consisting of Keck, Johannes, Chemical Abstracts, vol. 59, pages 35 547-8 (1963). NH R -Ci-N ALEX MAZEL, Primary Examiner. K ) N/ R1 X JOSE TOVAR, Assistant Examiner. 40 and X R / R3 -CH-N N R R I 45 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,336,308 August 15, 1967 Johannes Keck It is hereby certified that error appears in the above numbered pat ent requiring correction and that the said Letters Patent should read as corrected below. In the heading to the printed specification, line 7, after "Germany," insert -- Nov. 21, 1961, T 21, 147; -- ; column 1, line 51, for 'an' read -- and - - ; column 3, in the first formula, for "R" read - - R - - ; same formula, for "R" read - - R1 -- ; column 4, 1ine 74, for "chlorofoorm' read -- chloroform - - ; column 5, 1ine 56, for "acocmpanied" read - - accompanied - - ; column 8, in the last formula, for "rB' read -- Br - -; column 12, line 9, for '6' read - - 5 - -. Signed and sealed this 19th day of November 1968. (SEAL) Attest: Edward M. Fletcher, Jr. EDWARD J. BRENNER Attesting Officer Commissioner of Patents