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United States Patent Office Patented June 10, 1969

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United States Patent Office Patented June 10, 1969 3,449,427 United States Patent Office Patented June 10, 1969 2 l optical isomers. Unless otherwise specified in the descrip 3,449,427 AMINOCYCLOPROPANE DERVATIVES OF tion and accompanying claims, it is intended to include all 5H-DIBENZOadCYCLOHEPTENES isomers, whether separated or mixtures thereof. Carl Kaiser, Haddon Heights, N.J., and Charles L. Zirkle, The novel aminocyclopropane derivatives of 5H-di Berwin, Pa., assignors to Smith Kline & French Labora benzoadcycloheptenes of this invention are prepared tories, Philadelphia, Pa., a corporation of Pennsylvania by several methods, the choice of which depending on the No Drawing. Filed June 3, 1965, Ser. No. 461,176 definitions of m, n, R1 and R2. The starting materials for Int. CI. C07c87/28, 91/16, 149/42 these methods are generally 5H-dibenzo(a,d)cyclohep U.S. C. 260-570.8 8 Claims tenes having the formula: O ABSTRACT OF THE DISCLOSURE Y\ 5[2-(N-N di substituted amino) cyclopropyl)-10,11-di R hydro 5H dibenzo(a,d)cycloheptanes are prepared via the amides and acids. The compounds are antidepressants, 5 X transquillizers and anorectics. H Formula II This invention relates to novel aminocyclopropane de in which Y and R are as defined in Formula I. These rivatives of 5H-dibenzoadcycloheptenes having useful 20 compounds are prepared by reduction of the correspond pharmacodynamic activity. More specifically, the com ing 5H-dibenzo(a,d)cyclohepten-5-ones with, for example, pounds of this invention have central nervous system sodium in a lower alkanol, preferably, ethanol or by the activity such as antidepressant, tranquilizing and anorectic Wolff-Kishner method. activity. In one method of preparation of the aminocyclopro The novel aminocyclopropane derivatives of this inven 25 panes of this invention from the dibenzocycloheptenes of tion may be represented by the following general struc Formula II, the dibenzocycloheptene is alkylated with, tural formula: for example, ethyl 2-bromo- or 2-bromoethyl-cyclopro panecarboxylate followed by hydrolysis to give the corre Y sponding cyclopropanecarboxylic acids having the for R 30 mula: R / / B (C H) -cy to H-(C E2) n-N CE R 35 Formula I H ch)-CH-C H-COOH in which: N/ Y represents CHCH or CH=CH, preferably CHCH2; CE R represents hydrogen, chlorine, bromine, trifluoro methyl, methyl, methoxy or methylthio, preferably in the 40 Formula III 3-position of hite dibenzocycloheptene ring; in which Y and R are as defined in Formula I and m is 0 m and in each represent an integer from 0 to 1; and or 1. The useful compounds of Formula III are converted R and R2 each represent hydrogen, lower alkyl of to amino compounds of this invention by several routes. from 1 to 3 carbon atoms or when taken toegther with Reaction of the acid with a lower alkyl haloformate gives the nitrogen atom to which they are attached, represent 45 the corresponding cyclopropyl mixed anhydride which is a pyrrolidine, piperidine, N'-methylpiperazine, N'-(6-hy then treated with sodium azide to give the cyclopropyl droxyethyl)-piperazine or N'-(6-acetoxyethyl)-piperazine azide. The acid azide is then thermally decomposed by Ting. heating in an inert organic solvent to give the correspond Preferred compounds of this invention are represented ing isocyanate. The resulting isocyanate is converted to by the above Fomula I when m is 0 and n is 1. 50 aminocyclopropanes of Formula I where n is 0 by: (a) The nontoxic pharmaceutically acceptable acid addi hydrolysis with a mineral acid such as hydrochloric acid or tion salts of the compounds of Formula I are also in an alkali metal hydroxide such as sodium or potassium hy cluded within the scope of this invention. Both organic droxide at elevated temperatures to give the primary and inorganic acids can be employed to form such salts, aminocyclopropane or (b) reaction with a lower alkyl illustrative acids being sulfuric, nitric, phosphoric, hy 55 magnesium halide or lower alkanol to give an N-lower drochloric, citric, acetic, lactic, tartaric, pamoic, ethane acyl or N-lower carbalkoxy aminocyclopropane, respec disulfonic, sulfamic, succinic, cylohexylsulfamic, fumaric, tively, which is either reduced directly with, for example, maleic, benzoic and the like. These salts are readily pre lithium aluminum hydride to give an N-lower aminocy pared by methods known to the art. clopropane or further reacted with a lower alkyl iodide The compounds of this invention may be present as 60 to give an N-lower alkyl-N-lower acyl or N-lower alkyl cis-trans isomers due to the geometrical arrangement of N-lower carbalkoxy aminocyclopropane, respectively, the dibenzocycloheptene substituent and the amino moiety which is reduced with, for example, lithium aluminum with respect to the cyclopropane ring and further as d, hydride to give an N,N-dialkylaminocyclopropane. 3,449,427 3 4. These reactions may be summarized as follows where pared by alkylation of the dibenzocycloheptenes of For Y and R are as defined in Formula I, m is 0 or 1 and R. mula II with an active ester derivative of aminocyclo and R2 are lower alkyl: propyl carbinols, for example, a p-toluenesulfonate deriva -es R hydrolysis OOCY H (CH)-c circon -COCH (CH)n-CH-CHN-C=O H (CH)n-CH-CHNH N / OE CH C Rich NR.M.XY /Y\ /Y\ /Y\ R -new-res R R YX /N MN H (CH)m-OH-CHNCH3 / H (CH)n-CH-CHNCOOR H (CH)n-CH-CHNCOR N / /RI N / / N / CE. H. CH. H. R/ CH /Y\ /Y\ /Y\ R R R / CE)-cy to HNCoor, /y CH)-c CHNCOR, H N(CH)-c chNCH.R. C. R. CH. R. CE. H. /Y\ H. (CH)-CH-CHNCH3 N/ 00:(CH)n-C N CH-NCHR, C. R3 C To prepare the aminocylopropanes of Formula I where tive. These useful carbinol intermediates having the for m is 0 and n is 1, a dibenzocycloheptene of Formula II is mula: advantageously alkylated with 2-bromocyclopropanecar- R boxamide to form the carboxamide derivative which is N reduced with, for example, lithium aluminum hydride to 45 N-CH-cE CH-CH-OH give the corresponding aminomethylcyclopropanes as fol- R cá, lows: /Y\ R. /Y\ Y\ R. -- Br-citch-con --als R --> R CH R N/ R1 R1 H^H H^c to H-C oNC H^c to H-CHN C Ra C Yi, in which Y and R are as defined in Formula I, R is hy Formula IV drogen or lower alkyl, and R2 is lower alkyl or when R1 and R are taken together with the nitrogen atom to which in which R1 and R are lower alkyl or when taken together they are attached, represent a pyrrolidine, piperidine or with the nitrogen atom to which they are attached, rep N'-methylpiperazine ring. The 2-bromocyclopropanecar 60 resent a pyrrolidine, piperidine or N'-methylpiperazine boxamides are readily prepared from the corresponding ring are prepared by reaction of, for example, ethyl carboxylic esters by hydrolysis, conversion to the acid 1-bromocrotonate with an appropriate dialkylamine or chloride, and treatment with a secondary amine. heterocyclic amine to give the corresponding aminocro Alternatively, the aminocyclopropanes of Formula I tonate which is then reacted with a reagent formed from where n is 1 are prepared from the cyclopropanecar 65 trimethylsulfoxonium iodide. The latter in the presence of boxylic acids of Formula III by reacting the acid with a a strong base such as sodium hydride forms a reactive lower alkyl haloformate to give the corresponding cyclo substance called dimethylsulfoxonium methylide, propy mixed anhydride which is then treated with am monia, a monoalkyl amine, a dialkylamine or a hetero (CH) i=CH, cyclic amine to give the cyclopropanecarboxamide. Re 70 duction of the amide with, for example, lithium aluminum hydride gives the corresponding aminomethylcyclopro which produces the ethyl aminocyclopropylcarboxylate. panes. Similar reduction of the carboxylate with, for example, The novel aminocyclopropanes of this invention repre lithium aluminum hydride gives the aminocyclopropyl cars sented by Formula I above where m and n are 1 are pre 75 binols of Formula IV where n is 1, 3,449,427 5 6 The aminocyclopropyl carbinols of Formula IV above an additional 4.8 ml. of water. The resulting mixture is are advantageously employed in the dibenzocycloheptene filtered and the filtrate extracted with aqueous acetic acid. alkylation as the tosylates. Thus, reaction of the amino The acid extract is made alkaline with dilute sodium hy methylcyclopropyl carbinol tosylate with the appropriate droxide Solution and the mixture extracted with ether. dibenzocycloheptene gives the desired product. The dried ether extract is concentrated to give trans-5-2- The compounds of Formula I above where R1 and Ra (N,N - dimethylaminomethyl) - cyclopropyl) - 10, 11 together represent a heterocyclic amino moiety are pre dihydro-5H-dibenzo(a,d)cycloheptene. pared also from the corresponding primary amines. The Similarly, by employing in the above reaction sequence pyrrollidinyl and piperidinyl derivatives are prepared from 4.2 g. of 3-methyl-10,11-dihydro-5H-dibenzoadcyclo the primary amine and 1,4-dibromobutane and 1,5-di O heptene (prepared by sodium and ethanol reduction of the bromopentane, respectively in an organic solvent refluxing corresponding 5-one) there is obtained as the final product at a temperature from 100-150° C. and in the presence trans - 3 - methyl - 52 - (N,N-dimethylaminomethyl)- of potassium carbonate. Similar reaction of the primary cyclopropyl-10,11-dihydro-5H-dibenzoa,dcycloheptene. amine with methyl bis-(3-chloroethyl)-amine gives the N'-methylpiperazinyl derivative. EXAMPLE 2 In the above described preparation methods, when the first step of the reaction sequence consists of alkylation To a stirred mixture of 115 g.
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