3,126,373 United States Patent Office Patiented Mar. 24, 1964 2 invention, and 5-(3'-dimethylaminopropyl)-5H-dibenz 3,126,373 (b,fl-azepine (SK & F #5355) are given in Table 1. 5-MONOALKYAMNOPROPYL-5H The effective dose value for 50% of the test animals DBENZ-b,f-AZEPINES (ED50) is determined by subcutaneous (s.c.) administra Paul N. Craig, Roslyn, Pa., assignor to Smith Kline & 5 tion of the test compound at graduated doses to groups French Laboratories, Philadelphia, Pa., a corporation of 15 rats per dose. of Pennsylvania TABLE 1. No Drawing. Filled Feb. 2, 1962, Ser. No. 170,806 1 Claim. (C. 260-239) Calmative Activity Anti-Furmethide Protective Effect Activity This invention relates to 5-monoalkylaminopropyl-5H 10 Against Stress (Isolated Rabbit dibenz-b,f-azepines which have useful therapeutic activ Induced Ulcers Jejunum) ity, specifically as general central nervous system depres Structure and No. Mini sants and particularly as antiemetics, tranquilizers, calma ED50 Relative mum Relative mg/kg. Potency Dose, Potency tives, anti-histaminics, spasmolytics, antishock agents and S.C. mg.150 potentiators of analgetics or anesthetics. 15 CC. The novel 5-monoalkylaminopropyl-5H-dibenz-Ib,f- azepines of this invention are represented by the general SK & F #5355 formula: FORMUL.A. i 20 9 0 CEs-CE. 2.0 1. 0.01 1. 8 2 N CHs f b / 8-R, (CH2)3N NS H 25 CI 6 4. / CH2CH2CH-N SK & F #13943 R when: R1 and Ra represent hydrogen or chlorine; and 30 0.13 15.4 0.04 .25 R represents lower alkyl of from 1 to 4 carbon atoms, YN/A preferably methyl. (CE)3N This invention also includes salts of the above defined CH3 bases formed with nontoxic organic and inorganic acids. 35 Such salts are easily prepared by methods known to the The dimethylamino compound, SK & F #5355, pro art. The base is reacted with either the calculated amount duces protection in this stress induced situation, having an of organic or inorganic acid in aqueous miscible solvent, effective does for 50% of the test animals (ED) of 2.0 such as acetone or ethanol, with isolation of the salt by mg/kg. However, the monomethylamino compound, concentration and cooling or an excess of the acid in 40 SK & F #13943, is much more effective, with an EDs aqueous immiscible solvent, such as ethyl ether or chloro of 0.13 mg/kg, which is 15.4 times as potent as SK & F form, with the desired salt separating directly. Exem #5355. Both compounds were further compared for plary of such organic salts are those with maleic, fumaric, their local anti-chlolinergic effect by testing them accord benzoic, ascorbic, pamoic, succinic, bismethylene-Salicylic, ing to standard procedures for antagonism of furmethide methanesulfonic, ethanedisulfonic, acetic, propionic, tar 45 induced spasm of intestinal strips. The minimum anti taric, salicyclic, citric, gluconic, lactic, malic, mandelic, furmethide doses are given above in Table 1. SK & F cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, #13943 is only 4 as potent as SK & F #5355 in this atro glycolic, p-aminobenzoic, glutamic, benzene sulfonic and pine-like activity. theophylline acetic acids as well as with the 8-halotheo Therefore, the compound representative of this inven phyllines, for example, 8-bromotheophylline. Exemplary 50 tion, SK & F #13943, has greater protective activity (15.4 of such inorganic salts are those with hydrochloric, hydro times) than the dimethylamino compound, SK & FiF5355, bromic, sulfuric, sulfamic, phosphoric and nitric acids. in the stress induced ulcer procedure, even though its local Of course, these salts may also be prepared by the classi anti-cholinergic activity is only 4 as potent as SK & F cal method of double decomposition of appropriate salts #5355. It is concluded therefore, that SK & F if 13943 which is well-known to the art. 55 has a greater central nervous system protective activity The compounds of this invention are characterized by than SK & Fit 5355. Quantitatively, SK & F #13943 has singular central nervous system activity in comparison to 60 times (15.4/0.25) the central nervous system protec the 5-dialkylaminopropyl-5H-dibenz-Ib,f-azepines. The tive activity of SK & F #5355. unique central nervous system activity of the 5-monoalkyl Particularly significant in these test results is the fact amino derivatives of this invention is characterized particul 60 that not only is the degree of potency of the compounds larly by a calmative activity and may be best demon of this invention increased dramatically but the kind of strated by pharmacological testing of protective effects on activity demonstrated is distinct from corresponding 5-di stress induced ulcers in rats. In this test procedure, rats alkylamino derivatives. For example, as a calmative the are subjected to a severe psychological stress, namely 5-monomethylaminopropyl compound, SK & F #13943, complete restraint including limb immobilization. This 65 is considerably more potent than the 5-dimethylaminopro situation induces ulcers of the gastric mucosa after several pyl compound, SK & Fitis355, (15.4 times as seen in pro hours. This response (ulcers) is used as a measure of a tection of stress induced ulcers). However, since SK & F specific type of psychlogical stress. Test compounds are #13943 is only 4 as potent as SK & FiF5355 in the local evaluated in this procedure for their protective effect anti-cholinergic test procedure, it must be concluded that against such stress induced ulcers. Results in this test ob O the calmative activity of the compounds of this invention tained for 5-(3'-methylaminopropyl)-5H-dibenz-Ib,f- - is exerted on the level of the central nervous system rather azepine (SK & F #13943), a typical compound of this than on the peripheral level. Therefore it is this selective 3,126,373 3 4 quantitative increase in potency, achieved by a central tuted in the 5-position are prepared from the correspond nervous System activity, which distinguishes the com ing iminodibenzyls by dehydrogenation in accordance with pounds of this invention from the 5-dialkylaminopropyl the method disclosed in copending application Serial No. 5H-dibenz-Ib,f-azepines. 688,442, filed October 7, 1957, now Patent No. 3,074,931. Table 2 presents the data compared to the effects of As disclosed therein, the iminodibenzyl is heated in the atropine. 5 presence of a dehydrogenation catalyst either in the vapor TABLE 2

Anti-Furmethide Anti-Ulcer Activity Effect (isolated rabbit jejunun) Central Structure and No. ActivityIndex Mini- ya ED50 Atropine Inum Atropine (Ing./kg.) Ratio Dose Ratio (g) (mg.f50 (a) cc.) Atropine (H-H-CH, CHOH (H-CH-)H,N-CH, CH-O-co-ch 0.30 O007 1.

SK & Fis355

N ych, 2.0 .15 .0 08 1.9 (C) iN CH SK & Fis943

N yi 0.13 2. 31. .04 .02 15.5 ch) iN CHs

The monomethylamino compound, SK & F #13943 is phase, alone or in a solvent. Preferably the dehydrogen 2.3 times as potent as atropine in the protection of stress ation is carried out by vaporization of the iminodibenzyl induced ulcers, while the dimethylamino compound, under reduced pressure in the presence of palladium on SK & F #5355, is about 0.1 as potent as atropine. In 50 charcoal. The reaction product is purified by crystalliza the test for antagonism of furmethide induced spasm, tion or chromatography. both compounds were less active than atropine. Again The preparation of the 5-unsubstituted iminodibenzyls of particular significance is the fact that SK & F #13943 used as intermediates as outlined above is likewise dis has greater protective activity than atropine against stress closed in the aforesaid application Serial No. 688,442, induced ulcers even though its local anti-cholinergic ac 55 now Patent No. 3,074,931. tivity is only 0.02 that of atropine. Therefore on the The 5-unsubstituted dibenzazepines of Formula 2 are basis of central nervous system protective activity, the converted to the therapeutically valuable 5-monoalkyl monomethylamino compound, SK & F #13943, is 115 aminopropyl-5H-dibenz-Ib,f-azepines of Formula 1 as times more potent than atropine, whereas the dimethyl follows. The Sodio derivative of the 5-unsubstituted di amino compound, SK & F #5355, has only 1.9 times the 60 benzazepine is reacted with y-bromopropyl tetrahydro activity of atropine. These results further demonstrate pyranyl ether in Xylene, the pyranyl group is removed the striking selective potency of the compounds of this by careful hydrolysis with hydrochloric acid and the y invention. hydroxy compound is acylated with excess p-toluene The starting materials for preparing the 5-monoalkyl sulfonyl chloride in pyridine. The 5-(3'-hydroxypropyl)- aminopropyl-dibenzazepines have the following structural 65 5H-dibenz-Ib,f)-azepine p-toluenesulfonate thus prepared formula: is reacted with an excess of a lower alkyl amine in an FORMUL.A. 2 alkanolic solvent for approximately 10 hours at reflux CH-scCE N workup.or in a Sealed tube to give the product after suitable 70 The 5-monoalkylaminopropyl-5H-dibenz-b,f-azepines R N- R of this invention may be advantageously prepared from H Substituted dibenzyls in an alternative manner, namely, by alkylating a 2-amino-2'-halodibenzyl under conditions when: R1 and R2 represent hydrogen or chlorine. identical with those described above for the 5-alkylation The dibenzazepines of Formula 2 which are unsubsti 75 of the dibenzazepines and subsequently cyclizing the di 8,126,873 5 6 benzyl to form the alkylated iminodibenzyl which is in lene, removing the pyranyl group by careful hydrolysis turn dehydrogenated under conditions described here with hydrochloric acid and acylating the y-hydroxy com above to give the desired compounds. pound with excess p-toluenesulfonyl chloride in pyridine) The above cyclization of a 2-monoalkylaminopropyl and 1.0 g of methylamine in 25 ml. of ethanol is heated amino-2'-halodibenzyl is carried out by heating the com for 10 hours in a sealed tube. The solvent is removed pound in the presence of an acid-binding agent, present from the reaction mixture and the residue is extracted in at least an amount sufficient to neutralize the hydro with a water-chloroform mixture. The chloroform layer halic acid formed during the reaction. Exemplary of is extracted with dilute mineral acid and the extracts are such acid-binding agents are the carbonates, such as neutralized with sodium carbonate solution. The crude sodium carbonate, sodium bicarbonate or preferably po 10 product is extracted into ethyl acetate and removal of the tassium carbonate. The reaction is run in a Suitable, solvent yields 5-(3'-methylaminopropyl)-5H-dibenz-Ib,f- nonreactive organic solvent in which the reactants are azepine. at least partially soluble. Exemplary are dioxane, di Treating the free base in ether solution with ethereal methylaniline, diethylformamide, methylformamide, di hydrogen chloride gives the corresponding hydrochloride salt. methylformamide or dimethylacetamide. Preferably, the 15 Following the above procedure and using an excess of solvent is dimethylformamide and other similar lower ethylamine in a sealed tube, 5-(3'-ethylaminopropyl)-5H carbon amides. Optimum yields in this cyclization are obtained when dibenz-Ib,f-azepine is obtained. catalytic amounts of copper or copper bronze powder are Example 2 added, for instance up to 5% by weight of the dibenzyl. 20 Following the general procedure outlined in Example The reaction mixture is advantageously heated at from 1, 2.5 g. of 3,7-dichloroiminodibenzyl (Belgian Patent about 100 to 220 C. for long periods, such as from 4 to it 541,489) is sublimed through a glass column packed 60 hours. Preferably, the reaction mixture is heated with with 0.5 g. of 30% palladium on charcoal sprinkled on stirring at the boiling point of the solvent for from about glass wool. After two hours, the collected material from 8 to 24 hours. The reaction mixture is worked up by 25 the cooled part of the column is removed and purified to cooling, filtering and quenching in water. The separated give 3,7-dichloro-5H-dibenz-b,f-azepine as yellow crys product is washed and purified to give the desired imino tals. dibenzyl. A solution of 4.7 g. of 3,7-dichloro-5-(3'-hydroxy Alternatively, a 5-unsubstituted iminodibenzyl may be propyl)-5H-dibenz-Ib,f-azepine p-toluenesulfonate (pre alkylated as described above and the thus alkylated imino 30 pared from the reaction of the sodio derivative of 3,7- dibenzyl may be converted to the corresponding alkylated dichloro-5H-dibenz-b,fl-azepine with ?y-bromopropyl tet dibenzazepine by means of a dehydrogenation catalyst rahydropyranyl ether in xylene, removing the pyranyl in accordance with the process disclosed in copending group by careful hydrolysis with hydrochloric acid and application Serial No. 688,442, now Patent No. 3,074,931. acylating the y-hydroxy compound with excess p-toluene Further the 5-monoalkylaminopropyl-5H-dibenz-bf 35 sulfonyl chloride in pyridine) and 1.5 g. of butylamine azepines may be prepared by reacting the 5-unsubstituted in 30 ml. of ethanol is heated at reflux for ten hours. dibenzazepine with an excess of acrylonitrile or in an The solvent is removed from the reaction mixture and inert solvent such as benzene in the presence of a catalytic the residue is extracted with a water-chloroform mixture. amount of a strong base, such as a quaternary base, for 40 The chloroform layer is extracted with dilute mineral instance benzyltrimethylammonium hydroxide. The re acid and the extracts are neutralized with sodium carbo sulting b-cyanoethyl compound is then reduced, for in nate solution. The crude product is extracted into ethyl stance with lithium aluminum hydride to give the primary acetate and the solution is heated with maleic acid to amine. Further alkylation of the primary amine by for yield 3,7-dichloro-5-(3'-butylaminopropyl)-5H- dibenz example with a reactive ester such as an alkyl halide in Ib,f-azepine maleate. the presence of an acid-binding agent as described above 45 Following the above procedure and using an excess of in an inert solvent such as benzene or xylene gives com methylamine or ethylamine in a sealed tube, 3,7-dichloro pounds of this invention. 5-(3'-methylaminopropyl) - 5H-dibenz-Ib,f-azepine and Of particular advantage as preparative procedures for 3,7-dichloro-5-(3-ethylaminopropyl) - 5H - dibenz-Ib,fl obtaining the 5-monoalkylaminopropyl-5H-dibenz-bf azepine are obtained, respectively. Y azepines are the N-alkylation of dibenzazepines in the 5 50 This application is a continuation-in-part of copending position of the nucleus, and the dehydrogenation of 5 application Serial No. 688,442, filed October 7, 1957, alkylated iminodibenzyls by a suitable catalyst such as now Patent No. 3,074,931. palladium on charcoal. What is claimed is: The following examples are not limiting but are illus A chemical compound selected from the group con trative of compounds of this invention and the proce 55 sisting of a free base and the nontoxic acid addition salts dures for their preparation and will serve to make fully thereof, the free base having the formula: apparent all of the compounds embraced by the general 9 0 11 1. formula given above and the preparation thereof respec CH=CH tively. 8 2 Example 1 60 R NS 3-R. An electrically heated glass column, 35 mm. in diam 6 4. H eter and 30 cm. long, is packed with 1.0 g. of 30% pal / ladium on charcoal sprinkled on glass wool and 4.5 g. CHCH2CH2N of 10,11-dihydro-Ib,f-azepine is sublimed through the 65 R column at 0.5 mm. by heating until sublimation occurs. in which: The upper part of the column is surrounded by a Dry Ice R1 and R2 are members selected from the group con bath and after two hours the reaction is completed. The sisting of hydrogen and chlorine; and yellow sublimate is removed and purified by chromatog R is lower alkyl of from 1 to 4 carbon atoms. raphy through alumina, using benzene, to give the prod 70 uct, 5H-dibenz-Ib,f-azepine, M.P. 196.5-198 C. References Cited in the file of this patent A solution of 4.05 g. of 5-(3'-hydroxypropyl)-5H-di benz-b,f-azepine p-toluenesulfonate (prepared from the UNITED STATES PATENTS reaction of the sodio derivative of 5H-dibenz-b,f-aze 2,629,719 Cusic ------Feb. 24, 1953 pine, with y-bromopropyl tetrahydropyranyl ether in Xy 75 2,785,160 Jacob et al. ------Mar. 12, 1957