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United States Patent Office Patiented Mar 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.
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