CA1122528A - Chlorinated tetrahydro-2-benzazepines, n-methyl transferase inhibitors - Google Patents

Abstract

Abstract or the Disclosure This invention provides a series of novel chloro-and dichlorotetrahydro-1H-2-benzazepines which are useful as inhibitors of norepinephrine N-methyl transferase.

Description

~2;25Z~3 This invention provides a series of novel chloro-and dichlorotetrahydro-1~-2-benzazep;nes which are useful as inhibitors or norepinephrine N-methyl transferase.
Tetrahyàro-2-benzazepines and tetrahydro-3-benzazepines are both known in the art. von Braun and Zobel, Ber. C6, 690, (1923) prepared both compounds as did Deady, et al., J.C.C., Per.~in Trans 782 (1973) by a different route. In addition, Deady et al (loc. cit.) prepaxed the previously unreported 7-methyl derivati~-e of tetrahydro-lH-2-benzazepine as well as 7-chlorotetrahydro-lH-2-ben~azepine. No utility was given for any of these products.
According to Kasparek, writing in ~dvances in Heterocyclic Chemis.ry, Vol. 17, pp. 4~ et seq. (Katritzky and ~oulton, ed., Academic Press, 1974), 2-benzazepines ~ave been tested as anti-hypertensives, adrenergic b}ockers, and choline~terase innibitors. 3-Benzazepines have been tested as h-ypoglycemics, analgesics, depressants, anorectics, and ganglionic blocking agents. 1-3enzazepines have also been found to nave analgesic, antidepressant, anti-fibrillant, hypotensive, anti-neoplastic, diuretic, hypoglycemic, and anti-arrhythmic ac~ivities. N-Substituted 'etrahydro-2-benzazepines have been prepared [see for example, Chemical .bstracts 74, 53575a tl971); 72, 66776a (1970); and 6~, 59453g (196~)1. Belleau prepared ~ -chloroethyl)-2-benzazepine as an aaranergic blocking agent ~(~. Med._Pharm.
Chem. 1, 343 (1953)~. TAe compounà blocked epinephrine at ~ ;
a level about 2.5 times lower than did ibenamine.

X-~6~0 -~-~ , ~22~2~3 U.S. Patent 3,988,339 disclc es a number of 7-and/or ~-substituted 1,2,3,4-tetrahydroisoquinolines, use~ul as phenylethanolamine N-methyl transferase inhibitors ~NMT
inhibitors, also referred to as norepinephrine N-methyl transferase inhibitors). 7,8-Dichloro-1,2,3,4-tetrahydro-isoquinoline was said to inhibit NMT by 50 DerCent at a concentration of 1.2 x 10 7 molar. U.S. Patent 3,939,164, the parent of U.S. Patent 3,988,399, discloses a limited group of 7- and 8-halo-substituted tetrahydroiso-~uinolines~
The active pressor principle cf suprarenal extracts was named epinephrine by ~ble in 1899 and was synthesized soon thexeafter by Stolz and Dakin. Epinephrine is the major hormone produced by Ihe adrenal medulla. It is a potent vasopressor and yields a rapid rise in blood pressure upon intravenous injection. It constricts the smaller arterioles and precapillary sphincters as well as veins and large arteries. Epinephrine is a powerful cardiac stimu-lant; the compound can also cause cardiac arrhythmias.
Epinephrine is released in signiricant quantities into the blood stream during periods of stress. It is this burst of epinephrine which enables mammals, including humans, to take immediate evasive action. Continuous stress and therefore continuous injection of epinephrine into the blood stream, however, nas a deleterious effect in that blood pressure may be eleva~ed permanently or arrhyt~mias may be inducea. Continued stress over long periods may xesult in malignant hypertensicn or chronic heart disease.

X-46~0 -3- -`

~12;~5~8 The last stase in ~he biosynthesis or epinephrine in the mammal is the methylation of the r.eurohumoral trans-mitter for most sympathetic postganglionic fibers, nore-pinephrine. The enzyme responsible ror this final synthetic step is known as norepinephrine N-metnyl transIerase.
Inhibitors of this enzyme (~MT inhibitors) are useful in ~reventing the secretion by the adrenal into the blocd stream of large quantities of epinephrine during periods of stress by inhibiting the last step in the rormation of this compound.
This invention provides novel chlorinated tat-a-hydro-2-ben~azepines of the for~ula I n3~

wherein n is 1 or 2, provided that when n is 2, the chlorine atoms are vicinal, and that, when n is 1, the chlorine a~om occupies the 3-position; and pharmaceutically-acceptable acid addition salts the.reo~.
This invention also comprises novel and useful pharmaceutical compositions valuable ror reducing the forma-tion o~ epinephrine in a mammal whicn comprise a pharma-ceutically-acceptable inert carrier and a compound of the folmula X-~6~0 -~-~L~L22Si2~

~ 2 ~
Cl ~
\6~ \a 4/ II

wherein the chlorine atom occupies the 6, 7 or g position:
and pharmaceutically-acceptable acid addition salts thereof.

The compounds of Formulae I and II axe prepared by reacting a compound of the formula H H H H H
1~ /~ I I I I I :
t ~-C-!~I-C-C-C-Ha l o C l ~
n ~ H H H H III

wherein n is as defined aDove, provided that none of the chlorine atoms occupies a ~osition ortho to the side chain, with a Friedel~Crafts catalyst of the Lewis acid type or by reacting a compound of the formula wherein n is as defined above, with àn azide in the presence of a strong acid to pr~pare a compound of the formula /~ / ~'~
C I n~
\~ / V

~l~22~
and reacting the compound of formula V with a reducing agent;
and if desired recovering the compound of Formula I or II
in the form of a pharmaceutically-acceptable salt.
This invention also comprises a process or preparing a novel chlorinated tetrahydro-2-benzazepine of the formula lo ~ ~T, ~ I

wnerein n is l or 2, provided that no~e of the chlorine atoms occupies the 9-position, that when n is 2, the chlorine atoms are vicinal, and that, when n is l, the chlorine atom occupies the 8-position; and pharmaceutically-acceptable acid addition salts thereof; which process is characterized by reacting a compound of the formula H H H H H

~I-C-~C-C-C-Ha l o

2 0 \a~ I I I

wherein n ia as defined above, provided that none of the chlorine atoms occupies a position ortho to the side chain, with a Friedel-Crafts catalyst of the Lewis acid type.

- 5a -~lZ2~8 The pharmaceuticaily-acceptable acid addition salts of compounds useful in the process of this invention include salts derived from inorganic acids such as hydro-ch}orlc acid, nitric acid, phosphoric acld, sulfuric acid, hydrobromic acid, hydriodic acid, nitrous acid and phos-phorous acid, as well as salts derived from nontoxic organic acids such as aliphatic mono and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkancic and alkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such pharmaceutically-acceptable salts thus include sulfate, pyrosulfate, bisul~ate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphos-phate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, butyn-1,4-dioate, hexyn-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxyben20ate, phthalate, terephthalate, benzenesulfonate, toluenesulonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenyl-butyrate, citrate, lactate, ~-hydroxybutyrate, glycollate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-l-sulfonate, naphthalene-2-sulfonate and the likP salts.

X-4680 -6~

~2~;2~

When a starting compound of formula III is used, the halo atom at the end of the side chain is preferably bromine. The starting compound of ormula III is reacted with a Friedel-Crafts catalyst of the Lewis acid type, preferably aluminl~m chloride. Such other metal halides as aluminum bromide, zinc chloride, boron trifluoride, boron trichloride, boron tribromide, titanium tetrachloride, stannic chloride, bismuth trichloride and ferric chloride are also well known Lewis acid Friedel-Crafts catalysts and are useful in the present reaction.
The reaction may be carried out in a solvent or without one. If a solvent is used, it should be a high-boiling solvent such as decalin, because the reaction should be carried out at a high temperature from 100C. to 200C. If aluminum chloride is the catalyst, it is possible to use no solvent and to carry out the reaction at or above the fusion temperature.
When the process begins with a starting compound of formula IV, the first step is to react the starting compound with an azide. The azide may be supplied in the form of an azide salt, particularly and preferably an alXali metal azide, or in the form of hydrazoic zcid. Whichever ~orm of the azide is prererred, the reaction of the compound of formula IV is carried out in the presence o a strong X-~6~0 3d 1~22~21~

acid. Sulfuric acid is preferred, but other typical strong acids such as phosphoric acid and trifluoroacetic acid may also be used. The reaction of the starting compound of Formula IV with an azide is carried out in a solvent which is inert to the reactants. The nalogenated solvents are particularly useful. Such halogenated solvents as chloro-form, dichloromethane, the di~hloroethanes and the chlorinated be~zenas are particularly useful. The te~perature of the azide reaction is preferably from 0~C. to the ambient temperatu-e.
The intermediate compound of Formula V is then reduced to prepare the compound of Formulae I or II. The preferred reducing agent is diborane (B2H6). Other typical effective reducing a~ents, particularly lithium aluminum hydride, may also be used. The reduction may be carried out in any inert solvent, of which tetrahydrofuran is preferred.
Other ir.ert solvents, such as diethyl ether and 1,2-dimethoxy-ethane may also be effectively used. The reduction is best carried out at a temperature from the ambient temperature to 100C., pre~erably at the reflux temperature o the reaction mixture.
Preparation 1 A solution was prepared from 90 g. of o-chloro-benzyl chloride in 200 ml. of 3-aminopropanol. The solution immediately became hot, and external heating was applied slowly until reflux temperature was reached. The reaction mixture was tnen cooled, and the cooled solution was diluted X-46~0 -8-with one liter of water. The aqueous mixture was made basic with 2G0 ml. of 5N aqueous sodium hydroxide. 3-~o-~hloro-benzylamino)propanol formed in the above reaction, being insoluble in aqueous base, separated and was extracted into ether. The ether extract was separated, washed twice with water and once witk saturated aqueous sodium chloride solution. The ether e~tract was then dried and the ether removed by evaporation in vacuo, yieldins a residue con-sisting of 9% g. of a yellow llquid. Distillation of the residue yielded 3-(o-chlorobenzylamino)propanol distilling in th~ range 127-138C. at 0.1 mm/hg. Yield = 83.5 g.
~nalysis; ~alc.: C, 60.15; H, 7.07; N, 7.01; Cl, 17.75;
Found: C, 60.09; H, 7.01; ~, 6.99; Cl, 17.92 32.8 g. of 3-(_-chlorobenzylamino)propanol were added slowly to 100 ml. of 48 percent aqueous hydrobromic - acld and kept at about 0C. A 250 ml. round-bottom flas~
fitted with a mechanical stirrer and a distillation head was used as a reaction vessel. After the addition had been completed, the reaction mixture was heated to refluxing temperature and then to a temperature of about 127C. in order to remove constant boiling hydrobromic acid. The resldue remaining, containing 3-(o-chlorobenzylamino)propyl bromide hydrobromide, was cooled. The resulting solid was dissolved in acetore and the volatile constituents removed by evaporation in vacuo. This operation was repeated twice more and the resultirg residue was crystallized from ~00 ml.
of ethyl acetate and methanol to yield 38.76 g. of 3-~o-chlorobenzylamino)propyl bromide hydrobromide formed in the above reaction melting at 128-130C.

X-4680 _9_ ~1 ~22~
nalysis; Calc.: C, 34.97; H, 4.11; N, 4.08; Cl, 10.32;
Br, 46.12;
Found: C, 34.76; H, 3.94; N, 3.99~ Cl, 10.12;
Br, 46.41 ~2;~21~
Example 1 Preparation of 6,7-dichloro-2,3,4,5-tetrahydro-1~-2-benzazepine A solution of 10.1 g. of 5,6-dichloro-2-tetralone in 200 ml. of chloroform was prepared. 3.57 g. of sodium azide were added while the reaction mixture was being cooled to about 15C. 50 ml. of 36N aqueous sul uric acid were added in dropwlse fashion while maintaining the temperature in the range 15-20C. The reaction mixture was stirred for an additional 15 minutes after the addition of the acid had .

3~

1~2Z5Z~3 been completed and was then poured into an ice-water mixture.
The organic layer was separated and the separated layer washed with 10 percent aqueous sodium carbonate and saturated aqueous sodium chloride. After drying, evaporation of the volatile constituents from the organic layer yielded 10.42 g.
of a greenish oil consisting of a 50:50 mixture of 6,7-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one and 6,7-dichloro-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one îormed in the above reaction. Ten g. OI the reac~ion mixture containing the isomeric benzazepinones were dis-solved in chloroform and the chloroform solution chromato-graphed over 500 g. of silica gel (Woelm activitv IV). The chromatogram was developed with chloroform; 500 ml. fractions were taken. Fractions 17-18 were found to contain 100 percent of the 3-benzazepinone and fractions 20-2~ were found to contain predominately the 2-benzazepinone isomer.
Tho~e latter fractions were combined and recrystallized from 75 ml. of hot benzene. A yield o 1.422 g. o pure 6,7-dicnloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one melting at about 188-190C. was thus obtained.
Analysis; Calc.: C, 52.20; ~, 3.94; N, 6.09; Cl, 30.82;
Found: C, 52.18; d, 3.88; N, 6.00; Cl, 30.65 The structure of the isomer was verified by NMR.
1.30 g. or 6,7-dichloro-2,3,4,~-tetrahydro-lH-2-benzazepine-3-one were slurried in 20 ml. of tetrahydro-furan (THF). This suspension was added slowly to 20 ml. or a 1 molar diborane solution in THF maintained at ambient temperature. The consequent reaction mixtu_e was rerluxed for 16 hours under a nitrogen atmos~here and then cooled.

2~3 Excess diborane was destroyed with 2N aqueous hydrochloric acid. The THF was evaporated and the aqueous residue was made basic with 5N aqueous sodium hydroxlde and 6,7-dichloro-2,3,4,5-tetrahydro-lH-2-~enzazepine being insoluble in the alXaline layer was separated and extracted into ether. The ether extract was washed with saturated aqueous sodium chloride and dried. Evaporztion of the ether yielded 1.21 g. of a clear oily residue of 6,7-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine which crystallized upon standing.
10The hydrochloride salt of 6~7-dichloro-2r3~a~5 tetrahydro-lH-2-benzazepine was formed by dissolving the crystalline residue in ether and passing gaseous hydrogen chloride through the _esulting solution. The hydrochloride salt, being insoluble in ether, separated and was collected by filtration. Recrystallization of the filter cake from a 1:3 ethyl acetate/isopropanol solvent mixture yielded 1.12 g. of 6,7-dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine hydrochloride melting at 231-233C.
~nalysis; Calc.: C, 47.55; H, 4.79; N, 5.55; C1, 42.11;
20Found: C, 47.53; H, ~.54; N, 5.48; C1, 41.85 Example 2 Preparation of 7,8-dichloro-2,3,4,5-tetra-hydro-lH-2-benzazepine Following the procedure of Example 2, 6,7-dichloro-2-tetralon~ was reacted with sodium azide in the presence of sulfuric acid at 10C. to yield a mixtu-e of 7,8-dichloro-2,3,4,5-tetrahydro-1;~-2-benzazepine-3-one and ~22~2~

7~-dichloro-1,~,4,5-tetrahydro-2H-3-benzazepine-2-one. The isomer mixture was isolated by the procedure of Example 2 and its componerts separated by chromatography over silica gel (Woelm acti~ity IV) using chloroform to develop the chromatogram. The percentage of each lsomer in fractions shown to contain the compounds was determined by NMR.
Fractions containing predominately the 2-benzazepine-3-one isomer (weight 2.4 g.) were recxystallized from 125 ml. of ~enzene. The first fraction weighing 1.25 g. was shown by NMR to contain 88 percen~ of the desired iSQmer. The second rraction was obtained from the mo~her liquors and weighed 470 mg. It was shown to contain 85 percent of the desired isomer. Further recrystallization of these combined fractions from benzene yielded 1.258 g. of 7,8-dichloro~2,3,4,i-tetrahydro-lH-2-benzazepine-3-one melting at 199-204C.
shown to be 97 percent pure of the desired isomer by NMR.
Analysis; Calc.: C, 52.20; H, 3.94; N, 6.09; Cl, 30.82;
Found: C, 52.10; H, 3.73; N, 6.37; Cl, 30.74 ~ollowing the procedure of Example 2, the 2-ben~a2epine-3-one obtained as above was reduced with diborane in THF solution. 860 mg. oI 7,8-dichloro-2,3,4,;-tetra-hydro~lH-2-benzazepine were obtained. ~he free base was converted to the hydrochloride salt by the procedure of Example 2 and the salt recrystallized from an isopropanol-methanol solvent mixture. 7,8-Dichloro-2,3,4,5-tetrahydro-lH-2-benzazepine hydrochloride thus prepared sublimed at 250C; pKa = 8.4.

~2Z52~

Analysis; Calc.: C, 47.55; H, 4.79; N, 5.55; Cl, 42011;
Found: C, 47.73; H, 4.58; N, 5.80; Cl, 42.08 Example 3 Preparation of 7-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine Following the procedure of Example 2, 22.6 g. of 6-chloro-2-tetralone was reacted with sodium azide in the presence of sulfuric acid at 15C. to yield a mixture of 7-chloro-2,3,4,5-tetrahydro-lH-2-benzazeplne-3-one and 7-chloro-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one. The isomer mixture was purified by the procedure of Example 2 ~L~Z~2~
and chromatographed over Woelm activity IV silica gel using a chloroform-benzene mixture and pure chloroform as eluants.
Fractions shown to be rich in the 2-benzazepine-3-one isomer by NMR were collected and recrystallized from a 3:1 benzene~
cyclohexane solvent mixture. The first recrystallization yielded ~aterial containing more than 80 percent o~ the desired isomer. The 2-benzazepine-3-one free base was further recrystallized from the cyclohexane~benzene solvent mixture eventually yielding crystalline material shown to contain in excess of 95 percent of the desired isomer by NMR.
The 7-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one was reduced with diborane in THF according to the procedure of Example 2. 7-Chloro-2,3,4,5-tetrahydro-lH-2-benzazepine thus prepared was purified and converted to the hydrochloride salt by the procedure of Example 2. Re-crystallization of 7-chloro-2,3,4,5-tetrahydro-lH-2-benz-azepine hydrochloride from isopropanol yielded 1.5 g. of crystalline material melting at 246-249C. which was shown by NMR to be a pure isomer; pka 8.8.
Analysis; Calc.: C, 55.06; H, 6.01; N, 6.42; Cl, 32.5};
Found: C, 54.95; H, 6.11; N, 6.25; Cl, 32.2b Preparation 2 39.8 Grams of 4-(_-chlorophenyl)butyric acid were heated with 500 g. of polyphosphoric acid at 100C. for 4 hours. The reaction mixture was poured over ice and 7-chloro-l-tetralone formed in the above reaction was extraCt-~

'' ~

sz~

with ethyl acetate. The ethyl acetate extract was separated, washed successivel~ with water, 10 percent sodium carbonate and saturated aqueous sodium chloride and then dried.
Evaporation of the solvent yielded a yellow solid residue comprising 7-chloro-l-tetralone. The compound melted at 94-96C. after recrystallization from hexane.
Analysis; Calc.: C, 66.49; H, 5.02; Cl, 19.63;
Found: C, 66.30; H, 4.89; Cl, 19.65 16 Grams of 7-chloro-1-tetralone were added to a slurry of 7.8 g. of sodium borohydride in 250 ml. of anhydrous ethanol at about 0C. The reaction mixture was stirred at ambient temperature for about 20 hours, and was worked up in standard fashion to yield 16 g. of 7-chloro-1-tetralol.
Infrared spectrum showed an absence of peaks attributable to a carbonyl function indicating the reduction to the tetralol was substantially complete.
16 Grams of 7-chloro-l-tetralol were dissolved in 250 ml. of benzene and the solution placed in a 500 ml.
round-bottom flask fitted with Dean-Stark evaporator and condenser. 1.0 g. of ~-toluene sulfonic acid was added and the reaction mixture was refluxed overnight. 1.8 ml~ of water were collected indicating that the dehydration reaction to form 7-chloro-3,4-dihydronaphthalene had proceeded to completion. The reaction mixture was cooled, and the benzene layer washed twice with 10 percent aqueous sodium bicarbonate and once with saturated aqueous sodium chloride.
The benzene layer was dried and the benzene removed by evaporation in vacuo. The dihydronaphthalene derivative remaining as a residue was used without purification.

~L2Z5Z8 The dihydronaphthalene residue was mixed with 20 g. of 80 percent purity _-chloroperbenzoic acid in 250 ml. of chloroform at 0C. The reaction mixture was stirred at about 30C. for 18 hours, and then washed twice with 10 percent sodium carbonate solution and dried.
E~aporation of the solvent yielded 6-chlorooxlrano[a]-2,3-dihydronaphthzlere formed in the above reaction. The compound was again used without further purification.
The crude oxirane was dissolved in b~nzene and the solution was cooled to 0C. and then saturated with anhydrous boron trifluoride. The reaction mixture was stirred at ambient temperature for 1~5 hrs.; 19.3 g. of 7-chloro~2-tetralone were formed and were obtained as a residual dark pale liquid after a standard purification procedure.
Example 4 Preparation of 8-chloro-2,3,4,5-tetra-hydro-lH-2-benzazepine Following the procedure of Example 2, 14.3 g. of 7-chloro-2-tetralone were reacted with sodium azide in the presence of sulfuric acid at 5-10C. to yield 13.25 g. of a 50-50 mixture of 8-chloro-2,3,4,i-tetrahydro-lH-2-benz-azepine-3-one and 8-chloro-1,3,4,5-tetrahydro-2H-3-benz azepine-2-one. The isomer mixture was partially separated by chromatography over Woelm (activity IV) silica gel using chloroform as an eluant. ~actions shown by ~R to con~ain predominately the 2-benzazepine-3-one isomer were collected and combined. ~vaporation of the solvent yielded 4.0 g. of 1~22~i21~

solid which were recrystalliæed from 100 ml. of benzene.
2.93 g. of crystalline material containing predominately the desired 2-henzazepine-3-one isomer were obtained. Following the procedure of Example 2, the separated isomer was reduced with diborane in TH~ to yield 8-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine. The product was isolated and purified and the purified free base converted to the hydrochloride salt by the mPthod of Example 2. Recrystallization of the hydrochloride salt from isopropanol yielded 1.88 g. of 108-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine hydrochloride which sublimed at 260C.; pKa = 8.75.
Analysis; Calc.: C, i5.06; H, 6.01; N, 6.42; Cl, 32.51;
Found: C, 55.29; ~, 5.98; N, 6.23; Cl, 32.46 Example 5 -Preparation o~ 6-chloro-2,3,4,5-tetra-hydro-lH-2-benzazepine Following the procedure of Example 2, 15.9 g. of ;-chloro-2-tetralone were reacted with 7.15 g. of sodium azide and iO0 mL. of 36N sulfuric acid in 400 ml. of chlorororm at 5-10C. The mixture was then allowed to warm to ambient temperature over 30 minutes. The product of this r~action was shown by NMR to consist of equal amounts of 6-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one and 6-chloro-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one. The isomer mixture was separated by chromatograp~y over silica gel (Woelm Activity IV) using chloroform as the eluant and taking ~00 ml. fractions. Fractions 9 and 10 were shown by ~MR to _onsist of 100 percent of the 3-benzazepine-2 one isomer. Fractions 12-20, shown by ~MR to contain the Z~iZ8 2-ben~azepine-3-one isomer, were recrystallized from 175 ml.
of benzene. The first fraction was shown by NMR to be 97 percent pure ~-benzazepine-3-one isomer. Recrystallization of this fraction from 125 ml. of benzene yielded 3.40 g. of the desired isomer; mp = 18d-187C.; shown by NMR to be 100 percent pure.
Analysis; Calc.: C, 61 39; H, 5.15; N, 7.16; Cl, 18.12;
Found: C, 61.35; H, 5.23; N, 7.19; Cl, 17.99 Reduction of the 6-chloro-2,3,4,5-tetrahydro-lH-2-benzazepine-3-one with diborane by the procedure of Example 2 yielded 6-chloro-2,3,4,5-tetrahydro~ 2-benzazepine which was purified as the hydrochloride salt; mp = 235-8C. pKa =
8.75.
Analysis; Calc.: C, 55.06; H, 6.01; N~ 6.42; Cl, 32.51;
Found: C, 54.84; H, 5.98; ~, 6.58; Cl, 32.24 The rompounds of this invention, either in the form of the free base, or as a pharmaceutically-acceptable acid addition salt thereo, are enzyme inhibitors. In particular, as previously stated, they are inhibitors of norepinephrine N-me~hyl transferase ~NMT or phenethanol-amine N-methyl transferase--see Axelod, J. Bio. Chem. 237, 1657 (1962)~. Compounds which inhibit the conversion of norepinephrine to epinephrine are capable of lowering a high epinephrine-norepinephrine ratio in mammals, a physiological condition frequently associated with essential hypertension.
The compounds of this invention are thus capable of ameli-orating the epinephrine-norepinephrine imbalance in essen-tial hypertension, an important aspect of the treatment of this disease state.

2SZ~

The effectiveness of the compounds as N-methyl transferase inhibitors has been measured in vitro using NMT
from rabbit adrenals. By using a series of decreasing concentrations of the inhibiting amine, usually starting with 1 x 10 4M continuing with 3 x 10 5M, 1 x 10 5M, etc., it was possible to determine a concentration at which the 50 percent inhibition of ~T was achieved. The negative reciprocal logarithm (pI50) of this number was also cal-culated as a useful index. Table 1, which ~ollows, summarizes the information thus obtained; i.e., the determination of enzyme inhibition activity for the compounds of this invention.
In the table, column 1 gives the name of the compound, column 2, the concentration at which 50 percent inhibition of NMT is obtained and column 3, the pI50.

1~22~ 8 C~ o o ,~
O ~
~n ~D
H

~ ~ O O 1 10 0 ~ ~ x x X ~ x 5~
,~ ~r ~ u~ ,1 , O o ~ . ':

H

~1 N I I :
Q ~

I _ - 4 4 2 0 o -- 4 ~ ~ 4 J~ 4

4 a~ 4 0 5~ ~ I O I
8 ~ o ' o , o ~ o Z In ~1 1~'1 4 m 4 ` O ` ~
`~ ` O ' O 4 ~ .4 a) 1 ~;
-~ O '- O ~::
b4 ~ ~4 ~ o ,~ S",, S ~ S ~ .~ I N

X-~680 -22-il2~8 The compounds of this invention are used as N~IT
inhibitors, preferably in the form of an acid addition salt.
These salts can be mixed with one or more standard pharma-ceutical excipients and loaded into empty telescoping gelatin capsules or compressed into tablets. Aqueous solutions ol these salts can be employed for parenteral administration, with an isotonic solution being particuiarly adapted for IV use. The compounds can be administered in dosage unit form for oral administration comprising an amount effective to inhibit epinephrine N-methyl transferase comprising a pharmaceutical carrier and as the active ingredient a chlorinated tetrahydro-2-benzazapine of formula I or II above. The amount of chlorinated tetrahydro-2-benzazepine present is about iO-500 mg. per dosage unit.
The compounds are administered to mammals at concentrations varving from about 1 to about 100 mg./kg. orally per day.

X-~680 -23-

Claims (4)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A pharmaceutical composition comprising a pharmaceutically-acceptable inert carrier and a compound of the formula II

wherein the chlorine atom occupies the 6, 7 or 9 position;
and pharmaceutically-acceptable acid addition salts thereof.

2. A composition according to claim 1 wherein the compound of Formula II is 9-chloro-2,3,4,5-tetrahydro-1H-2-benz-azepine.

3. A composition according to claim 1 wherein the compound of Formula II is 7-chloro-2,3,4,5-tetrahydro-1H-2-benz-azepine.

4. A composition according to claim 1 wherein the compound of Formula II is 6-chloro-2,3,4,5-tetrahydro-1H-2-benz-azepine.