DE2827931C2 - Chlorinated tetrahydro-2-benzazepines, process for their preparation and pharmaceutical preparation containing them - Google Patents

Description

2. Process for the preparation of the compounds according to claim 1 and their pharmaceutically acceptable ones Acid addition salts, characterized in that a compound of the formula

dB)

with an azide in the presence of a strong acid to form a compound of the formula

Ν — Η

Cl, -4

implemented and treated the compound of formula IV with a reducing agent and optionally the compound of formula I obtained in the form of a pharmaceutically acceptable salt will.

3. A pharmaceutical preparation consisting of a pharmaceutically acceptable inert carrier and a compound of the formula

Ν —Η

(Π)

where η has the value 1 or 2. where, when η is 2, the chlorine atoms are arranged vicinally to one another, or their pharmaceutically acceptable acid addition salts.

Tetrahydro-2-benzazepine and tetrahydro-3-benzazepine are known compounds. According to Ber. 56.690 (1923) and J.GS, Perkin Trans 782 (1973) produced in different ways In Ber. 56, (1923) is also already the production of the 7-Mcthyklerivats of tetrahydro-ίΗ-2-benzazepine and described by 7 * chlorotetrahydro-1H-2-benzazepine. However, none of these products are in it any usability indicated.

According to Advances in Heterocyclic Chemistry, Vol. 17, p. 45 et seq. (Kätfitzky and Boullori, editors, Academic Press, 1974) use 2-benzazepines as agents against hypertension, adrenergic blockers and cholinesterase inhibitors been tested. 3-Benzazepines are used as hypoglycemic and analgesic agents, as Depressors, anorectics, and ganglionic blockers been checked. 1-Benzazepines have also proven themselves as substances with analgesic, antidepressant, antifibrillating, hypotensive, antineoplastic, diuretic, Proven hypoglycanic and antiarrhythmic efficacy. There are also already N-substituted ones Tetrahydro-2-benzazepine (Chemical Abstracts 74, 53 575a, 1971, 72, 66 776a, 1970 and 68, 59 453 &! 968). N- (O-chloroethyl) -2-benzazepine is from J. Med. Pharm. Chem. 1, 343, 1959 as adrenergic blocker known, and therefore blocks Epinephrine about 2 ^ times less than dibenamine.

US-PS 39 88 339 shows a number of 7- and / or 8-substituted 1,23,4-tetrahydroisoquinolines that work well suitable phenylethanolamine-N-methyltrisferase inhibitors (NMT inhibitors, also called norepinephrine-N-methyltransferase inhibitors are designated). Of 7,8-dichloro-1.23,4-tetrahydroisoquinoline it is stated that at a concentration of Ux10'm it inhibits NMT by 50% 39 39164 shows a small group of 7- and 8-halogen-substituted telrahydroisoquinolinea

The working principle of suprarenal extracts was proposed by Able in 1899 as epinephrine and shortly afterwards synthesized by Stolz and Dakin. Epinephrine is that of the adrenal medulla produced main hormone. It has a strong vasopressant effect and leads to intravenous injection a rapid rise in blood pressure. It narrows the smaller arterioles and precapillary sphincter arteries as well as veins and large arteries. Has epinephrine has a strong cardiac stimulating effect and can also cause cardiac arrhythmias.

In stressful situations, significant amounts of epinephrine enter the bloodstream. This upper offer to Epinephrine gives mammals, including humans, immediate evasive reactions. Continuous stress and hence continuous entry of epinephrine into the bloodstream, however, has a disadvantageous effect Effect because the blood pressure can be increased continuously or arrhythmias can be induced. Ober long Periods of prolonged stress can lead to malignant hypertension or chronic heart disease.

The final stage in the biosynthesis of epinephrine in mammals is the methylation of the neurohumoral Upper carrier for most sympathetic postganglial fibers, Norepinephrine. The enzyme responsible for the last stage of synthesis is called norepinephrine-N-ethyltransferase designated. Inhibitors of this enzyme (NMT inhibitors) are suitable for prevention the secretion of large amounts of epinephrine by the adrenal system and its entry into the bloodstream Stressful situations as they are the last stage of education inhibit this compound.

The known inhibitors of norepinephrine-N-methyltransferase are in their effectiveness now, however

J ₀ still needs improvement. The object of the invention is therefore to create new compounds which are characterized by a particularly interesting activity as norepinephrine-N-methyltransferase inhibitors, and this object is now achieved according to the invention by the new chlorinated tetrahydro-2'benzazepines emerging from the claims their manufacture and the pharmaceutical preparation obtained

To the pharmaceutically acceptable acid addition salts of chlorinated tetrahydro-2-benzazepines according to the invention include salts derived from inorganic acids, for example hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, Hydrobromic acid, hydroiodic acid, nitrous acid Acid and phosphorous acid, as well as those which are phenyl-substituted from aliphatic mono- and dicarboxylic acids Alkanoic acids, hydroxyalkanoic acids and hydroxyalkanedicarboxylic acids, aromatic acids, derive from aliphatic and aromatic sulfonic acids and the like. To those pharmaceutically acceptable Salts thus include the sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, Monohydrogen phosphates, dihydrogen phosphates, metaphosphates, Pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, Formates, isobutyrates, caproates, heptanoates, propiolates. Oxalates, malonates, succinates, suberates, sebacates, Fumarate, Maleafp Mandelate, Butin-l, 4-dioate, Hexyne-1,6-dioate, Benzosts, chlorobenzoates, methylbenzoates, Dinitrobenzoates, hydroxybenzoates, methoxybenzoates, Phthalates, terephthalates, benzenesulfonates, toluenesulfonates, Chlorobenzenesulfonates, xylene sulfonates, phenyl acetates, Phenylpropionate, Phenylbutyrate, Citrate, Lactate, 0-Hydroxybutyrate, Glycollate, Malate, Tartrate, Methanesulfonates, propanesulfonates, naphthalene-1-sulfonates and naphthalene-2-sulfonates.

The first stage of the process according to the invention consists in converting a compound of the Formula IH with an azide. The azide can be in the form of a Azide salt, preferably an alkali azide, or in the form of hydrazoic acid / earth. Independent of which form of the Az * d is used the reaction of the compound of formula III carried out in the presence of a strong acid sulfuric acid is preferred, but other typical strong acids such as phosphoric acid and trifluoroacetic acid can also be used. be used. The reaction of the starting compound of formula III with an azide is in one inert solvents carried out Particularly suitable are the halogenated solvents, such as chloroform, Dichloromethane, the dichloroethane and the chlorinated benzenes The preferred temperature for the Azide reaction is between 0 ° C and room temperature.

The compound of the formula IV formed as an intermediate is then reduced in a second stage to a compound of the formula I. The reducing agent preferably used is diborane. Other effective reducing agents, particularly lithium aluminum hydride, can also be used. The reduction can be carried out in an inert solvent, tetrahydrofuran being preferably used. Diethyl ether and 1 »2-dimethoxyethane are also suitable, for example. The reduction is carried out at room temperature to 100 ⁰ C at best, preferably at the reflux temperature of the reaction mixture.

60

example 1

Sodium azide is added. 50 ml of 36N aqueous sulfuric acid are added dropwise, the temperature being in the range from 15 to 20 ^° C. The reaction mixture is then stirred for a further 15 minutes and then poured into an ice-water mixture. The organic layer is separated and washed with 10 percent aqueous sodium carbonate solution and saturated aqueous sodium chloride solution. After drying and evaporation, 10.42 g of a greenish oil are obtained, which is a mixture of equal parts of 6,7-dichloro-23,44-tetrahydro-1H-2-bertiazepin-3-one and 6,7-dichloro-13 , 43-tetrahydro-2H-3-benzazepin-2-one represents 10 g of this mixture of isomeric benzazepinones dissolved in chloroform, and the solution is chromatographed on 500 g of silica gel (Woelm, activity IV). The chromatogram is developed with chloroform, whereby 500 ml fractions are collected. Fractions 17 and 18 contain 100% of the 3-benzazepinone, and fractions 20 to 25 contain predominantly the 2-benzazepinone isomer. The latter fractions are combined and recrystallized from 75 ml of warm benzene. 1.422 g of pure are obtained

6J-dichloro-23,4 ^ -tetrahydro-1H-2-benzazepin-3-one
obtained from m.p. = 188 to 190 ° C.

Analysis:
calculated:

C 52 ^ 0; H 3.94; N 6.09; 03052;
found:
C 52.18; H 3.88; N 6.00; Cl 30.65.

The structure of the isomer is demonstrated by NMR.

130 g of 6,7-dichloro-23.4,5-tetrahydro-1 H-2-benzazepin-3-one are slurried in 20 ml of tetrahydrofuran (THF). This suspension is slowly added to 20 ml of Im diborane solution in THF, which is kept at room temperature The reaction mixture is heated to reflux under nitrogen for 16 hours and then cooled. Excess diborane is destroyed with 2N aqueous hydrochloric acid. 2 ^, 4 ^ tetrahydro-1H-benzazepin-2 is extracted with ether the ether extract is washed with saturated aqueous sodium chloride solution and dried by evaporation of the ether are 1.21 g of a clear oily residue from 6,7-dichloro-2 _T 3,43-tetrahydro-1H-2-benzazepine which crystallizes on standing

The hydrochloride of 6.7-dichloro-23.4,5-tetrahydro-1 H-2-benzazepine is made by dissolving the crystalline residue in ether and passing in gaseous Obtain hydrogen chloride in the resulting solution. The hydrochloride, which is insoluble in ether, precipitates and becomes filter off By recrystallizing the filter residue 1.12 g of 6,7-dichloro-2J.4 ^ -tetrahydro-1 are obtained from a mixture of ethyl acetate with isopropanol in a ratio of 1: 3 H-2-benzazepine hydrochloride from iP. = 231 up to 233 ° C.

Production of e.T-

1 H-> 2-benzazepine

65

10.1 g of ö ^ -Dichlor ^ -tetralone are dissolved in 200 ml of chloroform and while cooling to about 15 ° C with 3.57 g of analysis:
calculated:
C 47.55; H 4.79;
found:
C 47.53; H 4.54;

N 5.55; α 42.11;
N 5.48; Cl 41.85.

Example 2

Heating of 7,8-dichloro-2,3,4,5-tetrahydro-1 H-2-benzazepine

Following the procedure described in Example 1, is 6,7-dichloro-2-tetralone in the presence of sulfuric acid at 10 ⁰ C was reacted with sodium azide to give a mixture of 7,8-dichloro-2,3,4,5-tetrahydro-lH -2-benzazepin-3-one and 7,3-dichloro-1,3,4,5-tetrahydro-2H-3-benzazc ^ in-2-one is obtained. The isolation mixture is as in the example! 1, and its components are separated by chromatography on silica gel (Woelm, activity IV) using chloroform to develop the chromatogram - The percentage of the individual isomers in the fractions containing the compounds is determined by NMR The predominantly 2-benzazepine Fractions containing -3-one isomers (weight 2.4 g) are recrystallized from 125 ml of benzene. The first fraction, weighing 1.25 g, is shown by NMR to contain 88% of the desired isomer. The second fraction is obtained from the mother liquors and amounts to 470 mg. It contains 85% of the desired isomer. By further recrystallizing the combined fractions of benzene 1.258 g of 7,8-dichloro-2_3,4,5-tetrahydro-lH-2-benzazepin-3-one, mp = 199-204 ⁰ C obtained. It is demonstrated by NMR that the desired isomer is 97% pure.

Analysis:
calculated:

C 52.20: H 354; N 6.09; CI 30.82;
found:
C 52.10; H 3.73; N 637; Cl 30.74.

Following the procedure described in Example 1, the 2-benzazepin-3-one obtained as described above is obtained reduced with diborane in TH F solution There are 860 mg of 7,8-dichloro ^ AS-tetrahydro-1 H-2-benzazepine get 1. Following the procedure described in Example 1, the free base is converted into the hydrochloride transferred, which is recrystallized from isopropanol / methanol. The 7,8-dichloro-23,4,5-tetrahydro-1H-2-benzazepine hydrochloride obtained in this way sublimed at 250 ° C; pKa = 8.4.

Analysis:
calculated:

C47.55; H 4.79; N 5.55; Cl 42.11;
found:
C 47.73; H 4.58; N 5.80; Cl 42.08.

35

50

Example 3

Preparation of 7-chloro-2,3,4,5-tetrahydro-1 H-2-benzazepine

55

According to the procedure described in Example 1, 22.6 g of 6-chloro-2-tetralone in the presence of Sulfuric acid at 15 ° C with sodium azide to a mixture of 7-chloro-2,3,4,5-tetrahydro-1H-2-benzazepin-J-one and Z-chloro-1 ^ .S-tetrahydrQ-ZH-a-benzazepin-2-one implemented. The isomer mixture is purified according to the procedure described in Example 1 And on silica gel using chloroform / Benzene and pure chloroform as eluants chromatograptvert. Based on the NMR spectrum the 2-benzazepin-3-one rich fractions combined and recrystallized from benzene / cyclohexane (3: 1) The first recrystallization gives material which contains over 80% of the desired isomer. The ireie The base of 2-benzazepin-3-one is made from cyclohexane / benzene further recrystallized to finally obtain a crystalline substance, the NMR spectrum of which indicates a desired isomer content of greater than 95%

The 7-chloro-23,4,5-tetrahydro-1H-2-benzazepin-3-one is described in Example 2 according to the method Procedure with diborane in THF reduced the 7-chloro-2,3,4,5-tetrahydro-1H-2-benzazepine obtained in this way is purified as described in Example 1 and converted into the hydrochloride. The latter provides on recrystallization from isopropanol 1.5 g of crystalline substance of m.p. = 246 to 249 ° C, based on the NMR spectrum represents pure isomer, pKa = 8.8.

Analysis:
calculated:

C 55.06: H 6.01; N 6.42: Cl 32.51;
found:
C 54.95; H 6.11; N 6.25, CI 32.28.

Example 4

Preparation of 8-chloro-23.4 _r 5-tetrahydro-1 H-2-benzazepine

39.8 g of 4- (p-chlorophenyl) butyric acid are heated to 100 ° C. with 500 g of polyphosphoric acid for 4 hours The reaction mixture is poured onto Fis and the 7-chloro-1-tetralone formed in the above reaction is extracted with ethyl acetate. The extract is separated off, one after the other with water, 10 percent strength Washed sodium carbonate and saturated aqueous sodium chloride solution and dried. By evaporation of the solvent, a yellow solid residue is obtained, which consists of 7-chloro-1-tetralone. After recrystallization from hexane, the compound melts at 94 to 96.degree.

Analysis:
calculated:
C 66.49;
found:
C 6630;

H 5.02; Cl 19.63;
H 4.89; Cl 19.65.

16g of 7-chloro-1-tetralone turn into a slurry of 7.8 g of sodium borohydride in 250 ml of anhydrous ethanol at about 0 ° C. The reaction mixture is stirred for about 20 hours at room temperature and worked up in the usual way, whereby 16 g of 7-chloro-1-tetralol are obtained. The infrared spectrum shows the absence of peaks that can be assigned to a carbonyl function and thus completeness the reduction / tetralol.

16 g of 7-chloro-1-tetralol are dissolved in 250 ml of benzene dissolved, and the solution is placed in a 500 ml round bottom flask fitted with a Dean-Stark evaporator and a condenser is equipped with 1.0 g of p-toluenesulfonic acid added and refluxed overnight. 1.8 ml of water are collected, indicating that the dehydration reaction to form 7-chloro-3,4-dihydronaphthalene is complete The reaction mixture is cooled down, and the benzene layer is used twice 10 percent aqueous sodium bicarbonate solution and once with saturated aqueous sodium chloride solution washed. The benzene layer is dried and evaporated in vacuo. That left behind as residue-

en Dihydronaphthalene derivative is used without purification.

The dihydronaphthalene residue is mixed with 20 g of m-chloroperbenzoic acid (purity 80%) in 250 ml of chloroform at 0 ^° C. The reaction mixture is ^{stirred at 30 °} C. for 18 hours and then washed twice with 10 percent sodium carbonate solution and dried 6-chloroxirano- [alpha] -2,3-dihydronaphthalene formed in the reaction described above. The compound is used again without further purification.

The crude oxirane is dissolved in benzene and the solution is cooled to 0 ° C and then with saturated anhydrous boron trifluoride. The reaction ge t5 mixture is stirred at room temperature for 1.5 hours and then worked up in the usual way, whereby 19.3 g of 7-chloro-2-tetralone were obtained as a dark pale oil

According to the procedure described in Example 1, 143 g of 7-chloro-2-tetralone are reacted with sodium azide in the presence of sulfuric acid at 5 to 10 ^° C., whereby 13.25 g of a mixture of equal parts of 8-chloro-2,3,4 ^ -tetrahydro-1 H-2-benzazepin-3-one and

will be. The mixture of isomers is partially separated by chromatography on silica gel using chloroform as the eluent. The fractions containing predominantly the 2-benzazepin-3-one isomer on the basis of the NMR spectrum are combined. Evaporation of the solvent gives 4.0 g of a solid which is recrystallized from 100 ml of benzene. This gives 2.93 g of crystalline substance which consists predominantly of the desired 2-benzazepin-3-one isomer. According to the procedure described in Example I, the separated isomer is reduced with diborane in THF to form 8-chloro-23.4 5 · tetrahydro-1 H-2-benzazepine. The product is isolated and purified, and the purified free base is converted into the hydrochloride using the procedure described in Example 1. Recrystallization of the hydrochloride from isopropanol 1.88 g of 8-chloro-23,4 ^ -tetrahydro-1 H-2-benzazepine hydrochloride was obtained which sublimes at 260 ⁰ C; pKa = 8.75.

Analysis:
calculated:

C 55.06; H 6.0t: N 6.42; Cl 32.51;
found:
C 55.29: H 558; N 6.23; Cl 32.46.

Example 6

55

45

50

Manufacture of e ^ -

1 H-2-benzazepine

Into a 41 equipped with a mechanical stirrer 370 ml of aqueous hydrochloric acid are added to a large beaker. 162 g of 23-dichloroaniline are then added with stirring

The solution of the thus formed eo hydrochloride is cooled in an ice bath to about 0 ⁰ C then a solution of 73 g sodium nitrite in 200 ml water was added, the temperature being on hold at about 5 ° C. After completion of addition of all the sodium nitrite the diazotization reaction is stirred for a further 45 minutes, whereupon all of the aniline hydrochloride has dissolved. The diazonium chloride solution is then neutralized by adding solid sodium carbonate. The reaction temperature is maintained below about 5 ° C during this addition. The reaction mixture foams and a precipitate separates out of the solution after it has become neutral. About 150 grams of sodium carbonate are used.

While the Diazolierungsreaklion is carried out in a separate one with a Mechanical stirrer provided 4 l beaker 138 g of 90 percent copper (l) -chlofid in 750 ml of water. 160 g of sodium cyanide are then added. The reaction temperature rises to about 70 ° C. That Reaction mixture, which contains the copper (I) cyanide formed in this way, is brought to room temperature cooled down.

The copper (I) cyanide solution is then brought to about 0 ° C cooled and mixed with 500 ml of toluene. The neutral diazonium solution prepared above becomes slow added with vigorous stirring to the copper / D cyanide solution, the temperature being adjusted as required Addition: keep ice to the reaction mixture below about 5 ° C. The reaction temperature is about Maintained between 0 ° C and 5 ° C for 30 minutes. After adding all of the diazonium carbonate solution, it can be the reaction mixture is allowed to come to room temperature overnight. The reaction mixture is then on heated to about 50 ° C and then cooled. The reaction mixture is extracted three times with toluene, whereby one the toluene extracts combined and freed from insoluble material by filtration. The combined toluene extracts are washed twice with water and once with saturated aqueous sodium chloride solution and then dried. The solvent is then removed under vacuum. By subsequent distillation the residue under vacuum leads to the 2,3-dichlorophenyl cyanide formed in the above reaction, which boils at 0.93 mbar between 108 and 116 ° C. The product obtained weighs 98.8 g. By recrystallization this 2,3-dichlorophenyl cyanide is obtained from hexane 87 g of a white crystalline material with a melting point of 59 to 60 ° C.

Analysis:
calculated:

C 48.88; H 1.76; N 8.14; Cl 41.72;
found:
C 48.65: H 1.83; N 8.28; 0 42.04 (41.94).

In a 2 l three-necked flask fitted with a magnetic stirrer, a cooler, a calcium sulfate drying tube and a dropping funnel is provided, one mole of methj 'is added under a nitrogen atmosphere magnesium bromide in ethyl ether. Then 87 g of 2,3-dichlorophenyl cyanide are added to 210 ml of tetrahydrofuran The solution thus obtained is then added dropwise at such a rate to the given above methyl Grignard reagent that the ether constantly refluxes slightly after When the addition is complete, the reaction mixture is heated to reflux temperature for two hours, whereupon one it is cooled and poured into 400 ml of a mixture of ice and 12N aqueous hydrochloric acid acidic reaction mixture is allowed to stand overnight at room temperature and then extracted three times with ether. The ether extracts are combined and the combined extracts with water, 10 percent washed aqueous sodium carbonate and saturated aqueous sodium chloride. Then the ether solution dried and the solvent from the

dried solution removed under vacuum. This leaves 96 g of a reddish oil in the reaction flask as a residue, which is 2,3-dichloroacetophenone. By distilling this residue, 88.9 g of 2,3-dichloroacetophenone are obtained, which boils ^{between 77 and 84 ° C. at 0.067 mbar.}

The 2,3-dichloroacetopienone prepared in the above manner is then converted into the corresponding phenylacetic acid via a Willgefodt reaction as follows transferred:

26.6 g of 2,3-dichloroacetophenone are placed in a 200 ml round bottom flask equipped with a magnetic stirrer, a condenser and a drying tube. Then 10 g of sulfur and 27.5 ml of morpholine are added to the whole. The reaction mixture is heated in an oil bath overnight at about 13O ⁰ C and then cooled. The cooled reaction mixture is poured into a mixture of toluene and water / water. The resulting mixture is stirred until most of the solid material it contains has dissolved. The mixture is then filtered through a filter aid based on kieselguhr in order to remove any insoluble material that may still be present. The toluene layer is then separated and the aqueous layer extracted twice with toluene. The toluene layers are combined and the combined layers washed first with water and then with saturated aqueous sodium chloride. The toluene solution is dried and evaporated in vacuo to remove the toluene. In this way, 33.2 g of a solid of N- (23-dichlorophenylthioacetyl) morpholine are obtained. The solid is heated to reflux temperature overnight in a 15 percent aqueous potassium hydroxide solution (88 g of 85 percent KOH plus 500 ml of water). The hydrolysis mixture thus obtained is cooled and then extracted three times with ether. The ether extracts are discarded. The alkaline aqueous layer is acidified by adding 2N aqueous hydrochloric acid. The acidic layer is extracted three times with ether. The ether extracts are combined and washed with saturated aqueous sodium chloride. The ether extracts are then dried and evaporated in vacuo to remove the ether. In this way, about 13.6 g of a residue from the 2,3-dichlorophenylacetic acid formed in the above reaction are obtained. After decolorization using activated carbon, this acid is recrystallized from water. This gives 6.4 g of 23-dichlorophenylacetic acid with a melting point of about 126 to 128 ° C

14.156 g of 2,3-dichlorophenylacetic acid and 200 ml of carbon tetrachloride are placed in a 500 ml round bottom flask equipped with a magnetic stirrer, a cooler and a drying tube. 29.5 ml of oxalyl chloride are added dropwise to the resulting solution. This reaction mixture is heated to reflux temperature for about three hours and then cooled. The excess oxalyl chloride and carbon tetrachloride are then removed by evaporation in vacuo. Subsequent distillation of the residue obtained at a pressure of 8 mbar _{gives 12.8 g of the 2 r} 3-dichlorophenyl acetate chloride formed in the above reaction, which melts at 126 to 127 ° C

A mixture of 152 g of anhydrous aluminum chloride and 200 ml of methylene dichloride is placed in a 500 ml four-necked flask equipped with a magnetic stirrer, a drying tube, a thermometer, a dropping funnel and a sintered glass inlet tube for ethylene and under a nitrogen atmosphere. The reaction mixture is cooled to about 5 ° C. and 12.8 g of 23-dichlorophenylacetyl chloride in 50 ml of methylene dichloride are added dropwise, the temperature being kept below 5 ° C. After the addition has ended, ethylene is passed into the reaction mixture, the temperature being kept ^{below about 10 ° C.} Ethylene is slowly passed in for a total of about six hours. The reaction mixture is then stirred at room temperature overnight and then poured onto ice. The methylene dichloride layer is separated off and the aqueous mixture is extracted twice with methylene dichloride. The methylene dichloride extracts are combined, washed with saturated aqueous sodium chloride solution and then dried. Subsequent evaporation of the methylene dichloride gives as residue 24.7 g of an oil from the 7,8-dichloro formed in the above reaction - /? - tetraIon. The oil is solidified by cooling and recrystallized from ether, whereby 6.67 g of 7,8-dichloro - /? - tetralone with a melting point of about 68 to 70 ^° C. are obtained

13.7 g of 7,8-dichloro-2-tetraion, 4.6 g of sodium azide and 200 ml of chloroform are placed in a 500 ml three-necked flask equipped with a magnetic stirrer, a drying tube, a thermometer and a dropping funnel. The reaction mixture is cooled to about 15 ° C and treated dropwise with 50 ml of 18 η sulfuric acid wherein the reaction temperature between 15 and 20 ^0C holds After complete addition of the sulfuric acid, the reaction mixture further two hours stirring at room temperature, whereupon it is poured onto ice The chloroform layer is separated and the aqueous mixture is extracted three times with chloroform. The chloroform extracts are combined with 10 percent aqueous sodium carbonate solution and washed with saturated aqueous sodium chloride solution and then dried. Evaporation of the chloroform in vacuo gives 14.4 g of a residue from a mixture from e ^ -Dichlor-S-benzazepin ^ -one and 83-dichloro-2-benzazepin-3-one. Recrystallization of this residue from toluene gives the desired 2-benzazepin-3-one isomer. A total of five recrystallizations leads to pure 83-dichloro-2-benzazepin-3-one with a melting point of about 192 to 194 ° C. in a yield of 1.8 g. A corresponding analysis of this product by thin-layer chromatography shows that it does not contain any eg-dichloro-S-benzazepin-2-one

Analysis:
calculated:

C 52 ^ 0; H 334; N 6.09;
found:
C 52.45; H 4.06; N 5.94,

Following the procedure described in Example 1, 1.7 g of 8,9-dicBlor-2-benzazepin-3-one are reduced with 23 ml of a 1 M diborane solution in tetrahydrofuran The resulting from this reaction 83-dichloro-23,4 ^ -tetrahydro-1H-2-benzazepine will then purified according to the procedure described in Example 1, yielding 1.667 g of a white Solid, which clicks at about 61 to 63 ° C

The above 8 ^ -Dichlor-2 ^, 4 ^ -tetrahydro-1H-2-benzazepine is then converted into ether in the usual way

1ί

corresponding hydrochloride transferred. Recrystallization of the insoluble precipitate from ether in a mixture of isopropanol and methanol (90: 10) gives 1.237 ge ^ -dichloro ^ ^ ASnelraliydroiH- benzazepine hydrochloride with a melting point of 259-261 ⁰ C.

Analysis:
calculated:

G 47.55; H 4.79; N 5.55; Cl 42.11;
found:
C47.79; H 5.03: N 5.65: Cl 42.21.

The compounds of the invention are both in the free base form and in the form of a pharmaceutically acceptable acid addition salts enzyme inhibitors. In particular, as already mentioned. Inhibitors of norepinephrine-N-methyltransferase (NMT or phenethanolamine-N-methyltransferase, cf. Axelod, J. Bio. Chem. 237, 1657, 1962). Connections that prevent the conversion of norepmephrine into epinephrine, high epinephrine-norepinephrih ratios in mammals can to lower, d. H. to counter physiological conditions, often with essentials Hypertension related. The compounds according to the invention can thus be used to remedy Disorders of the epinephrine-norepinephrine ratio in essential hypertension, a major one Part of the treatment of this condition.

The potency of the compounds as N-methyltransferase inhibitors has been determined in vitro using NMT from rabbit adrenal glands. Decreasing by a series concentrations of the inhibiting amine, usually starting with 1 χ 10- ⁴ mundniit3x 10 ~ ⁵ ni, 1 χ 10 ^"5 m etc. Continuing, can be determined a concentration at which a 50 percent inhibition of NMT achieved The negative reciprocal logarithm (plso) of this number is also calculated as a useful index The following table summarizes the information thus obtained, ie the determination of the enzyme inhibition activity of the compounds according to the invention.

link Concentration that too PI50 50% inhibition leads 8-atfor-2A4 ^ -tetrahydro-1H-2benzazepine- hydrochloride 4.9 X ΙΟ "' 6.310 öJ-dichlor ^^^ - tetrahydro-lH-lbenzazepine- hydrochloride 1.55X10-6 5.810 7,8-Di (^ or-2 ^ 4> tetiahydro-1H-2-benzazepine- hydrochloride: 2.11X10-? 6,681 8,94) icWor-2,3,4> tetnihydro-1H-2-benzazepine- hydrochloride 1.5 X10 " ⁷ 6.81 7.8 X ΙΟ- « 7.11 *

Rat brain norepinephrine-N-methyltransferase

The compounds according to the invention are used as NMT inhibitors, preferably in the form of an acid addition salt These salts can be used with one or more conventional pharmaceutical carriers mixed and filled into telescopic gelatine capsules or compressed into tablets. Aqueous solutions these salts can be used for parenteral administration are used, isotonic solutions are particularly well suited for intravenous use. The compounds can be in unit dosage form for oral administration which are an effective amount to inhibit epinephrine methyltransferase a chlorinated tetrahydro-2-benzazepine of the formula I or II and a pharmaceutical one Carrier contains The amount of chlorinated tetrahydro-2-benzazepine is usually 50 to 500 mg / dosage unit The compounds are administered orally to mammals at concentrations of 1 to 100 mg / kg per day administered

Claims (1)

Patent claims: 1. Chlorinated tetrahydro-2-benzazepines of the general formula Γ-iN — H Cl where π has the value 1 or 2, where, when π has the value 2, the chlorine atoms are arranged vicinally to one another, and when η has the value t, the chlorine atom is in the 8-position, and their pharmaceutically acceptable acid addition salts.