DE1795540A1 - New Benzazepines and Processes for Their Manufacture - Google Patents

Description

Novel Benzazepines and Processes for Their Preparation The Invention relates to l-phenyl-2,3,4,5-tetrahydro-1H, 3-benzazepine derivatives, a process for their manufacture and pharmaceutical preparations containing them.

The compounds prepared according to the invention are l-phenyl-2, 3,4, 5-tetrahydro-1H, 3-benzazepine derivatives which are hydrogen on the nitrogen atom of the 3 position and their pharmaceutically acceptable acid addition and quaternary ammonium salts.

The compounds in the form of their free bases and their acid addition and quaternary ammonium salts are useful therapeutically; they work in particular antibacterial, antidepressant, analgesic and blood pressure lowering.

Preferred within the large class of the 1-phenyl-2,3,4,5-tetrahydro-1H, 3-benzazepine compounds which this invention comprises are those of the general formula (I) and their pharmaceutically acceptable acid addition and quaternary ammonium salts. In this, X and Y are each hydrogen, hydropy, alkyl, alkoxy or halogen, or both taken together alkylenedioxy; A denotes phenyl or substituted phenyl and both R1 and R2 each denote hydrogen or alkyl.

The hydrocarbon part of the alkyl eder advantageously contains alkoxy groups no more than six carbon atoms and the alkenedioxy-3ubituent- no more than three carbon atoms; hereinafter such substituents are lower-alkyl, lower-alkoxy and called lower alkylenedioxy. The term "alkyl" etc. used here should be used here as well as in the claims cycloalkyl, hydroxycycloalkyl, cycloalkenyl etc. include.

The lower alkyl substituents include monovalent hydrocarbon radicals such as methyl, methyl, n-propyl, isopropyl, n-butyl and isobutyl. Is methyl the preferred lower alkyl substituent; the hydroxy-lower alkyls with 2 to 6 Carbon atoms streak hydroxypropyl, hydroxybutyl, but especially hydroxyethyl with a; Lower alkoxy includes any radical with up to 6 carbon atoms one that is bound to the remaining benzazepine molecule via the oxygen atom is such as methoxy, xthoxy, propoxy and butoxy; Alkylenedioxy is preferably methylenedioxy, Xthylenedioxy or propylenedioxy, phenyl includes phenyl itself and substituted Phenyl, including phenyl radicals, which are caused by halogen (especially chlorine), Lower alkoxy (especially methoxy) and lower alkyl (especially methyl) substituted are, preferably in the para position, but they can also be in ortho and Meta position of the phenyl ring may be substituted.

The acid addition salts, which sometimes increase the solubility and are better suited to the recipe than the free bases, for example such which are produced with the following acids or their reactive derivatives: Hydrochloric acid, phosphoric acid, sulfuric acid, maleic acid, citric acid, salicylic acid, Succinic acid, tartaric acid. The quaternary ammonium salts include, for example those made from organic halides such as methyl iodide, ethyl iodide, propyl chloride, Benzyl chloride and alkyl bromide are produced.

For example, the following compounds conform to the formula I belong to the scope of the invention and can according to a method according to the invention are produced: l-phenyl-2, 3,4, 5-tetrahydro-lH, 3-benzazepine 1-methyl-l-phenyl-2, 3,4,5-tetrahydro-1H, 3-benzazepine, 1-phenyl-4-methyl-2,3,4,5-tetrahydro-1H, 3-benzazepine, 1-phenyl-1,4-dimethyl-2,3,4,5-tetrahydro-1H, 3-benzazepine 1-phenyl-7-chloro-2,3,4,5-tetrahydro-1H, 3-benzazepine, 1-phenyl-7-methoxy-2,3,4,5-tetrahydro-1H, 3-benzazepine and 1-phenyl-7,8, -dihydroxy-2,3,4,5-tetrahydro-1H, 3-oenzazepine hydrobromide.

The compounds of this invention can be used as racemic mixtures their dextrorotatory and levorotatory isomers are produced; they can with help common, well-known methods such as fractional crystallization their salts with optically active acids. Where position 4 is an Asymmetrlezentrlm is, can also be optically with a suitable choice of the optically active starting material active products dire; <t be obtained.

The inventive method for the preparation of new 1-phenyl-2,3,4,5-tetrahydro-1H, 3-benzazepine derivatives consists essentially in the intramolecular condensation of a compound that the essential structural elements and substituents of the desired product already contains, but the desired azepine ring is "broken" at one point and a reactive position at one or both of the positions adjacent to the break point Group carries.

The expression "essential structural elements used here means that the compound has the necessary number of carbon and nitrogen atoms in contains an arrangement necessary for the formation of the benzazepine nucleus via a ring closure reaction suitable is.

As used herein, essential substituents "means those characteristic substituents of the desired product in the compound should be present before the benzazine nucleus is formed. The phenyl group on the carbon atom in position 1 is an example of an essential substituent ".

The term 11 reactive group 11 as used here means a group who is tied to a position close to the "office" and with a hydrogen atom bonded to the other position adjacent to the breaking point or a reactive group bonded to the other Stellurg adjacent to the breaking point reacts to form the azepine ring. This definition is aimed at each Given conditions: some groups are reactive in and of themselves, others need activation by suitable neighboring groups (e.g. the keto group), by catalysts, initiators, special pressure and / or temperature conditions.

The 1H, 3-benzazepine derivative obtained in the above intramolecular condensation can be used for conversion into the 1-phenyl-2,3,4,5-tetrahydrolH, 3-benzazepine compound required in each case subjected to one or more additional reaction steps, for example the following: (i) reduction of an oxo group, for example a 2-oxo group, to a methylene group; (ii) Introduction of one or more substituents into one the benzene rings; (iii) Conversion into a pharmaceutically usable one Acid addition salt by reaction with a pharmaceutically acceptable acid or a reactive derivative thereof; (iv) conversion into a quaternary ammonium salt; (v) Separation of a racemic mixture into optical isomers.

A suitable process for the preparation of the preferred compounds of the formula (I) starts from di / tß-phenyl) -ä.thyl7-amine or phenylacetic acid-N-phenethyl-amide derivatives of the formula (II), wherein X, Y, A, R1 and R2 have the same meaning as for the compounds of the formula (I), D is a reactive group and Z is a methylene or oxo group. The compound (II) is subjected to an intramolecular condensation, the reactive group D reacting to close the azepine ring with a hydrogen atom which is bonded to an adjacent carbon atom in the benzene ring.

The ring closure can be achieved by various methods. if z. B. D is a hydroxyl group, so can the ring closure among known Dehydration conditions or under the conditions of an intramolecular Friedel-Crafts reaction using catalysts such as aluminum chloride. Even if D is a other reactive organic or inorganic ester group, e.g. halogen, especially Is chlorine or bromine, or a sulfonic acid ester group such as O-tosyl or O-mesyl, ring closure takes place with or without catalysts such as aluminum chloride.

The di - [(ß-phenyl) ethyl] amine derivatives mentioned are the best in baskets by heating columnar molar amounts of a styrene oxide with a phenthylamine compound can be obtained. Heating is preferably carried out on a steam bath, however, the reaction can take place within a temperature range just above room temperature take place up to about 150 ° C. The carbinols (V) obtained in this way can then by means of the usual methods, for example by means of distillation and crystallization, can be isolated When a lower alkyl, such as methyl, as a substituent in the 1 position of the benzazepine is desired (i.e. if R1 in formula I is, for example, methyl), is used for the preparation of the corresponding starting material (V) expediently used an α-methylstyrene oxide; when a lower alkyl such as methyl @ as a substituent in the 4 position of the benzazepine is desired (i.e. when R2 in formula I is, for example, methyl), a branched chain Phenalkylamine such as amphetamine can be used; when X and / or Y as substituents on the benzene ring of the benzazepine nucleus are desired, they can be appropriately X, Y-substituted'phenalkylamines can be used.

The above di - [(ß-phenyl) ethyl] amine derivatives are converted into the desired benzazepines (I) by means of intramolecular ring closure, which is produced by dehydration of the di [(ß-phenyl) ethyl] amine intermediates ( V) is achieved. The dehydration can be effected by treating the alcohol (V) with reagents such as polyphosphoric acid, sulfuric acid, zinc chloride and other similar reacting dehydrating agents. The carbinols (v) are preferably heated within a temperature range of about 80 to 160 ° C. together with thyphosphoric acid, with dehydration taking place with simultaneous ring closure, whereas when using sulfuric acid it is preferred to carry out the dehydration at about -5 ° C to 20 ° C. The above reactions can be exemplified as follows: A. + <+ g 8 x AT NH CH2C1flNFf2 C%; pH2 R2 12 III IV V Dehydration wherein X, Y, A, R1 and R2 have the same meanings as before.

The preferred 1-phenyl-2,3,4,5-tetrahydro-1H, 3-benzazepines of the formula 1 can also be prepared from 1-phenyl-2-oxo-2,3,4,5-tetrahydro-1H, 3-benzazepines be prepared by reduction at the 2-oxo group, which in turn z, B. by condensing the appropriate phenalkylamine (III) together: with an ester of a mandelic acid (VI), such as ethyl mandelate, whereby the associated mandelic acid amide (YII) is obtained, and subsequent dehydration can be prepared. The condensation to (VII) is preferably achieved by heating the assembled starting materials on an oil bath at about 150-190 ° C. for two to six hours, although temperatures in the range of 150-2,000 ° C. can also be used. The mandelic acid amides (VII) are then dehydrated, preferably by reaction with an acidic dehydrating agent, such as one of those described above for the dehydration of the carbinol (V), the corresponding 2-oxobenzazepine (VIII) being obtained with ring closure. The reduction at the 2-oxo group can be carried out by known reduction processes, such as, for example, reduction with lithium alanate in dioxane. These reactions are exemplified below: A. A 0 R - -C = O 1 O II -C oxide III + R1-CCO-C2li5 X to NH OH CII R2 VI VII | Dehydration R1 A 1reduction XY7NH CII VIII R2 Another suitable process for the preparation of the preferred compounds of the formula 1 is based on a phenethylamine derivative of the formula (XI) as the starting compound, wherein X, Y, A, D, Z, @ R1 and R2 have the same meanings as before and E denotes hydrogen or a reactive group. The compound XI is subjected to an intramolecular condensation, the reactive group D reacting with the hydrogen atom or the reactive group (E) on the nitrogen atom and the compound forming the azepine ring with the formation of a carbon-nitrogen bond. In particular, the reactive group D in the starting compound can be a hydroxy, alkoxy, aryloxy or aralkoxy group or another group which can form a carbonium ion, and E can be a hydrogen atom. The starting compound of the formula XI is preferably a compound in which Z is an oxo group, D is a hydroxyl group and E is a hydrogen atom, ie a phenylacetic acid derivative (eg ester) of a phenethylamine compound. In this case, too, the ring closure can be achieved by dehydration according to known methods. If desired, a 2-oxo group present in the product thus obtained can be converted into a methylene group by reduction.

The starting materials of the formula XI (in the specific example of the formula scheme: XV) can be obtained by condensing together an N-Phenäthylcarbonsäureamidderivat XII (where R3 is an alkyl group) with an ester of a mandelic acid, e.g. an ethyl mandelate XIII, in the presence of an acid such as sulfuric or polyphosphoric acid, obtained; in this way, for example, the o- (phenylacetic acid ethyl ester) phenethylamine derivative is obtained XIV. The condensation is preferably carried out on a steam bath, but can the reaction in the temperature range from just above room temperature to about 150 ° C occur. The compound XIV can then, for example, on a steam bath in the presence an acid or an alkali, e.g. a dilute solution of sodium hydrogen carbonate, are heated, wherein the ester is hydrolyzed and the N-acyl group is split off. The thus obtainable starting material XV, a phenylacetic acid derivative of a phenethylamine derivative, is then in the context of the inventive method, for example by reaction with an acidic dehydrating agent or simply by heating in a vacuum, dehydrated, the corresponding 2-oxo-benzazepine intermediate product being formed with ring closure VIII forms. In order to obtain the preferred 1H, 3-benzazepine derivative I, it can do so obtained 2-oxo-benzazepine are then reduced. Anyone can do this in general known reduction processes are used, such as the reaction with lithium alanate in dioxane.

Schematic representation of these reactions: o O II, Xy / N / \ 0H +?; 1 {'- o25 To OC, H ,. o // \ R OH 2 5 acid R2 3 XII XIII XIV vcrdienni.es. Alkali or A vOrd ltt Stubborn I. 1 Reduction VIII dDehydrationllnsr C {o ;;; 2 OH 1 2 2 XV, S, The 1H, 3-benzazepine compounds obtained according to the above reaction schemes can, if desired, be converted into a pharmaceutically acceptable acid addition or quaternary ammonium salt.

Example 1 1-Phenyl-2,3,4,5-tetrahydro-1H, 3-benzazepine A: N - [(ß-Hydroxy-ß-phenyl) -ethyl] -N - [(ß-phenyl) -ethyl] -amin A well-stirred mixture of 82 g of styrene oxide and 100 g of phenethylamine is heated For 12 hours on a steam bath and the product obtained is distilled in vacuo, a viscous product is obtained which is recrystallized from petroleum ether.

B: 1-phenyl-2,3,4,5-tetrahydro-1H, 3-benzazepine. Add to 100 ml concentrated sulfuric acid (which is kept at 0 - 5 ° C) in small portions 15 g of the N- / tß-hydroxy-ß-phenyl) ethyl] -N - [(ß-phenyl ) äthyl7-amines and stir for one hour. The mixture obtained is poured over ice and water poured, made strongly alkaline with sodium hydroxide and the desired product / with Xther extracted. The ether extract is dried over anhydrous potassium carbonate, filtered and distilled to give the desired product (boiling point 166 - 1680 C / lmm). The hydrochloride salt (melting point 203-206 ° C), the hygroscopic is made with dry hydrogen chloride in ether and from isopropanol crystallized.

Example 2 Same as in Part A of the previous example given processes react homoveratrylamine and styrene oxide to the associated Amino alcohol (melting point 95-980C). This alcohol is then after that in part B of Example 1 for 1-phenyl-7,8-dimethoxy-2,3,4,5-tetrahydro-1H, 3-benzazepine (boiling point 198 - 2oo0C / 2 Torr) cyclized, which by reaction with Maleic acid is converted into its maleic acid salt (melting point 198-200 ° C).

Example 3 4-methyl-1-phenyl-2,3,4,5-tetrahydro-1H, 3-benzazepine A: N - [(ß-Hydroxy-ß-phenyl) -ethyl] -N - [(ß-phenyl) -isopropyl] amine One heats a well stirred mixture of 82 g of styrene oxide and 100 g of d-amphetamine for L2 hours one.

Steam bath. When the product obtained is distilled (in vacuo) it is obtained a viscous product (boiling point 160-180 ° C / l Torr) which crystallizes from petroleum ether Wirt, melting point 53-55 ° C, [α] D25 = + 14.6 ° (1% in ethanol).

B: 4-methyl-1-phenyl-2,3,4,5-tetrahydro-1H, 3-benzazepine slowly add 100 ml of concentrated sulfuric acid (kept at OOC) in small portions 15 g of a finely ground powder of the optically active product of Part A. Man stir for another hour, then pour the mixture into ice water, make the obtained Mixture with sodium hydroxide strongly alkaline and extracted with Xther. The Xtherextrakt dried over anhydrous potassium carbonate, filtered and distilled the desired Product from (boiling point 149 - 151 ° C / l Torr). Being with dry hydrogen chloride Bygroscopic hydrochloride obtained in ether is crystallized from isopropanol; Melting point 206-207 ° C., [α] D25 = -42.00 (n% in dimethylformamide).

Example 4 1-methyl-1-phenyl-2,3,4,5-tetrahydro-1H, 3-benzazepine A: N - [(ß-Phenyl-ß-methyl-ß-hydroxy) -ethyl] -N [(ß-phenyl) -äthyl7-amine well stirred mixture of 60 g of a-methylstyrene oxide and 66 g of phenethylamine for 6 hours on one Steam bath and distill the resulting reaction mixture.

The product (boiling point 160 - 168 ° C / l Torr) forms a hydrochloride, which, after recrystallization from acetonitrile, has a melting point of 142-1450C owns.

B: 1-methyl-1-phenyl-2,3,4,5-tetrahydro-1H, 3-benzazepine. Condense 28 g of N - [(ß-phenyl-ß-methyl-ß-hydroxy) -ethyl] -N - [(ß-phenyl) -ethyl] -amine in 250 ml concentrated sulfuric acid and extracted the desired product after demi in Part B of Example 3, procedure given with ether. The ether extract dries one over anhydrous potassium carbonate and the product is distilled at 15o - 16o0C / 1 torr. The product of this example is recrystallized from hexane (melting point 76-790C). The hydrochloride produced with dry hydrogen chloride in ether melts at 228-2290C.

From the previous examples it can be seen that when using the corresponding substituted starting materials are a whole series of other beazepins can be made in a similar manner. So by changing the starting materials and by following the essential features of those set forth in Examples 1-4 Process e.g. 1-phenyl-1,4-dimethyl-2,3,4,5-tetrahydro-1H, 3-benzazepine, 1-phenyl-1,4-dimethyl-7-chloro-2,3,4,5- tetrahydro-1H, 3-benzazepine, 1-phenyl-1,4,7-trimethyl-2,3,4,5-tetrahydro-1H, 3-benzazepine, 1-phenyl-4-methyl-8-hydroxy-2,3, 4,5-tetrahydro-1H, 3-benzazepine, 1-phenyl-1,4-dimethyl-8-methoxy-2,3,4,5-tetrahydro-1H, 3-benzazepine and 1-phenyl-7, 8-methylenedioxy-2, 3,4, 5-tetrahydro-1H, 3-benzazepine will. For the preparation of the foregoing Benzazepines by the process of Examples 1 - 4 necessary phenethylamine starting materials are either already known or can be prepared by known processes.

Example 5 According to the Invention This example illustrates the / preparation a benzazepine compound using a phenethylamide of almond acid as a starting material.

1-phenyl-7-methoxy-2,3,4,5-tetrahydro-1H, 3-benzazepine A: N- (β-m-methoxyphenethyl) -mandelic acid amide A well-stirred solution of 25 g of ß-m-methoxyphertäthylamine and 30 g is heated Ethyl mandelate in an oil bath at 180-190 ° C for hours. The reaction mixture is cooled and the desired product is crystallized from ether (melting point 75 - 7600).

B: 1-Phenyl-2-oxo-7-methoxy-2,3,4,5-tetrahydro-1H, 3-benzazepine Man slowly add 20 g of finely ground powder of N- (ß-m-methoxyphenethyl) -mandelic acid amide in small portions to 700 g of polyphosphoric acid and heat the mixture obtained slowly to 100 ° C. The mixture is heated to 100 ° C for an hour, then if you let it reach room temperature, pour the sealed mixture onto ice-water and extracted with chloroform. The chloroform is removed in vacuo and the formed 1-Phenyl-2-oxo-7-methoxy-2,3,4,5-tetrahydro-1H, 3-benzazepine from ethyl acetate recrystallized (melting point 169-1710C).

C: 1-Phenyl-7-methoxy-2,3,4,5-tetrahydro-1H, 3-benzazepine To one well stirred and refluxing suspension of 5 g of lithium alanate un A solution of lo g of 1-phenyl-2-oxo-7-methoxy-2,3,4,5-tetrahydro-1H, 3-benzazepine is added dropwise to 200 ml of dioxane in 250 ml of dioxane and the mixture obtained is refluxed for three hours. The resulting reaction mixture is cooled and added while it is kept at 200.degree is, dropwise 0.5 ml (4 times) water, 0.5 ml (4 times) 15% sodium hydroxide solution and 13.5 ml of water are added and the reaction mixture is stirred for one hour. The precipitation inorganic material is filtered off and the filtrate obtained by distillation freed from solvent. 100 ml of 5% hydrochloric acid are added to the residue and 200 ml of ether, stir the mixture until the residue dissolves, separating the aqueous Extract, make it alkaline with sodium hydroxide and extract with ether. Of the Ether extract is dried with aqueous potassium carbonate. One draws the solvent and converts the desired product of this example 3 into its hydrogen maleate, by adding it to a solution of maleic acid in ethyl acetate, whereby 1-phenyl-7-methoxy-2,3,4,5-tetrahydro-1H, 3-benzazepine hydrogen maleate is obtained (Melting point 196-1970C).

Example 6 1-Phenyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H, 3-benzazepine hydrobromide A mixture of 15 g of 1-phenyl-7,8-dimethoxy-2,3,4,5-tetrahydro-1H, 3-benzazepine and 100 ml of 48-finger hydrobromic acid is added under a nitrogen atmosphere for 2.5 hours heated to reflux temperature. The hydrobromide salt crystallizes on cooling the desired connection. After filtering and washing the crystals with alcohol 1-phenyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H, 3-benzazepine hydrobromide is obtained (Melting point 283-2850C).

Example 7 This example illustrates the representation of one of the Inventing the corresponding benzazepine compound by adding one as an intermediate Phenylacetic acid derivative of a phenethylamine compound used and the representation of the intermediate.

1-phenyl-7,8-dimethoxy-2,3,4,5-tetrahydro-1H, 3-benzazepine A: N- [3,4-dimethoxy-6- (61-carbethoxy-benzyl)] acetamide 750 g of polyphosphoric acid are heated to a temperature of 60 ° -70 ° C., adds below with continued stirring 18.1 g of N- / 3, 4-di-methoxy-6- (61-carbSthoxy-benzyl27-acetamide and heat the mixture on a steam bath until it is homogeneous, which is usually takes lo to 15 minutes.

Then one adds dropwise over a period of 5 to lo Minutes 18 g of ethyl mandelate added and heated for a further hour on the Steam bath at 90 to 95 ° C. The mixture obtained is poured onto 2.5 kg of ice water and the crude product, which is the desired acetamide, is extracted with chloroform.

B: 1-phenyl-7,8-dimethoxy-2-oxo-2,3,4,5-tetrahydroiH, 3-benzazepine The extracts obtained by the procedure in Part A of this example are combined and washed with water and dilute sodium hydrogen carbonate solution. The solvent is then drawn off on a steam bath and the residue in vacuo to constant weight heated on the steam bath. The l-phenyl-7, 8-dimethoxy-2-oxo-2,3,4,5-tetrahydrolH, 3-benzazepine formed is then crystallized from ethanol.

C: 1-phenyl-7,8-dimethoxy-2,3,4,5-tetrahydro-1H, 3-benzazepine 3 g of the obtained according to part B of this example compound to a suspension of Put 1 g of lithium alanate in 500 ml of dioxane and reflux and stir for 10 hours cooked. The cooled solution is successively added dropwise with 2.7 ml of water, 2.7 ml of 15 pointer sodium hydroxide solution and 8.1 ml of water and treated for one hour at room temperature touched. The precipitate of inorganic salts formed is filtered off with dioxane washed and the combined filtrates are evaporated on a steam bath in vacuo. The residue is taken up in ether and extracted with 50 ml of 5 pointer hydrochloric acid and the acid extract made alkaline with sodium hydroxide. The formed oil will extracted with ether, the extract dried with anhydrous potassium carbonate, filtered and the solvent al withdrew.

Since crude 1-phenyl-7,8-dimethoxy-2,3,4,5-tetrahydro -lH, 3-benzazepine is purified as the salt of maleic acid.

Example 8 This example illustrates the separation of racemic Mixtures of compounds obtainable by the process of this invention am Example of 1-phenyl-2,3,4,5-tetrahydro-1H, 3-benzazepine.

42 g of 1-phenyl-2,3,4,5-tetrahydro-1H, 3-benzazepine apply together with 37 g of (+) - phenylsuccinic acid dissolved in 9o an ethanol by heating. The solution is left to stand for several days at room temperature. The resulting Crystals are filtered off, washed with a small amount of cold alcohol and finally recrystallized from 150 ml of 90% ethanol.

The yield is 15 g of crystals, melting point 180 - 182 ° C, [α] D25 = + 55.2 ° (1% in dimethylformamide).

This salt is converted into the free base in the usual way by treatment set free with aqueous sodium hydroxide and extracted with ether and crystallization from hexane isolated: melting point 78 -80 ° C, [α] -D25 = -29.9 ° (1% in dimethylformamide).

The alcohol mother liquors from washing and recrystallization are combined, then concentrated in vacuo, and the free l-phenyl-2,3,4,5-tetrahydro-lH, 3-benzazepine is recovered using standard procedures, using aqueous caustic soda and ether to be used. The partially separated base is furthermore obtained by using (-) - Phenylsuccinic acid separated by the above procedure and it becomes so that (+) - isomer obtained, which also melts at 78 - 8o0C, but a [α] D @@ of + 29.9 °.

The 1-phenyl-2,3,4,5-tetrahydro-1H, 3-benzazepine derivatives of this invention can be administered in the form of pharmaceutical compositions containing a or more of these compounds together with a pharmaceutically acceptable and Compatible carrier substance included.

Such compositions may also contain other active compounds, with which they are compatible, such as analgesics, anti-depressants, antibiotics and proteolytic enzymes.

The compositions can be in solid form, e.g., tablets, pills or capsules, in liquid form, such as syrups, elixirs or emulsions for oral administration or as sterile injection solutions or in the form of creams full of lotions.

LXie pharmaceutical compositions can be used according to general the preparation of pharmaceutical compositions known methods which essentially combine the relevant 1-phenyl-2,3,4,5-tetrahydro-1H, 3-benzazepine derivative with a pharmaceutically acceptable carrier substance that is compatible therewith. Suitable carrier substances are e.g. water, gelatin, lactose, a starch, magnesium stearate, Talc, a vegetable oil, benzyl alcohol, a gum, a polyalkylene glycol and petroleum jelly.

Claims (1)

Claims 1. l-phenyl-2,3,4,5-tetrahydro-lH, 3-benzazepine derivatives, which have a hydrogen atom on the nitrogen atom in the 3-position and their pharmaceuticals acceptable acid addition salts and quaternary ammonium salts. 2. l-phenyl-2,3,4,5-tetrahydro-lH, 3-benzazepine derivatives according to claim 1 of the general formula wherein X and Y are identical or different and are hydrogen, hydroxy, alkyl, alkoxy or halogen or together with one another alkylenedioxy, A is phenyl or substituted phenyl and R1 andR2 are hydrogen or alkyl, and their pharmaceutically acceptable acid addition salts and quaternary ammonium salts. 3. 1-Phenyl-2,3,4,5-tetrahydro-1H, 3-benzazepine derivatives according to a of claims 1 and 2, characterized in that the alkyl or alkoxy substituents no more than 6 carbon atoms and the alkylenedioxy substituent no more than Contains 3 carbon atoms. 4. 1-phenyl-2,3,4,5-tetrahydro-1,3-benzazepine derivatives according to claim 1 or 2, wherein each of X and Y is alkoxy means. 5. 1-phenyl-2,3,4,5-tetrahydro-1H, 3-benzazepine derivatives according to claim 4 wherein each of X and Y is methoxy. 6. l-phenyl-2,3,4,5-tetrahydro-lH, 3-benzazepine derivatives according to claim 2 to 5, wherein each is R1 and hydrogen. 7. 1-phenyl-2,3,4,5-tetrahydro-1 H, 3-benzazepine 8. 1-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H, 3-benz azepin. 9. 1-Phenyl-4-methyl-2, 3, 4, 5-tetrahydro-1H, 3-benzazepine. 10. 1-Phenyl-1,4-dimethyl-2,3,4,5-tetrahydro-1H, 3-benzazepine. 11. 1-Phenyl-7-chloro-2,3,4,5-tetrahydro-1H, 3-benzazepine. 12. 1-Phenyl-7-methoxy-2,3,4,5-tetrahydro-1H, 3-benzazepine. 13. 1-Phenyl-7,8-dihydroxy-2,3,4,5-tetrahydrolH, 3-benzazepine hydrobromide. 14. 1-Phenyl-7,8-dimethoxy-2,3,4,5-tetrahydro-1H, 3 benzazepine. 15. 1-phenyl-7,8-dimethoxy-2,3,4,5-tetrahydro-1H, 3-benzazepine maleate. 16. A pharmaceutical composition containing as an active ingredient a l-phenyl-2,3,4,5-tetrahydro-lH, 3-benzazepine derivative according to claims 1 to 15, or a pharmaceutically acceptable acid addition salt or quaternary ammonium salt thereof together with a pharmaceutically acceptable and with the active ingredient compatible carrier. 17. Process for the preparation of l-phenyl-2,3 "4,5-tetrahydro-1H, 3-benzazepine derivatives according to claim L and its pharmaceutically usable acid addition and quaternary Ammonium salts, characterized in that a compound containing the essential Already contains structural elements and substituents of the desired product, whereby however, the desired azepine ring is 1'open'1 at only one point and is on a reactive group in one or more of the positions adjacent to the "breaking point" carries, is subjected to an intramolecular condensation by cyclization to form the azepine ring, and that the 1-phenyllH, 3-benzazepine derivative thus obtained if desired, subjected to one or more of the following reaction steps becomes: (i) reducing an oxo group to a methylene group; (ii) Introduction of a or more than one substituent in one of the benzene rings; (iii) Conversion into a pharmaceutical usable acid addition salt; (iv) conversion into a quaternary ammonium salt; (v) Separation of a racemic mixture into optical isomers. 18. The method according to claim 17, characterized in that as Starting material a Phenäthylaminoendstandgen methyl-benzyl derivative used, the on / carbon atom carries a reactive group. 19. Verrahren according to claim 18, characterized in that the phenethylaminomethyl-benzyl derivative has the formula IX wherein X and Y each X is hydrogen, hydroxy, alkyl, alkoxy or halogen or together alkylenedioxy; A is phenyl or substituted phenyl; D is a reactive group and R1 and R2 are hydrogen or alkyl. 20. The method according to claim 17, characterized in that as The starting material used is a phenethylcarbamylbenzyl derivative, which is at the terminal Carbon atom carries a reactive Gn'pe, and that the oxo group of the through intramolecular condensation obtained l-phenyl-2-oxo-2, 3,4, 5-tetrahydro-111, 3-benzazepine derivative is then reduced to the methylene group. 21. The method according to claim 20, characterized in that the phenethylcarbamyl-benzyl derivative has the formula X. wherein A, D. R1, R2, X and Y have the same meanings as in formula IX. 22. The method according to claim 17, characterized in that as Starting material used an orthobenzylphenäthylamine derivative, which is at the terminal Carbon atom and / or carries a reactive group on the nitrogen atom. 23. The method according to claim 22, characterized in that said compound has the formula XV3, wherein X, Y, A, D, R1 and R2 have the same meaning as in formula IX and E is hydrogen or a reactive group. 24. The method according to claim 17, characterized in that as Starting material is an o- (phenylacetic acid) -phenäthylamine derivative in the form of the free Acid or one of its functional derivatives is used and that the oxo group des l-phenyl-2-oxo-2,3,4,5-tetrahydro-lH obtained by its intramolecular condensation, 3-benzazepine derivative is then reduced to the methylene group. 25. The method according to claim 24, characterized in that the o- (phenylacetic acid) phenethylamine derivative has the formula XVII, wherein X, Y, A, D, R1 and R2 have the same meaning as in formula IX and E is hydrogen or eir. means reactive group. 26. The method according to claims 19, 21, 23 and 25, characterized in that that an alkyl, hydroxyalkyl, alkenyl or alkoxy substituent is not more than six Carbon atoms and one alkylenedioxy substituent no more than three carbon atoms contains. 27. The method according to claims 17-26, characterized in that the reactive group D or E is hydroxy and the intramolecular condensation at simultaneous cyclization takes place with dehydration of the starting compound. 28. The method according to claim 27, characterized in that the intramolecular Condensation is carried out by heating in a vacuum. 29. The method according to claim 27, characterized in that the intramolecular Condensation is carried out with the help of an acidic dehydrating agent. 3o. Method according to claim 29, characterized in that the intramolecular Condensation by treating the starting material with polyphosphoric acid at a Temperature between 80 and 160 ° C is achieved. 31. The method according to claim 29, characterized in that the intramolecular Condensation by treating the starting material with concentrated sulfuric acid is achieved at a temperature between -5 and + 20 ° C. 32. The method according to claims 20, 21 and 24 - 31, characterized in that that a reduction of an oxo group following the intramolecular condensation is carried out using lithium alanate in a solvent such as dioxane. 35. The method according to claims 17, 18 and 27 - 31, characterized in that that one by condensing together a styrene oxide compound with a Phenethylaminomethylbenzyl alcohol compound produced by Pn2näthylaminverbindungen used as raw material. 34. The method according to claim 33, characterized in that one by condensing styrene oxide with phenethylamine, homoveratrylamine, d-amphetamine or ß-p-methoxyphenylethylamine produced phenethylaminomethylbenzyl alcohol compound used as raw material. 35. The method according to claim 33, characterized in that one by condensing an @ -alkyl, preferably a <x -lower-alkylstyrene oxide Phenäthylaminomethylbenzyl-alcohol compound produced with Plaenäthylamin, Homoveratrylamin or d-amphetamine used as raw material. 36. The method according to claims 33-35, characterized in that the starting compounds are condensed in equimolar amounts. 37. The method according to any one of claims 33 to 36, characterized in that that the condensation of the styrene oxide with the phenethylamine compound in the temperature range from just above room temperature to about 150 ° C. 38. The method according to claims 20, 21 and 27-32, characterized in that that one can be obtained by merging a mandelic acid ester with a phenethylamine compound produced Phenäthylcarbamy] -benzyl alcohol compound used as a starting material. 39. The method according to nspruch 38, characterized in that one by condensing ethyl mandelate with phenethylamine, homoveratrylamine, Phenäthylcarbamylbenzyl alcohol produced by d-amphetamine or ß-p-methoxyphenylethylamine used as raw material. 40. The method according to claim 38 or 39, characterized in that the condensation of the mandelic acid ester with the phenethylamine compound in the temperature range from 150 - 200 ° C. 41. The method according to claims 24 to 32, characterized in that one by condensing together an N-Phenäthylcarbonsäureamid derivative with an ester of a mandelic acid and subsequent hydrolysis of the o- (phenylacetic acid ester) phenethylamine compound obtained to eliminate the ester grouping and the acyl group attached to nitrogen, produced o- (phenylacetic acid) -phenäthylamine compound used as a starting material. 42. Process for the preparation of a pharmaceutical composition according to claim 16, characterized in that a l-phenyl-2,3,4,5-tetrahydro-lH, 3-benzazepine derivative is brought into a form suitable for therapeutic administration. 43. The method according to claim 42, characterized in that the l-phenyl-2,3,4,5-tetrahydro-lH, 3 Benzazepine derivative with a pharmaceutical carrier substance that is compatible therewith is mixed.