DE2436075A1 - BASIC ETHERS OF 3,4-DIHYDRO-1BENZOXEPINE-5-ON-OXIME, THE PROCESS FOR THEIR MANUFACTURING AND THE MEDICINAL PREPARATIONS CONTAINING THEM - Google Patents

Description

PATENT LAWYERS

DR.-ING. BY KREISLER DR.-tNG. BEAUTIFUL FOREST DR.-ING. TH. MEYER DR.FUES DIPL.-CHEM. ALEK VON KREISLER DIPL.-CHEM. CAROLA KELLER DR.-ING. KLOPSCH DIPL.-ING. SELTING

5 COLOGNE 1, DEICHMANNHAUS

KoIn ₁ den _ AvK / Ax

Basic ethers of 3,4-dihydro-i-benzoxepin-5-one oxime. Process for their production and containing them

Medicinal preparations

The invention relates to new basic ethers of 3.4- Dihydro-1-benzoxepin-5-one oxime, yours with the amine function acid addition salts formed, a process for the preparation of these compounds and pharmaceutical preparations, which they contain.

An ether of 3,4-dihydro-1-benzoxepin-5-one oxime was made already in Collection Czechoslov. Chem. Commun 37. O 972) 868-886. This ether has the formula

, HCl

It differs from the compounds according to the invention in the position of the substitution in the benzene ring and, according to the authors of the article, showed only a slight, no, pharmacological examination utilizable spasmolytic activity.

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The basic ethers of 3,4-dihydro-1-benzoxepin-5-one-Qxim according to the invention have the general formula

Z. NO- (CH ₂ ) η-N ^ ^χ

in which R is a halogen atom or a lower alkoxy radical, η is 2 or 3, Z ^ and Z _? , which are identical or different, each represent a lower alkyl radical and, together with the nitrogen atom to which they are attached, a 5- to 7-membered N-heterocyclic group which contains a second heteroatom, in particular N, O and S can, can form.

Possible halogen atoms are fluorine atoms, chlorine atoms, bromine atoms and iodine atoms. Under lower alkyl and Alkoxy radicals are radicals with no more than 5 carbon atoms.

The oxime ethers according to the invention have in particular a very pronounced relaxing effect on the smooth intestinal fibers and can be used in human medicine in particular as intestinal regulators.

The invention thus includes pharmaceutical preparations in combination with a physiologically harmless Excipient or carrier at least one compound of the formula (I) or one of its pharmaceutically acceptable compounds Contain acid addition salts.

The products according to the invention can be administered orally in the form of capsules and tablets, rectally or parenterally will. The daily dose is between 50 and 500 mg, with the dosage units at least 25 contain.

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The compounds according to the invention are after, a Process produced, which is characterized by that one in the p-position R-substituted phenoxybutyric acid subjected to an intramolecular acylation and thereby a 3,4-dihydro-1-benzoxepin-5-one of the formula

(H)

forms, in which R has the abovementioned meaning, then the product of the formula (II) is reacted with a compound of the formula HpN-OA, in which A is a hydrogen atom or a group of the formula (CHp) -NZ ^ Zp, in which n , Z ^. and Zp have the abovementioned meanings, in cases in which A is a group of the formula (CHp) -NZ.Zp, in an alcoholic solvent in an acidic medium and at the reflux temperature of the solvent and in cases in which A is a Is hydrogen atom, works in pyridine or ethanol on the reflux condenser, and then reacts the intermediate product formed in this way in the presence of a base with a compound of the formula X- (CHO-NZ ^ Z ₂ , in which X is a halogen atom and n, Z ^ and Z _{2 have} the meanings given above.

The acid addition salts of the compounds of the formula (I) are prepared by reacting the amine with a mineral acid or organic acid in a suitable solvent.

It was found that the products prepared in this way consist of 95 to 100% of the geometric isomer of the oxime in the cis position to the benzene ring (determined by nuclear magnetic resonance, infrared spectrography and gas chromatography). That

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cis-Huinologist can therefore with excellent yields by successive recrystallizations of the mixture the addition salts of the amine function with in appropriately selected acids can be isolated, while this is not among satisfactory in the case of the trans homologues Conditions is possible. According to the invention it is proposed to this end, after the introduction of the Oxyimino function in the heterocycle is a partial isomerization according to a process known per se, namely by the action of a strong anhydrous acid, preferably a hydrohalic acid, in one aprotic solvents. When a compound of the formula

NOH-

is subjected to this treatment, there is then the general substitution of oxygen Procedure made. As in the case of the cis homologue, isolation is carried out by recrystallization of the Acid addition salts achieved, taking into account that the trans isomer is generally more soluble is called the cis homolog.

The invention is further illustrated by the following examples which describe the preparation of the compounds explained. The melting points mentioned there were determined on the Kofler block. The elemental analysis of the new connections was made. The results correspond to the generally recognized standards (quantitative elements: C, H, N, halogen). By paramagnetic Electron resonance could cause the substitution on the oxygen atom and not on the nitrogen atom of the Oxims are confirmed.

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2A36075

example 1

7-chloro-3, A - dihydro-1-benzoxepin-O- (dimethylaminoethyl) -

5-one oxime

A) 7-chloro-3,4-dihydro-i-bcnzoxepin-5-Ofl

30 ml of 85% phosphoric acid are added to 530 ml of anhydrous toluene (d = 1.71) cast. Then be slowly with good stirring 84 g of phosphoric anhydride added. The mixture is kept on the boiling water bath for 2 hours, whereupon while maintaining this temperature a lukewarm solution of 24 g of p-chlorophenoxybutyric acid (melting point 123 ° C) in 2 hours 800 ml of anhydrous toluene is added. The mixture is then heated for a further 5 hours, after which it is cooled.

The upper toluene phase is separated in the presence of the equal volume of water and then

after decanting, stirred twice with the same volume of a 5% sodium hydroxide solution. she will then washed neutral with water and dried over sodium sulfate. After evaporation of the solvent 11.5% of a yellow oil are obtained under reduced pressure.

The lower phosphoric acid phase is 3 times Poured volume of crushed ice. This solution is stirred twice with ether at room temperature. The ether phases are in the presence of 5% sodium hydroxide touched. After decanting the aqueous phase, they are neutralized and dried over sodium sulfate. After evaporating the solvent under reduced pressure, 5 g of a yellow oil are obtained.

The two oil fractions are combined and reduced Distilled pressure. Here, 12 g of ketone in the form of a colorless liquid with a boiling point of 105

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to 108 ° C / 0.02 mm Hg

A solution of 50 g of the benzoxepinone prepared in the manner described and 26 g of hydroxylamine hydrochloride in 200 ml of pyridine is kept at the reflux temperature of the pyridine for 5> 5 hours. The pyridine is then evaporated off under reduced pressure. 300 ml of water are poured onto the evaporation residue, whereupon the aqueous phase is extracted three times with ether. The organic solutions are washed neutral with water and dried over sodium sulfate and then over magnesium sulfate. The solvent is evaporated off under reduced pressure. The evaporation residue is recrystallized from absolute ethanol. Here, 4-7 g of pure oxime are obtained as a white product with a melting point of 101 to 102 ^° C.

C) 7-chloro ; 5,4 -dihydro-1-benzoxepin-Q (dimethylaminoethyl) -5-one oxime

To 30 ml of a solution of sodium ethylate in ethanol (prepared with 0.9 g of sodium) 7.1 g of the oxime prepared in the manner described above are added. The reaction mixture is brought to the reflux temperature of the solvent within one hour. Then 50 ml of anhydrous dimethylformamide added, whereupon the ethanol is evaporated off under reduced pressure. After adding 4 g of (2-chloro) ethyldimethylamine the mixture is kept at 80 ° C. for 6 hours. It is cooled, the mineral salts are filtered off and the solvent is evaporated off under reduced pressure.

The residue is dissolved in an aqueous 1N hydrochloric acid solution. The solution is extracted with ether and then made alkaline with a 1N sodium hydroxide solution

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power. The oxime ether is extracted with methylene chloride and the solvent is evaporated after drying. The oil remaining as residue is dissolved in ether, from which the amine hydrochloride is precipitated by adding ethereal hydrochloric acid. The hydrochloride is recrystallized from a mixture of ethyl acetate and isopropanol (75:25). It melts at 180 ^° C. The yield of this stage is 40%.

Example 2

7-chloro-3,4-dihydro-i-benzoxepin-O- (diethylaminoethyl) - ^ -on-oxime: isomer in cis configuration to the benzene ring

To a solution of 5 g of 7-chloro-3,4- dihydro-1-benzoxepin-5-one oxime in 25 ml of anhydrous dimethylformamide 1.2 g of 50% sodium hydride are slowly added with stirring while cooling slightly. This sodium salt can also be prepared by reaction with sodium ethylate in ethanol and then in dimethylformamide be solved.

After stirring for one hour at room temperature, 3.1 g are added to the reaction mixture in 15 minutes (2-chloro) ethyl diethylamine given. One hour after the addition has taken place, 200 ml of water are added. That Final product is extracted with ether. It is then freed from the ether in a 5% acetic acid solution. The aqueous phase becomes alkaline by adding KpCO2 made, whereupon the amine is extracted again with ether.

After the organic solution has been dried, the solvent is evaporated off and the oil which remains as a residue is distilled under reduced pressure. The basic oxime ether obtained as the end product boils at 137 ° C./0.2 mm Hg. The yield of distilled. Amine is 60 %.

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The hydrochloride produced in ether is recrystallized from a mixture of isopropyl ether and 1,2-dichloroethane (60:40). It melts at 115 to 116 ° C. This salt can also be recrystallized from ethyl acetate. However, if it is heated for a long time in this treatment, another crystalline form of the product appears with a melting point of 132 ^° C.

The geometric isomer of this oxime ether in the cis configuration to the benzene ring can advantageously be separated from traces of its trans homologue in the form of its addition salt with hydrobromic acid by recrystallization from isopropanol. This hydrobromide melts at 114 ^° C.

Example 3

7-chloro-3 »4-dihydro-1-benzoxepin-0- (diethylaminoethyl) -5-one oxime: trans isomer

A solution of 50 g of 7-chloro-3,4-dihydro-1-benzoxepin-5-one oxime in 800 ml of anhydrous chloroform is saturated with anhydrous hydrochloric acid. The mixture is stirred ^{at 20 °} C. for about 24 hours. The precipitate formed is then separated off. The filtrate is washed twice with a saturated aqueous sodium bicarbonate solution and then with water until neutral. The organic phase is dried with sodium sulfate and the solvent is evaporated off under reduced pressure. The evaporation residue is recrystallized from cyclohexane. This gives 40 g of product which melts at about 95 ° C. and consists of a mixture of essentially equal parts of the two geometric isomers of the oxime.

By chromatography of this mixture on a silica column using ethyl ether as The eluent can transform the geometric isomer into

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Configuration to the benzene ring can be separated from its homologue. After recrystallization from isopropanol, it melts at 150 ^° C.

The O-alkylation of the 50:50 mixture of the two isomers is carried out in dimethylformamide in the manner described in Example 2. The obtained raw Amine contains the isomers in essentially the same proportion as the starting product.

The hemifumarate of the amine function is then prepared as follows: 11.45 g of the oil obtained are dissolved in 50 ml of ethanol. 4.3 g of fumaric acid are added to the solution. The solution is brought to reflux temperature in 15 minutes and then cooled and an equal volume of ethyl ether is added. The deposited precipitate is isolated. It consists of at least 90 % of the isomer in the cis configuration to the benzene ring. The filtrate is made alkaline by adding sodium carbonate. The ethanol is then evaporated off under reduced pressure and the desired product in the form of the amine is extracted with ethyl ether. After the solution has dried, the amine hydrochloride is produced by adding anhydrous hydrochloric acid. The precipitate is filtered off and dried. The cleaning is then carried out in that solutions of this hydrochloride in a solvent, preferably ethanol, are prepared at 25 ° C. and the product is precipitated by adding ethyl ether. In this way, 1.5 g of the hydrochloride, melting at 144 G, of the geometric isomer in the trans configuration to the benzene ring of 7-chloro-3,4-dihydro-1-benzoxepin-0- (diethylaminoethyl) -5-one oxime are obtained .

Examples 4 and 5 illustrate two other 509807/1191

Working methods for making the product of Example 2.

Example 4-

Production of 7-chloro-3,4-dihydro-1-benzoxepin-O- (diethylaminoethyl) -5-one oxime from 7-chloro-5,4-dihydro-1-benzoxepin-5-one and 0- (diethylaminoethyl) hydroxylamine

To a solution of 19-65 g of 7-chloro-3,4-dihydro-1-benzoxepin-5-one in 100 ml of absolute ethanol 10.25 g of the dihydrochloride of O- (diethylaminoethyl) hydroxylamine given. The mixture is kept at the reflux temperature of the solvent for 5 hours. After refluxing for 1.5 hours, a further 10.25 g of dihydrochloride of 0- (diethylaminoethyl) hydroxylamine are added added to the mixture. The solvent is then evaporated under reduced pressure off, pour a dilute hydrochloric acid solution onto the residue, and wash the aqueous phase obtained with ether and then make it alkaline with sodium carbonate. The final product is extracted with ether. The organic Phase is dried over sodium sulfate and then over magnesium sulfate and the solvent under reduced Pressure evaporated. This gives 13.9 g of an oil.

The hydrochloride of the end product is produced in ether by reaction with gaseous hydrochloric acid. After recrystallization from a mixture of isopropyl ether and 1,2-dichloroethane (60: 4-0) in the presence of animal charcoal, 10.5 g of the hydrochloride of the desired product are obtained in the form of white crystals with a melting point of 115 to 116 ^° C.

The hemifumarate of the end product is dissolved in ethanol by adding fumaric acid in an equimolar amount to the amine

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solution prepared and then precipitated from this mixture by adding petroleum ether. After recrystallization from a mixture of isopropanol and isopropyl ether (50:50), the pure hemifumarate melts at 98 ⁰ C.

'Example 5

Preparation of 7 "chloro-3,4-dihydro-1-benzoxepin-0- (diethylaminoethyi) -5-one oxime from 7- chloro-3» 4-dihydro-1-benzoxepin-5-one-o ^ im

A mixture of 5.3 6 7-chloro-3,4-dihydro-1-benzoxepin-5-one oxime, 4.3 g of the hydrochloride of (2-chloro) ethyl diethylamine, 10.7 g of potassium carbonate and 50 ml of benzene is kept at the reflux temperature of the solvent for 15 hours, after which the inorganic precipitate is filtered off. The benzene phase is washed with an aqueous 1N sodium hydroxide solution and the end product is extracted with an aqueous 1N hydrochloric acid solution. The aqueous phase is washed with ether and then made alkaline by adding sodium carbonate. The final product is extracted with ether. After drying the solution and evaporating the solvent, 7.8 g of a Golben oil are obtained, from which 6.3 g of the hydrochloride of the desired basic Oximäthers be prepared. Melting point of the hydrochloride 115 to 116 ⁰ C.

Example 6

7-chloro-3,4-dihydro-1-benzoxepin ~ 0- (morpholinoethyl) -5-one oxime

In the manner described in Example 1, 11 g of this compound are obtained from 7.6 g of 7-chloro-3,4-dihydro-1-benzoxepin-5-one oxime and 6 g of N- (2-chloroethyl) morpholine are obtained.

The one made in essential hydrochloric acid and from 509807/1191

Ethyl acetate recrystallized hydrochloride melts at ⁰

Example 7

3 _T 4 ~ dihydro-1-benzoxepin-0- (1-pyrrolidinylethyl) -5-one

To a solution of 15 »7 g of 7-chloro-3,4 ~ dihydro-1-benzoxepin-5-one in 100 ml of 95% ethanol are ^em 16.5 g of the dihydrochloride of 0- (1-Pyrrolidinyläthyl)-hydro ~ xylamine (melting point 150 C) and a few drops of concentrated hydrochloric acid are added. The mixture is kept at the reflux temperature of the solvent for 6 hours. The solvent is evaporated off under reduced pressure. The residue is taken up in 1N hydrochloric acid, the unreacted ketone is extracted with ether, the aqueous phase is made alkaline by adding sodium carbonate and the amine formed as the end product is extracted with benzene. The benzene solution is washed well with water and then dried over magnesium sulfate. The solvent is evaporated off under reduced pressure.

The amine hydrochloride is produced in ethereal hydrochloric acid and then recrystallized from isopropanol. It melts at 154 · to 15 is 4-5 % based on the ketone.

lized. It melts at 154-155 ° C. The yield

Example 8

7-chloro-3,4- dihydro-1-benzoxepin-0- (dimethylaminopropyl) -5-cm-oxini

Using the manufacturing process described in Example 1 and by converting 7 »6 g of oxime and 4-, 9 g of O-chloro) propyldimethylamine in the stage (C) 7 g of the crude end product are obtained in the form of an oil. ,,.

0771 19-1 ■

The hydrochloride produced in essential hydrochloric acid after recrystallization from isopropanol melts at 166 ° C.

Example 9 ⁶ -Mothoxy-3,4-dihydro-1-benzoxepin-0- (dimethylamino ethyl) -5-one oxime

A. 6-Methoxy-5,4-dihydro-i-benzoxepine-5-cm

4-0 ml of concentrated toluene are added to 300 ml of anhydrous toluene Phosphoric acid (d = 1.71) given. With good honor 70 g of phosphoric anhydride are then slowly added. The mixture is kept on the boiling water bath for 2 hours. Then it will be at that temperature a lukewarm solution of 20 g of p-methoxyphenoxybutyric acid in 2 hours (Melting point 104 ° C.) in 1 l of anhydrous toluene. The mixture is another 3 hours kept on the water bath and then chilled. The upper toluene phase is decanted and the lower phase up poured twice the volume of crushed ice. After allowing the entire mixture to cool to room temperature the organic products are extracted with ethyl acetate. This phase is done with water and then washed with a sodium bicarbonate solution, neutralized and dried over magnesium sulfate. The solvent is evaporated under reduced pressure. This gives 15.4 g of an oil, its distillation 12 g of 7-methoxy-3,4-dihydro-1-benzoxepin-5-one from Boiling point 110 ° C / 0.02 mm Hg results.

B. 7-methox, γ-3,4-dihydro-1-benzoxepin - ^ - one oxime

To a solution of 19.2 g of 7-methoxy-3,4-dihydro-1-benzoxepin-5-one in 45 ml of ethanol, a solution of 6.95 g of hydroxylamine hydrochloride in 15 ml of 7 / water and Added 5.3 g of sodium carbonate. The mixture is stirred for 24 hours at a tree temperature. After adding 100 ml

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Water, the alcohol is evaporated. The aqueous solution is through. Addition of sodium hydroxide made alkaline, whereupon the unreacted benzoxepinone is extracted with ether. The aqueous phase is neutralized and the desired oxime is extracted with ether. After drying the organic solution and evaporation of the solvent under reduced pressure, a white solid is obtained the desired pure product are obtained of melting point 103 to 104 ⁰ C from the g after recrystallization from cyclohexane 17th

C · ? -Methox.y-5,4-dihydro-1-benzoxe pin ₇ 0 - (dim ethylamirio ethyl) -5-one oxime

To 50 ml of a sodium ethylate solution consisting of 0.8 g If sodium has been prepared, 5.84 g of the oxyine prepared in the above-described manner are obtained given. The mixture is heated on the boiling water bath for one hour. After adding 30 ml of anhydrous Dimethylformamide, the alcohol is evaporated off under reduced pressure. After adding 3> 2 g (2 ~ chlorine) ethyldimethylamine the reaction mixture is kept on the boiling water bath for one hour. The solvent is evaporated under reduced pressure and the residue is taken up in an aqueous 10% hydrochloric acid solution. This phase is washed once with ether and made alkaline by adding 10% sodium hydroxide made. The end product is extracted with methylene chloride, the organic phase is dried and the solvent evaporated under reduced pressure. The oil obtained is distilled. Boiling point 160 ° C / 0.5 mm Hg.

4.1 g of amine are obtained as the end product. The hydrochloride produced in ethereal hydrochloric acid and recrystallized from isopropanol melts at 178 ^° C.

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Example 10

7-Meth ox y-5 <4- dihydr o-1 -benzoxepin - 0- (diethylaminoethyl) -5-one-

Using the manufacturing process described in Example 9, where in stage (C) 7.25 g of oxime and 6.8 g of (2-chloro) ethyl diethylamine are reacted, 7 g of crude amine are obtained as the end product.

The hydrochloride prepared in ethereal hydrochloric acid and recrystallized from ethyl acetate melts at 108 ⁰ G.

Example 11

7-methoxy-2,4-dihydro-1-benzoxepin-0- (dimethylsmino propyl) -5-one oxime

Using the manufacturing process described in Example 9, where generally the stage (C) 5 * 85 g Oxime and 4 g (3-chloro) -propyldimethylamine reacted v / ground, the end product 6.2 g of amine in the form of a yellow oil.

The beroioxalate of the amine can be prepared in ethanol by reacting the amine and the acid in equimolar proportions. After recrystallization from ethanol the pure hemioxalate melts at 130 ⁰ C.

Example 12

7-Br o m-3,4-dihydro-i-benzoxepine-O- (diethylaminoethyl) -5-one oxime

A. 7-BrOm- ^ ₁ 4-dihydro-1-benzoxepin-5-one

This heterocyclic ketone is prepared in the manner described in Example 1 (A) from p-bromophenoxybutyric acid (Schnielz point 132 ° C.) in a yield of 40 % . It boils at 105 ° C / 0.06 mm Hg.

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B. 7-Bromo-3,4-dihydro-1-benzoxepine-O- (diethylaminoethy 1) -5-one oxime

The amine is prepared in the manner described in Example 4 by reacting the benzoxepinone prepared in the manner described above with the dihydrochloride of O- (diethylaminoethyl) hydroxylamine. From 7 g of 7-bromo-3,4-dihydro-1-benzoxepin-5-one, 4.5% of the end product is obtained in the form of an oil. The hydrochloride of this amine is produced in ether by reaction with gaseous hydrochloric acid and purified by dissolving in ethanol and subsequent precipitation by adding ethyl ether. It melts at 38 ^° C. The yield of hydrochloride from the ketone is

The pronounced strong effect of the products according to the invention compared to known products was due to toxicological and pharmacological examinations proven. The experiments were carried out with the acid addition salts of the amines carried out according to the above general formula.

The toxicity (LDp-Q) was determined on male Swiss C.D. mice with an average weight of 20 g when administered orally and intravenously.

The relaxing and slacking effect on the smooth Intestinal fibers were obtained in vitro on the isolated organ and in vivo on the anesthetized dog by the following methods proven:

Experiment on an isolated organ: an organ fragment, the duodenum the rat or the ileum of the guinea pig, is in 50 ml an oxygen-containing Tyrode solution kept constant at 37 ° C kept alive. The effectiveness of the compounds is determined by means of the spontaneous movements of the organ as well as by means of examined the contractions caused by adding a barium chloride solution or acetylcholine solution to the bath will. The movements are registered with the Roucaire physiograph DMP 4a.

In the experiment carried out in vivo, one becomes smaller

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Balloon in the terminal portion of the duodenum of the chloralose anesthetized animal. The intestinal movements are recorded on the Beckman polygraph using a strain gauge Statham PM 97 registered.

The results with regard to toxicity (LD, - ₀ ) and the relaxing and slacking effect in vitro are given in the following table.

link
of example

toxicity

(Mouse)

DL ₅₀ (mg / kg)

p.o,

i.v.

Isolated organs: minimum effective dose,
Concentration in µg / ral

Decontraction counteraction against tion (Duode- Acetylcholin num der (ileum of the sea-rat) pig)

1
(Hydrochloride) 150 32 0.06 5.5 2
(Hydrochloride) 420 37 0.1 1 6th
(Hydrochloride) > 1OOO 120 0.15 5.5 7th
(Hydrochloride 45O - 35 1.5 1.3 8th
(Hydrochloride) 500 60 0.12 3.5 9
(Hydrochloride) 500 35 0.12 1.5 10
(Hydrochloride) 450 45 0.5 0.5 11
(Hemioxalate) > 1000 _ 0.3 2.0 12th
(Hydrochloride) 250 40 0.1 1 Atropine sulfate 6OO 90 ineffective 0.006

The in vivo tests have shown that the products according to of the invention, in particular the compounds prepared according to Examples 1, 2, 7, 8 and 12, when administered intravenously Administration at a dose of 2 mg / kg

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had an effect on the decrease in tone and intestinal peristalsis that was similar to that of of atropine at a dose of 50 mg / kg or was even superior here. Unlike atropine, this one is relaxing and slack Effect, however, achieved without any anticholinergic and vagolytic effect.

The pharmaceutical preparations which contain as active ingredient at least one compound according to the invention, can for example be in the form of tablets or injection solutions. The tablets can be about 75 mg of active ingredient and the known excipients such as Contain microcrystalline cellulose, carboxymethyl starch, talc and magnesium stearate. The ampoules with injection solutions can contain about 25 mg of active ingredient and a sufficient amount of glycocolla to To make the product isotonic to blood.

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Claims (7)

Patent claims 1. Compounds of the general formula NO- (CH ₂ I _n -N ^ ¹ in which R is a halogen atom or a lower alkoxy radical, η stands for 2 or 3, Z. and Zp, which are identical to or are different, each stand for a lower alkyl radical or together with the nitrogen atom to which they are bound, a 5- to 7-membered N-heterocyclic Can form a group that has an oxygen Nitrogen atom or sulfur atom as a second hetero atom may contain, as well as their acid addition salts formed with the amine function including the ice and trans isomers on the double bond of the oxine to the benzene ring. 2. Compounds according to claim 1, characterized in that they consist of mixtures of the geometric isomers of the Oxime exist in proportions such that they contain at least 95% of one of the isomers in cis or trans configuration to the benzene ring. 3. Compounds according to claim 1 and 2 in the form of the geometric isomer in the cis configuration to the benzene ring of the compounds of formula (I) in which R is a halogen atom, and their acid addition salts. 4-. 7-chloro-3,4-dihydro-1-benzoxepin-0- (diethylaminoethyl) -5-one-oxime in the form of the geometric isomer in cis configuration to the benzene ring and its acid addition salts in their various crystal forms. 509807/1191 5. 7- · chloro-3,4-d.ihyd.ro-1 -benzoxepin-0- (diethylaminoethyl) -5-one oxime in the form of the geometric isomer in the trans configuration to the benzene ring and its acid addition salts. 6. Pharmaceutical preparations containing at least one compound according to claim 1 to M- as an active ingredient and physiologically acceptable auxiliaries and carriers, 7. A method for the preparation of 'compounds according to claim 1 to 5 »characterized in that one in the p-position R-substituted phenoxybutyric acid one Subjects to intramolecular acylation, the 3,4-- dihydro-1-benzoxepin-5-one of the formula II in which R has the abovementioned meaning, reacts with a compound of the formula HpN-OA, in which A is a group of the formula (CH ₂ ) -NZ _x . Z _; , in which n, Z _x , and Z "have the abovementioned meanings, or is a hydrogen atom, and the intermediate product obtained with a compound of the formula X- (CH ₂ ) -NZ ^ Z ₂ , in which X is an Ilalogen atom and n , Z _x , and Zp have the abovementioned meanings, and that, for the isolation of each of the geometric isomers of the pure oxime, the addition salts formed with the amine function are crystallized with acids selected in a suitable manner, after the isomer is in the trans configuration to the benzene ring Partial isomerization has been carried out in an anhydrous acidic medium, preferably in the stage of the oximes not substituted on the oxygen. 509807/1191