DE2610302A1 - ANTIDEPRESSIVE COMPOUNDS - Google Patents

Description

The invention relates to new antidepressant compounds.

British Patent 1 205 665 describes a large group of oxime ether compounds derived from alkyl phenyl ketone and having an antidepressant effect. The compounds have one or more substituents on a phenyl group which can be selected from a very large group. Any of the possible substituents can be bonded to the phenyl group in any position, but substitutions with nitro groups are restricted to the meta position according to this patent specification.

This gives the impression that oxime ether compounds derived from alkylphenone that are found in other than in

Meta position carry a nitro group, have no antidepressant effect.

The antidepressant effect of the known compounds is based on monoamine oxidase (MAO) inhibition and / or on norepinephrine potentiation.

Compounds that exhibit MAO inhibition are particularly difficult to handle. They often have serious side effects and are mostly incompatible with other medicines and with certain foods.

As a result of the ever increasing demands placed on pharmaceuticals, only compounds that are largely free of side effects are considered to be administered to humans.

The aim of the invention is to create compounds which have a strong antidepressant effect, which is expressed, inter alia, in an improvement in the mood of the patient being treated, but which have no component based on MAO inhibition. The desired compounds should be largely free of side effects.

It has now surprisingly been found that the compounds of the formula I of the formula sheet and salts thereof with pharmaceutically acceptable acids meet these requirements. In formula I, the symbols have the following meanings: R = hydrogen, methyl or chlorine; R [deep] 1 = oxygen or sulfur, R [deep] 2 = OCH [deep] 2, CH [deep] 2OCH [deep] 2, OC [deep] 2H [deep] 4OCH [deep] 2; R [deep] 3 = hydrogen or methyl; n = 0 or 1 and n + p = 0 or 1.

Surprisingly, it has been found that the antidepressant effect of these compounds is based to a considerable extent and, in the case of certain compounds, even exclusively on serotonin potentiation, which effect results in an improvement in mood in depressed patients. Most of the compounds show, in addition to serotonin potentiation, a very strong norepinephrine potentiation as an antidepressant component.

The lack of an action based on MAO inhibition is surprising, while the compounds are largely free of side effects, such as gastric ulceration and bronchial structure, and have a low toxicity.

The table below lists properties of compounds according to the invention and of the most closely related compounds known from British patent specification 1 205 665 for purposes of comparison.

* Fumarate 1: 1

In this table, the numbers indicate ED [low] 50 values, expressed in mg / kg.

It is noteworthy that compounds 9 and 10 neither potentiate adrenaline nor inhibit MAO. The antidepressant effects of these compounds are based entirely on serotonin potentiation.

These compounds - in particular compound 9 - are to be preferred if a very specific serotonin potentiation is intended.

For compounds 7 and 8, noradrenaline potentiation and serotonin potentiation are of the same order of magnitude. The activity is also at a high level.

In the case of compound 5, both noradrenaline potentiation and serotonin potentiation are at a high level, but the noradrenaline potentiation is a good factor of 4 higher.

The table shows that the compounds according to the invention are largely free from undesired side effects.

The known compounds B1 and B2 show a strong noradrenaline and serotonin potentiation, but also a strong MAO inhibition. In the case of compound B [deep] 3, not only the noradreanline potentiation and the serotonin potentiation are entirely different

Level, but the connection also causes gastric ulceration. None of the known compounds therefore fulfills the object of the invention.

The data mentioned in the table were determined in the following tests.

The noradreanalin potentiation was determined by means of the tetrabenazine test. An amount of the test compound was orally administered to five male albino mice. After 45 minutes, the animals were injected subcutaneously with 80 mg / kg tetrabenazine. After another 45 minutes, the degree of ptosis was determined and compared with the ptosis of animals to which only tetrabenazine had been administered. The ED [low] 50 value was determined from the results.

The serotonin potentiation was determined by means of the 5-hydroxytryptophan test. To this end, the test compounds were administered orally in a series of doses to isolated albino mice (five mice per dose) one hour before the intraperitoneal administration of 150 mg / kg dl-5-hydroxytryptophan. 30 minutes after this threshold dosage, the individual mice were observed with regard to the following parameters: stereotypical head shaking, spreading of the hind paws, tremor, tendency to flee, lordosis and clonic trampling with the front paws. The ED [low] 50 value was calculated from the results.

The monoamine oxidase (MAO) inhibitory effect was shown in

Experiments were determined in which five male albino mice were orally administered an amount of the test compound. One hour later, the animals were injected subcutaneously with tryptamine hydrochloride in an amount of 250 mg / kg. This amount does not cause mortality in animals not administered the test compound, but does cause mortality in animals administered an active test compound. 18 hours after administration of tryptamine hydrochloride, the number of dead animals from the treated group was determined. The ED [low] 50 value was determined from the results obtained.

Using the method of Metysova, Arzneimittelforschung, 13, 1039 (1963), it was determined whether oral administration of 200 mg of a test compound induces gastric ulceration.

With the method according to Konzett-Rössler, Arch. Exp. Path. Pharmacol. 195, 71 (1940), it was examined whether a test compound induces bronchostricture after intravenous administration of 3 mg / kg. A reduction in the respiratory function due to bronchial stricture is noticeable in the reduced volume of inhaled air.

Because of their properties, the compounds of the formula I and their salts are particularly suitable for use in the treatment of depressed patients.

This applies in particular to the compounds 5- (2-methoxy-ethoxy) -4'-nitrovalerophenone-0- (2-aminoethyl) oxime, 4'-nitro-3'-methylvalerophenone-0- (2-aminoethyl) oxime , 3´-chloro-5-methoxy-4´-nitrovalerophenone-0- (2-aminoethyl) -oxime, 4´-nitrovalerophenone-0- (2-aminopropyl) -oxime and 3´-chloro-4´-nitro- 5-methoxyvalerophenone-0- (2-aminopropyl) -oxime and their salts.

The amount, frequency and manner of administration of the compounds according to the invention can vary from case to case, also depending on the severity of the disorder to be treated.

In general, a daily amount of 25 to 500 mg orally and typically 50 to 200 mg is chosen.

The compounds are preferably used in the form of tablets, coated tablets, capsules, pills, powders, injection liquids and the like. They can be processed into such preparations by methods known per se.

The invention also relates to preparations containing a compound of the formula I or a salt thereof with a pharmaceutically acceptable acid as an active ingredient, as well as to methods with the aid of which the compounds and their salts are brought into a form suitable for administration, for example by that an active substance with solid or liquid pharmaceutical

Carrier materials is mixed or dissolved therein.

Examples of pharmaceutically acceptable acids with which the bases of the formula I can form salts include: inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, and organic acids such as malic acid, citric acid, pumaric acid, maleic acid, tartaric acid, benzoic acid and the like. like

The compounds of the formula I and their salts can be prepared by processes known for the preparation of compounds of this type and processes analogous thereto.

The invention further relates to the preparation of the compounds.

The compounds can be prepared, inter alia, by reacting a compound of the formula II with a compound of the formula III or a salt thereof. R [deep] 4 represents an oxygen atom, an oxime group or an alkylenedioxy group such as ethylenedioxy.

The reaction is preferably carried out in an inert solvent such as an alcohol, dioxane, dimethylformamide, tetrahydrofuran or a mixture thereof, at temperatures between room temperature and the boiling point of the mixture and optionally in the presence of an acid binder such as pyridine.

The connections are also obtained by that a compound of the formula IV, in which M represents a hydrogen or alkali metal atom, is reacted with a compound of the formula V or a salt thereof, in which formula Hal represents a halogen atom, preferably a chlorine or bromine atom.

The reaction is preferably carried out in an inert solvent such as alcohols, ethers or dimethylformamide.

If M represents a hydrogen atom, an acid binder, such as an alcoholate, is also preferably added. The reaction temperature is usually between 0 and 50 ° C.

The compounds can also be prepared by reacting a compound of the formula VI in which R [deep] 5 is a removable group, such as a mesyloxy or tosyloxy group, with ammonia. The reaction takes place preferably in an inert solvent such as an alcohol, usually at temperatures between room temperature and 150 ° C.

The compounds of the formula VI are prepared by reacting a compound of the formula IV in ethanol and in the presence of an alcoholate at temperatures of up to 60 ° C. with acetylene oxide or propylene oxide. The reaction product is then reacted with mezyl or tosyl chloride dissolved in methylene chloride.

The compounds can also be obtained in that in a compound of the formula VII a protecting group R [deep] 6 is split off by hydrolysis.

A trityl group, for example, can be mentioned as a protective group. The reaction is carried out, for example, in a water-miscible solvent under acidic conditions at a temperature between room temperature and 100 ° C.

The compounds can also be obtained by converting the aromatic amino group in a compound of the formula VIII into a nitro group.

The conversion can be achieved by reaction with nitrous acid at -10 to + 5 ° C and subsequent decomposition of the diazonium compound obtained in the reaction mixture at 20 to 75 ° C in the presence of copper.

The conversion of compounds in which R [deep] 1 is not sulfur can also be carried out with a peroxide such as hydrogen peroxide or m-chloroperbenzoic acid in an inert solvent such as methylene chloride or chloroform at temperatures between room temperature and the boiling point of the mixture.

Compounds of the formula I in which n + p = 1 can further be prepared by reacting a compound of the formula IX with a compound of the formula X. In these formulas q has the value 1, 4 or 5, M 'stands for an alkali metal atom and R [deep] 7 for a propyloxy, propylthio, methyloxy or

Methoxyethoxy group. Hal is a halogen atom, preferably a chlorine or bromine atom. The reaction can be carried out in, for example, aqueous alcohol at temperatures from 0 ° C, or optionally lower, to room temperature.

Compounds of the formula I in which n + p = 1 can also be obtained by reacting a compound of the formula XI with a compound of the formula XII. In these formulas q has the value 1, 4 or 5, R [deep] 8 stands for an oxygen or sulfur atom, M´ for an alkali metal atom, R´ [deep] 7 for a methyl, propyl or methoxyethyl group and Hal for a halogen atom, preferably a chlorine or bromine atom. The reaction can be carried out in a polar aprotic solvent such as hexamethylphosphoric triamide at a temperature between 0 ° C and room temperature.

In all formulas, the symbols that are not defined have the same meaning as in formula I.

The invention is explained in more detail below with the aid of a few examples.

1) 5-methoxy-4'-nitrovalerophenone-0- (2-aminoethyl) oxime hydrochloride

5.35 mmol (1.27 g (5-Methody-4'-nitrovalerophenone (melting point 64.5 to 65.5 ° C), 5.35 mmol (0.80 g) 2-aminoxyethylamine dihydrochloride and 0.43 ml of pyridine were refluxed in 5 ml of absolute ethanol for 2 hours the reaction mixture had been evaporated to dryness in vacuo, 25 ml of water and 10 ml of 2N sodium hydroxide solution were added and the mixture was extracted with 25 and 10 ml of methylene chloride, respectively.

The extracts were dried over sodium sulfate and then evaporated to dryness in vacuo. Two more toluene was added to the base obtained in this way, which was then evaporated off in vacuo. The residue was dissolved in absolute ethanol and an equimolar amount of alcoholic hydrochloric acid was added to this solution. After the addition of diethyl ether, the compound named in the title crystallized. Melting point 121.5 to 122.5 ° C.

2) 6-methoxy-4'-nitrohexanophenone-0- (2-aminoethyl) oxime hydrochloride

135 mmol (33.7 g) of 6-methoxy-4'-nitrohexanophenone (melting point 50 ° C.), 135 mmol (20.1 g) of 2-aminoxyethylamine dihydrochloride and 100 ml of pyridine were refluxed in 300 ml of absolute ethanol for 5 hours. The reaction mixture was evaporated to dryness in vacuo and the residue, after being dissolved in 200 ml of water, was washed twice with 100 ml of petroleum ether (40-60). The aqueous solution was made alkaline with 300 ml of 2N sodium hydroxide solution and then extracted four times with 100 ml of ether. The combined ether extracts were washed with 100 ml of water and dried over sodium sulfate and then evaporated to dryness. The oil obtained was evaporated to dryness in vacuo three times after addition of toluene and then dissolved in absolute ethanol. After adding an equivalent amount of alcoholic hydrochloric acid, the mixture was again evaporated to dryness in vacuo. The residue was crystallized from alcohol / ether. The crystals obtained were recrystallized twice from acetonitrile or alcohol / ether. Melting point 92 to 93 ° C.

3) 3'-methyl-4'-nitrovalerophenone-0- (2-aminoethyl) oxime fumarate (1: 1)

5.7 mmol of 3'-methyl-4'-nitrovalerophenone, 5.7 mmol of 2-aminooxyethylamine dihydrochloride and 0.9 ml of pyridine were refluxed in 15 ml of absolute ethanol for 3 hours.

The base was isolated from the reaction mixture in the manner described in Example 2. This was dissolved in an equimolar amount of ethanolic fumaric acid. The melting point after recrystallization from ethanol was 152.5 to 154 ° C.

4) 3'-chloro-5-methoxy-4'-nitrovalerophenone-0- (2-amino-ethyl) -oxime fumarate (1: 1)

In the manner described in Example 3, the compound mentioned in the title was obtained from 3'-chloro-5-methoxy-4'-nitrovalerophenone (melting point 54.5 to 56 ° C.) and 2-aminoxyethylamine dihydrochloride. After crystallization from ethanol the melting point was 148 to 148.5 ° C.

5) 4'-nitrovalerophenone-0- (2-aminopropyl) oxime hydrochloride

In the manner described in Example 2, the compound mentioned in the title was obtained from 4'-nitrovalerophenone (boiling point at 0.03 mm Hg 128 to 132 ° C. and 2-aminoxy-1-methylethylamine dihydrochloride. The melting point after recrystallization from acetonitrile / ether was 148 - 149 ° C.

6) 4´-nitro-2´-propoxyacetophenone-0- (2-aminopropyl) -oxime fumarate (1: 1)

In the manner described in Example 3, the compound mentioned in the title was obtained from 4'-nitro-2-propoxyacetophenone (melting point 49 to 50 ° C.) and 2-aminoxy-1-methylethylaminodihydrochloride. The melting point after recrystallization from ethanol was 141 to 142 ° C.

7) 3'-chloro-5-methoxy-4'-nitrovalerophenone-0- (2-aminopropyl) oxime fumarate (1: 1)

In the manner described in Example 3, the compound mentioned in the title was obtained from 3'-chloro-5-methoxy-4'-nitrovalerophenone (melting point 54.5 to 56 ° C.) and 2-aminoxy-1-methylethylamine dihydrochloride.

After crystallization from ethanol / acetonitrile, the melting point was 140 to 142 ° C.

8) 4'-nitrovalerophenone-O- (2-aminoethyl) oxime hydrochloride

10 mmol of 4'-nitrovalerophenone-0- (2-tritylaminoethyl) oxime was dissolved in 50 ml of 90% acetic acid. After it's three days had remained at room temperature, the reaction mixture was evaporated to dryness in vacuo, after which the residue was dissolved in 50 ml of ether.

The resulting solution was extracted with 50 ml of 0.2N hydrochloric acid and the extract, after being made alkaline with 10 ml of 2N sodium hydroxide solution, was extracted with 50 and 25 ml of methylene chloride, respectively. After drying over sodium sulfate and evaporation in vacuo, the base obtained was converted into the compound named in the title using alcoholic hydrochloric acid. After crystallization and recrystallization from ethanol / ether, the melting point was 107 to 108 ° C.

9) 4'-nitro-2-propoxyacetone phenone-0- (2-aminoethyl) oxime hydrochloride

10 mmol of 4'-nitro-21-propoxyacetophenone oxime, 10.4 mmol of 2-chloroethylamine hydrochloride and 1.4 g of powdered potassium hydrochloride were added to 25 ml of dimethylformamide with stirring at 10.degree. After stirring for two days at room temperature, the dimethylformamide was evaporated off in vacuo; the residue was brought into water and then 2N hydrochloric acid was added until a pH = 3 was reached. The remaining oxime was removed with the aid of ether, after which 30 ml of 2N sodium hydroxide solution was added. It was then extracted three times with ether. The collected ether layers were twice with one

Washed 5% sodium bicarbonate solution and then dried over sodium sulfate. After removing the ether in vacuo, the residue was dissolved in absolute ethanol and converted into the compound named in the title with the aid of alcoholic hydrochloric acid. After recrystallization from alcohol / ether, the melting point was 128 to 130.degree.

10) 4'-nitro-2-propoxyacetone phenone-0- (2-aminoethyl) oxime hydrochloride

a) In 30 mmol of 4'-nitro-2-propoxyacetophenone oxime in 50 ml of absolute ethanol, in which 0.007 g of lithium was initially dissolved, 2.3 g of acetylene oxide was introduced with stirring at 55 ° C by means of a stream of nitrogen, after which another Was stirred at 60 ° C for an hour. After adding 0.6 ml of acetic acid, the mixture was evaporated to dryness in vacuo. The residue was taken up in ether and washed with water. After drying over sodium sulfate and evaporation of the ether, a residue was obtained which was purified with the aid of a silica gel column, methylene chloride being used as the eluent.

After evaporation of the solvent, the 0- (2-hydroxyethyl) oxime was obtained as an oil.

b) A solution of 22 mmol of this oil in 120 ml of methylene chloride was added with stirring at -5 to -10 ° C, 4.5 ml of triethylamine, after which in 20 minutes dropwise

24 mmol (1.9 ml) of mesyl chloride was added. The mixture was stirred at 0 ° C. for half an hour and then the reaction mixture was washed with water, sodium bicarbonate solution and a saturated sodium chloride solution. After drying over sodium sulfate, the methylene chloride was evaporated off in vacuo. The 0-2-mesyloxyethyl oxime was thus obtained.

c) A mixture of 26 mmol of this oxime in 100 ml of methanol with 12 g of ammonia was kept at 80 ° C. in an autoclave for 16 hours. After cooling, the methanol was removed in vacuo. The residue was stirred up with 50 ml of 2N sodium hydroxide solution and extracted four times with ether.

The ether layer was washed twice with a 5% sodium bicarbonate solution. After drying over sodium sulfate and distilling off the ether under reduced pressure, the oil obtained was converted into the compound named in the title with the aid of alcoholic hydrochloric acid. After two crystallizations from alcohol / ether, the melting point was 128 to 130 ° C.

11) 5- (2-methoxyethoxy) -4´-nitrovalerophenone-0- (2-amino-ethyl) -oxime fumarate (1: 1)

10 mmol (3.25 g) of 5- (2-methoxyethoxy) -4'-nitrovalerophenone-ethyl ketal, 10 mmol (1.49 g) of 2-aminoxyethylamine dihydrochloride and 10 ml of methanol were refluxed for six hours cooked. The residue obtained after evaporation of the methanol was, after it had been dissolved in water, washed three times with ether. The aqueous solution, after being made alkaline with sodium hydroxide solution, was extracted three times with methylene chloride. The combined extracts were washed with a 5% sodium bicarbonate solution and then with water. After drying over sodium sulfate and evaporation of the methylene chloride, the free base was obtained, which was converted into the title compound with the aid of an equimolar amount of fumaric acid. After recrystallization from alcohol, the melting point was 134.5 to 135.5 ° C.

12) 4'-nitrovalerophenone-0- (2-aminoethyl) oxime hydrochloride

4 mmol (1.23 g) of 4'-aminovalerophenone-0- (2-aminoethyl) oxime dihydrochloride (melting point 175 to 177 ° C.) was converted into the free base with the aid of 2N sodium hydroxide solution.

A solution thereof in 5 ml of methylene chloride was added dropwise with stirring at 25 to 40 ° C., 12.3 mmol (2.5 g) of m-chloroperbenzoic acid (85%) in 10 ml of methylene chloride. The mixture was then stirred at 30.degree. To 35.degree. C. for a further three hours. The precipitate was filtered off with suction and washed with methylene chloride. After adding 50 ml of ether to the filtrate and the washing liquid, the mixture was washed three times with 2N sodium hydroxide solution and finally twice with a 5% sodium bicarnonate solution. To

Drying over sodium sulfate and removal of the ether under reduced pressure, the residue was chromatographed over silica gel with methylene chloride as the eluent. The methylene chloride was distilled off from the eluate, after which the residue was converted into the compound named in the title with the aid of alcoholic hydrochloric acid. After crystallization from alcohol / ether, the melting point was 107-108 ° C.

13) 4'-nitro-2-propylthioacetophenone-0- (2-aminoethyl) oxime hydrochloride

6 mmol (0.54 g) propyl mercaptan were added to a solution, cooled with ice water, of 6 mmol (0.24 g) sodium hydroxide in 10 ml 50% alcohol. The mixture was then stirred for 10 minutes and then 3 mmol (1.02 g) of 2-bromo-4'-nitroacetophenone-0- (2-aminoethyl) oxime hydrochloride (melting point 197 °) were added with stirring at a temperature between 0 and 5 ° C C) added in half an hour. The mixture was stirred for a further hour at 5 ° C. and for one hour at room temperature. The reaction mixture was evaporated in vacuo and the residue was washed with water and dissolved in methylene chloride.

The solution was washed with water and dried over sodium sulfate. After evaporation, a base was obtained which, with the aid of alcoholic hydrochloric acid, was converted into the compound named in the title became. After recrystallization from acetonitrile / ether, the melting point was 122.5 to 123.5 ° C.

14) 4'-nitro-2-propoxyacetone phenone-0- (2-aminoethyl) oxime hydrochloride

A solution of 2.0 mmol (0.48 g) of 2-hydroxy-4'-nitro-acetophenone-0- (2-aminoethyl) oxime (melting point 97 to 98 ° C) in 5 ml of hexamethylphosphoric acid triamide was stirred 0.09 g of 55 to 60% sodium hydride in mineral oil was added at room temperature. After 4 minutes, 0.20 ml of propyl bromide was added with stirring. The reaction mixture was then stirred for four hours at room temperature, diluted with 50 ml of water and extracted twice with 25 ml of ether. The combined ether extracts were dried over sodium sulfate and evaporated to dryness in vacuo. The residue was chromatographed over 15 g of silica gel with the aid of ethanol / ammonia 95/5. The eluate was evaporated to dryness in vacuo and then converted into the title compound with alcoholic hydrochloric acid. After crystallization from alcohol / ether, the melting point was 128 to 130 ° C.

15) tablet

50 mg 4'nitro-3'-methylvalerophenone-0- (2-aminoethyl) -oxime.HCl

335 mg of lactose

60 mg potato starch

25 mg talc

5 mg magnesium stearate

5 mg gelatin

16) suppository

50 mg 4´-nitrovalerophenone-0- (2-aminopropyl) -oxime.HCl,

1500 mg of suppository mass

17) injection fluid

25 g of 3'-chloro-4'-nitro-5-methoxyvalerophenone-0- (2-aminopropyl) -oxime.HCl

1.80 g of methyl p-hydroxybenzoate

0.20 g propyl p-hydroxybenzoate

9.0 g sodium chloride

4.0 g poly (oxyethylene) [deep] 20 sorbitan monooleate

Water up to 1000 ml

Claims (23)

1. Compounds of the formula I of the formula sheet and salts thereof with pharmaceutically acceptable acids, in which formula R is hydrogen, chlorine or methyl, R [deep] 1 is oxygen or sulfur, R [deep] 2 OCH [deep] 2, CH [deep] 2OCH [deep] 2 or OC [deep] 2H [deep] 4OCH [deep] 2, R [deep] 3 represent hydrogen or methyl, n and p are 0 or 1 and n + p is 0 or 1. 2. 4'-nitrovalerophenone-0- (2-aminoethyl) oxime and salts thereof with pharmaceutically acceptable acids. 3. 4'-Nitro-2-propylthioacetophenone-0- (2-amino-ethyl) -oxime and salts thereof with pharmaceutically acceptable acids. 4. 4'-Nitro-2-propoxyacetophenone-0- (2-aminoethyl) -oxime and salts thereof with pharmaceutically acceptable acids. 5. 5-methoxy-4'-nitrovalerophenone-0- (2-amino-ethyl) -oxime and salts thereof with pharmaceutically acceptable acids. 6. 5- (2-methoxyethoxy) -4'-nitrovalerophenone-0- (2-aminoethyl) oxime and salts thereof with pharmaceutically acceptable acids. 7. 6-Methoxy-4'-nitrohexanophenone-0- (2-aminoethyl) oxime and salts thereof with pharmaceutically acceptable acids 8. 3'-Methyl-4'-nitrovalerophenone-0- (2-aminoethyl) -oxime and salts thereof with pharmaceutically acceptable acids. 9. 3'-chloro-5-methoxy-4'-nitrovalerophenone-0- (2-aminoethyl) oxime and salts thereof with pharmaceutically acceptable acids. 10. 4'-nitrovalerophenone-0- (2-aminopropyl) oxime and salts thereof with pharmaceutically acceptable acids. 11. 4'-Nitro-2-propoxyacetophenone-0- (2-aminopropyl) -oxime and salts thereof with pharmaceutically acceptable acids. 12. 3'-chloro-5-methoxy-4'-nitrovalerophenone-0- (2-aminopropyl) oxime and salts thereof with pharmaceutically acceptable acids. 13. Pharmaceutical preparations, characterized by a content of a compound of the formula I or a salt thereof with a pharmaceutically acceptable acid, in which formula R for hydrogen, chlorine or methyl, R [deep] 1 for oxygen or sulfur, R [deep] 2 stands for OCH [deep] 2, CH [deep] 2OCH [deep] 2 or OC [deep] 2H [deep] 4OCH [deep] 2 and R [deep] 3 stands for hydrogen or methyl, and n and p the value 0 or 1, while the sum of n and p is also 0 or 1. 14. Process for the production of pharmaceutical preparations, characterized in that a compound of the formula I or a salt thereof is brought into a form suitable for administration with a pharmaceutically acceptable acid. 15. The method according to claim 14, characterized in that a compound of the formula I or a salt thereof is mixed with a pharmaceutically acceptable acid with solid or liquid carrier materials or dissolved therein. 16. Process for the preparation of new oxime ether compounds, characterized in that compounds of the formula I and salts thereof with pharmaceutically acceptable acids, in which formula R is hydrogen, methyl or chlorine, R [deep] 1 is oxygen or sulfur, R [deep] 2, OCH [ deep] 2, CH [deep] 2OCH [deep] 2 or OC [deep] 2H [deep] 4OCH [deep] 2 and R [deep] 3 represents hydrogen or methyl, n and p have the value 0 or 1 and the sum of n and p is 0 or 1, according to processes known for the preparation of compounds of this type or processes analogous thereto. 17. The method according to claim 16, characterized in that a compound of the formula II in which R [deep] 4 represents an oxygen atom, an oxime group or an alkylenedioxy group, is reacted with a compound of the formula III or a salt thereof. 18. The method according to claim 16, characterized in that a compound of the formula IV, in which M represents a hydrogen atom or an alkali metal atom, is reacted with a compound of the formula V or a salt thereof, in which formula Hal represents a halogen atom. 19. The method according to claim 16, characterized in that a compound of the formula VI, in which R [deep] 5 represents a group which can be split off, is reacted with ammonia. 20. The method according to claim 16, characterized in that the protective group R [deep] 6 in a compound of the formula VII is split off by hydrolysis. 21. The method according to claim 16, characterized in that in a compound of formula VIII the aromatic amino group is converted into a nitro group. 22. The method according to claim 16, characterized in that compounds of the formula I in which n + p = 1, and salts thereof are prepared in that a compound of the formula IX in which q has the value 1, 4 or 5 , is reacted with a compound of the formula X in which M 'is an alkali metal atom and R [deep] 7 is a propyloxy, propylthio, methoxy or methoxyethoxy group. 23. The method according to claim 16, characterized in that compounds of the formula I in which n + p = 1, and salts thereof are prepared in that a compound of the formula XI in which q has the value 1, 4 or 5 and R [deep] 8 is an oxygen or sulfur atom and N 'is an alkali metal atom, is reacted with a compound of the formula XII in which Hal is a halogen atom and R [deep] 7 is a methyl, propyl or methoxyethoxy group. Formula sheet: I. II III IV V VI VII VIII IX 4´R [deep] 7 X XI XI Hal R´ [deep] 7 XII