DE2337021A1 - 1-Phenoxy-2-hydroxylamino-alkanes - prepd by reducing corresponding oximino cpds. or oxidizing amino cpds - Google Patents

Abstract

1-Phenoxy-2-hydroxylamino-alkanes of formula (I): (where R is H or 1-3C alkyl, R1 is 1-6C alkyl, and R2-R6 are H or 1-5 (pref. 1-2)C alkyl) and their acid addition salts are new cpds. which may be prepd. by (a) reducing an oxime of the formula Ar-O-CH2-CR1=NOH (II) (where Ar is phenyl subst. by R2-R6) or (b) oxidizing an amine of the formula Ar-O-CH2-CHR1-NH-R (III) with H2O2 or its acyl deriv. in the presence of a suitable catalyst (e. g. a salt of tungstic, molybdenic or uranic acid) in an inert polar solvent (e. g. water, alcohol or a lower alkyl ester); the product obtained opt. being converted into its optically active form and/or converted into an acid addition salt with a pharmacologically tolerable anion. (I) have strong and long-lasting anticonvulsant activity with practically no sedative side-effects. They also have strong antiarrhythmic activity useful for the treatment of heart disorders. Dosage is 10-300 (pref. 30-200) mg per oral unit dosage.

Description

Case 1/493
Loe / sa

CH. BOEHRINGER SOHN, INGELHEIM AM RHEIN

New hydroxylamino compounds

The present invention relates to compounds of the general formula I.

.0 - CH ₂ - CH - R ₁ NOH
R.

wherein R is a hydrogen atom, an alkyl group having 1 to 3 Carbon atoms, R-, an alkyl group containing 1 to 3 carbon atoms and R "to R ^ - which are the same or different can be - hydrogen or alkyl groups with 1 to 5, preferably with i to 2 carbon atoms and their acid addition salts.

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Compounds of the general formula I can conveniently be prepared by

a.) Compounds of the general formula II

NOH

- 0 - CH ₂ - C - R ₁ II

wherein the radicals R- to R ^ have the meaning given above , reduced. The reduction can be carried out, for example, in an inert solvent at room temperature or at a moderately elevated temperature under elevated pressure in the presence of a hydrogenation catalyst, which may be inactivated; or that one

b.) Compounds of the general formula III

0 - CH ₂ - CH - R ₁

N-H

/ R

wherein R and R- to Rg have the meanings given above, oxidized with hydrogen peroxide or its acyl derivatives in the presence of suitable catalysts, such as

/ 3 509808/1 123

for example salts of tungsten, molybdenum or uranium acids in an inert polar solvent such as Water, alcohol or lower alkyl ester.

The starting products required for production are known from the literature or can be prepared by known methods.

The compounds of general formula I have an asymmetric carbon atom and can therefore be used as racemates as well as in their optically active form. The racemates can be in the usual way, for example by means of D-3-bromocamphorsulfonic acid or dibenzoyl-D-tartaric acid in split their optical antipodes.

The compounds of the formula I according to the invention can be used in are usually converted into their physiologically acceptable acid addition salts. Suitable acids are, for example Hydrochloric acid, hydrobromic acid, sulfuric acid, maleic acid, acetic acid, oxalic acid, methanesulfonic acid, etc.

The compounds of general formula I or their physiologically tolerable acid addition salts have valuable therapeutic properties Properties. In particular, they develop a strong and long-lasting anticonvulsant effect, which has always been with them so far This sedative side effect associated with this practically no longer occurs. In addition, have the invention Compounds have a strong anti-arrhythmic effect for the Treatment of heart disease.

The doubly substituted 1-phenoxy-2-hydroxylaminopropanes and their N-methyl derivatives have proven to be particularly valuable, especially those which contain ^{0 methyl groups in the 2- and 4- or 2- and 6-position of the henyl nucleus.} Particularly effective compounds are, for example

509808/1123

the l- (2 ', 6'-dimethylphenoxy) -2-hydroxylaminopropane and the 1- (2 ', 6'-Dimethylphenoxy) -2- (N-methyl-hydroxylamino) propane.

As a single dose for the oral use of the substances obtainable according to the invention or of their physiologically tolerable substances Acid addition salts 10-300 mg, preferably 30-200 mg, are suggested, although a combination is also possible with other pharmacodynamically active substances, for example Tranquilizers of the benzodiazepine or phenothiazine type. The individual active ingredients of the formula I, too can be combined with each other.

Suitable application forms for the substances of general formula I are, for example, tablets, coated tablets, powders, Suppositories, solutions or depot forms. The usual pharmaceutical auxiliaries, coating, Disintegrants, binders, glidants, lubricants, thickeners and / or diluents, flavorings, suspension auxiliaries or means for achieving a depot effect are used. Suitable carriers and diluents are e.g. calcium carbonate or phosphate and lactose. Suitable disintegrants are, for example, corn starch or Alginic acid, suitable binders, for example polyvinylpyrrolidone, Starch or gelatin, suitable lubricants for example magnesium stearate or talc, suitable Coating agents, for example cellulose esters, such as cellulose acetate phthalate, or polyvinyl compounds, such as polyvinyl acetate, suitable agents for the production of depot forms are, for example, carboxypolymethylene, carboxymethylcellulose or polyvinyl alcohols, suitable sweeteners and flavorings are e.g. sugar, sorbitol, saccharin, cyclamate, Vanillin or orange extract.

The following examples illustrate the invention without restricting it.

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Manufacturing examples

1- (2 ', 6 ^L dimethylphenoxy) -2-hydroxylamino-propane;

1.) to 35.6 g (0.2 mol) of 1- (2 ', 6'-dimethylphenoxy) -2-propanone in 200 ml of ethanol a mixture of 28 g of hydroxylamine hydrochloride, 50 ml of water and 40 ml of pyridine. After this the batch was stored overnight at room temperature, the reaction is by boiling for 2 hours Brought to the end of reflux and the solvent mixture was then distilled off. The residue is in ether taken up, extracted several times with water, dried over sodium sulfate. After evaporation of the organic Solvent remains 40 g of l- (2 ', 6'-dimethylphenoxy) -2-propanone oxime.

<:.) 46, L g (0.24 mol) 1- (2 \ Θ-Dimethy! Phenoxy) -propanone- (2) -oxime are dissolved in 500 ml. ethanol; the solution is concentrated with 22 ml (0.24 mol). Hydrochloric acid and 3 g of platinum oxide were added and hydrogenated in an autoclave at room temperature.

After the catalyst has been filtered off with suction, the solvent is distilled off, the residue is taken up in water and extracted 2 with ether. Jiatrium bicarbonate is added to the aqueous phase and the mixture is extracted with ether. The ether phase is shaken with water and dried over sodium sulfate. After concentration, 23.7 g of base remain, corresponding to a yield of 50.2 % of theory. The oxalic acid salt has a melting point of 137 - 40 ⁰ C.

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Formulate us Example I.

Manufacture of tablets with the following composition:

1- (2, 6'-dimethyl) -phenoxy-2-hydroxyl-

aminopropane oxalate 75.0 mg

Milk sugar 25.0 mg

secondary calcium phosphate 150.0 mg

Corn starch 206.0 mg

colloidal silica 12.0 mg

Stearic acid ^ »0 mg

soluble starch 8.0 mg

480.0 mg

The active ingredient is kneaded together with some of the excipients with an aqueous solution of the soluble starch and granulated in the usual way with the aid of a sieve. The granulate is mixed with the remaining auxiliaries, especially the stearic acid mixed and compressed in the usual way to tablets of 480 mg weight.

Example II

Production of coated tablets with the following composition:

l- (2, 6'-dimethylphenoxy) -2-N-methyl-

hydroxylamino propane oxalate 75 mg

secondary calcium phosphate 120 mg

Corn starch 91 mg

colloidal silica 7 mg

Magnesium stearate 4 mg

Polyvinylpyrrolidone 3 mg

300 mg 509808/1 1 23

The dragee core is produced according to Example 2 and in the usual way with the help of sugar, titanium dioxide, talc, Gum arabic and polyvinylpyrrolidone coated. Total weight 430 mg.

Example III

Production of capsules with the following composition:

1- (2 ^f , 6'-dimethyl-phenoxy) -2-hydroxylaminopropane oxalate 50 mg

Milk sugar 150 mg

200 mg

The active ingredient is mixed intensively with the milk sugar and the mixture is filled into hard gelatine capsules.

/ 8 50S808 / 1 1 23

Claims (8)

Claims j 1.) Compounds of the general formula I O - CH ₀ -CH-R, NOH where R is a hydrogen atom, R-, an alkyl group with 1 to 3 carbon atoms and Rp to Rg - the same ocer can be different - hydrogen or alkyl groups with 1 to 5, preferably with 1 to 2 carbon atoms and their acid addition salts. 2.) Process for the preparation of new compounds of the general formula I. 0 - CH ₀ - CH - R 50S808 / 1123 v / orin R or R-, a hydrogen or an alkyl group with ι to 3 carbon atoms and R ₂ to R ^ - which can be the same or different - hydrogen or alkyl groups rciLt 1 to 5, preferably 1 to 2 carbon atoms b «- π »Ηιten, characterized in that one a.) Compounds of the general formula II NOH 0 - CH ₂ - C - II in which the radicals R 1 to R 1 have the abovementioned meaning bp.-i reduced or that one b.) Compounds of the general formula III 0 - CH "- CH - R _n 2, 1 N-H III 509308/1 1 23 ίο wherein R and R- to Rg have the meanings given above, oxidized with hydrogen peroxide or its acyl derivatives in the presence of suitable catalysts, such as salts the tungsten, molybdenum or uranium acids in an inert polar solvent such as water, alcohol or lower alkyl ester and the compounds obtainable in this way in their optically active forms and / or in their acid addition salts with transferred pharmacologically acceptable anion. 3.) Pharmaceutical preparations, characterized by a content of active ingredients of the general formula I. 4.) Process for the production of pharmaceutical preparations according to claim 3, characterized in that one or more Active ingredients of the general formula I with customary pharmaceutical auxiliaries and / or carriers formulated in the customary manner. e3. 7.) 1- (2 ', 6'-Dimethylphenoxy) -2-hydroxylaminopropane oxalate. 8.) 1- (2 ', 6'-Dimethylphenoxy) -2- (N-methylhydroxylamino) propane oxalate. X
^ received on ... ZC * 509808/1123