DE1543369B2 - 1-ARYLOXY-2-AMINO ALKANES AND PHARMACEUTICAL PREPARATIONS ON THE BASIS OF THEM - Google Patents

Description

15th

in which either Ar is a p-tolyl radical and at the same time R an ethyl group or Ar a m-tolyl radical, a 2,6- or 3,4-dimethylphenyl radical and at the same time R a Is hydrogen atom, as well as their physiologically acceptable acid addition salts.

2. Pharmaceutical preparations containing one or more of the following compounds as active ingredient:

1- (4-methylphenoxy) -2-aminopropane

1- (2,4-dimethylphenoxy) -2-aminopropane

1- (2,6-dimethylphenoxy) -2-aminopropane

1 - (3,4-Dimethylphenoxy) -2-aminopropane

1- (3,5-dimethylphenoxy) -2-aminopropane

1- (3-methylphenoxy) -2-aminopropane

1 - (4-methylphenoxy) -2-aminopentane

and / or their physiologically acceptable acid addition salts together with auxiliary materials.

25 Ar-OCH ₇ -CH-CH ₇ -R

(II)

in which Ar and R have the meanings given above and A is a secondary or tertiary, represents amino group substituted with one or two protecting groups. Come as protecting groups for example the benzyl, phthalyl, toluenesulfonyl or formyl group. The connections of the general formula II can be obtained by reacting an appropriately substituted l-phenoxy-2-haloalkane with a primary or secondary amine correspondingly substituted with protective groups or by reacting an appropriately substituted l-phenoxy-2-oxoalkane with one with such Protective group substituted primary amine can be prepared under reducing conditions.

b) Implementation of an appropriately substituted compound of the general formula Ar-OM, in which M Means hydrogen or a cation with a compound of the general formula III

Z-CH ₇ -R

(III)

The invention relates to the subjects defined in the claims.

In CH patents 2 97 266 or 2 97 689, 2 97 690 or 2 97 692 and 2 97 693, some such l-phenoxy-2-aminoalkanes, namely -propanes, which are methyl-substituted in the core, are already mentioned (compounds with CH3 in 3,5-, 2,4- and 4-position). However, no physico-chemical indicators are given. In addition, no other, in particular pharmacological properties are mentioned for these compounds; Rather, they in turn serve only as intermediates for the preparation of pharmaceutically active compounds which result from the aforementioned precursors _{by (reductive) alkylation on the --NH 2 group.}

The three l-phenoxy-2-aminoalkanes mentioned in the CH patents mentioned are in addition to those according to the invention Compounds the pharmaceutical preparations according to the invention are based.

The new compounds correspond to the general formula I.

Ar-O-CH ₂ -CH-CH ₂ -R
NH,

(D

in which either Ar is a p-tolyl radical and at the same time R is a Ethyl group or Ar a m-tolyl radical, a 2,6- or in which R has the meaning given above and Z is the group

X — CH, -CH-

NH ₂

where X is the radical of a "reactive ester", for example a halogen atom such as chlorine or bromine, represents or in the Z the group

CH ₂

CH-

60

means The starting compounds of the general formula IH can be prepared by customary methods are shown, for example, in GB patent specification 7 65 849 or in Houben-Weyl, Methods of organic chemistry (4th edition, 1958), Vol. XI / 2, pp. 228-230, are described.

c) Reduction of compounds of the general formula IV

Tabel

Ar-OCH ₂ -C-CH ₂ -R

Il

N-Y

(IV)

in which Y is hydrogen, a hydroxyl group or an amino group, for example with catalytic excited hydrogen or complex metal hydrides. The starting compounds of the general formula IV ι ο can be prepared from appropriately substituted l-phenoxy-2-oxoalkanes (which in turn are produced by reacting Phenolates Ar-OM with l-halo-2-oxo-alkanes der desired chain length are accessible) by reaction with ammonia, hydroxylamine or hydrazine are obtained, this reaction also being equal to when using reducing conditions to the compounds of general formula I can be continued.

The compounds of general formula I have an asymmetric carbon atom on the free one Amino group and therefore occur as racemates as well as in optically active form. The racemates can in the usual way, e.g. B. with the help of D-3-bromo-camphor-8-sulfonic acid or dibenzoyl-D-tartaric acid can be split into their optical antipodes. Another The way to the optical antipodes is to start from optically active starting material, what for example in the process a) is possible.

The l-phenoxy-2-aminoalkanes of the general formula I according to the invention can be converted into their physiologically acceptable acid addition salts in the customary manner. Suitable acids are, for example, hydrochloric, hydrobromic, sulfuric, maleic, acetic, oxalic, lactic, tartaric, succinic or methanesulfonic acid .

The compounds of general formula I or their physiologically acceptable acid addition salts have valuable therapeutic properties. In particular, they develop a strong, long-lasting anticonvulsant Effect without the previously known agents of diphenylhydantoin or of the barbiturate type, sedation associated with this effect always occurs. It has proven to be particularly valuable that twice in the 2- and 6-position of the phenyl nucleus Methyl-substituted l-phenoxy-2-aminopropane highlighted.

A particularly effective compound is, for example, 1- (2,6-dimethyl) phenoxy-2-aminopropane hydrochloride.

The table shows the superiority of the compounds according to the invention. The dose is given (in mg / kg body weight) at which 50% of the test animals show the corresponding effect. The values SD ₅₀ (lateral position) and DD50 (supine position) relate to the position reflex, ie the reflex to correct the unusual position for the test animal. The failure of this reflex is a measure of the medication-induced central depression (sedation). It turns out that this undesirable side effect is more than about 7 times stronger in the case of the comparison substance than in the case of the compounds according to the invention.

The anticonvulsant effect was tested using the maximum electric shock method. It was with Phenobarbital found comparable values, the toxicity (LD50) of the comparison substance is higher than that the connections according to the application. The observation time here is 24 hours.

SD

DD

50

LD

50

1- (2,6-dimethyl) - 1944 1944 430 30

phenoxy-2-amino-

propane

Phenobarbital 275 290 420 30

As a single dose for oral use of the substances obtainable according to the invention or of their physiologically acceptable acid addition salts, optionally in the form of the pharmaceutical according to the invention Preparations present, 10-300 mg, preferably 30-200 mg, are suggested. The individual active ingredients of the formula I can also be combined with one another.

Suitable pharmaceutical application forms for the substances of general formula I are for example tablets, coated tablets, powders, suppositories, solutions or depot forms. For their production the usual pharmaceutical auxiliary, coating, blasting, binding, sliding, lubricating, thickening and / or diluents, flavorings, suspending aids or means for achieving one Depot effect can be used. Suitable carriers and diluents are, for. B. calcium carbonate or phosphate and lactose. Suitable disintegrants are, for. B. corn starch or alginic acid, suitable Binders e.g. B. polyvinylpyrrolidone, starch or gelatin, suitable lubricants z. B. Magnesium stearate or talc, suitable coating agents ζ. Β. Cellulose esters, such as cellulose acetate phthalate, or polyvinyl compounds, such as polyvinyl acetate; Means for the production of depot forms are, for example, carboxypolymethylene, Carboxymethyl cellulose or polyvinyl alcohol; as sweeteners and flavorings are e.g. B. These include sugar, sorbitol, saccharin, cyclamate, vanillin or orange extract.

The following examples illustrate the invention.

example 1

1- (2,6-Dimethylphenoxy) -2-aminopropane hydrochloride

245 g of l- (2,6-dimethylphenoxy) -2-propanone are dissolved in 1300 ml of methanol and 5 atm at 6O ⁰ C and hydrogenated over Raney-nickel. After the catalyst has been separated off, the methanol is distilled off and the remaining residue is dissolved in ethanol. After addition of ethereal hydrochloric acid, the hydrochloride crystallizes out. After cooling, this is filtered off with suction and recrystallized from ethanol with the addition of ether.

. Mp 203-205 ⁰ C; Yield 140.5 g (51.5% of theory).

Analogously to Example 1, l- (3,4-dimethylphenoxy) -2-aminopropane hydrochloride with a melting point of 162-164 ° C. and l- (4-methylphenoxy) -2-aminopentane hydrochloride with a melting point of 137 ° -138 ° C. and l - (3-methylphenoxy) -2-aminopropane hydrochloride, mp 139-140 ⁰ C prepared..

The simple or in 2,4- and 3,5-positions disubstituted l-phenoxy-2-aminoalkanes (cf. the above-mentioned CH patents) In the form of the hydrochloride, they have melting points 151 ° to 152 °, 213 ° to 214 ° and 211 °, respectively up to 213 ° C.

5 6

Typical formulation examples l- (2,4-dimethylphenoxy) -

brought: 2-aminopropane hydrochloride 45 mg

1 - (4-methylphenoxy) -2-amino-

propane hydrochloride 30 mg

Calcium secondary phosphate 120 mg

Corn starch 91 mg

Colloidal silica 7 mg

Magnesium stearate 4 mg

Polyvinylpyrrolidone 3 mg

ίο 300 mg

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.

⁴⁸⁰ ' ^0m S example 4

The active ingredient is used together with part of the production of capsules with the following

Auxiliaries with an aqueous solution of the soluble settlement: starch kneaded and in the usual way with the aid of 20

a sieve granulated. The granules are treated with the l- (2,4-DimethyIphenoxy) -

remaining excipients, especially stearic acid, 2-aminopropane maleate 50 mg

mixed and in the usual way to form tablets of lactose 150 mg

480 mg weight pressed. 200 mg

Example 3 _The active ingredient becomes intense with the milk sugar

Production of coated tablets with the following mixed together and the mixture with hard gelatine capsules setting:. bottled

example 2 Manufacture of tablets with following combination setting: 1 - (2,6-dimethylphenoxy) - 2-aminopropane hydrochloride 75.0 mg Lactose 25.0 mg Secondary calcium phosphate 150.0mg Cornstarch 206.0 mg Colloidal silica 12.0 mg Stearic acid 4.0 mg Soluble starch 8.0 mg

Claims (1)

Patent claims: t. Racemic or optically active l-aryloxy-2-aminoalkanes of the general formula I. Ar-O-CH ₂ -CH-CH ₂ -R
NH, (D 3,4-Dimethylphenyl radical and at the same time R is a hydrogen atom is. They can be prepared by methods already described for known l-phenoxy-2-aminoalkanes will. The following procedures have proven to be particularly effective: a) Cleavage of one or two monovalent or one divalent, easily removable protective group from compounds of the general formula