IE58999B1

IE58999B1 - Novel N-oxyde of NN-dimethyl ethylamine, a process for it's production and the pharmaceutical compositions containing it

Info

Publication number: IE58999B1
Application number: IE192586A
Authority: IE
Original assignee: Rolland Sa A
Priority date: 1985-07-22
Filing date: 1986-07-21
Publication date: 1993-12-15
Also published as: DE3674873D1; AU593562B2; EP0216646A3; EP0216646A2; AU6038586A; IE861925L; KR940011528B1; KR870001144A; EP0216646B1

Abstract

1. 2,2-bis phenoxy NN-dimethylethylamine N-oxyde having the formula see diagramm : EP0216646,P5,F3

Description

This invention relates to a novel derivative of NN-dimethyl ethylamine and more particularly to an N-oxyde.

This invention specifically provides the N-oxyde of 2,2-bis phenoxy NN-dimethyl ethylamine having the formula This invention also relates to the salts of N-oxyde with a mineral or organic acid and more precisely with a strong acid as hydrochloric acid, hydrobromic acid or sulphuric acid.

The N-oxyde of 2,, 2-bis phenoxy NN-dimethyl ethylamine is a weak base and leads to acid addition salts only with nonreducing strong acids.

The N-oxyde and the salts thereof are prepared according to a process which consists to react 2,2-bis phenoxy NN-dimethyl ethylamine or a salt thereof with a mineral or organic peroxyde in an inert solvent. Preferably, the peroxyde is perhydrol. It may also be a hydroperoxyde from an alkanol such as tert-butyl peroxyde; a hydroperoxyde from a ketone such as hexafluoro acetone peroxyde; a peracid such as p.nitroperbenzoic acid or 4-chloroperbensoic acid.

The solvent of the reaction medium is an inert solvent such as methanol, ethanol or an aromatic hydrocarbon such as toluene or xylol or a NN-disubstituted lower alkylamide such as dimethyl formamide or dimethyl acetamide. 2£ 2"bis phenoxy MN^dimethylethylamine M-oxyde and its salts show the characteristic properties of the common anti5 depressive agents on the classical pharmacological tests. They inhibit the hypothermizing effect of Reserpine and Apomorphine. They increase the group toxicity induced by injection of yohimbin and they antagonise the dispair test in the mice. 2,2-bis phenoxy NN-dimethylethylamine has already been disclosed in the literature as well as its salts (see French brevet special de Medicament 5498M). The salts of 2£, 2-bis phenoxy NN-dimethyTethylamine have been described as having anti-depressant activities. The testing performed by the applicant has evidenced the fact that these compounds show a significative acute toxicity in the mice which allows to locate the mean lethal doses to 800mg/kg.

In contrast thereof the N-oxyde which is the subject matter of this application shows a very weak toxicity while keeping about the same level of activity and consequently it has not been possible to determine at doses acceptable for the animals, a mean lethal doses.

Moreover j, the N-oxyde presents an antagonistic action in the test of apomorphine, and a positive action against the group toxicity with yohimbine clearly more marked than those shown by 21,2-bis phenoxy NN-dimethylethylamine. In other words , the M-oxyde is more active than the prior art compound from which it derives, while being clearly less toxic.

The French patent 2 , 384 £-495 has been cited to show the equivalency existing between a N-acylated pentane diamine and its N-oxyde. It may merely be stated that in a quite 1' different chemical family, the two kinds of compounds behave in pharmacology in a similar fashion. In contrast thereof, in the series of bis phenoxy ethylamine, the 2t2bis phenoxy NNdimethyl ethylamine and its oxyde possess very different pharmacological properties. It appears to be frequent in the literature to notice that a N-oxyde is less toxic or possess about the same level of toxicity that the tertiary amine, from which it derives, but this decrease is also the result of a lowering of the pharmacological activity in the animals. In the case of bis phenoxy NN-dimethyl ethylamine, not only the N-oxyde subject matter of this invention is much less toxic, but, in addition, it is markedly more active than the starting tertiary amine.

Due to their anti-depressive properties, they found an use in human or veterinary medicine in the treatment of depressive condition, of the involuting psychoses, of the maniacodepressive states, of the depressions of reaction or behaviour. These molecules being very weakly toxic, their therapeutical margin is very extended and they may be given without fear of side-effects (such as dryness of the mouth, extrapyramidal disturbances) which may occur with the antipressant drugs belonging to the tricyclic group.

The production of these pharmaceutical compositions is carried out according to the known methods of pharmacotechnology, namely to produce tablets, coated tablets, dragees, soft gelatine capsules, capsules, drops, injectable or drinkable solutions, preparations for percutaneous applications.

The following examples are merely intended for illustrating the invention. They do not limit it in any manner.

EZaWLE. 1 Preparation of the N-oxyde of 2,2-bis phenoxy NN-dimethyl ethylamine.

- In a three-neck flask of 100 ml fitted with a decantation 5 funnel, a thermometer, a cooling device, 5,15 g (0,02M) of NNdimethyl-2,2-bis phenoxy ethylamine previously dissolved in 50 ml methanol are introduced to which 5 ml 30% - perhydro 1 are dropwise added. After completion of the addition, stirring at room temperature is kept for 30 mn then the mixture is heated at about 35 0 for 12 hours.

Finally methanol is distilled off and water is discarded by azeotropic distillation with ethanol. The residual oily residue is taken up in ether; a white solid matter appears. After filtration and drying 3.08g N-oxyde of NN-dimethyl which melts at 104°C. The yield amounts to 56,5 % Rf = 0,14 (CHCI3/CH3OH 9sl) NMR: (CDCL3) 10H (m, 6,8-7,3) IH (t; 6,7) 2H (d; 3,7) SH (s; 3,2) NMR: (CDCL3) of MEDIFOXAMINE 10H (m; 6,8-7,3) IH (t; 5,8) 2H (d; 2,8) 25 6H (s? 2,32).

EXAMPLE II Study of the pharmacological characteristics of the N-oxyde of 2,2 bis phenoxy NN-dimethyl ethylamine, see Table I - 6 EXAMPLE II Pharmacological study on 2,2-bis phenoxy NN-dimethyl ethylamine N-oxyde PRODUCT CHEMICAL STRUCTURE ACUTE TOXICITY HYPOTHERMIA HYPOTHERMIA TOXICITY TO ON MICE TO RESERPINE TO APOMORPHINE YOHIMBINE p„O„ | 100 P.O.| j 50 P.O.j | 100 P.O, | t WO· P.O. ] DESPAIR TEST N-OXYDE MEDIFOXAMINE CHi • CHs 'CHs 600 0/10 700 3/10 300 5/10 + 2’5 + Γ1 + 0°3 /10 60% 500 0/10 1000 1/10 + 2° £ 0°7 + !e6 7/SO « 51% s TABLE I

Claims

1. CLAIMS,

1. The N-oxyde of

2. ,2 -bis phenoxy NN-dimethyl ethylamine of the formula 5 2. The acid addition salts of the N-oxyde of claim 1 with a mineral or organic acid.

3. A process for producing the N-oxyde of claim 1 in which a 2,, 2-bis phenoxy NN-dimethyl ethylamine or an acid addition salt thereof is reacted with a mineral or 10 organic peroxyde in an inert medium.

4. The pharmaceutical compositions having as active ingredient a compound according to any of claims 1 or 2 in combination or admixture with an inert non-toxic pharmaceutically-acceptable carrier or vehicle. 15 5. The pharmaceutical compositions according to claim 4 in which the carrier or the vehicle is one of those suitable for parenteral, oral, rectal or percutaneous ways of administration. β. The pharmaceutical compositions according to any of 20 claims 4 or 5 in which the content of active ingredient ranges from 0.05 g to 0.5 g per unit dosage.

5. 7. A compound substantially as hereinbefore described with reference to the Examples. -

6. 8 8. A process substantially as hereinbefore described with reference to the Examples.

7. 9. A composition substantially as hereinbefore described with reference to the Examples.