JPS6293262A - Novel derivative of diphenoxyethylamine, manufacture and drug composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel derivatives of diphenoxyethylamine and methods for their production.

The invention particularly relates to N-alkylated derivatives of 2,2-bisphenoxydiethylamine.

The present invention particularly relates to N-alkylated derivatives of 2,2-bisphenoxydiethylamine of the following general formula (1).

In this general formula (1), R represents a linear or branched chain lower alkyl group having 1 to 4 carbon atoms.

The present invention is based on the general formula (
It also relates to salts of the compounds of III).

The acid in this case is preferably one that is therapeutically compatible.

Salts that can be used in addition reactions include the following. i.e., bromide hydrate, chlorhydrate, codohydrate, sulfate, nitrate, phosphate, hypophosphate, thiosulfate, sulfite, formate, acetate, benzoate, naphtonite, nicotinate. , isonicotinate, trimethoxy 3°4.5-benzoate, syringoate,
0-rubetoxysyringoate, benzenesulfonate, methanesulfonate, isethionate, p.

Toluene sulfonate, naphthalene sulfonate, Toratrade, pyruvate, citrate, malate, fumarate, itaconate, citraconate, malonate, trathionate, lactobionate, curcose 1-
phosphate, glucose 1°6-diphosphate.

Salts of acids that cannot be used therapeutically, such as iodate, periodate, ferrocyanate, or Sl-IJ oxate, can be used as a means of identification or purification. These salts are then converted back into bases of general formula (1).

In the compound of general formula (III), R is preferably a methyl group, ethyl group or isopropyl group. This R may also be a tylbutyl group or a simple butyl group.

The present invention also relates to compounds of general formula (1) and methods for producing salts thereof. This method consists of 2,
The method involves converting 2-bisphenoxyacetic acid into a functional derivative, and reacting this derivative with a primary amine represented by the following general formula (II).

RNH2(II) (R is the same as defined above.) This reaction produces an amide shown in formula (III) below.

(R is as defined above.) The method of the invention then uses a mixture of an alkali metal and a hydride to
The generated amide is reduced to a compound of general formula (III). Compounds of general formula (III) can also be salified by addition of inorganic or organic acids.

As a variation of the above method, it is also possible to base tertiary amines such as medifuoxamine and non-alkylate them using quaternizing agents such as halogen cyanide or alkylated chloroform hydrochloride. .

In this case, a compound of general formula (III) is obtained. formula(
R in 1) is a methyl group.

In a preferred embodiment of the process according to the invention, the functional derivative of -2,2-bisphenoxyacetic acid is treated by the action of an acylating agent such as an albodiimide, carbonylbisimidazole or an alkyl pyrophosphate.

- The production of the amide of general formula (I[I) is carried out in an inert solvent such as an aromatic carbide, - General formula (II
The reduction of the amide in I) is carried out, for example, by the action of lithium and aluminum hydride, lithium and terbutoxyaluminum hydride, or lithium and aluminum hydride and an alkali metal, such as isopropylalumino hydride.

2.2 of menate or p, toluenesulfonate etc.
- Based on the sulfonic acid ester of bisphenoxyethanol, a compound of the general formula (III) can be obtained by reacting the following general formula (n) with a primary amine of NH2 in a high boiling point solvent. .

The present invention also relates to the general formula (
The present invention relates to a pharmaceutical composition containing at least one compound of III) or one of its salts as an active ingredient, mixed with pharmacologically acceptable harmless and inert excipients.

The excipients used are those suitable for parenteral, oral, dermal, or rectal administration.

The pharmaceutical composition can be in the form shown below. i.e. tablets with or without an envelope;
Dragee-coated tablets, pills, sachets, flavored or unflavoured powders, solutions or dispersions for drinking, ampnope various-dose vials or injectables dispensed in self-injecting syringes, frozen These include dried drugs, suppositories, polar solvents for transdermal administration, etc.

The pharmaceutical composition contains 0.025 to 0.250 g of the compound of general formula (III) or its salt as an active ingredient,
Preferably it is between 0.05 and 0.20 g.

The daily dose of the compound of general formula (III) or its salt varies depending on the patient's weight, age, therapeutic precautions, and symptoms. Generally, the daily dose for adults is 0.05
˜0.150 g, but this amount can vary considerably depending on therapeutic needs.

The compound of general formula (III) and its salts have uses as antidepressants. Therefore, these compounds are suitable for recovering or curing symptoms such as obsession, progressive illness, reactive psychosis, and weaning phenomenon.

These compounds are distinct from medifoxamine and other similar compounds in that they promote noradrenaline recovery and reduce tritamine recovery. These compounds also make it possible (at least in animal studies) to replenish the phyllonprenabus granules with adrenergic substances and thus to restore the granules to their normal functioning potential.

EXAMPLES Examples of the present invention will be shown below, but the present invention is not limited thereto.

Example I 2.2-Bisphenoxy N-methylaminoethane a) Methyl ester of bromo-2-phenoxyacetic acid The methyl ester of phenoxyacetic acid is
J, L, C0LIN) and /L, H5< -(L
DOBINOUX) [Synthesis 5
68.1983].

A mixture of ester (20 g; 0.12 mol), N-bromosuccinate (25.6 g; 0.14 mol) and a trace amount of benzoyl peroxide (loomg) was added to 500 ml.
of carbon tetrachloride. Then, a mixture of 30 parts of ethyl acetate and 70 parts of tohexane is mixed as an eluent, and the progress of the reaction is monitored by column chromatography. After 1 hour of reflux, the reaction is complete. After filtration and evaporation,
The resulting oil is sufficiently pure that no refining work is required.

Infrared spectroscopy 200-1770cm-' Nuclear magnetic resonance: 3.8pprn S (CH3); 6
．． 4 pprn s (CH); 7.2 ppm m (aromatic) b) 2.2-bisphenoxyacetic acid tetrabutylammonium bromide (0,0062 mol) 2
The crude bromine ester dissolved in 200 ml of toluene containing g of phenol (0,132 mol) 12.4
Added to a 50% aqueous soda solution (70 nil) containing 2 g. This aqueous mixture is stirred overnight. The aqueous phase of this mixture is acidified and extracted into ether.

In contrast, the organic phase is washed, dried and evaporated. 2.2-Bisphenoxyacetic acid was used as an eluent with CHa
Mix C12/MeOH9515 and purify by column chromatography.

Infrared spectroscopy 200"1750cm-' Nuclear magnetic resonance: 5.9ppm s (CH); 7p
pm m (aromatic); 8°8 ppm s (OH) c) 2.2 bisphenoxy N-methylacetamide 30 ml of water-free toluene in which 3 g of the above acid is dissolved
1.5 equivalents of oxalyl chloride is added thereto.

Keep at 40°C for 2 hours. The progress of the reaction is then followed by infrared spectroscopy. The resulting chloride of the above acid is very unstable but is used directly. Flow monomethylamine for 30 minutes. Stir at room temperature for 10 hours. After acid-base treatment, an amide with sufficient purity is obtained.

Infrared spectroscopy 'CO'1670cm-'Nuclear magnetic resonance: 2
．． 75ppm d (CH3); 5.7ppm s
(CH); 6.9 ppm n (aromatic) 6,8 ppm (NH) d) 2,2-bisphenoxy N-methyl-amino-ethane Aluminum hydride and lithium 0.4 in 30 ml of water-free ether 1 g of the amide dissolved in 50 ml of ether is added to the dispersion containing g (2.8 eq.) at a temperature of 0.degree. After 30 minutes, the temperature is allowed to return to room temperature and stirring is continued for 12 hours. After acid-base treatment, the corresponding amines are obtained.

Infrared spectroscopy: NH○”3300cm-'Nuclear magnetic resonance:
2.7ppm (large peak: Nl-1°CH,
3.4ppm (large peak: CH2); 6.41
]1] m t (CH)3 near ppm m (aromatic): 9.8 ppm (large peak; N It is converted to chlorhydrate by saturation. The precipitated chlorhydrate is separated, washed with ethanol and dried under vacuum.

In a similar manner, the maleate or fumarate salts of 2,2-bisphenoxy N-methylaminoethane are prepared by addition of an aqueous ethanolic solution of fumaric acid or maleic acid.

Example 2.2-Bisphenoxy N-isopropylaminoethane 2.2-Bisphenoxy N-isopropylaminoethane 2.2-Bisphenoxy N-isopropylaminoethane 2.2-Bisphenoxy acetic acid and isopropylamine are used as in Example 10C).
, 2-bisphenoxy N-isopropylacetamide is obtained.

This 2,2-bisphenoxy N-isopropylacetamide is reduced with aluminum hydride and lithium according to the procedure of Example 2, d).

2.2-Bis-phenoxy N-isopropylaminoethane is an oily product converted to chlorhydrate by the action of hydrochloric acid in an organic solvent.

Example ■ Drug testing of the compound according to the present invention Verification of whether it has properties as an antidepressant was carried out by conventional drug testing methods.

- antagonizing effect on hypothermia caused by injection of reserpine; - antagonizing effect on hypothermia caused by injection of apomorphine; - increased mass toxicity caused by injection of yohimbine.

- Antagonism to the limit test in mice.

The compounds according to the invention administered orally in doses of 50 or 100 mg/Kg show an activity in the above-mentioned test that is at least comparable to that of medifoxamine taken as reference substance.

Furthermore, in extreme tests in mice, the compounds according to the invention show similar activity at only 50 mg/kg orally as medifoxamine at 100 mg/Kg orally.

Table 1 below summarizes the main drug test results obtained.

Example ■ Average lethal dose Experiment To determine the average lethal dose in mice, mice in each loft were administered increasing doses of the compound according to the invention in a lot of 5 mice. An approximation of the average dose was given by Tainter and Miller (
Miller's method using a graph.

At a dose of 200 mg/Kg, the mortality rate was 0 and 350
mg/Kg kills 3 out of 5 animals, 50h+g/K
All mice died at g. Therefore, DLso is about 300
mg/g.

Example V Biological experiments of compounds according to the invention Activity of the main adrenergic media in control and recovery tests.

The test results obtained in comparison with conventional antidepressants are summarized in Table 2 below.

Example ■ 0.250 g tablet of 2,2-bis-phenoxy N-methylaminoethane hydrochloride.

Active ingredients 2.834 g Calcium sulfate 1,510 g Cellulose microcrystals 325 g Gum arabic
16g ethyl cellulose
24 g povidone contains 15 30 g talc 65 g per 10,000 tablets with an average weight of 0.48 g per tablet.

Patent author: Albert Rolland Nis, Ah.

Claims (8)

[Claims] (1) 2,2- represented by the general formula (I) shown below
Bisphenoxyethylamine. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (However, R in the above formula represents a lower alkyl group having 1 to 4 carbon atoms.) (2) The above general formula (
I) Salt of the compound. (3) 2,2-bisphenoxy N-methylaminoethane and its salt, which is a compound according to claim 1 or 2. (4) 2,2-bisphenoxy N-isopropylaminoethane and its salt, which is a compound according to claim 1 or 2. (5) A method for producing a compound according to claim 1 or 2, which comprises producing a functional derivative of 2,2-bisphenoxyacetic acid having the following general formula (II). Primary amine RNH_2
(II) (However, R is the same as the above definition.) Then, the secondary amide having the following general formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) is alkali By reducing with a mixture of metal and hydride,
A production method for producing a desired ethylamine represented by the general formula (I), and optionally adding an inorganic or organic acid to salt it. (6) A pharmaceutical composition containing at least one compound as set forth in claim 1 or 2 as an active ingredient and blended or mixed with a pharmacologically acceptable harmless and inert excipient. thing. (7) The pharmaceutical composition according to claim 6, wherein the excipient used is suitable for parenteral, oral, rectal or dermal administration. (8) The amount of the active principal ingredient is 25 to 250 per administration.
Pharmaceutical composition according to claim 6, which is between mg.