CS272921B1 - Basically substituted 2,3-dichlorodiphenylmethane derivatives of their salts - Google Patents

Abstract

The solution falls within the branch of synthetic pharmaceuticals. It deals with basically substituted 2,3'-dichlorodiphenylmethane derivates, more specifically, related 2-aminoethylethers or 0-(2-aminoethyl)oximes and their salts. The substances according to the solution show therapeutically utilizable pharmacodynamic effects, mainly anti-spastic, spasmolytic, antitussive and also properties indicating the possibility of antidepressive effect. Its formulation consists in reactions of 2,3'-dichlorobenzhydrol, 2,3'-dichlorobenzhydrylchloride and 2,3-dichlorobenzophenone oxime with related N-substituted 2-aminoethylchlorides or 2-aminoethanols. The acquired oily base is neutralised by acids to salts.<IMAGE>

Description

(57) The solution falls within the field of synthetic drugs. Accordingly, the present invention relates to basic substituted 2,3'-dichlorodiphenyjraathan derivatives, in particular the corresponding 2-aminoethyl ethers or O- (2-aminoethyl) oximes, and their eoli. The compounds according to the invention exhibit therapeutically useful pharmacodynamic effects, in particular anticonvulsant, spasmolytic, antitussive and, furthermore, properties indicative of the possibility of an antidepressant effect. _f 3ejich preparation consists in the reaction of 2,3 ^/ -dichlorbenzhydrolu. 2.3 ^From -dichlorbenzhydrylchloridu -dichlorbenzofenonoxirau and 2.3 with the appropriate N-substituted 2-aminoethylchíoridy or 2-aminoethanol. The oily bases obtained are converted by acid neutralization into salts.

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The invention relates to a compound of formula 1 (i) wherein R represents a dimethylamino or 4-methylpiperazino radical and X represents a residue of J 1 CH or SDC-N-; and salts thereof with pharmaceutically acceptable inorganic or organic acids.

The literature provides formulas for benzhydryl-2-dimethylaminoethyl ether (diphenhydramine)

II antihistainine and antiallergic effects (US Pat. 2,421,714) and for the basic oxime of the formula

III (noxiptiline) antidepree effects (US Pat. 3 S63 778).

The compounds of the formula I according to the invention / in particular in the form of a salt. exhibit a range of tharapeutically useful, particularly non-photrophic, pharmacodynamic effects, in particular antispasmodic, spasmolytic, antitussive, and indicative properties. possibility of antidepressant effect in patients. The pharmacodynamic properties of several compounds of the invention are listed below:

N, N-methyl-2- (2,3'-dichlorobenzhydrylpxy) ethylamine was tested as hydrogen oxalate. Acute toxicity in mice, LDg ₀ is 193 mg / fcg orally and 30 mg / kg iv respectively In the maximum electro-eye test in mice, an oral dose of 50 kg / kg fully protects against aviation, has a protective effect against convulsions in 60% of animals. Slightly inhibits binding of 4 nM / ³ H / imipramine (IC _SO »

142 nM) and 4 nM (1 H) desipramine (1650 718 nM) binding to the appropriate receptors in the rat brain hypothalamus. It has a spasmolytic effect on isolated rat duodenum at concentrations of 1 to 10 mg / l against both acetylcholine and barium chloride contractions.

At an oral dose of 30 mg / kg, my significant antitussive effect on guinea pigs: reduced the frequency of aerosol cough attacks by 24%.

1- (2- (2,3'-Oichlorobenzhydryloxy) ethyl) -4-methylpiperazine was tested as bis (hydrogen oxalate). Acute toxicity in mice, LDg ₀ is 3SS mg / kg orally * At an oral dose of 50 mg / kg, it has a mild anticataleptic effect: it antagonizes perfenazine-induced catalepsy in rats.

O- (2-Dimethylaminoethyl) -2,3'-dlchlorobenzophenone oxime was tested as the hydrochloride. Acute toxicity in mice, LDqq is 315 mg / kg orally. It has a protective effect in the maximum electro-eye test in mice (PDqq is 37 mg / kg orally); starting with an oral dose of 40 mg / kg it has a full protective effect against the lethal effect of electro-eye. At an oral dose of 50 mg / kg it shows mild antlcataleptic efficacy (against perfenazine catalepsy in rats). It has moderate affinity for imipramine and desipramine binding sites in rat brain hypathalamus: it inhibits binding of 4 nM / ³ M / imipramine (IC ₅₀ 1770 nM) as well as 4 nM / 1 H / desipramine binding (IC _go * _-1126 nM) .

The compounds of formula I according to the invention are prepared in various ways, briefly described in the examples. Thus, Ν, Ν-dimethyl-2- (2,3'-dichlorobenzhydryloxyjethylamine) is best obtained by reaction of 2,3'-dichlorobenzhydrol (Faith HE et al., O.Am.Chem.Soc. 77, 543 (1955) with 2- dimethylaminoethyl ethyl chloride in aprotic solvents, preferably toluene, in the presence of sodium hydrate.

1- (2- ^(2,3 -Oichlorbenzhydrylaxy) athyl) -4-methylpiperazine was prepared for example by heating a mixture of 2,3'-dichlorbenzhydrylchloridu with 2- (4-methyl-l-piperazinyl) ethanol and potassium carbonate at a temperature of 140 160 ° C. The required 2,3'-dichlorobenzhydryl chloride is a novel substance and its preparation is described in the example.

2- (4-methyl-1-piperazinyl) ethanol has been described in the literature (Cymerman-Craig O. et al.,

Aust.O.Chsra. 9, 89 (1956). O-.alpha.-Dimethylaminoethyl-.alpha.-.alpha.-dichlorobenzophenone oxime is obtained by reacting 2,3'-dichlorobenzophenone oxime with 2-dimethylaminoethyl chloride in aprotic solvents in the presence of sodium hydride. Said oxime is a novel substance and its preparation from the known 2,3 &apos; -dichlorobenzophenone (Haller HL et al., O. Am. Chem. Soc. 67, 1591 (1945)) is exemplified. characterized by spectra and neutralization with pharmaceutically acceptable inorganic or organic acids are converted to salts, which are also subject of the invention.

Example 1

N, N-Dimethyl-2- (2,3'-dichlorobenzhydryloxy) ethylamine

To a solution of 10.0 g of 2,3'-dichlorobenzhydrol in 50 ml of toluene is added 5.0 g of an 80% (w / w) oil suspension of sodium hydride and a solution of 8.5 g of 2-dimethylaminoethyl chloride in 15 ml of toluene is added dropwise with stirring. . The mixture was refluxed for 5 hours and quenched with water after cooling. The organic layer was washed with water and the basic product was extracted with dilute hydrochloric acid. The acidic aqueous layer ae is basified with aqueous ammonia and the product is extracted with diethyl ether.

11.1 g (87%} of the desired base olsjovlté. Mass spectrum m / z (%): 323 (M ^+, C ₁₇ H Cl ₂ N0 _ig. 0.005), 235 (0.6) 199 (2.3 ), 165 (8), 111 (1), 73 (18), 58 (100). 1 H NMR Spectrum (CDCl 3 DOC): 2.70 s, 6 H (N (CH ₃ ) ₂ ) δ 3.28 bt H (CH ₂ N) 3.68 bt, 2H (CH ₂ O) 5.80 s,

H (Ar ₂ CH-O); 7.30 m, 7 H and 7.65 m, 1H (ArH). The base was dissolved in ethanol and neutralized with a solution of 4.1 g of oxalic acid dihydrate in ethanol. Addition of diethyl ether induced crystallization of 11.6 g of hydrogen sulphate oxalate, mp 116.5-117 ° C.

Example 2 1- (2- (2,3'-Oichlorobenzhydryloxy) ethyl) -4-methylpiperazine

A mixture of 26.3 g of 2,3 ^/ -dichlorbenzhydrylchloridu, 14.0 g of 2- (4-methyl-l-piperazinyl) ethanol and 20 g of potassium carbonate is stirred and heated 11 hours at 150 ° C. After cooling, it is diluted with water and extracted with diethyl ether. The basic product is shaken into dilute hydrochloric acid, the acidic aqueous solution is basified with aqueous ammonia and the crude oil base is isolated by extraction with diethyl ether; 4.6 g (13%). Mass spectrum, m / z (%) ₃₇ 378 (M ⁺ , 0 _2θ Η ₂₄ 01 ₂ Ν ₂₀ , 0.1), 347 (0.4), 235 (2.5), 199 (4.2) 143 (10); 126 (18); 113 (100); 100 (10); 70 (55). Neutralization of the bass with oxalic acid dihydrate in ethanol is converted to crystalline bis (hydrogen oxalate), mp 187-189 ° C (ethanol).

The necessary starting 2,3'-dichloro-benzhydryl chloride is prepared as follows:

A mixture of 20 g of 2,3'-dichlorobenzohydride, 40 ml of toluene and 10 g of thionyl chloride is stirred and refluxed for 2.5 hours. After standing overnight, the mixture was distilled; 18.3 g (85%) of the desired oily product are obtained, m.p. 104 DEG-106 DEG C./0.6 mbar.

Example 3

O- (2-Dimethylaminoyl) -2,3'-dichlorobenzophenone oxime

To a solution of 7.7 g of 2,3'-dichlorobenzophenone oxime in 50 ml of toluene was added 5.0 g of 80% by weight sodium hydride (suspension in oil) and a solution of 6.3 g was added dropwise with stirring.

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Of 2-dimethylaminoethyl chloride in 10 ml of toluene. The mixture was refluxed for 4 hours. After standing overnight, it is quenched with water, the basic product is extracted from the organic layer with dilute hydrochloric acid, and the aqueous layer is basified with aqueous ammonia and the base is isolated by extraction with diethyl ether. Work-up of the extract gave 8.1 g (83%) of the desired oily base. Mass Spectrum, m / z (%): 336 (M @ ⁺ , C @ + H @ + H @ + ClClNgO 0.1), 2 SO (2.2), 199 (0.5), 177 (0.4), 137 (0, 3), 111 (5), 58 (100). Neutralization of the base with hydrogen chloride in a mixture of ethanol and diethyl ether gives the base a crystalline hydrochloride, mp 162-164 ° C (ethanol-diethyl ether-heptane). IR (Nujol): 695, 740, 788, 884.

890 (ar-H); 985, 1043 (= N-O-C); 1475, 1530, 1590, 3 010. 3055 (Ar); 1660 (C = N);

430, 2,508, 2,560, 2,580 (NH +).

The starting material 2,3 ^, -dichlorobenzophsnonoxime, which is a novel substance, is prepared as follows: Mixture

8.3 g of 2,3'-dichlorobenzophenone, 11.5 g of hydroxylamine hydrochloride and 40 ml of pyridine were stirred and refluxed for 48 hours. After cooling, the mixture was poured into water and extracted with diethyl ether. The extract was washed with dilute hydrochloric acid, 5% (w / w) sodium bicarbonate solution, dried and evaporated. The residue is crystallized from a mixture of acetone and heptane; 8.1 g (92%) of the desired oxime are obtained, m.p. 109-112 ° C (chloroform-heptane).

Claims (1)

SUBJECT OF THE INVENTION Basically substituted 2,3'-dichlorodiphanylmethane derivatives of the general formula I a (I) wherein R represents the residue of 4-dimethylamino or methylpiperszino and X represents a radical ICHnebo ^ 2 ^ C »N _F and their salts with pharmaceutically acceptable organic or inorganic acids.