SI20326A - 2-(4-(diphenylmethyl)-1-piperazinyl)-acetic acids and amides thereof - Google Patents

Abstract

New 2-(4-(diphenylmethyl)-1-piperazinyl)-acetic acids, their amides and their salts, processes for the preparation thereof and therapeutic compositions. These compounds have the formula wherein Y= -OH or -NH2; X and X' =H, halogen, alkoxy or trifluoromethyl; m = 1 or 2 and n = 1 or 2. The amides of the 2-(4-diphenylmethyl)-l-piperazinyl)-acetic acids are prepared either by reacting a 1-(diphenylmethyl)-piperazine with an omega-haloacetamide, or by reacting an alkali metal salt of an omega-(4-diphenyl-methyl)-1-piperazinyl)-alkanol with a 2-haloacetamide, or yet by reacting ammonia with a halide or alkyl ester of a 2-(4-(diphenylmethyl)-1-piperazinyl)-acetic acid, whereas the 2-(4-(diphenylmethyl)-1-piperazinyl)-acetic acids are prepared by hydrolysing the corresponding amide or lower alkyl ester. These compounds have in particular an antiallergic, spasmolytic and antihistaminic activity

Description

UCB, S. A. (Belgium)

2- [4- (Diphenylmethyl) -1-piperazinylacetic acid and their amides

The present invention relates to novel 2- [4- (diphenylmethyl) -1-piperazinyl] -acetic acids and their amides, as well as non-toxic, pharmaceutically acceptable salts, as well as to processes for their preparation and the pharmaceutical ingredients containing them.

The subject of the present invention are novel compounds having the following general formula:

CH

(D where Y

X and X 'hydroxyl group or -NH ₂ group, and X' independently represent a hydrogen atom, a halogen atom, a straight or branched chain lower alkoxy radical or a trifluoromethyl radical, m 1 or 2 and n 1 or 2, preferably 2, as well as their non-toxic, pharmaceutically acceptable salts.

The term " lower alkoxy " means that the residues of straight and branched chain aliphatic alcohols have from 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy and the like. The halogen atom is preferably a chlorine or fluorine atom.

The term non-toxic, pharmaceutically acceptable salts is understood to mean, in addition to salts of acids and amides of formula I, with pharmaceutically acceptable acids such as acetic, citric, succinic, ascorbic, hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as pharmaceutically acceptable salts of formula I are metal salts (e.g. sodium or potassium salts), ammonium salts, amine salts and amino acids.

These pharmaceutically acceptable salts can be obtained from compounds of formula I by per se known methods.

The present invention provides the following compounds:

- 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetic acid and its divoric chloride;

- potassium 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate;

- 2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] -acetic acid and its divoric chloride;

- 2- [2- [4 - [(4-fluorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] - acetic acid and its hydrate.

The compounds of formula I have interesting pharmacological properties. They are especially useful as anti-allergic, antihistamine, bronchodilator and antispasmodic agents.

Typically, their seconds have minimal effects on the stimulation or calming of the central nervous system, which are often observed in the case of conventional antihistamines. They show interesting anesthetic and anti-inflammatory properties. They are also effective in cases of cerebral and cardiovascular insufficiency.

In the contributions of H.B, WRIGHT, and D.L. MARTIN (J.med.Chem.ll, (1968), 390-391) addresses the action of 2- [4 - [(4-chlorophenyl) phenylmethyl-1-piperazinyl] acetamide (formula I: Υ = NH2; X - p-Cl; X '= H; but m = 0) as a hypocholesteremic agent, and the results obtained are not encouraging.

According to Belgian patent no. 763, 609 has 2- [4- (diphenylmethyl) -1-piperazinyl] -acetamide (formula I: Υ = NH2; X = X '= H; but m = 0) diuretic effect. The said patent also describes similar acetamides in which the nitrogen atom of the amide group is substituted and which exhibits many other pharmacological properties.

The pharmacological tests we performed showed that the antiallergic, antispasmodic and antihistamine effects of these acetamides and the corresponding acids were less important (see B. Pharmacology).

A. Acquisition procedures

I. The amides of formula I (Υ = -NH2) can be obtained by a number of methods, namely:

1.1. in the reaction of 1- (diphenylmethyl) -piperazine of formula II with omegahaloacetamide of formula III, according to the following equation:

NH + Zf (CH ₂ ) _n -O - / - CH— C,

Jm (ID

NH, (III) in which X, X ', m and n have the same meaning as before and Z is a halogen atom.

This reaction is generally carried out by heating the reaction mixture to within 150 hours in an inert solvent, which is preferably an aliphatic alcohol, an aliphatic ketone, such as methyl ethyl ketone, or an aromatic hydrocarbon such as toluene or xylene. The reaction is carried out in the presence of an acid acceptor such as a tertiary organic base such as triethylamine or an inorganic base such as sodium carbonate.

1.2. in the reaction of the alkali metal salt of omega- [4- (diphenylmethyl) -1-piperazinyl] -alkanol of formula IV with 2-haloacetamide of formula V, according to the following equation:

^ N - ^ (CH _; ) _n -O - ^ - Me + Z-CH 2 - (l) (Y = -NH ₂ )

NH, (IV) (V) in which X, X ', m and n have the same meaning as before, Z is a halogen atom and Me is an alkali metal atom.

The reaction between an alkali metal salt of formula IV and a haloacetamide of formula V is carried out in an inert solvent, for example toluene, xylene or dimethylformamide, at temperatures from 0 ° C to the reflux temperature of the reaction mixture.

The alkali metal salt of formula IV used in this reaction may be formed in situ by reacting the corresponding omega- [4- (diphenylmethyl) -1-piperazinyl] -alkanol with an alkali metal hydroxide, usually sodium hydroxide. The reaction is carried out in an inert solvent such as toluene, xylene or dimethylformamide.

The preparation of alcohols of formula IV (Me = H) is described in U.S. Pat. 2, 899, 436.

1.3. in the reaction of ammonia with the functional derivative of 2- [4- (diphenylmethyl) -1-piperazinyl] acetic acid, that is, with the halide or lower alkyl ester of formula VII, according to the following equation:

+ NH ₃ - * (l) (Y = -NH ₂ ) (VI) in which X, X ', m and n have the same meaning as before, W represents a halogen atom or -OR' radical, with R 'being lower alkyl radical.

For example, the halogen atom may be a chlorine atom, a bromine atom, and an alkyl radical a methyl or ethyl radical.

In case halogen is represented as W, an acid of formula I, wherein Y represents a hydroxyl group, is obtained first by method II described below and then converted into the corresponding halide by well-known methods for the preparation of compounds of this type. The acid halide thus obtained is subsequently reacted with ammonia in an inert solvent.

In the case where W is represented by an -OR radical, we first obtain an ester of formula VII by one of the methods described below. Subsequently, this ester is reacted with ammonia in an inert solvent at a temperature from 0 ° C to room temperature. This reaction may take place in the presence of a catalyst such as sodium methoxide.

II. The acids of formula I in which Y represents a hydroxyl group can be obtained by hydrolysis of the 2- [4- (diphenylmethyl) -1-piperazinyl] -acetic acid functional derivative in a basic medium. An amide or lower alkyl ester of the formula is formed:

X '

(Vlil) in which X, X ', m and n have the same meaning as before, Y' represents a -NH2 group or -OR 'group in which R' is a lower alkyl radical, such as a methyl or ethyl radical.

This hydrolysis is carried out using an inorganic base such as sodium or potassium hydroxide in an aqueous or aqueous alcoholic medium, for example in aqueous methanol, ethanol or the like, at a temperature of from 20 ° C to a reflux temperature of the reaction mixture.

The amides of formula VIII in which the Υ ′ -NH2 group can be obtained by one of the methods described above 1.1 to 1.3.

Esters of formula VII in which W is -OR 'group and esters of formula VIII in which Y' -OR 'group can be obtained by different methods. For example:

a) in the reaction of 1- (diphenylmethyl) -piperazine of formula II with lower alkyl omega-haloacetate of formula IX, according to the following equation:

(VII) (w = -OR ') or (VIII) (Y' = - OR ') in which X, X', m and n have the same meaning as above, R 'is a lower alkyl radical and Z is a halogen atom. Thus, R 'may for example be a methyl or ethyl radical and Z is a chlorine or bromine atom.

This reaction is generally carried out by heating the reaction mixture to 80 to 150 ° C for several hours in an inert solvent such as benzene, toluene or xylene, in the presence of an acid acceptor such as a tertiary organic base such as triethylamine or an inorganic base such as sodium carbonate.

b) in the reaction of the alkali metal salt of omega- [4- (diphenylmethyl) -1-piperazinyl] -alkanol of formula IV with the lower alkyl ester of 2-haloacetic acid of formula X, in accordance with the following equation:

(VII) (W = -OR ·) or (VIII) (Y '= -OR') in which R ', X, X', m and n have the same meaning as before and Me is an alkali metal atom.

The reaction between an alkali metal salt of formula IV and a halogenated ester of formula X is carried out in an inert solvent at a temperature from 0 ° C to the reflux temperature of the reaction mixture.

In order to illustrate the present invention, the following examples are given:

Example 1. Preparation of amides of formula I (Y = -NH?)

1.1. 2- (2- [4- (diphenylmethyl) -1-piperazinyl] ethoxyl-acetamide divoric chloride, (method II) A mixture of 37.8 g (0.15 mol) of 1- (diphenylmethyl) -piperazine, 27.5 g (0.2 mol) of 2- (2-chloroethoxy) ) -acetamide and 26.5 g of anhydrous sodium carbonate in 120 ml of xylene are heated to 90 ° C to 120 ° C for 4 hours. Then 120 ml of benzene was added to the reaction mixture, the precipitate formed was filtered off and the organic phase was extracted with dilute hydrochloric acid (30 ml of concentrated hydrochloric acid and 100 ml of water). 40 ml of concentrated aqueous sodium hydroxide solution are added followed by extraction with benzene. The benzene solution was washed with water, dried on anhydrous sodium carbonate and the benzene evaporated to dryness. The evaporation residue was crushed with diethyl ether and allowed to crystallize. 2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] acetamide is obtained in 73% yield; the melting point is 119-120 ° C. Divodic chloride prepared in ethanol melts at 230 ° C, decomposing.

Analysis for C21H27N3O2.2HCI in%

Calculated: C 59.15 H 6.85 N 9.85 Cl '16.63

Found: 58.99 6.80 9.79 16.46

The following compounds are also obtained by the method described above:

- 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetamide;

the yield is 47%; melting point 111-112 ° C after recrystallization from ethanol.

Analysis for C21H26CIN3O2 in%

Calculated: C 65.02 H 6.71 N 10.83 Cl 9.14

Found: 64.59 7.00 10.82 9.54

- 2- [2- [2 - [(4-diphenylmethyl] -1-piperazinyl] ethoxy] ethoxy] -acetamide;

the product obtained in the raw state in practically quantitative yield; it can be used to obtain the appropriate acids without further purification (see Example 2.2).

- 2- [2- [2- [4 - [(4-chlorophenyl] phenylmethyl] -1-piperazinyl] ethoxy] ethoxy] ethoxy-acetamide; the product obtained in the raw state in practically quantitative yield; to obtain the corresponding acids can be used without further purification (see Example 2.2).

- 2- [2- [4 - [(4-fluorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetamide;

the yield is 54.7%; melting point 105-107 ° C, after recrystallization from acetonitrile.

Analysis for C21H26FN3O2 in%

Calculated: C 67.90 H 7.09 N 11.31

Found: 68.3 7.40 11.21

- 2- [2- [4 - [(2-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetamide;

the yield is 57%; melting point is 129-130 ° C after recrystallization from benzene.

Analysis for C21H26CIN3O2 in%

C 65.0 H 6.75 N 10.8

Calculated:

Obtained:

66.3

7.0

10.6

Cl 9.4

9.7

Divodic chloride of this amide was also prepared; contains some monohydrogen chloride. The melting point was 218-220 ° C after recrystallization from isopropyl alcohol.

Analysis for C ₂ iH2 ₆ C1N ₃ O2.2HC1 in%

Calculated: C 54.72 H 6.12 N 9.11 Cl '15.38 Cl ^total 23.08

Found: 55.69 6.52 9.20 11.86 20.27

- 2- [2- [4 - [(4-methoxyphenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetamide divoric chloride; the efficiency is 20%; the melting point was 175-176 ° C after recrystallization from acetonitrile.

Analysis for C22H29N3O3.2HCI in%

Calculated: C 57.8 H 6.8 N 9.2 Cl '15.5

Found: 57.8 7.2 9.5 15.9

- 2- [2- [2- [4 - [[4- (trifluoromethyl) phenyl] phenylmethyl] -1-piperazinyl] -ethoxy] ethoxy] acetamide;

- 2- [2- [2- [4- [bis (4-fluorophenyl) methyl] -1-piperazinyl] -ethoxyethoxy] -acetamide;

1.2.2-r2-yl-4- (diphenylmethyl) -1-piperazinylethoxyethoxy-acetamide divoric chloride.

(method 1.2).

24.2 g (0.53 moles) of sodium hydride were added to a solution of 172.9 g (0.508 moles) of 2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] -ethanol in 180 ml of dimethylformamide. After the addition is complete, the reaction mixture is warmed to 40 ° C for 30 minutes. After cooling, 60 g (0.624 mol) of 2-chloroacetamide are added over a 10 minute time interval. The temperature of the reaction mixture was raised to 40 ° C and maintained at this temperature for a further minute. After cooling, 30 ml of water are added followed by evaporation to dryness. The evaporation residue was suspended in 1 liter of water and the resulting suspension was extracted with benzene.

The organic phase is dried on anhydrous potassium carbonate and then evaporated. After evaporation, the residue was purified by chromatography on a silica gel column (mobile phase: chloroform ethanol 95: 5 v / v). The resulting product was dissolved in 45 ml of ethanol, to which 24 ml of 5N ethanol hydrochloric acid was added. 19 g of 2- [2- [2- [4- (diphenylmethyl) -1piperazinyl] ethoxy] ethoxy] -acetamide of divoric chloride are obtained in a yield of 8%; melting point 196-197 ° C after recrystallization from acetonitrile.

Analysis for C23H31N3O3.2HCI in%

Calculated: C 58.72 H 7.07 N 8.93 Cf 15.07

Found: 58.29 6.83 8.44 15.01

The following compound is prepared by the method described above:

- 2- [2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] ethoxy] -acetamide divoric chloride; the product recrystallizes from isopropyl alcohol with one solvent molecule. The yield is 11%; melting point is 100-102 ° C.

Analysis for C23H30CIN3O3.C3H7OH.2HCI in%

Calculated: C 55.27 H 7.16 N 7.43 Cf 12.55 Cl ^total 18.22

Found: 53.10 6.93 7.18 12.56 18.79

1.3. 2- [2-1,4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinylethoxyacetamide. (method 1.3).

2.3 g (0.0057 mol) of methyl 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetate were dissolved in 100 ml of anhydrous methanol. This solution was cooled to a temperature of 5 to 10 ° C, and then was bubbled with ammonia for 20 hours. The solvent was evaporated in vacuo, the residue was triturated with diethyl ether and allowed to crystallize. 1.2 g of 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetamide are obtained; the yield is 54%; melting point is 109-110 ° C.

Analysis for C21H26CIN3O2 in%

Calculated: C 65.02 H 6.71 N 10.83 Cl 9.54

Found: 65.13 6.59 10.95 9.14

Methyl 2- [2- [4 - ((4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetate, which is used as starting material, is obtained as follows:

A mixture of 87 g (0.30 mol) of l - [(4-chlorophenyl) phenylmethyl] -piperazine, 58 g (0.38 mol) of methyl (2-chloroethoxy) -acetate and 40.3 g (0.38 mol) of sodium carbonate in 500 ml of anhydrous xylene for 40 hours heated under reflux, with good stirring. The reaction mixture was then cooled and filtered, the solids washed with benzene and discarded. The filtrate was evaporated to dryness and the residue after evaporation was purified by chromatography on a silica gel column (mobile phase: chloroform: methanol 97: 3 v / v). This gives 34 g of the desired methyl ester (yield 27.8%).

Analysis for C22H27CIN2O3 in%

Calculated: C 65.60

Found: 63.87

H 6.70 6.55

N, 6.95 6.59

The following two salts of this ester were prepared: - Divine chloride; mp 23-125 ° C.

Analysis for C ₂ 2H ₂ 7C1N ₂ O3.2HC1 in%

Calculated: C 55.50 H 6.10 N 5.89

Found: 55.20 6.23 5.65

Cl '14.92 13.2 dimaleate; mp 28-130 ° C.

Analysis for C3oH35C1N ₂ Oh%

Calculated: C 56.70 H 5.51 N 4.41

Found: 57.01 5.22 4.45

Example 2. Acid Formation of Formula I (Y = OH)

2.1. 2-R2- [4-r (4-chlorophenyl) phenylmethyl-1-piperazinyl] ethoxyl-acetic acid (method II).

Dissolve 16.8 g (0.0417 mol) of methyl 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetate (obtained as described above in Example 1.3) in 65 ml of absolute ethanol. 42 ml of 1 N ethanolic potassium hydroxide solution were added to the reaction mixture and refluxed for 4 hours. It is then cooled and the precipitate is removed by filtration after washing with diethyl ether. The filtrate was evaporated to dryness and the residue after evaporation was ground with diethyl ether and allowed to crystallize. 10.5 g of hygroscopic potassium 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] acetate are obtained. The yield is 59%; the melting point is 161 -163 ° C.

Analysis for C21H24CIN2O3K in%

Calculated: C 59.0 H 5.63 N 6.56

Found: 57.97 5.77 6.48

Dissolve the potassium salt in 100 ml of water and adjust the pH to 10 with hydrochloric acid. The pH of the solution is 4. The solution is extracted with chloroform and the organic phase is dried over anhydrous magnesium sulphate and then evaporated to dryness. After evaporation, the residue was ground with diethyl ether and allowed to crystallize. 7.5 g of 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetic acid are obtained. The yield is 81%; melting point is 110-115 ° C.

Analysis for C21H25CIN2O3 in%

Calculated: C 64.80 H 6.48 N 7.20

Found: 62.3 6.48 6.92

The corresponding divoric chloride obtained in toluene in 80% yield has a melting point at 225 ° C.

Analysis for C ₂ iH _{2 5} C1N ₂ O3.2HC1 in%

Calculated: C 54.60 H 5.85 N 6.07

Found: 54.42 5.60 6.01

CI '15.38 Cl ^common 23.07 15.29 23.08

2.2. 2- (2-14- (diphenylmethyl) -1-piperazinillethoxy acetic acid, (method II)

A mixture of 19g (0.054 mol) of 2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] -acetamide (obtained as described in Example 1.1) in 200 ml ethanol and 27 ml 4N ethanol sodium hydroxide solution under reflux for 3 hours. The pH of the reaction mixture was adjusted with 29.7 ml of 3.61 N hydrochloric acid to pH = 6.3, and then the ethanol was evaporated in vacuo. The precipitate is filtered off. Evaporation of the solvent gave 17.4 g of crude 2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] -acetic acid. The yield is 91%; melting point is 100 ° C.

Analysis for C21H26N2O3 in%

Calculated: C 71.1 H 7.39 N 7.90

Found: 69.1 7.07 7.12

The corresponding divoric chloride has a melting point at 217-218 ° C, after crystallization from isopropyl alcohol.

Analysis for C21H26N2O3.2HCI in%

Calculated: C 59.02 H 6.60 N 6.55 Cl '16.59

Found: 58.83 6.94 6.33 15.90

According to the method described above, the following compounds are obtained:

- 2- [2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] ethoxy] -acetic acid divoric chloride; the yield is 57%; melting point 85 ° C (lyophilized, decomposition).

Analysis for C23H30N2O4.2HCI in%

Calculated: C 58.60 H 6.84 N 5.94 Cl '15.04

Found: 56.82 7.82 6.02 16.76

- 2- [2- [2- [4 - [(4-chlorophenyl] phenylmethyl] -1-piperazinyl] ethoxy] ethoxy acetic acid divoric chloride; yield 82%; melting point 112 ° C (lyophilized).

Analysis for C23H29CIN2O4.2HCI in% Calculated: C 54.6 H 5.78 N, 5.54 Cl ^joint 21.03 Found: 52.48 6.10 5.72 22.19

- 2- [2- [4 - [(4-fluorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetic acid hydrate; the efficiency is 100%; melting point is not sharp (from 70 ° C onwards the product gradually softens).

Analysis for C21H25FN2O3.3 / 2H2O in%

Calculated: C 63.1 H 7.0 N 7.0

Found: 63.7 7.6 6.9

- 2- [2- [4 - [(4-methoxyphenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetic acid divoric chloride; the efficiency is 35%; melting point 214-217 ° C (acetonitrile; decomposition).

Analysis for C22H28N2O4.2HCI in%

Calculated: C 57.7 H 6.6 N 6.1 Cl '15.5

Found: 53.2 6.5 6.0 17.5

2- [2- [4 - [(2-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetic acid; the yield is 50%; mp 96-100 ° C (lyophilized).

Analysis for C21H25CIN2O3 in%

Calculated:

Obtained:

C 64.8 62.3

H 6.5 6.9

N 7.2 6.9

Cl 9.1 10.2

- 2- [2- [2- [4 - [[4- (trifluoromethyl) phenyl] phenylmethyl] -1-piperazinyl] ethoxy] ethoxy] -acetic acid.

- 2- [2- [2- [4- [bis (4-fluorophenyl) methyl] -1-piperazinyl] ethoxy] ethoxy] -acetic acid.

B. Pharmacology

According to the present invention, the following compounds have been subjected to pharmacological testing and yielded the results described below:

- 2- [2- [4- (diphenylmethyl) -1-piperazinylethoxy-acetamide divoric chloride (Compound A obtained in Example 1.1);

- 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetamide (compound B obtained in Examples 1.1 and 1.3);

- 2- [2- [4 - [(4-fluorophenyl] phenylmethyl] -1-piperazinyl] ethoxy] -acetamide (compound C obtained in Example 1.1);

- 2- [2- [4 - [(2-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetamide Divoric chloride (Compound D obtained in Example 1.1);

- 2- [2- [4 - [(4-methoxyphenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetamide Divoric chloride (compound E obtained in Example 1.1);

- 2- [2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] ethoxy] -acetamide divoric chloride (compound F obtained in Example 1.2);

- 2- [2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] ethoxy] acetamide divoric chloride (compound G obtained in Example 1.2);

- Potassium 2- [2- [4- [(4-chlorophenyl) phenylmethyl] -1-piperazinyl ethoxy] -acetate (compound H obtained in Example 2.1);

- 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetic acid (Compound I obtained in Example 2.1);

- 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetic acid divoric chloride (compound J obtained in Example 2.1);

- 2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] -acetic acid (Compound K obtained in Example 2.2);

- 2- [2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] ethoxy] -acetic acid divoric chloride (compound L obtained in Example 2.2);

- 2- [2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] ethoxy] -acetic acid divoric chloride (compound M obtained in Example 2.2)

- 2- [2- [4 - [(4-fluorophenyl) phenylmethyl] -1-piperazinyl] ethoxy] -acetic acid hydrate (Compound N obtained in Example 2.2);

The following compounds, which are not otherwise the subject of the present invention (general formula I in which m = 0) have also been tested pharmacologically:

- 2- [4- (diphenylmethyl) -1-piperazinyl] acetamide (compound 1, obtained by the method described in Belgian patent No. 763,609); mp 204 ° C.

• 2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] acetamide (compound 2; see HB WRIGHT and DL MARTIN, loc. Cit.) Also obtained by the method described in Belgian Patent Nos. 763, 609 ); melting point 145 ° C.

- 2- [4- (diphenylmethyl) -1-piperazinyl] -acetic acid (compound 3, obtained by method II, example 2.2); melting point 176 ° C.

- -2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] -acetic acid (compound 4, also obtained by method II, example 2.2); the melting point is 106-108 ° C.

1. Anti-allergic action

This function has been evaluated in rats on the basis of the passive anaphylaxis test (PCA) (see J. GOOSE and AMJN BLAIR, Immunology, J_6, (1969), 749-760; and U. MARTIN and D. ROEMER, Arzneimittel-Forshung, 28 , (5), (1978), 770-782).

We use female rats whose hips are partially shaved. In the shaved area, 0.05 ml of the diluted IGE anti-protein serum is injected intradermally intradermally so that a distinct area of about 100 mm ² occurs at the injection site during the PCA test.

hours after injection, 0.25 ml of the allergen solution containing the colored agent (5 mg of albumin and 6 mg of Evans Blue dye in 0.25 ml of 0.9% aqueous sodium chloride solution) is administered intravenously. At the site of intradermal injection, a distinct blue stain is observed and measured.

In order to test the performance of the compounds of the present invention, the process was conducted in the same manner but:

- the test solution was administered orally 72 hours after serum injection;

minutes after this administration, 0.25 ml of the allergen solution was injected intravenously;

- 30 minutes after the allergen was applied, the area of the blue stain was measured.

Table I lists the immunological doses (ID 50 in μηιοί / kg) that reduce the area of the stain area by 50% by the median number of animals included in the test.

From this table, it can be seen that the active compounds of the present invention are active. Sodium cromoglycate, which is well known for its anti-asthmatic activity when administered intravenously, is inactive. Compounds 1, 2, 3 and 4 (not the subject of the present invention; m = 0) have proven to be less effective.

Table 1

Tested snout ID 50 per axis in nmol / kg Sodium chromoglycate Inactive B 36.5 C 18.9 F 10.6 N 10.2 1 > 320 2 > 320 3 > 320

> 320

2, Antispasmodic and antihistamine action

This activity was evaluated on guinea pigs by the method of H. KONZETT and R. ROESSLER (Naunyn-Schmiedebergs Arch.exp.Path.Pharmakol. 195, (1940), 71-74) and compared with that of theophylline.

Anesthetized and poisoned guinea pigs underwent artificial respiration. Endotracheal pressure was recorded. By sequential and escalating intravenous injection of serotonin or. histamine was caused by recurrent bronchial spasms. Test compounds were also administered intravenously. The following Table II shows the doses of compounds (ID 50 in pmol / kg) that retain triggered bronchial spasms in 50% of the average number of animals:

Table II Tested compounds Serotonin Histamine theophylline 10 10 A 0.78 0.23 B 0.88 0.45 C 0.94 0.71 D 1.1 0.63 E 10.0 0.67 F 0.32 0.25 Mr 0.66 0.14 H 7.0 0.23 I 9.44 0.205 J 7.3 0.20 K 9.5 0.093 L 5.69 0.39 M 10.0 0.79 N 2.1 0.08 1 77 2.1 2 11 3.1 3 > 32 5 4 > 32 7.8

The compounds of the present invention do not act cholinergically. This table shows that they work extremely well for serotonin or bronchial spasms. histamine, with histamine being more selective. In contrast to these compounds, compounds 1, 2, 3 and 4, which are not the subject of the invention (m = 0), have significantly lower activity.

Furthermore, this test showed that some of the single-dose compounds had long-lasting antihistamine activity. Thus, for example, compound J, which was administered intravenously in the case of the guinea pig at a dose of 1 pmol / kg, remains 100% active after 5 hours.

3. General mouse behavior (Irwin test j

This behavior is studied using the Irvvin test (see S. IRWIN, 'General philosophy and methodology of screening: a multidimensional approach'; Gordon Research Conference on Medical Chemistry, August 3-7, 1959, at Colby Junior College, New London).

Increasing doses of test compounds are administered intraperitoneally to a group of three small mice (body weight 18 to 22 g). We observe the general behavior of animals according to known criteria.

The following reference compounds were used:

- hydroxyzine - 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl] -ethoxy] -ethanol.

- Oxazepam = 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one.

Table III shows the doses (in mg / kg) that trigger the first manifestation of animal calming:

Table III

a styrene compound Calming dose in mg / kg A > 255 B 38.7 C 115 D > 460 E 136 F 94 Mr 34 H 46.2 J 138 K 106 L 141 M 505 N 372 hydroxyzine 27 oxazepam 2.6

The table shows that the compounds of the present invention have little sedative effect compared to the reference compounds.

Furthermore, the compounds of the present invention exhibit very low toxicity.

Table IV lists the lethal doses in mg / kg (two animals out of three) for the compounds of this invention for their interperitinal use in mice:

Table IV

Tested compound

A

B

C

D

E

F

Mr

H

I

J

K

L

M

N

Flying dose (2/3) in mg / kg

255

232

386

460

456

282

339

277

116

138

708

942

505

372

Comparing Tables III and IV (sedative and lethal doses) we can see that in the case of some compounds, the sedative effect occurs at doses close to the lethal dose.

4. DL 50 flying dose

The low toxicity of the compounds of the present invention was confirmed by the toxicity measurements DL 50. Thus, for compound J in Wistar DL 50 rats, 70 703 mg / kg for male subjects and 865 mg / kg for female specimens.

In mice, DL 50 for the same compound is 600 mg / kg (male subjects). 752 mg / kg (female specimens).

5. Posology (eng, posologv) and application

The pharmaceutical ingredients contained in the compounds of the present invention may be administered orally, parenterally or rectally. They can also be used for nasal inhalation (aerosols) or in the form of ointments or creams. The pharmaceutical ingredients that can be used orally may be in solid or liquid form, for example, in the form of uncoated or coated tablets, pills, dragees, gelatin capsules, solutions, syrups and the like. Ingredients that may be used for parenteral use may be any of the ingredients known for such use, for example, aqueous and oily solutions, suspensions or emulsions. For rectal administration, ingredients containing the compounds of the present invention are generally used in the form of suppositories.

Pharmaceutical forms such as injectable solutions, spray suspensions, tablets, drops, suppositories and the like are prepared by conventional pharmaceutical methods. The compounds of the present invention are mixed with solid or liquid, non-toxic and pharmaceutically acceptable carriers and, if possible, also mixed with a dispersing agent, a disintegrating agent, a stabilizing agent and the like. Where appropriate, preservatives, sweeteners, colorants and the like can also be added.

The percentage of active compounds in the pharmaceutical ingredients may vary within a wide range depending on the patient and the route of administration, and especially on the frequency of use.

Depending on the posology, the percentage of active compounds in the pharmaceutical ingredients may vary within a wide range of echo units, for example, from 0.5 to 250 mg of the active compound.

As an example of an ingredient containing the compounds of the present invention, the following gelatin capsule composition is provided for use per axis:

compound J 100 mg lactose 67 mg magnesium stearate 1 mg silica (aerosil) 2 mg

DjZjure Marrif dipl. and with.

Claims (9)

PATENT APPLICATIONS 1. 2- [4- (Diphenylmethyl) -1-piperazinyl] -acetic acid or its amide of the formula X ' CH wherein Y The Xin X 'hydroxyl group or -NH ₂ group represents separately a hydrogen atom, a halogen, a straight or branched chain of lower alkoxy radicals or a trifluoromethyl radical, 1 or 2, and 1 or 2, or non-toxic, pharmaceutically acceptable salts thereof. A compound according to claim 1, namely 2- [2- [4 - [(4-chlorophenyl) -phenylmethyl] -1piperazinyl] ethoxy] -acetic acid or its divoric chloride. The compound of claim 1, namely potassium 2- [2- [4 - [(4-chlorophenyl) phenylmethyl] -1piperazinyl] ethoxy] -acetate. The compound of claim 1, namely 2- [2- [4- (diphenylmethyl) -1-piperazinyl] ethoxy] acetic acid or its divoric chloride. The compound of claim 1, namely 2- [2- [4 - [(4-fluorophenyl) -phenylmethyl] -1piperazinyl] ethoxy] -acetic acid or a hydrate thereof. 6. A process for the preparation of 2- [4- (diphenylmethyl) -1-piperazinyl] -acetic acid amide of the formula I is given in claim 1, wherein Y is -NH ₂ group, based on the reaction of 1- (diphenylmethyl) -piperazine of formula II X 'where X and X' have the same meaning as in claim 1, with omegahaloacetamide of formula r M Z - / - (CH ₂ ) _n -O-7-ch ₂ - c (III) wherein m and n have the same meaning as in claim 1 and Z is a halogen atom; the reaction takes place in an inert solvent and in the presence of an acid acceptor. 7. A process for the preparation of 2- [4- (diphenylmethyl) -1-piperazinyl] -acetic acid amide of the formula I is given in claim 1, wherein Y is -NH ₂ , characterized in that it is based on the reaction of an alkali metal salt of omega- [4- (diphenylmethyl) -1-piperazinyl] -alkanol of the formula -7- (CH ₂ ) _n - 0-7 - Me (iv) in which X, X ', m and n have the same meaning as in claim 1 and Me is an alkali metal atom with 2-haloacetamide of formula Z-CH-C (v) nh ₂ in which Z is a halogen atom; the reaction takes place in an inert solvent. 8. A process for the preparation of 2- [4- (diphenylmethyl) -1-piperazinyl] -acetic acid amide of the formula I is given in claim 1, wherein Y is -NH ₂ , characterized in that it is based on the reaction of ammonia with the functional derivative of 2- [4- (diphenylmethyl) -1-piperazinyl] -acetic acid of the formula wherein X, X ', m and n have the same meaning as in claim 1, W is a halogen atom or OR' group, and R 'is a lower alkyl radical, in an inert solvent. A process for the preparation of 2- [4- (diphenylmethyl) -1-piperazinyl] -acetic acid of the formula I as set forth in claim 1, wherein Y is a hydroxyl group, characterized in that it is based on the hydrolysis reaction of the functional derivative 2- [ 4- (Diphenylmethyl) -1-piperazinyl] -acetic acid of formula CH O ⁴ (ch ₇ ) 2'n Oh CH, - C, (Vlil) X 'where X, X', m and n have the same meaning as in claim 1, Y 'is a -NH ₂ group or OR' group, and R 'is a lower alkyl radical, with an inorganic base in aqueous or water-alcoholic medium. 9. A pharmaceutical ingredient comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable solid or liquid diluent or carrier.