GB2131024A - Therapeutically useful alkylbenzylidene derivatives - Google Patents

Abstract

Novel benzylidene derivatives of the general formula: <IMAGE> wherein n represents an integer from 1 to 12, R1 is alkyl or alkenyl radical having 2 to 6 carbon atoms, R2 represents an amino radical, a hydroxy radical, or a group -OM in which M represents an alkali metal or alkaline earth metal, and X1, X2 and X3 each represent, independently of one another, a hydrogen atom, the methoxy radical or alkyl radical having 1 to 4 carbon atoms, are useful as antidepressants, anticonvulsants, ulcer inhibitors and gastric secretion inhibitors and also as anxiolytic, analgesic and anti-inflammatory agents.

Description

SPECIFICATION New therapeutically useful alkylbenzylidene derivatives The present invention relates to new therapeutically useful alkylbenzylidene derivatives, to a process for their preparation and their application in therapy such as pharmaceutical compositions containing them.

The alkylbenzylidene derivatives of the present invention are those compounds of the general formula:

wherein n represents an integer from 1 to 12 (preferably 1 to 4), R1 represents a straight- or branchedchain alkyl or alkenyl radical having 2 to 6 carbon atoms, R2 represents an amino radical (-NH2), a hydroxy radical (-OH) or a group -OM in which M represents an alkali metal, e.g. sodium, or alkaline earth metal, e.g. calcium or magnesium, and Xr, X2 and X3 each represent, independently of one another, a hydrogen atom, a halogen atom, the methoxy radical or a straight- or branched-chain alkyl radical having 1 to 4 carbon atoms.

The preferred compounds of the invention are those of the general formula:

(wherein the various symbols are as hereinbefore defined), and more particularly those such compounds wherein X1 represents a chlorine atom or the methyl radical, X2 represents a chlorine atom or the methyl radical, and X3 represents a hydrogen atom. Amongst these the particularly preferred compounds are those wherein n represents 3 and R1 represents an ethyl, n-propyl, n-butyl or n-hexyl radical. Of outstanding importance are 4-[(5-chloro-2-hydroxy-3-npropylphenyl)(4-chlorophenyl)methylenej- aminobutanoic acid and 4-[(5-chloro-2-hydroxy-3-ethylphenyl)(4-chlorophenyl)methylene]- aminobutanoic acid, and their alkali metal and alkaline earth metal salts and their amides.

According to a feature of the present invention, the alkylbenzylidene derivatives of general formula I are prepared by the process which comprises reacting a benzophenone of the general formula:

(wherein the various symbols are as hereinbefore defined) with a compound of the general formula: H2N(cH2)nCOR2 (lV) (wherein n and R2 are as hereinbefore defined), optionally in the form of an acid addition salt such as the hydrochloride, at a temperature of 200 to 1 200C in an organic solvent medium, such as methanol, ethanol or a methanol/toluene mixture, in the presence of a base, for example an alkali metal alkoxide such as sodium methoxide or ethoxide.

The alkylbenzylidene derivatives of general formula I wherein R2 represents the amino radical can also be prepared by reacting a corresponding compound of general formula I wherein R2 represents the hydroxy radical with carbonyldiimidazole and ammonia.

The compounds of general formula I wherein R2 represents a group -OM (M being as hereinbefore defined) can be obtained from corresponding compounds wherein R2 represents the hydroxy radical by methods known per se, viz. methods heretofore used or described in the chemical literature for preparing alkali metal or alkaline earth metal salts of carboxylic acids.

The benzophenone starting materials of general formula Ill are new and can be prepared, for example, according to the following reaction scheme:

wherein the various symbols are as hereinbefore defined.

The Examples which follow illustrate the preparation of alkylbenzylidene derivatives of the present invention by the hereinbefore described process. The analyses and the IR and NMR spectra confirm the structures of the compounds obtained.

EXAMPLE 1 4-[(5-Chloro-2-hyd roxy-3-n-propylphenyl)-(4-chlorophenyl)methylene]-aminobutana mide.

[X1=5-CI, X2=4-CI, X3=H, n=3, R,=n-C3H7, R2=NH2] 1. (5-Chloro-2-hydroxy-3-n-propylphenyl)-(4-chlorophenyl)-methanone.

17.15 ml (0.123 mol) oftriethylamine are added to a stirred solution of 21 g (0.123 mol) of the phenol of the formula:

in 1.3 litres of methylene chloride and the mixture is heated to the reflux temperature. Heating is stopped and a solution of 21.54 g (0.123 mol) of the acid chloride of the formula:

in 100 ml of methylene chloride is introduced slowly into the solution so as to maintain the reflux. The mixture is then heated under reflux for 8 hours. The products are left in contact with one another overnight. 500 ml of cold water are then added to the solution. The organic phase is decanted and washed once with 250 ml of a saturated solution of sodium bicarbonate and once with 250 ml of water.

The organic phase is dried over MgSO4 and filtered and the filtrate is evaporated to dryness. This gives an oil which crystallises on trituration in 120 ml of petroleum ether.

The crystals are filtered off, drained and redissolved in 300 ml of boiling petroleum ether. The solution is treated with 2 g of vegetable charcoal for 1 5 minutes, with stirring, the mixture is filtered hot and the filtrate is concentrated to a volume of about 1 50 ml. The resulting ester crystallises on cooling.

It is filtered off, drained and dried in a desiccator.

Melting point = 49--500C.

29.7 g (0.096 mol) of 4-chloro-2-propylphenyl 4-chlorobenzoate (obtained as described above) are heated to 1000C under a well-ventilated hood, with stirring, and 29.7 g (0.223 mol) of aluminium chloride are added in portions over a period of 10 minutes. The reaction medium is then heated in an oil bath to 1 600C, still with stirring, and left for 1 5 minutes at this temperature before being allowed to cool to 500C. It is then cooled with solid carbon dioxide for 1 hour and the solid obtained is crushed and finely ground in a mortar. The complex, in powder form, is then hydrolysed by pouring it gradually into a vigorously stirred mixture of 1 litre of water, 500 g of ice and 300 ml of concentrated hydrochloric acid.

Extraction is carried out with a total of 3 litres of methylene chloride, the organic layer is washed with 500 ml of water, decanted, dried over MgSO4 and filtered and the filtrate is concentrated to a volume of about one hundred ml. The crude product is then purified by passage through a column containing 700 g of silica, elution being carried out with 3 litres of methylene chloride. The fractions containing the product are dried over MgSO4 and filtered and the filtrate is evaporated to dryness. The oil obtained crystallises from 1 50 ml of petroleum ether. The crystals are filtered off on a frit, drained and dried in a desiccator.

Melting point = 55-560C.

2.4-[(5-Chloro-2-hydroxy-3-n-propylphenyl)-(4-chlorophenylmethylene]-aminobutanamide.

A mixture of 6.2 g (0.020 mol) of the previously obtained ketone, 3.05 g (0.022 mol) of 4aminobutanamide hydrochloride and 1.25 g (0.22 mol) of sodium methoxide in 600 ml of methanol is evaporated to dryness (bath at 1000C). 600 ml of ethanol are then introduced into the round-bottomed flask and the mixture is evaporated to dryness under the same conditions. A further 600 ml of ethanol are added and evaporated off, under reduced pressure at the end of the evaporation. The residue is dissolved in 300 ml of methylene chloride and washed with 100 ml of water. The organic phase is decanted, dried over MgSO4 and filtered and the filtrate is evaporated to dryness under reduced pressure. The solid obtained is dissolved in 1 5 ml of hot ethyl acetate. About 100 ml of diethyl ether are introduced into the solution (until a slight turbidity appears). The amide product (identified by name above) crystallises on cooling. The crystals are filtered off on a frit, washed with 20 ml of diethyl ether, drained and dried in a heated desiccator at 600 C.

Melting point = 130-131 OC.

EXAMPLE 2 4-[(5-Chloro-2-hydroxy-3-ethylphenyl)-(4-chlorophenyl)methylene]-aminobutanoic acid and its sodium salt.

[X,=5-CI, X2=4-CI, X3=H, n=3, R1=C2H5, R2=OH and ONa] 1. (5-Chloro-2-hydroxy-3-ethylphenyl)-(4-chlorophenyl)-methanone.

By following the same procedure as in Example 1.1. but replacing the 4-chloro-2-n-propylphenol by 4-chloro-2-ethylphenol, 4-chloro-2-ethylbenzyl 4-chlorobenzoate is obtained, which is reacted with aluminium chloride under the same conditions. The resulting benzophenone melts at 47--495C.

2. 4-[(5-Chloro-2-hydroxy-3-ethylphenyl)-(4-chlorophenyl)-methylenej-aminobutanoic acid and its sodium salt.

9 g (3 x 10-2 mol) of the previously obtained benzophenone, 350 ml of methanol, 3.23 g (3.1 x 10-2 mol) of gabamide (viz. y-amino-butyric acid; abbreviated to GABA) and 1.72 g (3 x 10-2 mol) of sodium methoxide are introduced into a 1 litre round-bottomed flask. The mixture is heated under reflux for 4 hours and a further 1.6 g (1.5 x 10-2 mol) of GABA and 0.85 g (1.5 x 10-2 mol) of sodium methoxide are added.

The mixture is heated under reflux for a further 4 hours and evaporated to dryness, the residue is taken up in 2.5 litres of water and the mixture is acidified to pH 4 by adding citric acid. Extraction is carried out with 2 x 350 ml of methylene chloride, the organic phases are combined, washed with 400 ml of water, dried over Na2SO4 and filtered and the filtrate is evaporated to dryness.

The residue is carried onto a frit with petroleum ether, drained and dried in a vacuum desiccator.

The acid product is recrystallised from diisopropyl either.

Melting point= 131-1320C.

1 5.7 ml of a 0.748N solution of sodium methoxide are added to a solution of 4.5 g of the acid in 100 ml of methanol. The methanol is evaporated off at 800C, 100 ml of diethyl ether are then added and evaporated off and the sodium salt is carried onto a frit with diethyl ether, drained and dried in a vacuum desiccator.

Melting point of sodium salt > 2500C.

EXAMPLE 3 4-[(5-ChIoro-2-hydroxy-3-tert.-butylphenyl)-(4-chIorophenyl)methylenejaminobutanoic acid and its sodium salt.

[X1=5-CI, X2=4-CI, X3=H, n=3, R1=t-C4Hg, R2=OH and ONa] 1. (5-Chloro-2-hydroxy-3-tert.-butylphenyl)-(4-chlorophenyl)-methanone.

1.1. A solution of 56 g (0.32 mol) of p-chlorobenzoyl chloride in 200 ml of diethyl ether is added dropwise to a solution of 57 g (0.309 mol) of 4-chloro-2-tert.-butylphenol, 32.3 g (0.32 mol) of triethylamine and 3.7 g (0.03 mol) of 4-dimethylaminopyridine in 800 ml of diethyl ether. After the mixture has been stirred for 6 hours at ambient temperature and left to stand overnight, 500 ml of water are added. The organic phase is washed with a solution of sodium carbonate and then with water. After drying over MgSO4 and evaporation, a residue is obtained which is recrystallised from petroleum ether.

The resulting compound of the formula:

melts at 103-1 040C.

1.2. A solution of 4.5 g (0.0139 mol) of the previously obtained ester in 200 ml of pure benzene is introduced into a "Hanovia" photochemical reactor equipped with a 100 watt mercury lamp.

The solution is irradiated for 32 hours under a nitrogen atmosphere, with magnetic stirring. After the benzene has been evaporated off, the residue is chromatographed on a column in order to isolate the product (Merck 40 silica gel; eluent: 9/1 petroleum ether/methylene chloride).

The pure fraction is distilled in a buibed tube. This gives (5-chloro-2-hydroxy-3-tert.-butylphenyl) (4-chlorophenyl)-methanone.

Melting point = 86.5-870C.

2.4-[(5-Chloro-2-hydroxy-3-tert.-butylphenyl)-(4-chlorophenyl)methylene-aminobutanoic acid and its sodium salt.

0.128 g (1.24 mmol) of 4-aminobutyric acid and 0.4 g (1.24 mmol) of(5-chloro-2-hydroxy-3- tert.-butylphenyl)-(4-chlorophenyl)-methanone are added to 25 ml of a solution of sodium ethoxide containing 1.3 mmol of sodium.

1 5 ml of alcohol are distilled fairly slowly, 10 ml of absolute ethanol are added and a further 1 5 ml of alcohol are then distilled. After evaporation to dryness, the residue is dissolved in 20 ml of water and the solution is acidified to pH 4 with citric acid.

Extraction is carried out with methylene chloride and the extract is washed with water and dried over sodium sulphate. After evaporation of the extract, the residue is recrystallised from heptane and then washed with pentane.

Melting point = 118-119 C and melting point = 125-1 260C.

7.23 ml of an ethanolic solution of sodium ethoxide containing 0.332 mol/litre (i.e. 2.4 mmol) are added to a solution of 1 g (2.45 mmol) of the obtained acid in 10 ml of absolute ethanol. After evaporation to dryness, the oil is dissolved in 10 ml of cold cyclohexane. The sodium salt crystallises slowly. The salt is obtained after filtration, washing with pentane and drying in vacuo at 100 C for 8 hours.

Melting point = 2450C (decomposition).

Table I which follows show pictorially the compounds of the invention which were prepared by way of Examples.

TABLE I

Melting Compound n X1 X2 R1 R2 point( C) 1 3 5-CI 4-CI H n-C3H7 NH2 130-131 2 3 5-CI 4-CI H C2H5 NH2 128-130 3 3 5-CI 4-CI H C2H5 ONa > 250 4 3 5-Cl 4-CI H C2H5 OCa/2 245 (dec) 5 3 5-CI 4-CI H C2H5 OMg/2 165-175 6 3 5-CI 4-CI H n-C3H7 ONa 207-209 7 2 5-CI 4-CI H C2H5 NH2 190-192 8 3 5-CI 4-CI H n-C6H13 OH 61.5-62 9 2 5-CI 4-CI H n-C6H13 NH2 130.5-131 10 2 5-Ci 4-CI H n-C8H13 ONa 181-182 11 1 5-CI 4-CI H n-C5H13 NH2 132-133 12 3 5-CI 4-CI H n-C6H,3 NH2 92-92.5 13 2 5-CH3 4-CH3 H C2H5 NH2 167-168 14 1 5-CI 4-CH3 H n-C6H13 ONa 200-201 15 3 5-CI 4-CH3 H n-C6Hl3 NH2 120.5-121 TABLE I (continuation) Melting Compound n X1 X2 X3 R1 R2 point ( C) 16 1 5-CI 4-Cl H n-C6H,3 ONa 204-205 17 3 5-Cl 4-Cl H n-C4H9 NH2 116-117 18 2 5-Cl 4-Cl H n-C3H7 NH2 153-155 19 3 5-CH3 4-CH3 H C2H5 NH2 110-111 20 3 5-CH3 4-CH3 H C2H5 ONa 215 21 2 5-CI 4-Cl H n-C3H7 ONa > 250 22 2 5-Cl 4-Cl H i-C4Hg ONa 244 (dec) 23 3 5-CI 4-Cl H i-C4Hg NH2 105-107 24 3 5-CI 4-CH3 H n-C3H7 ONa 200-202 25 2 5-Cl 4-CH3 H n-C3H, NH2 146-147 26 2 5-Cl 4-CH3 H n-C5H13 NH2 139.5-140 27 1 5-Cl 4-Cl H n-C3H7 ONa 210-212 28 2 5-CH3 4-CH3 H C2H5 ONa 195 29 1 5-Cl 4-Cl H n-C4H9 NH2 142-142.5 30 2 5-Cl 4-Cl H n-C4H9 ONa 202-204 31 1 5-Cl 4-Cl H n-C4H9 ONa 180-185 32 2 5-Cl 4-CI H n-C3H7 ONa > 250 (dec) 33 3 5-CI 4-CH3 H n-C3H7 NH2 114-115 34 1 5-Cl 4-CH3 H n-C6H13 NH2 144.5-145 35 2 5-Cl 4-CH3 H n-C6Hg3 ONa 196-197 36 4 5-CI 4-CI H n-C6Hg NH2 145-146 37 3 5-CI 4-Cl H n-C4Hg OH 96.5-97.7 38 4 5-Cl 4-Cl H n-C4H9 ONa 190-196 39 3 5-Cl 4-Cl H i-C4H9 ONa 138 40 1 5-Cl 4-Cl H n-C3H7 NH2 145-146 41 2 5-Cl 4-Cl H i-C4H9 NH2 147-148 42 3 5-Cl 4-CH3 H i-C4Hg ONa > 250 43 2 5-Cl 4-Cl H n-C4H9 NH2 136.5-137.5 44 3 5-Cl 4-CH3 H i-C4Hg ONa 140-144 45 1 5-Cl 4-CH3 H i-C4Hg ONa > 250 TABLE I (continuation) Melting Compound n X1 X2 X3 n1 n2 point ( C) 46 2 5-Cl 4-CH3 H i-C4H9 NH2 130 and 138 47 3 5-CI 4-CH3 H i-C4Hg NH2 123-124 48 3 5-Cl 4-CH3 H n-C6H13 OH 69-70 49 3 5-F 4-Cl H CH2-CH=CH2 NH2 116.1 50 3 5-Cl 2-Br H CH2-CH=CH2 NH2 115.7-116.8 51 3 5-Cl 4-CH3 H n-C4Hg OH 119-120 52 1 5-Cl 4-CH3 H n-C4Hg NH2 142-143 53 1 5-Cl 4-CH3 H n-C4Hg ONa 201-203 54 2 5-CI 4-Ch3 H n-C4Hg ONa 211-213 55 3 5-CI 4-CH3 H n-C4Hg NH2 113.5-114.5 56 1 5-Cl 4-C2H5 H C2H5 ONa 249-250 57 3 5-Cl 4-C2H5 H C2H5 ONa > 225 58 1 5-Ci 4-CH3 H i-C4Hg NH2 135.5-136.5 and 155.5 59 2 5-Cl 4-C2H5 H C2H5 ONa 256-257 60 3 5-Cl 4-C2H5 H C2H5 NH2 162-163 61 2 5-Cl 4-CH3 H nC4H9 NH2 143-144 62 3 5-Cl 4-CH3 H C2H5 NH2 143-145 63 2 5-Cl 4-CH3 H C2H5 NH2 171-173 64 2 5-CH3 4-nC3H7 H C2H5 ONa 212-213 65 1 5-CH3 4-nC3H7 H C2H5 ONa 177-178 66 3 5-CH3 4-nC3H, H C2H5 ONa 170 67 1 5-CH3 4-nC3H7 H C2H5 NH2 132-133 68 3 5-CH3 4-nC3H7 H C2H5 NH2 135-136 69 2 5-CH3 4-nC3H, H C2H5 NH2 163-164 70 1 5-CI 4-C2H5 H C2H5 NH2 139-140 71 2 5-Cl 4-C2H5 H C2H5 NH2 146-147 72 3 5-Cl 4-Cl H iC3H7 NH2 166-167 73 3 5-Cl 4-Cl H t-C4H9 NH2 153-154 74 2 5-Cl 4-Cl H C2H5 ONa 265-267 TABLE I (continuation)

Melting Compound n X1 X2 X3 R1 R2 point (OC) 75 3 5-CI 4-Cl H t-C4Hg ONa 245 (dec) 76 3 5-Cl 4-CH3 H QH5 ONa 238-240 77 2 5-CI 4-CH3 H C2H5 ONa 258-260 yCH3 78 3 5-CI 4-CI H -CH NH2 135-136 CH=CH2 79 3 5-CH3 4-CH3 H t-C4Hg NH2 136-137 yCH3 80 3 5-CI 4-Cl H -CH OH 141-142 CH=CH2 81 3 5-Cl 4-iC3H H C2H5 NH2 156-157 82 3 5-CH3 4-CH3 H t-C4Hg ONa 271-273 83 3 5-Cl 4-Cl H i-C3Ho ONa 190 (dec) 84 3 5-CH3 4-CH3 H t-C4Hg OH 153-154 85 2 5-Cl 4-CH3 H C2H5 OH 145-147 86 3 5-Cl 4-CH3 H C2H5 OH 114-116 87 3 5-CI 4-Cl H t-C4Hg OH 118-119 88 2 5-CI 4-CI H C2H5 OH 148-150 89 3 5-CH3 4-nC3H7 H C2H5 OH 85-86 90 1 5-CH3 4-nC3H7 H C2H5 OH 152-153 91 2 5-CH3 4-nC3H, H C2H5 OH 94-95 92 2 5-CI 4-C2H5 H C2H5 OH 105-106 93 3 5-CI 4-C2H5 H C2H5 OH 83-84 94 1 5-Cl 4-C2H5 H C2H5 OH 179-180 95 2 5-CI 4-CH3 H n-C4Hg OH 118.5-119.5 96 1 5-Cl 4-CH3 H n-C4Hg OH 1 58 (dec) 97 1 5-Cl 4-CH3 H i-C4Hg OH 1 63 (dec) 98 3 5-Cl 4-CH3 H i-C4Hg OH 11 5-116 99 3 5-CI 4-CH3 H i-C4Hg OH 126 and 136 100 3 5-CI 4-Cl H i-C4Hg OH 103-104 TABLE I (continuation) Melting Compound n X1 X2 X3 R1 R2 point( C) 101 4 5-CI 4-Cl H n-C4Hg OH 123-123.5 102 2 5-CI 4-CH3 H n-C6H13 OH 130-130.5 103 2 5-Cl 4-Cl H n-C3H7 OH 130-131 104 1 5-Cl 4-Cl H n-C4H9 OH 162-162.5 105 2 5-Cl 4-CI H n-C4Hg OH 171-172 106 2 5-CH3 4-CH3 H C2H5 OH 132-133 107 1 5-Cl 4-Cl H n-C3H7 OH 175-176 108 3 5-CI 4-CH3 H n-C3H7 OH 107-108 109 2 5-CI 4-Cl H i-C4Hg OH 160-163 110 2 5-CI 4-CI H n-C3H7 OH 119-121 111 3 5-CH3 4-CH3 H C2H5 OH 115-116 112 1 5-CI 4-CI H n-C6H13 OH 156-157 113 1 5-Cl 4-CH3 H n-C6H,3 OH 146-146.5 114 2 5-Cl 4-Cl H n-C6H13 OH 149.5-150 115 3 5-CI 4-Cl H n-C3H, OH 88.5-91 116 3 5-Cl 4-Cl H C2H5 OH 131-132 117 5 5-CI 4-CI H n-C3H7 OH 114-115 118 4 5-Cl 4-Cl H n-C3H7 OH 128-129 119 4 5-CI 4-CH3 H n-C3H, OH 130-131 120 5 5-CI 4-CH3 H n-C3H7 OH 101-102 121 5 5-Cl 4-C2H5 H C2H5 OH 114-114.5 122 4 5-Cl 4-C2H5 H C2H5 OH 107-108 123 4 5-CI 4-CI H C2H5 OH 79 124 5 5-Cl 4-Cl H C2H5 OH 94-95 The starting benzophenones employed are shown in Table II.

TABLE II

Compound X1 X2 R1 Characteristics 1 5-CI 4-CI n-C3H, Melting point = 55-560C 2 5-CI 4-CI C2H5 Melting point = 47-490C 3 5-CI 4-CI n-C6H13 Oil, boiling point = 204CC (0.1 mm Hg) 4 5-CH3 4-CH3 C2H5 Melting point = 38-390C 5 5-CI 4-CH3 n-C6H13 Oil, boiling point = 1920C(0.1 mm Hg) 6 5-Ci 4-CI n-C4Hg Oil, boiling point = 168-1 700C (0.03 mm Hg) 7 5-CI 4-CI i-C4Hg Melting point = 65-660C 8 5-CI 4-CH3 n-C3H Melting point = 63-640C 9 5-CI 4-CH3 i-C4Hg Meltingpoint=71-720C 10 5-F 4-CI CH2-CH=CH2 Melting point = 44.60C 11 5-CI 2-Br CH2-CH=CH2 Oil 12 5-CI 4-CH3 n-C4Hg Oil, boiling point = 148-1500C (0.06 mm Hg) 13 5-CI 4-C2H5 C2H5 Oil, nD1 = 1.6060 14 5-CH3 4-nC3H7 C2H5 Oil, nod1 = 1.5861 15 5-CI 4-CI i-C3H, Melting point = 54-550C 16 5-CI 4-CI t-C4Hg Melting point = 86.5-870C 1 7 5-CI 4-CH3 C2H Melting point = 53-550C /CH3 1 8 5-CI 4-CI CH Melting point = 45--470C CH=CH2 19 5-CH3 4-CH3 tC H Melting point = 110-111 C 20 5-CI 4-iC3H, C2H5 Melting point = 42--430C The compounds of the invention were subjected to pharmacological tests which showed their activity on the central nervous system.

The acute toxicity was determined on mice by intraperitoneal administration. The LD50 (50% lethal dose), which causes the death of 50% of the animals, ranges from 250 to > 1000 mg/kg animal body weight.

The antidepressive activity of the compounds was shown by the antagonism towards the head twitches caused in mice by L-5-hydroxytryptophan (L-5-HTP).

The mice (males CD1, Charles River France; 18-22 g body weight) receive increasing doses of the products to be studied, or the solvent, simultaneously with a 250 mg/kg dose of L-5-HTP, administered subcutaneously. Forty-five minutes after this injection of L-5-HTP, the number of head twitches for each mouse is counted for one minute.

The average number of head twitches and the percentage variation relative to the control batch are calculated for each treatment.

Using the effect-dose curve, the AD50 (50% active dose or the dose which reduces the average number of head twitches by 50%) is determined by the graphical method of Miller and Tainter, Proc.

Soc. Exp. Biol. Med. (1944), 57-261.

The AD50 of the compounds of the invention varies from 40 to 60 mg/kg animal body weight administered intraperitoneally.

The anticonvulsant activity of the compounds was shown by the antagonism towards the mortality caused by bicuculline in mice.

Bicuculline is a relatively selective blocker of post-synaptic GABA-ergic receptors and its convulsant and lethal effects are antagonised by compounds which increase the level of GABA in the brain or which possess a GABA-mimetic activity.

The 50% active dose (AD50) of the substances studied, that is to say the dose which protects 50% of the animals against the effect of bicuculline, was evaluated.

The AD50 of the compounds of the invention varies from 10 to 100 mg/kg animal body weight, administered intraperitoneally.

The ulcer-inhibiting activity of the compounds was shown by the activity towards stress ulcers and ulcers induced by phenylbutazone.

The two tests, involving stress ulcers and ulcers induced by phenylbutazone, were carried out on fasted female Wistar rats weighing 180210 g, the compounds being administered orally in the form of a suspension in a 1% aqueous solution of Tween 80, immediately before the stress or 30 minutes after the oral administration of phenylbutazone. In both cases, examination of the stomach was carried out 2 hours after the beginning of the ulcer-forming process.

The compounds have a significant action above 30 mg/kg animal body weight in the case of stress ulcers and above 100 mg/kg animal body weight in the case of ulcers induced by phenylbutazone.

The gastric antisecretory activity of the compounds was shown on wake rats with a ligated pylorus.

Female Wistar rats weighing 200 to 220 g are fasted for 48 hours. The pylorus is ligated under ether anaesthetic. The compounds are then administered intraperitoneally at doses of 1, 5, 25 and 50 mg/kg animal body weight, immediately after ligature of the pylorus. The animals are sacrificed 4 hours after ligature of the pylorus. The volume of the gastric secretion is measured and the free acidity and total acidity are determined by titrimetry relative to a control determination. The compounds of the invention reduce the volume of the gastric secretion by 45 to 55%, 50 to 65% and 70 to 85% respectively, the free acidity by 60 to 70%, 65 to 75% and 85 to 95% respectively, and the total acidity by 55 to 65%, 60 to 70% and 85 to 95% respectively.

The compounds of the invention are active as anti-depressants, anticonvulsants, ulcer inhibitors and gastric secretion inhibitors and also possess anxiolytic, analgesic and anti-inflammatory properties.

They can be used in human and veterinary therapy for the treatment of various diseases of the central nervous system, for example for the treatment of depressions, psychoses and certain neurological diseases such as epilepsy, spasticity and dyskinesia, and for the treatment of various stress ulcers and gastric ulcers.

The invention consequently includes all pharmaceutical compositions which contain, as active ingredient, an alkylbenzylidene derivative of general formula (I) in association with any excipient(s) suitable for their administration, in particular their oral administration (tablets, coated tablets, gelatin capsules, ordinary capsules, cachets, or solutions or suspensions to be taken orally) or parenteral administration.

The daily dosage can range from 100 to 3000 mg.

Claims (14)

1. Benzylidene derivatives of the general formula:

wherein n represents an integer from 1 to 12, R1 represents a straight- or branched-chain alkyl or alkenyl radical having 2 to 6 carbon atoms, R2 represents an amino radical, a hydroxy radical, or a group -OM in which M represents an alkali metal or alkaline earth metal, and X1,X2and X3 each represent, independently of one another, a hydrogen atom, a halogen atom, the methoxy radical or a straight- or branched-chain alkyl radical having 1 to 4 carbon atoms.

2. Benzylidene derivatives according to claim 1 of the general formula:

wherein the various symbols are as defined in claim 1.

3. Benzylidene derivatives according to claim 1 or 2 wherein n represents an integer from 1 to 4.

4. Benzylidene derivatives according to claim 1,2 or 3 wherein X1 represents a chlorine atom or the methyl radical, X2 represents a chlorine atom or the methyl radical, and X3 represents a hydrogen atom.

5. Benzylidene derivatives according to claim 4 wherein n represents 3 and R1 represents an ethyl, n-propyl, n-butyl or n-hexyl radical.

6. An alkylbenzylidene derivative of the general formula depicted in claim 1 identified by reference to that general formula In TABLE I following Example 3.

7.4-[(5-Chloro-2-hydroxy-3-n-propylphenyl)-(4-chlorophenyl)methylene]-aminobutanoic acid, its alkali metal and alkaline earth metal salts and its amide.

8.4-[(5-Chloro-2-hydroxy-3-ethylphenyl)-(4-chlorophenyl)methylene]-aminobutanoic acid, its alkali metal and alkaline earth metal salts and its amide.

9. Process for the preparation of a benzylidene derivative of the general formula depicted in claim 1 which comprises reacting a benzophenone of the general formula:

(wherein the various symbols are as defined in claim 1) with a compound of the general formula: H2N(CH2)nCOR2 (IV) (wherein n and R2 are as defined in claim 1), optionally in the form of an acid addition salt, at a temperature of from 200 to 1 200C in an organic solvent medium in the presence of a base.

1 0. A process for the preparation of a benzylidene derivative of the general formula depicted in claim 1 wherein R2 represents the amino radical which comprises reacting a corresponding compound of that general formula wherein R2 represents the hydroxy radical with carbonyldiimidazole and ammonia.

11. A process for the preparation of a benzylidene derivative of the general formula depicted in claim 1 wherein R2 represents a group -OM (M being as defined in claim 1) which comprises converting by a method known perse a corresponding compound of that general formula wherein R2 represents the hydroxy radical into an alkali metal or alkaline earth metal salt.

1 2. A process for the preparation of a benzylidene derivative of the general formula depicted in claim 1 substantially as hereinbefore described with especial reference to Example 1,2 or 3.

1 3. Benzylidene derivatives of the general formula depicted in claim 1 when prepared by a process claimed in claim 9, 10, 11, or 12.

14. Pharmaceutical compositions which comprise, as active ingedient, a benzylidene derivative as claimed in any one of claims 1 to 8 in association with a pharmaceutically-acceptable excipient.

1 5. Benzylidene derivatives of the general formula depicted in claim 1 for use as medicaments and, more particularly, as antidepressants, anticonvulsants, ulcer inhibitors and gastric secretion inhibitors and also as anxiolytic, analgesic and anti-inflammatory agents.