NL8304070A - ALKYLBENZYLIDE DERIVATIVES, THEIR PREPARATION AND THE THERAPEUTIC USE. - Google Patents

Description

τ ί ^ 4 '-1- 23473 / Vk / mvl

Short designation: Alkylbenzylidene derivatives, their preparation and therapeutic application.

The invention relates to benzylidene derivatives and they are characterized in that they correspond to formula 1, stated on the formula sheet, where n is an integer from 1 to 12, Rj represents an alkyl or alkenyl radical straight or branched with 2 -6 carbon atoms, an NH2, OH or OM radical where M is an alkali or alkaline earth metal, X ^, X2 and X ^ each independently a hydrogen atom, a halogen atom, methoxy or an alkyl radical having 1-4 represent carbon atoms that are straight or branched.

The compounds of the invention which are preferably prepared and used correspond to formula 3, stated on the formula sheet, wherein the substituents have the same meaning as indicated above, especially preferred are compounds wherein Xj is a chlorine atom or a methyl radical, X2 is a chlorine atom or a methyl radical, X ^ is a hydrogen atom and the preferred compounds are those wherein n equals 3 and R1 is an ethyl, n-propyl, n-butyl or n-hexyl radical .

According to the invention, the compounds can be prepared as follows: a benzophenone of formula 2, stated on the formula sheet, is reacted with a compound of formula H2N- (CH2) n -CO2, optionally in the form of a salt such as the hydrochloride, at a temperature of 20-120 ° C in a solvent such as methanol, ethanol or a mixture of methanol / toluene in the presence of a base such as sodium ethylate or sodium methylate. The compounds of formula 1, wherein R 2 = NH 2, can also be prepared starting from the compounds of formula 1, wherein R 2 = OH, by amidification of carbonyldiimidazole and ammonia.

The starting benzophenone compounds are new materials and are prepared by following, for example, reaction scheme A as stated on the formula sheet.

The invention is further illustrated by the following examples. The analyzes and the IR and NMR spectra confirm the structure of the compounds.

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Example I

4 - [{(5-chloro-2-hydroxy 3-n-propylphenyl) (4-chlorophenyl) -methylene} amino] butanamide.

(X1 = 5-Cl, X2 = 4-Cl, X3 = Η, n = 3, R1 = n-C1, R2 = NHg).

1) (5-chloro-2-hydroxy 3-n-propylphenyl) (4-chlorophenyl) -methanone.

To a stirred solution of 21 g (0.123 mol) of the phenol compound of formula 4, mentioned on the formula sheet, in 1.3 L of methylene chloride, 17.15 ml (0.123 mol) of triethylamine was added and the mixture was heated to reflux. Heating was stopped and slowly added to the solution, such that reflux was maintained, 21.54 g (0.123 mol) of acid chloride of formula 5, stated on the formula sheet, dissolved in 100 ml of methylene chloride. The mixture was then heated to reflux for 8 hours. The products were left overnight. Swat then added 500 ml of cold water to the solution. The mixture was decanted and the organic phase washed once with 250 ml of a saturated sodium bicarbonate solution and once with 250 ml of water.

The organic phase was dried over MgSO4, filtered and the filtrate evaporated to dryness. This gave an oil which crystallized by rubbing in 120 ml of petroleum ether.

The mixture was filtered, dried and the crystals were redissolved in 300 ml of petroleum ether with boiling. The mixture was treated with 2 g of active charcoal for 15 minutes with stirring, the mixture was filtered hot and the filtrate was evaporated to a volume of about 150 ml. After cooling again, the ester crystallized out. This was filtered, dried and further dried in a desiccator. Melting point 49-50 ° C.

30 Heating was carried out at 100 ° C in a well-ventilated cabinet

stirring, 29.7 g (0.096 mol) 4-chlorobenzoate of (4-chloro-2-propyl) -phenyl and added in portions, within 10 minutes, 29.7 g (0.223 mol) aluminum chloride. It was then heated to 160 ° C on an oil bath with stirring, and the mixture was kept at this temperature for 15 minutes before the reaction mixture was allowed to cool to 50 ° C. The mixture was then cooled in solid ice for 1 hour, after which the solid obtained was crushed and the mixture was mashed in a 83 δ 4 Γ 73 * -3-23473 / Vk / mvl mortar. The complex was then hydrolysed, powdered and poured in small quantities into a vigorously stirred mixture of 1 L water, 500 g ice and 300 ml concentrated hydrochloric acid.

The mixture was extracted completely with 3 L of methylene chloride, washed the organic layer with 500 ml of water, decanted the mixture, dried over MgSO 4, then filtered off and the filtrate was evaporated to a volume of about 100 ml. The crude product was then purified by passing it over a 700 g column of silica eluting with 3 L of methylene chloride.

The good fractions were dried over MgSO4, then the filtrate was filtered and evaporated to dryness. The resulting oil crystallized in 150 ml of petroleum ether. This was filtered through a frit filter, air dried and further dried in a desiccator. Melting point was 55-56 ° C.

2) 4 - [{(5-chloro-2-hydroxy 3-n-propylphenyl) (4-chlorophenyl) -methylene} amino] butanamide.

A mixture of 6.2 g (0.020 mol) of the previously obtained ketone was evaporated to dryness on a 100 ° C bath with 3.05 g (0.022 mol) of 4-aminobutanamide hydrochloride and 1.25 g (0.22 mol) sodium raethylate 20 in 600 ml of methanol. 600 ml of ethanol were then added to the flask and the mixture was evaporated to dryness under the same conditions.

600 ral ethanol was again evaporated under reduced pressure until the end of evaporation. The residue, dissolved in 300 grams of methylene chloride, was washed with 100 ml of water. The mixture was decanted, the organic phase dried over MgSO4, filtered and evaporated to dryness under reduced pressure. The solid obtained was dissolved in 15 ml of warm ethyl acetate. About 100 ml of ether was added to the solution (until a slight cloudiness appeared). The amide (IX) crystallized out by cooling again. The mixture was filtered over a frit filter, washed with 20 ml ether, air dried and finally dried in a desiccator while heating to 60 ° C. The melting point was 130-131 ° C.

Example II

4 - [{(5-chloro-2-hydroxy-3-ethylphenyl) (4-chlorophenyl) methylene} -35 amino] butanoic acid and its sodium salt.

(X1 = 5-C1, X2 = 4-C1, X3 = Η, n = 3, R1 = C1, R2 = OH and ONa).

1) (5-chloro-2-hydroxy-3-ethylphenyl) (4-chlorophenyl) methanone.

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Proceed in the same manner as in Example 1.1, but replacing 4-chloro-2-n-propylphenol with 4-chloro-2-ethylphenol to obtain 4-chlorobenzoate of 4-chloro-2-ethylbenzyl, which is reacts with aluminum chloride 5 under the same conditions. The benzophenone melts at 47-49 ° C.

2) 4 - [{(5-chloro-2-hydroxy-3-ethylphenyl) (4-chlorophenyl) -methylene} amino] butanoic acid and its sodium salt. 9 g (0.03 mole) of benzophenone, previously obtained, 350 ml of methanol, 3.23 g (0.031 mole) of GABA and 1.72 g (0.03 mole) of sodium 10 methylate are placed in a 1 l flask. The mixture is brought to reflux for 4 hours and 1.6 g (0.015 mol) of GABA and 0.85 g (0.015 mol) of sodium methylate are again added.

The mixture is again refluxed for 4 hours, evaporated to dryness, the residue is taken up again in 2.5 liters of water and acidified to pH = 4 by adding citric acid. The mixture is extracted twice with 350 ml of dichloromethane, the organic phase is combined, washed with 400 ml of water, dried over Na 2 O 4, the mixture is filtered and evaporated to dryness.

The residue is passed over a ceramic filter with petroleum ether, air dried and dried in a desiccator under reduced pressure. The product was recrystallized from diisopropyl ether. The melting point is 131-132 ° C.

To 15.7 g of the acid dissolved in 100 ml of methanol, 15.7 g of a solution of 0.748N sodium methylate are added. The methanol is evaporated at 80 ° C, then 100 ml of ether is evaporated and the mixture is passed over a ceramic filter with ether, the sodium salt is dried in air and then the sodium salt is dried in a dessicator under reduced pressure. The melting point is higher than 250 ° C.

Example III

4 - [{(5-chloro-2-hydroxy 3-tert-butylphenyl) (4-chlorophenyl) -methylene} amino] butanoic acid and its sodium salt.

(X1 = 5-C1, X2 = 4-C1, X3 = Η, n = 3, R1 = t-C ^ Hg, R2 = 0H and ONa).

1) (5-chloro-2-hydroxy 3-tert-butylphenyl) (4-chlorophenyl) -methanone.

1.1 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-dimethyl-3-aminopyridine in 800 cm of ether a solution is added dropwise 8304070-523473 / Vk / mvl. ^ 3 of 56 g (0.32 mol) of p-chlorobenzoyl chloride in 200 ml of ether. After stirring for 6 hours at ambient temperature and leaving overnight, 3 500 cm 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 crystallized in petroleum ether.

The compound has formula 6, stated on the formula sheet, and melts at 103-104 ° C.

1.2 In a photochemical "Hanovia" reactor equipped with a 100 Watt mercury lamp, a solution of 4.5 g (0.0139 mol) of the 3 ester previously mentioned in 200 cm pure benzene is introduced. The mixture is irradiated, under stirring with a magnetic stirrer, under nitrogen atmosphere for 32 hours. After evaporation of the benzene, the residue is purified by chromatography on a column and the product is separated (Kieselgel 40 Merck; eluent: petroleum ether / methylene chloride 9/1).

The pure fraction is distilled through a bubble-filled tube.

This gives (5-chloro-2-hydroxy-3-tert-butylphenyl) - (4-chlorophenyl) methanone, mp 86.5-87 ° C.

2. 4 - [{(5-chloro-2-hydroxy 3-tert-butylphenyl) (4-chlorophenyl) -methylene} amino] butanoic acid and its sodium salt.

3

0.128 g (1.24 mmol) of 4-aminobutyric acid and 0.4 g (1.24 mmol) (5-chloro-2-hydroxy 3-) of 25 ml of a solution of sodium ethylate with 1.3 Hanoi 25 sodium are added. tert-butylphenyl) (4-chlorophenyl) -3 ftiethanone. 15 cm alcohol is distilled off sufficiently slowly and 3 cm 10 cm absolute ethanol is added, after which 15 cm alcohol 3 is distilled again. After evaporation to dryness, the residue is dissolved in 20 cm 3 of water and acidified to a pH of 4 with citric acid.

The mixture is extracted with methylene chloride, washed with water and dried over sodium sulfate. After evaporation of the extract, the residue is recrystallized in heptane and then washed with pentane. Melting points are 118-119 ° C and 125-126 ° C.

To a solution of 1 g (2.45 mmol) of the acid in 10 cm 3 of absolute ethanol, 7.23 cm of an ethanol solution of sodium ethylate is added at a concentration of 0.332 mol / liter (2.4 mmol). After evaporation to dryness, the oil is dissolved cold in 10 cm of cyclohexane. The sodium salt .... tg: ____ 8 3 ö 4 0 7 0 'l' »-6- 23473 / Vk / mvl slowly crystallizes out. After filtration and washing with pentane, drying is carried out at 100 ° C under reduced pressure for 8 hours, after which the salt is obtained. The melting point under decomposition is 245 ° C.

Table A lists further examples of compounds 5 of the invention which have been prepared.

TABLE A

Compound of formula 1 ~ melt-m ^ erbin "η X1 X? X. R. R? point 10 thing 1 2 3 12 ^ o ^ 1 3 5-C1 4-C1 H n "c3H7 NH2 130-131 2 3 5-C1 4-C1 HC ^ Hc NH_ 128-130 2 b 2 3 3 5-C1 4 -Cl H C0Hc ONa> 250 2 5 * 1) 4 3 5-C1 4-C1 H CnH.- OCa / 2 245 ic £ o 13 5 3 5-C1 4-C1 H C_Hc OMg / 2 165-175 2 b 6 3 5-C1 4-C1 H nC ^ - 0Na 207-209 7 2 5-C1 4-C1 H CJL NH- 190-192 2 b 2 8 3 5-Cl 4-C1 H n "C6Hi3 0H 61.5 -62 9 2 5-C1 4-C1 H nC, H10 NH “130.5-131 b IJ 2 2C 10 2 5-C1 4-C1 H n” C6Hi3 0Na 181-182 11 1 5-C1 4-C1 H n-CcH_ NH_ 132-133 b IJ 2 12 3 5-C1 4-C1 H n “C6Hi3 NH2 92-92,5 13 2 5-CH- 4-CH„ H CLR- NH0 167-168 3 3 2 5 2 14 1 5-C1 4-CH3 Η. ° “° 6Η13 0Na 200-201 25 15 · 3 5-C1 4-CH3 H n" C6Hi3 NH2 120,5-121 16 1 5-C1 4-C1 H nC, H_ ONa 204-205 ou 17 3 5-C1 4-C1 H n-C4Hg NH2 116-117 18 2 5-C1 4-C1 H nC ^ NH ^ 153-155 19 3 5-CH3 4-CH3 H NH2 110-111 30 20 3 5-CH3 4-CH3 H C2H5 ONa 215 21 2 5-C1 4-C1 H n-C3H7 ONa> 250 22 2 5-C1 4-C1 H i-C4Hg ONa 224 * 1) 23 3 5-C1 4-C1 H i-C4Hg NH2 105- 107 24 3 5-C1 4-CH3 H nC. ^ ONa 200-202 35 25 2 5-C1 4-CH3 H nC ^ NH2 146-147 26 2 5-C1 4-CH3 H n-CgH ^ NH2 139.5 -140 27 1 5-C1 4-C1 H n-C_H „ONa 210-212 t .118304070 -7- 23473 / Vk / mvl TABLE A (cont.) Melting connections χ χ χ R R point 1 2 3 1 ^ (° c) 5 28 2 5-CH3 4-CH3 H ONa 195 29 1 5-C1 4-C1 H nC ^ Hg NH2 142-142.5 30 2 5-C1 4-C1 H n ” C ^ Hg ONa 202-204 31 1 5-C1 4-C1 H n-c4Hg 0Na 180 "1 ^) 32 2 5-C1 4-C1 H n-C3H7 ONa> 250 10 33 3 5-C1 4-CH3 H n “C3H7 NH2 114-115 34 1 5-C1 4-CH3 H nC ^ NH2 i44'5" 145 35 2 5-C1 4-CH3 H n_C6H13 0Na 196-197 36 4 5-C1 4-C1 H n_C6H9 NH2 145 -146 37 3 5-C1 4-C1 H n "C4Hg 0H 96.5-97.7 15 38 4 5-C1 4-C1 H n" C4Hg 0Na 190-196 39 3 5-C1 4-C1 H i "C4H9" 0Na 138 40 1 5-C1 4-C1 H n_C3H7 NH2 145-146 41 2 5-C1 · 4-C1 H i-C4H9 NH2 147-148 42 '3 5- C1 4-CH3 H i_C4H9 0Na> 250 20 43 2 5-C1 4-C1 H n-C4Hg NH2 136.5-137.5 44 3 5-C1 4-CH3 H i_C4H9 ° Na 140-144 45 1 5-C1 4-CH3 H i_C4H9 0Na> 250 46 2 5-C1 4-CH3 H i-C4Hg NH2 130en138 47 3 5-C1 4-CH3 H i "C4H9 NH2 123-124 25 48. 3 5-C1 4-CH3 H n “C6HT3 0H 69-70 * 4g 3 5-f 4-C1 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-C1 4-CH3 H n-c4Hg 0H 119-120 52 1 5-C1 4-CH3 H nC ^ Hg NH2 142-143 30 53 1 5-C1 4-CH3 H n -C4Hg ONa 201-203 54 2 5-C1 4-CH3 H n_c4Hg 0Na 211-213 55 3 5-C1 4-CH3 H nC ^ Hg NH2 113.5-114.5 56 1 5-C1 4-C2H5 H C2H5 ONa 249-250 57 3 5-C1 4-C0H.- HCL ONa> 225 2 b 2 b 135 5-136 5 35 58 1 5-C1 4-CH3 H i-C4H9 NH2 and 155.5 59 2 5-C1 4-C2H5 H ONa 256-257 8 3 0 4 17 0 -8- 23473 / Vk / mvl

ψ Q

• I

TABLE A (continued) melting compound χ XXRR point 12 3 12 5 60 3 5-C1 4-c2H5 H C2H5 NH2 162-163 61 2 5-C1 4-CH3 H nC ^ Hg NH2 143-144 62 3 5-C1 4-CH3 H NHg 143-145 63 2- 5-C1 4-CH3 H NH2 171-173 64 2 5-CH- 4-nC_H „H C_HK ONa 212-213 3 3 7 2 5 10 65 1 5 -CH3 4-nC3H? H ONa 177-178 66 3 5-CH- 4-nC_H „H ONa 170 3 3 I 2 5 67 1 5-CH3 ^ -NC3H? H NHg 132-133 68 3 5-CH3 4-nC3H? H C2H5 NH2 135-136 69 2 5-CH3 4-nC3H? H C2H5 NH2 163-164 15 70 1 5-C1 4-C2H5 H NH2 139-140 71 2 5-C1 4-C ^ H C2H5 "NH2 146-147 72 3 5-C1 4-C1 H iC ^ NH2 166- 167 73 3 5-C1 4-C1 H tC ^ Hg NHg 153-154 74 2 5-C1 4-C1 H C0Hc ONa 265-267 ά ^ * 1) 20 75 3 5-C1 4-C1 H tC ^ Hg ONa 245 76 3 5-C1 4-GH3 H C2H5 ONa 238-240 77 2 5-C1 4-CH3 H C2H5 ONa 258-260 78 3 5-C1 4-C1 H -CH ^ yy: ^ NH2 135-136 79 ^ 3 5-CH3 4-GH3 H t-C4H9 NH2 136-137 25 80 '3 5-C1 4-C1 H "CH ^ h-CH2 ° H 141-142 81 3 5-C1 4-iC3H7 H c2H5 NH2 156- 157 82 3 5-CH3 4-CH3 H tC ^ Hg ONa 271-273 83 3 5-C1 4-C1 H i-CgH,., 0Na 190 * 1) 30 84 - 3 5-CH3 4-CH3 H tC ^ Hg OH 153-154 85 '2 5-C1 4-CH- HC „Hc OH 145-147 3 2 5 86 3 5-C1 4-CH_ HC„ Hc OH 114-116 3 2 5 87 3 5-C1 4- C1 H tC ^ Hg 0H '118-119 88 2 5-C1 4-C1 H OH 148-150 35 89 3 5-CH3 4-nC3H7 H C2H5 OH 85-86 90 1 5-CH3 4-nC ^ H OH 152 -153 8304070 —----,. ^ -9- 23473 / Vk / mvl TABLE A (continued) melting compound χ χ XR Rp point thing 12 3 1 2 (c> c) 5 91 2 5-CH3 4-nC3H7 H OH 94-95 92 2 5 -C1 4-C2H5 H C2H5 OH 105-106 93 3 5-C1 4-CpH ^ H C2H5 OH 83-84 94 1 5-C1 4-C2H5 H C2H5 OH 179-180 95 2 5-C1 4-CH3 H nC ^ Hg OH 118.5-119.5 10 96 1 5-C1 4-CH3 H n-C4Hg OH 158 * 1) 97 1 5-C1 4-CH3 H 0H 163 15 98 3 5-C1 4-CH3 H i «C4H9 OH 115-116 99 3 5-C1 4-CH3 H i-C4Hg 0H 126 and 136 100 3 5-C1 4-C1 H iC ^ Hg OH 103-104 15 101 4 5-C1 4-C1 H n- C4Hg OH 123-123.5 102 2 5-C1 4-CH3 H n_C6Hi3 0H 130-130.5 103 2 5-C1 4-C1 H nC ^ - OH 130-131 104 1 5-C1 4-C1 H n- C4Hg OH 162-162.5 105 2 5-C1 4-C1 H n-C4Hg OH 171-172 20 106 2 5-CH3 4-CH3 H OH 132-133 107 1 5-C1 4-C1 Η nC. ^ 0H 175-176 108 3 5-C1 4-CH3 H nC ^ OH 107-108 109 2 5-C1 4-C1 H i-C4Hg 0H 160-163 110 2 5-C1 4-C1 H nC ^ OH 119-121 25 111 3 5-CH3 4-CH3 H OH 115-116 112, 1 5-C1 4-C1 H n “C6Hi3 0H 156-157 * 113. 1 5-C1 4-CH3 H n-C6Hi3 0H 146-146.5 114 2 5-C1 4-C1 H n-C6Hl3 0H 149.5-150 115 3 5-C1 4-C1 H nC ^ OH 88.5 -91 30 116 3 5-C1 4-C1 H OH 131-132 117 5 5-C1 4-C1 H n-c3H7 0H 114-115 118 4 5-C1 4-C1 H nC ^ 0H 128-129 119 4 5 -C1 4_ch3 H n "C3H7 0H 130-131 120 5 5-C1 4-CH3 H nC ^ OH 101-102 121 5 5-C1 4-CpH5 HC ^ OH 114-114.5 35 122 4 5-C1 4- 0 ^ H OH 107-108 123 4 5-C1 4-C1 H ^ 124 5 5-C1 4-C1 H C2H5 OH 94-95

Note * 1) decomposition.

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The starting benzophenone compounds of formula 2 are shown in Table B.

TABLE B

Compounds of formula 2, wherein X3 = H

5 ----- connect χ χ R characteristics thing 121

1 5-C1 4-C1 n “c3H7 melting point = 55-56 ° C

2 5-C1 4-C1 CJL. melting point = 47-49 ° C

2 5

, oil, boiling point = 204 C

10 3 5'C1 4 "C1 n-C6H13 (at 0.1 Torr)

4 5-CH 3 4-CH 2 C 2 H 5 melting point = 38-39 ° C

c. c pi 4 ΓΗ „Γ μ“ He, boiling point = 192 ° C

5 5-C1 4-CH3 n-C6H13 (blJ o, 1 Torn)

6 5-C1 4-Cl n-C.HQ olle '^ 0kp “nL = T168: 170 ° C

49 (at 0.03 Torr)

7 5-C1 4-C1 i-C ^ Hg melting point = 5-66 ° C

15 8 5-C1 4-CH 3 n-C 2 H 3 melting point = 63-64 ° C

9 5-C1 4-CH3 i4C4H9 melting point = 71-72 ° C

5-F 4-C1 CH2-CH = CH2 melting point = 44.6 ° C

11 5-C1 4-Br CH2-CH = CH2 oil

12 5-C1 4-CH, n-C, HQ 0lie ΐ? °? ^ Ϊ́Α% 148Τ15 (ϊ ° C

3 49 (at 0.06 Torr) 20 13 5-C1 4-C ^ H, -C0Hc oil, n ^ 1 = 1.6060

do do D.

14 · 5-CH 3 4-nC 3 H 2 oil, n ^ 1 = 1.5861

5-C1 4-C1 i-c3H7 melting point = 54-55 ° C

16 5-C1 4-C1 t-C ^ Hg melting point = 86.5-87 ° C

17 5-C1 4-CH_CJEL melting point = 53-55 ° C

d do

CH

25 18 5-C1 4-C1 3 melting point = 45-47 ° C

19 5-CH3 4-CH3 t-C4Hg melting point = 110-111 ° C

5-C1 4-10 ^ c2H5 melting point = 42-43 ° C

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The compounds of the invention were subjected to pharmacological tests demonstrating activity towards the central nervous system.

The lethal dose was determined in mice by intraperitoneal administration. The DL 50 (50% lethal dose) value, which caused death in 50% of the animals, ranged from 250 to more than 1000 mg / kg.

The anti-depressant activity of the compounds was determined by antagonism to "head twitches" caused by L-5-hydroxytryptophan in mice.

The mice (male CD1, Charles River, France, 18-22 g body weight) were administered the test compounds with increasing doses or the solvent, simultaneously with L-5-HTP at a dose of 250 mg / kg by subcutaneous administration.

45 minutes after this 5-HTP injection, the number of mice with "head twitches" was counted, for each mouse for 1 minute. For each treatment, the average number of "head twitches" was counted and the percentage variation from the comparative number was calculated. Using the effective dose curve, the DA 50 value (active dose for 50% or the dose that reduces 50% of the average number of "head twitches") was determined using Miller's graphical method and Tainter (1944).

The DA 50 value of the compounds of the invention ranged from 40 to 60 mg / kg when administered intraperitoneally.

The anti-convulsive activity of the compounds was determined by antagonism to mortality caused by bicucullia in mice. The bicuculline is a blocking agent that selectively acts against the GABA ergic receptors with a post-synaptic action and the convulsive and lethal influence has been determined for the compounds that increase the GABA cerebral dose or have a GABA mimetic activity.

In addition, the 50% active dose (DA 50) was determined, which dose gave 50% of the animals protection against the action of bicuculline, 35 for the tested substances. The DA 50 value of the compounds of the invention ranged from 10 to 100 mg / kg when administered intraperitoneally.

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The anti-ulcer activity of the compounds was demonstrated by the activity against stress ulcer and ulcer caused by phenylbutazone. The two experiments, namely stressulcer and ulcer caused by phenylbutazone, were performed on female Wistar rats weighing 180-210g, who were fasted, the compounds being administered as a suspension in an aqueous solution of Tween 80 in an amount of 1% by oral administration immediately before stress or 30 minutes before the oral administration of phenylbutazone. In both cases, the examination of the stomach was performed two hours after the induction of the ulcerogenic examination. '

The compounds have a significant effect from 30 mg / kg on stress and from 100 mg / kg on phenylbutazone. The anti-secretory gastric activity of the compounds has been demonstrated in fasted rats with a ligated pylorus.

The female Wistar rats weighing 200-220 g were kept fast for 48 hours. The pylorus was bound under anesthesia with ether. Subsequently, the compounds were administered at a dose of 1, 5, 25 and 50 mg / kg by intraperitoneal administration immediately after the pylorus ligation. The animals were sacrificed 4 hours after the pylorus ligation. Thereby, the separated gastricity and the amount of free acid and the total amount of acid were measured by a titrimetric determination relative to a comparative dose. The compounds of the invention reduced gastric secretion by 45 to 55%, 50 to 65%, 70 to 85%, respectively; the free acid of 60-70%, 65-75% and 85-95%, respectively, and of the total acid of 55-65%, 60-70% and 85-95%, respectively.

The compounds of the invention are active as anti-depressant, anti-convulsive, anti-ulcer and anti-secretory gastric juice agents and even have anxiolytic, analgesic and anti-inflammatory activity. They are useful as a therapeutic agent for humans and animals for the treatment of various central nervous system diseases, for example, for the treatment of depressive states, psychoses, certain neurological diseases, such as epilepsy, spastic disorders, discynesia, for the treatment from various ulcers from stress and ulcers.

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The invention therefore also relates to all pharmaceutical compositions containing the compounds of formula 1 as active ingredient, together with all possible auxiliary substances suitable for administering the active substance, in particular for oral administration such as 5 tablets, dragees, gelules, capsules, cachets, solutions or suspensions that are drinkable or for parenteral administration. The daily dosage can range from 100 to 3000 mg.

83 04 v 7

Claims (5)

Benzylidene derivatives, characterized in that they correspond to formula 1, stated on the formula sheet, wherein n is an integer 5 from 1-12, is an alkyl or alcenyl radical, straight or branched, with 2-6 carbon atoms, R £ is an N 2 OH or OM radical, where M is an alkali or alkaline earth metal, X 1, X, and X 1 each independently hydrogen atom, halogen atom, methoxy radical or a straight or branched alkyl radical with 1-4 carbon atoms 10. Derivatives according to claim 1, characterized in that they correspond to formula 3 stated on the formula sheet, wherein the substituents have the same meaning as stated in claim 1. Derivatives according to claim 2, characterized in that X ^ 15 is a chlorine atom or a methyl radical, X ^ is a chlorine atom or a methyl radical and a hydrogen atom. 4. Derivatives according to claim 3, characterized in that n equals 2 or 3 and R 1 is an ethyl, n-propyl, n-butyl, n-pentyl or. is n-hexyl radical. 5. - [{(5-chloro-2-hydroxy-3-n-propylphenyl) {4-chlorophenyl) -methylene} amino] butanoic acid and the alkali metal salts, alkaline earth metal salts and the amide thereof. 6. 4 - [{(5-chloro-2-hydroxy-3-ethylphenyl) (4-chlorophenyl) -methylene} amino] butanoic acid and the alkali metal salts, alkaline earth metal salts and the amide thereof. Process for the preparation of compounds according to claim 1, characterized in that a benzophenone of the formula 2 is reacted with a compound of the formula ^ N-iC ^^ - CC ^ »optionally in the form of the salt as the hydrochloride, at a temperature of 20-120 ° C in a solvent such as methanol, ethanol or a mixture of methanol / toluene in the presence of a base such as sodium ethylate or sodium methylate. Medicament, characterized in that it contains a compound as set out in claims 1-6. Pharmaceutical composition, characterized in that it contains a compound as defined in any one of claims 1-6, together with an appropriate excipient. 8304070 Eindhoven, November 1983