LU85106A1 - ALKYL BENZYLIDENIC DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION - Google Patents

Description

* 1

The present invention relates to alkylated benzylidenic derivatives, their preparation and their therapeutic use.

The compounds of the invention correspond to formula (I) f1

",. X OH

vO

Çï = N- {CH,) -COR, 1 z n z X7 — V-. |) 2 j * 3 ··: 10 in which n is an integer ranging from 1 to 12,: ΚΊ represents a straight or branched alkyl or alkenyl radical of 2 to 6 carbon atoms, R2 represents a radical NH2, oh, OM (m = alkali metal or) alkaline earth),: X ^, X2 and X ^ each represent, independently of one another - a hydrogen atom, a halogen atom, the radical i methoxy or a radical (C ^ _4) straight or branched alkyl.

The preferred compounds of the invention are those which correspond to the formula! i Q- * ’25 * 2! 2 \ 5 in which the substituents have the meanings given above and more particularly the compounds in which X ^ is a chlorine atom or the methyl radical, X2 is a chlorine atom or the methyl radical, is a d atom. hydrogen, 10 and among these the compounds of choice are those in which n is equal to 3 and is an ethyl, n-propyl, n-butyl or n-hexyl radical.

4

According to the invention, the compounds of the invention can be prepared in the following manner *! 15 a benzophenone of formula (II) is reacted

xrOC

I f = 0 (II) I 20 \ -Îl-Xo

I J

ï with a compound of formula (III)! H2N- (CH2) n-COR2 (III) I _ optionally in the form of a salt such as the hydrochloride; 1 25 at a temperature of 20 to 120 ° C, in a solvent such as I. methanol, ethanol or the methanol / toluene mixture, in the presence of a base such as ethylate or methylate this sodium. The compounds (I, R2 ~ KH2) can also be pre-! prepared from the compounds (I., R2 = OH) by amidification I 30 with carbonyldiimidazole and ammonia.

I a

• 3

The starting benzophenones are new and are prepared, for example, according to the following reaction scheme: X- f1 Γ1 F1 rlu

. Jy A

ΓΊ ^) ch2ci2 ll ^ JJ

A- Y A1C1- or hu

3 x2 J

RjL '' JL 0H * 10 * 0 ^ <II>! ^

The following examples illustrate the invention.

The analyzes and the IR and NMR spectra confirm the structure of the compounds.

Example 1 ^ [(5-chloro-2-hydroxy-3-propyl-phenyl) (4-chloro-phenyl) methylene} amino ^ j -4 butanamide.

^ = 5-C1 X2 = 4-Cl X3 = H- n = 3 Rx = n-C3H? R2 = NH2J

120 1. (5-chloro-2-hydroxy-3-propyl-phenyl) (4-chloro-phenyl) methanone.

To a stirred solution of 21 g (0.123 mol) of phenol (I)

Jr / 25 (l) / if t _ 4 * in 1/3 1 of methylene chloride, 17.15 ml (0.123 mol) of triethylamine are added and the mixture is heated to reflux. The heating is stopped and slowly introduced into the solution, so as to maintain the reflux 21.54 g (0.123 mole) of 5-acid chloride (II) oCr '° (n) dissolved in 100 ml of methylene chloride . Then, the mixture is heated at reflux for 8 hours. The products are left in contact overnight. Then add 500 ml of cold water to the solution. The organic phase is decanted and washed 1 time with 250 ml of saturated sodium bicarbonate solution and 1 time with 250 ml of water.

The organic phase is dried over MgSO 4, filtered and the filtrate is evaporated to dryness. An oil is obtained which crystallizes by trituration in 120 ml of petroleum ether.

The crystals are filtered, filtered and redissolved in 300 ml of petroleum ether at boiling point. It is treated for 15 min 20 with stirring with 2 g of vegetable charcoal, filtered hot j and the filtrate is concentrated to a volume of about 150 ml.

Upon cooling, the ester crystallizes. It is filtered, wrung and dried in a desiccator.

, F = 49-50 ° C

25 In a well ventilated hood, heat to 100 °, with stirring, 29.7 g (0.096 mole) of 4-chloro benzoate (4-chloro-propyl-2) -! phenyl and add in portions, over 10 min, 29.7 g (0.223 j mol) of aluminum chloride. Then it is heated in an oil bath, still stirring, up to 160 ° and remains 15 minutes at this time-30 before allowing the reaction medium to cool to 50 °. Then cooled in dry ice for 1E, the solid obtained is broken and finely ground in mortar. The complex is then hydrolyzed in the form of a powder, gradually poured into a highly stirred mixture of 11 liters of water, 500 g of ice and 300 ml of concentrated hydrochloric acid.

Extracted with a total of 3 l of methylene chloride, the organic layer is washed with 500 ml of water, decanted, dried over MgSO 4, filtered and the filtrate concentrated to a volume of about a hundred ml. The crude product is then purified by passage through a column of 700 g of silica, eluting with 3 l of methylene chloride. The good fractions are dried over MgSO 4, filtered and the filtrate is evaporated to dryness. The oil obtained crystallizes in 150 ml of petroleum ether. I K is filtered on a frit, wrung and dried in a desiccator.

i 10 F = 55-56 ° C

2. £ [(5-chloro-2-hydroxy-3-propyl-phenyl) 4-chloro-phenyl) methylene3 aminoJ-4 butanamide.

A mixture of 6.2 g (0.020 mole) is evaporated to dryness (100 ° bath). from the previously obtained ketone, 3.05 g (0.022 mole) of 4-amino butanamide hydrochloride and 1.25 g (0.22 mole) of sodium methylate in 600 ml of methanol. Then 600 ml of ethanol are introduced into the flask and evaporated to dryness under the same conditions. 600 ml of ethanol are again evaporated off under reduced pressure at the end of the evaporation.

The residue dissolved in 300 ml of methylene chloride is washed with 100 ml of water. Decanted, the organic phase is dried over MgSO 4, filtered and evaporated to dryness under reduced pressure.

;! The solid obtained is dissolved in 15 ml of hot ethyl acetate. About 100 ml of ether are introduced into the solution (until a slight haze appears). Upon cooling, the amide (IX) crystallizes. Filtered on sintered, washed with!; . 20 ml of ether, wring and dry in a drying oven heated to 60 °.

[i

! F = 130-131 ° C

! , / L. .

ij r *

S

6

EXAMPLE 2 Acid £ |] (5-chloro-2-hydroxy-3-phenyl) (4-chloro-phenyl) methylene ^ amino J -4 butanol and its salt! sodium.

jXj ^ S-Cl X2 = 4-C1 X3 = H n = 3 R ^ C ^ R2 = OH and 0Na] i 5 1. (5-chloro-2-hydroxy-3-phenyl) (4-chloro-phenyl) methanone.

By proceeding in the same way as in Example 1.1., But by replacing 4-chloro-2-propyl-2-phenol with 4-chloro-2-ethyl-phenol, 4-chloro-4 benzoate of chloro-4 is obtained! 2-ethyl benzyl which is reacted with aluminum chloride | minium, under the same conditions. Benzophenone melts at! 47-49 ° C.

i! I 2. Acid (5-chloro-2-hydroxy-3-phenyl) (4-chloro-phenyl) methylene ^] amino ^ j -4 butanol and its sodium salt.

15 In ·, a 1 1 flask, 9 g (3.10 * ”^ mole) of the benzophenone, obtained previously, 350 ml of methanol, 3.23 g! (3.1-10 mole) of GABA and 1.72 g (3.10 mole) of methylate! sodium.

ί The mixture is brought to reflux for 4 hours and again 1.6 g are added; 20 (1.5-10 ^ mol) of GABA and 0.85 g (1.5-10 ^ mol) of sodium methoxide.

I The mixture is again refluxed for 4 hours, evaporated to dryness, resumed t! the residue with 2.5 l of water and acidifies to pH = 4 by adding a- ί! citric eide. Extraction is carried out with 2 x 350 ml of dichloromethane; 25 combines the organic phases, washing them with 400 ml of water, drying them over Na2 S04, filtering and evaporating to dryness.

| The residue is brought on sintered with petroleum ether, î! wrung and dried in a vacuum desiccator.

The product is recrystallized from diisopropyl ether.

j

30 F = 131-132 ° C

,% To 4.5 g of acid in solution in 100 ml of methanol, add ‘15.7 ml of a 0.748 N solution of sodium methylate. The methanol is evaporated at 80 ° C., then 100 ml of ether is evaporated! bring to ether sinter, spin and dry in a desiccator / 35 under vacuum the sodium salt.

7

Example 3 Acid (5-chloro-2-hydroxy-3-tert-butylphenyl) (4-chloro-phenyl) methylene] amino ^ -4 butanoïgue and its sodium salt.

[χχ = 5-Cl X2 = 4-Cl X3 B H n = 3 ÎL ^ t-C ^ R2 = OH and ONa 5 1. (5-chloro-2-hydroxy-3-tert-butyl-phenyl) (4-chloro-phenyl) methanone.

1.1. To a solution of 57 g (0.309 mol) of 4-chloro-tert-butyl-2-phenol, 32.3 g (0.32 mol) of triethvlamine and 3.7 g (0.03 mol) of 4-dimethylamino pyridine in 800 cm of e-10 ther, a solution of 56 g (0.32 mol) of p-chloro-benzoyl chloride in 200 cm3 of ether is added dropwise.

After 6 hours of stirring at room temperature and overnight standing, 500 * cm 3 of water are added.

The organic phase is washed with a sodium carbonate solution and then with water.

After drying over MgSO 4 and evaporation, a residue is obtained which is recrystallized from petroleum ether.

The compound of formula

Cl— COO- ^) Cl 20 melts at 103-104 ° C.

1.2. In a “Hanovia” photochemical reactor equipped with a 100 watt mercury lamp, a solution of 4.5 g (0.0139 mol) of the preceding ester is introduced into 2COcm3 of benzene: 'pure.

• 25 Irradiated with magnetic stirring and under a nitrogen atmosphere for 32 hours.

After evaporation of the benzene, the residue is chromatographed on a column in order to isolate the product (Kieselgel 40 Kerck; eluent: petroleum ether / methylene chloride 9/1). y 30 The pure fraction is distilled in a ball tube.

AT

"(5-chloro-2-hydroxy-3-tert-butylphenyl) (4-chloro-phenyl) methanone is obtained.

F = 86.5 - 7 ° C

12. Acid ^ (5-chloro-2-hydroxy-3-tert-butyl phenyl) 5 (4-chloro-phenyl) methylene]] aminoj -4 butanoic and its sodium salt.

I! To 25 cm 3 of a sodium ethylate solution containing 1.3 mmol I of sodium, 0.128 g (1.22ximol) of 4-amino-butyric acid and 0.4 g (1.24 mmol) are added. (5-chloro-2-hydroxy-! 10-butyl-3-phenyl) (4-chloro-phenyl) methanone.

s 15 cm ^ of alcohol are distilled fairly slowly, and 10 cm "* | of absolute ethanol are added and then 15 cm ^ of alcohol is redistilled.

1 · 3 | After evaporation to dryness, the residue is dissolved in 20 cm of water and acidified with citric acid to pH = 4.

ä fj 15 Extracted with methylene chloride, washed with water and 4 I dried over sodium sulfate.

I After evaporation of the extract, the residue is recrystallized I from heptane, then washed with pentane.

1 F = 118 - 9 ° C and F = 125 - 6eC

'1; ! To a solution of 1 g (2.45 mmol) of the acid in 10 cm3% fi of absolute ethanol, 7.23 cm3 of an ethanolic solution of 0.332 sodium ethoxide is added. mol / liter (i.e. 2.4 mmol).

i After dry evaporation, the oil is dissolved cold in I - 3 |; ‘10 cm of cyclohexane. Sodium salt slowly crystallized.

f "

I 25 After filtration and washing with pentane, drying at 100 ° C

i under vacuum for 8 hours, salt is obtained.

t.

I F = 245 ° c (dec.) I-; The following table shows the compounds of the in! yention prepared as examples.

ii 't TABLE (I) 9 V & - 5 C = N- (CH2) n-COR2 (I) LJ— * 2. - X3

Compound η Χχ X2 x3 R r2 f (° C) 1 3 5-Cl 4-C1 H n ~ C3H7 NH2 130-131 10 2 3 5-Cl 4-C1 H C2H5 NH2 128-130 j '3 3 5-Cl 4-C1 H C2H5 ONa> 250 I 4 3 5-Cl 4-C1 HC ^ OCa / 2 245 (dec) 1 5 3 5-Cl 4-C1 H C2H5 OMg / 2 165-175 | . 6 3 5-Cl 4-C1 H n-C ^ ONa 207-209.

13 7 2 5-Cl 4-C1 'H C „Hc NH- 190-19 2

ZD Z

8 3 5-Cl 4-C1 H n-CcE .., OH 61.5-62

b JL J

9 2 5-Cl 4-C1 H n-C6H13 KH2 130.5-131 I 10 2 5-Cl 4-C1 H n "C6H13 ONa 181-182 11 1 5-Cl 4-C1 H nC, H10 NH_ 132- 133 b xd z 20 12. 3 5-Cl 4-C1 H n-C6H13 NH2 92-92.5 i 13 2 5-CH3 4 "CH3 K c2H5 NH2 167-168 j 14 1 5-Cl 4-CH3 H n “C6K13 ONa 200-201; : 15 3 5-Cl 4-CH 3 H n "c6Hi3 NH2 1-20,5-121 16 1 5-Cl 4-C1 H nC.K-, - ONa 204-205 jb JLd I 25 17 3 5-Cl 4-Cl H nC.H. NH_ 116-117; 4 9 2 | 18 2 5-Cl 4-Cl H nC „H- NH0 153-155 i / j 7 2 î / ir / <i '10 TABLE I ( continued. 1) "

Compound η X · ^ X2 X3 R2 F (eC) 19 3 5-CH_ 4-CH- H C0Hc NH_ 110-111 20 3 5-CH 2 4-CH3 H C2H5 ONa 215 5 21 2 5-Cl 4-Cl H n-C3H7 ONa> 250 22 2 5-Cl 4-Cl H iC.H_ ONa 244 (dec) 4 9 23 3 5-Cl 4-Cl H i- ^ Hg NH2 105-107 24 3 5-Cl 4-CH3 H n-C3H? ONa 200-202 25 2 5-Cl 4 “CH3 h n_C3H7 NH2 146-147 10 26 2 5-Cl 4-CH3 H n-C6H13 NH2 139.5-140 i 27 1 5-Cl 4-Cl H nC. ^ ONa 210-212 28 2 5-CH3 4-CH3 H C2H5 ONa 195 29 1 5-Cl 4-Cl H nC ^ g NH2 142-142.5 d; 30 2 5-Cl 4-Cl 'H n-C4Hg ONa 202-204 1- 31 1 5-Cl 4-Cl H nC ^ ONa 180-1B5 32 2 5-Cl 4-Cl H nC ^ ONa> 250 (dec ) I: 33 3 5-Cl 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 iî-C6H13 ONa 19 6-19 7 I '20 36 4 5-Cl 4-Cl H n-CgHg NH2 145-146 37 3 5-Cl 4-Cl H nC ^ OH 96.5-9 7.7 38 4 5-Cl 4 -Cl H nC ^ ONa 190-196 39 3 5-Cl 4-Cl H iC ^ ONa 13c

HE

<TABLE I (continued 2) 11

Compound η X2 & 2 F (° c) 40 1 5-Cl 4-Cl H n-C3H? NH2 145-146 41 2 5-Cl 4-Cl H iC ^ g NH2 147-148 5 42 3 5-Cl 4-CS 3 H i-C4Hg ONa> 250 43 2 5-Cl 4-Cl H n-C4Hg 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; 46 2 5-Cl 4-CH3 H i-C4Hg NH2 130 and 138: '10 47 3 5-Cl 4 "CH3 h NH2 123-124 48 3 5-Cl 4-CH3 H n-C5H13 OH 69-70 49 3 5-F. 4-Cl H: H ^ -CH = CH2 NH2 116.1 50 3 5-Cl 2-Br H: H2-CH = CH2 NH2 115.7-116.8: 51 3 5-Cl 4_CH3 hn "C4Hg 0H 119-120 15 52 1 5-Cl 4-CH3 H n-C4Hg NHj 142-143 53 1 5-Cl 4-CH 3 H n-C4Hg ONa 201-203 54 2 5-Cl 4" CH3 H n -C4H9 ONa 211-213 I! 55 3 5-Cl 4-CH3 H nC ^ g NH2 113,5-114,5 j '56 1 5-Cl 4-0 ^ ,. HC ^ ONa 249-250 20 57 3 5-Cl 4 “c2Hi H C2H5 ONa> 225 135.5-136.5; 58 1. 5-Cl 4-CH3 H i-C4Hg NH2 and'155 # 5 'I 59 2 5-Cl 4 — C2Hi, H 0Na 256-257 d 60 3 5-Cl 4 ~ C2H, i H C2K5 NH2 162-163! / Il TABLE I (continued 3) 12

Compound η X ^ X2 X3 ^ 2 F (° C) 61 2 5-Cl 4 ~ CH3 h nC4H9 KH2 143-144 '62 3 5-Cl 4-CH3 H C2H5 NH2 143-145 5 63 2 5-Cl 4_CH3 h c2H5 ^ 2 171-173 64 2 5-CH 2 4-nC3H7 HC ^ ONa 212-213 65 1 5-CH 2 4-nC3H? H C2H5 ONa 177T178 66 3 5-CH3 4-nC3H? H C2H5 ONa 170 67 1 5-CH3 4-nC3H? H C2H5 NH2 132-133 10 68 3 5-CH3 4-nC3H7 H C2E5 NH2 135-136 69 2 5-CH3 4-nC3H7 H NH2 163-164 70 1 5-Cl 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 iC ^ NH2 166-167 15 73 3 5-Cl 4-Cl H tC ^ NH2 153-154 74 2 5-Cl 4-Cl H C2K5 ONa 265-267 75 3 · 5-Cl 4-Cl H t-C4Hg ONa 245 (âec); 76 3 5-Cl 4-CH3 H C2H5 ONa 238-240. 77 2 5-Cl 4_CH3 h c2H5 0Na 258-260 CH "20 78 3 5-Cl 4-Cl H -CH ^ 3 NH_ 135-136 nch = ch2 79 3 5-CH3 4“ CH3 H t-C4Hg NH2 136- 137 1 80 3 5-Cl 4-Cl H -CP <^ | CH OH 141-142 2 81 3 5-Cl 4-iC3H7 H C2H5 KH2 15.6-157 / / {t 13 TABLE I (continuation 4) »

Compound η X2 ^ 3 ^ ^ 2 F (6C) 82 3 5-CH3 4-CH3 H t-C4H9 ONa 271-273 83 3 5-C1 4-Cl H i-C3H7 Oïîa 190 (dec.) Σ 84 3 5 -CH- 4-CH, H tC.Hn OH 153-154 85 2 5-Cl 4_CH3 h C2H5 oh 145-147 86 3 5-Cl 4-CH_ H C-H_ OH 114-116 Ô Δ i> I 87 3 5-Cl 4-Cl H tC.H_ OH 118-119 4 9 88 2 5-Cl 4-Cl H OH 148-150 10 89 3 5-CH- î-nC_H_ H C-H_ OH 85-86 3 3 7 2 5 90 1 5-CH- î-nC_H- H C0Hc OH 152-153 3 0 1 Δ Ό 91 2 5-CH- î-nC_H_ H C-Hc OH 94-95

D J / Z D

92 2 5-Cl 1-C-Hc H CH ,, OH 105-106 2 5 2 5 93 3 5-Cl Î-C-Hc H C0H_ OH 83-84 2 5 2 5 15 94 1 5-Cl 5 “ C2H5 h C2H5 0H 179-180 95 2 5-Cl 4-CH3 H n-C4Hg OH 118.5-119.5 96 1 5-Cl 4 "CH3 H n-C4Hg OH 158 (âec) 97 1 5-Cl 4 -CH3 H i-C4Hg OH 163 (dec) 98 3 5-Cl 4-CH_ H iC.H- OH 115-116! 3 4 9 20 99 3 5-Cl 4-CH- H iC * H. OH 126 and 136 3 4 9 100 3 5-Cl 4-Cl H iC.H- OH 103-104 4 9 101 4 5-Cl 4-Cl H n-C4Hg OH 123-123.5 102 2 5-Cl 4-CH3 H n-CgH ^ OH 130-130,5 103 2 5-Cl 4-Cl H nC ^ OH 130-131 ί 25 104 1 5-Cl 4-Cl H nC.H- OH 162-162,5! / 49.

r / 1. _________________ ______ ί? i - 14 - TABLE I (Continuation 5.).

> CQnposà n Xx x2 X3 R1 * 2 F (° C)! 105 2 5-Cl 4-Cl E n-C ^ Hg OH 171-172 105 2 5-CH3 4-CH3 H C2H5 OH 132-133 5 107 1 5-Cl 4 — Cl H n-C ^ OH 175-176

108 3 5-Cl 4-CH3 E n-C3H7 OH 107-lOE

109 2 5-Cl 4-Cl H i-C ^ 0H 160-163! 110 2 5-Cl 4-Cl E n-C_S7 OH 119-121 111 3 5-CH3 4-CH3 H C2H5 OH 115-116 I '10 112 1 5-Cl 4 — Cl' H n-CgH ^ OH 156- 157 113 1 5-Cl 4-CH3 E u-C6H13 OH 14 6-14 6.5! j 114 2 5-Cl 4-Cl H n-CgH ^ OH 145.5-150 115 3 5-Cl 4-Cl H τι-C ^ OH BB.5-51; 116 3 5-Cl 4-Cl 'H C ^ OH 131-132! 15 117 5 5-Cl 4-Cl H nC ^ OH 114-115 ... 118 4 5-Cl 4-Cl H n-C3H7 OH 128-129 I * 119 4 5-Cl 4-CH H nc H- OH 130-131

! d37 D

î 120 5 5-Cl 4-CH- H n-C H OH 101-102 I 3 3 / I 121 5 5-Cl 4-C2H5 H c? H5 0H 114-114! 122 4 5-Cl 4-C „Hc H C-Hc OH 107-106 ·: έ 5 Z 5! 123 4 5-Cl 4-Cl H C_Hc OH 79; z b 124 5 5-Cl 4-Cl H C ^ OH 94-95 '/ - t 15

The starting benzophenones (II) are shown in Table II below.

TABLE II

5 X. ° h; î r --------- ----- - -------! Compound Χχ X2 'Characteristics

I 5-Cl 4-Cl n_C3H7 F = 55-56 ° C

; 10 2 5-Cl 4-Cl C0Hc F = 47-49 ° C

3 5-Cl 4-Cl n-CcH oil Eb = 204 ° C

b ± J (0, lTorr)

4 5-CH3 4 “ch3. C2H5 F = 38-39 ° C

5 5-Cl 4-CH- n-C-H., Oil, Eb = 192 ° C

-3 b (O, iTorr)

6 5-Cl 4-Cl n — C.Hq oil, Eb = 168-170 ° C

4 y (O, 03Torr)

15 7 5-Cl 4-Cl i-CI F = 65-66 ° C

4 9

8 5-Cl 4-Ch3 n_C3H7 F = 63-64 ° C

9 5-Cl 4-CH3 i "C4Hq F = 71-72CC

10 5-F 4-Cl CH2-CH = CH2 F = 44.6 ° C

II 5-Cl 2-Br CH2-CH = CH2 oil t

20 12 5-Cl 4-CH n-C.H oil, Eb = 148-150 ° C

-5 4 y (0.06 Tor) 13 5-Cl 4-C2H5 C2H5 oil / n2J = 1.6060 14 5-CH3 4 "nC3H7 C2H5 h“ island, ^ = 1/5861: / 116 TABLE II (continuation I)

Compound X ^ Xj R ^ Characteristics

15 5-Cl 4-Cl i_C3H7 F = 54-55eC

16 5-Cl 4-C1 t-C ^ Iîg F = 86.5-87 ° C

5 17 5-Cl 4 “CH3 C2H5 F = 53-55 ° C

18 5-Cl 4-Cl CïTCH3 F = 45-47 ° C

^ ch = ch2

19 5 “ch3 4 ~ CH3 t_C4H9 F = llO-llleC

20 5-Cl 4-iC3H7 C2H5 F = 42-43 ° C

.4 The compounds of the invention have been subjected to pharmacological tests showing their activity on the central nervous system.

Acute toxicity was determined in mice intraperitoneally. The LD 50 (50% lethal dose) inducing death in 50% of the animals ranges from 250 to 1000 mg / kg.

• · · The antidepressive activity of the compounds has been shown by the antagonism vis-à-vis the "head-twitches" (snorting- of the head) caused by L-5-hydroxy-tryptophan in the mouse.

10 The mice (CD1 males, Charles River France; 18-22 g of body weight) receive the products to be studied, in increasing doses or the solvent, simultaneously with L-5 — HT? at a dose of 250 mg / kg, subcutaneously. Forty five minutes later; this injection of 5-HTP, the number of "head-twitches" 15 (hoarseness of the head) is counted, for each mouse, for one minute. *. * · F ’For each treatment, ..the average of the“ bead-twitches ”, thus the percentage of variation compared to the control batch, is calculated.

20 From the effect-dose curve, the DA 50 is determined (active dose 50% or dose which reduces the average number of "bead-twitches" by 50%), using the graphic method of Miller and Tainte (1944).

s - w

The AD 50 of the compounds of the invention varies from 40 to 60 mg / kg 25 intraperitoneally.

The anticonvulsant activity of the compounds has been shown by antagonism with respect to the mortality induced by bicucu-lline in mice.

Bicuculline is a relatively selective blocker of post-synaptic GABA-ergic receptors and its con-, vulsant and lethal effects are antagonized by compounds raising the level of cerebral GABA or possessing mimetic GABA-5 activity.

The active dose 50% (DA 50) was evaluated, a dose protecting 50% of animals against the effect of bicuculline, the substances studied.

* 10 The DA 50 of the compounds of the invention varies from 10 to 100 mg / kg intraperitoneally.

The antiulcer activity of the compounds has been shown by the activity vis-à-vis stress ulcers and ulcers induced by phenylbutazone.

The two tests, stress ulcers and phenylbutazone-induced ulcers, were carried out on female Wistar rats weighing 180-210 g, on an empty stomach, the compounds being administered in the form of a suspension in a 1% aqueous solution of Tween 80 orally immediately before stress or 30 minutes before oral administration of phenylbutazone. In both cases, the stomach examination was performed 2 hours after the induction of the ulcerogenic process.

The compounds have a significant action from 30 mg / kg with respect to stress and from 100 mg / kg with respect to phenylbu-tazone.

The gastric antisecretory activity of the compounds has been shown in the vigilant rat with ligated pylorus.

AT

/ b t 19

Female Wistar rats weighing 200 to 220 g per day are fasted for 48 hours. The pylorus is ligated under ether anesthesia. The compounds are then administered at a dose of 1, 5, 25 and 50 mg / kg intraperitoneally immediately after ligation of the pylorus. The animals are sacrificed 4 hours after ligation of the pylorus. The volume of the gastric secretion is measured and the free acidity and the total acidity are measured by titrimetric compared to a control assay. The compounds of the invention decrease the volume of gastric secretion by 45 to 55%, 50 to 65%, 70 to 85% respectively; the free acidity by respectively 60 to 70%, 65 to 75%, 85 at 95%, and the total acidity of 55 to 65%, 60 to 70% and 85 to 95% respectively.

The compounds of the invention are active as antidepressants, anticonvulsants, antiulcers and gastric antisecretaries, 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, these psychoses, of certain neurological diseases such as epilepsy, spasticity, diskynesia, for "treatment various stress and gastric ulcers.

The invention therefore includes all pharmaceutical compositions containing the compounds (I) as active ingredients, in combination with any excipients suitable for their administration, in particular by oral route (tablets, dragees, capsules, capsules, cachets, solution or * oral) or parenteral suspensions.

The daily dosage can range from 100 to 3000 mg.

AT

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Claims (9)

1. Benzylidene derivatives corresponding to the formula (I) Λ-- 5 x ^ -Ul in p = îf- (CH2) n-COR2 xz-Çji in which ^ 10. is an integer ranging from 1 to 12, R ^ represents a straight or branched alkyl or alkenyl radical of 2 to 6 carbon atoms, R2 represents an NHj, OH, OM radical (M = alkali or alkaline earth metal), 15 X ^, X2 and X ^ each represent, independently of one another, a hydrogen atom, a halogen atom, the methoxy radical or a straight or branched (C ^ _4) alkyl radical. 2. Derivatives according to claim 1, corresponding to the formula "jàc C = N- (CH2) n-COR2 y-x3 * 2! J in which the substituents have the meanings given in claim 1. A I, 21" 3. Derivatives according to claim 2, in which X ^ is a chlorine atom or the methyl radical, Xg is a chlorine atom or the methyl radical, "X ^ is a hydrogen atom. 4. Derivatives according to claim 3, in which n is equal to 2 or 3 and ^ is an ethyl, n-propyl, n-butyl-, n-pentyl or n-hexyl radical. 5. The acid £ [(5-chloro-2-hydroxy-3-propyl-phenyl) (4-chloro-phenyl) methylene ^ aminoj -4 butanoic and its alkaline and alkaline earth salts and its amide. 6. Acid [[(5-chloro-2-hydroxy-3-phenyl) (4-chloro-phenyl) methylene J-aminoj-4 butanoic and its alkali and alkaline earth salts and its amide. 7. Process for the preparation of derivatives according to claim 15 1, process characterized in that a benzophenone of formula (II) réagir1 JL OH xi_uC is reacted C = 0 (II) X2 with a compound of formula (III) H2N- (CH2) n-C0R2 (III) optionally in the form of a salt such as the hydrochloride; at a temperature of 20 to 120 ° C, in a solvent such as methanol, ethanol or the methanol / toluene mixture, in the presence! a base, such as ethylate or sodium methylate. * 4 22 8. Medicament, characterized in that it contains a compound specified in any one of claims 1 to 6. 9. A pharmaceutical composition characterized in that it contains a compound specified in any one of claims 1 to 6 in combination with any suitable excipient. 'UAYiYu'