CH656876A5 - ALKYL BENZYLIDENIC DERIVATIVES, THEIR PREPARATION AND THEIR PHARMACEUTICAL COMPOSITIONS. - Google Patents

Description

The present invention relates to alkylated benzylidenic derivatives. their preparation and the pharmaceutical compositions containing them.

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

25

C = N— (CH „) —COR-Z n 2.

fc = N- (CH2) n-COR2

(I)

wherein the substituents have the meanings given in claim 1.

3. Compounds according to claim 2, in which X is a chlorine atom or the methyl radical,

X, is a chlorine atom or the methyl radical,

X3 is a hydrogen atom.

4. Compounds according to claim 3, in which n is equal to 2 or 3 and R! is an ethical radical. n-propyl, n-butyl, n-pentyl or n-hexyl.

5. [[(5-hydroxy-2-n-propyl-3-phenyl) (4-chloro-phenyl) methylene] amino] -4-butanoic acid, its alkali and alkaline-earth salts and its amide. as compounds according to claim 4.

6. [[(5-chloro-2-hydroxy-3-ethyl-phenyl) (4-chloro-phenyl) methyl] amino] -4-butanoic acid, its alkali and alkaline-earth salts and its amide, as compounds according to claim 4.

7. Process for the preparation of the compounds according to claim 1, characterized in that a benzophenone of the formula is reacted:

R.

(II)

30

in which 35 n 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 NH2 radical. OH, OM, M = alkali or alca-linoterrous metal,

40 X], Xz and X3 each represent, independently of one another, a hydrogen atom, a halogen atom, the methoxy radical or a (C, .4) straight or branched alkyl radical.

The preferred compounds of the invention are those which correspond to the formula:

45

in which the substituents have the meanings given above 60 and more particularly the compounds in which Xj is a chlorine atom or the methyl radical.

X2 is a chlorine atom or the methyl radical,

X3 is a hydrogen atom,

and among these the compounds of choice are those in which n is 65 equal to 3 and R, is an ethyl, n-propyl, n-butyl or n-hexyl radical. According to the invention, the compounds of formula I are prepared by the method according to claim 7. According to an advantageous embodiment of the method, the benzophenone of formula is reacted:

3

656,876

OH

■. <X

c = o

(II)

with the compound of formula:

H2N- (CH,) „- COR2

(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, etha-nol or the methanol, toluene mixture, in the presence of a base such as sodium ethylate or methylate. Compounds I, R2 = NH2 can also be prepared from compounds I, R2 = OH by amidification with carbonyldiimidazole and ammonia.

The starting benzophenones are new and are prepared, for example, according to the following reaction scheme:

Alclj or hu

(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] -4 butanamide.

[Xj = 5-C1, X, = 4-C1, X3 = H, n = 3, R! = n-C3H7, R2 =

NHZ]

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):

(I)

in 1.3 l 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 acid chloride (II):

(II)

dissolved in 100 ml of methylene chloride. Then, the mixture is heated at reflux for 8 h. The products are left in contact overnight. Then 500 ml of cold water is added to the solution. The organic phase is decanted and washed 1 time with 250 ml of a 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, drained and redissolved in 300 ml of petroleum ether at the boil. Treated for 15 min with stirring with 2 g of vegetable charcoal, filtered hot and concentrated the filtrate 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.

20 In a well ventilated hood, heat to 100 ', with stirring, 29.7 g (0.096 mole) of 4-chloro-4 (chloro-2-propyl-2) phenyl benzoate and add thereto in portions over 10 min. , 7 g (0.223 mole) of aluminum chloride. Then the mixture is heated in an oil bath, still stirring, to 160 ° C. and remains for 15 min at this temperature before allowing the reaction medium to cool down to 50 ". It is then cooled in dry ice for 1 h, the solid obtained is broken up and finely ground in a mortar, then the complex is hydrolyzed in the form of a powder, gradually poured into a highly stirred mixture of 1 1 of water, 500 g of ice and 300 ml of concentrated hydrochloric acid, 30 are extracted with a total of 3 l of methylene chloride, the organic layer is washed with 500 ml of water, decanted, dried over MgSO4, filtered and the filtrate is 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. oil obtained crystallizes in 150 ml of petroleum ether. It is filtered on a frit, wrung and dried in a desiccator. 55-56 C.

2. [[(5-Chloro-2-hydroxy-3-propyl-phenyl) (4-chloro-phenyl) -methylene] amino] -4 butanamide 40 A mixture of 6.2 g is evaporated to dryness 0.020 mole) of the ketone obtained previously, 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 introduced into the flask 600 ml of ethanol 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 dried over MgSO4, 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 cloudiness appears). By cooling, the amide (IX) crystallizes. Filtered on sintered, washed with 20 ml of ether, wrung and dried in a heated desiccator at 60 '~. F = 130-131C.

55 Example 2:

Butanoic acid [[(5-chloro-2-hydroxy-3-ethyl 3-phenyl) (4-chloro-phenyl) methyl]] butanoic acid and its sodium salt [X, = 5-C1, X2 = 4-C1, X3 = H, n = 3, Rj = C2H5, R2 = OH and ONa]

n / a 1. (5-Chloro-2-hydroxy-3-ethylphenyl) (4-chloro-phenyl) metha-none

Proceeding in the same manner as in Example 1.1, but replacing 4-chloro-2-propyl-2-phenol with 4-chloro-2-ethyl-phenol, 4-chloro-4-chloro-benzoate of 2-ethyl benzyl 65 which is reacted with aluminum chloride, under the same conditions. Benzophenone melts at 47-49c C.

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

656,876

4

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 are introduced into a 1 liter flask. (3.10 ~: mole) of sodium methylate.

It is refluxed for 4 hours and again added 1.6 g (1.5-10 ~~ mole) of GABA and 0.85 g (1.5-10_: mole) of sodium methylate.

The mixture is again refluxed for 4 hours, evaporated to dryness, the residue is taken up in 2.5 l of water and acidified to pH = 4 by addition of citric acid. Extracted with 2 x 350 ml of dichloromethane, the organic phases are combined, washed with 400 ml of water, dried over Na, SO 4, filtered and evaporated to dryness. The residue is brought on sintered with petroleum ether, drained and dried in a desiccator under vacuum. The product is recrystallized from diisopropyl ether. F = 131-132: C.

To 4.5 g of acid in solution in 100 ml of methanol, 15.7 ml of a 0.748 N solution of sodium methylate is added. The methanol is evaporated at 80 ° C., then 100 ml of ether is evaporated, the sodium salt is brought to a frit with ether, drained and dried in a vacuum desiccator. F> 2501 C.

Example 3:

Butanoic acid [[(5-chloro-2-hydroxy-3-tert-butyl-phenyl) (4-chloro-phe-nyl) methylene] amino] -4 and its sodium salt

[x, = 5-C1, X, = 4-C1, X3 = H, n = 3, Rj = t-C4H9, R2 = OH and ONa]

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

1.1. To a solution of 57 g (0.309 mole) of 4-chloro-2-tert-butylphenol, 32.3 g (0.32 mole) of triethylamine and 3.7 g (0.03 mole) of 4-dimethylamino pyridine in 800 cm3 of ether, a solution of 56 g (0.32 mole) of p-chlorobenzoyl chloride in 200 cm3 of ether is added dropwise.

After 6 hours of stirring at room temperature and overnight standing, 500 cm3 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:

/ T ^ \

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 mole) of the preceding ester is introduced into 200 cm3 of pure benzene. It is 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 Merck; eluent: petroleum ether / methylene chloride 9 1). The pure fraction is distilled in a ball tube.

Obtained (5-chloro-2-hydroxy-3-tert-butylphenyl) (4-chloro-phenyl) methanone. F = 86.5-87 C.

2. [[(5-chloro-2-hydroxy-3-tert-butyl phenyl) (4-chloro-phenyl) methylene] amino] -4-butanoic acid and its sodium salt 20 to 25 cm3 of a sodium ethylate solution containing 1 , 2 mmol of sodium, 0.128 g (1.24 mmol) of 4-amino butyric acid and 0.4 g (1.24 mmol) of (5-chloro-2-hydroxy-3-tert-butylphenyl) (chloro- 4 phenylJmethanone.

15 cm3 of alcohol are distilled relatively slowly, and 10 cm3 of absolute ethanol are added and then 15 cm3 of alcohol are redistilled.

After evaporation to dryness, the residue is dissolved in 20 cm3 of water and acidified with citric acid to pH = 4. It is extracted with methylene chloride, washed with water and dried over sodium sulfate.

After evaporation of the extract, the residue is recrystallized from heptane, then washed with pentane. F = 118-119 This F = 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 3 of an ethanolic solution of sodium ethylate at 0.332 mole liter (ie 2.4 mmol) is added. After evaporation to dryness, the oil is dissolved cold in 10 cm3 of cyclo-35 hexane. The sodium salt crystallizes slowly. After filtration and washing with pentane. drying at 100 ° C. under vacuum for 8 hours, the salt is obtained. F = 245 C! Dec.).

In Table 1 are shown the compounds of the invention prepared by way of examples.

Table I

c = N- (CH.) -COR, • 2 n z

Compound

not

X,

X2

x3

Ri r2

F (c)

1

3

5-c1

4-c1

h n-C3h,

nh2

130-131

2

3

5-c1

4-c1

h c2h5

nh2

128-130

3

3

5-c1

4-c1

h c2h5

We have

> 250

4

3

5-c1

4-c1

h c2hs

OCa / 2

245 (dec.)

5

3

5-c1

4-c1

h c2h5

OMg / 2

165-175

6

3

5-c1

4-c1

h n-C3H7

We have

207-209

7

2

5-c1

4-c1

h c2h5

nh2

190-192

8

3

5-c1

4-c1

h n-C „I 113

o ^

61.5-62

9

2

5-c1

4-c1

h n-CgH 13

nh2

130.5-131

10

2

5-c1

4-c1

H

n-C6HI3

We have

181-182

11

1

5-c1

4-c1

h n-C6HI3

nh2

132-133

12

3

5-c1

4-c1

H

n-CöHI3

nh2

92-92.5

13

2

5-ch3

4-ch3

h c2h5

nh.

167-168

14

1

5-c1

4-ch3

h n-CöH, 3

We have

200-201

15

3

5-c1

4-ch3

h n-C6HI3

nh2

120.5-121

16

1

5-c1

4-c1

h n-CöH13

We have

204-205

17

3

5-c1

4-c1

h n-C4H0

nh,

116-117

18

i

5-c1

4-c1

h n-C3H-

nh,

153-155

5

656 §76

Table 1 tsuite li

Compound

n x,

X;

x3

R!

R?

FCC)

19

3

5-CH,

4-CH3

h c, h5

NH,

110-111

20

3

5-CH3

4-CH3

h c, h <

We have

215

21

"Ì

5-C1

4-C1

H

n-C3H ~

We have

> 250

not

->

5-C1

4-C1

h i-C4HQ

We have

244 (dec.)

23

3

5-C1

4-C1

h i-C4H,

NH,

105-107

24

3

5-C1

4-CH3

h n-C3H7

We have

200-202

25

2

5-C1

4-CH3

H

n-C3H,

NH,

146-147

26

t

5-C1

4-CH3

h n-CfJH, 3

NH,

139.5-140

27

1

5-CI

4-C1

H

n-C3H7

We have

210-212

28

1

5-CH3

4-CH3

h c2h5

We have

195

29

1

5-C1

4-C1

H

n-C4H9

NH,

142-142.5

30

2

5-C1

4-C1

H

n-C4H9

We have

202-204

31

1

5-C1

4-C1

H

n-C4H0

We have

180-185

32

2

5-C1

4-C1

H

n-C3H7

We have

> 250 (dec.)

33

3

5-C1

4-CH3

H

n-C3H7

nh2

114-115

34

1

5-C1

4-CH3

H

n-c6h] 3

NH,

144.5-145

35

2

5-C1

4-CH3

H

n-c6h, 3

We have

196-197

36

4

5-C1

4-C1

H

n-C6H0

NH,

145-146

37

3

5-CI

4-C1

H

n-C4H „

OH

96.5-97.7

38

4

5-C1

4-C1

H

n-C4HQ

We have

190-196

39

3

5-CI

4-C1

h i-C4H0

We have

138

Table 1 (continued 2)

Compound

n xj x.

x3

R,

R,

F (C)

40

1

5-C1

4-C1

H

n-C3H,

nh,

145-146

41

2

5-C1

4-C1

H

i-C4H0

nh,

147-148

42

3

5-C1

4-CH3

H

Ì-C4Hg

We have

> 250

43

2

5-C1

4-C1

H

n-C4H „

nh2

136.5-137.5

44

3

5-C1

4-CH3

h

Î-C4Hq

We have

140-144

45

1

5-C1

4-CH3

H

i-C4Hg

We have

> 250

46

2

5-C1

4-CH3

h i-C4Hg

NH2

130 and 138

47

3

5-C1

4-CH3

H

i-C4Hg nh2

123-124

48

3

5-C1

4-CH3

H

n-C6Hl3

OH

69-70

49

3

5-F

4-C1

H

CH2-CH = CH2

NH2

116.1

50

3

5-C1

2-Br

H

ch2-chch2

nh2

115.7-116.8

51

3

5-C1

4-CH3

h n-C4H0

OH

119-120

52

1

5-C1

4-CH3

H

n-C4H0

nh2

142-143

53

1

5-C1

4-CH3

h n-C4Hp

We have

201-203

54

2

5-C1

4-CH3

h n-C4H9

We have

211-213

55

3

5-C1

4-CH3

H

n-C4H „

nh2

113.5-114.5

56

1

5-C1

4-C2H5

h c2h5

We have

249-250

57

3

5-C1

4-C2Hs h

c2h5

We have

> 225

58

1

5-C1

4-CH3

h i-C4Hg nh2

135.5-136.5 and 155.5

59

2

5-C1

4-C2H5

h c2h5

We have

256-257

60

3

5-C1

4-C, Hs h

c2h5

nh2

162-163

656,876

6

Table I> continued 31

Compose n

X,

X;

x3

R,

R,

F (C)

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

-> 3

T T

1

3 I

3 ->

1

3 3

1

3 3

2

5-Cl 5-Cl 5-Cl 5-CH, 5-CH, 5-CH3 5-CH3 5-ch3 5-CH, 5-Cl 5-Cl 5-Cl 5-CI 5-Cl 5-Cl 5- Cl 5-CI

4-CH, 4-CH3 4-CH3 4-nC3H-4-nC3H-4-nC3H ~ 4-nC3H-4-nC3H7 4-nC3H, 4-C, H5 4-C, H5 4-CI 4-Cl 4 -Cl 4-CI 4-CH3 4-CH3

H H H H H H H H H H H H H H H H H

nC4H „

C2H5

c2h5 c2h5 c2h5 c, h, c2hs c, h, c, h5 c2h5

C, H <iC3H-t-C.H (J C2H5 t-C4H0 C, H,

c2h5

NH, NH, NH, ONa ONa ONa NH, NH, NH, NH, NH, NH, NH, ONa ONa ONa ONa

143-144 143-145 171-173 212-213 177-178

170 132-133 135-136 163-164 139-140 146-147 166-167 153-154 265-267 245 (dec.) 238-240 258-260

78

3

5-Cl

4-Cl

H

^ • CH3 -ch \ ch =

CH,

NH,

135-136

79

3

5-CH,

4-CH3

H

t-c4ho

nh,

136-137

80

3

5-CI

4-Cl

H

-ch \ ch =

CH,

OH

141-142

81

3

5-CI

4-ÌC3H-

H

c2h5

NH,

156-157

Table I / continued 41

Compound

not

X,

X2

x3

Ri

R,

FCC ")

82

3

5-CH3

4-CH3

H

t-C4H „

We have

271-273

83

3

5-Cl

4-Cl

H

i-C3H,

We have

190 (dec.)

84

3

5-CH3

4-CH3

H

t-C4H0

OH

153-154

85

T

5-CI

4-CH3

H

C, H5

OH

145-147

86

3

5-Cl

4-CH3

H

c, h5

OH

114-116

87

3

5-Cl

4-Cl

H

t-C4IIr,

OH

118-119

88

1

5-Cl

4-Cl

H

C, H,

OH

148-150

89

3

5-CH3

4-nC3H,

h c2h5

OH

85-86

90

I

5-CH3

4-nC, H,

h c, h5

OH

152-153

91

2

5-CH3

4-nC3HT

H

c, h5

OH

94-95

92

T

5-Cl

4-C, H5

h c2h5

OH

105-106

93

3

5-Cl

4-C, H 5

H

C, H,

OH

83-84

94

1

5-Cl

4-C2H5

H

C, H5

OH

179-180

95

2

5-Cl

4-CH,

H

n-C4H „

OH

118.5-119.5

96

1

5-Cl

4-CH3

H

n-C4HQ

OH

158 (dec.)

97

1

5-Cl

4-CH3

h i-C4H9

OH

163 (dec.)

98

3

5-Cl

4-CH3

H

i-C4H0

OH

115-116

99

3

5-Cl

4-CH3

H

i-C4H0

OH

126 and 136

100

3

5-Cl

4-Cl h

i-C4H „

OH

103-104

101

4

5-Cl

4-Cl

H

n-C4H „

OH

123-123.5

102

->

5-Cl

4-CH3

H

n-c, jh, 3

OH

130-130.5

103

not

5-Cl

4-Cl

H

n-C3H-

OH

130-131

104

1

5-Cl

4-Cl h

n-C4H „

OH

162-162.5

Table 11 continued 5 ì

Compound

not

X,

x2

x3

ri r2

F (C)

105

->

5-Cl

4-Cl

H

n-C4H „

OH

171-172

106

2

5-CH,

4-CH,

H

C2H5

OH

132-133

107

1

5-Cl

4-Cl

H

n-C3H7

OH

175-176

108

3

5-Cl

4-CH3

H

n-C3H7

OH

107-108

109

T

5-Cl

4-Cl

H

i-C4H „

OH

160-163

110

2

5-Cl

4-Cl

H

n-C3H7

OH

119-121

111

3

5-CH,

4-CH3

H

c2h5

OH

115-116

112

1

5-Cl

4-Cl

H

n-CöH13

OH

156-157

113

1

5-Cl

4-CH3

H

n-c (jh13

OH

146-146.5

114

2

5-Cl

4-Cl

H

n-CrjHjj

OH

149.5-150

115

3

5-Cl

4-Cl

H

n-C3H7

OH

88.5-91

116

3

5-Cl

4-Cl

H

C2H5

OH

131-132

117

5

5-Cl

4-Cl h

n-C3H7

OH

114-115

118

4

5-Cl

4-Cl

H

n-C3H7

OH

128-129

119

4

5-Cl

4-CH,

h n-C3H7

OH

130-131

120

5

5-Cl

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-C, Hs

H

c2h5

OH

107-108

123

4

5-Cl

4-Cl

H

c2h5

OH

79

124

5

5-Cl

4-Cl h

c2h5

OH

94-95

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

Table II

Compound

x,

x2

Ri

Characteristics

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

5-Cl 5-Cl 5-Cl

5-CH3 5-Cl

5-Cl

5-Cl 5-Cl 5-Cl 5-F 5-Cl 5-Cl

5-Cl 5-CH3 5-Cl 5-Cl 5-Cl

4-Cl 4-Cl 4-Cl

4-CH3 4-CH3

4-Cl

4-Cl 4-CH3 4-CH 3 4-Cl 2-Br 4-CH3

4-C2H5 4-nC3H, 4-Cl 4-Cl 4-CH3

n-C3H7

c2h5

n-C6H13

C2Hs n-C6H13

n-C4H9

i-C4H „n-C3H7 i-C4H0 CH2-CH = CH,

ch2-ch = ch2

n-C4H0

c2h5 c2h5

Ì-C3H-7 t-C4H9 C2H5

F = 55-56 C F = 47-49 C oil, Eb = 204 C (0.1 Torr) F = 38-39 = C oil, Eb- 192 C (0.1 Torr)

oil, Eb = 168-170 C (0.03 Torr) F = 65-66 C F = 63-64 C F = 71-72C F = 44.6C oil oil, Eb = 148-150 C (0.06 Torr)

oil, nfj = 1.6060 oil, nj) '= 1.5861 F = 54-55 C F = 86.5-87 C F = 53-55-C

18

5-Cl

4-Cl r „^ CH 3 ^ ch = ch2

F = 45-47 = C

19

20

5-CH3 5-Cl

4-CH3

4-ÌC3H-

t-C4Hg c2h;

F = 110-lll C F = 42-43 'C

656,876

8

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 (lethal dose 50%) inducing death in 50 ° »of animals ranges from 250 to> 1000 mg kg.

The antidepressant activity of the compounds has been shown by the antagonism towards “head-twitches” caused by L-5-hydroxy-tryptophan in mice.

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-HTP at a dose of 250 mg kg, by the subcutaneous. Forty-five minutes after this injection of 5-HTP, the number of head-twitches is counted, for each mouse, for one minute.

For each treatment, the average of the head-twitches, as well as the percentage of variation compared to the control batch, are calculated.

From the effect-dose curve, the DA 50 is determined (active dose 50% or dose which decreases the average number of head-twitches by 50%) by the graphic method of Miller and Tainter (1944).

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

The anticonvulsant activity of the compounds has been shown by the antagonism vis-à-vis the mortality induced by bicuculline in mice.

Bicuculline is a relatively selective blocker of postsynaptic GABA-ergic receptors and its convulsive and lethal effects are antagonized by compounds raising the level of cerebral GABA or having GABA-mimetic activity.

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

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 the phenylbuta-zone.

The two tests, stress ulcers and uleeres induced by phenyl-butazone. were performed on female Wistar rats weighing 180-210 g. on an empty stomach, the compounds being administered in the form of a suspension in an aqueous solution of Tween 80 at 1% orally 5 immediately before stress or 30 minutes before the oral administration of phenylbutazone. In both cases. stomach examination was carried out 2 hours after the induction of the ulcerogenic process.

The compounds have a significant action from 30 mg, kg vis-à-vis stress and from 100 mg kg vis-à-vis phenylbutazone. The gastric antisecretory activity of the compounds has been shown in the alert rat with ligated pylorus.

Female Wistar rats weighing 200 to 220 g 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 15 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 titrimetry compared to a control assay. The compounds of the invention decrease the volume of gastric secretion by only 45 to 55 ° o, 50 to 65%, 70 to 85% respectively; the free acidity of 60 to 70%, 65 to 75%, 85 to 95% respectively, 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 have 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 depression, psychosis, certain neurological diseases such as epilepsy, spasticity, diskynesis, for the treatment of various stress and gastric ulcers.

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

The daily dosage can range from 100 to 3000 mg.

R

Claims (2)

656,876 -> I. Benzylidenic derivatives corresponding to formula (I):. Ri C = N- (CH2) n-COR2 with a compound of formula: H, N- (CH,) „- COR, (III) 5 or with a salt of this compound, in a solvent, in the presence of a base. 8. Pharmaceutical composition, characterized in that it contains as active substance a compound according to claim 1. 9. Pharmaceutical composition according to claim 8, in which the active substance is a compound according to one of claims 2 to 6. where n is an integer ranging from 1 to 12, Rt represents a straight or branched alkyl or alkenyl radical of 2 to 6 carbon atoms, R2 represents an NH2, OH, OM, M = alkali or alka-linoterrous metal radical, X ,, X, and X3 each represent, independently of one another, a hydrogen atom, a halogen atom, the methoxv radical or a straight or branched alkyl radical (CM). 2. Compounds according to claim 1, corresponding to the formula: