CA1204774A - Therapeutically useful alkylbenzylidene derivatives - Google Patents

Abstract

ABSTRACT
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, X2 and X3 each represent, independently of one another, a hydrogen atom, the methoxy radical or straight- or branched-chain alkyl radical having 1 to 4 carbon atoms, are new compounds useful in therapy, more particularly as antidepressants, anticonvulsants, ulcer inhibitors and gastric secretion inhibitors and also as anxiolytic, analgesic and anti-inflammatory agents.
They can be prepared inter alia by reacting a corresponding appropriately-substituted benzophenone with a compound H2N-(CH2)n-COR2, n and R2 being as defined above.

Description

"~EW I~I RAPEUTICALLY USEFUL ALKYLBE~ZYLIDE~E 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:

Rl (I) N (CH2)n 2 x2~
x3 wherein n represents an integer from 1 to 12 (preferably 1 to 4), Rl represents a straight or branched-chain 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 Xl, 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:

Rl OH

C ~ (CH2)n COR2 ~II) (wherein the various symbols are a~ hereinbefore defined3, and more particularly those such compounds wherein X
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-n-propylphenyl)(4-chlorophenyl3methylene~-~inobutanoic 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 f ~2~

benzophenone of the general formula:

Rl ~0 Xlt~
I=O (III) h ~ 3 (wherein the various symbols are as hereinbefore defined) with a compound of the general formula:

H2~(CH2)n CR2 (IV) (wherein n and R2 are as hereinbefore defined), optionally in the form of an acid addition salt such as the hydrGchloride, at a temperature of 20 to 120C 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 R represents the amino radical can also be prepared by reacting a corresponding compound of genr-~ral formula I wherein R2 represents the hydroxy radical with carbonyldiimidazole and ~mmonia.
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 ~ se, viz. methods heretofore used or described in the chemical literature for preparing alkali metal or alkaline earth 5 metal salts of carboxylic acids.
The benzophenone starting materials of general formula III are new and can be prepared, for example, according to the following reaction scheme:

~"OH~ 1~" ~x2 Xl X ~ CH2C12 ¦ AlC13 or h~

3 ~2 ~ ~
~ OH

~C=O
~ X2 3 wherein the various symbols are as hereinbefore defined.
The Examples which follow illustrate ~he preparation of alkylbenzylidene derivatives of the present invention by the hereinbefore described process. The analyses and the IR and ~MR spectra confirm the structures of the compounds obtained.

~%1947~9~

Example 1 4-[(5-Chloxo-2-hydroxy-3-n~propylphenyl~
(4-chlorophenyl)methylene~-aminobutanamide.
~Xl=5-Cl,X2=4-Cl,X3=H,n=3,Rl=n-C3H7,R2=MH2~

1. (5-Chloro-2-hydroxy-3-n-propylphenyl)-(4-chlorophenyl)-methanone.
17.15 ml (0.123 mol~ of triethylamine are added to a stirred solution of 21 g (0.123 mol) of the phenol of the formula:

Cl 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:
~ Cl Cl ~ ~ J

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 ~;~0~7~4 water are then added to the solution. The organic phase is decanted and washed once with 250 ml of a sakurated solution of sodium bicarbonate and once with 250 ml of water.
The organic phase is clried over MgS04 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 15 minutes, with stirring, the mixture is filtered hot and the filtrate is concentrated to a volume of about 150 ml. The resulting ester crystallises on cooling. It is filtered off, drained and dried in a desiccator.
Melting point = 49-50C.
29.7 g (0.096 mol) of 4-chloro-2-propylphenyl 4-chlorobenzoate (obtained as described above) are heated to 100C under a well-ventilated hood, with stirring, and 29.7 g (0~223 mol) of aluminium chloride are added in portions over a p~riod of 10 minutes. The reaction medium is then heated in an oil bath to 160C, still with stirring, and left for 15 minutes at this temperature before being allowed to cool to 50C. 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 .

7~

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 MgS04 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 10 3 litres of methylene chloride. The fractions containing the product are dried over MgS04 and filtered and the filtrate is evaporated to dryness~ The oil obtained crystallises from 150 ml of petroleum ether. The crystals are filtered off on a frit, drained and dried in a desiccator.
Melting point = 55-56C.

2. 4-C(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 4-aminobutanamide hydrochloride and 1.25 g (0.22 mol) of sodium methoxide in 600 ml of methanol is evaporated to dryness (bath at 100C~
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 MgS04 and filtered and the filtrate is evaporated to dryness under reduced pressure.
The solid obtained is dissolved in 15 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 60C.
Melting point = 130-131C.
Example 2 4-[(5-Chloro~2-hydroxy-3-ethylphenyl~
(4-chlorophenyl)methylene~-aminobutanoic acid and its sodium salt.

[xl=s-cl~x2=4-cllx3=Hln=3lRl=c2H5 R2=~ and o~a~
.
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-propylp~nol by 4-chloro-2-ethylphenol, 4-chlo~o-2-ethylbenzyl 4-chlorobenzoate is obtained, which is reacted with aluminium chloride under the same conditions. The resulting benzophenone melts at 47-49C.
2. 4-[(5-Chloro~2-hydroxy-3-ethylphenyl~
(4-chlorophenyl)-methylene~-aminobutanoic acid and its sodium salt.

~2~1L'7'7~
_ g 9 g (3xlO 2 mol) of the previously obtained benzophenone, 350 ml of methanol, 3.23 g (3.1x10 2 mol) of gabamide (viz. ~-amino-butyric acid; abbreviated to GABA3 and 1.72 g (3xlO 2 molj of sodium methoxide are introduced in~o a 1 litre round-bottomed flask. The mixture is heated under reflux for 4 hours and a further 1.6 g (1.5x10 mol~ of GABA and 0.85 g (1.5x10 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 pH4 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 ~a2S04 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 ether.
Melting point = 131 132C.
15.7 ml of a 0.748~ 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 80C, 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 >250C.

Example 3 4-[~5-Chloro-2-hydroxy-3-tert.-butylphenyl)-~4-chlorophenyl)methylene ~ nobutanoic acid and its sodium salt.
[X =S-~ 2-4-cl~x3--Hln=3~Rl=~-c4H9~R2 ...... .
1. ~5-Chloro-2-hydroxy-3-tert.-butylphenyl)-(4-chloxophenyl)-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 t~mperature 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 Cl - ~ COO- ~ 1 melts at 103-104C~
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 ~een evaporated off, the residue is chromatographed on a column in order to isolate the product tMerck 40 silica gel, eluent: 9/1 petroleum ether~methylene chloride).
m e pure fraction is distilled in a bulbed tube.
This gives (5-chloro-2-hydroxy-3-tert.-butylphenyl)-(4-chlorophenyl)-methanone.
Melting point - 86.5-87~C.
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.
15 ml of alcohol are distilled fairly slowly, 10 ml of absolute ethanol are added and a further 15 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 pH4 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 - 118-119C and melting point =
125-126C.
7.23 ml of an ethanolic solution of sodium ethoxide containing 0.332 mol/litre (ie. 2.4 mmol~ are added to a solution of l g (2.45 mmol) of the obtained acid in 10 ml of absolute ethanol. After evaporation to dryness, the oil is dissolved in lO ml of cold cyclohexane. The sodium salt crystallises slowly. The salt is obtained after filtration, washing with pentane and drying in vacuo at 100C for 8 hours.
Melting point = 245C (decomposition).
Table I which follows show pictorially the compounds of the invention which were prepared by way of Examples.

TABLE I

~OH
Xl~
N- 5CH2) n-COR2 ~2 ___ _ ~ __ jMeltin~
Compound n X~ X2 X3 Rl ~2 ¦ Pi nt ( C
__ _ __ __ __ _ __ __ 1 3 5-Cl 4-Cl H n~C3~7 NH2 130-131 2 3 5-Gl 4-Cl ~I C2R5 2 128-130

3 3 ~ -Cl 4-t:l H C2~ o~aa ,~ 250

4 3 5-Cl 4-Cl ~ C2E~ OCa/2 245 (dec) ; 5 Cl 4-Cl ~1 C 2~ OMy/2 165~17 5 6 3 50Cl a~-Cl ~1 n -C3~7 ONa 207-209 7 2 5-C:1 4~ ~ c2p.~ N~2 l9C~-19 2 8 3 S-Cl 4-Cl H n-._ H OH 61.5-62 9 2 5 ~::1 4-Cl ~3 n C6X13 N~12 130 . 5-13 2 S-Cl 4-Cl ~1 J~ C6P'13 O~la 181-182 11 1 ~-Cl ~-Cl ~ r~-C6~13 NH2 132~133 12 3 5-Cl 4-Cl ~ n C6~13 NH2 9 2-9 2 . 5 13 2 5-CE13 4--C}I3 R C2H5 NH2 167-168 14 1 5-Cl 4 C~I3 H n-C6~13 ONa 20~-201 lS 3 5-t:l 40CH3 H ~ C6 13 NH2 120 . 5-12 16 1 5 Cl 4; Cl H n ~6 13 ONa 204-205 17 3 5-Cl 4 -Cl ~ n~C~EIg NE~;~ 116-117 18 . . S-Cl 4-Cl ~I n-C3}~7 ~H2 153-155 _ ~ __ __ __ _ TABLE I (continuation ) __ __ _. __. _ ~
Me l t i ng poi nt Compound n Xl X2 ~3 Rl R2 tC) . __ ~ __ _ __ . ~
19 3 5-CH3 4 C~3 H C2}1~ NH2 110-111 3 5-C~3 4 C:~3 ~ C2~ ONa 215 21 2 s-cî ~-Cl ~1 n C3~37 ONa ~ 250 22 2 S Cl 4~1 H i-C,~9 o~la244 (dec) 23 3 5-Cl 4-C~ ~1 i-C4~9 N~2 105 107 24 3 5-Cl 4-CX3 ~1 n C8H7 O~a 200-202 2 5-Cl 40CH3 ~ n~~ 3~1'7 NH2 146-147 26 2 5-Cl 4_~3 }I n-C6H13 NH2139 . 5-140 27 1 5-Cl 4-Cl H a ~ 3~7 O~a 210-212 28 2 5-C~3 4-C~3 EI C2~5 ONa 19 5 29 1 S-Cl 4-Cl H n C4Pg NH2142-142 . 5 39 2 5-Cl 4-Cl ~ n~C4~9 ON~ 202 204 31 1 5-~1 4~ 1 ~ r~-C~,~g ONa 18~-185 - 32 2 5-C:1 4-Cl H n C3~7 O~a,~250 (dec) 33 3 ~ 1 . 3 H n C3Fi7 NE~2114-115 34 1 5-C:1 4-~3 ~I n C6~13 ~2 144.5-145 2 5 -Cl 4-~3 ~ 5l-C6El13 ONa 196-197 36 4 S-Cl 4-Cl H n-C6H9 ~H2 145-146 37 3 5-Cl 4~-Cl H n-C4~Ig OH9 6 . 5 9 7 . 7 38 4 5 Cl 4-Cl ~I n i~4Y.9 ONa 190-196 3 9 3 S-Cl 4-Cl _ ' -C41l9 ON~ 13 8 TABLE I ( cont i nua~ i on j -. . . _~ __ Me~ting poin-Compound n Xl X2 X3 ~l R2(C ) . __ ~ ___ . . __ 1 5-Cl 4-Cl Hn C3~7 NH2145-146 41 2 5-Cl 4--Cl Ri-C:4~9 ~2147- 148 42 3 5-Cl 4-C~3 ~,i-C4~9 ONa> 2;0 4 3 2 5~Cl 4-Cl ~n -C4H9 N~236 ~ 5-13 7 . 5 44 3 5--Cl 4-C~3 Hi-~4Hg ONa140-144 ~ ~-Cl 4-CR3 ~i-C.~E~g ONaa~ 250 46 2 5-Cl 4 ~R3 Hi-C4~9 ~R2130 and 138 47 3 5~ l 4-C~I3 Hi- C4~1g NH21~3- 124 48 3 S-Cl 4-C~3 ~1n C6 13 r~H~g-70 49 3 5_ ~ 4 C:l ~:~2~ H=CH2 N~,2116 .1 3 5-Cl 2-Br El:~2-CH=C~ N~I2lS . 7-116 . 8 51 3 5 Cl 4-C~3 ~n C4Hg OH~19-120 - 15 52 1 5-Cl 4~C~3 ~n C4~9 N~2142-143 53 1 5~Cl 4~CH3 ~n-C4~9 ONa201-20 54 2 5-C~1 4-CH3 ~n-~:4Hg ONa211-213 -- 55 3 5-Cl 4 C~3 }'n-C4~9 N~2113~5-114.5 56 1 S-Cl 4-C~ HC2H5 ONB2~9-250 57 3 5-Cl 4-C2~I ~~2H5 O~a3~ . 5-136 . 5 58 1 5-t:l 4-C~3 Hi-C4Hg N}~2nd 155 - 5 59 2 5-Cl 4-C2EI ~1C2~5 ONa2~6--257 6~ 3 S-CL 4- C2 3--C2}35 NH216 2 -16 3 ~ABLE I (continuation ) -__ ~
Compound _ L X2 X3. Rl . 2 Me Lt- ng pci nt 61 2 5 Cl 4 CH3 H nC4HgN~2 143-144 ~2 3 S-Cl 4 ~3 ~ C2~5 N~2 143-145 63 2 5-Cl 4-t::~3 H c 2~ N~2 171-173 6~g 2 5-CH3 4-nC3~17 ~ ~2~5 O~a 212-21 3 6~ 1 5-C~3 4-nC3H7 ~ C2 ~0~3a 177-178 6 6 3 5-C~3 4-nC3H7 ~ C2~5 ONa 170 67 1 5-CH3 4-nC3~7 ~ C2~5 N~2 ' 32-133 6 8 3 5-CH3 ~-nC3P7 ~1 C2~5 NB2 13 5-13 6 69 2 5-C~3 4 nC3~7 H ~2~5 ~2 163-16~
1 S-Cl 4-C2~ H C2~5N~;2 139-140 71 2 5--::1 4--C:2H5 H C2 5 N~2 146 14, 72 3 5-Cl 4-Cl ~ iC3~7N~2 16~-167 73 3 5~t:1 4-Cl ~ t-C4~9N~2 1~3-15 74 2 5-Cl 4-Cl ~ C2~5 ONa 26~-26~
3 5-Cl 4-- Cl % ~ ~ 4H9ONa 245 ~dec) 76 3 5-Cl 4-CH3 H ~2~5 ONa 238-240 77 2 5-Cl 4~CH3 ~ C2H~;H0~ 258-260 78 3 ~-C~ 4-Cl H ~C~- C~ NP.2 135-136 79 3 5-C~3 4-CH3 H t-e4~9N~2 13~-137 3 ¦ ~ C~ C~3CH OEI 1410142 C2)~51`~'2 ~6-lS7 ., .

TARLE I ( cont i nuat i on3 _ . . . --~ ~elting point Compound Y~ Xl X2 l X3 Rl ¦ 2 ( ~C) ____ _ __ _ 82 3 5_~34-C~3 H ~ C4~9 O~la~71-273 83 3 ~-Cl 4-Cl R i C3~7 0~3a190 (dec ) -84 3 5-CH34-C~I3 R ~ ~ 4~9 O}I153-154 2 ~-Cl 4-CH3 ~ C ~R~; OEI145-147 86 3 ~-Cl 4 C~3 , EI C2~5 D~114 -116 87 3 5-Cl 4- Cl ~ t C4E19 OB118-llg . 8 2 5-C~ ~-~1 ~ C2~5 9E~148-150 89 3 5_~3-n~:3~37 ~ ~ 2~5 O~I85-8~
~ 5-OE34-nC3~7 R c2~s OR152-153 91 2 5-~.3~-nC3~7 H C2}~5 0~9 4-g 5 9 2 2 5-C:1~ -C2H5 H C2H5 OH105-106 93 3 5-Cl ~ c2~ E~ C2~ 0~ 83-84 34 1 5-Cl ~-c2~s ~ C2~1~ 0~179-18C~
. 95 2 S-Cl 4~ 3 H ~ C4E~9 OR118.~-119.
9 6 1 S-Cl4 -C:R 3 EI n-t::4 IIg OEIlS 8 ~ de c ) 97 1 S-Cl 4-CE13 ~ i-C4~19 OH163 (dec ) ~8 3 S-Cl 4 CH3 H i-C4~39 OEI115~116 99 3 S-Cl 4-CH3 ~1 i-C,~Rg 0~126 and 13 100 3 5 Cl 4-Cl ~ i C4H9 o~103 104 101 4 5-C:14 Cl EI n-C4}Ig o~123-123 .
102 2 5-Cl 4-C~;3 H n ~6~13 0~130-130 . 5 103 2 5-t:l4 Cl ~ n C3~7 OE~13C~-131 104 1 5-~1 J-Cl ~ 9 01~162_162 . 5 TABLE I (continuation) __ ~__ . r~_ . __ . . _. . ... . ..
Me l t i ng poi nt Compound n Xl X2 X3 ~1 ~2( C ) __ __ ., . ~ __ ... ___ . . . ~. .
lD5 2 5-Cl ~Cl ~ ~ ~4~9 OH171-172 106 2 5-C~3 ~-C~ R ~2~5 0~132-133 5107 1 50Cl 4~C1 H n ~3~7 OR175-176 1~8 ~ 5 C~ ~`CR3~ ~-C3~7 0~1~7-108 109 2 5;~1 4-Cl ~ i~C4~9 0~150-163 110 2 5-Cl 4~Cl H n ~3~7 0~119-121 111 3 S-C~3 4-CR3 ~ C2~5 0~11~ 116 10112 1 5-Cl 4_rl ~ n C6~13 OB 156-157 113 1 ~-Cl 4-C~3 ~ ~-~6~13 0~146-14~,5 11~ 2 ~ ~ 4-Cl ~ ~-~6~13 0~149.~-150 115 3 5-Cl 4-Cl R n ~3~7 0~88.5-91 . 116 3 5=Cl 4-Cl ~ ~2~5 0~131-132 15117 5 5-Cl 4-Cl H 3 7 OH114-115 118 4 5-Cl 4-Cl H 3 7 OH128-129 119 4 5-Cl 4-CH3 H 3 7 OH130-131 ~~ 120 5 5-Cl 4-C~3 H n~C3H7 OH101-102 121 .5 S-Cl 4-C2H-5 H. C2H5 OH114-114.5 122 4 5-Cl 4-C2H-5 H C2H5 OH107-108 123 4 5-Cl 4-Cl H C2H5 OH79 124 5 5-Cl 4-C1 H C2H5 OH94-95 '`,~, __ ~___ ___ _ .___ __. __ The starting benzophen~nes employed are ~hown in Table II.
TABLE II

OH
Xl~ !
~=o ~X2 s comPoun~ ! ~1 X2 ~1 ¦ characteristics . ~
1 S~Cl 4-Ct n C3~7 Melting point = 55-56C
2 S-Cl 4-Cl ~2 ~ Melting point = 47-49 C
3 5 C9 4-Cl ~ 6 13 2046C (0~; mm Hg) 4 5-C~3 4~C~3 r2R; Melting point = 38-39C
10 5 5-C~ 4~ ~ 3 n ~ 13 C\il6 boiLing point =

- 6 5~Cl ~Cl n-C~9 Oil, boOling point =
168-170 C (0.03 mm Hg) 7 s-c~ 4 - el 4 9 MeLting point = 6~-66C
8 5 Cl 4-G~3 ~.~C3~7 Melt;ng point = 63~64 C
9 S~C~ 4-C~3 i - e ~B9 Mel.ing point = 71-72C
15lQ 5-F 4-C1 C~2 C~ ~2 Melting point = 44.6C
il 5 ~ ~ ~-~s ~2~ C~2 Oil . 12 S-Cl 4-C~ n~C~g Oil, boOling point =
3 1~8-150 C (0.06 mm Hg) 13 S-Cl ~-C2~ 2 ~ Oil, nD = 1~6060 l4 5 C~3 4-nC3~7 2 S Oil, n2 = 1.5~61 . ~ __ __ ~ABLE II (continuation) Co pound 1 ~ tharacteristics . . _ . ~ , ~

5-Cl ~-Cl ¦1_63H7 MeLting point = 54-55C
16 ~-6~ 4 Cl t-C4~9 Melting point = 8605-17 5-Cl 4-C~3 C2~5 MeLtin~ ~oint = 53-55C
lB 5-Cl 4-Cl ~ ~ C~3 Melting po;nt = 45-47 C
19 5-C~3 4-C~3 t; C~g Melting point 1100C
S-C~ ~_~c~l~7 ~5 ~ in~ ~in~

The compounds of the invention were subjected to pharmacological tests w~ich 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 twit~hes caused in mice by L-5-hydroxytr~ptophan (L-5-HTP)D
Th~ mice (males CDl, 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 ror one minute.
The average number of head twitc'nes 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 substancesstudied, 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 tolOO mg/kg animal body weight, administered intraperitoneally.

~%~

The ulcer-inhibiting ac-tivit~ 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 180-210 g, the compounds being administered orally in the form of a suspension in a 1%
aqueous solution of Twee~ 80, immediately before the stress or 30 minutes after the oral administration of phenylbutazone.
In koth cases, examination of the stomach was carried out 2 hours a~ter 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.
m e gastric antisecretor~ activity of the compounds was shown on wa~e 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 ~fter 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 5~ to 65%, 60 to 70/0 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 e~ample 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 e~cipient(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 (11)

The embodiments of the invention, in which an exclusive privilege or property is claimed, are defined as follows:

1. A process for the preparation of a benzylidene derivative of the general formula:

(I) 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, 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, which comprises (A) reacting a benzophenone of the general formula:

(III) (wherein R1, X1, X2 and X3 are as hereinbefore defined) with a compound of the general formula:

H2N-(CH2)n-COR2 (IV) (wherein n and R2 are as hereinbefore defined), optionally in the form of an acid addition salt, at a temperature of from 20° to 120°C in an organic solvent medium in the presence of a base, or (B) in the case of a benzylidene derivative of general formula (I) wherein R2 represents the amino radical, reacting a corresponding compound of that general formula wherein R2 represents the hydroxy radical with carbonyldiimidazole and ammonia, or (C) in the case of a benzylidene derivative of general formula (I) wherein R2 represents a group -OM (M being as hereinbefore defined), converting by a method known per se a corresponding compound of that general formula wherein R2 represents the hydroxy radical into an alkali metal or alkaline earth metal salt.

2. 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, 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, when prepared by a process claimed in claim 1.

3. A process according to claim 1 wherein the benzophenone of formula III has the structure

4. Benzylidene derivatives of the general formula:

(II) (wherein the various symbols are as defined in claim 3) when prepared by a process claimed in claim 3.

5. A process according to claim 1 wherein n represents an integer from 1 to 4.

6. A process according to claim 1, 3 or 5 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.

7. A process according to claim 1, 3 or 5 wherein n represents 3 and R1 represents an ethyl, n-propyl, n-butyl or n-hexyl radical.

8. A process according to claim 1 wherein X1 is 5-Cl, X2 is 4-Cl, X3 is H, n is 3, R1 is n-C3H7 and R2 is NH2.

9. 4-[(5-Chloro-2-hydroxy-3-n-propylphenyl)(4-chloro-phenyl)methylene]-aminobutanoic acid, its alkali metal and alkaline earth metal salts and its amide, when prepared by a process claimed in claim 8.

10. A process according to claim 1 wherein X1 is 5-Cl, X2 is 4-Cl, X3 is H, n is 3, R1 is C2H5, R2 is OH and ONa.

11. 4-[(5-Chloro-2-hydroxy-3-ethylphenyl)(4-chloro-phenyl)methylene]-aminobutanoic acid, its alkali metal and alkaline earth metal salts and its amide, when prepared by a process claimed in claim 10.