FR2536070A1 - HYDROXYLATED DIPHENYL-AZOMETHINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION - Google Patents

Abstract

BENZYLIDENIC DERIVATIVES RESPONDING TO FORMULA (I): (CF DRAWING IN BOPI) IN WHICH: N IS A WHOLE NUMBER RANGING FROM 1 TO 12, X, X AND X REPRESENT EACH, INDEPENDENT OF ONE OF THE OTHER, AN ATOM D 'HYDROGEN OR A HALOGEN ATOM, R REPRESENTS AN NH, OH OR OM RADICAL (ALKALINE OR ALKALINOTERROUS MMETAL). APPLICATION IN THERAPEUTICS.

Description

25360 00

  The present invention relates to benzylidene derivatives

  hydroxylated substances, their preparation and their therapeutic application. The compounds of the invention correspond to the formula C = N- (CH 2) n-COR X 29 X 3 in which n is an integer ranging from 1 to 12,

  X 1, X 2 and X 3 each independently represent one of the

  is a hydrogen atom or a halogen atom, R represents an NH 2 OH or OM radical (M = alkali metal or alkaline earth metal). The preferred compounds of the invention are those which correspond to the formula

X 1 C = N- (CH 2) 3-COR

x 3 X 2 in which

  R, X 1, X 2 and X 3 have the meanings given above.

  The compounds of the invention can be prepared

  either by chemical synthesis by reaction between the benzo

  corresponding phenone of formula (II) X 1- (II) x 3 with a compound of formula (IV) H 2 N- (CH 2) n-COR optionally in salt form 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 of a base;

  either by extraction after in vitro metabolisation of homo-

  liver genomes or in vivo animals, to which is administered a compound of formula OH X 1- (CH 2) n-CONH 2 x 3 compound described by the applicant in its patent

24065 and its addition 76 21922.

  The starting benzophenones (II) are obtained from benzophenones bearing a methyl radical at 3 according to the following reaction scheme:

CH 3 CH

  The following examples illustrate the invention. Analyzes and spectra, IR and NMR confirm the structure of the compounds. EXAMPLES OF THE PREFERRED EMBODIMENTS

Example 1

  E (5-fluoro-2,3-dihydroxyphenyl) (4-chlorophenyl)

4-methylenamino-butanamide.

  The animals (Charles River rats weighing approximately _ g) are treated intravenously with 20 mg / kg of 1 (4-chlorophenyl) (5-fluoro-2-hydroxyphenyl) methylol

aminol -4 butanamide.

  The bile of these animals is recovered by cannulation of the common bile duct for 6 h. The bile is hydrolyzed by glucuronidase at 37 ° C. for minutes at pH 6.5. The mixture is extracted with 6 times the volume of n-hexane, which makes it possible to eliminate the most lipophilic compounds.

present in the bile.

  The aqueous phase is recovered and the extract is extracted with ethyl acetate (6 volumes); the organic phase is evaporated and the extract

  Dry is taken up in hot methanol. It is allowed to cool.

  A precipitate is formed which is the desired compound

  recrystallize the product in hot methanol.

  F = 224-230 C (dec) measured with Tottoli The compound is in the form of a crystalline powder

bright orange.

  The IR spectrum measured in K Br has the following characteristics: 3400-3100 cm 3000-2900 cm 2800-2200 cm 1660 cm-1 -1 1600 cm 1270 130 cm 840 cm 1 The spectra: VNH 2 of the amide and OH with the link E intraouitiaterm Qlecular hydrogen -1

V: CH 2

  With the intramolecular H bond (OH N = C): v C = O of the amide: v C = N of the amide -1 v: C-O, phenol: benzene paradisubstitué

  UV and NMR confirm the structure of the compound.

  Example 2 11-Fluoro-2,3-dihydroxybenzyl acid (4-chloro)

  phenyl) methylenediaminol-4-butanoic.

  This compound passes and remains in the methanolic phase during the treatment of the dry extract with hot methanol described in

  Example 1 is extracted from the methanol phase by chromatography

  matography on silica (the eluent is a 7/3 benzene / ethanol mixture). (Example 3 5-chloro-2-dihydroxy-3-phenyl) (4-chlorophenyl)

methylenamino} -4 butanamide.

  1 (5-chloro-2,3-dihydroxyphenyl) (4-chlorophenyl) methanone) 1.1 In a two-necked flask of 0.5 l, 28.1 g (0.1 g) are introduced.

  mole) (5-chloro-2-hydroxy-3-methylphenyl) (4-chlorophenyl)

  nyl) methanone 150 ml chloroform and 0.5 g peroxide

  benzoyl, under a well ventilated hood.

  The reaction medium is brought to reflux temperature and

  turn on the ultraviolet lamp.

  25 ml (0.5 mol) of bromine are then introduced in one go and the reaction mixture is heated at reflux temperature in the presence of UV for 16 hours. The reaction is followed by RM No. The solvent is evaporated and the mixture is removed. bromohydric acid present by evaporating 3 times 50 ml

of benzene.

  The residue is then taken up in 600 ml of methanol and the mixture is refluxed for 6 hours.

the crystals appeared.

  After recrystallization from an ether / pentane mixture,

  holds benzophenone carrying a dimethyl acetal group in

position 3.

Mp 82-83 ° C .;

  1.2 In a flask of 0.5 l, 17.8 g (52 mmol) are introduced

  of the acetal obtained previously, 50 ml of sulfuric acid

  concentrated liquid, 200 ml of water and 250 ml of toluene.

  The reaction mixture is heated for 3 hours at room temperature.

  reflux, let it return to room temperature.

  cante the organic phase, washes it to neutrality,

  dry on Na2O4, then filter and evaporate to dryness.

  After recrystallization from tert-butyl-methyl-ethyl ester, there is obtained (3-chloro-2-hydroxy-3-phenylphenyl) (4-chlorophenyl) methanone, which is a polymorph product which has two

  melting points 109.9 C then 119.8 C.

  1.3 In a two-necked flask of 2 liters, 800 ml of distilled water and 1.60 g of pelletized sodium hydroxide are introduced. The reaction mixture is brought to reflux temperature by bubbling a gaseous stream of Argon. g (40 mmol) of benzophenone and heated to reflux until

total solubilization.

  An orange solution is thus obtained-still under argon, a solution of 16 ml of

  H 202 (110 volumes) in 144 ml of distilled water.

  Almost instantly the solution gets cloudy and the color

  becomes yellow A precipitate (yellow) is formed quickly.

  Refluxing is continued for 1/2 hour, filtered hot and

  Wash the precipitate 3 times with 100 ml of distilled water.

  The filter cake is placed in a 6N solution of HCl

  (500 ml) and stirred overnight.

  The precipitate is filtered off and filtered, the filter cake is taken up in ether and decanted, the organic phase is washed with water, with bicarbonate water, with water and dried over Na 2 O 2 O.

filter and evaporate to dryness.

  The crude product is dissolved in 40 ml of boiling toluene and 60 ml of pentane is slowly added. (2,3-Chloro-2,3-dihydroxyphenyl) (4-chlorophenyl) methanone having a melting point of 133 is thus obtained. 135 C o 2 l (5-chloro-2,3-dihydroxy phenyl) (4-chlorophenyl)

methylenic aminol 4 butanamide.

  A mixture of 1.96 g (14 mmol) of gabamide hydrochloride and 0.764 g (14.1 mmol) was heated at the reflux temperature.

  of sodium methoxide with 4 g (14.1 mmol) of (chlorine)

  2,3-dihydroxyphenyl) (4-chlorophenyl) methanone in

  400 ml of methanol for 10 hours and then leave the

  in contact for 48 hours. The dry residue is taken up in 2 liters of CH 2 C 12 and washed with

  500 ml of H 2 O decanted, dried over Mg SO 4, filtered and evaporated

  dry pore-then the residue is sintered by 100 ml

of petroleum ether.

  The product is dissolved in 1 liter of boiling ethyl acetate, treated with charcoal, filtered and concentrated to 100 ml. The product crystallizes. It is filtered, drained and washed twice.

ml of ether.

  The recrystallized product is analytically pure.

M = 224 225 C-

  In the following table are represented the compounds of the invention obtained by way of examples as well as in the

  Table II starting benzophenones (II).

compound N R x 1 x 2 x 3 F (1, C) i

Table I

(CH 2) n-CO-R

X, (I)

x 1

224-230

Dec

224-225

  NH 2 OH NH 2 -F-F -C 1 4 -Cl 4 -Cl 4 -Cl H H H Compound X 1 x 2 x 3 F ("C) i i

2536 O 7 O

Table II

x 1 (II)

124-126

133-135

4-Cl 4-Cl -F -Ci H ii

  The compounds of the invention have been subjected to pharmaceutical tests.

  in the field of the central nervous system.

  In particular, the compounds of the invention were tested in the antagonism test for bicuculline-induced mortality in mice. Bicuculline is a relatively selective blocker of

  post-synaptic GABA-ergic receptors and its effects.

  vulsants and lethal agents are antagonized by the high

  the level of cerebral GABA or having an activity -A 3 A-

mimetic.

  We then measure the dose that protects 50% of the animals against

the effect of bicuculline.

  The compounds of the invention are active as anticonvulsants

  and 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

  neurological diseases such as epilepsy.

  The invention therefore includes any pharmaceutical compositions containing the compounds (I) as active ingredients, in combination with any excipients suitable for

  their administration, particularly orally (including

  molds, dragees, capsules, capsules, cachets, solutions or

  oral suspensions) or parenteral.

  The daily dosage can range from 50 to 1000 mg.

Claims (7)

claims   Benzylidenic derivatives having the formula (I) where n is an integer ranging from 1 to 12, where X is an integer ranging from 1 to 12, O 10 X 1, X 2 and X 3 each represent, independently from each other, a hydrogen atom or a halogen atom, R represents an NH 2, OH or OM radical (M = alkali metal or alkaline earth metal). 2 Benzylidenic derivatives according to the formula of claim 1 and 1 = 1 - (CH 2) 3-COR in which 2   R, X 1, X 2 and X 3 have the meanings given in the sales 1.   3-Fluoro-5-dihydroxy-2,3-phenyl) (4-chlorophenyl) 4-methylenamino-butanamide.   4 11-Fluoro-2,3-dihydroxy-phenyl (4-chloro)   phenyl) methylenic aminol-4-butanoic.   1 (5-chloro-2,3-dihydroxyphenyl) (4-chlorophenyl) methylenejamino-4-butanamide.   Process for the preparation of the compounds according to claim 1, characterized in that either the benzophenone of formula (II) X 11 H 0 = o (II) is reacted & $ X 3 X 2   with a compound of formula (IV) H 2 N (CH 2) n-COR optionally in salt form such as hydrochloride; at a temperature of 20 to 120 ° C., in a solvent such as methanol, ethanol is mixed with methanol / toluene, in the presence of a base; either an extraction is carried out after in vitro metabolization of liver homogenates or in vivo of animals, to which a compound of formula H X 1 = N- (CH 2) n-CONH 2 CX 2 3   in which x 1, XI and X 3 each independently represent a hydrogen atom or a halogen atom, 7 a medicament characterized in that it contains a compound   as specified in any one of the claims 1 to 5.   A pharmaceutical composition characterized in that it contains a compound as specified in any one of   Claims 1 to 5 in association with any excipient   appropriate. Benzophenones, useful for the preparation of the compounds of claim 1, having the formula OH OH = O X 3 wherein X 1 i X 2 and X 3 each independently represent one of   the other, a hydrogen atom or a halogen atom.