LU85090A1 - HYDROXYL BENZYLIDENIC DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION - Google Patents

Description

"! '1 r

The present invention relates to hydroxylated benzylidéni-gués derivatives, their preparation and their therapeutic application.

The compounds of the invention correspond to the formula - & ·

C = N- (CH,) -COR

4 he

10 A

in which J

n is an integer ranging from 1 to 12, X ^, X2 and X3 each represent, independently of one another, a hydrogen atom or a halogen atom, 15 R represents a radical NH2, OH or OM (M = alkali or alkaline earth metal).

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

T

1 -.OH

XX

20 Χχ. Ç = N- (CH2) 3-COR 1 2 2 in which R, X ^ f X £ and have the meanings given above.

The compounds of the invention can be prepared - either by chemical synthesis by reaction between the corresponding benzo-phenone of formula (II)

OH

'eC

y = 0 (II) ÿ * · X2 with a compound of formula (IV) H0N- (CH0) -COR Zi n 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 of a base; - either by extraction after in vitro metabolism of liver homogenates or in vivo from animals, to which a compound of formula is administered

OH

•. xi_CjC

> P = N- (CH) -CONH „I in 2 I“ Π “19 25 X3 h 3 # compound described by the applicant in its patent 75 24065 and its addition 76 21922.

The starting benzophenones (II) are obtained from benzophenones carrying a methyl radical in 3 according to the following reaction scheme: CH, CH,

JL. V

I \ ^ N: = o 10 * 2_Θ x3 j a3 H SO »2 4 Φ

CHO

”V-. -P '* 4- * 3 \ 20 The following examples illustrate the invention. Analyzes and spectra, IR and NMR confirm the structure of the - compounds.

Example 1 | (fluoro ^ 5dihydroxy-2/3 phenyl) (4-chloro phenyl) methylene] 4-amino butanamide.

The animals (rats - Charles River weighing approximately 200 g) are treated, intravenously, with 20 mg / kg of | d (4-chloro-phenyl) (5-fluoro-2-hydroxyphenyl) methylene] n aminol -4 butanamide.

t i 4

The bile of these animals is recovered by cannulation, bile duct for 6 h.

The bile is hydrolyzed by β-glucuronidase at 37 ° C for 5 minutes at pH 6.5.

The mixture is extracted with 6 times the volume of n-hexane, which makes it possible to remove the most lipophilic compounds present in the bile.

The aqueous phase is recovered and the extract is made with ethyl acetate. (6 volumes); the organic phase is evaporated and the dry extract is taken up in hot methanol. Let cool.

A precipitate is formed which is the desired compound. The product is recrystallized from hot methanol.

F * 224-230 ° C (dec) - measured at Tottoli

The compound is in the form of a bright orange crystalline powder.

The IR spectrum measured in KBr has the following characteristics ï

3400-3100 cm “1 î VNH, amide and vOH with the H bond

intraiX> u “hydrogenated intermolecular 20 3000-2900 cm” 1: VCH, 2800-2200 cm: VOH with the intramolecular H bond (0H ... N-C) 1660 cm ”1; VC = 0 of amide 1600 cm ”1: ve = Nde amide 1270-1130 cm” 1: VC-6, phenol 25 840 cm ”1: δ benzene paradisubstituted

The UV and NMR spectra confirm the structure of the compound.

Example 2 Acid | j (5-fluoro-2,3-dihydroxy phenyl) (4-chloro-phenyl) methylene] aminoj -4 butanoic acid.

This compound passes and remains in the methanolic phase during the treatment of the dry extract with hot methanol described in Example 1. It is extracted from the methanolic phase by chromatography on silica (the eluent is a 7 / 3 benzene / / ethanol).

5

Example 3 | j (5-chloro-2,3-dihydroxy phenyl) (4-chloro-phenyl) methylenej aminoj-4 butanamide.

1. (5-chloro-2,3-dihydroxy phenyl) (4-chloro-phenyl) methanone) 1.1. 28.1 g (0.1 ® mole) of (5-chloro-2-hydroxy-3-methylphenyl) (4-chloro-phenyl) methanone 150 ml of chloroform and 0.5 are introduced into a 0.5 l two-necked flask g of benzoyl peroxide, in a well ventilated hood.

The reaction medium is brought to reflux temperature and the lamp with ultraviolet rays is switched on.

25 ml (0.5 mole) of bromine are then introduced in one go and the reaction mixture is heated at reflux temperature in the presence of UV for 16 h.

The reaction is followed by NMR. The solvent is evaporated off and the hydrobromic acid present is removed by evaporating 3 times 50 ml * 5 of benzene.

• The residue is then taken up in 600 ml of methanol and the mixture is heated under reflux for 6 h. The mixture is allowed to cool and the crystals which have appeared are filtered.

After recrystallization from an ether / pentane mixture, ob-20 holds the benzophenone carrying a dimethyl acetal group in position 3.

F = 82-83 ° C

1.2. 17.8 g (52 mmol) of the acetal obtained above, 50 "ml of concentrated sulfuric acid, 200 ml of water and 250 ml of toluene are introduced into a 0.5 liter flask.

The reaction mixture is heated for 3 h at reflux temperature, it is allowed to return to room temperature. The organic phase is decanted, washed until neutral, dried over Na2SO4, then filtered and evaporated to dryness.

After recrystallization from tert-butyl methyl ether, (5-chloro-2-hydroxy-3-phenyl) phenyl) (4-chloro-phenyl) methanone is obtained which is a polymorphic product which has two melting points 109.9 ° C and then 119 , 8 ° C.

AT

2 c- * '4, 6 1.3. 800 ml of distilled water and 1.60 g of sodium hydroxide pellets are introduced into a 2 liter three-necked flask. The reaction mixture is brought to · cia; reflux temperature * by bubbling a stream of Argon gas. 12 g 5 (40 mmol) of benzophenone are then introduced and the mixture is heated at reflux until complete dissolution.

An orange solution is then obtained, still under argon, a solution of 16 ml of H 2 O 2 (110 volumes) in 144 ml of distilled water is introduced in a single run.

10 Almost instantly the solution becomes cloudy and the color turns yellow. A precipitate (yellow) forms quickly.

The reflux is continued for 1/2 hour, filtered hot and the precipitate is washed 3 times with 100 ml of distilled water.

The filter cake is placed in a 6N solution of HCl 15 (500 ml) and stirred overnight.

The precipitate is filtered and drained, the filter cake is taken up in ether, decanted, the organic phase is washed with water, with bicarbonate water, with water, dried over Na ^ O ^, filter and evaporates to dryness.

The crude product is dissolved in 40 ml of boiling toluene and 60 ml of pentane is added slowly. This gives (2,3-chloro-2,3-dihydroxy phenyl) (4-chloro-phenyl) methanone having a melting point of 133. 135 ° C · 2. £ [(5-chloro-2,3-dihydroxy phenyl) ( 4-chloro-phenyl) methylene] amino-4-butanamide.

A mixture of 1.96 g is heated to reflux temperature. v (14, Immole) of gabamide hydrochloride and 0.764 g (14.1 mmol). of sodium methylate with 4 g (14.1 mmol) of (5-chloro-2,3-dihydroxyphenyl) (4-chloro-phenyl ) methanone in 30,400 ml of methanol for 10 hours and then the product is left in contact for 48 hours.

h t 7 * *

The dry residue is taken up in 2 l of CHjClj and washed with 500 ml of I ^ O. Decanted, dried over „, MgSO 4, filtered and evaporated to dryness. Then the residue is entrained on sintered with 100 ml of petroleum ether.

5 The product is dissolved in 1 l of boiling ethyl acetate, charcoal treated, filtered, concentrated to 100 ml. The product crystallizes. It is filtered, wrung and washed with 2 times 50 ml of ether. .

| The recrystallized product is analytically pure.

10 P = 224 - 225®C

In the following table are represented the compounds of the invention obtained by way of examples as well as in. Table II the starting benzophenones (II).

./S.

e 4 8

Table I OH 7

* -0C

C = N- (CH0) -CO-R (I> "

Compound n R Χχ X2 x3 F (° C) 1 3 NH2 5-F 4-C1 H 224-230 2 3 OH 5-F 4-C1 H dec 10. 3 3 NH2 5-C1 4-C1 H 224-225 / »9 *

Table II OH

»*> ~ ΖΧ C = Q (XI) X2

Compound Χχ X2 X3 F (° C) 10 1 5-F 4-C1 H 124-126 2 5-C1 4-C1 H 133-135 / ^^^^^ -— ♦ 10

The compounds of the invention have been subjected to pharmacological tests in the field of the central nervous system.

The compounds of the invention have in particular been studied in the test of antagonism with respect to the mortality induced by bicucullin in mice.

Bicuculline is a relatively selective blocker of post-synaptic GABA-ergic receptors and its convulsive and lethal effects are antagonized by the compounds which increase the level of cerebral GABA or which possess mimetic GABA-10 activity.

The dose which protects 50% of the animals against the effect of bicucullin is then measured.

The compounds of the invention are active as anticonvulsants and are therefore useful 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 all pharmaceutical compositions containing the compounds (I) as active principles, in combination with any excipients suitable for their administration, in particular by oral route (tablets, dragees, capsules, capsules, cachets, solutions or oral suspensions ) or parenteral.

The daily dosage can range from 50 to 1000 mg.

Γ

Claims (10)

11, Claims 1. Benzylidene derivatives' corresponding to formula (I) co, X3 in which n is an integer ranging from 1 to 12, 10 X ^, X2 and X3 each represent, independently of one another, a hydrogen atom or a halogen atom, IR represents an NH2, OH or OM radical (M = alkali or alkaline earth metal). 2. Benzylidenic derivatives corresponding to the formula (i) 15 OH I OH 0 = 7Ί- (0Ηο) —COR: X3 20 in which n is an integer ranging from 1 to A, Xj, X2 and x ^ each represent, independently one of the other, a hydrogen atom or a halogen atom, R represents an NH ,,, OH or OM radical (M = alkali or alkaline earth metal). 12 * c 3- Benzylidenic derivatives according to claim 1 and corresponding to the formula jC 5 ^ = 1 * - (CH2) 3-C0H φ-3 in which 2 R ,. X ^, X2 and X ^ have the meanings given in re 10 -yendi cation 1. 4. J (5-fluoro-2,3-dihydroxyphenyl) (4-chloro-phenyl) 4-methylenamino-butanamide. ' 5. The acid £ [(fluoro-5 dihydroxy-2f3 phenyl) (chloro-4 phenyl) methylene ^ aminoj-4 butanoic. . 6. Le; j [(5-chloro-2,3-phenylphenyl) (4-chloro-phenyl) methylenejaminoj -4 butanamide. 7. Benzylidenic derivatives according to the claim and corresponding to the formula <OH ·· * 'at “C = N- (CH2) 3-COR X2 in which R represents NH ^ or OH, X. represents F or Cl, X0 represents Cl and X, represents / 1 d. J; ‘12a * · · "8. Process for the preparation of the compounds according to claim <1, process characterized in that - either the benzophenone of formula (II) * 5c ^ (II) is reacted:: ώ · * 2 10 with a compound of formula (IV) H „N- (CH_) -COR 2 2 n 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, methanol / toluene is mixed, in the presence of a base y - either an extraction is carried out after in-vitro metabolization of homogenates of liver or in vivo of animals, to which a compound of formula * rGC C = N- (CH0) -CONH- "2 n 2 - HV s 25 in which x ^, X? and X ^ each represent, independently of one another, a hydrogen atom or a halogen atom, I u ': 13 * 4. * β • ·. »I. #. % ’· · - · - ··’ ♦ "· * ..", ♦ # ¥ • *. -9. Medicament, characterized in that it contains a compound as specified in any one of Claims 1 to 6. 10. Pharmaceutical composition characterized in that it contains a compound as specified in any one of claims 1 to 6 in combination with any excipient - suitable. 11. Benzophenones, useful for the preparation of the compounds of claim 1, corresponding to the formula 10 OH X3 in which X, X2 and X3 each represent, independently of one another, a hydrogen atom or a halogen atom.