LU85311A1 - HYDROXYLATED DIPHENYLAZOMETHINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION - Google Patents

Description

The present invention relates to hydro-xylated diphenylazomethines, their preparation and their therapeutic use.

The compounds of the invention correspond to the formula (I) -ic C = N- (CH_) -COR U) x3 in which n is an integer ranging from there 4,, X2 and X3 each independently represent one on the other hand, a hydrogen atom, a halogen atom, the methoxy radical or a straight or branched (0 ^ _4) alkyl radical, R represents the NH2, OH or OM radical (M = alkali or alkaline earth metal) and Z represents a radical COOH, COOalkyl, CONH2, CONH alkyl, CON (alkyl)?, CK ^ OH, CH2Oalkyl, Oalkyle.- NO2, KK2, Nualkyl or N (alkyl) 2, the alkyls having from 1 to 4 carbon atoms . The preferred compounds of the invention are those which correspond to the formula ir

X, C = N- (CH) -COR

1 I 2 n Φ X2 in which the radicals have the meanings given above, and more particularly those in which n is equal to 2 or 3, X. is a halogen atom or the methyl radical, / 1 /.

2 X2 is a halogen atom or the methyl radical, R is NH2, OH or ONa, and Z is a group CH2OCH3, OCH3 # N (CH3) 2 or NK2.

According to the invention, the compounds can be prepared in the following manner: a benzophenone of formula is reacted

1 OK

"* ^ CX

c = o (II) Ά with a compound of formula (III)

H0N- (CH0) -COR

optionally in the form of a salt, such as the hydrochloride; at a temperature of 20 to 80 ° C, in a solvent such as methanol or ethanol.

The starting benzophenones (II) are new and are prepared according to the methods described in the literature.

The following examples illustrate the invention. The analyzes and the IR and NMR spectra confirm the structure of the compounds.

Example 1.

j "£ (4-chloro-phenyl) (5-chloro-2-hydroxy-3-methoxyphenyl) methylene] aminoj> -4 butanamide.

L · w 3 To a suspension of 0.37 g (2.69 mmol) of gabamide hydrochloride in 20 cm3 of absolute ethanol, 10.4 cm3 of an ethanolic solution of 0.27N sodium ethylate ( or 2.8 mmol), and 0.8 g (2.69 mmol) of 4'-dichloro-5, 2-hydroxy-3-methoxy-benzophenone.

The mixture is heated to reflux temperature for 1 hour, then 20 cxn3 of alcohol are distilled. 200 cm3 of absolute alcohol are added, then the same volume is redistilled.

After evaporation to dryness, 20 cm 3 of water are added to the residue and extracted with methylene chloride.

The extract, washed with water and dried over MgSO 4, gives on evaporation a residue which is recrystallized from absolute ethanol. After washing with petroleum ether and drying for 8 hours at 100 ° C. under vacuum, the product is obtained which melts at 209-10 ° C.

Example 2.

^ £ (4-chloro-phenyl) acid (5-chloro-2-hydroxy-3-methoxy-methyl-phenyl) methylene-4-butanoic acid and its sodium salt.

J

-2 1. 5 g (1.61.10 mol) of (4-chloro-phenyl) (5-chloro-5-hydroxy-3-methoxymethyl-2-phenyl) methanone, 300 ml of methanol, 3.1 are introduced into a 1-liter flask g (3.10 mole). -2 γ-amino-butyric acid and 1.6 g (3.10 mole) of sodium methylate.

The reaction mixture is brought to reflux temperature for 8 h, evaporated to dryness, the residue is taken up in 1.8 l of distilled water, acidified to pH 4.5 by addition of citric acid. Extracted with twice 400 ml of dichlorometha-none, the organic phases are combined, washed with 500 ml of water, dried over Na2SO4, then filtered and evaporated to dryness.

The acid obtained is recrystallized from 25 ml of methanol.

F = 104 - 105 ° C

VS

-2 4 2. 4.7 g (1.19.10 mol) of the acid obtained above, 100 ml of methanol and 9.7 ml of sodium methylate in solution (1.22) are introduced into a 500 ml flask. NOT).

The reaction mixture is evaporated at 60 ° C., 200 ml of pentane are introduced and the mixture is stirred for 10 ran.

After filtration, spinning and drying in a desiccator at 60 ° C in the presence of P2 ° 5, the sodium salt is obtained.

M = 136 ° C.

Example 3.

jj (4-chloro-phenyl) (5-chloro-2-hydroxy-3-dimethylamino-phenyl) methylene] aminoj "-4 butanamide.

2.35 g (0.017 mole) of gabamide hydrochloride, 500 ml of ethanol, 17 ml of a molar solution of sodium methylate and 5.3 g (0.017 mole) of (4-chloro) are introduced into a flask phenyl) (5-chloro-2-hydroxy-3-dimethylamino phenyl) methanone.

The reaction mixture is heated to reflux temperature and the ethanol is distilled.

Evaporated to dryness, the residue is taken up in water and chloroform, the organic phase is decanted, dried over magnesium sulphate and evaporated.

The residue is triturated in pentane, filtered, and recrystallized from an ethyl acetate / isopropyl ether mixture.

F = 144.5 - 145 ° C

U

5 TABLE (I)

Xl ~ £ I

= N- (CH ") -CO R (I) * 4’ X3

Compounds n X2 ZRF (° C) 1 3 5-C1 4-C1 H COOCH3 NH2 168-169 2 3 5-C1 4-C1 H COOCH3 OH 141-142 3 3 5-C1 4-Cl H CONH2 NH2 143-144 4 3 5-Cl 4-Cl H COOH OH 235-236 5 3 5-Cl 4-Cl H NH2 107-8 6 3 5-Cl 4-Cl H CH2OH NH2 158.5-9.5 7 3 5-Cl 4-Cl H .CH2OCH3 OH 104-5 8 3 5-Cl 4-Cl H CH2OCH3 ONa 136 (dec) 9 3 5-Cl 4-Cl H C0NH9 OH 214-5 10 3 5-Cl 4-Cl H CONHC ^ NH2 202-3 11 3 5-Cl 4-Cl H C0NHCH3 NH2 242-3 12 3 5-Cl 4-Cl H OCH3 OH 153-4 13 3 5-Cl 4-Cl H CONHC ^ ONa 160-1 14 3 5 -Cl 4-Cl H CONHCH3 ONa> 250 (dec)

L

i 6 TABLE (continued) * ---- 1 --- j ----—-- 1 * - ~ r “1 1

Compounds η X ^ X2 X3 ZRF (° C) 15 3 5 — Cl 4-Cl H OCH3 NH2 209-210 16 3 5-Cl 4-Cl H N02 NH2 166-7 17 3 5-Cl 4-Cl HN (CH3 ) 2 ONa 153-158 18 3 5-Cl 4-Cl HN (CH3) 2 NH2 144.5-5 19 3 5-Cl 4-Cl H NC> 2 ONa 163-165 20 3 5-Cl 4-Cl H NH2 ONa 257-9 21 3 5-Cl 4-Cl H NHn NH0 219-220 v 22 3 5-Cl 4-Cl H CONHC3H7 OH 216-7 23 3 5-Cl 4-Cl H CONHCH3 OH 218-9 24 3 5-Cl 4-Cl HN (CH3) 2 OH 159-160 25 3 5-Cl 4-Cl H N02 OH 206-208 26 3 5-Cl 4-Cl H NH2 OH 169-170

L

7

TABLE II - BENZOPHENONES

-ec

Compounds X2 X3 z F (° C) 1 5-Cl 4-C1 H C02CH3 114-115 2 5-Cl 4-C1 H COMH2 205-206 3 5-Cl 4-Cl H C02H 198-199 4 5-Cl 4 -Cl H CH2OCH3 95-97 5 5-Cl 4-Cl H CH2OH 102-103 6 5-Cl 4-Cl H CONHC3H7 103-104 7 5-Cl 4-Cl H CONHCH3 169-170 8 5-Cl 4-Cl H OCH3 142.5-143 9 5-Cl 4-Cl H N02 112-112.5 ® Θ 10 5-Cl 4-Cl HN (CH3) 2, C1 164-166

H

11 5-Cl 4-Cl H NH2 94.5-95; u s The antidepressant activity of the compounds has been shown by the antagonism with respect to "head-twitches" caused by L-5-hydroxy-tryptophan in mice.

The mice (CD1 males, Charles River France; 18-22 o 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 subcutaneously. Forty five minutes after this injection of 5-HTP, the number “neac-tvitches” (head snatches) is counted, for each mouse, for one minute.

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

From this the dose-effect curve, gold. determines the DA 50 (active dose 5Ci or cose cui decreases by 501 the average number this "i.eac-twa tcr.es"} f pir 2a cratr.icue method of y.nller and Laar, ter (1944).

DA 50 these compounds this 1 ’i nve.nt i c-r. varies this 40 è 6Γ me. kg ir.trap§r ^ t oTjéale.

The activity ar.t ï ce; .vul si var. te these r: ru_ses has been re r.e:> £ ter - 1 antagoni srr.e vis vis vis the mortality induced by bicucu- 11j ne in mice.

Bicuculline is a relatively selective blocker of GAB7 -.- ergic post-synaptic receptors and its convulsive and lethal effects are antagonized by compounds raising the level of cerebral GABA or having G7-.ÜA-mimetic activity.

L

Claims (6)

1. Hydroxy diphenylazomethines corresponding to the formula (I) - <k C = N- (CH_) -COR (I) I 2 n X3 in which n is an integer ranging from there 4, Xr X2 ^ 3 ^ each present, independently of one another, a hydrogen atom, a halogen atom, the methoxy radical or a straight or branched (C ^^) alkyl radical, R represents the radical NH2, OH or OM (M = metal alkaline or alkaline earth) and Z represents a COOH, COOalkyl, CONH2, CONH alkyl, CON (alkyl) 2, CH20H, CH2Oalkyl, Oalkyl, NO2, NH2, NH2, NHalkyl or N (alkyl) 2 radical, the alkyls having from 1 to 4 atoms of carbon. 2. Compounds according to claim 1, corresponding to the formula A ’Λ1 C = N- (CH„) -COR. I 2 n Φ X2 in which the radicals have the meanings given - in claim 1. 3. Compounds according to claim 2, in which n is equal to 2 or 3, is a halogen atom or the methyl radical, 9 ψ The active dose was evaluated 50% (DA 50), dose protecting 50%> of 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 compounds of the invention are active as antidepressants and anticonvulsants and also have antiulcer, 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, diskynesia. 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 suspensions drinkable) or parenteral. The daily dosage can range from 100 to 3000 ng. if _ 'L. 11 X2 is a halogen atom or the methyl radical, R is NH ^, OH or ONa,! and Z is a CH2OCH3, n (CH3) 2 or nh2 group. 4. Process for the preparation of the compounds according to claim 1, process characterized in that a benzo-phenone of formula Z for C = 0 (II) X3 is reacted with a compound of formula (III) H0N- (CH- ) -COR 2. λ n 5. Medicament, characterized in that it contains a compound as specified in any one of claims 1 to 3. 6. Pharmaceutical composition characterized in that it contains a compound as specified in any one of claims 1 to 3 in association with any suitable excipient. prayed.