FR2544309A1 - HYDROXYLATED DIPHENYLAZOMETHINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION - Google Patents

Abstract

HYDROXYLATED DIPHENYLAZOMETHINES RESPONDING TO THE FORMULA: (CF DRAWING IN BOPI) IN WHICH N IS A WHOLE NUMBER RANGING FROM 1 TO 4, X, X AND X REPRESENT EACH, INDEPENDENT OF ONE OF THE OTHER, A HYDROGEN ATOM, A HALOGEN ATOM, RADICAL METHOXY OR A RADICAL (C1-4) STRAIGHT OR RAMIFIED ALKYL, R REPRESENTS THE RADICAL NH, OH OR OM (M ALKALINE OR ALKALINOTERREOUS METAL) AND Z REPRESENTS A RADICAL COOH, COOALKYL, CONH, CONH ALKYL , CON (ALKYL), CHOH, CHOALKYL, CHO, CN, OALKYL, SALKYL, NO, NH, NHALKYL, N (ALKYL), OR NHCOCH.

Description

The present invention relates to diph 6 -nylazomethines hydro-

  xy 11 es their preparation and their application in therapeutics.

  The compounds of the invention correspond to the formula (I) ## STR3 ## in which n is an integer ranging from 1 to 4 X 1, X 2 and X 3 each independently represent a hydrogen atom, a halogen atom, the methoxy radical or a straight or branched (C 1-14) alkyl radical, R represents the radical NH 2, OH or OM (M = alkali metal or alkaline earth metal) and Z represents a radical COOH, CO Oalkyl, CONH 2, CONH alkyl, CON (alkyl) 2, CH 2 H, CH 3 alkyl, CHO, CN, Oalkyl, Salkyl,

  NO 2, NH 2, NHalkyl, N (alkyl) 2, or NHCOCH 3.

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

X 1 O

  X 1 = C = N- (CH 2) n-COR in which the radicals have the meanings given above, and more particularly those in which n is equal to 2 or 3, X 1 is a halogen atom or the methyl radical,

2 2544309

  X 2 is a halogen atom or the methyl radical,

R is NH 2, OH or O Na,

  and Z is CH 3 CH 3, O CH 3, CHO, N (CH) 2 or NH 2.

  According to the invention, the compounds of the

  next step: a benzophenone of formula XOH X 11 is reacted

C = O (II)

  X 2 with a compound of formula (III) H 2 N- (CH 2) n-COR optionally in salt form, such as the hydrochloride at a temperature of 20 to 80, in a solvent such as

methanol or ethanol.

  The starting benzophenones (II) are new and are

  according to the methods described in the literature.

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

Example 1

  (1-chloro-4-phenyl) (5-chloro-2-hydroxy-3-methoxyphenyl)

methylenellamino} -4 butanamide.

  To a suspension of 0.37 g (2.69 mmol) of gabamide hydrochloride in 20 cm 3 of absolute ethanol, 10.4 cm 3 of an ethanolic solution of 0.27 N sodium ethoxide ( 2.8 mmol), and 0.8 g (2.69 mmol) of 4'-dichloro-2-hydroxy

3-methoxy benzophenone.

  The mixture is heated at reflux temperature for 1 hour, then distilled with 3 ml of alcohol. 200 cm 3 of absolute alcohol are then added.

redistille the same volume.

  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 Mg 504, gives the evaluation

  poration, a residue which is recrystallised from

  absolute ethanol After washing with petroleum ether and

  drying 8 h at 100 C under vacuum we get the product that melts

at 209-10 C

Example 2

  1- (4-chlorophenyl) (5-chloro-2-hydroxy-methoxy-methyl) acid

  Phenyl) methyl-4-aminol butanoic acid and its sodium salt.

  1 g of a 1-flask is charged with 5 g (1.61 × 10 -2 mol) of (4-chlorophenyl) (5-chloro-2-hydroxy-3-methoxymethylphenyl) methanone, 300 ml of methanol, 3.1 g. g (3 10-2 mol) -2

  of γ-amino-butyric acid and 1.6 g (3 10 -2 mol) of methyl

sodium late.

  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 acid.

  citric extracted with 2 times 400 ml of dichloromethane

  none, combines the organic phases, washed with 500 ml of water, dried over Na2O4, then filtered and evaporated to dryness.

  The acid obtained is recrystallized from 25 ml of methacrylate.

nol.

F = 104-105C

4 2544309

  2 g 4.7 g (1.19 10 -2 mol) of the acid obtained above, 100 ml of methanol, are introduced into a 500 ml flask.

  and 9.7 ml of sodium methoxide solution (1.22 N).

  The reaction mixture is evaporated at 60 ° C., introduced

  ml of pentane and stirred for 10 minutes.

  After filtration, spinning and drying in a desiccator

   In the presence of P 205, the sodium salt is obtained.

F = 136 C.

Example 3

  {1-chloro-4-phenyl) -5-chloro-2-hydroxy-dimethylamino-3

  phenyl) methylene amino -4 butanamide.

  In a flask, 2.35 g (0.017 mole) of chlorhydrin are introduced.

  gabamide drate, 500 ml of ethanol, 17 ml of a solution of

  sodium methoxide and 5.3 g (0.017 mol) of (4-chlorophenyl) (5-chloro-2-hydroxy-3-dimethylamino phenyl) methanone. The reaction mixture is heated to reflux temperature

and distil the ethanol.

  Evaporate to dryness, take up the residue with water and chlorine

  roform, decant the organic phase, dry on sulphate of

magnesium and evaporates.

  The residue is triturated in pentane, filtered and recrystallized.

  tallize in a mixture of ethyl acetate / isopropyl ether.

M.p. 144.5 to 145 ° C .;

  (O.) aa 2 1 úx 1 zx 1 xu sgsodulo D (Dap) osz -e No úHDHROD H ID-V ID-9 T-091 VNO LHEDHIZOO H ID-t '10-9 91 S'PLI-S'LLI HO úHDS it ID-t 'li-9 if P-EST HO Hio ID-P 10-Ci E t Fl 9 Hu EHDHNOD H ID-P ID-9 AND z HN LHEDHROD H ID-P ID-S E zi HO? : HNOD H ID-P ID-9 E II ziz-olz HO Ni H TD-t 'ID-9 E 01 L-9 te l H N H H ID-P ID-9 E 6 (09 P) MI - ## EQU1 ##, ## EQU1 ##, ## STR2 ## where ## STR2 ## 9 z ZHI S-LOI HN HDO R 10-t 'li-S E 9 9 úZ-SúZ HO HOOD H ID-fi-9 E "TM z HN z HMOD H TD-P ID-S E zl TT Pl HO ## EQU1 ## where: ## EQU1 ## where: ## EQU1 ##

usz

  TABLE (cont'd> Compounds NJ 21 XZ -1 R 1 F (OC) * 5 -Cl -Cl -Cl -Cl Cl -Cl -Cl -cl -Cl -Cl -Cl -Cl -Cl -Cl -Cl -Cl - Cl 4-Cl 4-Cl 4-Cl 4-Cl 4 Cl 4-Cl 4-Cl 4-Cl 4-Cl 4-Cl 4-Cl 4-Cl 4-Cl 4-Cl 4-Cl 4-Cl 4-Cl HHHHHHHHHHHHHHHHH OCH 3 CHO NO 2

N (CH 3) 2

N (CH 3) 2

NO 2 NH 2 NH 2 SCH 3

NHCOCH 3

NHCOCH 3

"ONHCH

CONHCH 3

N (CH 3) 2

NO 2 NH 2

NHCOCH 3

  NH 2 NH 2 O Na NH 2 O Na O Na NH 2 NH 2 O NaH 2 OH OH OH OH

209 -210

129-130

166 -7

153-158

144, 5-5

163-165

257-9

219-220

196-7 196-8 -6 216-7 218-9

159-160

206-208

169-170

199-200

(30) 1 z Exxx TX S 9 soduioa

úHDODHN

  To H HH aa HHHH fi Ti-t 'ID-t' TD-S ID-9 ID-9 TD-S TD-S TD-S TD9 TD-S ID-9 TD-S TD-S TD-S TD -S Ti-9 TD-S if wire úl zi it OT LPE z

SLT-PLI

96-Sl P 6 99 T-f 791 s 1 ZTT-ZTT

OTI-601

S'SET-sopci E: t T-G ', z Pl

OLI-691

DIOT Col.

LST-95 T

Pass-ZOT

L 6-96

66 T-861

  9 oz-soz STI-t'Ti z Hu H ID It z (úHD) m z ON OHD CHDS c HDO

E HDHROD

  M ED ED HN HN z z 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 3-f 7 TD-P TD-t SSNO Na Hd O Mag He has VTIEMI L úsz zx o-, xz

  Antidepressant activity of the compounds has been shown by the

  tagonism towards "head-twitches" (snorts of the

  head) caused by L-5-hydroxy-tryptophan in mice.

  The mice (CD1 males, Charles River France, 18-22 g body weight) receive the products to be studied, in increasing doses, or the solvent, simultaneously with L-5-Hi TP at the dose of 250 mg / kg. , subcutaneously Forty-five minutes after this injection of 5-HTP, the number of "head-twitches"

  (snorting of the head) is counted, for each mouse,

one minute.

  For each treatment, the average of the "head-twitches", as well as the percentage of variation compared to the control group, are calculated. Starting from the dose-response curve, omex determines the DA 50 (active dose 50% or dose which decreases by 50 S the average number of head-twitches), by the graphical method of Miller and Tainter.

(l 944).

  The DA 50 of the compounds of the invention ranges from 40 to 60 mg / kg

intraperitoneally.

  The anticonvulsant activity of cc zses was reported by

  the antagonism towards the mortality induced by the bicus-

lline in the mouse.

  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 GABA-

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

studied -

  The DA 50 of the compounds of the invention ranges from 10 to 100 mg / kg

intraperitoneally.

  The compounds of the invention are active as antidepressants and anticonvulsants and also possess properties,

  antiulcer, anxiolytic, analgesic and anti-inflammatory

  They can be used in human therapy and clothing Grinai-

  for the treatment of various diseases of the central nervous system, for example for the treatment of depressions,

  psychoses, certain neurological diseases such as epilepsy

  lepsy, spasticity, diskynésie.

  The invention therefore comprises any pharmaceutical compositions containing the compounds (I) as active ingredients, in combination with any excipients suitable for their administration, in particular orally (tablets, dragees, capsules, capsules, cachets, solutions or suspensions

drinkable) or parenteral.

  The daily dosage can range from 100 to 3000 mg.

Claims (4)

claims   1 hydroxylated diphenylazomethines having the formula (I) xl (CH 2) nCOR (I) x 2 x 3 wherein n is an integer from 1 to 4, X 1, X 2 and X 3 each independently represent one of the other, a hydrogen atom, a halogen atom, the methoxy radical or a (C 1 -C 4) straight or branched alkyl radical, R represents the radical NH 2, OH or OM (M = alkali metal) or alkaline earth) and Z represents a radical COOH, CO Oalkyl, CONH 2, CONH alkyl, CON (alkyl) 2, CH 2 OH, CH 2 Oalkyl, CHO, CN, Oalkyl, Salkyl,   NO 2, NH 2, NHalkyl, N (alkyl) 2, or NHCOCH 3.   Compounds according to claim 1, having the formula Z OH X (C = N (CH 2) n-COR i in which the radicals have the in claim 1.   3: Compounds according to claim 2, wherein n is 2 or 3, X 1 is a halogen atom or the methyl radical, X 2 is a halogen atom or the methyl radical, R is NH 2, OH or O Na,   and Z is CH 2 OCH 3, CHO, N (CH 3) 2 or NH 2.   4 Proc 6 of 1, phinone process for the preparation of comps Qsés according to the claim   characterized in that a benzo-benzene is reacted   formula Z xl (II) with a compound of formula (III) H 2 N- (CH 2) n-COR Medicinal product characterized in that it contains a compound   as specified in any one of claims 1 to 3.   6 Pharmaceutical composition characterized in that it   holds a compound as specified in any of the   Claims 1 to 3 in association with any suitable excipient prayed.