LU81146A1 - BENZYLIDENIC ESTERS AND THEIR THERAPEUTIC APPLICATION - Google Patents

Description

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The present invention relates to benzylidenic esters, their preparation and their therapeutic use.

The Applicant has described in patent No. 75 24065 and its CA No. 76 21922 benzylidenic derivatives of formula H0C "

= N-C H - -COR

x / I n 2n 6- * · 10 in which X. ^ X2 and X ^ r which are identical or different, each represent, independently of one another, a hydrogen or halogen atom, in particular the chlorine or fluorine, or a methyl or methoxyl radical, 15 n represents an integer at least equal to 1 and at most equal to 10, and R represents a hydroxyl radical, OM, NH2 / NH (CHj) ^ -COOH, -NH (CH2I3 "COOM, (It represents an alkali metal atom, in particular sodium), NH (CH2) 3-COOC2H5, 20 NH. - cycloalkyl, NK - phenyl, NH - benzyl (the benzyl radical being able to carry a substituent chosen from halogen atoms and the trifluoromethyl radical), NH - alkyl, N - (alkyl) 2, N - (alkyl) - (benzyl), linear or branched alkyl radicals having from 1 to 4 carbon atoms , cycloalkyl radicals having 3 to 6 carbon atoms, with the exception of the compound for which Χ ^ Χ -, ^ Η, X2 = 5-C1, n = 1 and R = GH.

The compounds of the present application correspond to formula (I)

° H

30 xrC ϊ = N ~ CnH2n ** C00R (I) \ _Û_.X, _ _______L 3______ ί ΓΤ ~ 1 / ϊ i I in which 1! ! Χ ^, and Χ ^, identical or different, each represent a hydrogen or halogen atom, or a methyl or methoxy radical, η = 1 to 10 and j ^ R represents |,. an alkyl radical of 1 to 16 carbon atoms. a radical CI ^ COOR ^ in which R ^ is a higher alkyl di 11 to. 15 carbon atoms,. a radical (CH2) 2 ^ 2 ^ years LeÇRel R2 is one from 1 to 6 | '10 carbon atoms or | j! .a radical CH2 CO - *

t i 1 »VwV

The compounds (I) are active in therapy in the field of the central nervous system.

t According to the invention, the compounds (I) \ 15i are prepared. by reaction between the acid of formula (II)

j ^ .OH

x YY

x! -k il * N ”cnH2n ~ C00H {II)! ; ti§ 20 or one of its functional derivatives (alkaline salt, ester, acid chloride 1 and a compound of formula RX or ROH or ROMe. (X = halogen - Me = I | 'alkali metal) or' I. by reaction between a benzophenone of formula i: / ^ l = 0 {III) il - Λ i * i '30 and a compound of formula j H2N - CnH2n-COOR (IV) or ca

Shot “1. by reaction between an acid (II)

OH

v = N-C H- -COOH (II) j n Zn Xî ~ 0

and a ROH compound

in the presence of carbonyldiimidazole or sulfonyl-diimidazole.

"

Reaction 1 is carried out in a solvent such as dimethyl sulfoxide (DMSO) at a temperature of 40 to 100 ° C.

.0 Reaction 2 is carried out in a solvent such as ethanol at a temperature of 60 to 100 ° C in the presence of sodium bicarbonate!

, I

Reaction 3 is carried out in a solvent such as toluene at the boiling point of this solvent.

The starting acids (II) and the benzophenones (III) are described in L5 patent 75 24065 and CA 76 21922.

The compounds (IV) are obtained by reaction between an H2N-cnH2n ~ COOH acid and a ROH compound in the presence, for example, of thionyl chloride.

The following examples illustrate the invention.

The IR and NMR analyzes and spectra confirmed the structure of the compounds.

"

! CO

* ΐ ^ '__-_ r

Example 1 N- ["- (4-chloro-phenyl) 5-fluoro-2-hydroxy benzy- *; n-butyl butenylj-4-amino butyrate.

j [n = 3, X ^ S-F, X2 = H, X3 = 4C1, R = nC4H9] ί | 1. N-Butyl ^ -amino-butyrate hydrochloride.

5 20.6 g (0.2 mole) of amino-butyric acid and 200 ml of n-butanol are introduced into a 500 ml flask.

The mixture is heated to 60 ° C. and 25 ml of thionyl chloride are added dropwise and the mixture is then brought 2 hl / 2 to reflux temperature.

1! We evaporate at. dry, evaporate twice 100 ml of benzene and ground in dan:! - 10 | cold ether. The hydrochloride crystallizes. We filter it, | 1‘ spin, wash with ether, spin and dry in a desiccator | in the presence of soda spray. '1 It is recrystallized from a chloroform / ether mixture.

2. N- | o <s (4-chloro-phenyl) 5-fluoro-2-hydroxy benzylidenyl-4-amino-n-butyl butyrate.

12.5 g (0.05 mole) of 4-chloro-5 fluoro-5 hydroxy-2-benzophenone, 9.8 g (0.05 mole) of ^ -amino-butyrate hydrochloride are introduced into a 1000 ml flask of n-butyl, 350 ml of ethanol and 4.2 of sodium bicarbonate. The ethanol is evaporated under atmospheric pressure 2 (i phique (9Q ° C), 300 ml of methanol and 5 ml of water are added, 1 evaporated and repeated 3 times.

I.

j Then evaporated to dryness, taken up in ether, filtered the insoluble matter, washed with. water, dries over MgSO., and evaporates to dryness. We get ί! * i · an oil which is first purified on a dry column of

2 $ silica with chloroform as eluent and a second time on “normal silica column with a chloroform 90 / ether IC mixture

as eluent.

We get an oil

Example 2 phenyl fluoro-5 hydroxy-2 benzyliaényl J-amino-4 tétacécyloxycarbonylméthyl butyrate.

Jx ^ SF, X2 = X3 = H, n = 3, R * = CH2COO (CH2) 13CH3j In a 500 ml round flask, 10 g (0.0309 mole) are introduced a · iCt — Whomrl fltinrn-ζ h ' jHrnvv-9 Ή ^ η7; ν1 înériVl ^ —srair.n — 4 bntvrato m

• ΠΓ I

sodium and 8.99 g (0.0390 mole) of tetradecyloxy-car-bonyl-methyl chloride, 100 ml of D.M.S.O. and 2 drops of triethylamine.

This mixture is heated at 90 ° C for 1 h. Leave to cool, then evaporate to dryness. The residue is taken up in ether and the insoluble material is filtered. We dry dream after having dried several times over MgSO 4, a yellow oil is obtained which is purified by passage over a column of silica.

i

Example 3 N — Joi - (4-chloro-phenyl) 5-fluoro-2-hydroxy benzy-lidenyl-4-amino-ethyl butyrate.

£ n = 3, X1 = 5-F, X2 = H, X3 = 4-Cl, E ^ C ^ O (CH2) J

5.79 g of carbonyldiimidazole are added to 11.19 g (1/30 mol) of (4-chloro-phenyl) fluoro-5-hydroxy-2-benzylidenyl-4-amino-butyric acid dissolved in 1000 ml of tetrahydrofuran. I shake 2 h at. Room temperature. Evaporated to dryness, 200 ml of toluene and 3.6 g of ethoxyethanol are added. The mixture is brought to reflux for 3 h. The residue is taken up in ether, the ethereal phase is washed with water, then with bicarbonate water and with water and dried over lgSO ^.

The ether is evaporated and the oil is purified. Obtained by chromatography on a silica column with a CHC1390 / Et2o mixture as eluent. 10 An oil is obtained.

Example 4 N-jô (- (4-chloro-phenyl) 5-fluoro-2-hydroxy-benzylidenylJaminc-4 butyrate ce (4-phenylphenacyl).

• 25 [n = 3, X1 = 5-F, X2 = H, X3 = 4-C1, R * J

To 10.07 g (0.03 mole) of 4-chloro-phenyl) 5-fluoro-2-hydroxy-benzylidenyl-4-amino butyric acid in 200 ml of methanol is added, 1.6 g of .CH30Iïa.0n evaporated to dryness under reduced pressure and dry the sodium salt of the acid in a heated desiccator, 30 (140 ° under 1 mm).

300 ml of DMSO and 8.2 g of (4-phenylphenacyl) -methyl bromide are added to the residue and the mixture is evaporated to dryness under reduced pressure (bath at 100 °). The residue is dissolved in ether and treated with charcoal! he'

i i

I I The filtrate is filtered and concentrated to dryness. We dissolve the product dar | ΐ · minimum chloroform and si column chromatography | ; vice (high flow), eluting with chloroform. The oil obtained crystallizes from petroleum ether. It is drained and dried at 60 ° C. with a heated desiccator.

i] F = 80.5-81.5 * 0.

K i * j \ In the following table I are represented the compounds of the! | vention prepared as examples according to one of the modes of pre-! j exemDlified paration.

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* (1 *; L-Λ | * * i i! I.

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ni O r-i lO en (Tl CN

S U3 tn “3 LO TT x * ri m in m m m m

MiH Ή Ή Ή c-l Q

-h J J1 "" "H tn V. CN CN CN CN CN (N 's \ O CN Q CN Q U CNQCNQCNQCNQ r-t ï î, c β" = "= <f 2 7 7 il ^ eJot ^ aiiuneuQjdjQj ^

U ^ H H H H H H H H

Tj Il ή -H] | -H -H -H -w II

233 30 03 33 I ___ Z'Z’ZtoA'Zlfo & JZjZJZXu m rn rn Î3 £ 0 £ 3

U O U I II

r-i rn LO rn ^ y

Pi "H r-l r— (- ^ ^ m in £ d> v, WN mn n rn a K \ o (V \\

S m £ C [J N v U

U U u U u U

r- r x ο ο ο o Y

g O O in cn cm cm cm I

O O O in m m - ^ _ q

U U U Ö3 r-l K CN CN CN (NU

S * S1 S1 u κ ω κ a x ta cn

►mKhmiS y C £> r — i ÇJ CJ U CJ £ B

U a O U

H

K mmmmcommmmmmm

D

^ - —__________ H -——--

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CQ

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E *> CO · “ΙΉγΗγΗιΗγ-Ir-HiHiH

x isatsouuouuaau

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X ü £ 5S! 3î3! 3E5 £ 5 £ 5Î3 £ 5î3 l, h X 1 i i I I i i i i] i t inminmininininmininin --- -—-———--- "* rn v

<2 -i XX

. ® x x ο o! 3 G) 3 - - v— “·>" ”Ό)

w r-rcNm-q'tneor'cocnor-iCN

O r-l r — l —I

Ca e o o ί ~ * ~ 1 "

The compounds of the invention have been subjected to pharmacological tests showing their activity on the central nervous system.

Acute toxicity was determined in mice by the intraperitoneal route. The LD 50 (lethal doses 50%) inducing death in 50% of the animals are shown in Table II.

The activity of the compounds has been shown by the antagonism towards convulsions induced by bicucullin in mice.

1 ·

Bicuculline is a relatively selective blocker of receptors: post-synaptic GABA-minergic and its convulsive effects and the LO rate are antagonized by the compounds raising the level of GABA in the brain; or having a GABA-mimetic activity.

The active doses 50% (DA 50) were evaluated, doses protecting 50% of animals against the effect of bicuculline, the substances studied. The results are presented in Table II.

.15 TABLE II

Compound n ° DL 50 DA 50 (mg / kg) (mg / kg) ip, 4 ^ 1000 70 5> 1000 80! 0 6 1000 80 8 ^ 1000 100 9 ^ 1000 100 10> 1000 85 11 80 '£ 5 Les compounds of the invention are active as anticonvulsants. 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 psychoses and certain neurological diseases.

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 oral suspensions) or parenteral.

The daily dosage can range from 5 to 400 mg.

• He

i i

! _______

Claims (3)

1. Benzylidene esters corresponding to the formula (I) OH * 5 - "* CnH2n-C00R"> Λ 3 4 in which X. ei: X3 ', identical or different, each represent an atc 10 me of hydrpgene or halogen or a methyl or methoxy radical, η = 1 to 10 and R represents 1. an alkyl radical of 1 to 16 carbon atoms ii! :. a radical C ^ COOR ^ in which R ^ is a higher alkyl 15 of 11 to 15 carbon atoms,. a radical (CH ^) 2 ^ 2 ^ ans ^ es ^ an a ^ Y ^ e of 1 to 6 carbon atoms or. a radical CH2CO * j 1 # |, 2. Esters according to claim 1, characterized in that n = t \ ί 20 3. Esters according to claim 2, characterized in that X ï. ^ 2 ei X3 are each, independently of one another, an atom of h] 1 drocene or halogen. i î 4. Esters according to claim 3, characterized in that ik ^ = 5-F, X2 = H and X3 is a hydrogen or chlorine atom in posit: I 25 5. Process for the preparation of the compounds according to claim 1 ; ; I cédé characterized in that an acid of formula (II) t is reacted. . lulU! OH i j xi-CT = N - C H- -COOH (II) | / Tn Zn! X2 JL! 5 XH ^ JJ | ! t '<t · I 5 t «»; i J! bu one of its functional derivatives with a compound of formula jj • RX or ROMe or ROH (in the presence or not of carbonyl-diimidazole or f I | of sulfonyldiimidazole), the symbols X ^, X ^, X ^, n and R having the meanings given in claim 1, (Me = alkali metal jiq and X - halogen). 5. A process for the preparation of the compounds according to claim 1, process characterized in that a benzophenone of formula (III) is reacted; ? * 3 xi - “/ Il (III) fo ·“ **%) with a compound of formula (IV)! ELN-C -COOR I 2 n 2n! · | 2Πthe symbols X ^, X2, Xn and R having the meanings given in | [claim 1. | Ί, Medicament, characterized in that it contains a compound as specified in any one of claims 1 to 4. î I "N *.