LU82958A1 - BENZYLIDENIC DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION - Google Patents

Description

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

The compounds of the invention correspond to formula (I) NR.R.

^ C = N - CH - COR.

in which n and m are independently of each other 1,2 or 3, 10 R ^ is a hydrogen or halogen atom, R2 is a hydrogen or halogen atom, R3 and are independently from each other a hydrogen atom, an alkyl or acyl radical, Rÿ is a hydrogen atom or an alkyl radical, Rg is an amino, alkylamino, dialky. amino, hydroxyalkylamino group or a nitrogen heterocycle which may contain another heteroatom and / or which may carry an alkyl radical, the alkyl radicals having from 1 to 4 carbon atoms.

Λ A group of preferred compounds of the invention is formed by those in which R is a chlorine atom in position 5 and R2 is H or a halogen atom.

In this group, the compounds of choice are those in which R- and R. are H, Rc is H and R. is NH ~.

3 4 - 5 6 2! The compounds of the invention can exist in the 2 stereochemical forms I syn and anti 1 / · * - 2> WR R NR_R.

- ’· ίζ Λ" '",, H0C. ·. ·.

,, - ό Γ. '5 syn anti

In general, the separation is carried out by fractional crystallizations.

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The hydroxylated intermediate compounds (III) can also exist in the 2 syn and anti forms, 10 Furthermore, the compounds in the cruel is a radical> b alkyl can exist in the form of racemate or enantiomers which are part of the invention.

According to the invention, the compounds (I) can be prepared according to the following reaction scheme: À ο b 3

Schematic: NR3R4

(Rl> n- ^ lj ^ + H2N - CH2 - CH20H

Jx, (II)

'R2'm I

· * * Ψ

Nr3R4

(r.) _L I

ln-- = N - ch2 - ch2oh; ni) (R.) - | + H_N - CH - CORc (IV) 2 m DD 2 d 6 R5 Φ <Vn - \ - | = N - CH - C0R ^ I 6 (A * 5 (Vm-- (I,

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The starting benzophenones (II) are known.

Amino compounds (IV) are known.

The reaction of benzophenone (II) with ethanol-amine is carried out at a temperature of 100 to 140 ° C.

5 The reaction between the hydroxylated intermediate compound (III) and the amino compound H-N-CH-COR .. (IV) possibly under ·

Δ \ O

form of hydrochloride, is carried out at a temperature of 20 to 150 ° C in a polar protic or aprotic solvent such as methanol, ethanol, DMSO or DMF.

Furthermore, the compounds in which R- is H and R. is a - -1 3 4 acyl radical obtainable from the corresponding compounds (I) in which R3 and R ^ are H, by acylation in pyridine, by example. 1

The following examples illustrate the invention.

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

DMSO = dimethyl sulfoxide. DMF = dimethylformamide

In Table (I) are shown the compounds of the invention prepared by way of examples.

The melting points marked with an asterisk were measured by differential thermal analysis.

EXAMPLE 1 n- (2-Phenyl-2-amino-5-chloro-benzylidenyl) -2-aminoacetamide.

Jrj "Cl-5, R2 = R3 = R4 = R5 = H, Rg = NH2 J

syn and anti forms 5 1. N- (fc (-phenyl-amino-2-chloro-5 benzylidenyl) amino-2 ethanol.

Heated to 135 ° C, under an inert atmosphere, 30g of 2-amino-5-chloro-benzophenone in 85 ml of ethanolamine while stirring for 4 h. After cooling, the reaction mixture is poured into 1.5 l of water. The oil formed is extracted with chloroform ^ 10 The organic phase is washed 4 times with water, dried over MgSO ^, filtered and evaporated until crystallization.

The product is filtered and recrystallized from chloroform. After filtration, 3 successive washes with 1. ether. Drying in a desiccator a product melting at 15 128 ° C. is obtained.

This product is in the anti form.

2. N- (o (-phenyl-amino-2-chloro-5 benzylidényl) amino-2 acetamide.

33 g of glycinamide hydrochloride are dissolved in 300 ml of DMSO and 27.4 g of N- (2-phenyl-2-amino-5-chloro-benzylidenyl) -2-amino ethanol are then dissolved in this solution. The mixture is heated at 60 ° C for 6 hours and poured into 4 1 of water. Extraction is carried out 4 times with 500 ml of chloroform. The organic phages are combined, washed with 4 times 1 l of water, dried over MgSO 4, filtered and evaporated to dryness.

The solid obtained is washed 3 times with ether, filtered and dried in a desiccator.

We obtain the mixture of the two syn and anti forms.

- By recrystallization from a methanol / ether mixture, one obtains; holds the syn compound.

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The recrystallization waters are drained to dryness. A solid is obtained which is recrystallized from ethanol. It is the compound i * nti.

The syn compound melts at 180 ° C with decomposition (measure effec-5 killed by differential thermal analysis).

The anti-melting compound at 143.5 ° C. then at 177 ° C. (measurement carried out by differential thermal analysis).

These measurements show that the anti compound is transformed into compound r * yn by heating.

EXAMPLE ^ N- (o (-phenyl-2-amino-5-chloro-benzylidenyl) - 2-amino-2-methyl-acetamide (anti-racemate form)

= Cl-5, R2 = R3 = R4 = R, R5 = CH3, .Rg = NH2J

We heat,?. 60 ° C, 17.6 g (0.1413 mole) dl-aianiuamide hydrochloride and 12.95 g (0.0471 mole) N- (o ^ -phenyl amino-15 2 chlorc-5 benzylidenyl) -amino -2 ethanol in anti form in 80 ml of DMSO, for 10 hours * up to 70 ° C. for 16 hours; then at 16 ° C for 16 hours and at 90 ° C for 8 hours.

The reaction mixture is then poured into 2.5 l of water, slowly stirring; the insoluble material is left to crystallize and then wrung out, washed with water and then quickly dried on cold.

It is a sticky yellow solid.

The compound is stirred in approximately 100 ml of cold ether and then the fine insoluble material is filtered, rinsed with small amounts of this same cold solvent and then dried under vacuum at ordinary temperature. It is a very light beige solid.

It is dissolved hot in isopropyl ether and a minimum quantity of ethyl acetate; a resin is filtered, then the solid recrystallizes overnight in the refrigerator; '' wring, wash and dry (40 ° C on P2 ° 5 and vacuum).

Mp 143.5-144 ° C.

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The compounds (I) have been subjected to various pharmacological tests.

Their acute toxicity, determined in CD 1 mice, is respectively 1000 mg / kg i.p. and ^ 2000 mg / kg orally.

In the test of antagonism with respect to convulsions induced by bicucullin in mice (Curtis, DR, et al. Brain Res. 1971, 33, 57 i Worms P. et al., Life Science, 1979,, 25 , p. 607) the active dose 50% (DA 50), 10 ie the dose which protects 50% of the animals against the effects of bicuculline is approximately 5 mg / kg by ip route and varies from 4.5 to 17 mg / kg orally.

In the "Eating test" (Stephens R.J., Brit. J. Pharmacol. 1973, £ 9, 146) the compounds are administered at different doses orally in mice.

For each dose the percentage increase in food consumed ·:. Is determined in relation to the control.

In the table the percentages are indicated for different doses of compounds (I) 20 Dose (mg / kg)%. _P.o · __ 3 + 7 to + 44 10 + 25 to + 68 30 + 20 to + 9i 25 The tests show that the compounds of the invention have anticonvulsant and / or anxiolytic properties and can be used for the treatment of epilepsies, seizures and anxiety, for example.

y- '· 10 * The compounds may be presented in any pharmaceutical pharmaceutical form in combination with any excipient suitable for oral or parenteral administration, for example in the form of capsules, tablets, capsules, dragees, solutions. and suspensions .....

The daily dosage can range from 5 to 500 mg.

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Claims (2)

1. Benzylidenic derivatives in the syn forms: .anti or of syn / anti mixture corresponding to the formula (I) _ / NR R, • “'' -OC, C = N - ÇH - COR, (I) Λ 1 in which n and m are independently of each other 1, 2 or 3, 10 is a hydrogen or halogen atom, R2 is a hydrogen or halogen atom, Rg and are independently of one on the other, a hydrogen atom, an alkyl or acyl radical, Rç. is a hydrogen atom or an alkyl radical, Rg is an amino, alkylamino, dialkylamino, hydroxyalkylamino group, or a nitrogenous heterocycle which may contain another heteroatom and / or which may carry an alkyl radical, the alkyl radicals having from 1 to 4 carbon atoms. 2. Benzylidenic derivatives (I) in which R ^ is an alkyl, * 20 in the form of racemate or enantiomers. 3. Derivatives according to claim 1 or claim 2, characterized in that R ^ is a chlorine atom in position 5 and R2 is H or a halogen atom. 4. Derivatives according to claim 3, characterized in that R_, and R. are H, R, is H and R ,, is NH_. o 4 O bd 5. A process for preparing the compounds according to claim 1, a process characterized in that a benzo-phenone (II) t (II) "12 'is reacted. / NR. R. 5 with ethanolamine, then reacting the hydro-xylc compound (III) obtained * ^ \ / NR3R4 (Ri> n ~ CïC | C = N - CH2 - CH2OH (III) with an amino compound (IV ), optionally in the form of hydrochloride, HN - CH - C0Rc (IV) 2 I 6 R5 '* 15 6. Medicament, characterized in that it contains a compound specified in any one of claims 1 to 4. i ï \ î l f \ V' \ V_ ^ 'v. 'V.' V.