LU82833A1 - OXAYOHIMBANE-CARBOXYLIC ACID DERIVATIVES - Google Patents

Description

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The present invention relates to oxayo-himbane-carboxylic acid derivatives, their addition salts with pharmaceutically acceptable acids, their preparation and their therapeutic use.

The compounds of the invention correspond to the general formula (I)

Cpcfl "" I J H I m E! (I), <sJo m3 r20 ^ in which is a hydrogen atom, a (C1-4) -alkoxycarbonyl radical, a phenoxycarbonyl radical, the phenyl of which may carry a halogen atom or a nitro group,, a radical ( C ^^) -acyl, a radical (C ^ _4) -alkoxycarbonyl- (C ^ _4) -alkyl, is the hydroxy radical, an OMe radical (Me = alkali or alkaline earth metal), a radical (C1__4) -right alkoxy or branched, a (C3_g) -cycloalkyl- (C1_4) -alkoxy radical, a (C) - çyclo-alkoxy radical, 3-6 the amino radical, a (C1-4) -alkylamino radical, 11 "ravinai AA _ ί Γ * \ - a TV * r1 - aam * î "λ 2 a radical (C3_g) -cycloalkyl-amino, with the exception of the compounds for which R is H and R is

X M

CH30 or oh.

The addition salts of conrooses (I) with Dharmaceuti-cuement acceDtables acids are part of the invention.

The starting material is raubasine (or ajmalicine) (R ^ H, r2 = och3).

It is also possible to use a pseudo-aromatic quaternary base as the starting material, the serpentine and to reduce the latter by catalytic hydrogenation or by an alkali metal borohydride to a drogenated tetrahydro compound.

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The preferred compounds of the invention are those in which is an alkoxycarbonyl radical or an alkoxycarbo-nylalkyl radical.

According to the invention, the compounds can be prepared as follows:

Acid I (R = H, R = 0H) is prepared from raubasin 2 (R = H, R = CH 0) by saponification. Esters X Δ 3 (I) can be obtained according to conventional methods, in particular either by direct esterification of the acid (by reaction between the acid chloride and the alcohol R2H or one of its alkaline salts) or by transesterification raubasine.

The friends of (I) are obtained from the acid (I) R ^ H, R2 = 0H) or one of its functional derivatives by conventional amidification.

The compounds (I) carrying a radical R ^ H are obtained from the compounds (I) in which R ^ is H by reaction of the compound with an alkoxycarbonyl or alkoxycarbonyl alkyl halide, that is to say that the the anion of raubasine is formed, for example by dissolving the base in dimethylformamide and the action of sodium hvdrm * e, nnic nn s-imvt-o alnra rnm-ins 3

RjX (X = Cl or Br).

The reaction is carried out at a temperature of 0 to 20 ° C.

The following examples illustrate the invention.

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

EXAMPLE 1 Ethoxycarbonylmethyl-1 dehydro-16,17 methyl-19c> methyl oxayohimbane-carboxylate-16.

£ rx = ch2cooch2ch3, r2 = ch3 ° J

% To 6 g of raubasine (ajmalicine) dissolved in 100 ml of dry dimethylformamide is added 1.8 g of sodium hydride while stirring and under argon.

After 50 minutes, 3.7 ml of ethyl chloro-acetate are added over 10 minutes using a dropping funnel while stirring, under argon and at a temperature close to +10 ° C.

After 20 minutes a precipitate forms. 500 ml of water are then added and the precipitate is filtered.

The precipitate is dissolved in 200 ml of methylene chloride. Wash with water, dry over sodium sulfate and evaporate to dryness.

The product crystallizes from methanol.

F = 203 ° C Hr "-116.6 ° (c = l; CHCl ^ \

The compounds of the invention prepared by way of examples are collated in the following table (I).

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The compounds of the invention have been subjected to pharmacological tests.

The toxicity of the compounds was determined intraperitoneally in mice.

The LD 50 ranges from 300 to 1000 mg / kg.

The compounds were subjected to the hypobaric anoxia test.

CD1 strain mice are maintained in an oxygen-depleted atmosphere, by carrying out a partial vacuum (190 mm of mercury corresponding to 5.25% of oxygen).

The survival time of the animals is noted. This time is increased by agents capable of promoting tisr ... sular and in particular cerebral oxygenation. The test compounds are administered, in several doses, intraperitoneally, 10 minutes before the test. The percentages of increase in survival time compared to the values obtained in the control animals are calculated. The average active dose (AMD), which increases the survival time by 100%, is determined graphically.

The AMD of the compounds of the invention varies from 10 to 60 mg / kg i.p.

- 'The pharmacological study of the compounds of the invention shows that they are active in the hypobaric anoxia test in mice while being only slightly toxic.

The compounds of the invention, having anti-anoxic activity, can be used in therapy for the treatment of disorders of alertness, in particular for combating behavioral disorders attributable to cerebrovascular damage and to cerebral sclerosis in geriatrics. , as well as for the treatment of absences due to head trauma, and for the treatment of depressive states.

The invention therefore includes all compositions r.

/ - _. - _ ^ 7, as active ingredients, in combination with any excipients suitable for their administration, in particular by oral or parenteral route.

The routes of administration can be the oral and parenteral routes. . _____________

The daily dosage can range from 10 to 200 mg.

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Claims (6)

1. Derivatives of oxayohimbane-carboxylic acid, reacting to; the formula (I) l I 'ch3 R2OG ^ S> s> / 0 in which is a hydrogen atom, a (C1-4) -alkoxycarbonyl radical, a phenoxycarbonyl radical whose phenyl can bear a d atom halogen or a nitro group, J a (C1_4) -acyl radical, I a (C3_4) -alkoxycarbonyl- (0 ^ _4) -alkyl radical, | r2 is the hydroxy radical, a radical 02-le (Me = alkali metal | u or alkaline-earth), * 'a racical (C1-4) -right or branched alkoxy, a radical (C3 <_g) -cycloalkyl- (C1- 4) -alkoxy, a radical (C_,) - cyclo-alkoxy, 3 "o the amino radical, a (C1-4) -alkylamino radical, a di- (C1_4) -alkyl-amino radical, a radical (C g ) -cycloalkyl-amino, with the exception of the compounds for which R.sup.1 is H and R2 is CH30 or OH. 2. Addition salts of the compounds of formula (I) with therapeutically acceptable acids. 3. Derivatives according to claim 1, characterized in that R is an alkoxycarbonyl or alkoxycarbonyl-alkyl radical. 1 4 4. Methoxycarbonyl-1 didehydro-16,17 methyl-190 ^ oxayohimba-methyl carboxylate-16. 5. Process for the preparation of the compounds according to claim 1, process characterized in that the acid I (R ^ H, R2 = OH) is prepared from raubasine (R ^ H, R2 = CH30) by saponification ,. then the esters (I) are preoared according to conventional methods, in particular either by direct esterification of the acid, (by reaction between the acid chloride and the alcohol R2H or one of its alkaline salts) or by transesterification of raubasine; the amides (I) are prepared from the acid (I) R ^ = H, R2 = OH) or one of its functional derivatives by conventional amidation; and the compounds (I) carrying a radical H are prepared from • I from the compounds (I) in which R ^ is H by reaction of the compound with a halide R ^ X: the anion of raubasine is formed, by example by solubilization of the base in dimethyl-formamide and action of sodium hydride, then the compound R ^ X (X = Cl or Br) is then added. 6. Medicinal product characterized. that it contains a compound according to any one of claims 1 to 4.