GB2029405A

GB2029405A - Brominated Derivatives of Vincamine

Info

Publication number: GB2029405A
Application number: GB7920355A
Authority: GB
Original assignee: Omnium Chimique SA
Current assignee: Omnium Chimique SA
Priority date: 1978-06-12
Filing date: 1979-06-12
Publication date: 1980-03-19
Also published as: ES8306150A1; CH642655A5; ES481998A0; IT7923464A0; IT1121787B; DE2922316A1

Abstract

Novel compounds of the formula I. <IMAGE> wherein either R1 represents an alkoxycarbonyl group, branched or not, having 1 to 7 carbon atoms, and R2 and R3 represent, respectively, a hydroxyl and a hydrogen or together an additional carbon-carbon bond, or R1 and R2 are together an oxygen atom, and R3 is hydrogen, and R4 and R5 are hydrogen atoms or together an additional carbon-carbon bond; and corresponding addition salts thereof, show antianoxic and psychotropic activity. Some of the compounds I show anti-epileptic, anticonvulsant and muscle relaxant activity. A multistep synthesis for the compounds I is claimed.

Description

SPECIFICATION Brominated Derivatives of Vincamine The present invention relates to new brominated derivatives of vincamine, their preparation and to pharmaceutical compositions including such derivatives.

The present invention in one aspect provides a compound of the formula (I)

wherein either R, represents an alkoxycarbonyl group, branched or not, having 1 to 7 carbon atoms, and R2 and R3 represent, respectively, a hydroxyl and a hydrogen or together an additional carboncarbon bond, or R, arid R2 are together an oxygen atom, and R3 is hydrogen, and R4 and R5 are hydrogen atoms or togethcr an additional carbon-carbon bond; or a corresponding addition salt thereof.

The invention in another aspect provides a process for preparing 1 O-bromovincamine or derivatives thereof according to claim 1, comprising: (a) optionally effecting transesterification of vincadifformine or tabersonine in the presence of an acid and a C2-C6 alcohol, (b) selectively brominating the 10 position of vincadifformine or a derivative thereof by means of N-bromosuccinimide in a C2-C4 perfluoroorganic acid, (c) effecting oxidation with an organic peracid to afford a N-oxy-1 6-hydroxyaspidospermidine derivative, (d) rearranging the latter compound in the presence of triphenylphosphine in an acidic medium to afford 1 O-bromovincamine or a derivative thereof, and (e) optionally transforming a said bromo-derivative to the corresponding 1 O-bromopovincamine or 1 O-bromovincamone or derivative thereof.

The invention in a further aspect provides a pharmaceutical composition which comprises a compound according to the invention together with a pharmaceutically acceptable carrier or diluent.

The numbering of vincadifformine and derivatives thereof shown in formula (I) is in accordance with Le Men and Taylor (Experientia 21, 508, 1965).

The novel compounds of general formula I may be provided as optical isomers (16 S, 20 S, 21 S or 16 R, 20 R, 21 R) or racemic compounds.

Vincamine of formula ll and some of its derivatives such as vincamone of formula Ill are wellknown for their therapeutical properties (see Symposium on Pharmacology of Vinca Alkaloids, Akademiai Kiado, Budapest, 1976).

Vincamine II is active on the central nervous system and the circulatory system (see L. Sporny and K. Szasz Arch. Exptl, Pathol. Pharmak, 236, 296, 1959 wherein hypotensive and sedative properties are described). Vincamine is presently used mainly for the treatment of cerebral vascular disorders.

Some halogenated derivatives of vincamine have already been described, for example in U.S.

Patent Application No. 968147 and in Belgian Patent No. 823409.

Tabersonine, an alkaloid of formula IV wherein R=Me and X=H, is the starting raw product of a particularly advantageous hemisynthesis of vincamine (U.S. Patent No. 3892755).

The first step of this synthesis is a hydrogenation of tabersonine to give vincadifformine (formula V wherein R=Me and X=H).

Vincadifformine Va is then oxidised to N-oxy-1 6-hydroxy-1 ,2-dehydro-aspidospermidine which is then subjected to an acid rearrangement to yield vincamine.

It has now been found that it is possible to brominate vincadifformine and its derivatives selectively in the 10 position. This selective bromination gives the possibility to obtain a large number of 1 0-bromovincamine derivatives which appear to possess more interesting pharmacological properties than the corresponding unbrominated analogs.

Furthermore, it has been found that replacement of the methoxy group of the halogenated derivatives by another alkoxycarbonyl group, preferablv the ethoxycarbonyl group, is easily achieved.

This replacement affords new derivatives which in most cases have superior phannacological properties to the methoxycarbonyl analogs, particularly as the cerebral oxygenating and toxicity properties are concerned.

Ethyl vincaminate and ethyl apovincaminate themselves are known compounds with anti-anoxic properties. In this case they are obtained starting from the corresponding carboxylic acid derivatives using ethanol or ethyl bromide as esterifying agent (Arzneim. Forschung 26, 1 Oa, 1 907, 1 976). No halogen derivatives thereof have beenoreported.

Selective bromination in the 10 position of vincadifformine is best achieved by reacting with a Nbromo derivative in a strong acid medium, for example by using a solvent such as trifluoroacetic acid.

Furthermore, the so obtained 1 0-bromovincadifformines afford, after oxidation and acid rearrangement, the corresponding 10-bromovincamines.

The preparation of the new compounds of the present invention is mainly characterised by the fact that the bromination step is effected in a strong acid, such as a C2-C4 perfluoro acid, preferably trifluoroacetic acid. This reaction is carried out at a temperature between -200C and 600 C, advantageously between 5 and 1 50C, by addition of 1 to 2 equiva!ents of a N-brominated compound such as N-bromosuccinimide. The perfluoro acid used may be diluted in an inert solvent.

After 1 to 5 hours, the reaction mixture is neutralized by a base such as sodium hydroxyde in water and extracted with a water-immiscible solvent, such as methylene chloride or benzene. After crystallization, the new bromo derivatives are obtained with yields superior to 80%.

Alternatively, the bromination step may be conducted starting with the acid addition salts of vincadifformine or tabersoninine, for example the salts obtained with hydrochloric acid or oxalic acid.

The oxidation of the 1 0-bromovincadifformines is best achieved in the presence of an organic peracid such as m-chloroperbenzoic acid, perphtalic acid or p-nitroperbenzoic acid. The latter reagents are dissolved in an organic solvent such as methanol, toluene or benzene. Other oxidation systems may be used, for example oxygen or hydrogen peroxide in the presence of a metal salt catalyst.

The resulting N-oxy-16-hydroxy-aspidospermidines are preferably not isolated. These derivatives are extracted with an acidic aqueous phase and added to a reagent able to reduce a N-oxide.

Preferably, a phosphine such as triphenyl phosphine is employed. The reaction is carried out between 0 and 600 C, preferably around 350C.

The acid employed in this step is preferably a low molecular weight organic acid such as acetic acid or propanoic acid. The concentration in acid may vary between 10 and 90% by volume.

Depending on the utilized conditions and the nature of the starting vincadifformine, the reaction is completed after a duration varying between 10 hours and 10 days. The resulting bromo-vincamines are isolated, after neutralization of the reaction mixture, by extraction with a water immiscible solvent.

Methylene chloride is generally preferred. After evaporation to dryness, recrystallization in a solvent such as acetone affords the pure 10 bromo-vincamine. From the mother liquor, a small quantity of the corresponding epi-1 6 derivative is isolated.

If desired and starting from the resulting 1 0-bromovincamines, the corresponding 10bromoapovincamines (I, R2 and R3=additional bond) and vincamones (R, and R2=O) are easily prepared with good yield and utilizing known procedures.

The 1 0-bromoapovincamines can indeed be advantageously obtained from the 10bromovincamines by deshydratation. This is best effected by solubilization of the vincamine in trifluoroacetic acid. The reaction may be carried out at room temperature. This deshydratation may also be conducted in a solvent such as pure formic acid at reflux for 1 to 6 hours.

1 0-bromovincamone and derivatives thereof are obtained starting from the 1 0-bromovincamines by reacting with a strong base dissolved or suspended in a solvent inert under these conditions.

It is generally preferred to employ a solvent such as an alcohol or an aromatic solvent such as xylene, toluene, benzene or a mixture thereof. If the solvent used is able to form an azeotrope, the reaction mixture can be advantageously dried by azeotropic reflux through a water-separator.

The strong base is preferably sodium or potassium alcoholate. Such base can be present in a catalytic amount but one to several equivalents can also be utilized. More particularly the alcoholate is preferably potassium or sodium t-butylate or t-amylate.

The reaction is carried out between 10 and 1 800C, advantageously between 70 and 11 O0C, in an inert atmosphere (N2, Ar). Reaction time may vary between 3 and 36 hours depending on the conditions and the nature of starting 1 0-bromovincamine.

The resulting 1 0-bromovincamones are isolated by concentration, dissolution with water, then extracting with a water-immiscible solvent such as chloroform or methylene chloride. Concentration affords crystalline products with a yield superior to 80%. The novel bromo derivatives are best crystallized from acetone, methanol or diethyl ether.

Another aspect of the present invention is the process of making alkyl vincadifformate (I, X=H, R=C2-C6 alkyl) which may be employed as starting material in the bromination step. These compounds afford, after applying the hereabove described process, alkyl vincaminate or apovincaminates (I, R,=alkoxycarbonyl differing from methoxycarbonyl) in good yield.

The choice of the transesterification method is limited. It has indeed been demonstrated that vincadifformic acid (V, X=H, R=H) is unstable and gives the corresponding decarboxylated product dehydro-1,2 aspidospermidine (Zsabon and Otto, Acta Cim., Budapest, 69, 87, 1971).

The resulting esters are novel compounds and are important intermediates for the obtention of alkoxycarbonyl derivatives different from the methoxycarbonyl analogs. These latter compounds characterise most of the natural alkaloids in the aspidospermidine and eburnamenine series.

The first step of the process of obtaining these alkylvincaminates and apovincaminates is thus a transesterification of vincadifformine or tabersonine.

This is best carried out in a mixture of alcohol and hydrochloric acid. The appropriate alcohol is chosen according to the desired alkoxycarbonyl group of the resulting product. It is thus an alcohol, branched or not, containing from 2 to 6 carbon atoms.

If tabersonine (14,1 5-dehydro-vincadifformine) has been employed in the transesterification step, it is still possible, if desired, to hydrogenate the double bond of the resulting alkyl tabersonate before subjecting it to the oxidation acid rearrangement sequence.

For this purpose, the tabersonine derivative is dissolved in an alcohol and hydrogenated under atmospheric pressure in the presence of a catalyst such as Put02, Pd/C, Pt/C, until the theoretical volume has been absorbed. The catalyst is then removed by filtration, for example through diatomaceous earth.

If the 1 0-bromo-1 4,1 5-dihydrovincamines or apovincamines are desired, the 10bromotabersonines are not hydrogenated. The above mentioned oxidation rearrangement sequence affords then directly the corresponding vincamines with a double bond in the 14-1 5 positions.

The starting vincadifformine or tabersonine used in this synthesis may be the (-)vincadifformine (7, 20a, 21 a), the (+)vincadifformine (7a, 20, 2 1 or the racemic mixture, or the corresponding tabersonine derivatives.

When the (-)vincadifformine is utilized the resulting vincamine will have configurations in the 20 and 21 positions identical with that of the natural vincamine 20a, 21 a).

The racemic vincadifformine affords racemic 1 0-bromovincamines and is preferably obtained by total synthesis (see for example U.S. Patent No. 3987048).

As mentioned, the new compounds of the present invention may be used in the form of their acid addition salts. Such salts are obtained by conventional practice, i.e. by treating the free base form of the compounds with an acceptable organic or inorganic acid. Suitable acids for this purpose include hydrobromic, sulfuric, phosphoric, nitric, benzoic, methyl sulfonic, citric and lactic acids.

Of particular importance are the compounds of the invention in the form of acid addition salts of pharmaceutically acceptable acids.

The novel compounds of the present invention may indeed be used as therapeutically active agents. These compounds have been found by pharmacological testing procedures to have interesting antianoxic and psychotropic activity.

Acute toxicity The compounds of the invention and vincamine were administered by intragastric route to Charles River stock mice. The lethal doses for 50% (LDso) were determined graphically according to the method of Lichtfield and Wilcoxon (J. Pharm. Exp. Therap. 1946, 96, 99). The results are summarized in Table 1.

Hypobaric anoxia test on mice Charles River stock mice of the same sex, weighting about 20+2 g are shared into three lots of 10 animals each. The lots 1 and 2 comprise treated animals, i.e. those having received either a substance to be tested or vincamine. The third lot comprises control animals, i.e. those having only received solvent at 1 ml/l 00 g of body weight. The compounds examined are administered p.o. 30 minutes before the experiment.

The animals are placed in an atmosphere impoverished in oxygen by creating a partial vacuum (190 mm Hg, corresponding to 5.25% oxygen), in about 30 seconds.

The survival time of the mice is measured with a chronometer. This time is increased by the agents capable of enhancing oxygenation of tissues and more particularly brain oxygenation.

Under the above described conditions, the dose which provides a 50% increase of the average survival time of the animals may be expressed as the 50% effective dose (here abbreviated as ED50).

The results obtained with vincamine and the compounds of formula I are given in Table I.

In addition, it has been found that at 1/5 of the lethal dose (400 mg/kg), compound Id (table I) increase the survival time of the mice by 412%. At an equivalent dose (LD/5) vincamine increases the survival time by 54% only.

Table I LD50P p.o. i.v. ED50 p.o. LD5gED5 Vincamine Il 970 47 200 5 10-bromovincamine (la, R -OH, R -CO2Me,R3=R4=R5=H) 1100 32 180 6 Ethyl 1 0-bromovincaminate (Ib, Rt=OH, R2=CO2Et, R3=R4=R5=H)* > 2000 69 - 1 0-bromoapovincamine HCI (Ic, R,-CO,Me, R2 et R3=liaison, R4=R5=H) > 2000 45 200 > 10 Ethyl 1 0-bromoapovincaminate (Id, R1=CO2Et, R2 etR3=C-C bond, R4=R5=H)* > 2000 90 25 > 80 1 O-bromo-1 4,1 5-dehydroapovincamine (le, R,=CO2Me, R2R3 and R4R5= C-C bonds)* 1950 210 85 23 1 0-bromo-1 4,1 5-dehydrovincamone (If, R1, and R2=O, R3=H, R4R5= C-C bonds)* 1660 90 63 26 10-bromovincamone (Ig, R, and R2=O, R3=R4=R5=H) > 2000 25 > 80 *: as a methanesulfonate salt.

Moreover, some compounds of the present invention, for example 1 0-bromoapovincamine Ic, have also demonstrated interesting anti-epileptic, anticonvulsant and muscle relaxant actions.

For their therapeutical use, the compounds of the invention will be provided in the form ot bases or addition of salts with pharmaceutically acceptable acids.

The compounds of the invention, having both anti-anoxic and psychotropic activities, may be used therapeutically for treating troubles of vigilance, particularly to fight against behaviour troubles due to cerebral vascular damages and brain sclerosis in geriatrics. They also may be used as sedatives as well as for treating absences due to cranium injuries and for treating conditions of depression. They may also be used generally for treating cerebro-vascular or cardiocirculatory diseases.

For their therapeutical use, the compounds of formula I may be administered either orally in the form of capsules, tablets, pellets, dragees, cachets, solutions or suspensions or by parenterally as buffered sterile solutions, prepared beforehand or extemporaneously, in which the active substance, base or salt, is present in an amount of 0.5 mg to 700 mg per unit. The daily dose may vary between 1 mg and 500 mg according to the disease.

For therapeutical use, the compounds of the invention are provided as pharmaceutical compositions containing as the active substance at least one of such compounds possibly in admixture with other active substances and diluents or carriers as well as dyestuffs sweeteners, preserving agents, anti-oxidizers, etc, which are commonly used in pharmaceutical compositions.

The preparation of pharmaceutical compositions is effected according to usual methods substantially consisting of incorporating or admixing the active substance or substances with the adjuvant used.

If the compounds are administered in the form of their acid addition salts, it is necessary to use pharmaceutically acceptable acids.

The following examples are illustrative of the process and products of the present invention.

In these examples, unless otherwise indicated, the configurations of the described compounds are those characterising the natural vincamine.

Example 1 10-bromovincadifformine (V, X=H, R=CH3) 10.8 g of N-bromosuccinimide are added to a solution of 20 g of vincadifformine in 500 ml of trifluoroacetic acid, with stirring at room temperature.

After two hours, the reaction mixture is carefully poured on 1.5 kg of ice and the resulting mixture is rendered alkaline by the addition of 30% sodium hydroxyde. The aqueous phase is repeatedly extracted with methylene chloride.

The combined organic phases are washed with water, dried (MgSO4) and evaporated to dryness.

A white solid (24.7 g) is obtained and shown to be pure by thin layer chromatography. Yield 100%.

a,=-5800 (CHCl3, C=0.25).

I.R. (CCl4, cm 3370 (NH); 1690 (C=O conjugated ester).

U.V. nm (log E) C=3.076 10-2 g/l, methanol: 310(4.24); 330 (4.22); 321 (4.23); 265 (3.22).

N.M.R. (CDCl3, ppm,#): 8.98 (s, NH); 7.37 (d, J=2 Hz, H8); 7.30 (dxd, J=8 and 2 Hz, H"); 6.72 (d, J=8 Hz, H,2); 3.83 (s, CO2Me); 0.62 (t,3H12).

Mass spectrum: M+ 416 and 418 (m/e).

Example 2 10-bromovincamine (I, R,=OH: R2=CO2CH3, R3=R4=R5=H) 1. 1 O-bromo-N-oxy-l 6-hydroxy-l ,2-dehydro-aspidospermidine: 447 mg (2.2 mmoles) of 85% m-chloroperbenzoic acid are added by portions to a solution of 418 mg (1 mmole) of 1 0-bromovincadifformine in 50 ml of anhydrous benzene. Stirring is continued overnight at room temperature.

2. The benzene phase is extracted with 64 ml of 76% acetic acid, then with 20 ml of water. With stirring 400 mg of triphenylphosphine (1.5 mmole) is added to the combined aqueous phases. Stirring is continued for 24 hours at 350C. After extraction of the aqueous reaction mixture with 3x20 ml of benzene, the reaction mixture is rendered alkaline with 30% sodium hydroxyde and extracted with methylene chloride. The combined organic phases, washed with water, dried on MgSO4 and evaporated to dryness yield a white residue weighing 400 mg which is crystallized from acetone. 10bromovincamine crystallises first. From the mother liquor, 1 0-bromo-1 6-epivincamine is isolated.

10-bromovincamine M.P.=204.5-205.5 C.

a,=+54.7 (CHCl3; C=0.25).

I.R. (CCl4, cm-l): 3520 (OH); 1 745 (CO2Me).

U.V. (methanol, C=15.3 mg/l), nm (log E): 300 (3.76); 290 (3.89); 285 (3.88); 258 (3.51); 233 (4.53).

N.M.R. (CDCl3, ppm, S): 7.58 (d, J=2 Hz, H9; 7.20 (dxd, J=8 and 2 Hz, H"); 6.93 (d, J=8 Hz, H,2); 4.61(s, OH); 3.83 (s, H2,); 3.78 (s, CO2Me); 0.83 (t,3H,8).

Mass spectrum: M+ 432 and 434 (m/e).

10-Bromo 16-epi vincamine M.P.=1 85-1 860C (acetone).

(t,=+70 (C=0.37; CHCl3).

I.R. (KBr; cm-': 3420 (OH); 1755 (CO2Me).

U.V. (methanol, C=15.6 mg/l), nm (log E): 300 (3.72 ep.); 289 (3.89); 286 (3.88); 283 (3.88); 232 (4.50).

N.M.R. (CDCl3, ppm, b): 7.55 (d, Hg); 4.43 (s, OH), 3.70(s, CO,Me); 2.60 (d, J=14 Hz, H,7); 0.8 (t, J=7 Hz,3H,8) Mass spectrum: M+ (m/e) 432 and 434 calculated for C2,H25N203Br 432 and 434.

Example 3 10-Brnmo-14,15-dehydrovincadifformine (lV, X=Br, R=CH3) 1.12 g of 14,1 5-dehydrovincadifformine (tabersonine, 3 mmoles) are dissolved in 30 ml of trifluoroacetic acid. 540 mg (3 mmoles, 1 equiv.) of N-bromosuccinimide are then added.

After two hours at room temperature, the reaction mixture is diluted with water, made alkaline with sodium hydroxide in the presence of ice, then extracted with methylene chloride.

The dry residue (1.2 g, yield: 96%) is purified by thin layer chromatography.

αp:-320 (CHCl3; C=0.57).

I.R. (CCl4, cm-l): 3460 (NH); 1680 (conj. ester).

U.V. (methanol; C=14.78 mg/l), nm (log E): 331 (4.23); 320 (4.21); 309 (4.24); 264 (3.20).

N.M.R. (CDCl3, ppm, X): 9.00 (s, NH); 7.37 (d, J=2 Hz, Hs); 7.25 (dxd, J=J'=2 Hz, H"); 6.68 (d, J=8 Hz, H,2); 3.77 (s, CO2Me); 0;66 (t,3H,8).

Mass spectrum: M+ 414 and 416 (m/e) calculated for C2,H2302N2Br.

Example 4 10-bromo-14,15-dehydrovincamine (I, R,=OH; R2=CO2; R3=H; R4 and R5=additional CC bond) 7.5 ml of a methanol/NClO4 mixture (64/l v/v) then 170 mg of m-chloroperbenzoic acid are added to 311 mg of 10-bromo-14,1 5-dehydrovincadifformine (0.75 mM) in 5 ml of methanol.

After one week at room temperature, the reaction mixture is diluted with water, washed with hexane, alkalised with sodium hydroxide to a pH of 9 and extracted with methylene chloride.

The residue obtained after evaporation to dryness weighs 221 mg (yield: 68%) and is composed of two products as shown by thin layer chromatography. These two derivatives of vincamine are separated by crystallization.

a) 10-bromo-14,1 5-dehydrovincamine αD=+141 (CHCl3).

I.R. (KBr, cm-1): 1750 (ester).

U.V. (ethanol), nm (log ): 300 (3.69); 291(3.81); 284 (3.81); 235 (4.37).

N.M.R. (CDCl3, ppm, b): 7.60 (d, J=2 Hz, Hg); 7.23 (dxd, J=8 and 2 Hz, H13); 6.90 (d, J=8 Hz, H,2); m between 5.4 and 6.0 (H,4 and H,5); 4.07 (s, H2,); 3.86 (s, CO2Me); 2.33 (2H,7); 1.00 (t, 3H,8).

Mass spectrum: M+ (m/e) 430-432 calculated for C2,H2303N2Br.

b) Bromo-10-dehydro-14,15--16 epivincamine M.P.=200-201 OC.

D=+530 (CHCl3).

I.R. (KBr, cm-'): 1735 (ester).

U.V. (methanol, C=1 7.26 mg/l), nm (log E): 299 (0.22); 289 (0.31); 285 (0.30); 283 (0.30); 260 (0.16);233 (1.28).

N.M.R. (CDCl3, ppm, b): 7.60 (d, J=2 Hz, H9); 7.37 (d, J=8 Hz, H,2); 7.13 (dxd, J=8 and 2 Hz); 5.50 (dxt, J=1 0 and 3 Hz, H,4); 5.18 (d, J=1 0 Hz, H,5); 4.43 (s, OH); 3.63 (s, H2,); 3.43 (s, CO2Me); 2.51 (d, J=14 Hz, H,7); 0.85 (t, J=7 Hz).

Mass spectrum: M+ (m/e) 430432 calculated for C2,H2303N2Br.

Example 5 10-bromoapovincamine (I. R,=CO2CH3; R2R3= additional C-C bond; R4R5=H) 1 ) 1 0-bromo-N-oxy-1 6-carbomethoxy- 1 6-hydroxy-1 ,2-dehydroaspidospermidine: 447 mg (2.2 mM) of 85% m-chloroperbenzoic acid are added by portions to a solution of 418 mg (1 mM) of 1 0-bromovincadifformine in 50 ml of anhydrous benzene. Stirring is continued overnight at room temperature.

2) The preceeding benzene solution is washed with 50 mi of an aqueous solution of sodium bicarbonate. The benzene is then evaporated and replaced by 50 ml of anhydrous formic acid. 400 mg of triphenylphosphine (1.5 mM) are added with stirring and the reaction mixture refluxed with continued stirring for 4 hours. 50 ml of water are then added and the reaction mixture is extracted with 3x30 ml of benzene.

The aqueous phase is then rendered alkaline with 30% sodium hydroxide and extracted with methylene chloride. The combined organic phases, washed with water, dried over MgSO4 and concentrated to dryness, yields a residue (340 mg, yield 81%) which is recrystallized from acetone).

M.P.=206.5-208 C.

a=+1500 (CHCl3, C=0.25).

I.R. (KBr, cm-'): 1730 (C=O ester); 1630 (C=C).

U.V. (methanol, C=1 5.36 mg/l), nm (log E): 320 (3.90); 302 (3.72); 280 (4.13); 255 (3.75); 235 (4.50).

N.M.R. (CDCl3, ppm, d): aromatic ABX system 7.63 (H9); 7--7.5 (H11+H12); 6.28 (s, H,7); 4.13 (s, H2,); 4.00 (s, CO2Me); 1.00 (t, 3H,8).

Mass spectrum: M+ (m/e) 411--416 calculated for C2,H23N202Br.

Example 6 1 0-bromo-14,1 5-dehydroapovincamine (I, Rt=CO2CH3, R2R3 and R4R5=additional CC bonds) 600 mg of 1 0-bromo-1 4,1 5-dehydro-vincamine are dissolved in 9 ml of trifluoroacetic acid. After 1 h at room temperature, some water is added to the reaction mixture which is then rendered alkaline with sodium hydroxide in the presence of ice. The aqueous phase is extracted with chloroform. After evaporation of the solvent and crystallization from acetone, 470 mg of 10-bromo-14,15- dehydroapovincamine are isolated. Yield: 82%.

M.P.=1 67-1 690C.

aD=+103 (CHCl3).

I.R. (CCl4, cm-'): 1 735 (C=O).

U.V. (methanol, C=15.33 mg/l), nm (log ): 321 (3.90); 302 (3.68); 280 (4.11); 255 (3.71); 235 (4.48); N.M.R. (CDCl3, ppm, ): 6.8-7.7: 6.10 (5, H,7); 5.1-5.8 massif, H,4+H,s); 4.22 (s, H2,); 3.93 (s, CO2Me); 1.00 (t, 3H,8).

Mass spectrum: M+ (m/e) 412-414 calculated for C2,H2,N202Br.

Example 7 10-bromo-vincamone (I. R,R2=O; R3=R4=Rs=H) 400 mg of potassium t-butylate are added to 1.3 g (3 mM) of 10-bromo-vincamine dissolved in 200 ml of anhydrous benzene. The benzene solution has been dried by azeotropic distillation through a Dean-Starck water-separator. After 24 hours at reflux, the reaction mixture is concentrated under vacuum to a volume of around 50 ml. 200 ml of distilled water is then added and the aqueous phase is thoroughly extracted with methylene chloride. The organic extracts are washed with water, dried (MgSO4) and evaporated to dryness.

The thus obtained residue (1.05 g) is recrystallized from acetone.

M.P.=137.5--139 C.

a0=-300 (chloroform, C=0,25).

I.R. (KBr, cm-l): 1705 (C=O(.

U.V. (methanol, C=1 5.09 mg/l), nm (log E): 308 (3.65); 304 (3.59); 298-292 (broad, 3.72); 275 (4.04); 248 (4.43).

N.M.R. (CDCl3, ppm, 8): 8.25 (d, J=8 Hz, H,2); 7.53 (d, J=2 Hz, H9); 7.42 (dxd. J=8 and 2 Hz, H"); 3.93 (s, H2,); 2.63 (s, 2H,7); 0.93 (t, J=7 Hz, 3H,8).

Mass spectrum: M+ 372-374 (m/e) calculated for C,H2,N2OBr.

Example 8 10-bromo-14,15-dehydrovincamone (I, R,R2=O, R3=H, R4R5=additional C-C bond) 400 mg of potassium t-butylate are added to 1.2 g of 1 0-bromo-1 4,1 5-dehydro-vincamine dissolved in 200 ml of anhydrous benzene.

The reaction mixture is refluxed under nitrogen for 24 hours. The solvent is then concentrated under vacuum to a volume of 50 ml. 200 ml of water are added and the mixture is extracted with methylene chioride. The organic extracts are washed with water, dried over MgS04, and evaporated to dryness. The residue (1.0 g) is recrystallized from diethyl ether (600 mg) to afford the pure compound.

M.P.=113-1150C.

αD=+54.5 (C=0.25; CHCi3), I.R. (KBr, cm-'): 1705 (C- 0).

U.V. (methanol, C=15.42 mg/l), nm (log E): 308 (3.66); 305 (3.63); 295 (3.75); 275 (4.03); 268 (4.02); 249 (4.41).

N.M.R. (CDCl3, ppm, â): 8.27 (d, J=8 Hz, H,2); 7.60 (d, J=2 Hz H9); 7.45 (dxd, J=8 and 2 Hz, H"); 5.2-5.8 (m, H,4+H15); 4.07 (s, H2,); 2.77 (s, 2H,7), 1.00 (t, J=7 Hz, 3 H,8).

Mass spectrum: M+ (m/e) 370-372 calculated for C,9H,9N2OBr.

Example 9 Ethyl vincadifformine (V, X=H, R=CH2CH3) A solution of 35 g of vincadifformine dissolved in 350 ml of anhydrous ethanol saturated with hydrochloric acid, is heated under reflux conditions in nitrogen for 22 hours.

The alcohol is then removed under reduced pressure. The residue is taken up in methylene chloride, washed with diluted amonia, dried over MgSO4 and the solvent is then removed under vacuum.

The residue (34.9 g) is subjected to a chromatographic treatment over 1050 g of siiica gel.

Elution with methylene chloride gives, after concentration, 13.9 g of the crystallized compound (38%).

M.P.=1 15-11 60C.

D=607 (CHC13; C=0.5).

U.V. (methanol, C=l 5.072 mg/l), nm (log E): max 225 (4.09); 301 (4.05); 328 (4.20) min 260 (3.14); 307 (4.04).

I.R. (film, cm-'): NH a 3360; conjugated ester at 1670; 1 2-disubstituted benzene at 740 cm-' N.M.R. (CDCl3): NH, s. at 9.07 ppm between 6.7 and 7.5 ppm; C02-CH2-CH3, q. 4.30 ppm (J=7.5 cps); CO2-CH2-CK2; t. 1.33 ppm (J=7.5 cps); C(18H3 t. at 0.63 ppm.

Example 10 Ethyl 1 0-bromovincadifformate (V, X=Br, R=CH2CH3) 6.08 g of N-bromo-succinimide are added in small portions to a solution of 11.2 g of ethyl vincadifformate in 320 ml of trifluoroacetic acid. After 1 hour with stirring at room temperature, the reaction mixture is poured into a ice-water mixture. The resulting mixture is made alkaline by means of 30% sodium hydroxide and extracted with methylene chloride. After washing with water and drying (MgSO4), the solvent is removed under reduced pressure to give a dry residue (12.7 g, 92.6%) which is practically purified by thin layer chromatography.

a0=-51 70 (C=0.5, CHCI3).

U.V. (methanol, C=1 5.09 mg/l) max 310 (4.20) 330 (4.19) nm min 264 (3.33) 321 (4.19) nm.

I.R. (film): NH at 3360; conjugated ester at 1670 cm-1; 1,2,4 trisubstituted benzene at 790 cm-'.

N.M.R. (CDCl3): NH, s. 9.05 ppm; H9; d. 7.30 ppm (J=2 cps); H11 d.d. 7.25 ppm (J=8 cps, J'=2 cps); H d. at 6.72 ppm (J=8 cps); COCH2CH3, q. 4.20 ppm (J=7.5 cps); COCH2CK3, t.

1.32 ppm (J=7 cps); Cl,8)H3, t. 0.63 ppm.

Example 11 Ethyl 10-bromovincaminate (I. R,=CO2CH2CH3; R2=OH; R3=R4=Rs=H) and 16-epi isomer To a solution of 12.4 g of ethyl 1 O-bromo-vincadifformate in 290 ml of toluene, there is added in small portions 16.4 g of 85% m-chloroperbenzoic acid.

Stirring is continued overnight at a temperature between 25 and 30 C. 144 ml of acetic acid and 58 ml of water are then added. The organic phase is separated and extracted twice with 30 ml of water.

To the combined aqueous phase, there are added 1 7.3 g of triphenylphosphine and the reaction mixture is stirred overnight at 30--35 .

After extraction with 2x60 ml of toluene, the aqueous phases are made alkaline by means of 30% sodium hydroxide, then extracted with methylene chloride.

The combined organic phases are consecutively washed with water, dried over MgSO4 and evaporated to dryness to give a residue (7 g) which is recrystallized from acetone. 4 g of a mixture of ethyl-1 O-bromovincaminate and ethyl 1 0-bromo-1 6-epi-vincaminate are obtained. The two components are separated by several crystallizations from acetone.

Ethyl 1 0-bromovincaminate (R,=OH) M.P.=21 1.5213.5 C (acetone).

c'D=+700 (C=0.50; CHCI3).

U.V. (methanol, C=l 5 mg/l), nm (log E): max: 234 (4.48) 290 (3.76) min: 258 (2.87).

l.R. (KBr): 0=0 ester 1740 cm-1.

N.M.R. (CDCI3): no NH, H9, d. 7.70 ppm (J=2 cps); H", d.d. 7.30 ppm (J=9 cps; J'=2 cps); H,2, d.

7.05 ppm (J=9 cps); OH, s. 4.77 ppm; CO2CH2CH3, q. 4.35 ppm (J=7 cps); 2Hf,7X, s. 2.17 ppm; CO2CH2CH3, t. 1.20 ppm (J=7 cps): 3H(18), t. 0.85 ppm (J=7 cps).

Ethyl 1 0-bromo-1 6-epi vincaminate M.P.=-190 --191 C (acetone).

a0=-150 (CHCI3; C=0.86).

U.V. (methanol): max 231 and 286 nm min 260 nm.

I.R. (KBr): 0=0 ester 1740 cm-1.

N.M.R. (CDCl3): aromatic A2B system; 1 H centered at 7.67 ppm; 2H between 7.2 and 7.4 ppm; OH, s. 4.40 ppm; CO2CH2CH3, q. 4.23 ppm (J=7 cps); H21, s. 3.82 ppm; H"7), d. 2.63 ppm (J=1 4 cps H(7), d. 1.93 ppm (J=1 4 cps); CO2CH2CH3, t. 1.13 ppm (J=7 cps); 3H(18), t.

0.85 ppm J=7 cps).

Example 12 Ethyl 10-bromo-apovincaminate (I. R,=CO2CH2CH3, R2R3=additional CC bond, R4=R 5=H) A solution of 4 g of a mixture of ethyl 1 O-bromovincaminate and its 1 6-epi isomer is refluxed under an atmosphere of nitrogen in 40 ml of pure formic acid.

After 4 hours, the mixture is poured into icewater and made alkaline by means of diluted ammonia.

Extraction with methylene chloride and evaporation of the solvent afford a residue (3.8 g, 100%) purified by thin layer chromatography.

U.V. (methanol): max 233.5; 179; 319.5 nm, min 255 and 303 nm.

I.R. (KBr): 0=0 at 1725 cm-1.

M.M.R. (CDCl3): A2B system: 1 H 7.50, 2H between 6.90 and 7.40 ppm; H,7, s. 6.08 ppm; CO2CH2CH3 q. 4.37 ppm (J=7 cps); H21, s. 4.03 ppm; CO2CH2CH3, t. 1.40 ppm (J=7 cps); 3H(18) t. 1.02 ppm (J=7 cps).

Ethyl 10-bromo 6-epi-apovincaminate methane sulfonate To a solution of 3.9 g of ethyl 1 O-bromo-apovincaminate in acetone, there is added 0.88 g of methylsulfonic acid. 3.55 of the desired salt is isolated and recrystallized from acetone or acetone diethyl ether.

M.P.=202 1040C.

αD=+68 (C=0.25, methanol).

U.V. (methanol) C=15.036 mg/l: max: 233 (4.60); 279 (4.17) 320 (3.90), min. 255 (3.83); 301 (3.70).

I.R. (KBr): N-H at 2520 cm-1, 0=0 ester at 1720 cm-1 Example 13 Ethyl tabersonate (IV, X=H, R=CH2CH3) A solution of 5 g of tabersonine hydrochloride in 50 ml of dry methanol saturated with hydrochloric acid is refluxed under nitrogen for 45 hours.

The alcohol is then evaporated under reduced pressure. The residue is taken up in methylene chloride, washed with diluted ammonia, dried over MgSO4 and the solvent is removed under vacuum.

The residue is chromatographed through a silica gel column. Elution with methylene chloride affords 2.16 g (yield: 45%) of pure ethyl tabersonate in crystalline form. This compound may be recrystallized from heptane or methanol.

M.P.=1 13-1 140C (methanol).

a,=--3820 (C=0.25; methanol).

U.V. (methanol; C=10.22 mg/l), nm (log E): max: 225 (4.15), 300 (4.11), (4.26), min: 259 (3.05), 307 (4.09).

I.R. (KBr, cm-'): 3320, 1 665, 1 600.

N.M.R. (CDCl3): NH at 9.17 ppm, aromatic protons at 6.8 and 7.5 ppm; H,4+H,5 ABX system centered at 5.83 ppm; CO2CH2-, q. 4.33 ppm, J=7 cps; CO2CH2CH3, t. 1.33 ppm (J=7 cps); 3H,8t.0.73 ppm.

Claims

1. A compound of the formula I

wherein either R, represents an alkoxycarbonyl group, branched or not, having 1 to 7 carbon atoms, and R2 and R3 represent, respectively, a hydroxyl and a hydrogen or together an additional carboncarbon bond or R, and R2 are together an oxygen atom, and R3 is hydrogen, and R4 and R5 are hydrogen atoms or together an additional carbon-carbon bond; or a corresponding addition salt thereof.

2. 1 0-bromovincamine as claimed in claim 1.

3. 1 0-bromoapovincamine as claimed in claim 1.

4. 1 0-bromovincamone as claimed in claim 1.

5. Ethyl 1 0-bromoapovincaminate as claimed in claim 1.

6. Ethyl 1 0-bromovincaminate as claimed in claim 1.

7. 1 O-bromo-1 4,1 5-dehydrovincamone as claimed in claim 1.

8. A compound according to claim 1, as described in any of the foregoing Examples.

9. A process for preparing 1 0-bromovincamine or derivatives thereof according to claim 1, comprising: a) optionally effecting transesterification of vincadifformine or tabersonine in the presence of an acid and a C2-C8 alcohol, b) selectively brominating the

10 position of vincadifformine or a derivative thereof by means of N-bromosuccinimide in a C2-C4 perfluoroorganic acid, c) effecting oxidation with an organic peracid to afford a N-oxy-16-hydroxyaspidospermidine derivative, d) rearranging the latter compound in the presence of triphenylphosphine in an acidic medium to afford 1 0-bromovincamine or a derivative thereof, and e) optionally transforming a said bromo-derivative to the corresponding 1 0-bromoapovincamine or 1 0-bromovincamone or derivative thereof.

1 0. A process according to claim 9, substantially as herein described in any of the foregoing Examples.

11. As intermediates of the process claimed in claim 9, the ethyl vincadifformate or the ethyl 14,1 5-dehydrovincadifformate.

12. As intermediates of the process claimed in claim 9, the 1 0-bromovincadifformine, the 10 bromo-1 4,1 5-dehydrovincadifformine or the derivatives thereof resulting from transesterification with an alcohol containing from 2 to 6 carbon atoms.

13. A pharmaceutical composition which comprises a compound as claimed in any of claims 1 to 8, together with a pharmaceutically acceptable carrier or diluent.

14. A pharmaceutical composition for use in medicine in treating cerebro-vascular, cardiocirculatory or epileptic affections, containing an effective amount of 0.5 to 700 mg of an active ingredient comprising at least one compound as claimed in any of claims 1 to 8, together with a pharmaceutically acceptable carrier or diluent.