CH642655A5 - BROMINATED VINCAMINE DERIVATIVES, THEIR PROCESS FOR OBTAINING AND THEIR APPLICATION AS MEDICAMENTS. - Google Patents

Description

The present invention relates to new derivatives of vincamine brominated in position 10, in the form of the base or of salt, as well as their process for obtaining and their application as active principles of medicaments.

The new compounds of the invention correspond to the general formula I

Br.

Vincamine acts on the central nervous system and on the circulatory system (see eg L. Szporny and K. Szasz "Arch. Exptl. Pathol. Pharmak.", 236, 196 (1959) which report its sedative and hypotensive properties ).

Vincamine is currently mainly used for the treatment of cerebrovascular insufficiency.

Some halogenated derivatives of vincamine, including bromo-10 vincamine itself, have already been described, in particular in French patent application No. 77.20856 and in Belgian patents No. s 823409 and 862019.

Tabersonin, an alkaloid of formula IV in which R = CH3 and X = H, is the starting material for a particularly advantageous hemisynthesis of vincamine (Swiss patent of the holder No 559208).

x

(I)

Rr

(IV)

co2r

In this formula:

is

R1 represents an alkoxycarbonyl group comprising from 2 to 7 carbon atoms with or without branched chain, and R2 and R3 represent respectively a hydroxyl group and a hydrogen atom or, together, an additional carbon-carbon bond;

is

R 1 and R 2 together represent an oxygen atom, and R 3 represents a hydrogen atom, and R 4 and R 5 represent either, jointly, an additional carbon-carbon bond, or hydrogen atoms.

The numbering adopted in general formula I is that proposed by Le Men and Taylor "Experientia", 21, 508, (1965).

The compounds of general formula I can be in the form of optical isomers (16S, 20S, 21S or 16R, 20R, 21R) or racemates. All these forms are part of the present invention.

The vincamine of formula II is known for its therapeutic properties, properties which it shares with some of its derivatives such as vincamone III or ethyl apovincaminate (see “Symposium on Pharmacology of vinca alkaloids”, Akadémiai Kiado, Budapest 1976) .

(ii)

X

(v)

C02R

(III)

The first step in this synthesis process is to hydrogenate tabersonin to provide vincadifformin (V, X = H, R = CH3). Vincadifformin is then oxidized to N-oxy hydr-oxy-16 dehydro-1,2 aspidospermidine which is subjected to a rearrangement in acid medium to provide vincamine.

It has now been found that it is possible to bromine vinca-40 difformin and its derivatives selectively in position 10. This selective bromination provides access to a large number of bromo-vincamine derivatives which have pharmacological properties. more interesting than the corresponding non-brominated derivatives.

It has also been found that the replacement of the meth-45 oxycarbonyl group of halogenated derivatives of vincamine by a different alkoxycarbonyl group, preferably the ethoxycarbonyl group, can be easily carried out.

This substitution leads to certain derivatives having comparatively higher pharmacological properties than their methoxycarbonyl analogues, in particular in terms of cerebral oxygenation and from the point of view of toxicity.

Ethyl vincaminate and ethyl apovincaminate are also known compounds whose antianoxic properties have been the subject of numerous studies.

55 In this case, they are obtained from the corresponding acids using, as esterifying agent, ethanol or ethyl bromide (Arzneim. Forschung 26,10a, p. 1907,1976).

Selective bromination at position 10 of vincadifformin and its derivatives can be easily carried out by the action of a brominated N-60 compound in a strong acid medium, for example using as solvent trifluoroacetic acid.

In addition, the bromovincadifformins thus obtained provide, by oxidation and rearrangement in acidic medium, the corresponding bromo-vincamines, new derivatives according to the invention. The synthesis process of the present invention is notably characterized in that the bromination step is carried out in a strong acid, such as a perfluorinated acid from C2 to C4, preferably trifluoroacetic acid.

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It is usually carried out between -20 and + 60 ° C, preferably between 5 and 15 ° C, by adding one to two equivalents of an N-brominated compound such as N-bromo succinimide, to vincadifformin or dehydro-14 , 15 vincadifformin (tabersonine).

The perfluorinated acid used can be diluted in an inert solvent.

After 1 to 5 hours, the reaction medium is normally neutralized with a base such as sodium hydroxide and extracted with an inert solvent not soluble in water, such as methylene chloride or benzene. The corresponding brominated derivatives are thus obtained with a yield greater than 90%.

Alternatively, the bromination step can be carried out using acid addition salts, such as hydrohalic acids or oxalic acid, on vincadifformin or dehydro-14.15 vincadifformin.

The oxidation of the brominated derivatives thus obtained takes place in the presence of peracid such as m-chloroperbenzoic acid, perphthalic acid or paranitroperbenzoic acid, in solution in a simple organic solvent such as toluene, methanol or benzene. Other oxidative systems can be used, for example oxygen or hydrogen peroxide in the presence of catalysts based on heavy metal salts.

This step provides the N-oxy aspidospermidine derivatives which may not be isolated for the subsequent operations. These derivatives are extracted in an acidic aqueous phase and placed in the presence of a reagent capable of removing oxygen from the N-oxides. A phosphine such as triphenylphosphine is preferably used and it is operated between 0 and 60 ° C, preferably around 35 ° C. Under these conditions, the N-oxy-hydroxy-16 aspidospermidine compounds rearrange to provide the corresponding bromo-10 vincamine derivatives .

The acid in aqueous solution used in this step is preferably a low molecular weight organic acid such as acetic acid or propanoic acid.

The concentration can vary from 10 to 90% by volume.

Depending on the conditions used and the nature of the starting vincadifformin, the reaction is complete after a period varying from 10 h to 10 days.

The bromovincamines are isolated, after neutralization of the reaction medium, by extraction with a solvent immiscible with water. Preferably methylene chloride is used. After concentration to dryness, recrystallization from a solvent such as acetone provides the pure bromo-10 vincamines.

Acetonic mother liquors, the corresponding epi-16 derivatives are also isolated in small quantities.

From the bromo-10 vincamines thus obtained, it is easy to access, with good yields and using known methods, the corresponding apovincamine derivatives (R2 and R3 = additional C-C bond) and vincamone (Ri and R2 = O).

The bromo-10 apovincamines are obtained from the bromo-10 vincamines by dehydration in an acid medium.

The operation is preferably carried out by dissolving the brominated vincamine in trifluoroacetic acid at room temperature.

This dehydration can also be easily carried out using as solvent pure formic acid brought to reflux for 1 to 6 h.

The bromo-10 vincamones are obtained from the bromo-10 vincamines by the action of a strong base in suspension or in solution in an inert solvent under the reaction conditions.

A solvent such as an alcohol or an aromatic solvent such as xylene, toluene, benzene or a mixture of several of these solvents is preferably used.

If a solvent capable of forming an azeotrope with water is used, the reaction medium can advantageously be made anhydrous, before the addition of the alcoholate, by azeotropic reflux through a water separator.

The base used is preferably an Na or K alcoholate. The alcoholate can be in a catalytic amount but one to several equivalents can be present in the reaction medium.

The alkali alcoholate used is preferably potassium t-butoxide or potassium t-amylate.

The reaction is usually carried out between 10 and 180 ° C, preferably between 70 and 110 ° C.

Normally the operation lasts from 3 to 36 h depending on the reaction conditions and is carried out under an inert atmosphere (Ar, N2).

The bromo-10 vincamones thus obtained are isolated by concentration, extraction with water, passage through an organic solvent immiscible with water such as chloroform or methylene chloride, and concentration to provide the crystalline products with yields greater than 80%.

These can then be recrystallized from acetone, methanol or ethyl ether.

For the preparation of C2-C6 alkyl (methyl # alkyl) vincadifformates which are used as starting material or intermediate in the inventive processes, vincadifformin or tabersonine is transesterified. The alkyl vincadifformates (alkyl # methyl) provide, by applying the reaction scheme described above, the alkyl vincaminates and apovincaminates with good yields (I, R! = Alkoxycarbonyl different from methoxycarbon-yl).

The choice of transesterification method is limited. It has indeed demonstrated that vincadifformic acid is unstable and decarb-oxylates rapidly to 1,2-dehydro-aspidospermidine (Zsabon and Otta, "Acta Chim.", Budapest, 69, 87,1971).

The esters thus obtained are new and constitute important intermediates for obtaining alkoxycarbonyl derivatives other than methoxycarbonyl, the latter group characterizing most of the natural alkaloids of the series of aspidospermidines and eburnamenines.

The first step in a process of the invention consists in trans-verifying vincadifformin or tabersonin, usually in an alcohol-hydrochloric acid medium.

The alcohol is chosen according to the nature of the alkoxycarbonyl group which it is desired to obtain.

It will therefore be chosen from alcohols containing from 2 to 6 carbon atoms, branched or not.

If tabersonin (dehydro-14.15 vincadifformin) was used in the transesterification step, the double bond can possibly be hydrogenated before carrying out the oxidative rearrangement into vincamine.

In this case, the tabersonin dissolved in an alcohol is hydrogenated under ordinary pressure in the presence of a PtO2, Pd / C, Pt / C ... catalyst until absorption of the theoretical volume.

The catalyst is separated from the solution by filtration, e.g. ex. on diatomaceous earth.

If the bromo-10 tabersonine or the starting alkyl tabersonate is not hydrogenated, the rearrangement leads to the series of bromo-10 dehydro-14,15 vincamines or apovincamines corresponding.

In the synthesis method described above, the starting vincadifformin can be (-) vincadifformin (7ß, 20a, 21a), (+) vincadifformin (7a, 20ß, 21P) or the racemic mixture. If (-) vincadifformin is used, the alkyl vincaminates and apovincaminates obtained will have the same C20 and C21 configurations as natural vincamine (20a, 21a).

The racemic mixture of vincadifformin used to obtain the bromo-10 vincamines or racemic apovincamines is obtained by total synthesis (see for example French patent N ° 2242395 of the holder).

The compounds according to the invention form addition salts with acids and from these salts, the free base can be formed conventionally in an alkaline medium.

The compounds of the invention have been subjected to pharmacological tests which have revealed advantageous properties in particular an antianoxic activity and a psychotropic activity. The reference substance chosen was vincamine.

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Acute toxicity:

The compounds of the invention, as well as vincamine, were administered intragastrically and intravenously to mice of the Charles River strain. The lethal doses 50% (LD50) were determined graphically according to the method of Lichfield and Wilcoxon "J. Pharmacol. Exp. Therap. ”, 96, 99, (1946). Some results are collated in Table I below.

Hypobaric hypoxia test in mice:

Same sex mice, Charles River strain, weighing approximately 20 + 2 g are divided into three batches of 10 animals. Lots I and 2 include the treated animals, that is to say having received the test substance or vincamine, plus the solvent at a rate of 1 ml / 100 g of body weight. 15

A third batch contains control animals, that is to say animals which have received only the solvent at a rate of 1 ml / 100 g of body weight.

The test compounds are administered intragastrically 30 min before the test. The animals are placed in an oxygen-depleted atmosphere by carrying out a partial vacuum (190 mm Hg, corresponding to 5.25% of oxygen), these conditions being obtained in 30 s.

The survival time of the animals is measured using a stopwatch.

Agents capable of promoting tissue and in particular cerebral oxygenation lead to an increase in survival time and it is therefore possible to express, by the effective dose 50% (DES0), the dose which increases the average survival time of mice by 50%. placed under the conditions described above.

Table I collates the pharmacological results obtained.

We have found, moreover, that at the fifth of the lethal dose (400 mg / kg), the compound of the invention Id increases the survival time of the animals by 412%.

At an equivalent dose (DLS0 / 5) vincamine increases this survival time by only 54%.

Table I

DLjo p.o.

i.v.

DES0 p.o.

DL50 / DE50

Vincamine II

970

47

200

5

Bromo-10 vincamine

(la, R1 = OH, R2 = C02Me, R3 = R4 = R5 = H)

1100

32

180

6

Bromo-10 ethyl vincaminate *

(Ib, Rt = OH, R2 = COzEt, R3 = R4 = Rs = H)

<2000

69

-

-

Bromo-10 apovincamine • HCl

(le, Rj = C02Me, R2 and R3 = bond, R4 = R5 = H)

<2000

45

200

<10

Bromo-10 ethyl apovincaminate *

(Id, Rj = C02Et, R2 and R3 = bond, R4 = R5 = H)

<2000

90

25

<80

Bromo-10 dehydro-14.15 apovincamine *

(le, R! = C02Me, R2R3 and R4R5 = connections)

1950

210

85

23

Bromo-10 dehydro-14.15 vincamone *

(If, Rj and R2 = 0, R3 = H, R4Rs = bond)

1660

90

63

26

Bromo-10 vincamone

(le, Rj and R2 = 0, R3 = R4 = R5 = H)

<2000

-

25

<80

* In the form of methane sulfonate.

The compounds of the invention, having both an anti-anoxic activity and a psychotropic activity, can be used in therapy for the treatment of disorders of alertness, in particular for combating disorders attributable to vascular damage. cerebral and cerebral sclerosis in geriatrics, as well as for the treatment of the absences due to cranial traumas and the treatment of the depressive states, of the cardio-circulatory or cerebrovascular affections. These compounds, like vincamine itself, can also be used with success in opthalmology and O.R.L., for example for the treatment of cochleovestibular disorders.

It has also been demonstrated that some of the compounds of the invention, in particular bromo-10 apovincamine le, also have interesting antiepileptic and myorelachant properties (test for protection against electric shock convulsions).

For their therapeutic application, the compounds of the invention can be administered either by the digestive route, in the form of capsules, capsules, tablets, dragees, cachets, solution or suspension, or by parenteral route, in the form of sterile buffered solution, prepared in advance or extemporaneously, in which the active substance, in the basic or salified state, is present in an amount of 0.5 mg to 150 mg of active substance per unit dose.

The daily dosage can vary from 1 mg to 300 mg of active substance depending on the condition.

With a view to their therapeutic application, the compounds of the invention are presented in the form of pharmaceutical compositions containing as active substance at least one compound according to the invention, optionally in admixture with other active substances and the adjuvants, diluents, vehicles or usual excipients in pharmacies as well as colors, sweeteners, preservatives, antioxidants, etc.

The pharmacological or galenic preparation is carried out by conventional methods, essentially by incorporating or mixing the active substances in the adjuvants used.

In the case where the compounds are administered in the form of their mineral or organic acid addition salts, pharmaceutically admissible acids which are well known in pharmacy should be used.

By way of nonlimiting example of a composition containing compounds of formula I, an example of a formula for tablet is given below:

Product (I) 60 mg

Starch 50 mg

Polyvinylpyrrolidone 8mg

Talc 20 mg

Magnesium stearate 5 mg

The following examples, given by way of illustration and without limitation, illustrate the process leading to the compounds of the invention and provide some physical constants associated with them.

In the absence of an indication to the contrary, the configurations of the compounds described are identical to that of natural vincamine.

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Example 1:

Preparation of bromo-10 vincadifformin from vincadifformin

At room temperature and with stirring, 10.8 g of N-bromosuccinimide are added to a solution of 20 g of vincadifformin in 500 ml of trifluoroacetic acid.

After 2 h, the mixture is poured onto crushed ice (1.5 kg) and made alkaline with 30% sodium hydroxide. The aqueous solution is exhausted with methylene chloride. The combined organic phases are washed with water, dried (MgSO 4) and evaporated to dryness.

A pure white mass (24.7 g) is thus obtained by thin layer chromatography.

Yield: about 100%.

aD = -580 ° (CHC13, C = 0.25).

IR spectrum (CC14, cm- '): 3370 (NH), 1690 (C = O conjugated ester).

UV nm spectrum (log s): C = 3.076 10-2 g / 1, neutral methanol 310

(4.24), 330 (4.22), 321 (4.23), 265 (3.22).

NMR spectrum (CDC13, ppm, 5): 8.98 (s, NH), 7.37 (d, J = 2Hz,

H9), 7.30 (d of d, J = 8 and 2Hz, Hn), 6.72 (d, J = 8Hz, H12), 3.83

(s, C02Me), 0.62 (t, 3H1S).

Mass spectrum: M + at 416 and 418.

Example 2:

Preparation of bromo-10 vincamine from bromo-10 vincadifformin (V, X = Br, R = CH3)

1) Bromo-10 N-oxy hydroxy-16 dehydro-1,2 aspidospermidine:

To a solution of 50 ml of dry benzene containing 418 mg

(1 mmol) of bromo-10 vincadifformin are added in portions 447 mg (2.2 mmol) of m-chloroperbenzoic acid at 85%. Agitation is continued overnight at room temperature.

2) The above benzene solution is exhausted with 64 ml of 76% acetic acid and then with 20 ml of water.

To the combined aqueous phases is added, with stirring, 400 mg of triphenylphosphine (1.5 mmol) and the mixture is stirred at 35 ° C for 24 h. After extraction of the aqueous reaction mixture with 3 × 20 ml of benzene, the medium is basified with 30% NaOH and extraction is carried out with methylene chloride. The combined organic phases, washed with water, dried with MgSO4 and evaporated to dryness provide a clear residue which weighs 0.40 g and which crystallizes in acetone.

The first crystallization jets consist of pure bromo-10 vincamine.

In acetone mother liquors, bromo-10 epi-16 vincamine is isolated.

Physical properties of bromo-10 vincamine la:

P.f. = 204.5-205.5 ° C (sealed capillary tube).

aD = + 54.7 ° (CHC13, C = 0.25).

IR spectrum (CC14, cm-i): 3520 (OH), 1745 (C02Me).

UV spectrum (methanol, C = 15.3 mg / 1) nm (log e), 300 (3.76), 290

(3.89), 285 (3.88), 258 (3.51), 233 (4.53).

NMR spectrum (CDC13, ppm, S): 7.58 (d, J = 2Hz, H9), 7.20 (d of d, J = 8 and 2Hz, Hlx), 6.93 (d, J = 8Hz, H12), 4.61 (s, OH), 3.83 (s, H21), 3.78 (s, C02Me), 0.83 (t, 3H1S).

Mass spectrum: M + at 432 and 434.

Physical properties of bromo-10 epi-16 vincamine:

P.f. = 185-186 ° C (acetone).

aD = + 7 ° (C = 0.37, CHCl3).

IR spectrum (KBr, cm-i): 3420 (OH), 1755 (C02Me).

UV spectrum (methanol, C = 15.6 mg / 1), nm, (log s), 300 (3.72 ep.),

289 (3.89), 286 (3.88), 283 (3.88), 232 (4.50).

NMR spectrum (CDCI 3, ppm, 8): 7.55 (d, H 2), 4.43 (s, OH), 3.70 (s,

C02Me), 2.60 (d, J = 14Hz, H17), 0.8 (t, J = 7Hz, 3HÎS).

Mass spectrum calculated for C21H25N203Br: 432 and 434.

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

Example 3:

Synthesis of bromo-10 A-14.15 vincadifformin (IV, X = Br, R = Ch3) by action of N-bromo succinimide on A-14.15 vincadifformin (tabersonine)

1.12 g of A-14.15 vincadifformin hydrochloride (3 mmol) are dissolved in 30 ml of trifluoroacetic acid. 540 mg (3 mmol, 1 equivalent) of N-bromosuccinimide are added.

After 2 h at room temperature, the mixture is diluted with water, basified with sodium hydroxide in the presence of ice and then extracted with methylene chloride.

The dry residue weighs 1.2 g (yield: 96%) and shows only one spot in thin layer chromatography.

Physical properties:

aD = -320 ° (CHC13, C = 0.57).

IR spectrum (CC14, cm-1): 3460 (NH), 1680 (conjugated ester).

UV spectrum (methanol, C = 14.78 mg / 1), nm (log s), 331 (4.23), 320 (4.21), 309 (4.24), 264 (3.20).

NMR spectrum (CDC13, ppm, 8): 9.00 (s, NH), 7.37 (d, J = 2Hz, H9), 7.25 (dxd, J = J '= 2Hz, H „), 6 , 68 (d, J = 8Hz), 3.77 (s, C02Me), 0.66 (t, 3HJS).

Mass spectrum: M + 414 and 416 calculated for C2iH2302N2Br. Example 4:

Rearrangement of bromo-10 A-14.15 vincadifformin:

A 311 mg bromo-10 Â-14.15 vincadifformin (0.75 mmol)

in 5 ml of methanol, 7.5 ml of methanol / HC104 mixture (64/1 v / v) is added, then 170 mg of metachloroperbenzoic acid (1 equivalent).

After one week at room temperature, the reaction medium is diluted with water, washed with hexane, basified to pH 9 with sodium hydroxide and extracted with CH2Cl2.

The dry residue weighs 221 mg (yield: 68%) and has two spots on thin layer chromatography.

The two vincamine derivatives are separated by crystallization.

Physical properties of bromo-10 A-14.15 vincamine:

<xD = + 141 ° (CHC13).

IR spectrum (KBr, cm-1): 1750 (ester).

UV spectrum (ethanol), nm (log e): 300 (3.69), 291 (3.81), 284 (3.81), 235 (4.37).

NMR spectrum (CDC13, ppm, 8): 7.60 (d, J = 2Hz, H9), 7.23 (dxd, J = 8 and 2Hz, Hn), 6.90 (d, J = 8Hz, H12) , m between 5.4 and 6.0 (H14 and Hj5), 4.07 (s, H21), 3.86 (s, C02Me), 2.33 (2H17), 1.00 (t, 3Hla). Mass spectrum: M + (m / e) 430-432 calculated for C21H2303N2Br.

Physical properties of bromo-10 A-14.15 epi-16 vincamine:

M.p .: 200-201 ° C.

aD = + 53 ° (CHC13).

IR spectrum (KBr, cm-1): 1735 (ester).

UV spectrum (methanol, C = 17.26 mg / 1), nm (log e), 299 (0.22), 289 (0.31), 285 (0.30), 283 (0.30), 260 (0.16), 233 (1.28).

NMR spectrum (CDC13, ppm, 8): 7.60 (d, J = 2Hz, H9), 7.37 (d, J = 8Hz, H12), 7.13 (dxd, J = 8 and 2Hz), 5 , 50 (dxd, J = 10 and 3Hz, H14), 5.18 (d, J = 10Hz, H15), 4.43 (s, OH), 3.63 (s, H21), 3.43 (s , C02Me), 2.51 (d, J = 14Hz, H17), 0.85 (t, J = 7Hz).

Mass spectrum: M + (m / e) 430-432 calculated for C21H2303N2Br.

Example 5:

Preparation of bromo-10 apovincamine (le) from bromo-10 vincadifformin (V, X - Br, R = CH3)

1) Bromo-10N-oxycarbomethoxy-16hydroxy-16dehydro-1,2 aspidospermidine:

To a solution of 50 ml of dry benzene containing 418 mg (lmmol) of bromo-10 vincadifformin are added in portions 447 mg (2.2 mmol) of m-chloroperbenzoic acid at 85%. Agitation is continued overnight at room temperature.

2) The above benzene solution is washed with 50 ml of a solu5

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aqueous sodium bicarbonate. The benzene is then evaporated and replaced with 50 ml of anhydrous formic acid. 400 mg of triphenylphosphine (1.5 mol) are then added, with stirring, and the mixture is stirred at reflux of formic acid for 4 h. 50 ml of water are then added and the reaction mixture is extracted with 3 x 30 ml of benzene.

The medium is then basified with 30% NaOH and extracted with methylene chloride.

The combined organic phases, washed with water, dried over MgSO4 and concentrated to dryness provide a residue which weighs 340 mg (81%) and which can be recrystallized from acetone.

Physical properties:

Mp: 206.5-208 ° C (sealed capillary tube).

aD = + 150 ° (chci3, C = 0.25).

IR spectrum (KBr, cm-1): 1730 (C = O ester), 1630 (C = C).

UV spectrum (methanol, C = 15.36 mg / 1), nm (log e): 320 (3.90), 302 (3.72), 280 (4.13), 255 (3.75), 235 (4.50).

NMR spectrum (CDC13, ppm, 8): 6.8-7.7 (aromatic solid), 6.10 (s, H17), 5.1-5.8 (solid HI4 + H15), 4.22 (s , H21), 3.93 (s, C02Me), 1.00 (t, 3H18).

Mass spectrum: M + (m / e) 412-414 calculated for C21H2] lN202Br. Example 6:

Preparation of bromo-10 A-14,15 apovincamine (le) from bromo-10 vincamine

600 mg of bromo-10 A-14.15 vincamine are dissolved in 9 ml of trifluoroacetic acid. After 1 hour of contact at room temperature, water is added to the reaction medium which is then basified 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 bromo-10 A-14.15 apovincamine are isolated. Yield: 82%.

Physical properties:

M.p .: 167-169 ° C.

aD = + 103 ° (chci3).

IR spectrum (CC14, cm-1): 1735 (C = O).

UV spectrum (neutral methanol, C = 15.33 mg / 1), nm (log e): 321

(3.90), 302 (3.68), 280 (4.11), 255 (3.71), 235 (4.48).

NMR spectrum (CDC13, ppm, 8): 6.8-7.7 (aromatic mass), 6.10 (s,

H17), 5.1-5.8 (massive H14 + H15), 4.22 (s, H21), 3.93 (s, C02Me),

1.00 (t, 3H1S).

Mass spectrum: M + (m / e) 412-414 calculated for C2iH21N202Br. Example 7:

Synthesis of bromo-10 vincamone (compound Ig) from bromo-10 vincamine (compound la)

To a solution of 1.3 g (3 mmol) of bromo-10 vincamine in 200 ml of anhydrous benzene, 0.40 g of potassium t-butoxide is added after having brought the solution to reflux under argon through a separator. Dean-Stark water. After 24 h at reflux, the benzene solution is concentrated under vacuum to a volume of 50 ml. 200 ml of distilled water are then added and the aqueous phase is exhausted with methylene chloride.

The organic extracts are washed with water, dried (MgSO 4) and evaporated to dryness. The residue obtained (1.05 g) crystallizes from acetone.

Physical properties of bromo-10 vincamone:

M.p .: 137.5-139 ° C.

aD = —30 ° (chloroform, C = 0.25).

IR spectrum (KBr, cm-1): 1705 (C = O).

UV spectrum (methanol, C = 15.09 mg / 1), nm (log e): 308 (3.65), 304 (3.59), 298-292 (plateau, 3.72), 275 (4, 04), 248 (4.43).

NMR spectrum (CDC13, ppm, S): 8.25 (d, J = 8Hz, H12), 7.53 (d, J = 2Hz, H9), 7.42 (d of d, J = 8 and 2Hz, Hn), 3.93 (s, H21), 2.63 (s, 2H17), 0.93 (t, J = 7Hz, 3H18).

Mass spectrum: M + 372-374 calculated for Ci9H2iN2OBr.

Example 8:

Preparation of bromo-10 A-14.15 vincamone (compound If) from bromo-10 A-14.15 vincamine

To a solution of 1.2 g of bromo-10 A-14.15 vincamine in 200 ml of anhydrous benzene, 0.4 g of potassium t-butoxide is added and the mixture is brought to reflux under nitrogen. After 24 h, the reaction is complete. The benzene is concentrated under vacuum to a volume of 50 ml. 200 ml of water are then added and the mixture is exhausted with methylene chloride.

The organic extracts are washed with water, dried with MgSO4, evaporated to dryness. The residue (1 g) crystallizes from ethyl ether (0.6 g).

Physical properties of bromo-10 A-14.15 vincamone (If):

P.f. = 113-115 ° C.

aD = + 54.5 ° (C = 0.25, CHCl3).

IR spectrum (KBr, cm-1): 1705 (C = O).

UV spectrum (methanol, C = 15.42 mg / 1), nm (log s): 308 (3.66), 305 (3.63), 295 (3.75), 275 (4.03), 268 (4.02), 249 (4.41).

NMR spectrum (CDC13, ppm, 5): 8.27 (d, J = 8Hz, H12), 7.60 (d, J = 2Hz, H9), 7.45 (dxd, J = 8 and 2Hz, H „ ), 5.2-5.8 (m, H14 + H15), 4.07 (s, H21), 2.77 (s, 2H17), 1.00 (t, J = 7Hz, 3HI8). Mass spectrum: M + (m / e) 370-372 calculated for Ci9Hi9N2OBr.

Example 9:

Preparation of ethyl vincadifformate (V, X = H, R = CHZCH3) by transesterification of vincadifformin (V, X = H, R = CH3)

A solution of 35 g of vincadifformin in 350 ml of absolute ethanol saturated with hydrochloric acid is brought to reflux, under an inert atmosphere.

After 10 p.m., the alcohol is evaporated off under reduced pressure. The residue is taken up in methylene chloride, washed with dilute ammonia, dried with MgSO 4 then the solvent is removed under vacuum.

The residue (34.9 g) and chromatographed on a column of 1050 g of silica gel 60.

Elution with methylene chloride allows 13.9 g of pure ethyl vincadifformate to be isolated in crystalline form (yield: 38%).

Ethyl Vincadifformate: physicochemical characteristics (7ß, 20a, 21a):

P.f. = 115-116 ° C.

aD = -607 ° (chci3, C = 0.5).

UV spectrum (methanol, C = 15.072 mg / 1), nm (log s): max. at 225 (4.09), 301 (4.05), 328 (4.20); min. at 260 (3.14), 307 (4.04).

IR spectrum (film, cm-1): NH at 3360, ester conjugated at 1670 (vinyl-urethane); 1,2-disubstituted benzene at 740 cm-1.

NMR spectrum (CDCI3): NH, s. at 9.07 ppm, 4H aromatic bulk between 6.7 and 7.5 ppm; C02 — CH2 — CH3, q. at 4.30 ppm (J = 7.5 cps); C02 — CH2 — CH2, t. at 1.33 ppm (J = 7.5 cps); C (18) H3, t. at 0.63 ppm.

Example 10:

Action of N-bromo succinimide on ethyl vincadifformate in solution in trifluoroacetic acid: ethyl bromo-10 vincadifformate (V, X = Br, R = CH3)

To a solution of 11.2 g of ethyl vincadifformate in 320 ml of trifluoroacetic acid, 6.08 g of N-bromo succinimide is added in small portions.

After 1 h of stirring at room temperature, the reaction mixture is poured onto ice, basified with 30% sodium hydroxide and the aqueous solution is extracted with methylene chloride.

After washing with water and drying the organic phases, the evaporation of the solvent provides a dry residue which weighs 12.7 g (yield: 92.6%).

The product is practically pure in TLC.

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Ethyl bromo-10 vincadifformate: physicochemical characteristics (7ß, 20a, 21a):

aD = -517 ° (C = 0.5, CHC13).

UV spectrum (methanol, C = 15.09 mg / 1), max. at 310 (4.20) and 330 (4.19) nm; min. at 264 (3.33) and 321 (4.19) nm.

IR spectrum (film): NH at 3360; ester conjugated to 1670 cm-1; 1,2,4-trisubstituted benzene at 790 cm-1.

NMR spectrum (CDCI3): NH, s. at 9.05 ppm; H9, d at 7.30 ppm (J = 2 cps); Hu, d.d. at 7.25 ppm (J = 8 cps, J '= 2 cps); H12, d. at 6.72 ppm (J = 8 cps); COCH2 -CH3, q. at 4.20 ppm (J = 7.5 cps); COCH2 —CH3, t. at 1.32 ppm (J = 7.5 cps); C (I8) H3, t.at 0.63 ppm.

Example 11:

Oxidation and rearrangement of ethyl bromo-10 vincadifformate: ethyl bromo-10 vincaminate and ethyl bromo-10 epi-16 vincaminate (Ib and lb ')

To a solution of 12.4 g of ethyl bromo-10 vincadifformate in 290 ml of toluene, 16.4 g of 85% m-chloroperbenzoic acid is added in small portions.

After stirring overnight at a temperature of 27-29 ° C, 144 ml of pure acetic acid and 58 ml of water are added. The mixture is decanted and the organic phase is extracted with twice 30 ml of water.

To the combined acidic aqueous phases, 17.3 g of triphenylphosphine are added and the solution is stirred overnight at 30-35 ° C.

After extraction with twice 60 ml of toluene, the aqueous phases are made alkaline with 30% sodium hydroxide, then extraction is carried out with methylene chloride.

The combined extracts, washed with water, dried and evaporated to dryness provide a residue (7 g) which is crystallized from acetone.

4 g of a mixture of ethyl bromo-10 vincaminate and of bromo-10 epi-16 ethyl vincaminate are obtained.

These two compounds are separated by fractional crystallization in acetone.

Bromo-10 ethyl vincaminate: physicochemical characteristics (20a, 21a):

P.f. = 211.5-213.5 ° C (acetone).

aD: + 70 ° = (C = 0.50, CHCl3).

UV spectrum (methanol, C = 15 mg / 1), nm (log s): max. to 234 (4.48)

and 290 (3.76); min. at 258 (2.87).

IR spectrum (KBr) C = O ester at 1740 cm-1.

NMR spectrum (CDCl3): no NH; H9, d. at 7.70 ppm (J = 2 cps);

Hn, d.d. at 7.30 ppm (J = 9 cps, J '= 2 cps); H12, d. at 7.05 ppm

(J = 9 cps); OH, s. at 4.77 ppm; C02CH2 —CH3, q. at 4.35 ppm

(J = 7 cps); 2H (17), s. at 2.17 ppm; C02 — CH2 — CH3, t. at 1.20 ppm

(J = 7 cps); 3H (1S), t. at 0.85 ppm (J = 7 cps).

Bromo-10 epi-16 ethyl vincaminate:

P.f. = 190-191 ° C (acetone).

aD = -15 ° (CHC13, C = 0.86).

UV spectrum (methanol): max. at 231 and 286 nm; min. at 260 nm. IR spectrum (KBr) C = O ester at 1740 cm-1.

NMR spectrum (CDC13): aromatic protons: A2B system peak of 1H centered on 7.67 ppm, mass of 2H between 7.2 and 7.4 ppm; OH, s. at 4.40 ppm; C02CH2 — CH3, q. at 4.23 ppm (J = 7 cps); H21, s. at 3.82 ppm; H (17), d. at 2.63 ppm (J = 14 cps); C02CH2 — CH3, t. at 1.13 ppm (J = 7 cps); 3H (i8d, t. At 0.85 ppm (J = 7 cps).

Example 12:

Dehydration of ethyl bromo-10 vincaminate and ethyl bromo-10 epi-16 vincaminate: ethyl bromo-10 apovincaminate (Id)

A solution of 4 g of mixture of ethyl bromo-10 vincaminate and ethyl bromo-10 epi-16 vincaminate is brought to reflux under an inert atmosphere in 40 ml of pure formic acid.

After 4 h the medium is poured onto ice and made alkaline with ammonia.

Extraction with methylene chloride and evaporation of the solvent provides a dry residue which weighs 3.8 g (yield: 99%) and which is pure in TLC.

P. f. = amorphous product.

UV spectrum (methanol): max. at 233.5, 179, 319.5 nm; min. at 255 and 303 nm.

IR spectrum (KBr) C = O at 1725 cm- '.

NMR spectrum (CDC13): A2B system of aromatic protons: mass 1H at 7.50 and mass 2H between 6.90 and 7.40 ppm; H17, s. at 6.08 ppm; C02CH2CH3, q. at 4.37 ppm (J = 7 cps); H2I, s. at 4.03 ppm; CQ2CH2CH3, t. at 1.40 ppm (J = 7 cps); 3H (18), t. at 1.02 ppm (J = 7 cps).

Methanesulfonate:

To a solution of 3.9 g of ethyl bromo-10 apovincaminate in solution in acetone, 0.88 g of methane sulfonic acid is added.

3.55 g of salt are isolated, which crystallizes from acetone or the acetone / ether mixture.

P.f. = 202-204 ° C.

"D = + 68 ° (C = 0.25, methanol).

UV spectrum (methanol, C = 15.036 mg / 1): max. at 233 (4.60), 279

(4.17), 320 (3.90); min. at 255 (3.83), 301 (3.70).

IR spectrum (KBr): NH at 2520 cm-1; C = O ester at 1720 cm-1.

Example 13:

Preparation of ethyl tabersonate (IV, X = H, R = CH2CH3) by transesterification of tabersonine (IV, X = H, R = CH3)

A solution of 5 g of tabersonine hydrochloride in 50 ml of anhydrous ethanol is refluxed under an inert atmosphere and saturated with hydrochloric acid.

After 45 h, the alcohol is evaporated under reduced pressure.

The residue is taken up in methylene chloride, washed with dilute ammonia, dried over MgSO 4, then the solvent is removed in vacuo.

The residue is chromatographed on a column of silica gel. Elution with methylene chloride allows 2.16 g (45%) of pure ethyl tabersonate to be isolated in crystalline form. This compound can be recrystallized from heptane or methanol.

Ethyl tabersonate: physicochemical characteristics: P.f. = 113-114 ° C (methanol).

aD = —382 ° (C = 0.25, methanol).

UV spectrum (methanol, C = 10.22 mg / 1), nm (log e): max. at 225 (4.15), 300 (4.11), 330 (4.26); min. to 259 (3.05), 307 (4.09).

IR spectrum (KBr, cm-1): 3320.1665.1600.

NMR spectrum (CDCI3): NH, s. at 9.17 ppm; aromatic range between 6.8 and 7.5 ppm; H14 + Hls ABX system centered on 5.83 ppm; C02CH2 -, q. at 4.33 ppm (J = 7 cps); C02CH2CH3, t. at 1.33 ppm (J = 7 cps); 3Hla, t. at 0.73 ppm.

Mass spectrum: M + (m / e) 350 calculated for C22H2602N2: 350.46.

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Claims (12)

642,655 1. Indole compounds of general formula (I) Br CH, CH in which, is Rj represents an alkoxycarbonyl group comprising from 2 to 7 carbon atoms, whether or not branched, and R2 and R3 represent respectively a hydroxyl group and a hydrogen atom or, together, an additional carbon-carbon bond; is Rj and R2 jointly represent an oxygen atom, R3 represents a hydrogen atom, and R4 and Rs represent either, jointly, an additional carbon-carbon bond, or hydrogen atoms, in the form of bases or salts of addition of mineral or organic acid, and in the form of racemates or optically active compounds. 2. Compounds according to claim 1, characterized in that they are in the form of addition salts of a pharmaceu-tically acceptable acid. 3. Compound according to Claim 1, characterized in that it is chosen from the group of following compounds, optionally in the form of an acid addition salt: - bromo-10 vincamine - bromo-10 épi-16 vincamine - bromo-10 A-14.15 vincamine - bromo-10 A-14.15 epi-16 vincamine - bromo-10 vincamone - bromo-10 A-14.15 vincamone - ethyl bromo-10 vincaminate - bromo-10 epi-16 ethyl vincaminate - ethyl bromo-10 apovincaminate 4. Process for the synthesis of the compounds according to claim 1, of formula (IA) br (IA) ROOC OH in which R + and R5 represent hydrogen atoms or, together, an additional carbon-carbon bond and R represents a Q-Cg alkyl group, characterized in that it consists of: a) bromination by an N- derivative brominated in an acid medium with vinca-difformin or a vincadifformin derivative of formula (IV) X C0 „R co2r in which R represents a Q-C6 alkyl group and X represents a hydrogen atom, to obtain corresponding compounds of formula (IV) or (V) in which X represents a bromine atom; b) oxidation followed by rearrangement in an acid medium to form bromovincamines of formula (IA) in which R4 and R5 are defined as above. 5. Method according to claim 4, characterized in that the N-bromine derivative is N-bromosuccimide. 6. Method according to claim 5, characterized in that the bromination takes place in trifluoroacetic acid. 7. Method according to claim 4, characterized in that the starting compound is ethyl vincadifformate or ethyl A-14.15 vincadifformate or their addition salts with an organic or mineral acid. 8. A process for the synthesis of the compounds according to claim 1, of formula (IA), in which R and R5 represent hydrogen atoms or, together, an additional carbon-carbon bond and R represents a C2-C6 alkyl group, characterized in that it consists of: a) transesterification of vincadifformin or of A-14.15 vincadifformin in the presence of an alcohol containing from 2 to 6 carbon atoms to obtain compounds of formula (IV) or (V), in which X represents an atom hydrogen and R represents a C2-C6 alkyl group; b) bromination with an N-brominated derivative in an acid medium of the vincadifformin derivative obtained to obtain compounds of formula (IV) or (V), in which R represents a C2-C6 alkyl group and X represents an atom of bromine; c) oxidation followed by rearrangement in an acid medium to form the corresponding bromovincamines of formula (IA), in which R4, R5 and R are defined as above. 9. A process for the synthesis of the compounds according to claim 1 of formula (I), in which R! and R2 jointly represent an oxygen atom, R3 represents a hydrogen atom and R4 and Rs are defined as in claim 1, characterized in that, according to the process of claim 4, a compound of formula ( IA), in which R4, R5 and R are defined as in claim 4 and the compound obtained is subjected to a reaction with a strong base in suspension or in solution in an inert solvent to obtain vincamone or A-14, 15 vincamone brominated in position 10 of formula (I), in which Rj to Rs are defined as above. 10. Process for the synthesis of the compounds according to claim 1 of formula (I), in which R2 and R3 represent, together, an additional carbon-carbon bond and Rlt R4 and R5 are defined as in claim 1, characterized in that a compound of formula (IA) is prepared, in which R4, Rs and R are defined as in claim 4, according to the process of claim 4 and the compound obtained is subjected to dehydration in an acid medium to obtain an apovincamine of formula (I), in which Rj to R5 are defined as above. 11. Medicines for the treatment of epileptic states or cardiovascular diseases or resulting from insufficient cerebral oxygenation, characterized in that they contain, as active principle, one or more of the compounds according to claim 1. 12. Medicines according to claim 11, in the form of tablets, capsules or injectable solutions, dosed unitarily with 0.5 to 150 mg of active products alone or in combination 2 5 10 15 20 25 30 35 40 45 50 55 60 65 3 642,655 with pharmaceutically acceptable adjuvants, diluents, vehicles or excipients.