WO1992019620A1 - Novel derivatives of pyrrolo [1, 4]-benzodiazepines, method of preparation and medicaments containing them - Google Patents

Abstract

The invention discloses novel derivatives of pyrrolo[1, 4]-benzodiazepines of formula (I) in which: n is 1 or 2, preferably 1; R1, R2, R3 are the same or different and stand for a hydrogen or halogen atom, a hydroxyl, alkoxyl, alkanyloxyl radical or two adjacent substituants together form a methylenedioxyl chain, R1 possibly also representing the radical 0-1'-sibirosamin; R4 is a hydrogen atom or an alkyl or alkanyl radical; X is a hydrogen atom, a hydroxyl, alkoxyl, alkanyloxyl, mercapto, alkylthio, cyano, amino, phosphonate, sulpho(SO3H), alkali metal or alkali metal sulphonate radical; or R4 and X together form a double Δ bond (compound of formula Ia); Y, Z are the same or different and represent a hydrogen atom or an alkyl, alkoxycarbonyl, aminocarbonyl or N-alkyl or N,N-dialkylamino carbonyl, cyano, phosphonate radical. The invention also discloses medicaments related to these derivatives.

Description

NOVEL PYRROLOC DERIVATIVES ^ J-BENZODIAZEPINES, THEIR

PREPARATION PROCESS AND MEDICINES CONTAINING THEM

The present invention relates to new pyrrolo [1] -benzodiazepine derivatives, their preparation process and their use as medicaments.

It also relates to the new compounds useful in particular as intermediates in the preparation processes according to the invention.

The family of pyrrolo- [l, - +] - benzodiazepines is generally known as having antibiotic and antitumor properties.

These compounds are for example described in US Pat. No. 3,522 <+ SΨ9.

However, these sometimes also exhibit high toxicity, such as anthramycin for example.

Thus one of the objects of the present invention is to provide other derivatives of the family of pyrrolo- [1, <+] - benzodiazepines.

Another object of the invention is to provide derivatives of the family of pyrrolo- [1,1] -benzodiazepines having a lower toxicity.

Another object of the invention is to propose an original process allowing access to the pyrrolo- [1,4] -benzodiazepine derivatives, some of these compounds having already been described.

The present invention therefore relates primarily to pyrroio- [l, <] -benzodiazepine derivatives of the formulas:

dans laquelle : n = 1 ou 2, de préférence 1. R . , R_?, R, identiques ou différents représentent un atome d'hydrogène ou d'halogène, un radical hydroxyle, alcoxyle, alcanoyloxyle ou deux substituants adjacents ensemble forment une chaîne methylenedioxyle, R . pouvant en outre correspondre au radical O-l'-sibirosamine, R. représente un atome d'hydrogène ou un radical alkyle ou alcanoyle, X représente un atome d'hydrogène, un radical hydroxyle, alcoxyle, alcanoyloxyle, mercapto, alkylthio, cyano, amino, phosphonate, sulfo(SO,H), sulfonate de métal alcalin ou alcaiino terreux ou bien R_ft et X forment ensemble une double liaison Δ (composé de formule la), Y, Z identiques ou différents représentent un atome d'hydrogène ou un radical alkyle, alcoxycarbonyle, aminocarbonyle ou N-alkyl ou N,N-diaIkyl- amino carbonyle, cyano, phosphonate, à la condition que :

in which: n = 1 or 2, preferably 1. R. , R _? , R, identical or different, represent a hydrogen or halogen atom, a hydroxyl, alkoxyl, alkanoyloxyl radical or two adjacent substituents together form a methylenedioxyle chain, R. can also correspond to the radical O-l'-sibirosamine, R. represents a hydrogen atom or an alkyl or alkanoyl radical, X represents a hydrogen atom, a hydroxyl, alkoxyl, alkanoyloxyl, mercapto, alkylthio, cyano radical, amino, phosphonate, sulfo (SO, H), alkali metal sulfonate or alkaline earth metal or else R _ft and X together form a double bond Δ (compound of formula la), Y, Z identical or different represent a hydrogen atom or an alkyl, alkoxycarbonyl, aminocarbonyl or N-alkyl or N, N-diaIkylamino carbonyl, cyano, phosphonate radical, provided that:

- when Y represents a dimethylaminocarbonyl group and Z represents a hydrogen atom, R, and X do not each represent a methoxyl radical (porothramycin B) or, when R, represents a methoxyl radical, X does not represent a hydroxyl radical (porothramycin A) and that

- when Y represents an aminocarbonyl or methyiamino carbonyl group, Z represents a hydrogen atom and R- a methyl radical, R and X do not each represent a hydroxyl radical (anthramycin, mazethramycin)

- when Y represents a methyl group and Z a hydrogen atom, R. , R ₂ , Rj, R _ft and X do not respectively and simultaneously represent an O-i'sibirosamine, methyl and hydroxyl (sibiromycin) radical.

It has been found that, in order to meet the aims proposed by the invention, R, preferably corresponds to the hydrogen atom. More preferably, R,, R ₂ , R, correspond to the hydrogen atom.

According to an advantageous variant, taken or not taken in combination with the previous one, Z is a hydrogen atom.

According to another advantageous variant, taken or not taken in combination with the previous ones, R. is the hydrogen atom. According to another advantageous variant, taken or not taken in combination with the preceding ones, Y is an optionally N, or N, N-alkylsubstituted aminocarbonyl radical.

In the present description, the alkyl, alkoxy, aicoylthio and alkyloxy radicals preferably have at most 6 carbon atoms.

The invention also relates to the drugs consisting of one of the compounds according to the invention, as described above and the pharmaceutical compositions containing at least one of these drugs and an acceptable carrier. These drugs and compositions are useful for medical or veterinary treatment as antibiotics and anti-tumor.

The pharmaceutical compositions are in particular formulated to be ingested orally or to be injected. However, other presentations can also be envisaged in the context of the present invention. The dosage will depend partly on the disease to be treated as well as its severity and also on the type of individual (weight, age).

The present invention also relates to a process for preparing pyrrolo- [l-] -benzodiazepine derivatives of formula I:

in which: n = 1 or 2, preferably 1,

R,, R ₂ , R-, identical or different, represent a hydrogen atom or halogen, a hydroxyl, alkoxyl, alkanoyloxyl radical or two substituents adjacent together form a methylenedioxyl chain,

R. can also correspond to the radical O-l'-sibirosamine,

R. represents a hydrogen atom or an alkyl or alkanoyl radical,

X represents a hydrogen atom, a hydroxyl, alkoxyl, alkanoyloxyl, mercapto, alkylthio, cyano, amino, phosphonate, sulfo (SO, H), alkali or alkaline earth metal sulfonate radical or alternatively

R. and X together form a double bond Δ (compound of formula la),

Y, Z identical or different represent a hydrogen atom or an alkyl, alkoxycarbonyl, aminocarbonyl or N-alkyl or N, N-dialkyi- a ino carbonyl, cyano, phosphonate radical, the process is characterized in that one reduces a derivative of N-orthonitrobenzoyl-5-carboxyaldehyde dihydro [*, 5] substituted pyrroles of formula:

dans laquelle : n, R. , R-, R,, Z, Y ont la même signification que dans la formule I au moyen d'un réducteur approprié. Parmi les réducteurs qui peuvent être utilisés, on peut citer l'hydrogène en présence d'un catalyseur tel que le platine, le nickel, le palladium, de préférence le nickel.

in which: n, R., R-, R ,, Z, Y have the same meaning as in formula I by means of an appropriate reducing agent. Among the reducing agents which can be used, mention may be made of hydrogen in the presence of a catalyst such as platinum, nickel, palladium, preferably nickel.

The compound of formula la is obtained in which R ^, and X form a Δ bond and the substituents R. , R- _> R ,, Z and X have the same meaning as in formula (I) previously defined. In order to obtain the compounds of formula (I) in which R and X have the other possible definitions, the compound of formula la is brought into contact with a nucleophilic reagent of formula R _α -X (III) preferably the hydrogen sulfite of sodium which makes the compound soluble in water or methanol.

The invention also relates to a process for the preparation of the compounds of formula II.

The compound of formula II which is a derivative of N-orthonitrobenzoyl-5-carboxaldehyde dihydro [, 5] pyrrole substituted can be obtained by oxidation of the compounds of formula IV

in which n, R. , R ₂ , R., Σ and Y have the same meaning as in formula I and R _ is a halogen atom or a hydroxyl radical or optionally a protected hydroxyl group such as an alkanoyl¬ oxyl radical which must be eliminated the protective group before the reaction, for example by acid or alkaline hydrolysis.

Such an oxidation is for example carried out advantageously by dimethylsulfoxide in the presence of a known activating agent such as SO-pyridine, oxalyl chloride, silver tetrafluoroborate or by periodinane.

The compounds of formula IV can be obtained by ittig reaction of a compound of formula R ₆ R ₇ R _g P = CYZ (V), R ₆ , R-., R _{g representing} an alkyl radical or else R, represents an oxygen atom and R ₇ , R „represent an alkoxyl radical and Y and Z have the same meaning as in formula I on a compound which is a derivative of N-orthonitrobenzoyl 5-CH ₂ -R ₅ 3 -carboxaldehyde dihydro [, 5] pyrrole of formula:

preferably under the following conditions: - aprotic polar solvent.

The compounds of general formula VI are obtained by treating with the reagent formed by an equimolecular amount of dimethylformamide and phosphorus oxychloride, in an anhydrous solvent such as, for example, dichloromethane, a compound which is a derivative of N-orthonitro- benzoyl - (- 5-CH_ - R dihydroO, 5] pyrrole of general formula VII:

in which: n, R., R, _" R-3 _" Re are as defined in the general formula IV previously described. The compounds of general formula VII in which R 1 is a hydroxyl, protected hydroxyl or halogen group, n, R to R - as defined with regard to general formula I are obtained by heating preferably in the presence of a catalyst such as pyridinium paratoluene sulfonate or quinolinium camphor sulfonate, a compound which is a derivative of N-orthonitrobenzoyl - (- 5-CH ₂ * - * R -) - (2-OR g) tetrahydropyrrole of general formula VIII

in which :

R. is a protected hydroxyl or hydroxyl group, for example an alkanoyloxyl radical, or halogen atom,

R ₉ is a hydrogen atom or an alkyl or alkanoyl radical, n, R _j , R ₂ , R, as defined with respect to the general formula I in an anhydrous solvent such as, for example, toluene, at a temperature less than or equal to 1 10 ° C.

The compounds of f. Ule VIII are obtained from compounds of general formula IX as described by N. Langlois, RZ Andriamialisoa, French patent application No. 85 12882 and Tetrahedron Letters, 1986, 27, 11Ψ9, by reaction of a reducing agent advantageously chosen from borohydrides or aluminum hydrides, in particular diisobutyl aluminum hydride used at low temperature, for example -70 ° C., according to the following reaction scheme:

2Û

The partial regioselective reduction of the compounds of general formula IX in which:

R. is a hydroxyl group is protected or a halogen, n, R _j , R ₂ , R, as defined with respect to the general formula I leads to the compounds of general formula VIII in which: Rc is a hydroxyl group is protected or halogen, R _Q is a hydrogen atom, n, R _j , R ₂ , R- as defined in connection with the general formula I.

These compounds can be treated with an alcohol in an acid medium and / or with an anhydride or an acid chloride, to give the compounds of general formula VIII in which;

R - is a protected hydroxyl or hydroxyl group, for example advantageously forming an alkanoyloxyl radical, R „is an alkyl or alkanoyl radical,

R _j , R ₂ , R, as defined with respect to the general formula I. The hydroxyl can then be deprotected if necessary.

It should be understood that the process as described and claimed in the terms indicated above can be extended to other variants consisting, for example, of transforming the substituents R 1, X, Y, R, to one either of the steps described above. Also, the order of the steps leading from IV to II can be reversed by first reducing the group NO _? of IV (compound IVa) then by oxidizing the group R -, which leads directly to compound la.

A subject of the invention is also the compounds of formula II, IV, IVa, VI, VII and VIII as described above. The compounds are especially useful as intermediates in the process for preparing the compounds of formula I.

The invention will be described in more detail with the aid of nonlimiting examples illustrating the synthesis of different pyrrolo [1, <+] benzodiazepine derivatives of general formula I gathered in the table below:

BOARD

N ° R,

Dans la description qui suit, R . =R₂= ₃=Z=H ; Y=CON(CH,)₂

In the following description, R. = R ₂ = ₃ = Z = H; Y = CON (CH,) ₂

Example I: Preparation of Compound No. 1

I-i - Preparation of N-orthonitrobenzoyl 5-acetyloxymethyl 3-carboxaIdehyde dihydro [, 5] pyrrole of formula VI with R. is acetyloxy. The preparation is carried out according to the following scheme:

A une solution du composé 1 (1,6 g, 4,97 mmoles , on ajoute dans le toluène anhydre (12 ml) le camphosulfonate de quinoléinium (0,283 g,

To a solution of compound 1 (1.6 g, 4.97 mmol, is added in anhydrous toluene (12 ml) quinolinium camphosulfonate (0.283 g,

0.78 mmol) for two hours with stirring under nitrogen at 110 ° C. The solvent is removed by evaporation under reduced pressure. The residue after chromatography on a silica column provides 90%.

IR: cm ^"1 3100, 2925, 2850, 1730, 1640, 1615, 1520.

The formylation is carried out by a Vilsmeier-Haack reaction for 2 h 30 min at room temperature with a quantitative yield.

IR: 2900, 2825, 1735, 1650, 1600.

1-2 - Preparation of the compound of formula IV where R, is acetyloxy or hydroxyl

To a solution of diethyl [2-dimethylamino) -2-oxoethyl] phosphonate (1.56 g, 7.0 mmol) in anhydrous THF (30 ml) maintained under an inert atmosphere at 0 ° C., the mixture is added with stirring. nBuli (7.16 mmol, 1.5 M solution in hexane). After 30 minutes, the aldehyde obtained in II R -≈OCOCH ,, (1.75 g, {5.5 mmol) is added in solution in anhydrous THF (30 ml). After complete reaction (20 minutes) and addition of one aqueous ammonium chloride solution, the reaction medium is extracted with ethyl acetate. After usual treatment, the constituents of the crude product (2.1 g) can be separated by chromatography on a silica column (eluent dichloromethane-methanol (95-5). This gives 1.83 g (86%) of protected compound IV ( R - = acetyloxy):

IR (CH ₂ C1 ₂ , cm ^"1 ): 2950, 1730, 1640, 1590 and 0.247 g

(13%) of the hydroxyl compound IV (R - = OH):

IR (CHC1 ₃ , cm ^"1 ): 3400, 2950, 2700, 1630. The hydroxylated compound IV can be obtained by deprotection of the compound IV protected by hydrolysis.

To a solution of acetate IV (1.6 g, 4.13 mmol) in dioxane

(60 ml), maintained under an inert atmosphere, an aqueous solution of baryte Ba (OH) ₂ lN (27 ml) is added. The reaction medium is stirred at room temperature (+ 20 ° C) until complete reaction (4 hours). The mixture is brought to pH 7 by the addition of carbon dioxide gas. After filtration, the medium is extracted with dichloromethane. The usual treatments provide compound IV (I, 4g, 98%).

I ~ - Preparation of the compound of formula II

To a solution of oxalyl chloride (0.144 mi, 1.65 mmol) in anhydrous dichloromethane (2 ml), kept stirring and under argon at -30 ° C., a solution of dimethyl sulfoxide (0.234) is added dropwise. ml, 3.3 mmol) in the same solvent (2 ml). After 15 minutes of stirring at -30 ° C, the hyroxylated compound IV (0.316 g, 0.916 mmol) in solution in anhydrous dichloromethane (4 ml) is added and stirring is continued at -30 ° C for 1 h 30 , before the addition of diisopropylethylamine (0.862 ml, 4.95 mmol). The reaction medium is stirred for 10 minutes at -30 ° C then 30 minutes at 0 ° C before hydrolysis with a buffer at pH 5.6 (citrate-phosphate, 90 ml). The aldehyde is extracted 3 times with ethyl acetate (100 ml, 90 ml, 90 ml). After 3 washes with distilled water (10 ml, 9 ml, 9 ml) and usual treatments, the organic phases provide compound II 267 mg (85%): IR (cm ^-1 ): 3300 (hydrated form), 2920, 1720 (weak), 1630, 1595.

1-4 - Preparation of the compound of formula I where R _fc and X together form a Δ bond (formula la) compound No. 1

A solution of compound II (0.34 g, 1 mm 3) in an ethyl acetate-methanol mixture 85-15 (12 ml) is added to an excess of Raney nickel maintained with stirring at ordinary temperature. After complete reaction, the mixture is filtered through a small column of silica (70-230 mesh) and the silica is rinsed with an ethyl acetate-methanol 85-15 mixture. The solvent is evaporated under reduced pressure to give the compound I: MS (m / z): 295 (M +), 120 (100%).

Example H: Preparation of Compound No. 2

Compound No. 1 is transformed without purification into Compound No. 2.

To compound No. 1, in solution in a dichloromethane-methanol mixture 9-1 (2 ml), a solution of trifluoroacetic acid in dichloromethane (15 μl%, 3.6 ml) is added. The mixture is stirred at room temperature for 15 hours before evaporation of the solvents under reduced pressure. The residue is crystallized from anhydrous methanol (147 mg, 45%).

Chromatography of the mother liquors on silica still provides 20% of product:

M.p. (dec): 228 ° C,

IR (cm ^"1 ) = 3300, 2924, 2850, 1620.

Example III Preparation of Compound No. 3 To a solution of compound No. 2 (65.4 mg, 0.2 mmol) in anhydrous dichloromethane (1.3 ml) cooled to 0 ° C., added under argon and under stirring cyanotrimethyisilane (29.7 mg, 0.3 mmol) and a catalytic amount of tin tetrachloride. After a complete reaction controlled by TLC and elimination of the volatile products by evaporation under reduced pressure, the product, in solution in ethyl acetate, is washed with an aqueous solution of sodium carbonate at 1%. The aqueous phase is extracted twice more with ethyl acetate. The organic phases provide, after usual treatments, compound No. 3 (55 mg) which can be purified by chromatography on a thick layer of silica (eluent: ethyl acetate): IR = 3390, 3320, 3000, 2305, 1645.

Example IV: Preparation of Compound No. 4 a) To a solution of the mother liquors of crystallization of Compound No. 2 (32.7 mg, 0.1 mmol) in anhydrous dichloromethane (0.15 ml), the following is added under argon at room temperature a 10% solution of ethanethiol in anhydrous dichloromethane (0.33 ml) and a catalytic amount of zinc dichloride. After one hour of stirring, the product is separated by chromatography on a thick layer of silica (eluent: ethyl acetate), 12 mg (35%): IR = 3300, 2925, 1628. b) In a solution of compound n ° 1 prepared according to example 1

(29.5 mg, 0.1 mmol), in solution in anhydrous dichloromethane (0.3 ml), a 10% solution of ethanethiol in anhydrous dichloromethane (0.2 ml) is added under argon at room temperature . After 3 hours of stirring at room temperature, the reaction medium is treated as above to provide 9 mg (25%) of compound No. 4.

Bioassays

These tests are carried out on compound No. 2.

Antibiotic activity:

On Staphylococcus, the minimum inhibition concentration (MIC) experimentally established over a concentration range of 0 to 1 mg / ml gives a MIC of the order of 60 μg / ml. Cytotoxic activity

On the KB line [(human nasopharyngeal cancer cells)]

Cμg / ml 1 0.5 0.1 0.05 0.01

C mol / 1 3.06.I0 ^"6 i.53.10 ^{" 6} 3.06.10 ^"7 1.53.10 ^{" 7} 3.06.10 ^"8

% inhibition 100 100 100 100 38

- On the VERO line (monkey kidney cells) LD50 on KB: 0.87 10 ^"7 M

LD50 on VERO: 0.75 10 ^"7 M

- On two KB lines, the first wild KB 3-1 and the second, derived from the first KB-Vl presenting a phenotype of resistance to vinblastine (the resistant strain is maintained in the presence of lμg / ml of vinblastine):

LD50 on KB _R = LD50 on KB _$ approximately 0.8.10 M - On two human K562 erythroleukemic lines respectively resistant and sensitive to doxorubicin (adriblastine), the resistant line, -7 is maintained in the presence of 10 M adriblast:

LD50 on 562 _R = LD50 on K562 _s approx 0.85.10 ^"7 M.

Claims

CLAIMS 1. Pyrrolo [1,4] -benzodiazepine derivatives of formula

in which: n = 1 or 2, preferably 1, R _j, R _2, R, identical or different, represent a hydrogen or halogen atom, hydroxyl, alkoxyl, alkanoyloxy or two adjacent substituents together form a methylenedioxyle chain, R _j may additionally ^'correspond to the radical Ol' -sibirosamine, R. represents a hydrogen atom or an alkyl or alkanoyl radical, X represents a hydrogen atom, a hydroxyl, alkoxyl, alkanoyloxyl, mercapto, alkylthio, cyano, amino, phosphonate, sulfo (SO, H) radical , alkali or alkaline earth metal sulfonate or else R ^ and X together form a double bond Δ (compound of formula la), Y, Z identical or different represent a hydrogen atom or an alkyl, alkoxycarbonyl, aminocarbonyl or N-alkyl or N, N-dialkylamino carbonyl radical , cyano, phosphonate, provided that: - when Y represents a dimethylaminocarbonyl group and Z represents a hydrogen atom, R, and X does not each represent a methoxyl radical (porothramycin B) or, when R, represents a methoxyl radical, X does not represent a hydroxyl radical (porothramycin A) and that - when Y represents an aminocarbonyl or methylamino carbonyl group, Z represents a hydrogen atom and R ₂ a methyl radical, R and X do not each represent a hydroxide radical (anthramycin, mazethramycin) - when Y represents a methyl group and Z a hydrogen atom, R. , R ₂ , R ,, R _ft and X do not simultaneously represent respectively an Ol 'sibirosamine, methyl and hydroxyl (sibiromycin) radical. 2. Derivatives according to claim 1, characterized in that R, is the hydrogen atom. 3. Derivatives according to claim 2, characterized in that R. , R_ correspond to the hydrogen atom. 4. Derivatives according to claim 2 or 3, characterized in that Z is a hydrogen atom. 5. Derivatives according to one of claims 2 to 4, characterized in that R _ft is the hydrogen atom. 6. Derivatives according to one of claims 2 to 5, characterized in that Y is an optionally N or N, N, -N-alkyl substituted aminocarbonyl radical. 7. Process for the preparation of compounds of formula I:

in which: n = I or 2, preferably 1, R. , R ₂ , R, identical or different, represent a hydrogen or halogen atom, a hydroxyl, alkoxyl, alkanoyloxyl radical or two substituents adjacent together form a methylenedioxyl chain, R. can also correspond to the radical Ol '-sibirosamine, R. represents a hydrogen atom or an alkyl or alkanoyl radical, X represents a hydrogen atom, a hydroxyl, alkoxyl, alkanoyloxyl, mercapto, alkylthio, cyano, amino radical, phosphonate, sulfo (SO, H), alkali or alkaline earth metal sulfonate or else R ^ and X together form a double bond Δ (compound of formula la), Y, Z identical or different represent a hydrogen atom or a alkyl, alkoxycarbonyl, aminocarbonyl or N-alkyl or N, N-dialkylamino carbonyl, cyano, phosphonate radical, characterized in that a substituted N-orthonitrobenzoyl-5-carboxaldehyde dihydropyrroles of general formula II is reduced

in which R. , R ₂ , R ,, Y and Z have the meanings given with regard to the general formula I and in that, where appropriate, the derivative of general formula la thus obtained:

is reacted with a nucleophilic reagent of formula RX (III) to obtain a compound of general formula I in which R. represents a hydrogen atom or an alkyl or alkanoyl radical, X represents a hydrogen atom or a hydroxyl radical , alkanoyloxyl, mercapto, alkylthio, cyano, amino, phosphonate, sulfo (-SO, H) or sulfonate of alkali or alkaline earth metal. 8. Method according to claim 7, characterized in that the reduction of the compound of formula II is carried out by means of a catalyst, in particular nickel, palladium or platinum in the presence of hydrogen. 9. Method according to claim 7, characterized in that the nucleophilic reagent is sodium hydrogen sulfite or methanol. 10. Process for preparing the compounds of formula II, characterized in that they are obtained by oxidation of compounds of general formula IV:

in which n, R _j , R-, R ,, Z and Y have the same meaning as in formula I and R_ is a hydroxyl radical or a halogen atom or a protected hydroxyl group with in the latter case prior deprotection . 11. Method according to claim 10, characterized in that the oxidation is carried out by dimethylsulfoxide in the presence of an activating agent or by periodinane. 12. Process for the preparation of formula of formula IV, characterized in that they are obtained by contacting a reagent of general formula (V) R, R, RgP = CYZ in which R _g , R ^, Rg represent a alkyl radical or else R, represents a hydrogen atom, R, and R “representing an alkoxy radical and where Y and Z have the same meaning as in formula I of a compound of general formula VI:

in which R represents a protected hydroxyl or hydroxyl group or a halogen atom, R. , R_, R, have the meanings given in claim 1. 13. Derivatives of formula II, IV, VI, useful in particular as intermediates for the preparation of the compounds of formula I according to the methods of claims 7 to 12. 14. Medicament consisting of a compound of formula I according to one of claims 1 to 6. 15. Pharmaceutical composition containing at least one medicament according to claim 14 and an acceptable carrier.