FR2676230A1 - NOVEL PYRROLO [1,4] -BENZODIAZEPINES DERIVATIVES, PROCESS FOR THEIR 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 DELTA 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

 The present invention relates to new pyrrolo [1,4] -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- [1,4] -benzodiazepines is generally known as having antibiotic and antitumor properties.

These compounds are for example described in US Pat. No. 3,524,849.

 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- [1,4] -benzodiazepines.

 Another object of the invention is to provide derivatives of the family of pyrrolo- [I, 4J-benzodiazepines having a lower toxicity.

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

dans laquelle n = I ou 2, de préférence 1.The present invention therefore relates primarily to pyrrolo- [1,4] -benzodiazepine derivatives of formulas

in which n = I or 2, preferably 1.

R1, R2, R3, which are identical or different, represent a hydrogen or halogen atom, a hydroxyl, alkoxyl, alkanoyloxyl radical or two substituents adjacent together, form a methylenedioxyl chain,
R1 can also correspond to the radical O-l'-sibirosamine,
R4 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 3H), alkali or alkaline earth metal sulfonate radical or else
R4 and X together form a double bond n (compound of formula Ia),
Y, Z identical or different represent a hydrogen atom or an alkyl, alkoxycarbonyl, aminocarbonyl or N-alkyl or N, N-dialkylamino carbonyl, cyano, phosphonate radical, with the proviso that - when Y represents a dimethylaminocarbonyl group and Z represents a hydrogen atom, R3 and X do not each represent a methoxyl radical (porothramycin B) or, when R 3 represents a methoxyl radical, X does not represent a hydroxyl radical (porothramycin A) and that - when Y represents an aminocarbonyl group or methylamino carbonyl, Z represents a hydrogen atom and R2 a methyl radical,
R3 and X do not each represent a hydroxyl radical (anthramycin, mazethramycin) - when Y represents a methyl group and Z a hydrogen atom, R1,
R2, R3, R4 and X do not represent, respectively and simultaneously, a radical 0-l'sibirosamine, methyl and hydroxyls (sibiromycin).

 It has been found that, in order to meet the aims proposed by the invention, R3 preferably corresponds to the hydrogen atom. More preferably, R1, R2, R3 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, R4 is the hydrogen atom.

According to another advantageous variant, taken or not taken in combination with the previous ones, Y is an aminocarbonyl radical optionally N, or
N, N-alkyl substituted.

 In the present description, the alkyl, alkoxy, alkylthio 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 antitumors.

 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 in part on the disease to be treated as well as its severity and also on the type of individual (weight, age).

dans laquelle n = 1 ou 2, de préférence 1,
R1, R2, R3 identiques ou différents représentent un atome d'hydrogène ou d'halogène, un radical hydroxyle, alcoxyle, alcanoyloxyle ou deux substituants adjacents ensemble forment une chaîne méthylènedioxyle, R 1 pouvant en outre correspondre au radical O-l'-sibirosamine,
R4 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(SO3H), sulfonate de métal alcalin ou alcalino terreux ou bien
R4 et X forment ensemble une double liaison 8 (composé de formule Ia),
Y, Z identiques ou différents représentent un atome d'hydrogène ou un radical alkyle, alcoxycarbonyle, aminocarbonyle ou N-alkyl ou N,N-dialkylamino carbonyle, cyano, phosphonate,
le procédé est caractérisé en ce que l'on réduit un dérivé de
N-orthonitrobenzoyl-5-carboxyaldéhyde dihydro[4,5]pyrroles substitués de formule

dans laquelle n, R1, R2, R3, Z, Y ont la même signification que dans la formule I au moyen d'un réducteur approprié.The present invention also relates to a process for preparing pyrrolo- [1-4] -benzodiazepine derivatives of formula I:

in which n = 1 or 2, preferably 1,
R1, R2, R3, identical or different, represent a hydrogen or halogen atom, a hydroxyl, alkoxyl, alkanoyloxyl radical or two substituents adjacent together form a methylenedioxyl chain, R 1 possibly further corresponding to the radical O-l'-sibirosamine ,
R4 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 (SO3H), alkali metal or alkaline earth metal sulfonate radical or else
R4 and X together form a double bond 8 (compound of formula Ia),
Y, Z identical or different represent a hydrogen atom or an alkyl, alkoxycarbonyl, aminocarbonyl or N-alkyl or N, N-dialkylamino carbonyl, cyano, phosphonate,
the process is characterized in that a derivative of
N-orthonitrobenzoyl-5-carboxyaldehyde dihydro [4,5] substituted pyrroles of formula

in which n, R1, R2, R3, 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 Ia is obtained in which R4 and X form a bond and the substituents R1, R2, R3, Z and X have the same meaning as in formula (I) previously defined.

 In order to obtain the compounds of formula (I) in which R4 and X have the other possible definitions, the compound of formula Ia is brought into contact with a nucleophilic reagent of formula R4-X (III), preferably sodium hydrogen sulfite. 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.

dans laquelle n, R1, R2, R3, Z et Y ont la même signification que dans la formule I et R5 est un atome d'halogène ou un radical hydroxyle ou éventuellement un groupe hydroxyle protégé tel qutun radical alcanoyloxyle dont il faut éliminer le groupe protecteur avant la réaction par exemple par hydrolyse acide ou alcaline.The compound of formula II which is a derivative of N-orthonitrobenzoyl-5carboxaldehyde dihydro [4,5] pyrrole can be obtained by oxidation of the compounds of formula IV

in which n, R1, R2, R3, Z and Y have the same meaning as in formula I and R5 is a halogen atom or a hydroxyl radical or optionally a protected hydroxyl group such as an alkanoyloxyl radical from which the group must be eliminated protective before the reaction, for example by acid or alkaline hydrolysis.

 Such an oxidation is for example advantageously carried out with dimethylsulfoxide in the presence of a known activating agent such as SO 3 -pyridine, oxalyl chloride, silver tetrafluoroborate or by periodinane.

de préférence, dans les conditions suivantes
- solvant polaire aprotique.The compounds of formula IV can be obtained by reaction of
Wittig of a compound of formula R6R7R8P = CYZ (V), R6, R7, R8 representing an alkyl radical or else R6 represents an oxygen atom and R7,
R8 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-CH2-R5 3-carboxaldehyde dihydro [4,5] pyrrole of formula

preferably under the following conditions
- aprotic polar solvent.

dans laquelle n, R1, R2, R3, R5 sont tels que définis dans la formule générale IV précédemment décrite. 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-orthonitrobenzoyl - (- 5-CH2 - R5) dihydro [4,5] pyrrole of general formula VII

in which n, R1, R2, R3, R5 are as defined in the general formula IV previously described.

dans laquelle
R5 est un groupe hydroxyle ou hydroxyle protégé, comme par exemple un radical alcanoyloxyle, ou atome d'halogène, R9 est un atome d'hydrogène ou un radical alkyle ou alcanoyle, n, R1, R2, R3 tels que définis à propos de la formule générale I dans un solvant anhydre tel que par exemple, le toluène, à une température inférieure ou égalé à 110 C. The compounds of general formula VII in which R5 is a hydroxyl, protected hydroxyl or halogen group, n, R1 to R3 as defined with regard to general formula I are obtained by heating preferably in the presence of a catalyst such as paratoluene pyridinium sulfonate or quinoline camphor sulfonate, of a compound which is a derivative of N-orthonitrobenzoyl - (- 5-CH2 -R 5) - (2-OR9) tetrahydropyrrole of general formula VIII

in which
R5 is a protected hydroxyl or hydroxyl group, such as for example an alkanoyloxyl radical, or halogen atom, R9 is a hydrogen atom or an alkyl or alkanoyl radical, n, R1, R2, R3 as defined in connection with general formula I in an anhydrous solvent such as, for example, toluene, at a temperature less than or equal to 110 C.

The compounds of formula 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, 1149, by reaction of a reducing agent advantageously chosen from borohydrides or aluminohydrides in particular diisobutylaluminum hydride used at low temperature, for example -70 C, according to the following reaction scheme

The partial regioselective reduction of the compounds of general formula IX in which
R5 is a protected hydroxyl group or a halogen, n, R1, R2, R3 as defined with respect to the general formula I leads to the compounds of general formula VIII in which
R5 is a hydroxyl group is protected or halogen, Rg is a hydrogen atom, n, R1, R2, R3 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
R5 is a protected hydroxyl or hydroxyl group, for example advantageously forming an alkanoyloxyl radical, R9 is an alkyl or alkanoyl radical, RI, R2, R3 as defined with regard 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, in transforming the substituents R4, X, Y,
R1 in one or other of the steps described above.

Also, the order of the steps leading from IV to II can be reversed by first reducing the NO2 group of IV (compound
IVa) then by oxidizing the R5 group, which leads directly to compound Ia.

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.

N" R4 X
1 liaison b
2 H OCH3
3 H CN
4 H SC2H5
Dans la description qui suit, R1=R2=R3=Z=H ; Y=CON(CH3)2
Exemple I : Préparation du composé n"l
I-l - Préparation du N-orthonitrobenzoyl 5-acétyloxyméthyl 3-carboxaldéhyde dihydro[4,5] pyrrole de formule VI avec R5 est acétyloxy.The invention will be described in more detail with the aid of nonlimiting examples illustrating the synthesis of different pyrrolo [1,4] benzodia zepine derivatives of general formula I gathered in the table below
BOARD

N "R4 X
1 link b
2 H OCH3
3 H CN
4 H SC2H5
In the following description, R1 = R2 = R3 = Z = H; Y = CON (CH3) 2
EXAMPLE I Preparation of Compound No. 1
II - Preparation of N-orthonitrobenzoyl 5-acetyloxymethyl 3-carboxaldehyde dihydro [4,5] pyrrole of formula VI with R5 is acetyloxy.

The preparation is carried out according to the following scheme

 To a solution of compound 1 (1.6 g, 4.97 mmol), quinolinium camphosulfonate (0.283 g, 0.78 mmol) is added in anhydrous toluene (12 ml) 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.

I-2 - Preparation of the compound of formula IV where R5 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 nBuli is added with stirring (7.16 mmol, 1.5 M solution in hexane). After 30 minutes, the aldehyde obtained in Il
R5 = OCOCH3, (1.75 g, (5.5 mmol) is added in solution in anhydrous THF (30 ml). After complete reaction (20 minutes) and addition of an aqueous solution of ammonium chloride, the reaction medium is extracted with methyl acetate After the usual treatment, the constituents of the crude product (2, lu) can be separated by chromatography on a silica column (eluent dichloromethane-methanol (95-5).

1.83 g (86%) of protected compound IV are thus obtained (R5 = acetyl oxy)
IR (CH2Cl2, -1): 2950, 1730, 1640, 1590 and 0.247 g (135o) of the hydroxylated compound IV (R5 = OH):
IR (CHC13, cl1): 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) 21N (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 addition of carbon dioxide gas. After filtration, the medium is extracted with dichloromethane. The usual treatments provide compound IV (1.4 g, 98%).

I-3 - Preparation of the compound of formula II
To a solution of oxalyl chloride (0.144 ml, 1.65 mmol) in anhydrous dichloromethane (2 ml), maintained with stirring and under argon at -300C, a solution of dimethyl sulfoxide (0.234 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 maintained at -30 C for 1 h 30 min before the addition of diisopropylethylamine (0.862 ml, 4.95 mmol). The reaction medium is stirred for 10 minutes at -30 ° C. and then 30 minutes at 00C before hydrolysis with a buffer at pH 5.6 (citrate-phosphate, 90 ml). The aldehyde is extracted 3 times with acetate. ethyl (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-l): 3300 (hydrated form), 2920, 1720 (weak), 1630, 1595.

I-4 - Preparation of the compound of formula I where R4 and X together form a bond A (formula Ia) compound n0l
A solution of compound II (0.34 g, 1 mmol) 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 II: Preparation of Compound 2
Compound n 1 is transformed without purification into compound n 2. 2.

 To compound No. 1, in solution in a dichloromethane / methanol mixture 9-1 (2 ml), a solution of trifluoroacetic acid in dichloromethane (15 p1%, 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
PF (dec): 228 "C,
IR (cm 1) = 3300, 2924, 2850, 1620.

Example III Preparation of Compound No. 3
To a solution of compound n 2 (65.4 mg, 0.2 mmol) in anhydrous dichloromethane (1.3 ml) cooled to 0 C, cyanotrimethylsilane (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 96. The aqueous phase is extracted two more times times 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 for crystallization of compound No. 2 (32.7 mg, 0.1 mmol) in anhydrous dichloromethane (0.15 ml), a 10% solution is added under argon at ordinary temperature. 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) To a solution of compound n "I prepared according to Itexample 1 (29.5 mg, 0.1 mmol), in solution in anhydrous dichloromethane (0.3 ml), a 10% solution is added under argon at room temperature % ethanethiol in anhydrous dichloromethane (0.2 ml) 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 I mg / ml gives a MIC of the order of 60 pg / ml.

Cytotoxic activity
On the line KB [(human cancer cells nasopharynx) j Cpg / ml 1 0.5 0.1 0.05 0.01
C mol / l 3.06.10-6 1.53.10-6 3.06.10-7 1.53.10-7 3.06.10-8 G 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-V1 with a phenotype of resistance to vinblastine (the resistant strain is maintained in the presence of 1 g / ml of vinblastine)
LD50 on KBR = LD50 on KBS approx. 0.8.10-7 M
- On two human erythroleukemic K562 lines respectively resistant and sensitive to doxorubicin (adriblastine), the resistant line is maintained in the presence of 10 7 M adriblastine
LD50 on K562R = LD50 on K5625 approx. 0.85.10 7 M.

Claims (15)

R2, R3, R4 and X do not respectively represent simultaneously a 0-1 'sibirosamine, methyl and hydroxyls (sibiromycin) radical. R3 and X do not each represent a hydroxide radical (anthramycin, mazethramycin) - when Y represents a methyl group and Z a hydrogen atom, R1, Y, Z identical or different represent a hydrogen atom or an alkyl, alkoxycarbonyl, aminocarbonyl or N-alkyl or N, N-dialkylamino carbonyl, cyano, phosphonate radical, with the proviso that - when Y represents a dimethylaminocarbonyl group and Z represents a hydrogen atom, R3 and X do not each represent a methoxyl radical (porothramycin B) or, when R3 represents a methoxyl radical, X does not represent a hydroxyl radical (porothramycin A) and that - when Y represents an aminocarbonyl group or methylamino carbonyl, Z represents a hydrogen atom and R2 a methyl radical, R4 and X together form a double bond (compound of formula Ia), X represents a hydrogen atom, a hydroxyl, alkoxyl, alkanoyloxyl, mercapto, alkylthio, cyano, amino, phosphonate, sulfo (SO3H), alkali metal or alkaline earth metal sulfonate radical or else R4 represents a hydrogen atom or an alkyl or alkanoyl radical, R1 can also correspond to the radical O-l'-sibirosamine, R1, R2, R3, which are identical or different, represent a hydrogen or halogen atom, a hydroxyl, alkoxyl, alkanoyloxyl radical or two substituents adjacent together, form a methylenedioxyl chain,  in which n = 1 or 2, preferably 1,

 1. Pyrrolo [1,4] -benzodiazepine derivatives of formula  2. Derivatives according to claim 1, characterized in that R3 is the hydrogen atom.  3. Derivatives according to claim 2, characterized in that R1, R2 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 R4 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-alkyl substituted aminocarbonyl radical. 7. Process for the preparation of compounds of formula I

 in which n = 1 or 2, preferably 1, R1, R2, R3, which are identical or different, represent a hydrogen or halogen atom, a hydroxyl, alkoxyl, alkanoyloxyl radical or two substituents adjacent together, form a methylenedioxyl chain, R1 can also correspond to the radical 0-l'-sibirosamine, R4 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 (SO3H), alkali or alkaline earth metal sulfonate radical or else R4 and X together form a double bond ss (compound of formula Ia), Y, Z identical or different represent a hydrogen atom or an alkyl, alkoxycarbonyl, aminocarbonyl or N-alkyl or N, N-dialkylamino carbonyl, cyano, phosphonate radical, characterized in that an N-orthonitrobenzoyl-5 is reduced -carboxaldehyde substituted dihydropyrroles of general formula II

 in which R1, R2, R3, Y and Z have the meanings given in connection with the general formula I and in that, where appropriate, the derivative of general formula Ia thus obtained

  is reacted with a nucleophilic reagent of formula R4X (III) to obtain a compound of general formula I in which R4 represents a hydrogen atom or an alkyl or alkanoyl radical, X represents a hydrogen atom or a hydroxyl, alkanoyloxyl, mercapto, alkylthio, cyano, amino, phosphonate, sulfo (-SO3H) or sulfonate radical 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 the preparation of compounds of formula II, characterized in that they are obtained by oxidation of compounds of general formula IV

 in which n, R1, R2, R3, Z and Y have the same meaning as in formula I and R5 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 bringing into contact a reagent of general formula (V) R6R7R8 P = CYZ in which R6, R7, R8 represent an alkyl radical or else R6 represents a hydrogen atom, R7 and R8 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 R5 represents a protected hydroxyl or hydroxyl group or a halogen atom, R1, R2, R3 have the meanings given in claim I.  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.