FR2680790A1 - New decladinosylated derivatives of erythromycin, process for preparing them and their application as medicinal products - Google Patents

Abstract

The subject of the invention is the compounds of formula (I): in which, - either X and X' form C=O or C=NOR with R=H, heterocycle, alkyl, alkenyl, alkynyl, optionally substituted, Ra, Rb being a hydrocarbon radical or forming with the nitrogen atom a heterocycle, and X' = H, - Y and Y' have the same meaning as X and X', - B = H, OR4, R4 = H, or forms with A a carbonate or a carbamate, - A = OR'4, R'4 = H or forms with B a carbonate n = integer from 1 to 6 R2 = alk or CONH2, CONHCOR11 or CONHSO2R11, R11, hydrocarbon up to 18c.

Description

 The present invention relates to novel cladinosyl derivatives of erythromycin, to a process for their preparation and to their use as medicaments.

dans laquelle, ou bien X et X' forment ensemble avec l'atome de carbone auquel ils sont liés un groupement C=O ou C=NOR, dans lequel R représente - un atome d'hydrogène, - un radical hétérocyclique renfermant au moins un atome d'azote et éventuellement un autre hétéroatome, mono ou bicyclique, saturé ou insaturé, aromatique ou non aromatique comportant jusqu'à 12 chaînons, éventuellement substitué sur l'atome d'azote par un radical alkyle renfermant jusqu'à 4 atomes de carbone, - un radical alkyle, alkényle ou alkynyle linéaire, ramifié ou cyclique, renfermant jusqu'à 18 atomes de carbone éventuellement substitué par un ou plusieurs groupements
. hydroxyle,
. halogène,
. cyano,
. nitro,
. amidinyle,
. guanidinyle,
. hétérocyclique, tel que défini précédemment,
. alkyloxy, alkényloxy ou alkynyloxy ayant au plus 6
atomes de carbone,
. alkylthio, alkénylthio ou alkynylthio ayant au plus 6
atomes de carbone, l'atome de soufre étant éventuellement
oxydé en sulfoxyde ou en sulfone,
. aryloxy, aralkyloxy,
. arylthio, aralkylthio, l'atome de soufre étant éven
tuellement oxydé en sulfoxyde ou en sulfone, (chacun de ces radicaux alkyloxy, alkényloxy, alkynyloxy, alkylthio, alkénylthio ou alkynylthio, aryloxy, aralkyloxy, arylthio ou aralkylthio étant éventuellement substitué par un ou plusieurs des groupements suivants : hydroxy, alkyloxy, alkylthio ayant de 1 à 6 atomes de carbone, alkénylthio, alkynylthio ayant jusqu'à 6 atomes de carbone, amino, monoalkylamino ayant jusqu'à 6 atomes de carbone, dialkylamino ayant jusqu'à 12 atomes de carbone, un radical amidinyle, guanidinyle, un radical hétérocyclique tel que défini précédemment, les radicaux aryloxy, arylthio, araîkyloxy et aralkylthio étant de plus éventuellement substitués par les radicaux méthyle, éthyle, propyle, carbamoyle, aminométhyle, diméthylaminométhyle, aminoéthyle, diméthylaminoéthyle, carboxyle, méthyloxycarbonyle, éthyloxycarbonyle)

dans lequel ou bien R'1 et R'2 identiques ou différents représentent un atome d'hydrogène, un radical alkyle, alkényle ou alkynyle, linéaire, ramifié ou cyclique renfermant jusqu'à 18 atomes de carbone, un radical aryle ou aralkyle, chacun de ces radicaux R'1 et R'2 étant éventuellement substitué par un ou plusieurs radicaux hydroxy, alkyloxy, alkényloxy, alkynyloxy, alkylthio, alkénylthio ou alkynylthio renfermant jusqu'à 8 atomes de carbone, amino, monoalkylamino renfermant jusqu'à 4 atomes de carbone, dialkylamino renfermant jusqu'à 8 atomes de carbone, cyano, carboxyle libre, estérifié ou salifié, acyle ou carbamoyle, renfermant jusqu'à 8 atomes de carbone, par un radical Si(alc)3 ou Si(Oalc)3 dans lequel alc représente un radical alkyle renfermant jusqu'à 4 atomes de carbone, par un radical hétérocyclique tel que défini précédemment, ou bien R'1 et R'2 forment ensemble avec l'atome d'azote auquel ils sont liés un radical hétérocycle mono ou bicyclique, renfermant éventuellement un autre hétéroatome, saturé ou insaturé, aromatique ou non aromatique, comportant jusqu'à 12 chaînons . un groupement ammonium quaternaire, . 1,2-époxyéthyle ou 2,2-diméthyl 1,2-époxyéthyle ou un radical résultant de l'ouverture de ce groupement par un réactif nucléophile,

dans lequel B1 représente soit un radical aîkyle ou alkyloxy ayant au plus 6 atomes de carbone, . aryle, aralkyle, aryloxy ou aralkyloxy, . formyle libre ou protégé, carboxyle libre, estérifié ou salifié, thiocyanate, acyle ou carbamoyle, . (CH2)nR', R' représentant le reste d'un acide aminé, et n représentant un nombre entier compris entre o et 6, ou bien X représente un radical

- Ra et Rb identiques ou différents l'un de l'autre, représentant un atome d'hydrogène ou un radical.hydrocarboné renfermant jusqu'à 18 atomes de carbone, renfermant éventuellement un ou plusieurs hétéroatomes, éventuellement substitué par un ou plusieurs groupements fonctionnels, ou par un radical hétérocyclique renfermant au moins un atome d'azote et éventuellement un autre hétéroatome choisi parmi l'oxygène, le soufre et l'azote, mono ou bicyclique, saturé ou insaturé, aromatique ou non aromatique comportant jusqu'à 12 chaînons, éventuellement substitué sur l'atome d'azote par un radical alkyle renfermant jusqu'à 4 atomes de carbone, - Ra et Rb pouvant éventuellement former avec l'atome d'azote auquel ils sont lies un radical hétérocycle, renfermant au moins un atome d'azote et éventuellement un autre hétéroatome choisi parmi l'oxygène, le soufre et l'azote, mono ou bicyclique, saturé ou insaturé, aromatique ou non aromatique comportant jusqu'à 12 chaînons, - Ra et Rb pouvant former avec le radical A un cycle 9-N, a et X' représente un atome d'hydrogène,
Y et Y' identiques ou différents de X et X' ont la signification de X et X'
B représente un atome d'hydrogène ou un radical OR4, R4 représentant un atome d'hydrogène ou forme avec A un radical carbonate ou carbamate, A forme avec le carbone qui le porte et le carbone en 10, une double liaison, ou A represente un radical OR'4, R'4 représentant un atome d'hydrogène ou forme avec B un radical carbonate, ou A représente un radical

The subject of the invention is the compounds of formula (I):

wherein either X and X 'together with the carbon atom to which they are attached form a group C = O or C = NOR, wherein R represents - a hydrogen atom, - a heterocyclic radical containing at least one nitrogen atom and optionally another heteroatom, mono- or bicyclic, saturated or unsaturated, aromatic or nonaromatic having up to 12 members, optionally substituted on the nitrogen atom by an alkyl radical containing up to 4 carbon atoms a linear, branched or cyclic alkyl, alkenyl or alkynyl radical containing up to 18 carbon atoms optionally substituted with one or more groups
. hydroxyl,
. halogen,
. cyano,
. nitro,
. amidinyl,
. guanidinyl,
. heterocyclic, as defined above,
. alkyloxy, alkenyloxy or alkynyloxy having not more than 6
carbon atoms,
. alkylthio, alkenylthio or alkynylthio having not more than 6
carbon atoms, the sulfur atom possibly being
oxidized to sulfoxide or sulfone,
. aryloxy, aralkyloxy,
. arylthio, aralkylthio, the sulfur atom being
oxidized to sulfoxide or sulfone (each of said alkyloxy, alkenyloxy, alkynyloxy, alkylthio, alkenylthio or alkynylthio, aryloxy, aralkyloxy, arylthio or aralkylthio radicals being optionally substituted by one or more of the following groups: hydroxy, alkyloxy, alkylthio having 1-6 carbon atoms, alkenylthio, alkynylthio having up to 6 carbon atoms, amino, monoalkylamino having up to 6 carbon atoms, dialkylamino having up to 12 carbon atoms, amidinyl radical, guanidinyl, heterocyclic radical as defined above, the aryloxy, arylthio, aralkyloxy and aralkylthio radicals being additionally optionally substituted by the methyl, ethyl, propyl, carbamoyl, aminomethyl, dimethylaminomethyl, aminoethyl, dimethylaminoethyl, carboxyl, methyloxycarbonyl or ethyloxycarbonyl radicals)

in which R'1 and R'2, which may be identical or different, represent a hydrogen atom, a linear, branched or cyclic alkyl, alkenyl or alkynyl radical containing up to 18 carbon atoms, an aryl or aralkyl radical, each of these radicals R'1 and R'2 being optionally substituted with one or more hydroxyl, alkyloxy, alkenyloxy, alkynyloxy, alkylthio, alkenylthio or alkynylthio radicals containing up to 8 carbon atoms, amino, monoalkylamino containing up to 4 carbon atoms, carbon, dialkylamino containing up to 8 carbon atoms, cyano, free carboxyl, esterified or salified, acyl or carbamoyl, containing up to 8 carbon atoms, with a radical Si (alk) 3 or Si (Oalc) 3 in which alk represents an alkyl radical containing up to 4 carbon atoms, with a heterocyclic radical as defined above, or R'1 and R'2 together with the nitrogen atom to which they are attached form a mono or heterocyclic radical; bicyclic optionally containing another heteroatom, saturated or unsaturated, aromatic or nonaromatic, having up to 12 members. a quaternary ammonium group, 1,2-epoxyethyl or 2,2-dimethyl-1,2-epoxyethyl or a radical resulting from the opening of this group by a nucleophilic reagent,

in which B1 represents either an alkyl or alkyloxy radical having at most 6 carbon atoms, aryl, aralkyl, aryloxy or aralkyloxy, free or protected formyl, free carboxyl, esterified or salified, thiocyanate, acyl or carbamoyl, (CH2) nR ', where R' represents the residue of an amino acid, and n represents an integer between 0 and 6, or X represents a radical

- Ra and Rb identical or different from each other, representing a hydrogen atom or a hydrocarbon radical containing up to 18 carbon atoms, optionally containing one or more heteroatoms, optionally substituted with one or more functional groups or with a heterocyclic radical containing at least one nitrogen atom and optionally another heteroatom selected from oxygen, sulfur and nitrogen, mono or bicyclic, saturated or unsaturated, aromatic or nonaromatic having up to 12 members optionally substituted on the nitrogen atom by an alkyl radical containing up to 4 carbon atoms, - Ra and Rb may optionally form with the nitrogen atom to which they are attached a heterocycle radical, containing at least one atom nitrogen and optionally another heteroatom selected from oxygen, sulfur and nitrogen, mono- or bicyclic, saturated or unsaturated, aromatic or nonaromatic having up to 12 hp lesions, - Ra and Rb being able to form with the radical A a 9-N ring, a and X 'represents a hydrogen atom,
Y and Y 'identical or different from X and X' have the meaning of X and X '
B represents a hydrogen atom or a radical OR4, R4 representing a hydrogen atom or forms with A a carbonate or carbamate radical, A forms with the carbon which carries it and the carbon at 10, a double bond, or A represents a radical OR '4, R' 4 representing a hydrogen atom or form with B a carbonate radical, or A represents a radical

R'5 representing a group C = O forming with B a carbamate group, R'6 representing a hydrogen atom or an alkyl, aralkyl or alkyloxy radical having up to 12 carbon atoms or a grouping

Rg et R10 representant un atome d'hydrogène ou un radical alkyle renfermant jusqu'à 8 atomes de carbone, ou formant avec l'atome d'azote un hétérocycle tel que défini précédemment, n représentant un nombre entier compris entre 1 et 6,
R2 représente un radical alkyîe renfermant jusqu'à 8 atomes de carbone, ou un radical CONH2 ou CONHCOR11 ou CONHS02R1l dans lesquels R11 représente un radical hydrocarboné renfermant jusqu'à 18 atomes de carbone comportant éventuellement un ou plusieurs hétéroatomes, R3 en position alpha ou béta représente un atome d'hydrogène ou un radical alkyle, renfermant jusqu'à 8 atomes de carbone ou un radical

dans lequel R12 et R13 représente un atome d'hydrogène, un radical alkyîe renfermant jusqu'à 8 atomes de carbone ou formant avec l'atome d'azote un hétérocycle tel que défini précédemment n représentant un nombre entier compris entre 1 et 6 ou un radical

R7 and R8 identical or different representing a hydrogen atom or an alkyl or aralkyl radical, containing up to 18 carbon atoms, or forming with the nitrogen atom a heterocycle as defined above, q representing an integer between 1 and 6, where A represents a radical

Rg and R10 representing a hydrogen atom or an alkyl radical containing up to 8 carbon atoms, or forming with the nitrogen atom a heterocycle as defined above, n representing an integer between 1 and 6,
R2 represents an alkyl radical containing up to 8 carbon atoms, or a radical CONH2 or CONHCOR11 or CONHS02R11 in which R11 represents a hydrocarbon radical containing up to 18 carbon atoms optionally comprising one or more heteroatoms, R3 in the alpha or beta position; represents a hydrogen atom or an alkyl radical, containing up to 8 carbon atoms or a radical

in which R12 and R13 represents a hydrogen atom, an alkyl radical containing up to 8 carbon atoms or forming with the nitrogen atom a heterocycle as defined above n representing an integer between 1 and 6 or a radical

R14 and R15, identical or different, representing a hydrogen atom or an alkyl radical containing up to 8 carbon atoms or a heteroatom or an alkyl or alkyloxy radical containing up to 8 carbon atoms, Z represents a hydrogen atom or the remainder of a carboxylic acid containing up to 18 carbon atoms the oximes that can represent X and X 'or Y and Y' can be of syn or anti configuration as well as the addition salts with acids of the compounds of formula (I).

 As examples of addition salts of the present derivatives with the mineral or organic acids, mention may be made of the salts formed with acetic, propionic, trifluoroacetic, maleic, tartaric, methanesulphonic, benzenesulphonic, p-toluenesulphonic, hydrochloric, hydrobromic and hydroiodic acid acids. sulfuric, phosphoric and especially stearic, ethylsuccinic or laurylsulfuric acids.

 In the definition of the products of the invention - the heterocyclic radical is preferably pyrrolyl, pyrrolidinyl, pyridyl, pyrazinyl, pyrimidyl, piperidinyl, piperazinyl, quinuclidinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, imidazolyl, benzimidazolyl, triazolyl, thiazolyl, azetidinyl, aziridinyl. The heterocyclic radicals mentioned below may, of course, preferably be mentioned in the experimental part; the alkyl, alkenyl or alkynyl radical is preferably a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or terbutyl radical; decyl or dodecyl, vinyl, allyl, ethynyl, propynyl, cyclobutyl, cyclopentyl or cyclohexyl, the halogen is preferably fluorine or chlorine, or bromine, the aryl radical is preferably the phenyl radical, the radical aralkyl is preferably a radical (C6H5) (CH2) a, a being an integer from 1 to 6, for example the number 1, 2, 3 or 4 or a naphthyl radical.

 Among the protected formyl radicals, there may be mentioned more particularly the radicals of the acetal type. The following radicals are preferred: 1,3-dioxolan-2-yl, dimethoxymethyl, diethoxymethyl.

 Esterified carboxyl radicals include alkoxycarbonyl radicals having at most 7 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl.

 Alkyloxyalkyloxycarbonyl radicals such as methoxymethoxycarbonyl, isopropyloxymethoxycarbonyl, alkylthiomethoxycarbonyl radicals such as methylthiomethoxycarbonyl, isopropylthiomethoxycarbonyl, and acyloxyalkyloxycarbonyl radicals such as pivaloyloxymethoxycarbonyl and acetoxyethoxycarbonyl may also be mentioned.

 Among the salts formed with the carboxyl group, mention may be made of sodium, potassium, lithium, calcium, magnesium or ammonium salts, or salts formed with aminated organic bases such as trimethylamine, diethylamine, triethylamine and tris (hydroxymethyl). ) aminomethane.

 Among the acyl radicals, mention may in particular be made of acetyl, propionyl, butyryl, isobutyryl, n-valeryl, isovaleryl, tert-valeryl and pivalyl radicals.

The subject of the invention is more particularly the compounds of formula (I) in which X and X 'together with the carbon atom to which they are attached form a group
C = NOR, R retaining the same meaning as before.

Among these compounds, the subject of the invention is in particular the compounds of formula (I) in which R represents an alkyl radical containing up to 6 carbon atoms substituted by a radical.

R'1 and R'2 retaining the same meaning as above, for example those in which the radical R is a radical

R'1 and R'2 representing an alkyl radical containing up to 4 carbon atoms and especially a radical (CH2) 2-N (CH3) 2
Among the preferred compounds of the invention, mention may also be made of the compounds in which R represents an alkyl radical containing up to 6 carbon atoms, substituted by an alkoxy radical containing up to 6 carbon atoms optionally substituted with a methoxy radical. , for example those in which R represents a radical

Among the preferred compounds of the invention, mention may be made of the compounds of formula (I) in which Y and Y 'together form a C = O group, the compounds of formula (I) in which Y and Y' together form a group C = NOR, R retaining its previous meaning and in particular a benzyl radical, - the compounds of formula (I) in which R 2 represents an alkyl radical containing from 1 to 4 carbon atoms, for example a methyl radical, - the compounds of formula (I) in which R3 represents a hydrogen atom, (alpha or beta), - the compounds of formula (I) in which A represents an OH radical, - the compounds of formula (I) in which B represents an OH radical, - the compounds of formula (I) in which A and B together form a cyclic 11,12 carbonate group, - the compounds of formula (I) in which A and B together form a radical

R '6 representing a hydrogen atom or an alkyl, aralkyl or alkyloxy radical having up to 12 carbon atoms or a group

R7 and R8 identical or different representing a hydrogen atom or an alkyl or aralkyl radical, containing up to 18 carbon atoms, or forming with the nitrogen atom a heterocycle as defined above, and q represents a whole number between 1 and 6.

 Among these compounds, there may be mentioned more particularly the compounds in which R '6 represents an aralkyl radical having up to 12 carbon atoms, for example a radical (CH 2> 4C 6 H 5.

 Among the preferred compounds of the invention, mention may be made of the compounds of formula (I) in which Z represents a hydrogen atom, and the compounds of formula (I) in which there is no unsaturation. in 10.11.

 Among the preferred compounds of the invention, mention may be made of the compounds described in the experimental part and in particular the products of Examples 1, 2, 7 and 10.

 The products of general formula (I) have a very good antibiotic activity on grays bacteria such as staphylococci, streptococci, pneumococci.

The compounds of the invention can therefore be used as medicaments in the treatment of infections with susceptible germs and, in particular, in that of staphylococci, such as staphylococcal septicemia, staphylococcal malignancies of the face or cutaneous, pyoderma, septic or suppurative wounds. , boils, anthrax, phlegmons, erysipelas and acne, staphylococcal diseases such as acute or post-influenza acute tonsillitis, bronchopneumonia, pulmonary suppuration, streptococcal diseases such as acute tonsillitis, otitis, sinusitis, scarlet fever, pneumococcal diseases such as pneumonia, bronchitis; brucellosis, diphtheria, gonorrhea.The products of the present invention are also active against infections due to germs such as
Haemophilus influenzae, Rickettsiae, Mycoplasma pneumoniae,
Chlamydia, Legionella, Ureaplasma, Toxoplasma.

 The subject of the present invention is therefore also, as medicaments and, in particular, antibiotic medicaments, the products of formula (I) as defined above, as well as their addition salts with pharmaceutically acceptable inorganic or organic acids.

 The invention more particularly relates, as medicaments and, especially antibiotic drugs, the preferred products of formula (I) defined above and their pharmaceutically acceptable salts.

 The invention also relates to pharmaceutical compositions containing as active ingredient at least one of the drugs defined above.

 These compositions can be administered orally, rectally, parenterally or locally by topical application to the skin and mucous membranes, but the preferred route of administration is the oral route.

 They can be solid or liquid and be in the pharmaceutical forms commonly used in human medicine, for example, tablets, single or coated tablets, capsules, granules, suppositories, injectables, ointments, creams, they are prepared according to the usual methods. The active ingredient (s) can be incorporated into excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non aqueous vehicles. fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

 These compositions may also be in the form of a powder intended to be dissolved extemporaneously in a suitable vehicle, for example sterile pyrogen-free water.

 The dose administered varies according to the condition being treated, the subject, the route of administration and the product under consideration. It may be, for example, between 50 mg and 300 mg per day orally, in humans, with the product described in Example 1.

dans laquelle X, X', B et A conservent leur signification précédente, à l'action d'un acide en milieu aqueux pour obtenir le composé de formule (III)

que l'on soumet à l'action d'un agent de blocage de la fonction hydroxyle en 2', pour obtenir un composé de formule (IV)

dans laquelle OM représente un groupement hydroxyle bloqué, et les autres substituants conservent leur signification précé dente, que l'on soumet à l'action d'un agent d'oxydation de la fonction hydroxyle en 3, pour obtenir le composé de formule (V)

que l'on soumet, si désiré, à l'action d'un réactif susceptible d'introduire le radical R'3, R'3 ayant la même valeur que
R3 à l'exception de l'hydrogène, puis ou bien à l'action d'un agent de libération de la fonction hydroxyle en 2' pour obtenir le composé de formule (IA)

c'est-à-dire un composé de formule (I) dans laquelle Y et Y' forment ensemble avec l'atome de carbone auquel ils sont liés une fonction cétone, puis soumet si désiré, ce composé de formule (IA) à l'action d'un agent de fonctionnalisation de la cétone ou béta-céto ester pour obtenir le composé de formule (I) recherché, puis si désiré soumet le composé obtenu à l'action d'un agent d'estérification de l'hydroxyle en 2', ou bien d'abord à l'action d'un agent de fonctionnalisation de la fonction cétone béta-céto ester, et ensuite à l'action d'un agent de libération de la fonction hydroxyle en 2' pour obtenir le composé de formule (I) recherché puis si désiré soumet le composé de formule (I) ainsi obtenu à l'action d'un acide pour en former le sel.The subject of the invention is also a process for the preparation of the compounds of formula (I) as defined above, characterized in that a compound of formula (II) is subjected

wherein X, X ', B and A retain their previous meaning, to the action of an acid in an aqueous medium to obtain the compound of formula (III)

that is subjected to the action of a blocking agent of the hydroxyl function in 2 ', to obtain a compound of formula (IV)

in which OM represents a blocked hydroxyl group, and the other substituents retain their previous meaning, which is subjected to the action of an oxidation agent of the hydroxyl function at 3, in order to obtain the compound of formula (V )

that is subjected, if desired, to the action of a reagent capable of introducing the radical R'3, R'3 having the same value as
R3 with the exception of hydrogen, or else with the action of a 2 'hydroxyl-releasing agent to obtain the compound of formula (IA)

that is to say a compound of formula (I) in which Y and Y 'together with the carbon atom to which they are attached form a ketone function and then, if desired, subject this compound of formula (IA) to action of a ketone or beta-keto ester functionalizing agent to obtain the desired compound of formula (I), then, if desired, subjecting the compound obtained to the action of a hydroxyl esterifying agent to 2 ', or firstly to the action of a functionalizing agent of the ketone beta-keto ester function, and then to the action of a hydroxyl-functional release agent in 2' to obtain the compound of formula (I) and then sought if desired the compound of formula (I) thus obtained to the action of an acid to form the salt.

 In a preferred embodiment of the process of the invention - the hydrolysis of cladinose is carried out by means of aqueous hydrochloric acid or in methanol, the blocking of the hydroxyl at 2 'is carried out using an acid or a functional derivative of acid, for example an acid anhydride, an acid halide, or silicon derivatives, the oxidation of the hydroxyl in 3 is carried out using either chromic anhydride in sulfuric acid diluted according to the Jones oxidation reaction, ie diimides in the presence of dimethylsulfoxide (DMSO), the functionalization of the ketone is carried out using a compound of formula RONH 2 when it is desired to obtain derivatives of oximes, - 2 'esterification is carried out according to conventional methods, - the salification is carried out using acids according to conventional methods.

 The compounds of formula (II) used as starting products are prepared from known products described in European Patents 0216169, 41355 and 0180415 using the methods described below in the experimental part.

 The oxime of 6-O-methyl erythromycin is described for example in EP 0180415.

 The subject of the invention is also a variant of the preceding method in which the different steps are carried out in a different order.

The invention also has a variant of the process described above for preparing the products of formula (I) in which X and X 'together form a group C = NOR, characterized in that the product of formula (IVA) used in which X and X 'represent the group C = N-OR is prepared from the corresponding ketone of formula (II) by action of NH 2 OR in acidic medium, to obtain, according to the pH of the reaction, the product of formula (IVA) corresponding saturated or unsaturated in 10 (11)

Where A represents an OH radical if there is no unsaturation at 10 (11) or a hydrogen atom if there is unsaturation at 10 (11),
R, R2, B and Z retain the same meaning as above.

The invention finally relates to a variant of the process for preparing the compounds of formula (I) in which X and
X 'form a C = NOR group, R being defined as above, characterized in that a compound of formula (IA) in which X and X' together form a keto group to the action of the compound of formula NH2OR is subjected to to obtain the corresponding compound of formula (I), wherein X and X 'form a group C = NOR.

 The intermediate products obtained during the implementation of the process of the invention are new and are in themselves an object of the present invention.

 The following examples illustrate the invention without limiting it.

EXAMPLE 1: 9-EO-E2- (dinethylamino) ethyl] oximes of 3 del (2,6-dideoxy-3-C-methyl-3-O-methyl-L-ribo-hexopyranosyl) -decidated 6-O-methyl-3-oxo erythromycin
STAGE A: 9- [O- [2- (dimethylamino) ethyl oxime] 3-O-diene (2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl) 6-O-methyl erythromycin
100 mg of the product obtained in Preparation 1 and 0.3 cm 3 of a hydrochloric acid solution at 22 ° B are suspended in 3 cm 3 of water. The solution is stirred for 3 hours at room temperature. .

 Is brought to basic pH by adding a few drops of ammonia at 20%, 2 cm3 of a saturated solution of sodium chloride, extracted with ethyl acetate and chloroform. The solvents are dried and evaporated.

 Chromatography on silica eluting first with pure ethyl acetate and then with ethyl acetate ethylamine mixture (98/2).

 50 mg of desired product is thus obtained.

ANALYZES
IR: (Nujol on Nicolet)
CO: 1733 cml
MS (FAB) (M + H) + = 676+
STAGE B: 9- [O-r 2 - (dimethylamino) ethyl] oxime] 3-de [(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-O- methyl 3-oxo erythromycin
150 mg of the product prepared in the preceding stage, 38 mg of potassium carbonate and 33 microliters of acetic anhydride are suspended in 2 cm3 of acetone. The suspension thus obtained is stirred for 20 hours.

 Ice (1 cc) is added, the mixture is stirred for 5 minutes and saturated with sodium chloride. 1 cm3 of water is added, the mixture is extracted with ethyl acetate, dried over magnesium sulphate and the solvents are evaporated off. 110 mg of crude product is obtained which is chromatographed on silica, eluting with ethyl acetate-triethylamine (96/4). 110 mg of desired product are isolated.

ANALYZES
MS (FAB) (M + H) + = 718+
STAGE C: 9- [O- (2- (dimethylamino) ethyl] oxime] 3-de [(2,6-Dideoxy-3-C-methyl-3-O-methyl-L-ribo-hexopyranosyl) oxy] 6-O Methyl 3-oxo erythromycin
Stage C1: Oxidation
Under argon, in 2 cm3 of methylene chloride, 110 mg of the product of the preceding stage, 0.21 cm3 of dimethylsulfoxide and 165 mg of 1- [3- (dimethylamino) propyl] hydrochloride are dissolved in a solution. ethyl carbodiimide (EDAC). The solution is stirred for 20 minutes and 165 mg of pyridinium trifluoroacetate is added. After 2 hours, 70 microliters of dimethylsulfoxide and 55 mg of EDAC are added. Stir 20 minutes and add 55 mg of pyridinium trifluoroacetate.

 2 cm 3 of water are added to the solution obtained, the mixture is stirred for 10 minutes, taken up with methylene chloride, washed with water, dried over magnesium sulphate and the solvents evaporated.

240 mg of crude product is obtained which is chromatographed on silica eluting with ethyl acetate, triethylamine (95/5). 85 mg of desired product is obtained.

Stage C2: Release of hydroxyl in 2 '
85 mg of the product obtained previously is dissolved in 3 cm3 of methanol. Stirred for 24 hours. The solvent is evaporated under reduced pressure. A product is obtained which is purified by chromatography eluting with ethyl acetate-triethylamine (95/5). 75 mg of desired product is obtained.

ANALYZES
IR: (CHC13 on Nicolet)
OH: 3606, 3510, 3415 cm 1
C = O: 1744, 1714 cm -1
UV: max 287 nm E = 10900
SM: (FD)
M + = 673+
NMR: (CDCl3, 400 MHz, sppm) 3.86 (H2), 3.12 (H4), 4.31 (H5), 1.39 (CH3 at 6), 2.74 (OCH3 at 6), 3.56 (H8), 2.5-2.65 (H10, CH2-N), 3.89 (H11), 1.22 (12-CH3), 5.17 (H13), 0.86 (H15) ), 4.09 (O-CH 2 -CH 2), 2.27 (CH 3 -N), 0.97-1.16-1.26-1.3-1.32 (CH 3), 4.31 (H 1), 3.19 (H'2), 2.5 (H'3), 3.64 (H'5).

 (a1pha] = +4 (c = 0.5% CHCl3).

PREPARATION 1: 9-EO-E2- (dimethylamino) ethyl] oxime 6-Omethyl erythromycin
160 mg of chloro-2-N, N-dimethylamine hydrochloride are dissolved under a nitrogen atmosphere in 1.5 cm3 of dimethylsulfoxide. 60 mg of 50% sodium hydride in oil are added. It is stirred for 30 minutes under a nitrogen atmosphere and 380 mg of 9-oxime of 6-O-methylerythromycin, 0.5 cm3 of tetrahydrofuran and 30 mg of sodium hydride are added. The solution thus obtained is maintained for 4 hours under a nitrogen atmosphere.

 A few drops of a saturated solution of ammonium chloride are added. 20 cm3 of ethyl acetate are added, washed with a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated aqueous sodium chloride solution. It is dried over magnesium sulphate. The solvents are evaporated. A residue is obtained which is chromatographed on silica eluting with a mixture of chloroform, methanol, ammonia 97/7 / 0.5. 200 mg of desired product is obtained.

 [alpha] D = -99 (c = 1%, chloroform).

IR spectrum: (CHC13)
OH: 3600 cm-1
C = O: 1728 cm -1
C = N: 1626 cm -1
Mass Spectrum: (FAB) (M + H) + = 834+
EXAMPLE 2: 9α-EO-E (2-methoxyethoxy ethoxy) methyl] oximes of 3α-[(2,6-dideoxy-3-C-methyl-3-O-methyl-L-ribohexopyranosyl) oxy) 6-O- methyl 3-oxo erythromycin
STAGE A: 9- (2,6-Dideoxy-3-C-methyl-3-O-methyl-L-ribohexopyranosyl) -6- (OF-2-methoxyethoxy) methyl] oxime] 6-O-methyl erythromycin
Working as in Example 1, Stage A from 1.7 g of the product obtained in Preparation 2, 1.25 g of the desired product was obtained.

 Falpha] = -28 + 1.5 (c = 0.95% CHCl3).

IR spectrum: (CHCl3 on Nicolet)
OH: 3420 cm -1
C = O: 1725 cm -1
C = N: 1636 cm -1
Mass Spectrum: (FAB) (M + H) + + = 693+
STAGE B: 9'- [O - [(2-methoxyethoxy) methyl] oxime] 2'-Oacetyl 3-diene (2,6-dideoxy-3-C-methyl-3-O-methyl-L-ribohexopyranosyl) 6 -O-methyl erythromycin
By operating as in Example 1, Stage B, starting from 346 mg of the product obtained in Stage A, 351 mg of the desired product was obtained.

ANALYZES
IR: (CHC13 on Nicolet)
OH: 3620, 3600 cm 1
C = O: 1730 cm -1
MS: (FAB) (M + H) + = 735 + [alpha] D = -52.5 + 1 (c = 1% CHCl3)
STAGE C: 9 - [O - [(2-methoxyethoxy) methyl] oxime] 2'-Oacetyl 3-dice (2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy ] 6-O-methyl-3-oxo-erythromycin
4 g of product prepared in Stage B and 2.71 cc of Jones' reagent are dissolved in 100 cm3 of acetone. The reaction mixture is stirred for 1 hour at 0 C.

 10 cm3 of 1-propanol are added and stirring is continued at 0 ° C. for 20 minutes. The acetone is evaporated under reduced pressure. The residue is taken up with 50 cm3 of methylene chloride and 20 cm3 of water. It is brought to pH 8 with potassium carbonate. It is extracted with methylene chloride, washed with water, dried over magnesium sulphate, filtered and then evaporated to dryness under reduced pressure. 4.5 g of product are obtained which are chromatographed on silica (eluent: ethyletriethylamine acetate 98-2) to give 2.45 g of the desired product.

IR spectrum: (CHCl3 on Nicolet)
C = N: 1630 cm-1
C = O: 1742, 1716 cm -1
OH: 3510, 3410 cm 1
STAGE D: 9 - ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-O- (E- (2-methoxyethoxy) methyl] oxime] Methyl 3-oxo erythromycin
Working as in Step C2 of Example 1, from 300 mg of the product obtained in Step C above, 0.27 g of the desired product is obtained.

ANALYZES
IR: (CHCl3 on Nicolet)
OH: 3430, 3505 cm -1
C = O: 1744, 1714 cm NMR: (CDCl3, 400 MHz) 0.86 ppm (ethyl CH3), 1.00-1.17 ppm 1.26-1.30-1.32 ppm (unassigned CH3) , 1.23 ppm (CH3 at 12), 1.38 ppm (CH3 at 6), 2.37 ppm (N (CH3) 2), 2.61 ppm (H10 and H3), 2.73 ppm (OCH at 6), 3.13 ppm (H4), 3.26 ppm (H2,), 3.38 ppm (OCH3 MEM), 3.53 ppm, 3.76 ppm (MEM OCH2CH2O), 3.59 ppm (H5,), 3.70 ppm (H8), 3.86 ppm (H2), 3.91 ppm (H11), 4.33 ppm (H1, and H5), 5.14 ppm (OCH2O), 5, 18 ppm (H13).

MS: molecular peak (M +): 690+
PREPARATION 2: 9- [O - [(2-methoxyethoxy) n-ethyl) oxime 6
O-methyl erythromycin
To a solution of 15.2 g of 9-oxime of 6-O-methylerythromycin in 80 cm3 of tetrahydrofuran is added at +5 ° C., 1.35 g of sodium methylate, stirred for 15 minutes at +5 ° C. Then added in 1 hour: 2.85 cm3 of (2methoxyethoxy) methyl chloride in solution in 20 cm3 of tetrahydrofuran; it is stirred for 30 minutes at + 5 ° C. and then allowed to return to ambient temperature, the tetrahydrofuran is evaporated under reduced pressure, the residue is taken up with methylene chloride, washed with water, dried and evaporated to dryness. 16.1 g) on silica (eluent: methylenemethanol-ammonia 95-5-0.1) gives a first fraction of 8.1 g and then a second fraction of 3.56 g of the desired product.

IR spectrum (CHCl3)
OH: 3600 cm 1
C = O: 1728 cm 1
C = N: 1630 cm -1
Mass Spectrum (FAB) (M + H) +: 851+
EXAMPLE 3 3 - [(2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-hexopyranosyl) oxy] 6-O-methyl-3-oxo-erythromycin
STAGE A: 3-O-diene (2,6-dideoxy-3-C-methyl-3-O-methyl-L-hexyl-hexopyranosyl) 6-O-methyl-erythromycin
380 mg of 6-O-methyl erythromycin are suspended in 3 cm 3 of water. 0.3 ml of 22% hydrochloric acid is added. The reaction mixture is stirred for 2 hours.

 Bitter at basic pH (> 8) by adding a few drops of ammonia at 20 ° C, and then diluted with 5 cm3 of ethyl acetate.

The aqueous phase is saturated with sodium chloride, decanted and extracted with ethyl acetate. It is dried over magnesium sulphate and the solvent is evaporated off. 350 mg of crude product is obtained which is chromatographed on silica, eluting with ethyl acetate-triethylamine (96-4). 200 mg of desired product is obtained.

IR spectrum (CHC13 on Nicolet)
OH: 3450 cm 1
C = O: 1725, 1689 cm -1
Mass Spectrum (FAB) (M + H) +: 590+
STAGE B: 2'-O-acetyl 3-O-diene (2,6-dideoxy-3-C-methyl-3-O-methyl-L-ribo-hexopyranosyl) 6-O-methyl erythromycin
4 g of acetone, 310 g of the product of the preceding stage, 80 microliters of acetic anhydride and 90 mg of potassium carbonate are dissolved under stirring and under a nitrogen atmosphere. After 12 hours at room temperature, 20 microliters of acetic anhydride and 10 mg of potassium carbonate are added. It is stirred again for 12 hours at room temperature.

 Ice is added, stirred and extracted with methylene chloride. It is dried over magnesium sulphate and the solvent is evaporated off.

 The product obtained is chromatographed on silica eluting with ethyl acetate-triethylamine (96-4). The desired product is obtained.

ANALYSIS
Mass Spectrum (FAB) (M + H) +: 631+
STAGE C: 3-D ((2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-hexopyranosyl) oxy] 6-O-methyl-3-oxo-erythromycin
Stage C1: Oxvdation
5 g of methylene chloride, 420 mg of the product of the preceding stage, 0.84 cm 3 of dimethyl sulfoxide and 0.84 g of 1- [3- (dimethylamino) propyl] 3-ethyl carbodiimide hydrochloride are dissolved in methylene chloride (5 cc). The resulting solution is stirred for 4 hours at room temperature.

 4 cm3 of water are added to the solution. Stirred 10 minutes and taken up with 20 cm3 of methylene chloride. Wash with water. It is dried over magnesium sulphate and the solvents are evaporated.

 The product obtained is chromatographed on silica eluting with a mixture of isopropyl ether and triethylamine (9-1). 130 mg of desired product is obtained.

Stace C2: Hydrolysis
By operating as in stage C2 of Example 1, starting from 130 mg of the product prepared above, after chromatography on silica (eluent: isopropyl ether-triethylamine (9-1)), 100 mg of desired product is obtained.

ANALYZES
IR: (CHC13 on Nicolet)
OH: 3475 cm-1
C = O: 1745, 1714, 1689 cm -1
SM: (M + H) + = 588+
NMR: (CDCl3, 300 MHz, 6 ppm) 3.86 (H2), 2.6 (H4), 1.35 (6-CH3), 2.7 (6-OCH3), 3.1 (H8), 2.97 (H10), 3.91 (H11), 1.22 (H12) 5.12 (H13), 0.86 (H15) 432 (H1), 3.18 (H'2), 246 (H); 3), 2.26 (N-CH 3), 3.57 (H, 5).

alpha = +21 (c = 0.5, CHCl3)
EXAMPLE 4: 9- [O - [(2-methoxyethoxy) methyl] oximes of 3 of [(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6- O-methyl 3 - [(phenylmethoxy) imino] erythromycin
500 mg of the product prepared in Example 2 are dissolved in 10 cm of ethanol. 172 microliters of triethylamine and 543 mg of O-benzylhydroxylamine hydrochloride are added. We bring to reflux. Reflux is maintained for 4 days. 172 microliters of triethylamine and 543 mg of O-benzyl hydroxylamine hydrochloride are added. Reflux is maintained for a further 3 days. The reaction medium is filtered. The solvents are evaporated. The residue is taken up in methylene chloride and with water. It is neutralized with ammonia.

Decanted, the aqueous phase is extracted with methylene chloride. The organic phases are combined, washed with water, dried over magnesium sulphate, filtered and concentrated to dryness. 800 mg of an oil are obtained which is chromatographed on silica, eluting first with ethyl acetate alone and then with an AcOEt / TEA mixture (99-1). 500 mg of a solid are recovered which is purified by preparative HPLC.

Eluent: acetonitrile-ammonium acetate 0.2M (4-1)
Recovering: 130 mg of the desired product.

NMR: (CDCl 3) 300 MHz 0.86 (t) ppm (ethyl CH 3), 0.90 to 1.45 (the other methyls), 2.27 (s) (N (Me) 2), 2.90 ( dq) (H1o) 2.30 (m) (H31), -3.28 (m) (H4 or H5, shielded), 4.52 (q) (H2), 2.70 (s) (6-OMe) ), 3.54 (m) and 3.76 (m) (MEM OCH 2 CH 2 O), 5.13 (MEM OCH 2 O and OCH 2 O), 4.00 (s wide) (H 11), 4.59 (d) ( H1,), 3.18 (dd) (H2,), 4.01 (d) (H5), 5.29 (dd) (H13), -7.31 (phenyl).

Mass Spectrum: Molecular peak (M + H) + = 796+
IR spectrum: (CHC13 on Nicolet)
OH: 3600 cm 1 + complex partner
C = O: 1730 "
C = N: 1636
1606 "
Aromatic: 1494 "
EXAMPLE 5: 9-LO - ((2-Methoxyethoxy) methyl] oxime of 3 (2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy] -3-hydroxyimino ) 6-O-methyl erythromycin
110 mg of the product prepared in Example 4 are dissolved in 12.5 cm 3 of ethanol. 52 mg of 10% palladium on activated charcoal are added. It is kept under hydrogen pressure for 2 days. We filter. This is evaporated. A product is obtained which is purified by chromatography on silica eluting with isopropyl ether-methanol-triethylamine (90-55). 39 mg of desired product (1 isomer) is recovered.

NMR: (CDCl3) 300 MHz 0.87 (t) ppm (ethyl CH3), 0.99 (d) 1.18 (d) 1.26 (d) 1.40 (d) (the other methyl), 1 , 23 (s) (12-Me), 1.36 (s) (6-Me), 2.23 (s) (N (Me) 2), 2.90 (dq) (ho), 2.30 (m) (H3, + 1 other H), 4.49 (q) (H2), 2.86 (s) (6-OMe), 3.38 (s) (OMe of MEM), 3.54 ( m) and 3.76 (m) (MEM OCH2CH2O), 5.15 (MEM OCH2O), 4.56 (d) (H1), 3.27 (dd) (H2,), 4.05 (m.p. s large) 4.20 (d) (H5 and
H1l), 5.31 (dd) (H13), 3.31; 4.39 (s); 1.80 (mobile H),
MS: M + molecular peak = 705+
IR: (CHC13 on Nicolet)
OH: -3590 cm 1 + associate
C = O: 1725
EXAMPLE 6 9- (O- <2-nieethoxyethoxy) methyl oximes of 3 (2,6-dideoxy-3-C-methyl-3-O-methyl-L-ribo-hexopyranosyl) oxy] -2-methyl O-methyl 3-oxo erythromycin
STAGE A: 9'-Oacetyl 3-de [(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) - [- [(2-methoxyethoxy) methyl] oxime] oxy] 2-methyl 6-O-methyl-3-oxo-erythromycin
0.1 g of the product prepared in Example 2, Stage B and 17 microliters of methyl iodide are dissolved in 1 cm3 of methylene chloride. 0.046 g of tetrabutylammonium hydrogen sulfate, 0.20 g, is then added. cm3 of water and 0.27 cm3 of a normal solution of sodium hydroxide. Stirred for 5 hours. It is extracted with methylene chloride. Wash with water. The organic phases are combined, the dry ones. We shoot. It is evaporated to dryness under reduced pressure. It is taken up in ethyl acetate and filtered. The filtrate is evaporated to dryness. 130 mg of product are obtained which is chromatographed on silica eluting with ethyl acetate-triethylamine (98-2). 49 mg of desired product is obtained rf = 0.2.

ANALYZES
NMR: (CDCl3, 300 MHz)
We note the disappearance of the proton at 2 and a modification of the proton H4.

0.85 ppm (CH3 (-CH2)), 0.99 - 1.28 - 1.88 ppm (CH3 (-CH)), 1.25 - 1.36 - 1.50 ppm (CH3 (-C)) ), 2.03 ppm (OAc), 3.30 ppm (dq, J = 3 and 7 hz) (H4), 3.4 to 3.8 ppm (OCH2CH2O).

STAGE B: 9- (O - ((2-methoxyethoxy) methyl] oxime] 3-di ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl) oxy] 2 methyl 6-O-methyl-3-oxo-erythromycin
0.095 g of product prepared as in Stage A is stirred in 5 cm of methanol. The mixture is stirred for 24 hours at room temperature. 0.95 mg of product is obtained which is purified by chromatography on silica eluting with ethyl acetate-triethylamine (98-2). 46 mg of desired product is obtained.

ANALYZES
NMR: (CDCl3, 300 MHz)
We note the disappearance of the protons of the group "OAc".

0.85 ppm (CH 3 (-CH 2)), 0.99 - 1.18 - 1.23 - 1.35 ppm (CH 3 (
CH)), 1.26 - 1.32 - 1.37 - 1.52 ppm (CH 3 (-C)), 2.82 ppm (6).
OMe), 3.54 to 3.76 ppm (OCH2CH2O), 3.35 - 4.33 ppm (mobile H).

SM: (M + H) +: 705+
EXAMPLE 7: 11,12-cyclic carbonate of 3 - ((2,6-dideoxy-3-methyl-O-methyl-alpha-L-ribohexopyranosyl) oxy] 6-O-methyl-3-oxo-erythromycin
STAGE A: 2'-acetate 11,12-cyclic carbonate of 3-O-de (2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl) 6-O-methyl erythromycin
To a suspension of 876 mg of 2'-acetate 4 "- (phenylmethyl carbonate) 11,12-cyclic carbonate of 6-O-methyl erythromycin (obtained according to WR Baker, JD Clark, RL Stephens and
KH Kim, J. Org. Chem., 1988, 53, 2340-2345) in 25 cm3 of methanol, 952 microliters of 22% hydrochloric acid are added, the mixture is stirred for 16 hours at room temperature, the methanol is evaporated off, the medium is neutralized with 2N sodium hydroxide solution. The mixture is extracted with methylene chloride, dried, filtered and evaporated to dryness and the residue is chromatographed on silica, eluting with ethyl acetate-triethylamine (95-5) to obtain 463 mg of desired product.

NMR Spectrum: (CDCl3) 300 MHZ 0.87 (t) ppm (ethyl CH3), 1.28 (s) (6-Me), 0.94 (d) 1.11 (d) -1 , 19 (d) - 1.24 (d) - 1.25 (d) (other Me), 1.49 (s) (12-Me), 2.06 (s) (OAc), 2.26 ( s) (N (Me) 2), 2.5 to 2.75 (H 2, H 3 and H 8), 2.95 (q) (H 10), 2.92 (s) (6-OMe), 3.49 ( m) (H5, and H3), 3.70 (d, J = 2.5) (H5), 4.73 (s) (H11), 4.58 (d, J = 7.5) (H1, ), 4.75 (dd) (H2,), 5.13 (dd) (H13).

STAGE B: 2-deF (2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-O-methyl cyclic 11,12-cyclic carbonate 3-oxo erythromycin
To a solution of 368 mg of the product obtained in Stage A above, 962 microliters of dimethyl sulfoxide and 752 mg of 1-ethyl-3- (3-dimethylamino propyl) carbodiimide hydrochloride (EDAC) are added, the mixture is stirred for 20 minutes at room temperature. and added 742 mg of pyridinium trifluoroacetate and the stirring is continued for 16 hours. 10 cm3 of water are added, stirred and extracted with methylene chloride, washed with sodium bicarbonate solution, dried, filtered and evaporated to dryness. The residue is chromatographed on silica, eluting with ethyl acetate-triethylamine (98-2). 278 mg of desired product is obtained, used as such for the next stage.

STAGE C: 11,12-cyclic carbonate of 3 - ((2,6-dideoxy-3-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl) oxy) 6-O-methyl-3-oxo-erythromycin
16 mg at room temperature are stirred for 278 mg of the product obtained in Stage B, dissolved in 20 cm3 of methanol. The solvent is evaporated and the residue is chromatographed (245 mg to which 75 mg of a previous preparation are added) to silica, thus obtaining 254 mg of desired product which is crystallized from ether to give 176 mg of expected product.

[alpha] D + 63 (c = 0.45%, CHCl 3)
NMR Spectrum: (CDCl3) 400 MHz ppm 2.65 (s) (6-OCH3), 2.68 (m) (H8), 2.97 (q) (H10) I 3.04 (q) (H4) ), 3.18 (dd) (H2), 3.81 (q) (H2), 4.31 (d) (H1), 4.18 (d) (ho), 4.61 (H11) .

EXAMPLE 8 (9S) 3 - [(2,6-Dideoxy-3-C-methyl-3-O-methylalpha-L-ribo-hexopyranosyl] oxy) -9-deoxo-6-O-methyl-3-oxo piperidinyl) erythromycin
STAGE A: 9-deoxo 9-imino 6-O-methyl erythromycin
To a solution of 8.4 g of 6-O-methyl erythromycin 9-oxime (obtained according to EP 0180415) with 220 cm3 of methanol and 44 g of ammonium acetate, 45.1 cm3 of sodium chloride are added. 15% titanium. Stirred for 3 hours at room temperature, poured over 500 cm3 of methylene chloride. A solution containing 10% of potassium carbonate is added, filtered, decanted, washed with water, dried and evaporated to dryness. We obtain 7.08 g of the expected product, which is used as such for the next stage.

STAGE B: 9-amino 9-deoxo 6-O-methyl erythromycin
7.0 g of the product obtained in the preceding stage are dissolved in 140 cm3 of acetic acid and catalytically reduced in the presence of 700 mg of 80% platinum oxide under an atmosphere of hydrogen at a pressure of 1400 mbar. The absorption is complete, filtered, washed with methylene chloride and evaporated to dryness. It is taken up with methylene chloride, washed with sodium bicarbonate solution, dried and evaporated to dryness, giving 6.71 g of the expected product which is used as such for the next stage.

STAGE C: 9-amino-3-O-de (2,6-dideoxy-3-C-methyl-3-O-methylalpha-L-ribo-hexopyranosyl) 9-deoxo 6-O-methyl-erythromycin
The mixture is stirred for 5 hours at room temperature, 2 g of the product obtained above, with 40 cm3 of water and 1 cm3 of 22 ° hydrochloric acid. Sodium chloride is then added and then brought to pH 8-9 with ammonia. It is extracted with methylene chloride and brought to dryness under reduced pressure. The residue (2.2 g) is chromatographed on silica eluting with ethyl acetate-methanol-triethylamine (92-5-3). 1.22 g of the desired product are obtained, used as such for the next stage.

STAGE D: (9S) 3-O-de-2,6-dideoxy-3-C-methyl-3-O-methyl-alpha
L-ribo-hexopyranosyl) 9-deoxo 6-O-methyl-9- (1-piperidinyl) erythromycin
To a solution of 0.59 g of the product obtained in Stage C, in 2.8 cm3 of methanol, 0.28 cm3 of acetic acid and 0.6 cm3 of 50% glutaraldehyde in water are added, followed by 0.125 g. of sodium cyanoborohydride. It is stirred for 1 hour 30 minutes at room temperature. The reaction medium is poured into 90 cm 3 of an aqueous solution of monosodium phosphate at 5%, extracted with methylene chloride, dried, filtered and evaporated to dryness. 0.7 g of residue are obtained which is chromatographed on silica (eluent ethyl acetate-triethylamine (98-2)). 328 mg of desired product is obtained.

IR spectrum: (CHC13 on Nicolet)
OH complex 3490 - 3390 cm'l
C = O 1723 cm -1
NMR Spectrum: (CDCl3) 300 MHz 0.85 (t) ppm (ethyl CH3), 1.01 (s) (12-CH3), 1.28 (s) (6)
CH3), 2.72 (dq) (H2), 3.84 (d1) (H3), ~ 1.54 (m) (H4), ~ 3.39 (masked) (H5), 3.10 (s). ) (6-OMe), 5.02 (dd) (H13), 1.47 (m) and 1.89 (m) (ethyl CH2), 3.93 (s) (H11), 2.85-3 , 1 (m) (Hg and H1o), 2.65 (mixture) and 2.86 (mixture) (NCH2,) 4.62 (d) (H1,), 3.24 (dd) (H2,), 2.50 (m) (H3), 1.27 (m) and 1.66 (m) (CH2 at 4 '), 3.53 (m) (H5).

STAGE E: (9S) 2'-3-O-de-2,6-dideoxy-3-C-methyl-3-acetate
O-methyl-alpha-L-ribo-hexopyranosyl) 9-deoxo 6-O-methyl-9 (1-piperidinyl) erythromycin
To a solution of 160 mg of the product obtained in Stage D, in 9 cm3 of acetone is added 242.8 mg of potassium carbonate and 172.7 microliters of acetic anhydride. Stirred 72 hours at room temperature. The reaction medium is poured onto ice, extracted with ether, washed with sodium bicarbonate solution and then with water, dried and evaporated to dryness, 164 mg of the desired product is obtained.

IR spectrum: (CHC13 on Nicolet)
OAc 1743 cm 1 lactone 1723 cml
OH ~ 3520 cm -1
NMR spectrum: (CDCl 3) 250 MHz 0.84 (t) ppm (ethyl CH 3), 1.05 to 1.30 (CH 3 CH 3 CH), 2.11 (s) (OAc), 3.12 (ss) ) (6-OMe), ~ 5.01 (H13), 3.94 (br) (H11), 2.6 to 3.1 (CH2N and H2, Hg, H10), 4.85 (d) ( H1,), 4.65 (dd) (H2,), 1.44 (H5,).

STAGE F: (9S) 3-det (2,6-dideoxy) -3-C-methyl 3 acetate
O-methyl-alpha-L-ribopyranosyl) oxy] 9-deoxo 6-O-methyl-3-oxo-9- (1-piperidinyl) erythromycin
The procedure is as in Step B of Example 7, starting from 207 mg of product obtained as in Step E, using 489 microliters of dimethyl sulfoxide, 374 mg of (1-ethyl 3- (3-dimethylaminopropyl) carbodiimide] (EDAC) and 374 mg of pyridinium trifluoroacetate After chromatography on silica (eluent isopropyl ether-methanol-triethylamine (955-5)) 120 mg of the expected product is obtained, used as such for the next stage.

STAGE G: (9S) 3-de (2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha
L-ribo-hexopyranosyl) oxy] 9-deoxo 6-O-methyl-3-oxo-9- (1-piperidinyl) erythromycin
The procedure is as in Step C of Example 7, from 120 mg of the product obtained in Step E, above. After chromatography on silica (eluent isopropyl ether-methanoltriethylamine (95-5-5)) and then Microbondapack C18 eluent acetonitrile-water (80-20) (with 0.075 t of trifluoroacetic acid), 70 mg of the desired product is obtained.

Ealpha] D + 39 (c = 1% CHCl 3)
NMR spectrum: (CDCl3> 300 MHz 0.88 (t) ppm (ethyl CH3), 1.08 (s) (12-Me), 1.23 (s) (6-Me), 1.01 to 1 , 28, 1.44 (d) (CH3 CH3 CH), 2.34 (s) (N (Me) 2), 2.5 to 2.8 (CH2N, H3, and others), 3.13 (s). ) (OMe), 3.51 (m) (H5, and
H2,), 3.22 (s) (H11,), 3.98 (q> (H2), 4.35 (d> (H1 ') 4.78 (d) (H5'), 5.05 ( dd) (H13,).

EXAMPLE 9 (9S) 9-amino-3-deE (2,6-dideoxy-3-C-methyl-3-methyl-alpha-L-ribo-hexopyranosyl) oxy] -9-deoxo-6-O-methyl-3-oxo-erythronylcin
STAGE A: 2 '- (phenylmethyl carbonate) 3-O-de (2,6-dideoxy)
C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl) 9-deoxo 6-methyl-9 - [[(phenylmethoxy) carbonyl] amino] erythromycin
To a mixture of 1.5 g of product obtained in Stage C of Example 8 with 11 cm 3 of dioxane and 0.88 g of potassium carbonate, 0.8 cm 3 of benzyl chloroformate is added. It is stirred for 5 hours at room temperature and 0.44 g of potassium carbonate and 0.4 g of benzyl chloroformate are added.

Stirring is continued for another 2 hours, taken up with methylene chloride, washed with water, dried and evaporated to dryness under vacuum. The residue is chromatographed (2.5 g) on silica (eluent: methylene chloride-methanol-triethylamine (96-3-1)). 1.71 g of the desired product are obtained, used as such for the next stage.

STAGE B: (9S) 2 '- (phenylmethyl carbonate) of 3 - ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl) oxy] -deoxo 6- O-methyl 3-oxo 9 - [[(phenylmethoxy) carbonyl] amino] erythromycin
The procedure is as in Step B of Example 7, from 2 g of the product obtained as in Step A above, using 1.5 cm3 of dimethylsulfoxide, 1.8 g of EDAC and 1.8 g of trifluoroacetate. pyridinium. After chromatography on silica (eluent methylene chloride-methanol (97-3), 757 mg of desired product is obtained, used as such for the next stage.

STAGE C: (9S) 3-de (2,6-Dideoxy-3-C-methyl-3-O-methyl-alpha
L-ribo-hexopyranosyl) oxy] 9-deoxo 6-O-methyl-3-oxo-9 ([(phenylmethoxy) carbonyl] amino] erythromycin
The procedure is as in Step C of Example 7, from 0.75 g of the product obtained above. After chromatography on silica, 372 mg of the desired product is collected, used as such for the next stage.

STAGE D: (9S) 9-Amino-3 - ((2,6-dideoxy-3-C-methyl-3-methyl-alpha-L-ribohexopyranosyl) oxy) -9-deoxo-6-O-methyl-3-oxo-erythromycin
The mixture is stirred for 24 hours under hydrogen pressure (1.5 bar), 150 mg of the product obtained in Stage E, 6 cm 3 of acetic acid and 150 mg of 9.5% palladium on activated charcoal. Filtered, washed with methanol and evaporated to dryness. The residue is taken up with methylene chloride, washed with 2N sodium hydroxide solution and then with water, dried and evaporated to dryness. After chromatography on silica (eluent chloroform-methanol-ammonia (9-1-0.1)) 50 mg of the desired product is obtained.

NMR spectrum: (CDCl3> ppm 1.88 (H8), 1.94 (H10), 2.48 (H3), 2.55 (Hg), 3.08 (H4), 3.28 (H2, > 3.65 (H11) 3.8 (H2), 4.3 (H1 '), 5.13 (H13).

EXAMPLE 10 11,12-dideoxy-3 - [(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy] -6-O-methyl-3-oxo - 12,11-toxycarbonyl [(4-phenylbutyl) iminol] erythromycin
Step A: 11,12-Dideoxy-3-O-de (2,6-dideoxy-3-Cmethyl-3-O-methyl-alpha-L-ribohexopyranosyl) -6-O-methyl-12,11-2-acetate - [oxycarbonyl [(4-phenylbutyl) imino]] erythromycin
649 mg of 4'- (phenylmethyl carbonate) of 11,12-dideoxy-6-O-methyl-12,11- [oxycarbonyl E (4-phenylbutyl) imino]] erythromycin are introduced, the preparation of which is described. hereinafter in a solution containing 13 cm3 of methanol and 0.23 cm3 of concentrated hydrochloric acid.The reaction mixture is stirred for 48 hours at room temperature, the methanol is evaporated under reduced pressure and 10 cm3 of water are added. ethyl acetate is ice-cold, neutralized and decanted The aqueous phase is extracted with ethyl acetate, washed and dried to give 626 mg of a product which is chromatographed on silica: eluent ethyl acetate , methanol (95-5), to give 339 mg of the desired product.

IR spectrum in CHCl3
OH 3618cm 1 3594cm ~
C = O 1740cm ~ 1711cm ~ l
C6H5C 1492cm-1
Spectrum of molecular peak mass 789.6 = MH +
NMR spectrum CDCl3 300MHz 2.45-2.8 (m) CH2Ph + H2 + H8 + H3, ax 3.42 (dd) H3 3.65 (m) CH2N-C = O 4.76 (dd) H2, ax Aromatic 7,11-7,28
Stage B: 1112-dideoxy-3 - [(2,6-dideoxy-3-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy] -6-O-methyl-2-2'-acetate, 11- [oxyzarbonyl [(4-phenylbutyl) imino]] erythromycin
A solution containing 300 mg of product prepared in the preceding stage and 2.15 cm 3 of methylene chloride in a suspension containing 0.4 cm 3 of DMSO, 1.6 cm 3 of methylene chloride and 438 mg of toluene are added at 21 ° C. EDAC. The reaction mixture is stirred at room temperature for 30 minutes. It is cooled to 15 ° C. and a solution of 438 mg of pyridinium trifluoroacetate in 1.5 cm 3 of methylene chloride is introduced. Washed with sodium bicarbonate solution and then with water, dried and evaporated to dryness. 348 mg of a product is obtained which is used as such in the next stage. rf = 0.13.

3,00 H4 3,89 (q) H2 3,66 Cm >

7,10 à 7,30 H aromatique 4,74 (dd) H2,
STADE C : 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-méthyl-3-O- méthyl-alpha-L-ribohexopyrannosyl) oxy] > -6-O-méthyl-3-oxo- 12,11-[oxycarbonyl[(4-phénylbutyl)imino]]-érythromycine
On met en suspension 278 mg de produit préparé au stade précédent dans 3 cm3 de méthanol. On maintient le mélange réactionnel sous agitation pendant 60 heures à la température ambiante. On chromatographie sur silice en éluant avec le mélange acétate d'éthyle-méthanol (95-5). On évapore le méthanol sous pression réduite.On obtient 280 mg d'un produit que l'on chromatographie avec un mélange chlorure de méthylène méthanol (9-1). On obtient 133mg de produit recherché.NMR CDC13 2.07 (s)

3.00 H4 3.89 (q) H2 3.66 Cm>

7.10 to 7.30 H aromatic 4.74 (dd) H2,
STAGE C: 11,12-dideoxy-3 - [(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy] -6-O-methyl-3- oxo-12,11- [oxycarbonyl [(4-phenylbutyl) imino]] - erythromycin
278 mg of product prepared in the preceding stage are suspended in 3 cm 3 of methanol. The reaction mixture is stirred for 60 hours at room temperature. Chromatography on silica eluting with ethyl acetate-methanol (95-5). The methanol is evaporated under reduced pressure. 280 mg of a product is obtained which is chromatographed with a mixture of methylene chloride (9-1). 133 mg of desired product is obtained.

IR spectrum
OH: 3440cm 1
C = O: 1747cm ~
1711cm-1
NMR 2.49 (dd) H3, 3.20 dd H2, 3.10 H4 3.86 H2 Preparation of the starting material of Example 10.

 830 mg of 4-phenylbutylamine are introduced under an argon atmosphere in a suspension containing 1.17 g of 2'-acetate-12- (1H-imidazole-1-carboxylate) -4 "- (phenylmethyl carbonate) of 10, 11-didehydro-11-deoxy-6-O-methylerythromycin prepared as described in J. Org CHem. (1988) 53, 2340-2345, 2.7 cc of methylene cyanide and 0.27 cc of water The reaction mixture is stirred for 2 hours at 50 ° C. 150 cm 3 of methylene chloride are added and the mixture is cooled in an ice-bath and 30 cm 3 of a 0.5 M sodium hydrogen phosphate solution are added. decanted, extracted with methylene chloride, washed, dried and evaporated to dryness The product obtained is chromatographed on silica: eluent ethyl acetate-methanol (95-5) to obtain 952 mg of the desired product.

IR spectrum
C = O 1739 cm -1
1711 cm'l
C6H5C 1495 cm-
Ultraviolet spectrum inf: 216 nm E1 = 103 inf: 259 nm E1 = 4.5 inf: 266 nm E1 = 3
Molecular peak mass spectrum = 1081.7 = MH +
NMR spectrum
In CDCl3 on 400 MHz.

3,60 H1, 710 à 7,25 C6H5 (CH2)4 7,35 C6H5 CH2O
EXEMPLE 11 : 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-méthyl-3-O- méthyl-alpha-L-ribohexopyrannosyl) oxy]-6-O-méthyl-3-oxo- 12,11-[oxycarbonyl[[2-[méthyl(phénylméthyl)amino]éthyl] imino]] érythromycine
Stade A :: 11,12-dideoxy-3-O-de(2,6-dideoxy 3-C-méthyl 3
O-méthyl-alpha-L-ribohexopyranosyl)-6-O-méthyl-12,11-toxyCar- bonyl[[2-[méthyl(phénylméthyl)amino]éthyl]imino]] érythromycine
On maintient sous agitation pendant une heure à la température ambiante 460 mg du produit préparé ci-après (préparation du produit de départ de l'exemple 11), 9,2 cm3 de méthanol et 0,23 cm3 d'une solution d'acide chlorhydique concentré, puis 48 heures à la température ambiante. On reprend le résidu à l'eau puis au chlorure de méthylène. On amène à PH basique.2.5 to 2.8 N CH2C6HsH8H3 • 3.66

3.60 H1, 710 to 7.25 C6H5 (CH2) 4 7.35 C6H5 CH2O
EXAMPLE 11: 11,12-Dideoxy-3 - [(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy] -6-O-methyl-3-oxo 12,11- [oxycarbonyl [[2- [methyl (phenylmethyl) amino] ethyl] imino]] erythromycin
Step A :: 11,12-dideoxy-3-O-de (2,6-dideoxy-3-C-methyl)
O-methyl-alpha-L-ribohexopyranosyl) -6-O-methyl-12,11-toxycarbonyl [[2- [methyl (phenylmethyl) amino] ethyl] imino]] erythromycin
460 mg of the product prepared below (preparation of the starting material of Example 11), 9.2 cm 3 of methanol and 0.23 cm 3 of an acid solution are stirred at room temperature for one hour. concentrated hydrochloric acid, then 48 hours at room temperature. The residue is taken up in water and then in methylene chloride. We bring to basic pH.

After settling, the aqueous phase is extracted with methylene chloride.

Wash, dry and evaporate to dryness. 432 mg of a product is obtained which is chromatographed on silica: eluent ethyl acetate-methanol (9-1). 312 mg of the desired product is thus obtained.

4,74 H2,
Stade B : 2'-acétate de 11,12-dideoxy-3-de[(2,6-dideoxy-3-Cméthyl 3-O-méthyl-alpha-L-ribohexopyranosyl) oxy]-6-O-méthyl- 12,11-[oxycarbonyl[2-[méthyl(phényl méthyl) amino] éthyl] imino]] erythromycine
On ajoute à 20"C 200 mg du produit préparé au stade précédent en solution dans 1,4 cm3 de chlorure de méthylène dans une suspension renfermant 286 mg d'EDAC, 0,26 mg de DMSO et 1,2 cm3 de chlorure de méthylène.On maintient le mélange réactionnel sous agitation pendant 30 minutes à la température ambiante. On refroidit à 14"C et introduit à cette température une solution renfermant 286 mg de trifluoroacétate de pyridinium et 1,3 cm3 de chlorure de méthylène. On agite pendant 30 minutes à 15"C et laisse revenir à la température ambiante. On traite avec du bicarbonate de sodium, dilue au chlorure de méthylène, lave, sèche et évapore à sec. On obtient 350 mg du produit recherché brut que l'on purifie par chromatographie sur silice éluant : acétate d'éthyle-méthanol (95-5).On obtient 145 mg de produit recherché
Spectre W dans EtOH max 258 nm e.= 400 dans EtOH-NaOH 0,1N max 292 nm e.= 20100
Présence B ceto ester
RMN 2,17(s) 2,25(s)

3,48(d)-3,70(d)N-CH2- 3,80 H2 3,87

4,74(dd) H2, 7,17 à 7,30 aromatiques
Stade C : 11,12-dideoxy-3-det(2,6-dideoxy-3-C-méthyl 3
O-méthyl-alpha-L-ribohexopyranosyl) oxy] 6-O-méthyl-3-oxo 12,11- [oxycarbonyl t[2-[méthyl(phénylmethyl) amino] éthyl] imino] érythromycine
On maintient sous agitation pendant une nuit à la température ambiante 106 mg du produit préparé au stade précédent et 6 cm3 de méthanol. On maintient le mélange réactionnel pendant une nuit à la température ambiante.On évapore le méthanol. On obtient 106 mg d'un produit que l'on chromatographie sur silice éluant : acétate d'éthyle-triéthylamine (95-5) on obtient 55 mg du produit recherché.IR spectrum: OH: 3618 cm -1
3594
C = O: 1742 cm -1
1709 cm'l
NMR in CDCl3 over 300 MHZ 1.42 (s) 6Me 1.24 (s) 12Me 2.20 (s) 3.48 (d) -3.77 (d) 3.80 (m) -3.95 ( m) 3.40

4.74 H2,
Step B: 11,12-Dideoxy-3 - [(2,6-dideoxy-3-Cmethyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy] -6-O-methyl-2'-acetate 11- [oxycarbonyl [2- [methyl (phenyl methyl) amino] ethyl] imino]] erythromycin
200 mg of the product prepared in the preceding stage in solution in 1.4 cm 3 of methylene chloride in a suspension containing 286 mg of EDAC, 0.26 mg of DMSO and 1.2 cm 3 of methylene chloride are added at 20 ° C. The reaction mixture is stirred for 30 minutes at room temperature, cooled to 14 ° C. and a solution containing 286 mg of pyridinium trifluoroacetate and 1.3 cm 3 of methylene chloride is introduced at this temperature. It is stirred for 30 minutes at 15 ° C. and allowed to return to ambient temperature, treated with sodium bicarbonate, diluted with methylene chloride, washed, dried and evaporated to dryness to give 350 mg of the crude desired product which is obtained. purified by chromatography on silica eluent: ethyl acetate-methanol (95-5). 145 mg of desired product is obtained
W spectrum in EtOH max 258 nm e = 400 in EtOH-NaOH 0.1N max 292 nm e = 20100
Presence B ceto ester
NMR 2.17 (s) 2.25 (s)

3.48 (d) -3.70 (d) N-CH2- 3.80 H2 3.87

4.74 (dd) H2, 7.17 to 7.30 aromatics
Stage C: 11,12-dideoxy-3-det (2,6-dideoxy-3-C-methyl)
O-methyl-alpha-L-ribohexopyranosyl) oxy] 6-O-methyl-3-oxo-12,11- [oxycarbonyl] [2- [methyl (phenylmethyl) amino] ethyl] imino] erythromycin
106 mg of the product prepared in the preceding stage and 6 cm 3 of methanol are stirred overnight at room temperature. The reaction mixture is kept overnight at room temperature. The methanol is evaporated. 106 mg of a product which is chromatographed on silica eluent: ethyl acetate-triethylamine (95-5) gives 55 mg of the desired product.

3,00 à 3,24 H2, et H4 3,57 (s) H11 4,23 (d) et 4,28 (d) H1. et H5 2,48 H3, H8 et CH29
Préparation du produit de déPart de l'exemple 11 11,12-dideoxy-6-O-méthyl-12,11-[oxycarbonyl[[2-[méthyl(phényl- méthyle amino] éthyl] imino]] érythromycine
Stade A : : 11,12-dideoxy-6-O-méthyl-12,11-[oxycarbonyl[[2- t(phénylméthyl) amino] éthyl] imino]] érythromycine
On introduit 1,1 g de 2'-acétate-12-(lH-imidazole-l- carboxylate > -4"- (phénylméthyl carbonate > de 10,11-didehydro- ll-deoxy-6-O-méthyl-érythromycine, dans un mélange de 2,7 cm3 de cyanure de méthyle et 0,27 cm3 d'eau. On introduit 1,8 cm3 de N-benzyléthylènediamine. On maintient le mélange réactionnel sous agitation à 50 C pendant 5 heures. On dilue au chlo rure de méthylène et refroidit au bain de glace. On ajoute 30 cm3 d'une solution 0,5 M de phosphate monosodique. On décante, extrait au chlorure de méthylène, lave, sèche et évapore à sec.On obtient 1,6 g de produit que l'on purifie par chromatographie sur silice éluant acétate d'éthyleméthanol (98-2). On obtient 800 mg de produit recherché.Analysis for C41H65 N3O10 = 759-99 NMR 1.34 (s) 12Ms 1.48 (s) 6Ms 2.18 (s) 2.27 (s)

3.00 at 3.24 H 2, and H 3.57 (s) H 11 4.23 (d) and 4.28 (d) H 1. and H5 2.48 H3, H8 and CH29
Preparation of the product of Example 11 11,12-dideoxy-6-O-methyl-12,11- [oxycarbonyl [[2- [methyl (phenylmethylamino) ethyl] imino]] erythromycin
Step A:: 11,12-dideoxy-6-O-methyl-12,11- [oxycarbonyl [[2- (phenylmethyl) amino] ethyl] imino]] erythromycin
1.1 g of 2'-acetate-12- (1H-imidazole-1-carboxylate) -4- (phenylmethyl carbonate) 10,11-didehydro-11-deoxy-6-O-methyl-erythromycin are introduced, in a mixture of 2.7 cm 3 of methyl cyanide and 0.27 cm 3 of water, 1.8 cm 3 of N-benzylethylenediamine are introduced and the reaction mixture is stirred at 50 ° C. for 5 hours. Methylene chloride and cooled in an ice bath, 30 cm3 of a 0.5 M solution of monosodium phosphate are added, decanted, extracted with methylene chloride, washed, dried and evaporated to dryness. product which is purified by silica chromatography eluting with ethylmethanol acetate (98-2) to obtain 800 mg of desired product.

Physical Analvses
Infra-red spectrum
C = O 1739 cm 1
1710 cm 1
C6H5 1494 cm 1
Mass spectrum
Molecular peak = 1082 = MH +
NMR spectrum
In CDCl3 over 300 MHZ 3.07 (q) H10 3.34 (s) 3 "0Me 3.61 (s) H11 3.83 (m) CH2N-C = O and N-CH2Ph 7.15-7.35 aromatic N-CH2Ph
Stage B: 11,12-dideoxy-6-O-methyl-12,11- [oxycarbonyl [[2- [methyl (phenylmethyl) amino] ethyl] imino]] erythromycin
50 cm3 of a solution of 37% formic aldehyde and formic acid are added to a solution containing 13 cm 3 of methylene chloride and 0.60 g of the product prepared in the preceding stage. The reaction mixture is stirred with stirring. for 4 hours at room temperature and then at 70 ° C for 7 hours, diluted with methylene chloride, added water and neutralized with sodium bicarbonate.

Decant, wash, dry and evaporate to dryness. Chromatography on silica: eluent ethyl acetate-methanol (95-5). 480 mg of desired product is obtained.

Analvses
IR spectrum
C = O 1737 cm -1
1708 cm -1
C6H5 1494 cm -1
SM
MH + = 1096.9+
NMR Spectrum: 1.12 (s) 12 Me 1.40 (s) 6 Me 2.19 CH3-N <2.96 (s) 60 Me 3.62 (sl) H11 4.30 (m) H5 "ax 4.73 (dd) H2 "ax 7.15 to 7.39 aromatics 2.87 H 2
As examples of the products of formula (I), mention may be made of the following products, corresponding to the product of Example 1 or the product of Example 10, in which X and X 'have the following meaning

<tb><SEP> = NO <SEP> R = H, CH3
<tb><SEP> R = H, <SEP> CH3
<tb><SEP>><SEP> RH, <SEP> CH3
<tb><SEP> NO
<tb> CO <SEP> R
<tb> C <SEP> = <SEP> NO <SEP> 2 <SEP> = H, <SEP> CH3
<tb><SEP> R <SEP> R "<SEP> remains <SEP> acid <SEP> amine
<tb><SEP> R <SEP> R
<tb> = NOMNN <SEP> OH
<tb><SEP> R
<tb><SEP> Nv
<tb> = <SEP> NÓ <SEP> mO
<tb><SEP> R / NS
<tb> NO <SEP> R = H.CH
<tb><SEP> NO ~ <SEP> | <SEP> N <SEP> ~
<tb><SEP> R <SEP> | <SEP> RH, <SEP> CH3
<Tb>

EXAMPLES of pharmacological compositions
Compounds containing
Product of Example 1 ........................ 150 mg
Excipient qsp ............................... 1 g
Detail of the excipient: starch, talc, magnesium stearate.

Product of Example 7 ........................ 150 mg
Excipient qsp ............................... 1 g
Detail of the excipient: starch, talc, magnesium stearate.

Product of Example 10 ....................... 150 mg
Excipient qsp ............................... 1 g
Detail of the excipient: starch, talc, magnesium stearate.

PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION.

A) In vitro activity.

Dilution method in a liquid medium.

 A series of tubes is prepared in which the same amount of sterile nutrient medium is distributed. Increasing amounts of the test product are dispensed into each tube, and then each tube is inoculated with a bacterial strain.

 After incubation for twenty-four hours in an oven at 37 ° C, inhibition of growth is assessed by transillumination, which makes it possible to determine the minimum inhibitory concentrations (C.M.I.) expressed in micrograms / cm3.

 The following results were obtained 1) Product of Example 1 - Reading after: 24 h.

Staphylococcus aureus 011UC4 0.08
Staphylococcus aureus 011HT17 0.08
Staphylococcus aureus 011G0251 1,2
Streptococcus pyogenic S 0.01
group A 02AlUCi
Streptococcus agalactiae S 0.01
group B 02BlHTl
Streptococcus sp 0.02
group C 02COCB3
Streptococcus faecalis 0.04
group D 02D2UC1
Streptococcus faecium 0.04
group D 02D3HT1
Streptococcus sanguis # 0.01
02sgGR18
Streptococcus mitis 0.02 02mitCB1
Streptococcus mitis 0.3
02mitGR16
Streptococcus pneumoniae 0.15
032UC1
Streptococcus pneumoniae 2,5
030SJ1
Streptococcus pneumoniae 0.15 030SJ5 2) Product of ltexemDle 2 - Reading after: 24 h.

Staphylococcus aureus 0llUC4 0.3
Staphylococcus aureus OllHT17 0.3
Staphylococcus aureus 011G0251 1.25
Streptococcus pyogenes 0.15
group A 02AlUCl
Streptococcus agalactiae 0.08
group B 02BlHTl
Streptococcus sp 0.3
group C 02COCB3
Streptococcus faecalis 0.6
group D 02D2UC1
Streptococcus faecium 0.6
group D 02D3HT1
Streptococcus sp 0.3
group G 02GOGR5
Streptococcus sanguis 0.3
02sgGR18
Streptococcus mitis 0,15
02MitCB1
Streptococcus sp 5.0
group C 02COCB1 3) Product of Example 7 - Reading after: 24 h.

Staphylococcus aureus 011UC4 0.15
Staphylococcus aureus 011HT17 0.08
Staphylococcus aureus 0llG0251 0.3
Streptococcus pyogenes S 0.02
group A 02AlUC1
Streptococcus agalactiae S 0.02
group B 02BlHTl
Streptococcus sp 0.04
group C 02COCB3
Streptococcus faecalis 0.04
group D 02D2UC1
Streptococcus faecium 0.04
group D 02D3HT1
Streptococcus blood 2.5
02sgGR18
Streptococcus mitis <0.02
02mitCB1
Streptococcus pneumoniae # 0.02
032UC1
Streptococcus pneumoniae 0.3
030SJ5 4) Product of Example 10 - Reading after: 24 h.

Bacterial strains at GRAM +
Staphylococcus aureus 011UC4 0.04
Staphylococcus aureus 011HT17 0.04
Staphylococcus aureus 0llG0251 0.04
Staphylococcus epidermidis 012GOllC 0.04
Streptococcus pyogenes <0.02
group A 02AlUCi
Streptococcus agalactiae <0.02
group B 02BlHTl
Streptococcus sp S 0.02
group C 02COCB3
Streptococcus faecalis S 0.02
group D 02D2UC1
Streptococcus faecium # 0.02
group D 02D3HT1
Streptococcus sp # 0,02
group G 02GOGR5
Streptococcus sanguis 0.3
02sgGR18
Streptococcus mitis # 0,02 02mitCB1
Streptococcus agalactiae 0.3
group B 02BlSJ1
Streptococcus sp 0.15
group C 02COCB1
Streptococcus sanguis 0.08
02sgGR10
Streptococcus mitis 0,15
02mitGR16
Streptococcus pneumoniae # 0.02
032UC1
Streptococcus pneumoniae 0.3 030SJ1
Streptococcus pneumoniae 0.04
030SJ5
Bacterial strains at GRAM
Haemophilus influenzae 2,5
351HT3
Haemophilus influenzae 2,5
351CB12
Haemophilus influenzae 5
35lCAl
Haemophilus influenzae 5
351GR6
B) In vivo activity.

Experimental infection with Stahvlococcus aureus
The action of the product of Example 2 on experimental Staphylococcus aureus infection of the mouse was studied.

Lots of ten male mice weighing 18 to 20 g were infected by intraperitoneal injection of 0.5 cm 3 of a 22 hour broth culture at pH 7 of the
Staphylococcus aureus n 54 146, diluted 1/6 with physiological saline.

 Oral infection was given at the time of infection and 4 hours after infection a determined amount of product.

The results obtained are as follows

<tb> MORTALITY <SEP> ANIMALS <SEP> I
<tb> I <SEP> I <SEP> I <SEP> I
<tb> I <SEP> DOSAGE <SEP> J1 <SEP> J2 <SEP> J3 <SEP> I <SEP> SURVIVORS <SEP> I
<tb> J <SEP> in <SEP> mg <SEP> 1 <SEP> 24 <SEP> h <SEP> 1 <SEP> 48 <SEP> h <SEP> 1 <SEP> 72 <SEP> h <SEP > I <SEP> AFTER <SEP> 3 <SEP> DAYS <SEP> J <SEP>
<tb><SEP> I <SEP> I <SEP> I <SEP> I
<tb> J <SEP> Control <SEP> 9 <SEP> I <SEP> I <SEP> 1 <SEP> 1/10 <SEP> I <SEP>
<tb> 0.1 <SEP> 1 <SEP> 7 <SEP> 1 <SEP> 3 <SEP> 1 <SEP> I <SEP> 0/10 <SEP> I
<tb> 0.3 <SEP> ss <SEP> 1 <SEP> J <SEP> 1 <SEP> J <SEP> 2 <SEP> J <SEP> 6/10 <SEP> I <SEP>
<tb> I <SEP> 1 <SEP> I <SEP> 0 <SEP> 1 <SEP> I <SEP> l <SEP> 10/10 <SEP> I <SEP>
<tb> 3 <SEP> 3 <SEP> J <SEP> 0 <SEP> 1 <SEP> 1 <SEP> 1 <SEP> 10/10 <SEP> I <SEP>
<Tb>
DP50 Total administration: 12.49 mg / kg (Reed and Muench method).

 Conclusion: the products of the invention have good antibiotic activity in vivo.

Claims (30)

1) The compounds of formula (I)

 wherein either X and X 'together with the carbon atom to which they are attached form a group C = O or C = NOR, wherein R represents - a hydrogen atom, - a heterocyclic radical containing at least one nitrogen atom and optionally another heteroatom, mono- or bicyclic, saturated or unsaturated, aromatic or nonaromatic having up to 12 members, optionally substituted on the nitrogen atom by an alkyl radical containing up to 4 carbon atoms a linear, branched or cyclic alkyl, alkenyl or alkynyl radical containing up to 18 carbon atoms optionally substituted by one or more groups  . hydroxyl,  . halogen,  . cyano,  . nitro, amidinyl,  . guanidinyl,  . heterocyclic, as defined above,  . alkyloxy, alkenyloxy or alkynyloxy having not more than 6  carbon atoms,  alkylthio, alkenylthio or alkynylthio having not more than 6  carbon atoms, the sulfur atom possibly being  oxidized to sulfoxide or sulfone,  . aryloxy, aralkyloxy,  . arylthio, aralkylthio, the sulfur atom being  oxidized to sulfoxide or sulfone (each of said alkyloxy, alkenyloxy, alkynyloxy, alkylthio, alkenylthio or alkynylthio, aryloxy, aralkyloxy, arylthio or aralkylthio radicals being optionally substituted by one or more of the following groups: hydroxy, alkyloxy, alkylthio having 1-6 carbon atoms, alkenylthio, alkynylthio having up to 6 carbon atoms, amino, monoalkylamino having up to 6 carbon atoms, dialkylamino having up to 12 carbon atoms, amidinyl radical, guanidinyl, heterocyclic radical as defined above, the aryloxy, arylthio, aralkyloxy and aralkylthio radicals being further optionally substituted by the methyl, ethyl, propyl, carbamoyl, aminomethyl, dimethylaminomethyl, aminoethyl, dimethylaminoethyl, carboxyl, methyloxycarbonyl or ethyloxycarbonyl radicals>

 in which R'1 and R'2, which may be identical or different, represent a hydrogen atom, a linear, branched or cyclic alkyl, alkenyl or alkynyl radical containing up to 18 carbon atoms, an aryl or aralkyl radical, each of these radicals R'1 and R'2 being optionally substituted with one or more hydroxyl, alkyloxy, alkenyloxy, alkynyloxy, alkylthio, alkenylthio or alkynylthio radicals containing up to 8 carbon atoms, amino, monoalkylamino containing up to 4 carbon atoms, carbon, dialkylamino containing up to 8 carbon atoms, cyano, free carboxyl, esterified or salified, acyl or carbamoyl, containing up to 8 carbon atoms, with a radical Si (alk) 3 or Si (Oalc) 3 in which alk represents an alkyl radical containing up to 4 carbon atoms, with a heterocyclic radical as defined above, or else R11 and R'2 together with the nitrogen atom to which they are attached form a mono or bicyclic heterocycle radical; , optionally containing another heteroatom, saturated or unsaturated, aromatic or nonaromatic, having up to 12 members a quaternary ammonium group,. 1,2-epoxyethyl or 2,2-dimethyl-1,2-epoxyethyl or a radical resulting from the opening of this group by a nucleophilic reagent,

Formed with the carbon which carries it and the carbon at 10, a double bond, where A represents a radical OR '4, R' 4 representing a hydrogen atom or forms with B a carbonate radical, where A represents a radical B represents a hydrogen atom or an OR4 radical, R4 representing a hydrogen atom or form with A a carbonate or carbamate radical, Y and Y 'identical or different from X and X' have the meaning of X and X '  - Ra and Rb identical or different from each other, representing a hydrogen atom or a hydrocarbon radical containing up to 18 carbon atoms, optionally containing one or more heteroatoms, optionally substituted with one or more functional groups, or with a heterocyclic radical containing at least one nitrogen atom and optionally another heteroatom chosen from unsaturated, aromatic, mono or bicyclic, mono or bicyclic, up to 12-membered aromatic or non-aromatic, optionally substituted on the nitrogen atom by an alkyl radical containing up to 4 carbon atoms, - Ra and Rb may optionally form with the nitrogen atom to which they are attached a heterocycle radical, containing at least one nitrogen atom and optionally a another heteroatom selected from oxygen, sulfur or nitrogen atoms, mono or bicyclic, saturated or unsaturated, aromatic or nonaromatic having up to 12 links, - Ra and Rb being able to form with the radical A a 9-N ring, a and X 'represents a hydrogen atom,

 n represents an integer from 0 to 6, or X represents a radical  salified, thiocyanate, acyl or carbamoyl, s. (CH2) nR ', R' representing the residue of an amino acid, and  . free or protected formyl, free carboxyl, esterified or  . aryl, aralkyl, aryloxy or aralkyloxy,  alkyloxy having not more than 6 carbon atoms,  wherein B1 represents either an alkyl radical or

R'5 and R'6 representing a group C = O forming with B a carbamate group, R'6 representing a hydrogen atom or an alkyl, aralkyl or alkyloxy radical having up to 12 carbon atoms or a grouping

 in which R12 and R13 represents a hydrogen atom, an alkyl radical containing up to 8 carbon atoms or forming with the nitrogen atom a heterocycle as defined above, n representing an integer between 1 and 6, or a radical

 Rg and R10 representing a hydrogen atom or an alkyl radical containing up to 8 carbon atoms, or forming with the nitrogen atom a heterocycle as defined above and n represents an integer between 1 and 6, R2 represents an alkyl radical containing up to 8 carbon atoms, or a radical CONH2 or CONHCOR11 or CONHSO2R11 in which R11 represents a hydrocarbon radical containing up to 18 carbon atoms optionally comprising one or more heteroatoms, R3 in the alpha or beta position represents a hydrogen atom or an alkyl radical, containing up to 8 carbon atoms or a radical

R7 and R8 identical or different representing a hydrogen atom or an alkyl or aralkyl radical, containing up to 18 carbon atoms, or forming with the nitrogen atom a heterocycle as defined above, and q represents a whole number between 1 and 6, where A represents a radical R14 and R15, identical or different, representing a hydrogen atom or an alkyl radical containing up to 8 carbon atoms or a heteroatom or an alkyl or alkyloxy radical containing up to 8 carbon atoms, Z represents a hydrogen atom or the remainder of a carboxylic acid containing up to 18 carbon atoms oximes that can represent X and X 'or Y and Y' can be of syn or anti configuration, as well as the addition salts with acids of the compounds of formula (I). 2) The compounds of formula (I) as defined in claim 1 in which X and X 'together with the carbon atom to which they are attached form a group C = NOR, R retaining the same meaning as in claim 1 . 3) The compounds of formula (I) as defined in claim 2 in which R represents an alkyl radical containing up to 6 carbon atoms substituted by a radical;

R'1 and R'2 retaining the same meaning as in claim 1. 4) The compounds of formula (I) as defined in claim 3 in which the radical R is a radical

R'1 and R'2 representing an alkyl radical containing up to 4 carbon atoms. 5) The compounds of formula (I) as defined in claim 4 in which R represents a (CH 2) 2 -N (CH 3) 2 radical. 6) The compounds of formula (I) as defined in claim 2 in which R represents an alkyl radical containing up to 6 carbon atoms, substituted with an alkyloxy radical containing up to 6 carbon atoms optionally substituted by a radical; methoxy. 7) The compounds of formula (I) as defined in claim 6 in which R represents a radical

 8) The compounds of formula (I) as defined in any one of claims 1 to 7 wherein Y and Y 'together form a group C = 0. 9) The compounds of formula (I) as defined in any one of claims 1 to 8 wherein Y and Y 'together form a C = NOR group, R retaining its previous meaning and in particular a benzyl radical. 10) The compounds of formula (I) as defined in any one of claims 1 to 9 wherein R2 represents an alkyl radical containing 1 to 4 carbon atoms. 11) The compounds of formula (I) as defined in claim 8, wherein R2 represents a methyl radical. 12) The compounds of formula (I) as defined in any one of claims 1 to 9 wherein R3 represents a hydrogen atom (alpha or beta). 13) The compounds of formula (I) as defined in any one of claims 1 to 9 wherein A represents an OH radical. 14) The compounds of formula (I) as defined in any one of claims 1 to 9 wherein B represents an OH radical. 15) The compounds of formula (I) as defined in any one of claims 1 to 9, wherein A and B together form a group 11,12 cyclic carbonate. 16) The compounds of formula (I) as defined in any one of claims 1 to 15 wherein A and B together form a divalent radical

R '6 representing a hydrogen atom or an alkyl, aralkyl or alkyloxy radical having up to 12 carbon atoms or a grouping R7 and R8 identical or different representing a hydrogen atom or an alkyl or aralkyl radical, containing up to 18 carbon atoms, or forming with the nitrogen atom a heterocycle as defined above, and q represents a whole number between 1 and 6, 17) The compounds of formula (I) as defined in claim 16 wherein R'6 represents an aryl radical having up to 12 carbon atoms. 18) The compounds of formula (I) as defined in claim 17 wherein R'6 represents a radical (CH2) 4C6H5. 19) The compounds of formula (I) as defined in any one of claims 1 to 18 wherein Z represents a hydrogen atom. 20) The compounds of formula (I) as defined in any one of claims 1 to 19, in which there is no unsaturation in 10,11. 21) The compound of formula (I) as defined in claim 1 whose name follows - 9-tO- [2- (dimethylamino) ethyl] oxime] 3-de [(2,6-dideoxy) C-methyl-3-O-methyl-L-ribo-hexopyranosyl) oxy] 6-O-methyl-3-oxo-erythromycin. 22) The compound of formula (I) as defined in claim 1, the name of which follows - 11, 12-dideoxy-3-E (2,6-dideoxy-3-C-methyl-3-O-methyl alpha- L-ribohexopyranosyl) oxy] 6-O-methyl-3-oxol2,11- [oxycarbonyl [(4-phenylbutyl) imino]] erythromycin. 23) The compounds of formula (I) as defined in claim 1, whose names follow: [-] - [O - [(2-methoxyethoxy) methyl] oxime] 3-de [(2,6-dideoxy) -3-C methyl-3-O-methyl-L-ribo-hexopyranosyl) oxy] 6-O-methyl-3-oxo-erythromycin, 3-de [(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha) L-ribohexopyranosyl) oxy] 6-O-methyl-3-oxo-erythromycin, cyclic 11,12-carbonate of 3 - [(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L- ribohexopyranosyl) oxy] oO-methyl-3-oxoerythromycin. 24) As medicaments, the compounds of formula (I) as defined in any one of claims 1 to 20 and their addition salts with pharmaceutically acceptable acids. 25) As medicaments, the compounds of formula (I) as defined in claim 21, 22 or 23 and their addition salts with pharmaceutically acceptable acids. 26) Pharmaceutical compositions containing as active ingredient at least one drug defined in claim 24 or 25. 27) Process for the preparation of the compounds of formula (I) as defined in any one of claims 1 to 23, characterized in that a compound of formula (II) is subjected

 in which X, X ', R2, B and A retain their previous meaning, the action of an acid in an aqueous medium to obtain the compound of formula (III) ::

  that is subjected to the action of a blocking agent of the hydroxyl function in 2 ', to obtain a compound of formula (IV)

 in which OM represents a blocked hydroxyl group, and the other substituents retain their previous meaning, which is subjected to the action of an oxidation agent of the hydroxyl function at 3, to obtain the compound of formula (V)

  if it is subjected, if desired, to the action of a reagent capable of introducing the radical R'3, R'3 having the same value as R3 with the exception of hydrogen, then either at action of a 2 'hydroxyl liberation agent to obtain the compound of formula (IA)

 that is to say a compound of formula (I) in which Y and Y 'together with the carbon atom to which they are attached form a ketone function and then, if desired, subject this compound of formula (IA) to action of a ketone or beta-keto ester functionalizing agent to obtain the desired compound of formula (I), then, if desired, subjecting the compound obtained to the action of a hydroxyl esterifying agent to 2 ', or firstly to the action of a functionalizing agent of the ketone beta-keto ester function, and then to the action of a hydroxyl-functional release agent in 2' to obtain the compound of formula (I) and then sought if desired the compound of formula (I) thus obtained to the action of an acid to form the salt. 28) As new industrial products, the compounds of formula (II), (III), (IV) and (V) defined in claim 27. 29) Alternative method of claim 27 for preparing the products of formula (I) wherein X and X 'together form a group C = NOR, characterized in that the product of formula (IVA) used in which X and X' represent the C = N-OR group is prepared from the corresponding ketone of formula (II) by action of NH 2 OR in acidic medium, to obtain, according to the pH of the reaction, the product of formula (IVA) corresponding saturated or unsaturated (11)

R, R2 and Z retain the same meaning as above. Where A represents an OH radical if there is no unsaturation at 10 (11) or a hydrogen atom if there is unsaturation at 10 (11), C = NOR.  30) variant of the process according to claim 27, for preparing the compounds of formula (I) in which X and X 'form a C = NOR group, R being defined as above, characterized in that a compound of formula (IA) in which X and X 'together form a keto group to the action of the compound of formula NH 2 OR to obtain the corresponding compound of formula (I), in which X and X' form a group  Process according to Claim 27, characterized in that the product of formula (II) initially used does not carry 10 (11) unsaturation.