FR2732023A1 - New erythromycin derivs. have antibiotic activity - Google Patents

Abstract

Erythromycin derivs. of formula (I) and their acid addn. salts, are new. R1, R2 = H or 1-24 C hydrocarbon radical which is opt. unsatd., opt. interrupted by one or more heteroatoms and opt. carrying one or more functional gps.; or NR1R2 = heterocyclic gp. contg. one or more heteroatoms O, N or S; or R1+R2 = =C(R1')(R2'); R1', R2' = H or 1-23 C hydrocarbon radical which is opt. unsatd., opt. interrupted by one or more heteroatoms and opt. carrying one or more functional gps.; Z = H or 1-18 C carboxylic acid residue; and the wavy bond in position 10 indicates that the methyl gp. is in R or S position or a mixt. of these is present.

Description

 The present invention relates to new erythromycin derivatives, their preparation process and their use as medicaments.

dans lesquels ou bien R1 et R2 identiques ou différents représentent un atome d'hydrogène, ou un radical hydrocarboné renfermant jusqu'à 24 atomes de carbone, saturé ou insaturé, éventuellement interrompu par un ou plusieurs hétéroatomes et portant éventuellement un ou plusieurs groupements fonctionnels, ou bien R1 et R2 forment avec l'atome d'azote auquel ils sont liés un hétérocycle renfermant éventuellement un ou plusieurs hétéroatomes choisis parmi l'azote, l'oxygène et le soufre, ou bien R1 et R2 forment ensemble un radical

dans lesquels R'1 et R'2 identiques ou différents représentent un atome d'hydrogène ou un radical hydrocarboné renfermant jusqu'à 23 atomes de carbone, saturé ou insaturé, éventuellement interrompu par un ou plusieurs hétéroatomes et portant éventuellement un ou plusieurs groupements fonction nels et Z représente un atome d'hydrogène ou le reste d'un acide carboxylique renfermant jusqu'à 18 atomes de carbone, le trait ondulé en position 10 indiquant que le méthyl peut être de configuration R ou S, ou un mélange de configuration
R et S, ainsi que les sels d'addition avec les acides des composés de formule (I).The subject of the invention is the compounds of general formula (I)

in which either R1 and R2, which are identical or different, represent a hydrogen atom, or a hydrocarbon radical containing up to 24 carbon atoms, saturated or unsaturated, optionally interrupted by one or more heteroatoms and optionally carrying one or more functional groups, either R1 and R2 form with the nitrogen atom to which they are linked a heterocycle optionally containing one or more heteroatoms chosen from nitrogen, oxygen and sulfur, or else R1 and R2 together form a radical

in which R'1 and R'2, which are identical or different, represent a hydrogen atom or a hydrocarbon radical containing up to 23 carbon atoms, saturated or unsaturated, optionally interrupted by one or more heteroatoms and optionally carrying one or more functional groups nels and Z represents a hydrogen atom or the remainder of a carboxylic acid containing up to 18 carbon atoms, the wavy line in position 10 indicating that the methyl may be of R or S configuration, or a mixture of configuration
R and S, as well as the addition salts with acids of the compounds of formula (I).

 Among the addition salts with acids, mention may be made of the salts formed with acetic, propionic, trifluoroacetic, maleic, tartaric, methanesulfonic, benzenesulfonic, p-toluenesulfonic acids and especially stearic, ethylsuccinic or laurylsulfonic acids.

R a et Rb identiques ou différents, représentant un atome d'hydrogène ou un radical alkyle renfermant jusqu'à 12 atomes de carbone, le radical

The hydrocarbon radical that can represent R1 or R2 and
R'1 or R'2 can be interrupted by one or more heteroatoms chosen from nitrogen, oxygen and sulfur and can carry one or more groups chosen from the group consisting of hydroxyl radicals, halogen atoms, NO2 radicals, C - N radicals, alkyl, alkenyl or alkynyl, O-alkyl, O-alkenyl or O-alkynyl, Salkyl, S-alkenyl or S-alkynyl and N-alkyl, N-alkenyl or
N-alkynyl, containing up to 12 carbon atoms optionally substituted by one or more halogen atoms, the radical

R a and Rb identical or different, representing a hydrogen atom or an alkyl radical containing up to 12 carbon atoms, the radical

R3 representing an alkyl radical containing up to 12 carbon atoms, or an optionally substituted aryl or heteroaryl radical, the aryl, O-aryl or
S-aryl carboxylic or aryl, 0-aryl or S-aryl heterocyclic with 5 or 6 members comprising one or more heteroatoms, optionally substituted by one or more of the substituents mentioned above.

The hydrocarbon radical that can represent R1 or R2 and
R'1 or R'2 can be an alkyl, alkenyl, alkynyl, aralkyl, aralkenyl or aralkynyl radical. In the definition of the substituents, the alkyl, alkenyl or alkynyl radical is preferably a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, decyl or dodecyl, vinyl, allyl, ethynyl, propynyl, propargyl, cyclobutyl radical, cyclopentyle or cyclohexyle.

 The aryl radical can be a phenyl or naphthyl radical.

 The aryl radical can also be a substituted or unsubstituted heterocyclic radical such as the thienyl, furyl, pyrolyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, pyrazolyl or isopyrazolyl radical, a pyridyl, pyrimidyl, pyridazinyl or pyrazinyl radical, or also an indolyl benzof radical. benzothiazyl or quinolinyl. These aryl radicals can comprise one or more of the groups mentioned above.

 When R1 and R2 form with the nitrogen atom to which they are linked a heterocyclic radical, it is preferably a pyrrolyl, pyrrolidinyl, pyridyl, pyrazinyl, pyrimidyl, piperidinyl, piperazinyl, quinuclidinyl, oxazolyl, isoxazolyl radical, morpholinyl, indolyle, imidazolyle, benzimidazolyle, triazolyle, thiazolyle, azétidinyle, aziridinyle.

 A more particular subject of the invention is the compounds of formula (I) in which Z represents a hydrogen atom, the compounds of formula (I) in which R1 represents a hydrogen atom, the compounds of formula (I) in which R1 and R2 each represent a hydrogen atom.

Among the preferred compounds of the invention, mention may be made of the compounds of formula (I) in which R'1 represents a hydrogen atom, mention may be made of compounds in which R1 and R2 together form a radical
= CH (CH2) nArl in which Arl represents an optionally substituted aryl or heteroaryl radical and n represents an integer which can vary from 0 to 8.

 Arl has as preferred value one or the other of the preferred values indicated above for the aryl and heteroaryl radicals. The optional substituent (s) of Arl are those indicated above as functional groups.

dans lequel p et q identiques ou différents, représentent un nombre entier variant de 0 à 6, A et B identiques ou différents représentent un atome d'hydrogène ou d'halogène ou un radical alkyle renfermant jusqu'à 8 atomes de carbone, la géométrie de la double liaison étant E ou Z ou un mélange
E + Z, ou bien A et B forment une troisième liaison avec les atomes de carbone auxquels ils sont liés et Ar2 représente un radical aryle ou hétéroaryle, mono ou polycyclique, éventuellement substitué.Among the preferred compounds of the invention, mention may be made of the compounds of formula (I) in which R1 and R2 together form a radical

in which p and q identical or different, represent an integer varying from 0 to 6, A and B identical or different represent a hydrogen or halogen atom or an alkyl radical containing up to 8 carbon atoms, the geometry of the double bond being E or Z or a mixture
E + Z, or A and B form a third bond with the carbon atoms to which they are linked and Ar2 represents an aryl or heteroaryl radical, mono or polycyclic, optionally substituted.

 Among these compounds, special mention may be made of the compounds in which p and q represent the number 0, as well as those in which A and B represent a hydrogen atom.

Among the preferred compounds of the invention, mention may be made of the compounds of formula (I) in which R2 represents a radical (CH2) Ar3 in which r represents an integer varying from 0 to 6 and Ar3 represents an aryl or heteroaryl radical optionally substituted, and more particularly those in which
Ar3 represents a 4-quinolinyl radical optionally mono or polysubstituted on one and / or the other of the 2 quinoline rings, for example those in which Ar3 represents an unsubstituted 4-quinolinyl radical, 4-quinolinyl substituted by a radical methoxy or a thiazolyl radical substituted by a pyridinyl radical.

 A very particular subject of the invention is the compounds of formula (I) in which r represents an integer varying from 1 to 4.

 Among the preferred compounds of the invention, mention may be made of the compounds whose preparation is given below in the experimental part and more particularly the compounds whose names follow - 11,12-dideoxy 3-de ((2,6- dideoxy 3-C-methyl 3-O-methyl alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,11- (oxycarbonyl (2- (3- (4-quinolinyl) propyl) hydrazono)) erythromycin , - 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-0-methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- (oxy- carbonyl (2- (3- (7-methoxy-4-quinolinyl) propyl) hydrazono)) erythromycin, - 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-0-methyl alpha) -L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,11- (oxycarbonyl (2- (3- (2- (3-pyridinyl-4-thiazolyl) propyl) hydrazono)) erythromycin.

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

 The compounds of the invention can therefore be used as medicaments in the treatment of infections with sensitive germs and in particular, in that of staphylococcal diseases, such as staphylococcal septicemia, malignant staphylococcal disease of the face or skin, pyoderma, septic or suppurative wounds, boils, carbuncles, phlegmons, erysipelas and acne, staphylococcal diseases such as acute primary or post-flu angina, bronchopneumonia, pulmonary suppuration, streptococcia such as acute angina, otitis, sinusitis, scarlet fever, pneumococcal disease such as pneumonia , bronchitis; brucellosis, diphtheria, gonococcal disease.

The products of the present invention are also active against infections caused by germs such as
Haemophilus influenzae, Rickettsies, Mycoplasma pneumoniae,
Chlamydia, Legionella, Ureaplasma, Toxoplasma, or germs of the genus Mycobacterium.

 The present invention therefore also has as an object, 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.

 A more particular subject of the invention is, as medicaments and, in particular antibiotic medicaments, the products of Examples 5 or 11, 12 and 13 and their pharmaceutically acceptable salts.

 A subject of the invention is also the pharmaceutical compositions containing as active principle at least one of the medicaments defined above.

 These compositions can be administered by the oral, rectal, parenteral route or by the local route as a topical application to the skin and the mucous membranes, but the preferred route of administration is the oral route.

 They can be solid or liquid and come in the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, capsules, granules, suppositories, injections, ointments, creams, gels. ; they are prepared according to the usual methods. The active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not , fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

 These compositions can 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 is variable depending on the condition treated, the subject in question, the route of administration and the product considered. It can be, for example, between 50 mg and 300 mg per day orally, in adults for the product of Example 5.

dans laquelle Z conserve sa signification précédente, ou bien à l'action de l'hydrazine NH2NH2 pour obtenir le composé de formule (IA)

que l'on soumet si désiré à l'action d'un aldéhyde R'2CHO ou d'une cétone

dans lesquels R'1 et R'2 ont la signification indiquée ci-dessus, pour obtenir le composé de formule (zig) correspondant

dans laquelle R'1 et R'2 conservent la même signification que précédemment, que l'on soumet si désiré à l'action d'un agent de réduction pour obtenir le composé de formule (IC) corres pondant

dans laquelle R'1 et R'2 conserve sa signification précédente, c'est-à-dire un composé de formule (I) dans lequel R1 est l'hydrogène et R2 représente un radical CHR'1-R'21 puis si désiré, soumet le composé de formule (IC) à l'action d'un agent susceptible de remplacer l'atome d'hydrogène du groupement NH par un groupement R1 tel que défini précédemment à l'exception de la valeur d'hydrogène, puis si désiré, soumet le composé obtenu à l'action d'un acide pour en former le sel et/ou à l'action d'un agent d'estérification du groupement OH en 2'.The subject of the invention is also a process for preparing the compounds of formula (I), characterized in that a compound of formula (II) is subjected

in which Z retains its previous meaning, or else to the action of hydrazine NH2NH2 to obtain the compound of formula (IA)

which is subjected if desired to the action of an aldehyde R'2CHO or a ketone

in which R'1 and R'2 have the meaning indicated above, to obtain the compound of formula (zig) corresponding

in which R'1 and R'2 retain the same meaning as above, which is subjected if desired to the action of a reducing agent to obtain the corresponding compound of formula (IC)

in which R'1 and R'2 retains its previous meaning, that is to say a compound of formula (I) in which R1 is hydrogen and R2 represents a radical CHR'1-R'21 then if desired , subjects the compound of formula (IC) to the action of an agent capable of replacing the hydrogen atom of the NH group with a group R1 as defined above with the exception of the hydrogen value, then if desired, subject the compound obtained to the action of an acid to form the salt and / or to the action of an esterification agent for the OH group in 2 '.

 The compounds of formula (II) used as starting materials for the process of the invention are described and claimed in European patent application EP 0596802.

 In a preferred embodiment of the invention - the operation is carried out in the presence of an excess of hydrazine, at a temperature above ambient temperature, for example a temperature between 40 and 800C, in a solvent such as acetonitrile, dioxane, dimethylformamide, tetrahydrofuran, dimethoxy ethane or dimethyl sulfoxide, (in the presence or in the absence of a base), - the reaction with the aldehyde or ketone takes place under the same conditions of temperature and solvent, - the reducing agent is NaBH3CN or hydrogen in the presence of a catalyst such as palladium, platinum and indifferently in the presence or in the absence of an acid such as hydrochloric acid or acid acetic, - the 2 'esterification is carried out according to conventional methods, - salification is carried out using acids according to conventional methods.

dans lequel Z conserve sa signification précédente, à l'action d'un composé de formule NH2NHR2 pour obtenir le composé de formule (I'A)

que l'on soumet si désiré, à l'action d'un agent susceptible de remplacer l'atome d'hydrogène du groupement NH par un radical R1 tel que défini ci-dessus à l'exception de la valeur hydrogène pour obtenir le composé de formule (I'B) correspondant

que l'on soumet si désiré, à l'action d'un agent d'estérification du groupement OH en 2' ou à l'action d'un acide pour en former le sel, les conditions préférentielles de température et de pression sont celles décrites ci-dessus.The invention also relates to a variant of the preceding method, characterized in that the compound of formula (II) is subjected

in which Z retains its previous meaning, to the action of a compound of formula NH2NHR2 to obtain the compound of formula (I'A)

which is subjected if desired, to the action of an agent capable of replacing the hydrogen atom of the NH group with a radical R1 as defined above with the exception of the hydrogen value to obtain the compound of corresponding formula (I'B)

which is subjected if desired, to the action of an esterification agent of the OH group in 2 ′ or to the action of an acid to form the salt thereof, the preferential conditions of temperature and pressure are those described above.

 The following examples illustrate the invention.

EXAMPLE 1: 11,12-dideoxy 3-de - ((2,6-dideoxy 3-C-methyl 3-Omethyl alpha L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- (oxyearbonyl (hydrozono ) erythromycin isomer 10 (R) and isomer 10 (s) corresponding
Suspended in 5 ml of methyl cyanide and 0.5 ml of water 353 mg of 2'-acetate of ll-deoxy 10,11-didehydro 3-de (2,6-dideoxy 3-C-methyl 3 -O-methyl alpha-L-ribohexopyranosyl) oxy) 12-O - ((1H-imidazol-l-yl) carbonyl) 6-O-methyl 3oxo erythromycin prepared as indicated in European patent application EP 0596802 and 0.097 ml d hydrazine hydrate.

The reaction mixture is heated at 60 ° C. for 3 hours. The reaction mixture is poured into water, extracted with ethyl acetate, washed and dried. The reaction mixture is chromatographed on silica eluting with the isopropyl ether mixture , triethylamine, methanol (90/10/10). 101 mg of sought product (product A) are obtained. Rf = 0.45 and 106 mg of corresponding product 10 (S) (product B).

Product A
Analysis% calculated% found
Pdt (A) Pdt (B)
C 59.31 59.3 59.3
H 8.51 8.4 8.4
N 6.69 6.7 6.8
Product A: NMR CDC13 ppm Product B: NMR CDC13 ppm 3.09 H10 (m) 3.53 H10 (m) 3.59 H11 (s) 3.46 (d, J = 3Hz) H11 (s) 1.35 12 Me (s) 1.32 12 Me (s) 5.03 H13 (dd) 4.95 H13 (dd) 0.86 15 Me (t) 0.87 15 Me (t) 3.85 H2 (q) 3.88 H2 (q) 2.30 N-Me (s) 2.31 N-Me (s) 2.67-6 OMe (s) 2.83 6-OMe (s) 4.44 NH (s) 3.84 NH (s) 2.67 H8 (m) 2.78 H8 (m)
EXAMPLE 2: 11,12-dideoxy 3-de (2,6-dideoxy 3-C-methyl 3-Omethyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxycarbonyl (2- ( 3-phenylpropylidene) hydrazono)) arythromycin
Was dissolved in 2 ml of THF on molecular sieve (4AO), 285 mg of product A obtained in Example 1 and 156 mg of 3-phenylpropionaldehyde. 100 m of molecular sieve (4AO) are added and the mixture is heated at 600C for 24 h. Filtered, concentrated and purified by chromatography on silica, eluting with a mixture of ethyl acetate, triethylamine (964). The fractions of rf = 0.41 are collected and 330 mg of sought product is obtained rf = 0.3.

Analysis% calculated% found
C 64.58 64.3
H 8.26 8.3
N 5.65 5.5
NMR CDC13 ppm 3.04 H10 (q) 4.46 H11 (d, j = 3 Hz) 5.05 H13 (dd) 3.85 H2 (q) 2.38 NMe (s) 2.79 6 OMe (s ) 7.96 N = CH (t) 2.86 CH2 q 7,2,7,35 H aromatic 2,61 NH = CH-CH2 (m).

EXAMPLE 3: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O methyl alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,11 (oxycarbonyl (2 - (3-phenylpropyl) hydrazono)) erythromycin
23 mg of sodium cyanoborohydride (NaBH3CN) are added to a solution containing 1.5 ml of methanol 88 mg of the product of Example 2 and 50 l of acetic acid. Concentrate, take up in ethyl acetate, add water and bring to pH 8 using a 2N sodium hydroxide solution. Decanted, washed with saturated sodium chloride solution and dried. The product obtained is chromatographed on silica (eluent: isopopyl ether-methanol-triethylamine 90-10-10). The fractions of rf = 0.33 are collected. The mixture obtained is taken up in an ether-pentane mixture and filtered. After evaporation, 70 mg of the expected product is obtained.

Analysis% calculated% found
C 64.4 64.2
H 8.51 8.3
N 5.63 5.6
NMR CDC13 ppm 3.74 H10 (s) 5.03 H13 (dd) 3.86 H2 (q) 2.27 N (CH3) 2 (s) 2.64 6 OMe (s) 2.72 CH2- + 7 , 13-7.28 H aromatic 5.35 H NH (t).

EXAMPLE 4: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-Omethyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxycarbonyl (2- (3- (4-quinolâinyl) 2 (E) -propenylidene) hydrazono)) erythromycin
125 mg of product A prepared in Example 1, 73 mg of 4-quinolinyl propenal, the preparation of which is given below and 40 l of acetic acid, are stirred at ambient temperature for 5 hours. The methanol is removed under reduced pressure and taken up with a methylene chloride-water mixture.

It is brought to pH 9 using a concentrated ammonia solution. Decanted, dried over magnesium sulfate, filtered and evaporated to dryness. 211 mg of a product are obtained which is chromatographed on silica eluting with a methylene chloride-methanol mixture (92-8). Impasto in an ethyl acetate-pentane mixture (1-1), the product of rf = 0.4. It is filtered, rinsed with the minimum of ethyl acetate-pentane mixture, dried in an oven under reduced pressure the product obtained. 109 mg of the sought product are thus obtained.

PREPARATION OF EXAMPLE 4: 4-quinoline propenal
Is dissolved in 80 ml of methylene chloride, 3.9 g of 4-quinoline carboxaldehyde. Cool to 100C + 50C and add in 1 h 30 and maintaining the temperature at 100C, 8.3 g of 3- (triphenylphosphine) propenal (C6H5) 3P = C
CHO. The temperature is allowed to return to 20 ° C. and the stirring is continued for 24 hours. It is again cooled to around 100C and 0.4 g of (C6H5) 3P = C-CHO is added. Stirred again for 3 hours at room temperature The methylene chloride is evaporated and a product is obtained which is chromatographed on silica eluting with an ethyl acetate-cyclohexane mixture (4-6), 2.12 g of sought product is isolated.

EXAMPLE 5: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-Omethyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxycarbonyl (2- (3- (4-quinolinyl) 2-propyl) hydrazono)) erythromycin
Is dissolved in 10 ml of ethyl acetate, 0.38 g of product prepared in Example 4 and 38 mg of platinum oxide.

Hydrogenation is carried out with vigorous stirring for 24 hours. It is filtered, rinsed with ethyl acetate and evaporated under reduced pressure. 0.375 g of product is obtained which is taken up in 5 ml of methanol, 175 l of acetic acid and 90 mg of sodium borohydride. The mixture is stirred for 3 hours at room temperature. The methanol is removed and taken up using the methylene chloride-water mixture. It is brought to pH 8-9 with a 28% ammonia solution. Decanted, washed with water, dried, filtered and evaporated to dryness. 0.37 g of product is obtained which is chromatographed on silica, eluting with an ethyl acetate-triethylamine 96-4 mixture. 127 mg of a product are obtained (rf = 0.25) which is drained, washed and dried. 90 mg of the desired product F = 1890C are obtained.

NMR CDCl3 ppm, 300 MHz 1.34 (s) -1.48 (s): 6 and 12 CH3; 2.30 (s): N (CH3) 2 2.65 (s): 6-OCH3; 3.06 (dq): H4; 3.19 (q): H10; 3.74 (s): H11; 5.50 (mobile t): NH-CH2; 7.30 (d): H3 quinoline; 7.53-7.68 (dt): H6-H7 quinoline; 8.10 (m)
H5-H8 quinoline; 8.79 (d): H2 quinoline.

EXAMPLE 6: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-Omethyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- (oxycarbonyl (2 - (3- (1H-benzimidazol-1-yl) propyl) hydrazono)) erythromycin
A solution of 300 mg of the product obtained in Example 1, 168 mg of 3-imidazolylpropanal (the preparation of which is given below) and 90 ml of acetic acid in 9 ml of agitation are stirred for 18 hours at room temperature. methanol, 40 mg of sodium cyanoborohydride are added after this time, the mixture is stirred for another 5 h and then 120 mg of sodium cyanoborohydride and 200 ml of acetic acid are added. Stirring is continued for 48 h, a mixture of methylene chloride and water is added, the pH is adjusted to 8-9 with 32% ammonia, the organic phase is separated, dried and evaporated to dryness. 0.6 g of residue which is chromatographed on silica (eluent ethyl acetate-methanol-TEA: 92-6-2) the product obtained is pasted in an ether-pentane mixture 1-5. 143 mg of the crude desired product are collected which are dissolved in 1 ml of ethyl acetate, filtered and crystallized by the addition of 3 ml of pentane, 85 mg of sought product is obtained after drying (F = 1970C).

Analysis for C41H63N5 10,785.98
CHN% calculated 62.65 8.08 8.91% found 62.5 8.1 8.8
NMR CDCl3 ppm 3.18: H10; 3.69 (s): H11; 0.84 (t): 15 CH3; 3.86 (q)
H2; 2.45: N- (CH3) 2; 2.60 (s): 6 OCH3; 5.56 (t): NH; 2.65-2.81: NH-CH2-; 4.50: -CH2-N; 7.26 to 8.02: 5H benzimidazole.

PREPARATION OF EXAMPLE 6: 3-imidazolyl propanal
Stage A: 2- [2- (3-imidazolyl) ethyl] 1,3-dioxolane
To a solution of 1.2 g of benzimidazole in 15 ml of dimethylformamide, 0.49 g of sodium hydride at 50% in dispersion in oil is added. The temperature rises to 350C, ten minutes near the end of the evolution of gas, is added while allowing the temperature to rise to 350C, 1.2 ml of 2- (2bromoethyl) 1,3-dioxolane. Stir two hours, add water saturated with sodium chloride, extract with ether, dry, filter and evaporate under reduced pressure, 2 g of residue are obtained which are chromatographed on silica eluting with chloride methylene-methanol (95-5). 1.6 g of sought product are thus collected.

CDCl3 NMR: 2.25 and 4.35: ethyl CH2; 3.85 to 4.00: CH2 of dioxolane; 4.87: CH dioxolane; 7.29-7.45-7.81: 4H benzimidazole; 7.92: H in 2 of imidazole.

STAGE B: 3-imidazolyl propanal
A solution of 1.6 g of the product obtained in Stage A, 1.45 g of paratoluene sulfonic acid in 60 ml of methanol is stirred for 5 hours at reflux. Adjusted to pH 8 with potassium carbonate, removed methanol under reduced pressure, extracted with methylene chloride, washed with water, dried and evaporated to dryness under reduced pressure, 1.45 g of intermediate ketal dimethoxy are obtained which is stirred at 40 ° C. for 18 h, in the presence of 70 ml of acetone and 34 ml of 2N hydrochloric acid, the acetone is evaporated under reduced pressure and the pH is brought to 8-9 by addition of ammonia to 32%, extracted with methylene chloride, washed with water, dried and evaporated to dryness under reduced pressure, 1.13 g of product are collected which is chromatographed on silica, eluting with methylene chloride-methanol 95- 5. 0.76 g of the desired product is obtained.

NMR CDCl3 250 MHz 3.07 (t) -4.52 (t): ethyl CH2; 7.25 to 7.50: aromatics; 9.79 (s): CH of the aldehyde.

EXAMPLE 7: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- (oxycarbonyl ( 2- (3- (2-phenyl 5-thiazolyl) propyl) hydrazono)) erythromycin
The mixture is stirred for 4 hours at room temperature, 200 mg of the product obtained in Example 1, 139 mg of 3- (2-phenyl 5-thiazolyl) propanal (the preparation of which is given below), 180 ml of acetic acid and 7 ml of methanol then add 60 mg of sodium cyanoborohydride. The mixture is stirred for 18 hours at ambient temperature, evaporated to dryness under reduced pressure, the residue is taken up with a water-ethyl acetate mixture and adjusted to pH 9 with an aqueous ammonia solution. Extracted with ethyl acetate, washed with water, dried, evaporated to dryness under reduced pressure. 354 mg of product is collected which is chromatographed on silica, eluting with ethyl acetate then ethyl acetate. -triethylamine (96/4).

170 mg of product are collected which are crystallized from the 1/5 ethyl acetate-pentane mixture. 80 mg of the sought product are thus obtained.

Analysis for C43H64N4 10S 829.07
CHNS% calculated 62.3 7.78 6.76 3.87% found 62.0 7.8 6.8 4.0
NMR CDCl3 300 MHz 3.17 (m): H10; 1.07 (d): 14 CH3; 1.48: 15 CH3; 3.87 (q): H2; 2.26 (s): N- (CH3) 2; 3.53 (m): 2'OH; 2.67 (s) 6-OCH3; 5.43 (t): NH; 2.86 (m) -1.95 (m) -3.03 (m): CH2 propyl; 7.55 (s): H of thiazole; 7.39 (m) 3H and 7.89 (m) 2H: aromatics; 1.19 (d): H8.

PREPARATION OF EXAMPLE 7: 2-phenyl 5-thiazole propanal
Stage A: 2-phenyl 5-carbethoxy thiazole
To a suspension of 78 g of thiobenzamide in 200 ml of benzene, a solution of formyl beta ethyl chloroacetate in 240 ml of benzene is added. The mixture is heated at reflux for 3 hours 30 minutes, eliminating the water formed. Cooled and slowly added 320 ml of a 20% potassium carbonate solution and 220 ml of water, extracted with ether, washed, dried and distilled under reduced pressure to obtain 75.5 g of the desired product.

Stage B: 2-phenyl 5-thiazole carboxylic acid
To a solution of 75.5 g of the product obtained in Stage A, in 130 ml of ethanol, 28.56 g of potassium hydroxide pellets in solution in 410 ml of ethanol are added, the mixture is heated at reflux for 15 minutes, cooled and wring out the potassium salt, wash it with ether and dry under reduced pressure. 53.5 g of intermediate potassium salt are obtained which are dissolved in 1.2 liters of water and acidified to pH 1 with a solution of concentrated hydrochloric acid after filtration, 29 g of sought product are collected (F = 1920C). 24.5 g of product are recrystallized from 750 ml of toluene. 20 g of sought product is obtained. F = 1950C.

Analysis for C1oH7NO2S 205.2
CHNS% calculated 58.52 3.43 6.82 15.6% found 58.5 3.7 6.8 15.2
Stage C: methyl 2-phenyl 5-thiazole carboxylate
To a solution of 4.77 g of the acid obtained in Stage B in 160 ml of methanol, 2.5 ml of acetyl chloride is added and the mixture is heated at reflux for 18 h. The mixture is brought to dryness under reduced pressure, taken up in ethyl acetate, filtered, concentrated to a reduced volume and the crystals obtained are drained. The mother liquors are washed with sodium hydroxide, extracted with ethyl acetate, washed with water and evaporated to dryness, the 2 crystallized fractions are combined to obtain 4.54 g of sought product (F = 108 " VS).

Stage D: 2-phenyl 5-formyl thiazol
Reduction:
To a suspension of 1.45 g of lithium aluminum hydride in 65 ml of tetrahydrofuran cooled to 100C, a solution of 4.5 g of the product obtained in Stage C in 35 is added over 20 minutes and maintaining the temperature at 100C ml of tetrahydrofuran, stirred 45 minutes at 100C, then 2 h at room temperature. Tetrahydrofuran is added to 10 then 50% of water while maintaining the temperature below 200C, 15 ml of a potassium and sodium tartrate solution are added, filtered, rinsed and brought to dryness under reduced pressure; the residue obtained is pasted in hexane, drained and dried at 400C under reduced pressure, 3.6 g of product are collected. F = 820C.

Oxidation:
3.57 g of the product obtained above are stirred for 2 h 30 at room temperature with 143 ml of toluene and 17.9 g of manganese bi-oxide. It is filtered and brought to dryness under reduced pressure. The residue is taken up with hexane, drained and dried at 400C under reduced pressure, 3.09 g of sought product is collected. F = 940C.

Stage E: 3- (2-phenyl 5-thiazolyl) propenal
5 g of (formylmethylene) triphenylphosphorane are added over 10 minutes to a solution of 2.098 g of the product obtained in stage D, and the mixture is stirred for 27 h at room temperature. Evaporated to dryness under reduced pressure and collected 6.60 g of product which is chromatographed on silica eluting with ethyl acetate-cyclohexane (2-8). 1.22 g of product are obtained which is pasted in pentane to obtain 1.047 g of the desired product (F = 1040C).

NMR CDCl3 (250 MHz) 8.04 (s): H triazole; 6.49 (ddJ = 7.5) and 7.69 (dJ = 15.5) H propene; 9.67 (J = 7.5) CHO; 7.50 (m) 3H and 7.97 (m) 2H: aromatics.

Stage F: 3- (2-phenyl 5-thiazolyl) propenol
To a suspension of 475 mg of sodium borohydride in 50 ml of ethanol, 900 mg of the aldehyde obtained in stage E above are added in portions, the mixture is stirred, then 20 minutes at room temperature and then the excess of sodium borohydride by adding acetone. Evaporated to dryness under reduced pressure and taken up with ethyl acetate, washed with brine, dried and brought to dryness under reduced pressure, 960 mg of product is obtained as it is for the following step.

Stage G: 2-phenyl 5-thiazolyl propanol
Hydrogenate for 12 h under 1 atm. then 9 h under 1.4 atm. a solution of 960 mg of the product obtained in stage F in 10 ml of methanol in the presence of 150 mg of palladium on carbon. After filtration, the mixture is evaporated to dryness under reduced pressure and the residue is chromatographed on silica (eluent ethyl acetate-cyclohexane (4-6). 759 mg of sought product is collected.

NMR CDCl3 200 MHZ 1.52 (m): OH; 3.74 (m) - 1.97 (m) - 2.92 (dt): CH2; 7.40 to 7.90 (m): 5H aromatic; 7.53 (t, J = 1): H thiazole.

Stage H: 2-phenyl 5-thiazole propanal
To a solution cooled to 100C of 584 mg of the product obtained in the preceding stage, 800 ml of dimethylsulfoxide, 1.15 ml of triethylamine and 8 ml of methylene chloride, the temperature is added at 100C, 1.27 g of complex pyridinium sulfotrioxide, stirred 1 h 15 at 100C, then allowed to return to room temperature, extracted with methylene chloride, washed with water, dried and evaporated to dryness under reduced pressure, 806 mg of product is collected which l 'is chromatographed on silica (eluent ethyl acetate cyclohexane (3-7)), to obtain 450 mg of the desired product.

NMR CDC13 200 MHz 2.88-3.20 (t): CH2 propyl; 7.55 (s): H thiazole; 7.40 (m): 3H and 7.87 (m) 2H: aromatic H; 9.85 (sl): CHO.

EXAMPLE 8: 11,12-did9oxy 3-de ((2,6-didâoxy 3-c-methyl 3-O methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- (oxycarbonyl ( 2- (3- (4-phenyl 1H-imidazol l-yl) propyl) hydrazono)) ârythromycin
125 mg of the product obtained in Example 1, 80 mg of 3- (4-phenyl 1H-imidazole 1-yl) propanal (the preparation of which is given below) and 2 ml of methanol are stirred for 20 hours. 54 mg of sodium cyanoborohydride are added. Concentration is carried out under reduced pressure, the residue is taken up in 20 ml of ethyl acetate, washed with sodium hydroxide and then with water saturated with sodium chloride, dried and evaporated to dryness under pressure. reduced, and chromatograph the residue on silica (eluent chloroform-methanol-ammonia 95/5 / 0.5) the crude product is taken up in an ether-ethyl acetate mixture, filtered, evaporated to dryness and collected 85 mg of the desired product .

Analysis for C43H65N5O10 812.02
CHN% calculated 63.6 8.07 8.62% found 63.4 8.2 8.3
NMR CDCl3 400 MHz 3.70 (s): H in 11; 4.98 (dd): H13; 3.86 (q): H in 2; 2.26 (s): N- (CH3) 2; 2.63: 6-OCH3; 5.54 (t): NH; 4.27 and 1.97: CH2 propyl; 7.3 (d) - 7.57 (d): 2H imidazole; 7.2 - 7.35 - 7.8: aromatics.

PREPARATION OF EXAMPLE 8: 3- (4-phenyl 1H-imidazol 1-yl) propanal.

Stage A: 3- (4-phenyl 1H-imidazol 1-yl) ethyl 1,3-dioxolane.

 The procedure is carried out as in stage A of the preparation of Example 6, using 1.44 g of 4-phenylimidazole and 1.17 ml of bromoethyldioxolane at the start, after 1.8 g of silica chromatography (eluent ACOEt), expected product.

CDCl3 NMR 2.19 (d, t) and 4.13 (t): CH2 propyl; 3.8-4.05: CH 2 dioxolane; 4.88 (t): H oxolane; 7.23 and 7.53: CH imidazole; 7.23 - 7.37 - 7.75: aromatics.

Stage B: 3- (4-phenyl 1H-imidazol l-yl) propanal
Heated 20 h at 600C 1.77 g of product obtained in the stage
A above, 35 ml of acetone and 30 ml of 2N hydrochloric acid. The acetone is then removed under reduced pressure and the solution neutralized by adding sodium bicarbonate in branches, then it is extracted with ethyl acetate, dried and evaporated to dryness under reduced pressure. The residue is chromatographed on silica (eluent ethyl acetate-methanol (97-3)). 900 mg of sought product is collected.

250 MHz CDCl3 NMR 9.81 (s): CHO; 7.10 to 7.76: imidazole and aromatic H; 3.01 (t) and 4.29 (t): the H propyls.

EXAMPLE 9 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 12,11 (oxycarbonyl (2- (3 - (3-phenyl 1,2,4-oxodiazol 5-yl) propyl) hydrazono) erythromycin
The procedure is as in Example 6, starting with 125 mg of the product obtained as in Example 1, using 40 mg of 3 (3-phenyl 1,2,4-oxadiazol 5-yl) propanal (the preparation of which is described below). After chromatography on silica, eluting isopropyl ether-triethylamine-methanol (90-10-10) and crystallization from isopropyl ether-methanol, 107 mg of expected product is obtained.

Analysis for C42H63N5 11,814.00
CHN% calculated 61.97 7.8 8.6% found 61.7 7.9 8.5
NMR CDC13 300 MHz 3.74 (s): H11; 5.03 (dd): H13; 3.87 (q): H2; 2.27 (s) 6-OCH3; 2.27 (s): N- (CH3) 2; 5.49 (t): NH; 3.17 (m) and 2.11 (m): CH2 propyl; 7.47 to 8.08: aromatics.

PREPARATION OF EXAMPLE 9: 3- (3-phenyl 1,2,4-oxadiazol 5yl) propanal
Stage A: 3- (3-phenyl 1,2,4-oxadiazol 5-yl) propanol
A solution of 2.5 ml of borane-methyl sulfide complex, in 2M solution in tetrahydrofuran, 920 mg of 3- (3-phenyl 1,2,4-oxadiazol 5- yl) propanoic (prepared according to RM SRIRASTAVA et al.

J. Heterocycl. Chem., 21, 1193 (1984) and 20 ml of tetrahydro furan. 10 ml of methanol are added over 5 minutes. Evaporated to dryness under reduced pressure and the residue is chromatographed on silica (eluent ethyl acetate-hexane (6-4)). 485 mg of expected product are collected.

NMR CDCl3 250 MHz 2.07 (sl): OH; 2.14 (m) - 3.10 (t) - 3.8 (t): CH2; 7.41 - 7.54 - 8.06: aromatics.

Stage B: 3- (3-phenyl 1,2,4-oxadiazol 5-yl) propanal
1.07 g of pyridinium sulfotrioxide complex is added to a solution cooled to 100C of 460 mg of the product obtained in stage A, 680 ssl of dimethyl sulfoxide and 970 l of triethylamine in 5 ml of methylene chloride. , allow to return to room temperature, add 15 ml of methylene chloride, wash with water, dry, evaporate to dryness under reduced pressure and chromatography on silica (eluent ethyl acetate-hexane 4-6) to obtain 365 mg of the product sought.

NMR CDC13 3.13 (m) - 3.26 (m): CH2; 7.49 to 8.05: aromatics.

EXAMPLE 10 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-Omethyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- (oxycarbonyl (2 - (3- (2-chlorophenyl) propyl) hydrazono) erythromycin
The procedure is as in Example 6 from 125 mg of the product obtained in Example 1, using 67 mg of 2-chlorophenyl propanal (the preparation of which is given below).

After chromatography on silica (eluent isopropyl ether triethylamine-methanol (90-10-10)), 48 mg of sought product is collected.

Analysis for C40H62ClN3010 780.40
CHN Cl% calculated 61.56 8.01 5.38 4.45% found 61.4 8.0 5.4 4.5
NMR CDCl3 400 MHz 3.73 (s): H in 11; 5.13 (dd): H at 13; 3.87 (q): H in 2; 2.26 (s): N- (CH3) 2; 2.64 (s): 6-OCH3; 5.36 (t): NH; 1.83 (m) - 2.70 (m) - 2.79 (m): CH2; 7.05 to 7.2: aromatics.

PREPARATION OF EXAMPLE 10: 3- (2-chlorophenyl) propanal
Stage A: 3- (methyl 2-chlorophenyl propanoate)
4.35 g of metachlorocinamic acid, 430 mg of palladium on active carbon and 70 ml of methanol are stirred for 1 hour under an inert atmosphere. Then stirred for 3 hours under a hydrogen atmosphere. Filtered and evaporated to dryness under reduced pressure and the residue is chromatographed on silica (eluent ethyl acetate-hexane (2-8)), 3.1 g of sought product is obtained.

NMR CDCl3 250 MHz 2.6 (t) - 2.8 (t): CH2; 3.6 (s): OCH3; 7.05 - 7.37 aromatics.

Stage B: 3- (2-chlorophenyl) propanol
To a solution of 1.85 g of the product obtained in Stage A, in 20 ml of tetrahydrofuran, 30 ml of diisobutylaluminum hydride in 1M solution in tetrahydrofuran are added to OOC. The mixture is left to return to ambient temperature and stirred for 2 hours. A solution of mixed sodium-potassium tartrate is added, diluted with tetrahydrofuran, filtered and evaporated to dryness under reduced pressure. The residue is chromatographed on silica (eluent ethyl acetate-hexane (2-8)) to obtain 1 g of the desired product.

Stage C: 3- (2-chlorophenyl) propanal
The procedure is carried out as in stage B of preparation 9, starting from 1 g of the product obtained in stage B above, using 2.5 ml of triethylamine, 1.75 ml of dimethyl sulfoxide and 2.8 g of pyridinium complex. sulfotrioxide. After chromatography on silica eluting ethyl acetate-hexane (1-9), 425 mg (43%) of the desired product are obtained.

NMR CDCl3 250 MHz 2.79 (m) and 2.94 (m): CH2; 7.05 to 7.25: aromatics; 9.82 (t): CHO.

EXAMPLE 11: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O- methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxycarbonyl ( 2- (3- (1-quinolinyl) 2-propyl) hydrazono)) erythromycin
Stage A: 11,12-dideoxy 3-of - ((2,6-dideoxy 3-C-methyl 3-O methyl alpha L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- (oxycarbonyl ( hydrazono) erythromycin isomer 10 (R) and isomer 10 (S) corresponding.

Is dissolved in 176 ml of methyl cyanide 17.65 g of 2'-acetate of 11-deoxy 10,11-didehydro 3-de (2,6dideoxy 3-C-methyl 3-O-methyl alpha-L- ribohexopyranosyl) oxy) 12-O- ((1H-imidazol-1-yl) carbonyl) 6-O-methyl 3-oxo erythromycin. 4.07 g of cesium carbonate and 25.5 ml of hydrazine hydrate are added. It is heated for 10 minutes at 85 ° C., the solvent is removed under reduced pressure at 40 ° C., extracted with methylene chloride, washed with water, dried, the solvent is evaporated off, the residue is taken up in methanol, the precipitate is filtered off, dried at 50 ° C under reduced pressure and collects 6.04 g of product. The mother liquors are concentrated to dryness, the residue is chromatographed on silica (eluent: isopropyl ether / methanol-triethylamine 80-10-10) and 0.83 g of isomer is recovered.
A (rf = 0.4) and 2.65 g of isomer B (rf = 0.2).

Stage B: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-Omethyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12, ll (oxycarbonyl (2- (3- (4-quinolinyl) 2-propyl) hydrazono)) erythromycin.

 13 g of product obtained as in Stage A and 4.66 g of 4-quinoline propanal prepared as indicated below are suspended in 130 ml of methanol. 4.8 ml of acetic acid are added and the mixture is stirred for 20 hours at room temperature.

5.3 g of sodium cyanoborohydride are then added and the stirring is continued for 4 hours. The methanol is removed under reduced pressure, extracted with ethyl acetate, washed with an aqueous solution of sodium hydroxide N then with water; the solvent is evaporated from the organic phase, the residue is chromatographed on silica (eluent: ethyl acetate-triethylamine 97-3) and 12.7 g of product are collected rf = 0.15. After a new chromatography on silica (eluent: methylene chloride-methanol 95-5 then 85-15) and crystallization from isopropyl ether, the pure product is obtained
F = 183 C, the analyzes of which are identical to those of Example 5.

PREPARATION OF EXAMPLE 11: 4-quinoline propanal.

Stage A: 2- (4-quinolinyl ethenyl) 1,3-dioxolane.

 Ion suspended in 40 ml of tetrahydrofuran 3.15 g of 4-quinoline carboxaldehyde and 8.6 g of [1,3- (dioxalan-2-yl) methyl] triphenylphosphonium bromide, cooled to -30 ° C then add 2.5 g of potassium terbutylate and stir for 1 hour. The mixture is left to return to room temperature, stirred for 3 hours, poured into a water / ice mixture, extracted with methylene chloride, washed with water, dried, the solvent evaporated under reduced pressure, taken up in an ethyl ether-pentane 3 mixture. 7, stir for 2 hours, filter and evaporate the solvent from the filtrate and obtain 3.99 g of the expected product.

Stage B: 2- [2- (4-quinolinyl) ethyl] 1,3-dioxolane.

 4.3 g of product obtained in stage A are dissolved in 40 ml of methanol, 0.215 g of activated carbon containing 10% palladium and hydrogen is added for 2 hours under a pressure of 1500 mbar. Filtered, rinsed with methanol, the solvent is evaporated and 4.2 g of expected product used as is in the next stage.

Stage C: 4-quinoline propanal.

 4.2 g of the product obtained in Stage B are dissolved in 70 ml of acetone and 70 ml of 2N hydrochloric acid are added. The mixture is heated at 40 ° C. for 6 hours, the acetone is removed under reduced pressure, extracted with ethyl acetate, washed with water, the aqueous phase is brought to pH = 9 with an aqueous ammonia solution. Extraction is carried out with ethyl acetate, the organic phases are combined, dried and the solvent evaporated. Obtained after chromatography on silica (eluent: ethyl acetate-cyclohexane 6-4) 1.36 g of the expected product.

EXAMPLE 12: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- (oxycarbonyl 2 - (3- (7-methoxy-4-quinoleinyl) propyl> hydrazono)) ârythromycin.

 299 mg of 7-methoxy 4quinoline propanal prepared as indicated below and 313.9 mg of product A prepared in Example 1 and 120 μl of acetic acid are dissolved in 2 ml of methanol. The mixture is stirred for 2 hours 15 minutes at room temperature and then 62.84 mg of sodium cyanoborohydride are added. The mixture is stirred for 20 hours at room temperature. The reaction medium is poured onto 50 ml of ethyl acetate, washed with 15 ml of sodium hydroxide then with water, dried, the solvent is evaporated under reduced pressure and 549 mg of product is collected which is purified by chromatography on silica (eluent: ispropyl ether-methanol-triethylamine 80-10-10) then (chloroform-methanol ammonia 96-4-0.4). 37.2 mg of expected product are recovered rf = 0.2.

Ana lyse
CHN% calculated 63.84 8.04 6.77% found 63.8 8.1 6.6
NMR CDC13 300 MHz 3.74 (s): H11; 3.17 (m): NH-CH2; 3.95 (s): quinoline OCH3 7.16-7.41 (d) -8.00 (d) -8.70 (d): H quinoline; 3.87 (q): H2; 2.65 (s): 6-OCH3; 2.65 (m): H8 0.82 (t): CH3-CH2
PREPARATION OF EXAMPLE 12: 7-methoxy 4-quinoline propanal.

Stage A: 2 - [(7-methoxy 4-quinolinyl) ethenyl] 1,3dioxolane.

 The procedure is as in the preparation of Example 11, stage A, initially using 787 mg of 7-methoxy 4-quinoline carboxaldehyde. 2.61 g of product are obtained which is chromatographed on silica (eluent: chloroform-ethyl acetate 7-3). 931 mg of expected product is obtained.

Stage B: 2- [2- (7-methoxy 4-quinolinyl) ethyl] 1,3dioxolane.

 The procedure is as in the preparation of Example 11 stage B using 931 mg of product prepared in stage A and 869 mg of expected product is obtained.

Stage C: 2- (7-methoxy 4-quinoline) propanal.

 The procedure is as in the preparation of Example 11 stage C using 845 mg of product obtained in stage B. We obtain 310 mg of expected product rf = 0.15.

EXAMPLE 13 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- (oxycarbonyl 2 - (3- (2- (3-pyridinyl-4-thiazolyl) propyl) hydrazono)) erythromycin.

 The procedure is as in Example 12, using initially in 3.7 ml of methanol, 158 mg of 2- (3-pyridinyl) 4-thiazole propanal, 370 mg of product A prepared in Example 1 and 70 μl acetic acid then after 4 hours of stirring at room temperature 75 mg of sodium cyanoborohydride. After 16 hours of stirring at room temperature, 16 mg of aldehyde and 20 mg of reducing reagent are again added and stirring is continued for 3 hours. Add water, ethyl acetate, basify to pH = 9 with ammonia, wash the organic phase with water, dry and evaporate the solvent under reduced pressure. After chromatography on silica (eluent: isopropyl ether-methanol-triethylamine 80-10-10), 203 mg of expected product are obtained.

3.18 (m): H10; 3.74 (s): H11; 7.05 (s): H5 thiazole; 7.37 (dd) -8.24 (ddd) -8.62 (dd) -9.13 (dd): pyridine; 3.86 (q): H2; 2.65 (s): 6-OCH3; 2.66 (m): H8; 0.85 (t): CH3-CH2.

PREPARATION OF EXAMPLE 13: 2- (3-pyridinyl) 4-thiazole propanal.

Stage A: [[2- (3-pyridinyl) 4-thiazolyl] ethenyl] 1,3-dioxolane.

 The procedure is as in the preparation of Example 11 stage A using at the start 2.6 g of 2- (3-pyridinyl) 4-thiazolyl carboxaldehyde. Obtained after chromatography on silica (eluent: ethyl acetate-hexane 2-1) 4.8 g of the expected product (rf = 0.35) used as it is for the following stage.

Stage B: 2- [2 - ((3-pyridinyl) 4-thiazolyl) ethyl] 1,3-dioxolane.

 The procedure is as in the preparation of Example 11 stage B using initially 4.8 g of product prepared in stage A and obtained after chromatography of the residue on silica (eluent ethyl acetate-cyclohexane 2-1) 1.4 g of expected product.

Stage C: 2- (3-pyridinyl) 4-thiazolyl propanal.

 The procedure is as in the preparation of Example 11 stage C using at the start 1.2 g of product prepared in stage B.

468 mg of expected product is obtained after chromatography on silica (eluent: ethyl acetate-hexane 2-1).

By operating as in the previous examples using at the start the compound of Example 1 and the appropriate aldehyde, the following products were prepared
EXAMPLE 14: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-Omethyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- (oxycarbonyl 2- (3- (1H-imidazol-1-yl) propyl) hydra sono)) arythromycin.

NMR (CDCl3) 300 MHz 0.83 (t): CH3-CH2; 1.08 (d) -1.17 (d) -1.25 (d) -1.3 (d) -1.35 (d): CH3-CH; 1.3 (s) -1.47 (s): 6 and 12 Me; 2.12 (m) CH2-CH2-CH2; 2.27 (s): N (Me) 2; 2.45 (m): H'3; 2.59 (s): 6-OMe; 3.05 (m): H4; 2.6 to 3.2: H'2, H10: H8 and CH2NH; 3.53 (m): H'5; 3.72 (s): H11; 3.85 (q): H2; 4.27: H'1 and H5; 4.63 (m): CH2-N; 4.99 (dd): H13; 5.46 (t): NH-CH2; 7,10-7,64-7,66-7,97: aromatic.

EXAMPLE 15: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-Omethyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- (oxycarbonyl 2- (3- (3H-imidazo (4,5-b) pyridin-3-yl) propyl) hydrazono)) erythromycin.

NMR (CDCl3) 300 MHz 0.85 (t): CH3-CH2; 1.09-1.19 (d) -1.25 (d) -1.31 (d) -1.34 (d): CH3CH; 1.33 and 1.48: 6 and 12 Me; 1.57 and 1.96
CH2 at 14; 1.66 and 1.87: CH2 in 7; 2.05 and 2.18: CH2-CH2-CH2; 2.26 (s): N (CH3) 2; 2.44 (m): H3; 2.6 (s): 6-OCH3; 2.66 (m): H8; 2.70 to 2.85: CH2NH; 3.04 (m): H4; 3.18: H2, H10; 3.70 (s): H11; 3.85 (q): H2; 4.27: H'1 and H5; 4.42-4.70: CH2-N; 4.97 (dd): H13 5.56 (t): Nu; 8.22 (dd) -8.05 (d) -8.28 (s) -8.38 (d) aromatic.

EXAMPLE 16: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-Omethyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- (oxycarbonyl 2- (3- (1,1'-biphenyl-4-yl) propyl) hydrazono)) ârythromycin.

NMR (CDCl3) 300 MHz 0.87 (t): CH3-CH2; 1.08 (d) -1.18 (d) -1.23 (d) -1.32 (d) -1.38 (d): CH3-CH; 1.34 (s) and 1.48 (s): 6 and 12 Me; 2.26 (s): N (CH3) 2; 2.44 (m): H'3; 2.65 (s): 6-OCH3; 2.65 (m) H8; 2.77 (m) CH2-Ar; 2.85 (t): CH2NH; 3.07 (m)
H4; 3.18 (m): H'2, H10; 3.25 (m): H'5; 3.76 (s): H11 3.87 (q): H2; 4.27: H'1 and H5; 5.04 (dd): H13; 5.37 (t): NH-CH2; 7.25 to 7.6: aromatics.

EXAMPLE 17: 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-ethyl 3-O methyl alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,11- (oxycarbonyl 2 - (3- (2-phenyl 4-thiazolyl) propyl> hydrazono)) arythromycin.

NMR (CDCl3) 300 MHz 0.86 (t): CH3-CH2; 1.07 (d) -1.19 (d) -1.24 (d) -1.31 (d) -1.35 (d): CH3-CH; 1.32 (s) -1.48 (s): 6-CH3 and 12-CH3; 2.26 (s): N (CH3) 2; 2.65 (s): 6-OCH3: 2.45 (m): H'3; 2.65 (m): H8; 2.8 to 3.25 (m): H4, H10, H '2' CH2-Ar and
CH2N; 3.53 (m): H'5; 3.76 (m): H11; 3.86 (q): H2; 4.27 (d): H'1 and H5; 5.04 (dd): H13; 5.36 (t): NH; 6,967.40-7.93: aromatic.

EXAMPLE 18 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- (oxycarbonyl 2 - (3- (5-phenyl 1,2,4-thiadiazol-3-yl) propyl> hydrazono)) erythromycin.

NMR (CDCl3) 300 MHz 0.87 (t): CH3-CH2; 1.33 and 1.47: 6 and 12 Me; 2.17 (m) CH2-CH2-CH2; 2.26 (s): N (CH3) 2; 2.67 (s): 6-OCH3; 2.67 (s): H8; 3.76 (s): H11; 3.85 (q): H2; 5.06 (dd)
H13; 5.39 (t): Nu-CH2; 7.49-7.94: aromatic.

EXAMPLE 19: 11,12-dideoxy 3-de ((2,6-dideoxy 3-c-methyl 3-O methyl alpha-L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,11- (oxycarbonyl 2 - 2- (3- (4- (4-chlorophenyl-1H-imidazol-1-yl) propyl) hydrazono)) erythromycin.

EXAMPLE 20 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- (oxycarbonyl 2 - (3- (6-methoxy-4-guinoline) propyl) hydrazono)) arrythromycin.

 By operating as in Example 12, the desired product was obtained.

NMR CDCl3 300 MHz 3.74 (s): H11; 5.52 (tl): NH-CH2; 3.98 (s): quinoline OCH3; 7.25-7.35 (d) -7.99 (d) -8.65 (d): H quinoline; 3.87 (q): H2; 2.64 (s): 6-OCH3; 2.64 (m): H8; 5.02 (dd): H13.

représente le radical

By operating as above, the compounds of formula (I) were prepared in which the radical

represents the radical

EXAMPLE OF A PKARMACEUTIOUE COMPOSITION
Tablets containing
Product of Example 5 .................... 150 mg
Excipient qs .......................... 1 g
Details of the excipient: starch, talc, magnesium stearate
PHARNACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION
Liquid dilution method
A series of tubes is prepared in which the same quantity of sterile nutritive medium is distributed. Increasing quantities of the product to be studied are distributed in each tube, then each tube is seeded with a bacterial strain.

 After incubation for twenty-four hours in an oven at 370C, the growth inhibition 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 with the product of Example 5: (reading after 24 hours)
GRAM + bacterial strains
Staphylococcus aureus 0llUC4 0.02
Staphylococcus aureus 0llG0251 0.08
Staphylococcus epidermidis 012GOllI 0.04
Streptococcus pyogenes <0.02
group A 02AlUC1
Streptococcus agalactiae <0.02
group B 02BlHTl
Streptococcus faecalis <0.02
group D 02D2UC1
Streptococcus faecium <0.02
group D 02D3HT1
Streptococcus sp <0.02
group G 02GOGR5
Streptococcus mitis <0.02
02mitCB1
Streptococcus agalactiae <0.02
group B 02B1SJ1
Streptococcus pneumoniae <0.02 032UC1
Streptococcus pneumoniae <0.02
030SJ5
In addition, the product of Example 5, showed an interesting activity on bacterial strains with GRAM
Haemophilus Influenzae 351HT3, 351CB12, 351CA1 and 351GR6.

 The products of Examples 12 and 13 also demonstrated excellent activity on the gram (+) and gram (-) bacterial strains.

 Thus, by operating as indicated above, the following results were obtained with the products of Examples 12 and 13 (reading after 24 hours).

Bacterial strains with GRAM + Ex. 12 Ex. 13
Staphylococcus aureus 0.08 0.04 0llUC4
Staphylococcus aureus 0.08 0.15 011G0251
Staphylococcus epidermidis 0.04 0.04 012 GOllI
Streptococcus pyogenes <0.02 <0.02 02 AlUCl
Streptococcus agalactiae S 0.02 0.02 02BlHTl
Streptococcus faecalis # 0.02 # 0.02
02D2UC1
Streptococcus faecium # 0.02 # 0.02
02D3HT1
Streptococcus pneumoniae 0.04 # 0.02
032UC1
Streptococcus pneumoniae # 0.02 0.02 030SJ5I
Streptococcus pneumoniae 0.6 0.6
030CR18C
Haemophilus inflienzae 1.2 0.6 351HT3
Haemophilus inflienzae 1.2 1.2
35lCB12

Claims (21)

R and S, as well as the addition salts with acids of the compounds of formula (I).  in which R'1 and R'2 identical or different represent a hydrogen atom or a hydrocarbon radical containing up to 23 carbon atoms, saturated or unsaturated, optionally interrupted by one or more heteroatoms and optionally carrying one or more functional groups and Z represents a hydrogen atom or the remainder of a carboxylic acid containing up to 18 carbon atoms, the wavy line in position 10 indicating that the methyl may be of R or S configuration, or a mixture of configuration

 in which either R1 and R2, which are identical or different, represent a hydrogen atom, or a hydrocarbon radical containing up to 24 carbon atoms, saturated or unsaturated, optionally interrupted by one or more heteroatoms and optionally carrying one or more functional groups, either R1 and R2 form with the nitrogen atom to which they are linked a heterocycle optionally containing one or more heteroatoms chosen from nitrogen, oxygen and sulfur, or else R1 and R2 together form a radical

 CLAIM8 8 1) The compounds of general formula (I) 2) The compounds of formula (I) as defined in claim 1 in which Z represents a hydrogen atom. 3) The compounds of formula (I) as defined in claim 1 or 2 in which R1 represents a hydrogen atom. 4) The compounds of formula (I) as defined in claim 1 or 2 in which R1 and R2 each represent a hydrogen atom. 5) The compounds of formula (I) as defined in claim 1 or 2 in which R'1 represents a hydrogen atom. 6) The compounds of formula (I) as defined in claim 1, 2 or 5 in which R1 and R2 together form a radical  = CH (CH2) nArl in which Ar1 represents an optionally substituted aryl or heteroaryl radical and n represents an integer which can vary from 0 to 8. 7) The compounds of formula (I) as defined in claim 1, 2 or 5 in which R1 and R2 together form a radical

 in which p and q, which are identical or different, represent an integer varying from 0 to 6, A and B which are identical or different, represent a hydrogen or halogen atom or an alkyl radical containing up to 8 carbon atoms, the geometry of the double bond being E or Z or a mixture E + Z, or A and B form a third bond with the carbon atoms to which they are linked and Ar2 represents an aryl or heteroaryl radical, mono or polycyclic, optionally substituted. 8) The compounds of formula (I) as defined in claim 7, in which p and q represent the number 0. 9) The compounds of formula (I) as defined in claim 7 or 8, in which A and B represent a hydrogen atom. 10) The compounds of formula (I), as defined in claim 1, 2 or 3 in which R2 represents a radical (CH2) rAr3 in which r represents an integer varying from 0 to 6 and Ar3 represents an aryl radical or possibly heteroaryl, slightly substituted. 11) The compounds of formula (I) as defined in claim 10, in which Ar3 represents a 4-quinolinyl radical optionally mono or polysubstituted on one and / or the other of the 2 cycles of quinoline. 12) The compounds of formula (I) as defined in claim 10, in which Ar3 represents an unsubstituted 4-quinolinyl radical. 13) The compounds of formula (I) as defined in claim 10, in which Ar3 represents a 4-quinolinyl radical substituted by a methoxy radical. 14) The compounds of formula (I) as defined in claim 10 in which Ar3 represents a thiazolyl radical substituted by a pyridyl radical. 15) The compounds of formula (I) as defined in any one of claims 10 to 14, in which r represents an integer varying from 1 to 4. 16) The compounds of formula (I) whose names follow - 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-methyl alpha) L-ribohexopyranosyl) oxy) 6-0-methyl 3-oxo 12,11- (oxycarbonyl (2- (3- (4-quinolinyl) 2-propyl) hydrazono)) erythromycin, - 11,12-dideoxy 3-de ( (2,6-dideoxy 3-C-methyl 3-O-methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- (oxycarbonyl 2- (3- (7-methoxy-4- quinoline) propyl) hydrazono)) erythromycin, - 11,12-dideoxy 3-de ((2,6-dideoxy 3-C-methyl 3-O-methyl alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3- oxo 12,11- (oxycarbonyl 2- (3- (2- (3-pyridinyl-4-thiazolyl) propyl) hydrazono)) erythromycin. 17) As medicaments, the compounds of formula (I) as defined in any one of claims 1 to 15 as well as their addition salts with pharmaceutically acceptable acids. 18) As medicaments the compound defined in claim 16 as well as its addition salts with pharmaceutically acceptable acids. 19) The pharmaceutical compositions containing as active principle at least one medicament defined in claim 17 or 18. 20) Process for the preparation of compounds of formula (I) as defined in claim 1, characterized in that a compound of formula (II) is subjected

 wherein Z retains the meaning indicated in claim 1, or else to the action of hydrazine NH2NH2 to obtain the compound of formula (IA):

 which is subjected if desired to the action of an aldehyde R'2CHO or a ketone

 in which R'1 and R'2 have the meaning indicated in claim 1, to obtain the compound of formula (zig) corresponding

 in which R'1 and R'2 retain the same meaning as above, which is subjected if desired to the action of a reducing agent to obtain the corresponding compound of formula (IC)

 in which R'1 and R'2 retain the preceding meaning, that is to say a compound of formula (I) in which R1 represents a hydrogen atom and R2 represents a radical CHR'1-R'2, then if desired, subjects the compound of formula (IC) to the action of an agent capable of replacing the hydrogen atom of the NH group with an R1 group as defined in claim 1 except for the value hydrogen, then if desired, subjects the compounds obtained to the action of an acid to form the salt and / or to the action of an esterification agent for the OH group at 2 ′. 21) Method according to claim 20, characterized in that the compound of formula (II) is subjected

 in which Z retains the meaning indicated in claim 1, by the action of a compound of formula NH2NHR2 in which R2 has the meaning indicated in claim 1 to obtain the compound of formula (I'A)

 which is subjected if desired, to the action of an agent capable of replacing the hydrogen atom of the NH group with a radical R1 as defined in claim 1 with the exception of the hydrogen value to obtain the compound of corresponding formula (I'B)

 wherein R1 and R2 have the meaning indicated above which is subjected if desired, to the action of an esterification agent of the OH group at 2 'or to the action of an acid to form the salt.