Title of Invention	"THE ERTHROMYCIN COMPOUNDS AND PROCESS THEREOF"
Abstract	The erthromycin compounds of formula (I): in which A and B form together with the atoms to which they are linked a group: R1 represents an NH2 radical or an NH-alkyl, NH-alkenyl or NH-alkynyl radical containing up to 18 atoms of carbon or a (CH2)nAr radical or an NH(CH2)nAr or N=CH(CH2)nAr radical in which n represents an integer comprised between 1 and 6, and Ar represents an optionally substituted aryl or heteroaryl.

Title of Invention

"THE ERTHROMYCIN COMPOUNDS AND PROCESS THEREOF"

Abstract

The erthromycin compounds of formula (I): in which A and B form together with the atoms to which they are linked a group: R1 represents an NH2 radical or an NH-alkyl, NH-alkenyl or NH-alkynyl radical containing up to 18 atoms of carbon or a (CH2)nAr radical or an NH(CH2)nAr or N=CH(CH2)nAr radical in which n represents an integer comprised between 1 and 6, and Ar represents an optionally substituted aryl or heteroaryl.

Full Text	The present invention relates to the erthromycin compounds and process thereof. The invention relates to new derivatives of erythromycin, their preparation process and their use as medicaments. The present invention relates to the erthromycin compounds of formula (I): (Formula Removed) in which A and B form together with the atoms to which they are linked a group: (Formula Removed) R1 represents an NH2 radical or an NH-alkyl, NH-alkenyl or NH-alkynyl radical containing up to 18 atoms of carbon or a (CH2)nAr radical or an NH(CH2)nAr or N=CH(CH2)nAr radical in which n represents an integer comprised between 1 and 6, and Ar represents an optionally substituted aryl or heteroaryl radical, Z represents a hydrogen atom or the remainder of a carboxylic acid containing up to 18 carbon atoms, and R represents: a hydrogen atom, a heterocyclic radical containing at least one nitrogen atom and optionally another heteroatom aromatic or non aromatic, saturated or unsaturated, mono or bicyclic, containing up to 12 members, optionally substituted on the nitrogen atom, a linear, branched or cyclic alkyl, alkenyl or alkynyl radical, containing up to 18 carbon atoms optionally substituted by one or more group: • hydroxyl, . halogen, . cyano, . nitro, . amidinyl, . guanidinyl, . heterocyclic, as defined previously, . alkyloxy, alkenyloxy or alkynyloxy having at most 6 carbon atoms, . alkylthio, alkenylthio or alkynylthio having at most 6 carbon atoms, the sulphur atom being optionally oxidized into the sulphoxide or into the sulphone, . aryl, aralkyl, . aryloxy, aralkyloxy, . arylthio, aralkylthio, the sulphur atom being optionally oxidized into the sulphoxide or into the sulphone, (Figure Removed) in which: either R and R', 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 R'^ and R'2 radicals being optionally substituted by one or more of the following radicals hydroxy, alkyloxy, alkenyloxy, alkynyloxy, alkylthio, alkenylthio or alkynylthio containing up to 8 carbon atoms, amino, monoalkylamino containing up to 4 carbon atoms, dialkylamino containing up to 8 carbon atoms, cyano, free, esterified or salified carboxy, acyl or carbamoyl, containing up to 8 carbon atoms, by an Si(alk)3 or Si(0alk)3 in which alk represents an alkyl radical containing up to 4 carbon atoms, by a heterocyclic radical as defined previously, or R1^ and R2 form together with the nitrogen atom to which they are linked a mono or bicyclic heterocycle radical, optionally containing another aromatic or non aromatic, saturated or unsaturated heteroatom, containing 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, (Figure Removed) in which B-j_ represents either an alkyl or alkyloxy radical having at most 6 carbon atoms, or an aryl, aralkyl, aryloxy or aralkyloxy radical, . free or protected formyl, free, esterified or salified carboxy, thiocyanate, acyl or carbamoyl, . (CH2)nR', R1 representing the remainder of an amino acid, and n representing an integer comprised between 0 and 6, as well as the addition salts with acids of the compounds of formula (I). As an example of the addition salts of the present derivatives with mineral or organic acids, there can be mentioned the salts formed with the following acids: acetic, propionic, trifluoroacetic, maleic, tartaric, methanesulphonic, benzenesulphonic, p-toluenesulphonic, hydrochloric, hydrobromic, hydroiodic, sulphuric, phosphoric and especially stearic, ethylsuccinic or laurylsulphuric acids. In the definition of the products of the invention: - the heterocyclic radical is preferably the pyrrolyl, pyrrolidinyl, pyridyl, pyrazinyl, pyrimidyl, piperidinyl, piperazinyl, quinuclidinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, imidazolyl, benzimidazolyl, triazolyl, thiazolyl, azetidinyl, aziridinyl radical. Naturally there can be preferably mentioned the heterocyclic radicals mentioned hereafter in the experimental part, - the alkyl, alkenyl or alkynyl radical is preferably a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, decyl or dodecyl, vinyl, allyl, ethynyl, propynyl, cyclobutyl, cyclopentyl or cyclohexyl radical, - the halogen is preferably fluorine or chlorine, or bromine, - the aryl radical is preferably the phenyl radical, - the aralkyl radical is preferably a (CgH5)-(CH2)a radical, a being an integer comprised between 1 and 6, for example the number 1, 2, 3 or 4 or a naphthyl radical, - the alkyloxy radical is preferably a methoxy, ethoxy, propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert- butyloxy, n-pentyloxy, isopentyloxy, sec-pentyloxy, tert- pentyloxy, neopentyloxy, n-hexyloxy, sec-hexyloxy, tert- hexyloxy radical, - the corresponding alkylthio radical can be used by taking the same values and by replacing the oxygen atom with a sulphur atom, example: methylthio, ethylthio .... Moreover, the sulphur atom can be oxidized, example: methylsulphinyl, methylsulphonyl .... the alkenyloxy radical is preferably a vinyloxy, 1-propenyloxy, allyloxy, l-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methyl-1-butenylox, pentenyloxy, hexenyloxy, 3-methyl 2-butenyloxy radical, - the corresponding alkenylthio radical can be used by taking the same values and by replacing the oxygen with a optionally oxidized sulphur, - the alkynyloxy radical is preferably an ethynyloxy, propargyloxy, propynyloxy, butynyloxy, pentynyloxy, hexynyloxy radical, - the corresponding alkynylthio radical can be used by taking the same values and by replacing the oxygen with an optionally oxidized sulphur. - the aryloxy radical is preferably a phenyloxy, thienyloxy, furyloxy, thiazolyloxy, thiadiazolyloxy, oxazolyloxy, tetrazolyloxy, pyrrolyloxy, imidazolyloxy, pyrazolyloxy, isothiazolyloxy, isoxazolyloxy, criazolyloxy, thiatriazolyloxy, pyridyloxy radical, as well as the condensed groups such as benzothienyloxy, benzofuryloxy, indolyloxy, benzimidazolyloxy, - The corresponding optionally oxidized arylthio groups can of course be used, for example: phenylthio, phenylsulphonyl, phenylsulphinyl ... - the aralkyloxy radical is preferably a benzyloxy, phenylethyloxy, phenylpropyloxy, thienylmethyloxy, thienylethyloxy, thienylpropyloxy, furfuryloxy, furylethyloxy, furylpropyloxy, thiazolylmethyloxy, thiazolylethyloxy, tetrazolylmethyloxy, thiadiazolylmethyloxy, thiadiazolylethyloxy radical, - The corresponding optionally oxidized aralkylthio groups can of course be used. Among the protected formyl radicals, there can be mentioned more especially the radicals of acetal type. The following radicals are preferred: 1,3-dioxolan-2-yl, dimethoxymethyl, diethoxymethyl. As esterified carboxyl radicals, the following radicals can be mentioned: alkoxycarbonyl having at most 7 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl. There can also be mentioned the alkyloxyalkyloxycarbonyl radicals such as methoxymethoxycarbonyl, isopropyloxymethoxy-carbonyl, the alkylthiomethoxycarbonyl radicals such as methylthiomethoxycarbonyl, isopropylthiomethoxycarbonyl, the acylxyalkyloxycarbonyl radicals such as pivaloyloxymethoxy-carbonyl, acetocyethoxycarbonyl. Among the salts formed with the carboxyl group, there can be mentioned sodium, potassium, lithium, calcium, magnesium, ammonium salts or the salts formed with amino organic bases such as trimethylamine, diethylamine, triethylamine, tris(hydroxymethyl) aminomethane. Among the acyl radicals, the can be mentioned in particular acetyl, propionyl, butyryl, isobutyryl, n-valeryl, isovaleryl, tert-valeryl and pivalyl radicals. Among the preferred compounds according to the invention, there can be mentioned those in which Z represents a hydrogen atom, those in which R-^ represents an NH(CH2)nAr radical, n and Ar retaining their previous meaning, and in particular those in which Ar represents a radical: (Figure Removed) and in which X represents a hydrogen atom, a CH3, OH, OMe radical, or a halogen atom, quite especially those in which Ar represents a radical: (Figure Removed) and as well as those in which n represents the number 3. Among the preferred compounds, there can also be mentioned the compounds of formula (I), in which R represents a hydrogen atom, a radical: (Figure Removed) or a radical: optionally substituted on the nitrogen atom by a radical: (CH2)m—(CzzC)nXA A B in which m represents an integer comprised between 0 and 20, n represents the number 0, 1, 2, or 3, and either A and B, identical or different, represent a hydrogen atom or a halogen atom or an alkyl or aryl radical, containing up to 8 carbon atoms, the geometry of the double bond being E or Z or an E + Z mixture, or A and B form a third bond between the carbon atoms to which they are linked, and XA represents: . a saturated or unsaturated, linear or branched alkyl radical containing 6 to 20 carbon atoms, optionally interrupted by one or more heteroatoms and optionally substituted by one or more halogen atoms, . a cyclic alkyl radical containing 3 to 8 carbon atoms optionally substituted by a carbocyclic aryl radical, . a halogen atom, . a C=sN radical, . an OR3, COR4, C02R5, SRg, (Figure Removed) radical in which R3 , R4 , Rq , Rg , R7/ Rg and Rg represent a hydrogen atom, an alkyl radical containing up to 8 carbon atoms, optionally interrupted by one or more heteroatoms and optionally substituted by one or more halogen atoms, a carbocyclic or heterocyclic aryl or aralkyl radical containing up to 14 carbon atoms, optionally substituted by one or more radicals chosen from the group constituted by free, salified, esterified or amidified carboxy radicals, hydroxyl radicals, halogen atoms, N02 radicals, ON radicals, alkyl, alkenyl and alkynyl, 0- alkyl, 0-alkenyl and 0- alkynyl, S- alkyl, S- alkenyl and S- alkynyl, SO -alkyl, SO -alkenyl, SO -alkynyl, S02 - alkyl, S02 - alkenyl, S02- alkynyl radicals, containing up to 12 carbon atoms optionally substituted by one or more halogen atoms, carbocyclic or heterocyclic aryl, 0-aryl, S-aryl radicals containing up to 14 carbon atoms, the radicals: (Figure Removed) R'x and R2/ identical or different, representing a hydrogen atom or an alkyl radical, containing up to 12 carbon atoms, aryl radicals themselves optionally substituted by one of the substituents indicated above as substituents of aryl radicals, an NR1R2 radical in which either R^ and R2, identical or different, represent a hydrogen atom or an alkyl radical containing up to 20 carbon atoms, -CO-alkyl or -C02-alkyl containing up to 8 carbon atoms, or an aryl, -CO-aryl or ~C02-aryl aralkyl, -CO-aralkyl or -C02-aralkyl radicals containing up to 14 carbon atoms, the aryl radicals being themselves optionally substituted by one of the substituents indicated above as substituents of aryl radicals, or R^ and R2 form together with the nitrogen atom to which they are linked a ring with 3 to 8 members optionally containing another heteroatom and optionally substituted by one of the substituents indicated above as substituents of aryl radicals, . a carbocyclic aryl radical optionally substituted by one or more of the radicals mentioned above as substituents of aryl radicals, . a heterocyclic aryl radical containing one or more heteroatoms, optionally substituted by one or more of the radicals mentioned above as substituents of aryl radicals, . an OC{Ar)3 radical in which Ar represents a carbocyclic aryl radical optionally substituted by one or more of the substituents mentioned above as substituents of aryl radicals. Quite especially a subject of the invention is the compounds the preparation of which is given hereafter in the experimental part and quite particularly the product of Example 3. The products of general formula (I) have a very good antibiotic activity on gram ® bacteria such as staphylococci, streptococci, pneumococci. The compounds of the invention can therefore be used as medicaments in the treatment of infections caused by susceptible germs and in particular, in that of staphylococcia, such as staphylococcal septicemias, malignant staphylococcia of the face or skin, pyodermatitis, septic or suppurating wounds, boils, anthrax, phlegmons, erysipelas and acne, staphylococcia such as acute primary or post-influenzal angina, bronchopneumonia, pulmonary suppuration, streptococcia such as acute angina, otitis, sinusitis, scarlet fever, pneumococcia such as pneumonia, bronchitis; brucellosis, diphteri, gonococcal infection. 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 by germs of the Mycobacterium genus. Therefore a subject of the present invention is 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 mineral or organic acids. More particularly a subject of the invention is, as medicaments and, in particular antibiotic medicaments, the product of Example 3 and its pharmaceutically acceptable salts. A subject of the invention is also the pharmaceutical compositions containing at least one of the medicaments defined above, as active ingredient. These compositions can be administered by buccal, rectal, parenteral route or by local route as a topical application on the skin and mucous membranes, but the preferred administration route is the buccal route. They can be solid or liquid and be presented in the pharmaceutical forms commonly used in human medicine, such as for example, plain or sugar-coated tablets, capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared according to the usual methods. The active ingredient can be incorporated with 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, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives. These compositions can also be presented in the form a powder intended to be dissolved extemporaneously in an appropriate vehicle, for example apyrogenic sterile water. Also a subject of the invention is a preparation process characterized in that a compound of formula (II): (Figure Removed) in which A, B and Z retain their previous meaning is subjected to the action of a compound of formula (III! HNoOR in which R retains its previous meaning in order to obtain the corresponding compound of formula (I), then if desired, the hydroxyl in position 2' is released and/or subjected to the action of an acid in order to form the salt, and/or to the action of" an agent which modifies the R radical. The compounds of formula (I) used as a starting product can be prepared according to the process described in the European Patent 0676409. In a preferred implementation: - the release of the hydroxyl in position 2' is carried out by methanolysis, - the salification is carried out according to standard processes. 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-(4-quinolinyl)propyl)hydrazono)) erythromycin is called hereafter product A, the product is described in Example 5 of the Patent EP 0676409. EXAMPLE 1; (E) 9-0-(phenylmethyl) oxime of 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribohexopyranosyl) oxy)-€-0-methyl-3-oxo-12,ll-(oxycarbonyl(2-(3-(4-quinolinyl)propyl)hydrazono)) erythromycin A mixture of 1 g of product A, 25 cm3 of ethanol, 0.91 g of benzylhydroxylamine hydrochloride is agitated under reflux for 10 days. Extraction is carried out with ethyl acetate, followed by washing with a 10% solution of ammonium hydroxide, drying over magnesium sulphate and evaporating to dryness. The product obtained is chromatographed eluting with a methylene chloride, methanol, ammonium hydroxide mixture 97-3-0.4. 0.69 g of product is obtained which is purified by chromatography on silica eluting with a methylene chloride, isopropyl alcohol, ammonium hydroxide mixture (94-6-0.4). 120 mg of product is obtained which is taken up in ethyl ether, the precipitate is filtered off, followed by evaporating to dryness, taking up in ethyl acetate, washing with ammonium hydroxide, drying over magnesium sulphate and evaporating to dryness. 90 mg of sought product is obtained. NMR CDC13 ppm 0.78 (t): CH3-CH2; 0.98 (d): 8-Me; 1.09 (d): 10-Me; 1.27 (d): 5'-Me; 1.31 (d): 2-Me; 1.43 and 1.46: 6 and 12-Me; -1.25 and 1.69: CH2 in position 4'; -1.40 and 1.69: CH2 in position 7; -1.55 and 1.95: CH9 central chain; 2.29 (s): N(Me)9; «2.33 £* £4 and 2.80 (m)-5.84 (t): CH2NH; 2.48 (m): H'3; 2.66 (q): H10; 2.70 (s) : 6-OMe; 3.09 (m): H5; 3.20 (dd): H'2; 3.10 to 3.30: CH2C=; 3.55 (mi : H'5; 3.78 (m): Hg --> E isomer; 3.87 (s): HII; 3.88 (q) : H2; 4.29: H^ and H5; 4.87 (d) and 4.98 (d) : OCH2$ ; 5.02 (dd): H13 ; 7.15 to 7.30: phenyl and H3 quinoline; 7.51 and 7.67: H6 and Hy-8.09 and 8.13: H5 and HQ: quinoline; 8.78 (d): H2. EXAMPLE 2; 9(E) 9-oxime of 11,12-dideoxy-3-de[(2,6-dideoxy-3 -C-methyl-3-O-methyl-alpha-L-ribohexopyranoayl) oxy]-6-0-methyl-3-oxo-12,ll-[oxycarbonyl[[3-(4-quinolinyl)propyl3-hydrazono]] erythromycin A mixture of l g of product A, 25 cm3 of ethanol and 311 mg of hydroxylamine hydrochloride is agitated for 6 weeks at 105°C, followed by chromatography on silica eluting with a methylene chloride, methanol, ammonium hydroxide mixture 92-8-0.6. The product obtained is evaporated to dryness, taken up in ethyl acetate, washed with a 5% solution of ammonium hydroxide, dried and evaporated to dryness. 1.029 g of product is obtained which is purified by chromatography on silica eluting with a methylene chloride, methanol, ammonium hydroxide mixture 96-4-0.4. 430 mg of product is obtained which is purified on silica eluting with a methylene chloride-methanol-ammonium hydroxide mixture (96-4-0.4). 272 mg of sought product is obtained. NMR CDC13 ppm 0.86 (t): CHo-CH9; 1.06 (dl)-1.19 (d)-1.29 (d)-1.33 (d)-1.38 •J £* (d): the CH3-CH's; 1.51 (s)-1.60 (s) 6 and 12-Me; 2.28 (s): N(Me)2; 2.47 (m): H'3; 2.73 (ql): HIQ; 2.84 (m): CHo-NH; 2.89 (S): 6-OMe; 2.90 to 3.15: CH2-0=; -3.14 (dd): H'2; 3.58 (m): H'5; 3.92 (s): H2; 3.95 (s): HII; -3.95 (m) : H8 --> E isomer; -4.31: H^ and H5; 5.09 (dd) : H13; 6.75 (d): H3; 8.35 (d): H2; 7.43 and 7.61: Hg and H?-7.89 and 7.99: H5 and Hg: guinoline; =6.20 and 11.45: OH oxime and NH; + ether =1/3 of a mole. EXAMPLE 3; (9E) 9-[0-(3-piperidinyl) of 11,12-dideoxy-3-de t(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribohexo-pyranosyl}-oxy]-6-0-methyl-3-oxo-12,11-[oxycarbonyl[ [3-{4-quinolinyl)-propyl]hydrazono]] erythromycin 8 cm3 of a 0.5N hydrochloric acid solution in ethanol is added to a solution containing 1.12 g of N-methylbenzyl-3-hydroxylamine piperidine and 5 cm3 of ethanol. 1 g of product A in solution in 10 cm3 of ethanol is added to the solution obtained. Agitation under reflux is carried out for 4 days. Another 0.76 g of hydroxylamine in solution in 5 cm3 of ethanol is added, the pH is adjusted to 3.5 by the addition of a solution of hydrochloric acid and ethanol, followed by evaporating to dryness, taking up in ethyl acetate, washing with ammonium hydroxide, drying and evaporating to dryness. Purification is carried out by eluting with an ethyl acetate, triethylamine mixture 95-5, 585 mg of product is obtained. 357 mg of this product B is dissolved in a solution containing 10 crcr1 of mechanol and 53 mg of palladium on charcoal. Agitation is carried out under a hydrogen atmosphere for 5 hours, followed by filtering, rinsing with itiethanol and evaporating to dryness. Chromatography on silica is carried out eluting with a methylene chloride-methanol-ammonium hydroxide mixture (96-4-1). 150 mg of product is obtained. NMR CDC13 ppm =N-0-CH=, localized; 0.73 (t)-0.76 (t): CH3-CH2; 1.00 (d): 8-Me; 1.14 (d): 10-Me; 1.26 (d): 5'-Me; 1.30 (d): 4-Me; 1.36 (d): 2-Me; 1.42-1.47: 6 and 12-Me; 2.27 (s) N(Me)2; 2.69-2.71: 6-OMe; 2.45 (m): H'5; -2.71 (masked): H10; 3.08 (m): H4: 3.19 (dd): H'2; -2.79 (m): CH2NHNC; 2.65 to 3.35: the CH2N and CH2*'s ; 3.55 (m): H'5; 3.74 (m): Hg --> DE, does not seem to be in deficit; 3.82-3.98: 0-CH=; 3.87 (s) : H11: 5.03 (dd): H13; 3.89 (q): H2; 6.06-6.10: NH-NC=0; -7.31: H3; 8.77: H2-7.52 and 7.66: Hg and H?-«8.09 and 8.12: H5 and Hg: quinoline. EXAMPLE 4; (9E) 9-[0-(4-piperidinyl) oxime] of 11,12-dideoxy-3-deC(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy]-6-0-methyl-3-oxo-12,11-[oxycarbonyl[[3 -(4-quinolinyl)propyl] hydrazono]] erythromycin A solution containing 311 mg of product A, 10 cm3 of ethanol, 400 mg of N-methylbenzyl 4-hydroxylamine piperidine is agitated under reflux for 9 days. After evaporating to dryness, extraction is carried out with ethyl acetate, followed by washing with a 5% aqueous solution of ammonium hydroxide, drying over magnesium sulphate and evaporating to dryness. 760 mg of product is obtained which is chromatographed on silica eluting with an ethyl acetate- triethylamine mixture (98-2). 170 mg of product is obtained. A mixture of 105 mg of this product, 6 cm3 of methanol, 15 mg of palladium on charcoal is agitated under a hydrogen atmosphere for 4 hours, followed by filtering, rinsing and evaporating to dryness. 69 mg of sought product is obtained after purification. EXAMPLE 5: (E) 9-(0-2-bromoethyl) oxime of 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 [[3-(4-quinolinyl)propyl] hydrazono]] erythromycin A solution containing 303 mg of product A and 1000 mg of Br(CH2)2ONH2' HBr ^s agitated under reflux for 14 days, followed by evaporating to dryness, talcing up in ethyl acetate, washing with a 5% solution of ammonium hydroxide, drying over magnesium sulphate and evaporating to dryness. 550 mg of product is obtained which is chromatographed on silica eluting with an ethyl acetate triethylamine mixture (98-2). 60 mg of sought product is obtained. NMR CDC13 ppm 0.79 (t): CH3-CH2; 1.02 (d)-1.13 (d)-1.2 (dd)-1.30 (d)-1.36 (d) - 1.30 (d}-1.36 (d)-1.43-1.48: 6 and 12-Me; 2.27 (s): N(Me)2; 2.45 (m): H'3; 2.70 (s): 6-OMe; «3.08 (m): H4; 3.19 (dd) : H'2; «3.19 (dd) : H'2; «3.27 (m) : HIO; 2.4 3.0-3.27 (m) : CH2-C= and CH2NH; 3.45 (t): CH2Br; 3.54 (m): H'5; 3.73 (m): H8 --> E isomer; 3.88 (s) : HII(- 3.88 (q) : H2; 4.1 to 4.3: CH2ON=; 4.29: E'l and H5; 5.03 (dd): H13 ; 5.88 (t): NHCH2; 7.29 id): H3; 7.53 and 7.68: Hg and H?-8.09 and 8.13: H5 and Ho-8.78: H0: quinoline. o £ -1 EXAMPLE 6; (E) 9 -[0-[2-[(4-phenylbutyl) amino] ethyl] oxime of 11,12-dideoxy-3-de[(2,6 -dideoxy-3 -C-methyl-3 -0-methyl-alpha-L-ribohexopyranosyl)-oxy]-6-0-methyl-3-oxo-12,ll-[oxycarbonyl[[3-(4-quinolinyl) propyl] hydrazono]] erythromycin A mixture of 144 mg of the product prepared in the previous example and 1.41 g of 4-phenyl butylamine is agitated for 2 days at ambient temperature. The product obtained is chromatographed on silica eluting with a methylene chloride-methanol-ammonium hydroxide mixture (96-4- 1), then it is purified for a second time with an ethyl acetate triethylamine mixture (95-5). 66 mg of product is obtained. NMR CDCL3 ppra 0.78 ft): CH3-CH2; 0.99 (d): CH2 in position 8; 1.12 (d): CH3 in position 10; 1.24 (d): CH^ in position 5'; 1.30 (d): CH3 in position 4; 1.36 (d): CH3 in position 2; 1.40 and 1.46 (s): CH3 in position 6 and 12; 2.27 (s): N(CH3)2; 2.69 (s): CH30 in position 6; 2.46 (m): H3'; -1.20 (m) -1.70 (m): CH2 in position 4'; =1.40 (m) «°1.70 (m) : CH2 in position 7; 1.60 (m) =1.95 (m): CH2 in position 14; 1.50 2.10 (m): central CH2's of chains; 2.61 (m): 4H-2.70 3.30 (m): the N-CH2's and CH2-Ar's; ~2.69 (masked): H10; 3.07 (m): H4; 3.19 (dd, J = 10 and 7.5): H2'; 3.54 (m) : HS ' : 3.67 (m) : Hg; 3.86 (s) : H^; 3.87 (q): H2; 3.92 to 4.08 (m): 0-CH2-CH2; 4.27 (m): E^' + H5; 5.02 (dd): H13; 5.99 (t): mobile 1H. EXAMPLE 7; (E) 9 -[0-[2 -(dimethylamino) ethyl] oxime] of 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[[3-(4-quinolinyl) propyl] hydrazono]] ery t hr omyc in 250 mg of the product obtained in Example 5 in solution in 10 cm3 of dimethylamine with 33% EtOH is agitated for 1 hour at 75°C. Chromatography on silica is carried out eluting with a methylene chloride-methanol-ammonium hydroxide mixture (96-4-1). 210 mg of product is obtained which is taken up in ethyl acetate, washed with a 5% aqueous solution of ammonium hydroxide, dried over magnesium sulphate and evaporated to dryness. 190 mg of sought product is obtained. NMR CDC13 ppm 0.78 It): CH3-CH2; 3.07 (m): H4; 3.88 By operating as previously the 9-methyloxime of compound A was prepared, starting from compound A and CH3ONH2. EXAMPLE 9; (E) 9-[O-[2-[4-(3-pyridinyl)-1H-imidazol-1-yl] ethyl] oxime] of 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-O-methyl-3-oxo-12,12-[oxycarbonyl-[[3-(4-quinolinyl) propyl] hydrazono]] erythromyc in This product was prepared starting from the product of Example 5 by operating as in Example 6 using pyridino-imidazole. EXAMPLE 10; (E) 9-[0-piperidinyl] of 11,12-dideoxy-3-de[(2,6-dideoxy-3 -C-methyl-3 -0-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(hydrazono)] erythromycin. Stage A: (E) 9-[0-[1-[(phenylmethoxy) carbonyl] 3-piperidinyl] oxime] of 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-0-methyl-3-oxo-12,11-[oxycarbonyl-(hydrazono)] erythromycin. 1.19 g of N-methyl benzyl 3-hydroxylamine piperidine and 1 g of 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-0-methyl-3-oxo-12,11-[oxycarbonyl-(hydrazono)] erythromycin obtained as indicated in the European Patent Application EP 0676409 in 10 ml of ethanol are mixed together at ambient temperature. The reaction medium is heated to 105°C for 6 days then the solvent is eliminated under reduced pressure, the residue is taken up in ethyl acetate, washed with water, dried and the solvent is evaporated off. After purification by chromatography on silica (eluant: CH2Cl2-MeOH-NH4OH 96-4-0.5), 1 g of expected product is obtained. Stage B: (E) 9-[0-3-piperidinyl] of 11,12-dideoxy-3-de[(2,6-dideoxy- 3 -C-methyl- 3 - 0-methyl- alpha-L-ribo-hexopyranosyl) oxy] 6-0-methyl-3-oxo-12,11-[oxycarbonyl-(hydrazono)] erythromycin. 250 mg of product obtained in Stage A is mixed at ambient temperature with 10 ml of dichloromethane in the presence 150 mg of palladium on activated charcoal. Hydrogenation and agitation are carried out at ambient temperature for 24 hours, followed by filtering, rinsing with dichloromethane, the solvent is evaporated off under pressure reduced, the residue is chromatographed on silica (eluant: CH2Cl2-MeOH-NH4OH 92-8-0.5), and 166 mg of pure product is obtained which is taken up in ethyl acetate, washed with dilute ammonium hydroxide, dried, the solvent is evaporated off and 130 mg of expected product is obtained. NMR CDC13 ppm 0.85: CH3-CH2; 1.00: 8-Me; 1.16: 10-Me; -1.27: 5'Me and 4Me; 1.35: 2-Me; 1.27 and 1.45: 6-Me and 12-Me; 2.27: NMe2; 2.48: H3' ; 2.68: HIQ; 2.70: 6-OMe; -2.70-2.83-3.08: the CHUNK'S; 3.08: H4; 3.19: H2' ; 3.55: H5' ; «3.72: HII; 3.72 (m) : Hg E isomer; 3.85: H2; 3.92: 0-CH H13- EXAMPLE 11; (E) 9 - [0-3-piperidinyloxime] of 11,12-dideoxy-3- de [ (2, 6-dideoxy-3-C-metliyl-3-0-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-0-methyl- 3 -oxo-12,11-[oxycarbonyl-(propyl-hydrazono)] erythromycin. Stage A: (E) 9- [0-[1- [(phenylmethoxy) carbonyl] 3-piperidinyl] oxime] of 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-0-methyl- 3-oxo-12,11-[oxycarbonyl-(propylhydrazono)] erythromycin. 250 mg of the product obtained in Stage A of Example 10 in 5 ml of methanol is agitated for 24 hours at ambient temperature in the presence 50 ,ul of propanaldehyde and 52 mg of glacial acetic acid. Then 55 mg of sodium cyanoborohydride is added, followed by agitation for 3 days at ambient temperature, ethyl acetate is added, followed by washing with an N aqueous solution of soda then with water, drying, the solvent is evaporated off under pressure reduced, the residue is chromatographed on silica (eluant: CH2Cl2-MeOH-NH4OH 96-4-0.5) and 262 mg of expected product is obtained. Stage B: (E) 9-[0-3-piperidinyloxime] of 11,12-dideoxy-3-de [(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribo-hexopyranosyl } oxy] 6-0-methyl-3-oxo-12,11-[oxycarbonyl-(propylhydrazono)] erythromycin The operation is carried out as in Stage B of Example 10 using at the start 262 mg of the product obtained in the preceding stage, 150 mg of palladium on activated charcoal in 10 ml of dichloromethane. After purification, 136 mg of expected product is obtained. NMR CDC13 ppm 0.86: H15; 0.97: CH3; 1.00: 8Me; 1.13: lOMe; 1.26: 5'Me; 1.3: 4Me; 1.36: 2Me; 1.39: H?; 1,42-1.47: 6Me and 12Me; 1.53: CH2; 1.63: 4"; 1.64-1.46: 5"; 1.68-1.23: 4'; 1.97-1.56: H14; 2.28: NMe; 2.47: 3'; 2.66: HIQ; 2.68: CH2; 2.7-2.83: 6" ; 2.72: 60Me; 3.07-2.78: 2"; 3.09: H4; 3.19: 2'; 3.55: 5 ' ; 3.74: H8; 3.87: HII; 3.88: H2; 3.9: 3"; 4.27: H5; 4.29: 1'; 5.06: H13; 5.87: NH. EXAMPLE 12; (E) 9-[0-3-piperidinyloxime] of 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-0-methyl-3-oxo-12,11-[oxycarbonyl-[(3-phenylpropyl) hydrazono)]] erythromycin. Stage A: (E) 9- [0-[1- [(phenylmethoxy) carbonyl] 3-piperidinyl] oxime] of 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-0-methy1- 3 -oxo-12,11-[oxycarbonyl-[(3 -phenylpropy1) hydrazono)]] erythromycin. The operation is carried out as in Stage A of Example 11 using at the start 311 mg of the product obtained in Stage A of Example 10, 99 mg of phenylpropanaldehyde, 66 mg of acetic acid in 10 ml of methanol then 69 mg of sodium cyanoboro-hydride. After chromatography, 270 mg of expected product is obtained. Stage B: (E) 9-[0-3-piperidinyloxime] of 11,12-dideoxy-3-de [(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-0-methyl-3-oxo-12,11-[oxycarbonyl-[(3 -phenylpropyl) hydrazono)]] erythromycin. The operation is carried out as in Stage B of Example 10 using at the start 270 mg of the product of the stage above, 100 mg of palladium on activated charcoal and 10 ml of methanol. After purification, 83 mg of expected product is obtained. NMR CDC13 ppm 0.85: CH3-CH2; 1.00: 8Me; 1.12: lOMe; 1.22-1.68: CH2 in position 4'; 1.26: 5'Me; 1.3: 4Me; 1.36: 2Me; 1.38-1.7: CH2 in position 7; 1.39: H7; 1.41-1.47: 6Me and 12Me; 1.5 to 2: cycl. CH2C ; 1.57-1.95: CH2CH3; 1.83: central CH2; 2.28: NMe2; 2.45: 3'; 2.67 to 2.87: HIQ and 6-OMe; 2.68: CH2; 3.1: H4; 3.18: 2'; 3.55: 5'; 3.73: HQ; 3.86: CH-OH; 3.87: HII; 3.88: H2; 3.9: 3"; 4.27: H5; 4.29: 1'; 5.07: H13; 7.15 to 7.25: phenyl. EXAMPLES OF PHARMACEUTICAL COMPOSITIONS Compounds were prepared containing: Product of Example 3 150 mg Excipient s . q. f „ ., „ 1 g Detail of excipient: starch, talc, magnesium stearate. PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION Method of dilutions in liquid medium A series of tubes are prepared in which the same quantity of sterile nutritive medium is distributed. Increasing quantities of the product to be studied are distributed into each tube, then each tube is sown with a bacterial strain. After incubation for twenty-four hours in a heating chamber at 37°C, the growth inhibition is evaluated by transillumination, which allows the minimal inhibitory concentrations (M.I.C.) to be determined, expressed in micrograms/cm . The following results were obtained (Table Removed) WE CLAIM: 1. The erthromycin compounds of formula (I): (Formula Removed) in which A and B form together with the atoms to which they are linked a group: (Formula Removed) R1 represents an NH2 radical or an NH-alkyl, NH-alkenyl or NH-alkynyl radical containing up to 18 atoms of carbon or a (CH2)nAr radical or an NH(CH2)nAr or N=CH(CH2)nAr radical in which n represents an integer comprised between 1 and 6, and Ar represents an optionally substituted aryl or heteroaryl radical, Z represents a hydrogen atom or the remainder of a carboxylic acid containing up to 18 carbon atoms, and R represents: a hydrogen atom, a heterocyclic radical containing at least one nitrogen atom and optionally another heteroatom aromatic or non aromatic, saturated or unsaturated, mono or bicyclic, containing up to 12 members, optionally substituted on the nitrogen atom, a linear, branched or cyclic alkyl, alkenyl or alkynyl radical, containing up to 18 carbon atoms optionally substituted by one or more group: • hydroxyl, • halogen, • cyano, • nitro, • amidinyl, • guanidinyl, • heterocyclic, as defined previously, • alkyloxy, alkenyloxy or alkynyloxy having at most 6 carbon atoms, • alkylthio, alkenylthio or alkynylthio having at most 6 carbon atoms, the sulphur atom being optionally oxidized into the sulphoxide or into the sulphone, • aryl, ar alkyl, • aryloxy, aralkyloxy, • arylthio, aralkylthio, the sulphur atom being optionally oxidized into the sulphoxide or into the sulphone, (Formula Removed) in which: either R'1 and R'2, 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 R'i and R'2 radicals being optionally substituted by one or more of the following radicals hydroxy, alkyloxy, alkenyloxy, alkynyloxy, alkylthio, alkenylthio or alkynylthio containing up to 8 carbon atoms, amino, monoalkylamino containing up to 4 carbon atoms, dialkylamino containing up to 8 carbon atoms, cyano, free, esterified or salified carboxy, acyl or carbamoyl, containing up to 8 carbon atoms, by an Si(alk)3 or Si(Oalk)3 in which alk represents an alkyl radical containing up to 4 carbon atoms, by a heterocyclic radical as defined previously, or R'1 and R'2 form together with the nitrogen atom to which they are linked a mono or bicyclic heterocycle radical, optionally containing another aromatic or non aromatic, saturated or unsaturated heteroatom, containing 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, (Formula Removed) in which Bi represents either an alkyl or alkyloxy radical having at most 6 carbon atoms, or an aryl, aralkyl, aryloxy or aralkyloxy radical, • free or protected formyl, free, esterified or salified carboxy, thiocyanate, acyl or carbamoyl, • (CH2)nR, R' representing the remainder of an amino acid, and n representing an integer comprised between 0 and 6, as well as the addition salts with acids of the compounds of formula (I) such as herein described. 2) The compounds of formula. (I) as claimed in claim 1, in which Z represents a hydrogen atom. 3) The compounds of formula (I) as claimed in claim 1 or 2, in which Ri represents an NH(CH2)nAr radical, n and Ar retaining their meaning indicated in claim 1. 4) The compounds of formula (I) as claimed in any one of claims 1 to 4 in which Ar represents a radical: (Formula Removed) and in which X represents a hydrogen atom, a CHa, OH, OMe radical, or a halogen atom. 5) The compounds of formula (I) as claimed in claim 4 in which Ar represents a radical: (Formula Removed) rf (Formula Removed) The compounds of formula (I) as claimed in claim 3, 4 or 5 in which n represents the number 3. 6) The compounds of formula (I) as claimed in claim 1, in which R represents a hydrogen atom, a radical: (Formula Removed) or a radical: (Formula Removed) optionally substituted on the nitrogen atom by a radical: in which m represents an integer comprised between 0 and 20, n represents the number 0, 1,2, or 3, and either A and B, identical or different, represent a hydrogen atom or a halogen atom or an alkyl or aryl radical, containing up to 3 carbon atoms, the geometry of the double bond being E or Z or an E + Z mixture, or A and B form a third bond between the carbon atoms to which they are linked, and XA represents: • a saturated or unsaturated, linear or branched alkyl radical containing 6 to 20 carbon atoms, optionally interrupted by one or more heteroatoms and optionally substituted by one or more halogen atoms, • a cyclic alkyl radical containing 3 to 8 carbon atoms optionally substituted by a carbocyclic aryl radical, • a halogen atom, • a ON radical, • an ORs, COR4, COaRs, SRe, (Formula Removed) radical in which R3, R4, R5, R6, R7, R8 and R9 represent a hydrogen atom, an alkyl radical containing up to 8 carbon atoms, optionally interrupted by one or more heteroatoms and optionally substituted by one or more halogen atoms, a carbocyclic or heterocyclic aryl or aralkyl radical containing up to 14 carbon atoms, optionally substituted by one or more radicals chosen from the group constituted by free, salified, esterified or amidified carboxy radicals, hydroxyl radicals, halogen atoms, NOa radicals, CSN radicals, alkyl, alkenyl and alkynyl, O-alkyl, O-alkenyl and O-alkynyl, S-alkyl, S-alkenyl and S-alkynyl, SO-alkyl, SO-alkenyl, SO-alkynyl, SO2-alkyl, SO2-alkenyl, SO2-alkynyl radicals, containing up to 12 carbon atoms optionally substituted by one or more halogen atoms, carbocyclic or heterocyclic aryl, O-aryl, S-aryl radicals containing up to 14 carbon atoms, the following radicals: R'I and R'a, identical or different, representing a hydrogen atom or an alkyl radical, containing up to 12 carbon atoms, aryl radicals themselves optionally substituted by one of the substituents indicated above as substituents of aryl radicals, • an NRiR2 radical in which either Ri and Ra, identical or different, represent a hydrogen atom or an alkyl radical containing up to 20 carbon atoms, -CO- alkyl or - CO2-alkyl containing up to 8 carbon atoms, or am aryl, - CO-aryl or -CO2-aryl aralkyl, -CO-aralkyl or -CO2- aralkyl radicals containing up to 14 carbon atoms, the aryl radicals being themselves optionally substituted by one of the substituents indicated above as substituents of aryl radicals, or R1 and R2 form together with the nitrogen atom to which they are linked a ring with 3 to 8 members optionally containing another heteroatom and optionally substituted by one of the substituents indicated above as substituents of aryl radicals, • a carbocyclic aryl radical optionally substituted by one or more of the radicals mentioned above as substituents of aryl radicals, • a heterocyclic aryl radical containing one or more heteroatoms, optionally substituted by one or more of above-mentioned radicals as substituents of aryl radicals, • an OC(Ar)3 radical in which Ar represents a carbocyclic aryl radical optionally substituted by one or more of the substituents mentioned above as substituents of aryl radicals. 8) The compounds of formula (I) as claimed in claim 1, the name of which follow: (9E) 9- [0- (3-piperidinyl) oxime] of 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-[[3-(4-quinolinyl) propyl] hydrazono]] erythromycin. 9) The pharmaceutical compositions comprising the compound of formula (I) as claimed in any of the preceding claims. 10) Preparation process for the compound of formula (I) as claimed in claim 1, characterized in that a compound of formula (II): (Formula Removed) in which A, B and Z retain their previous meaning is subjected to the action of a compound of formula (III) (Formula Removed) in which R retains its previous meaning in order to obtain the corresponding compound of formula (I), then optionally, the hydroxyl in position 2 is released and/or subjected to the action of an acid in order to form the salt, and/or to the action of an agent which modifies the R radical 11) The compounds of general formula (I) substantially as hereinbefore described with reference to the foregoing examples. 12) Preparation process for the compounds of formula I substantially as herein described with reference to the foregoing examples.

Full Text

The present invention relates to the erthromycin compounds and process thereof.
The invention relates to new derivatives of erythromycin, their preparation process and their use as medicaments.
The present invention relates to the erthromycin compounds of formula (I):

(Formula Removed)
in which A and B form together with the atoms to which they are linked a group:

(Formula Removed)
R1 represents an NH2 radical or an NH-alkyl, NH-alkenyl or NH-alkynyl radical containing up to 18 atoms of carbon or a (CH2)nAr radical or an NH(CH2)nAr or N=CH(CH2)nAr radical in which n represents an integer comprised between 1 and 6, and Ar represents an optionally substituted aryl or heteroaryl
radical, Z represents a hydrogen atom or the remainder of a carboxylic acid containing up to 18 carbon atoms, and R represents:
a hydrogen atom,
a heterocyclic radical containing at least one nitrogen atom and optionally another heteroatom aromatic or non aromatic, saturated or unsaturated, mono or bicyclic, containing up to 12 members, optionally substituted on the nitrogen atom,
a linear, branched or cyclic alkyl, alkenyl or alkynyl radical, containing up to 18 carbon atoms optionally substituted by one or more group:
• hydroxyl,

. halogen,
. cyano,
. nitro,
. amidinyl,
. guanidinyl,
. heterocyclic, as defined previously,
. alkyloxy, alkenyloxy or alkynyloxy having at most 6 carbon atoms,
. alkylthio, alkenylthio or alkynylthio having at most 6 carbon atoms, the sulphur atom being optionally oxidized into the sulphoxide or into the sulphone,
. aryl, aralkyl,
. aryloxy, aralkyloxy,
. arylthio, aralkylthio, the sulphur atom being
optionally oxidized into the sulphoxide or into the
sulphone,
(Figure Removed)
in which:
either R and R', 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 R'^ and R'2 radicals being optionally substituted by one or more of the following radicals hydroxy, alkyloxy, alkenyloxy, alkynyloxy, alkylthio, alkenylthio or alkynylthio containing up to 8 carbon atoms, amino, monoalkylamino containing up to 4 carbon atoms, dialkylamino containing up to 8 carbon atoms, cyano, free, esterified or salified carboxy, acyl or carbamoyl, containing up to 8 carbon atoms, by an Si(alk)3 or Si(0alk)3 in which alk represents an alkyl radical containing up to 4 carbon atoms, by a heterocyclic radical as defined previously, or R1^ and R*2 form together with the nitrogen atom to which they are linked a mono or bicyclic heterocycle radical, optionally containing another aromatic or non aromatic, saturated or unsaturated heteroatom, containing 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,
(Figure Removed)
in which B-j_ represents either an alkyl or alkyloxy
radical having at most 6 carbon atoms, or an aryl,
aralkyl, aryloxy or aralkyloxy radical,
. free or protected formyl, free, esterified or salified
carboxy, thiocyanate, acyl or carbamoyl,
. (CH2)nR', R1 representing the remainder of an amino
acid, and n representing an integer comprised between 0
and 6,
as well as the addition salts with acids of the compounds of
formula (I).
As an example of the addition salts of the present
derivatives with mineral or organic acids, there can be mentioned the salts formed with the following acids: acetic, propionic, trifluoroacetic, maleic, tartaric, methanesulphonic, benzenesulphonic, p-toluenesulphonic, hydrochloric, hydrobromic, hydroiodic, sulphuric, phosphoric and especially stearic, ethylsuccinic or laurylsulphuric acids.
In the definition of the products of the invention:
- the heterocyclic radical is preferably the pyrrolyl,
pyrrolidinyl, pyridyl, pyrazinyl, pyrimidyl, piperidinyl,
piperazinyl, quinuclidinyl, oxazolyl, isoxazolyl,
morpholinyl, indolyl, imidazolyl, benzimidazolyl, triazolyl,
thiazolyl, azetidinyl, aziridinyl radical. Naturally there
can be preferably mentioned the heterocyclic radicals
mentioned hereafter in the experimental part,
- the alkyl, alkenyl or alkynyl radical is preferably a
methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,
terbutyl, decyl or dodecyl, vinyl, allyl, ethynyl, propynyl,
cyclobutyl, cyclopentyl or cyclohexyl radical,
- the halogen is preferably fluorine or chlorine, or bromine,
- the aryl radical is preferably the phenyl radical,
- the aralkyl radical is preferably a (CgH5)-(CH2)a radical,
a being an integer comprised between 1 and 6, for example the number 1, 2, 3 or 4 or a naphthyl radical,
- the alkyloxy radical is preferably a methoxy, ethoxy,
propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-
butyloxy, n-pentyloxy, isopentyloxy, sec-pentyloxy, tert-
pentyloxy, neopentyloxy, n-hexyloxy, sec-hexyloxy, tert-
hexyloxy radical,
- the corresponding alkylthio radical can be used by taking
the same values and by replacing the oxygen atom with a
sulphur atom, example: methylthio, ethylthio .... Moreover,
the sulphur atom can be oxidized, example: methylsulphinyl,
methylsulphonyl ....
the alkenyloxy radical is preferably a vinyloxy, 1-propenyloxy, allyloxy, l-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methyl-1-butenylox, pentenyloxy, hexenyloxy, 3-methyl 2-butenyloxy radical,
- the corresponding alkenylthio radical can be used by taking
the same values and by replacing the oxygen with a optionally
oxidized sulphur,
- the alkynyloxy radical is preferably an ethynyloxy,
propargyloxy, propynyloxy, butynyloxy, pentynyloxy,
hexynyloxy radical,
- the corresponding alkynylthio radical can be used by taking
the same values and by replacing the oxygen with an
optionally oxidized sulphur.
- the aryloxy radical is preferably a phenyloxy, thienyloxy,
furyloxy, thiazolyloxy, thiadiazolyloxy, oxazolyloxy,
tetrazolyloxy, pyrrolyloxy, imidazolyloxy, pyrazolyloxy,
isothiazolyloxy, isoxazolyloxy, criazolyloxy,
thiatriazolyloxy, pyridyloxy radical, as well as the
condensed groups such as benzothienyloxy, benzofuryloxy,
indolyloxy, benzimidazolyloxy,
- The corresponding optionally oxidized arylthio groups can
of course be used, for example:
phenylthio, phenylsulphonyl, phenylsulphinyl ...
- the aralkyloxy radical is preferably a benzyloxy,
phenylethyloxy, phenylpropyloxy, thienylmethyloxy,
thienylethyloxy, thienylpropyloxy, furfuryloxy,
furylethyloxy, furylpropyloxy, thiazolylmethyloxy,
thiazolylethyloxy, tetrazolylmethyloxy,
thiadiazolylmethyloxy, thiadiazolylethyloxy radical,
- The corresponding optionally oxidized aralkylthio groups
can of course be used.
Among the protected formyl radicals, there can be mentioned more especially the radicals of acetal type. The following radicals are preferred: 1,3-dioxolan-2-yl, dimethoxymethyl, diethoxymethyl.
As esterified carboxyl radicals, the following radicals can be mentioned: alkoxycarbonyl having at most 7 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl.
There can also be mentioned the alkyloxyalkyloxycarbonyl radicals such as methoxymethoxycarbonyl, isopropyloxymethoxy-carbonyl, the alkylthiomethoxycarbonyl radicals such as
methylthiomethoxycarbonyl, isopropylthiomethoxycarbonyl, the acylxyalkyloxycarbonyl radicals such as pivaloyloxymethoxy-carbonyl, acetocyethoxycarbonyl.
Among the salts formed with the carboxyl group, there can be mentioned sodium, potassium, lithium, calcium, magnesium, ammonium salts or the salts formed with amino organic bases such as trimethylamine, diethylamine, triethylamine, tris(hydroxymethyl) aminomethane.
Among the acyl radicals, the can be mentioned in particular acetyl, propionyl, butyryl, isobutyryl, n-valeryl, isovaleryl, tert-valeryl and pivalyl radicals.
Among the preferred compounds according to the invention, there can be mentioned those in which Z represents a hydrogen atom, those in which R-^ represents an NH(CH2)nAr radical, n and Ar retaining their previous meaning, and in particular those in which Ar represents a radical:

(Figure Removed)

and in which X represents a hydrogen atom, a CH3, OH, OMe radical, or a halogen atom, quite especially those in which Ar represents a radical:

(Figure Removed)

and as well as those in which n represents the number 3.
Among the preferred compounds, there can also be mentioned the compounds of formula (I), in which R represents a hydrogen atom, a radical:

(Figure Removed)

or a radical:

optionally substituted on the nitrogen atom by a radical:
(CH2)m—(CzzC)nXA A B
in which m represents an integer comprised between 0 and 20,
n represents the number 0, 1, 2, or 3,
and either A and B, identical or different, represent a
hydrogen atom or a halogen atom or an alkyl or aryl radical,
containing up to 8 carbon atoms, the geometry of the double
bond being E or Z or an E + Z mixture,
or A and B form a third bond between the carbon atoms to
which they are linked,
and XA represents:
. a saturated or unsaturated, linear or branched alkyl
radical containing 6 to 20 carbon atoms, optionally
interrupted by one or more heteroatoms and optionally
substituted by one or more halogen atoms,
. a cyclic alkyl radical containing 3 to 8 carbon atoms
optionally substituted by a carbocyclic aryl radical,
. a halogen atom,
. a C=sN radical,
. an OR3, COR4, C02R5, SRg,

(Figure Removed)
radical
in which R3 , R4 , Rq , Rg , R7/ Rg and Rg represent a hydrogen atom, an alkyl radical containing up to 8 carbon atoms, optionally interrupted by one or more heteroatoms and optionally substituted by one or more halogen atoms, a carbocyclic or heterocyclic aryl or aralkyl radical containing up to 14 carbon atoms, optionally substituted by one or more radicals chosen from the group constituted by free, salified, esterified or amidified carboxy radicals, hydroxyl radicals, halogen atoms, N02 radicals, ON radicals, alkyl, alkenyl and alkynyl, 0- alkyl, 0-alkenyl and 0- alkynyl, S- alkyl, S- alkenyl and S- alkynyl, SO -alkyl, SO -alkenyl, SO -alkynyl, S02 - alkyl, S02 - alkenyl, S02- alkynyl radicals, containing up to 12 carbon atoms optionally substituted by one or more halogen atoms, carbocyclic or heterocyclic aryl, 0-aryl, S-aryl radicals containing up to 14 carbon atoms, the radicals:
(Figure Removed)
R'x and R*2/ identical or different, representing a hydrogen atom or an alkyl radical, containing up to 12 carbon atoms, aryl radicals themselves optionally substituted by one of the substituents indicated above as substituents of aryl radicals,
an NR1R2 radical in which either R^ and R2, identical or different, represent a hydrogen atom or an alkyl radical containing up to 20 carbon atoms, -CO-alkyl or -C02-alkyl containing up to 8 carbon atoms, or an aryl, -CO-aryl or ~C02-aryl aralkyl, -CO-aralkyl or -C02-aralkyl radicals containing up to 14 carbon atoms, the aryl radicals being themselves optionally substituted by one of the substituents indicated above as substituents of aryl radicals, or R^ and R2 form together with the nitrogen atom to which they are linked a ring with 3 to 8 members optionally containing another heteroatom and optionally substituted by one of the substituents indicated above as substituents of aryl radicals, . a carbocyclic aryl radical optionally substituted by one or more of the radicals mentioned above as substituents of aryl radicals,
. a heterocyclic aryl radical containing one or more heteroatoms, optionally substituted by one or more of the radicals mentioned above as substituents of aryl radicals,
. an OC{Ar)3 radical in which Ar represents a carbocyclic aryl radical optionally substituted by one or more of the substituents mentioned above as substituents of aryl radicals.
Quite especially a subject of the invention is the compounds the preparation of which is given hereafter in the experimental part and quite particularly the product of Example 3.
The products of general formula (I) have a very good antibiotic activity on gram ® bacteria such as staphylococci, streptococci, pneumococci.
The compounds of the invention can therefore be used as medicaments in the treatment of infections caused by susceptible germs and in particular, in that of staphylococcia, such as staphylococcal septicemias, malignant staphylococcia of the face or skin, pyodermatitis, septic or suppurating wounds, boils, anthrax, phlegmons, erysipelas and acne, staphylococcia such as acute primary or post-influenzal

angina, bronchopneumonia, pulmonary suppuration, streptococcia such as acute angina, otitis, sinusitis, scarlet fever, pneumococcia such as pneumonia, bronchitis; brucellosis, diphteri, gonococcal infection.
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 by germs of the Mycobacterium genus.
Therefore a subject of the present invention is 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 mineral or organic acids.
More particularly a subject of the invention is, as medicaments and, in particular antibiotic medicaments, the product of Example 3 and its pharmaceutically acceptable salts.
A subject of the invention is also the pharmaceutical compositions containing at least one of the medicaments defined above, as active ingredient.
These compositions can be administered by buccal, rectal, parenteral route or by local route as a topical application on the skin and mucous membranes, but the preferred administration route is the buccal route.
They can be solid or liquid and be presented in the pharmaceutical forms commonly used in human medicine, such as for example, plain or sugar-coated tablets, capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared according to the usual methods. The active ingredient can be incorporated with 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, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.
These compositions can also be presented in the form a
powder intended to be dissolved extemporaneously in an appropriate vehicle, for example apyrogenic sterile water.
Also a subject of the invention is a preparation process characterized in that a compound of formula (II):

(Figure Removed)
in which A, B and Z retain their previous meaning is subjected to the action of a compound of formula (III!
HNoOR
in which R retains its previous meaning in order to obtain the corresponding compound of formula (I), then if desired, the hydroxyl in position 2' is released and/or subjected to the action of an acid in order to form the salt, and/or to the action of" an agent which modifies the R radical.
The compounds of formula (I) used as a starting product can be prepared according to the process described in the European Patent 0676409. In a preferred implementation:
- the release of the hydroxyl in position 2' is carried out
by methanolysis,
- the salification is carried out according to standard

processes.
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-(4-quinolinyl)propyl)hydrazono)) erythromycin is called hereafter product A, the product is described in Example 5 of the Patent EP 0676409. EXAMPLE 1; (E) 9-0-(phenylmethyl) oxime of 11,12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribohexopyranosyl) oxy)-€-0-methyl-3-oxo-12,ll-(oxycarbonyl(2-(3-(4-quinolinyl)propyl)hydrazono)) erythromycin
A mixture of 1 g of product A, 25 cm3 of ethanol, 0.91 g of benzylhydroxylamine hydrochloride is agitated under reflux for 10 days. Extraction is carried out with ethyl acetate, followed by washing with a 10% solution of ammonium hydroxide, drying over magnesium sulphate and evaporating to dryness. The product obtained is chromatographed eluting with a methylene chloride, methanol, ammonium hydroxide mixture 97-3-0.4. 0.69 g of product is obtained which is purified by chromatography on silica eluting with a methylene chloride, isopropyl alcohol, ammonium hydroxide mixture (94-6-0.4). 120 mg of product is obtained which is taken up in ethyl ether, the precipitate is filtered off, followed by evaporating to dryness, taking up in ethyl acetate, washing with ammonium hydroxide, drying over magnesium sulphate and evaporating to dryness. 90 mg of sought product is obtained. NMR CDC13 ppm
0.78 (t): CH3-CH2; 0.98 (d): 8-Me; 1.09 (d): 10-Me; 1.27 (d): 5'-Me; 1.31 (d): 2-Me; 1.43 and 1.46: 6 and 12-Me; -1.25 and 1.69: CH2 in position 4'; -1.40 and 1.69: CH2 in position 7; -1.55 and 1.95: CH9 central chain; 2.29 (s): N(Me)9; «2.33
£* £4
and 2.80 (m)-5.84 (t): CH2NH; 2.48 (m): H'3; 2.66 (q): H10; 2.70 (s) : 6-OMe; 3.09 (m): H5; 3.20 (dd): H'2; 3.10 to 3.30: CH2C=; 3.55 (mi : H'5; 3.78 (m): Hg --> E isomer; 3.87 (s): HII; 3.88 (q) : H2; 4.29: H^ and H5; 4.87 (d) and 4.98 (d) : OCH2$ ; 5.02 (dd): H13 ; 7.15 to 7.30: phenyl and H3 quinoline; 7.51 and 7.67: H6 and Hy-8.09 and 8.13: H5 and HQ: quinoline; 8.78 (d): H2.

EXAMPLE 2; 9(E) 9-oxime of 11,12-dideoxy-3-de[(2,6-dideoxy-3 -C-methyl-3-O-methyl-alpha-L-ribohexopyranoayl) oxy]-6-0-methyl-3-oxo-12,ll-[oxycarbonyl[[3-(4-quinolinyl)propyl3-hydrazono]] erythromycin
A mixture of l g of product A, 25 cm3 of ethanol and 311 mg of hydroxylamine hydrochloride is agitated for 6 weeks at 105°C, followed by chromatography on silica eluting with a methylene chloride, methanol, ammonium hydroxide mixture 92-8-0.6. The product obtained is evaporated to dryness, taken up in ethyl acetate, washed with a 5% solution of ammonium hydroxide, dried and evaporated to dryness. 1.029 g of product is obtained which is purified by chromatography on silica eluting with a methylene chloride, methanol, ammonium hydroxide mixture 96-4-0.4. 430 mg of product is obtained which is purified on silica eluting with a methylene chloride-methanol-ammonium hydroxide mixture (96-4-0.4). 272 mg of sought product is obtained. NMR CDC13 ppm 0.86 (t): CHo-CH9; 1.06 (dl)-1.19 (d)-1.29 (d)-1.33 (d)-1.38
•J £*
(d): the CH3-CH's; 1.51 (s)-1.60 (s) 6 and 12-Me; 2.28 (s): N(Me)2; 2.47 (m): H'3; 2.73 (ql): HIQ; 2.84 (m): CHo-NH; 2.89 (S): 6-OMe; 2.90 to 3.15: CH2-0=; -3.14 (dd): H'2; 3.58 (m): H'5; 3.92 (s): H2; 3.95 (s): HII; -3.95
(m) : H8 --> E isomer; -4.31: H^ and H5; 5.09 (dd) : H13; 6.75 (d): H3; 8.35 (d): H2; 7.43 and 7.61: Hg and H?-7.89 and 7.99: H5 and Hg: guinoline; =6.20 and 11.45: OH oxime and NH; + ether =1/3 of a mole. EXAMPLE 3; (9E) 9-[0-(3-piperidinyl) of 11,12-dideoxy-3-de
t(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribohexo-pyranosyl}-oxy]-6-0-methyl-3-oxo-12,11-[oxycarbonyl[ [3-{4-quinolinyl)-propyl]hydrazono]] erythromycin
8 cm3 of a 0.5N hydrochloric acid solution in ethanol is added to a solution containing 1.12 g of N-methylbenzyl-3-hydroxylamine piperidine and 5 cm3 of ethanol. 1 g of product A in solution in 10 cm3 of ethanol is added to the solution obtained. Agitation under reflux is carried out for 4 days. Another 0.76 g of hydroxylamine in solution in 5 cm3 of ethanol is added, the pH is adjusted to 3.5 by the

addition of a solution of hydrochloric acid and ethanol, followed by evaporating to dryness, taking up in ethyl acetate, washing with ammonium hydroxide, drying and evaporating to dryness. Purification is carried out by eluting with an ethyl acetate, triethylamine mixture 95-5, 585 mg of product is obtained.
357 mg of this product B is dissolved in a solution containing 10 crcr1 of mechanol and 53 mg of palladium on charcoal. Agitation is carried out under a hydrogen atmosphere for 5 hours, followed by filtering, rinsing with itiethanol and evaporating to dryness. Chromatography on silica is carried out eluting with a methylene chloride-methanol-ammonium hydroxide mixture (96-4-1). 150 mg of product is obtained. NMR CDC13 ppm
=N-0-CH=, localized; 0.73 (t)-0.76 (t): CH3-CH2; 1.00 (d): 8-Me; 1.14 (d): 10-Me; 1.26 (d): 5'-Me; 1.30 (d): 4-Me; 1.36 (d): 2-Me; 1.42-1.47: 6 and 12-Me; 2.27 (s) N(Me)2; 2.69-2.71: 6-OMe; 2.45 (m): H'5; -2.71 (masked): H10; 3.08 (m): H4: 3.19 (dd): H'2; -2.79 (m): CH2NHNC; 2.65 to 3.35: the CH2N and CH2*'s ; 3.55 (m): H'5; 3.74 (m): Hg --> DE, does not seem to be in deficit; 3.82-3.98: 0-CH=; 3.87 (s) : H11: 5.03 (dd): H13; 3.89 (q): H2; 6.06-6.10: NH-NC=0; -7.31: H3; 8.77: H2-7.52 and 7.66: Hg and H?-«8.09 and 8.12: H5 and Hg: quinoline.
EXAMPLE 4; (9E) 9-[0-(4-piperidinyl) oxime] of 11,12-dideoxy-3-deC(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy]-6-0-methyl-3-oxo-12,11-[oxycarbonyl[[3 -(4-quinolinyl)propyl] hydrazono]] erythromycin
A solution containing 311 mg of product A, 10 cm3 of ethanol, 400 mg of N-methylbenzyl 4-hydroxylamine piperidine is agitated under reflux for 9 days. After evaporating to dryness, extraction is carried out with ethyl acetate, followed by washing with a 5% aqueous solution of ammonium hydroxide, drying over magnesium sulphate and evaporating to dryness. 760 mg of product is obtained which is chromatographed on silica eluting with an ethyl acetate-

triethylamine mixture (98-2). 170 mg of product is obtained. A mixture of 105 mg of this product, 6 cm3 of methanol, 15 mg of palladium on charcoal is agitated under a hydrogen atmosphere for 4 hours, followed by filtering, rinsing and evaporating to dryness. 69 mg of sought product is obtained after purification.
EXAMPLE 5: (E) 9-(0-2-bromoethyl) oxime of 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 [[3-(4-quinolinyl)propyl] hydrazono]] erythromycin
A solution containing 303 mg of product A and 1000 mg of Br(CH2)2ONH2' HBr ^s agitated under reflux for 14 days, followed by evaporating to dryness, talcing up in ethyl acetate, washing with a 5% solution of ammonium hydroxide, drying over magnesium sulphate and evaporating to dryness. 550 mg of product is obtained which is chromatographed on silica eluting with an ethyl acetate triethylamine mixture (98-2). 60 mg of sought product is obtained. NMR CDC13 ppm
0.79 (t): CH3-CH2; 1.02 (d)-1.13 (d)-1.2 (dd)-1.30 (d)-1.36 (d) - 1.30 (d}-1.36 (d)-1.43-1.48: 6 and 12-Me; 2.27 (s): N(Me)2; 2.45 (m): H'3; 2.70 (s): 6-OMe; «3.08 (m): H4; 3.19 (dd) : H'2; «3.19 (dd) : H'2; «3.27 (m) : HIO; 2.4 3.0-3.27 (m) : CH2-C= and CH2NH; 3.45 (t): CH2Br; 3.54 (m): H'5; 3.73 (m): H8 --> E isomer; 3.88 (s) : HII(- 3.88 (q) : H2; 4.1 to 4.3: CH2ON=; 4.29: E'l and H5; 5.03 (dd): H13 ; 5.88 (t): NHCH2; 7.29 id): H3; 7.53 and 7.68: Hg and H?-8.09 and 8.13: H5 and Ho-8.78: H0: quinoline.
o £ -1
EXAMPLE 6; (E) 9 -[0-[2-[(4-phenylbutyl) amino] ethyl] oxime of 11,12-dideoxy-3-de[(2,6 -dideoxy-3 -C-methyl-3 -0-methyl-alpha-L-ribohexopyranosyl)-oxy]-6-0-methyl-3-oxo-12,ll-[oxycarbonyl[[3-(4-quinolinyl) propyl] hydrazono]] erythromycin
A mixture of 144 mg of the product prepared in the previous example and 1.41 g of 4-phenyl butylamine is agitated for 2 days at ambient temperature. The product obtained is chromatographed on silica eluting with a methylene chloride-methanol-ammonium hydroxide mixture (96-4-
1), then it is purified for a second time with an ethyl acetate triethylamine mixture (95-5). 66 mg of product is obtained. NMR CDCL3 ppra
0.78 ft): CH3-CH2; 0.99 (d): CH2 in position 8; 1.12 (d): CH3 in position 10; 1.24 (d): CH^ in position 5'; 1.30 (d): CH3 in position 4; 1.36 (d): CH3 in position 2; 1.40 and 1.46 (s): CH3 in position 6 and 12; 2.27 (s): N(CH3)2; 2.69 (s): CH30 in position 6; 2.46 (m): H3'; -1.20 (m) -1.70 (m): CH2 in position 4'; =1.40 (m) «°1.70 (m) : CH2 in position 7; 1.60 (m) =1.95 (m): CH2 in position 14; 1.50 2.10 (m): central CH2's of chains; 2.61 (m): 4H-2.70 3.30 (m): the N-CH2's and CH2-Ar's; ~2.69 (masked): H10; 3.07 (m): H4; 3.19 (dd, J = 10 and 7.5): H2'; 3.54 (m) : HS ' : 3.67 (m) : Hg; 3.86 (s) : H^; 3.87 (q): H2; 3.92 to 4.08 (m): 0-CH2-CH2; 4.27 (m): E^' + H5; 5.02 (dd): H13; 5.99 (t): mobile 1H. EXAMPLE 7; (E) 9 -[0-[2 -(dimethylamino) ethyl] oxime] of 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[[3-(4-quinolinyl) propyl] hydrazono]] ery t hr omyc in
250 mg of the product obtained in Example 5 in solution in 10 cm3 of dimethylamine with 33% EtOH is agitated for 1 hour at 75°C. Chromatography on silica is carried out eluting with a methylene chloride-methanol-ammonium hydroxide mixture (96-4-1). 210 mg of product is obtained which is taken up in ethyl acetate, washed with a 5% aqueous solution of ammonium hydroxide, dried over magnesium sulphate and evaporated to dryness. 190 mg of sought product is obtained. NMR CDC13 ppm
0.78 It): CH3-CH2; 3.07 (m): H4; 3.88 By operating as previously the 9-methyloxime of compound A was prepared, starting from compound A and CH3ONH2. EXAMPLE 9; (E) 9-[O-[2-[4-(3-pyridinyl)-1H-imidazol-1-yl] ethyl] oxime] of 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-O-methyl-3-oxo-12,12-[oxycarbonyl-[[3-(4-quinolinyl) propyl] hydrazono]]

erythromyc in
This product was prepared starting from the product of Example 5 by operating as in Example 6 using pyridino-imidazole.
EXAMPLE 10; (E) 9-[0-piperidinyl] of 11,12-dideoxy-3-de[(2,6-dideoxy-3 -C-methyl-3 -0-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-0-methyl-3-oxo-12,ll-[oxycarbonyl-(hydrazono)] erythromycin.
Stage A: (E) 9-[0-[1-[(phenylmethoxy) carbonyl] 3-piperidinyl] oxime] of 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-0-methyl-3-oxo-12,11-[oxycarbonyl-(hydrazono)] erythromycin.
1.19 g of N-methyl benzyl 3-hydroxylamine piperidine and 1 g of 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-0-methyl-3-oxo-12,11-[oxycarbonyl-(hydrazono)] erythromycin obtained as indicated in the European Patent Application EP 0676409 in 10 ml of ethanol are mixed together at ambient temperature. The reaction medium is heated to 105°C for 6 days then the solvent is eliminated under reduced pressure, the residue is taken up in ethyl acetate, washed with water, dried and the solvent is evaporated off. After purification by chromatography on silica (eluant: CH2Cl2-MeOH-NH4OH 96-4-0.5), 1 g of expected product is obtained.
Stage B: (E) 9-[0-3-piperidinyl] of 11,12-dideoxy-3-de[(2,6-dideoxy- 3 -C-methyl- 3 - 0-methyl- alpha-L-ribo-hexopyranosyl) oxy] 6-0-methyl-3-oxo-12,11-[oxycarbonyl-(hydrazono)] erythromycin.
250 mg of product obtained in Stage A is mixed at ambient temperature with 10 ml of dichloromethane in the presence 150 mg of palladium on activated charcoal. Hydrogenation and agitation are carried out at ambient temperature for 24 hours, followed by filtering, rinsing with dichloromethane, the solvent is evaporated off under pressure reduced, the residue is chromatographed on silica (eluant: CH2Cl2-MeOH-NH4OH 92-8-0.5), and 166 mg of pure product is obtained which is taken up in ethyl acetate, washed with dilute ammonium hydroxide, dried, the solvent is evaporated

off and 130 mg of expected product is obtained.
NMR CDC13 ppm
0.85: CH3-CH2; 1.00: 8-Me; 1.16: 10-Me; -1.27: 5'Me and 4Me;
1.35: 2-Me; 1.27 and 1.45: 6-Me and 12-Me; 2.27: NMe2; 2.48:
H3' ; 2.68: HIQ; 2.70: 6-OMe; -2.70-2.83-3.08: the CHUNK'S;
3.08: H4; 3.19: H2' ; 3.55: H5' ; «3.72: HII; 3.72 (m) : Hg E
isomer; 3.85: H2; 3.92: 0-CH H13-
EXAMPLE 11; (E) 9 - [0-3-piperidinyloxime] of 11,12-dideoxy-3-
de [ (2, 6-dideoxy-3-C-metliyl-3-0-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-0-methyl- 3 -oxo-12,11-[oxycarbonyl-(propyl-hydrazono)] erythromycin.
Stage A: (E) 9- [0-[1- [(phenylmethoxy) carbonyl] 3-piperidinyl] oxime] of 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-0-methyl- 3-oxo-12,11-[oxycarbonyl-(propylhydrazono)] erythromycin.
250 mg of the product obtained in Stage A of Example 10 in 5 ml of methanol is agitated for 24 hours at ambient temperature in the presence 50 ,ul of propanaldehyde and 52 mg of glacial acetic acid. Then 55 mg of sodium cyanoborohydride is added, followed by agitation for 3 days at ambient temperature, ethyl acetate is added, followed by washing with an N aqueous solution of soda then with water, drying, the solvent is evaporated off under pressure reduced, the residue is chromatographed on silica (eluant: CH2Cl2-MeOH-NH4OH 96-4-0.5) and 262 mg of expected product is obtained. Stage B: (E) 9-[0-3-piperidinyloxime] of 11,12-dideoxy-3-de [(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribo-hexopyranosyl } oxy] 6-0-methyl-3-oxo-12,11-[oxycarbonyl-(propylhydrazono)] erythromycin
The operation is carried out as in Stage B of Example 10 using at the start 262 mg of the product obtained in the preceding stage, 150 mg of palladium on activated charcoal in 10 ml of dichloromethane. After purification, 136 mg of expected product is obtained. NMR CDC13 ppm 0.86: H15; 0.97: CH3; 1.00: 8Me; 1.13: lOMe; 1.26: 5'Me;

1.3: 4Me; 1.36: 2Me; 1.39: H?; 1,42-1.47: 6Me and 12Me; 1.53: CH2; 1.63: 4"; 1.64-1.46: 5"; 1.68-1.23: 4'; 1.97-1.56: H14; 2.28: NMe; 2.47: 3'; 2.66: HIQ; 2.68: CH2; 2.7-2.83: 6" ; 2.72: 60Me; 3.07-2.78: 2"; 3.09: H4; 3.19: 2'; 3.55: 5 ' ; 3.74: H8; 3.87: HII; 3.88: H2; 3.9: 3"; 4.27: H5; 4.29: 1'; 5.06: H13; 5.87: NH.
EXAMPLE 12; (E) 9-[0-3-piperidinyloxime] of 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-0-methyl-3-oxo-12,11-[oxycarbonyl-[(3-phenylpropyl) hydrazono)]] erythromycin. Stage A: (E) 9- [0-[1- [(phenylmethoxy) carbonyl] 3-piperidinyl] oxime] of 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-0-methy1- 3 -oxo-12,11-[oxycarbonyl-[(3 -phenylpropy1) hydrazono)]] erythromycin.
The operation is carried out as in Stage A of Example 11 using at the start 311 mg of the product obtained in Stage A of Example 10, 99 mg of phenylpropanaldehyde, 66 mg of acetic acid in 10 ml of methanol then 69 mg of sodium cyanoboro-hydride. After chromatography, 270 mg of expected product is obtained.
Stage B: (E) 9-[0-3-piperidinyloxime] of 11,12-dideoxy-3-de [(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-0-methyl-3-oxo-12,11-[oxycarbonyl-[(3 -phenylpropyl) hydrazono)]] erythromycin.
The operation is carried out as in Stage B of Example 10 using at the start 270 mg of the product of the stage above, 100 mg of palladium on activated charcoal and 10 ml of methanol. After purification, 83 mg of expected product is obtained. NMR CDC13 ppm
0.85: CH3-CH2; 1.00: 8Me; 1.12: lOMe; 1.22-1.68: CH2 in position 4'; 1.26: 5'Me; 1.3: 4Me; 1.36: 2Me; 1.38-1.7: CH2 in position 7; 1.39: H7; 1.41-1.47: 6Me and 12Me; 1.5 to 2: cycl. CH2C ; 1.57-1.95: CH2CH3; 1.83: central CH2; 2.28: NMe2; 2.45: 3'; 2.67 to 2.87: HIQ and 6-OMe; 2.68: CH2; 3.1: H4; 3.18: 2'; 3.55: 5'; 3.73: HQ; 3.86: CH-OH; 3.87: HII; 3.88: H2; 3.9: 3"; 4.27: H5; 4.29: 1'; 5.07: H13; 7.15 to

7.25: phenyl.
EXAMPLES OF PHARMACEUTICAL COMPOSITIONS
Compounds were prepared containing:
Product of Example 3 150 mg
Excipient s . q. f „ ., „ 1 g
Detail of excipient: starch, talc, magnesium stearate.
PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION
Method of dilutions in liquid medium
A series of tubes are prepared in which the same quantity of sterile nutritive medium is distributed. Increasing quantities of the product to be studied are distributed into each tube, then each tube is sown with a bacterial strain. After incubation for twenty-four hours in a heating chamber at 37°C, the growth inhibition is evaluated by transillumination, which allows the minimal inhibitory concentrations (M.I.C.) to be determined, expressed in
micrograms/cm .
The following results were obtained
(Table Removed)

WE CLAIM:
1. The erthromycin compounds of formula (I):
(Formula Removed) in which A and B form together with the atoms to which they are linked a group:
(Formula Removed)
R1 represents an NH2 radical or an NH-alkyl, NH-alkenyl or NH-alkynyl radical containing up to 18 atoms of carbon or a (CH2)nAr radical or an NH(CH2)nAr or N=CH(CH2)nAr radical in which n represents an integer comprised between 1 and 6, and Ar represents an optionally substituted aryl or heteroaryl
radical, Z represents a hydrogen atom or the remainder of a carboxylic acid containing up to 18 carbon atoms, and R represents:
a hydrogen atom,
a heterocyclic radical containing at least one nitrogen atom and optionally another heteroatom aromatic or non aromatic, saturated or unsaturated, mono or bicyclic, containing up to 12 members, optionally substituted on the nitrogen atom,
a linear, branched or cyclic alkyl, alkenyl or alkynyl radical, containing up to 18 carbon atoms optionally substituted by one or more group:
• hydroxyl,
• halogen,
• cyano,
• nitro,
• amidinyl,
• guanidinyl,
• heterocyclic, as defined previously,
• alkyloxy, alkenyloxy or alkynyloxy having at most 6 carbon atoms,
• alkylthio, alkenylthio or alkynylthio having at most 6 carbon atoms,
the sulphur atom being optionally oxidized into the sulphoxide or into
the sulphone,
• aryl, ar alkyl,
• aryloxy, aralkyloxy,
• arylthio, aralkylthio, the sulphur atom being
optionally oxidized into the sulphoxide or into the sulphone,
(Formula Removed) in which:
either R'1 and R'2, 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 R'i and R'2 radicals being optionally substituted by one or more of the following radicals hydroxy, alkyloxy, alkenyloxy, alkynyloxy, alkylthio, alkenylthio or alkynylthio containing up to 8 carbon atoms, amino, monoalkylamino
containing up to 4 carbon atoms, dialkylamino containing up to 8 carbon atoms, cyano, free, esterified or salified carboxy, acyl or carbamoyl, containing up to 8 carbon atoms, by an Si(alk)3 or Si(Oalk)3 in which alk represents an alkyl radical containing up to 4 carbon atoms, by a heterocyclic radical as defined previously, or R'1 and R'2 form together with the nitrogen atom to which they are linked a mono or bicyclic heterocycle radical, optionally containing another aromatic or non aromatic, saturated or unsaturated heteroatom, containing 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,
(Formula Removed) in which Bi represents either an alkyl or alkyloxy radical having at most 6 carbon atoms, or an aryl, aralkyl, aryloxy or aralkyloxy radical,
• free or protected formyl, free, esterified or salified carboxy, thiocyanate,
acyl or carbamoyl,
• (CH2)nR, R' representing the remainder of an amino acid, and n
representing an integer comprised between 0 and 6,
as well as the addition salts with acids of the compounds of formula (I) such as herein described.
2) The compounds of formula. (I) as claimed in claim 1, in which Z
represents a hydrogen atom.
3) The compounds of formula (I) as claimed in claim 1 or 2, in which Ri
represents an NH(CH2)nAr radical, n and Ar retaining their meaning
indicated in claim 1.
4) The compounds of formula (I) as claimed in any one of claims 1 to 4 in
which Ar represents a radical:
(Formula Removed) and in which X represents a hydrogen atom, a CHa, OH, OMe radical, or a halogen atom.
5) The compounds of formula (I) as claimed in claim 4 in which Ar represents a radical:
(Formula Removed)
rf (Formula Removed)

The compounds of formula (I) as claimed in claim 3, 4 or 5 in which n
represents the number 3.
6) The compounds of formula (I) as claimed in claim 1, in which R
represents a hydrogen atom, a radical:
(Formula Removed) or a radical:
(Formula Removed)
optionally substituted on the nitrogen atom by a radical:
in which m represents an integer comprised between 0 and 20, n represents the number 0, 1,2, or 3, and either A and B, identical or different, represent a
hydrogen atom or a halogen atom or an alkyl or aryl radical, containing up to 3 carbon atoms, the geometry of the double bond being E or Z or an E + Z mixture, or A and B form a third bond between the carbon atoms to which they are linked, and XA represents:
• a saturated or unsaturated, linear or branched alkyl radical
containing 6 to 20 carbon atoms, optionally interrupted by one or
more heteroatoms and optionally substituted by one or more halogen
atoms,
• a cyclic alkyl radical containing 3 to 8 carbon atoms optionally
substituted by a carbocyclic aryl radical,
• a halogen atom,
• a ON radical,
• an ORs, COR4, COaRs, SRe,
(Formula Removed) radical
in which R3, R4, R5, R6, R7, R8 and R9 represent a hydrogen atom, an alkyl radical containing up to 8 carbon atoms, optionally interrupted by one or more heteroatoms and optionally substituted by one or more halogen atoms, a carbocyclic or heterocyclic aryl or aralkyl radical containing up to 14 carbon atoms, optionally substituted by one or more radicals chosen from
the group constituted by free, salified, esterified or amidified carboxy radicals, hydroxyl radicals, halogen atoms, NOa radicals, CSN radicals, alkyl, alkenyl and alkynyl, O-alkyl, O-alkenyl and O-alkynyl, S-alkyl, S-alkenyl and S-alkynyl, SO-alkyl, SO-alkenyl, SO-alkynyl, SO2-alkyl, SO2-alkenyl, SO2-alkynyl radicals, containing up to 12 carbon atoms optionally substituted by one or more halogen atoms, carbocyclic or heterocyclic aryl, O-aryl, S-aryl radicals containing up to 14 carbon atoms, the following radicals:

R'I and R'a, identical or different, representing a hydrogen atom or an alkyl radical, containing up to 12 carbon atoms, aryl radicals themselves optionally substituted by one of the substituents indicated above as substituents of aryl radicals,
• an NRiR2 radical in which either Ri and Ra, identical or different, represent
a hydrogen atom or an alkyl radical containing up to 20 carbon atoms, -CO-
alkyl or
- CO2-alkyl containing up to 8 carbon atoms, or am aryl,
- CO-aryl or -CO2-aryl aralkyl, -CO-aralkyl or -CO2- aralkyl radicals
containing up to 14 carbon atoms, the aryl radicals being themselves
optionally substituted by one of the substituents indicated above as
substituents of aryl radicals, or R1 and R2 form together with the nitrogen
atom to which they are linked a ring with 3 to 8 members optionally
containing another heteroatom and
optionally substituted by one of the substituents indicated above as substituents of aryl radicals,
• a carbocyclic aryl radical optionally substituted by one or more of the
radicals mentioned above as substituents of aryl radicals,
• a heterocyclic aryl radical containing one or more heteroatoms, optionally
substituted by one or more of above-mentioned radicals as substituents of
aryl radicals,
• an OC(Ar)3 radical in which Ar represents a carbocyclic aryl radical
optionally substituted by one or more of the substituents mentioned above
as substituents of aryl radicals.
8) The compounds of formula (I) as claimed in claim 1, the name of
which follow:
(9E) 9- [0- (3-piperidinyl) oxime] of 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-[[3-(4-quinolinyl) propyl] hydrazono]] erythromycin.
9) The pharmaceutical compositions comprising the compound of
formula (I) as claimed in any of the preceding claims.
10) Preparation process for the compound of formula (I) as claimed in claim 1, characterized in that a compound of formula (II):
(Formula Removed) in which A, B and Z retain their previous meaning is subjected to the action of a compound of formula (III)
(Formula Removed)
in which R retains its previous meaning in order to obtain the corresponding compound of formula (I), then optionally, the hydroxyl in position 2 is released and/or subjected to the action of an acid in order to form the salt, and/or to the action of an agent which modifies the R radical
11) The compounds of general formula (I) substantially as hereinbefore
described with reference to the foregoing examples.
12) Preparation process for the compounds of formula I substantially as
herein described with reference to the foregoing examples.

Documents:

0441-del-1998-abstract.pdf

0441-del-1998-claims.pdf

0441-del-1998-correspondence-others.pdf

0441-del-1998-description (complete).pdf

0441-del-1998-form-1.pdf

0441-del-1998-form-18.pdf

0441-del-1998-form-2.pdf

0441-del-1998-form-6.pdf

0441-del-1998-gpa.pdf

441-del-1998-Abstract-(06-11-2008).pdf

441-DEL-1998-Abstract-(07-02-2008).pdf

441-del-1998-Claims-(06-11-2008).pdf

441-DEL-1998-Claims-(07-02-2008).pdf

441-del-1998-Correspondence-Others-(06-11-2008).pdf

441-DEL-1998-Correspondence-Others-(07-02-2008).pdf

441-del-1998-Description (Complete)-(06-11-2008).pdf

441-DEL-1998-Description (Complete)-(07-02-2008).pdf

441-del-1998-Form-1-(06-11-2008).pdf

441-DEL-1998-Form-1-(07-02-2008).pdf

441-del-1998-form-13-(07-02-2008).pdf

441-del-1998-Form-2-(06-11-2008).pdf

441-DEL-1998-Form-2-(07-02-2008).pdf

441-del-1998-Form-3-(06-11-2008).pdf

441-DEL-1998-Form-3-(07-02-2008).pdf

441-DEL-1998-Form-4.pdf

441-DEL-1998-GPA-(07-02-2008).pdf

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Patent Number

226066

Indian Patent Application Number

441/DEL/1998

PG Journal Number

01/2009

Publication Date

02-Jan-2009

Grant Date

05-Dec-2008

Date of Filing

20-Feb-1998

Name of Patentee

AVENTIS PHARMA S.A.,

Applicant Address

20 AVENUE, RAYMOND-ARON, F-92160 ANTONY, FRANCE.

Inventors:

#	Inventor's Name	Inventor's Address
1	CONSTANTIN AGOURIDAS	107, BOULEVARD DE STRASBOURG, F 94130 NOGENT SUR MARNE, FRANCE.
2	JEAN-FRANCOIS CHANTOT	7, RUE PASTEUR, F 94130 NOGENT SUR MARNE, FRANCE.
3	ALEXIS DENIS	37, RUE GODEFROY CAVAIGNAC, F 75011 PARIS, FRANCE.
4	CLAUDE FROMENTIN	16, RUE DE FLANDRES, F 75019 PARIS, FRANCE.
5	JEAN-MARIE PEJAC	5, RUELLE SAINTE BARBE, F 93140 BONDY, FRANCE.

PCT International Classification Number

A61K 31/7048

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	9702352	1997-02-27	France