AU728182B2

AU728182B2 - New derivatives of erythromycin, their preparation process and their use as medicaments

Info

Publication number: AU728182B2
Application number: AU67347/98A
Authority: AU
Inventors: Constantin Agouridas; Jean-Francois Chantot; Alexis Denis; Claude Fromentin; Jean-Marie Pejac
Original assignee: Hoechst Marion Roussel; Hoechst Marion Roussel Inc
Current assignee: Aventis Pharma SA
Priority date: 1997-02-27
Filing date: 1998-02-26
Publication date: 2001-01-04
Anticipated expiration: 2018-02-26
Also published as: ES2179475T3; ZA981482B; JP2001513101A; KR100529980B1; CN1162442C; ATE219097T1; PL335375A1; HUP0001245A1; WO1998038199A1; FR2760017B1; EA199900765A1; CA2282666A1; NO994150D0; FR2760017A1; IL131340A0; EP0968222A1; NO994150L; CN1248261A; AU6734798A; HUP0001245A3

Abstract

The invention concerns compounds of formula (I) in which A and B form with the atoms to which they are bound a group (a): R1 = NH2, NH-alkyl, NH-alkenyl, NH-alkynyl, (CH2)nAr, NH(CH2)nAr or N=NH(CH2)nAr, Ar = aryl or heteroaryl, optionally substituted; R = H, alkyl optionally substituted, optionally interrupted by one or several heteroatoms, aryl or heteroaryl, optionally substituted, as well as the salts of compounds of formula (I). The compounds of formula (I) have interesting antibiotic properties.

Description

New derivatives of erythromycin. their preparation process and their use as medicaments.

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

A subject of the invention is the compounds of formula

NOR

I'l11111111111111111111111 0

OZ

in which A and B form together with the atoms to which they are linked a group: 0 IIl

R

1 represents an NH 2 radical or an NH-alkyl, NH-alkenyl or NH-alkynyl radical containing up to 18 atoms of carbon or a

(CH

2 )nAr radical or an NH(CH 2 )nAr or N=CH(CH 2 )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, Shalogen, Scyano, Snitro, Samidinyl, .guanidinyl, Sheterocyclic, as defined previously, Salkyloxy, 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, Saryl, aralkyl, Saryloxy, aralkyloxy, Sarylthio, aralkylthio, the sulphur atom being optionally oxidized into the sulphoxide or into the sulphone,

R'

N

R'2 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' 1 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; Sa 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,

O-C-B

II

in which B1 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,

S(CH

2 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 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 (C 6

H

5

)-(CH

2 )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, tertbutyloxy, n-pentyloxy, isopentyloxy, sec-pentyloxy, tertpentyloxy, neopentyloxy, n-hexyloxy, sec-hexyloxy, terthexyloxy 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, 1propenyloxy, allyloxy, 1-butenyloxy, 2-butenyloxy, 3butenyloxy, 2-methyl-l-butenylox, pentenyloxy, hexenyloxy, 3methyl 2-butenyloxy radical, a I 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, triazolyloxy, 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, isopropyloxymethoxycarbonyl, the alkylthiomethoxycarbonyl radicals such as methylthiomethoxycarbonyl, isopropylthiomethoxycarbonyl, the acylxyalkyloxycarbonyl radicals such as pivaloyloxymethoxycarbonyl, 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 1 represents an NH(CH 2 )nAr radical, n and Ar retaining their previous meaning, and in particular those in which Ar represents a radical: Nr X

N

or

N

and in which X represents a hydrogen atom, a CH 3 OH, OMe radical, or a halogen atom, quite especially those in which Ar represents a radical: 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 in which R represents a hydrogen atom, a radical: 7 /H3

CH

2

CH

2

-N

CH

3 or a radical:

NH

optionally substituted on the nitrogen atom by a radical:

(CH

2 )m-(C=C)nXA I I A B in which m represents an integer comprised between 0 and 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=N radical, .an OR 3

COR

4 C02R 5

SR

6

SR

7 7 0 S0 2 0 8 or

O

radical in which R 3

R

4

R

5

R

6

R

7

R

8 and R 9 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, NO 2 radicals, C=N radicals, alkyl, alkenyl and'alkynyl, 0-alkyl, O-alkenyl and O-alkynyl, S-alkyl, S-alkenyl and S-alkynyl, SO-alkyl, SO-alkenyl, SO-alkynyl, S0 2 -alkyl, S0 2 -alkenyl, S0 2 -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 radicals: R'1

N

R' 2 R' 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 NR 1

R

2 radical in which either R 1 and R 2 identical or different, represent a hydrogen atom or an alkyl radical containing up to 20 carbon atoms, -CO-alkyl or -C0 2 -alkyl containing up to 8 carbon atoms, or an aryl, -CO-aryl or -C0 2 -aryl aralkyl, -CO-aralkyl or -C0 2 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, Sa 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 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 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): 0

H

3

C

,,1111 H 3

IOCH

3

(II)

iiiiiiiilllll111111iiii in which A, B and Z retain their previous meaning is subjected to the action of a compound of formula (III): in which R retains its previous meaning in order to obtain the corresponding compound of formula 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 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-O-methylalpha-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: 9-O-(phenylmethyl) oxime of 11,12-dideoxy-3de(( 2 ,6-dideoxy-3-C-methyl-3-0-methyl-alpha-Lribohexopyranosyl) oxy)-6-0-methyl-3-oxo-12,11- (oxycarbonyl(2-(3-( 4 -quinolinyl)propyl)hydrazono)) erythromycin A mixture of 1 g of product A, 25 cm 3 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- 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 CDC1 3 ppm 0.78 CH 3

-CH

2 0.98 8-Me; 1.09 10-Me; 1.27 1.31 2-Me; 1.43 and 1.46: 6 and 12-Me; -1.25 and 1.69: CH 2 in position -1.40 and 1.69: CH 2 in position 7; -1.55 and 1.95: CH 2 central chain; 2.29 N(Me) 2 -2.33 and 2.80 (m)-5.84 CH2NH; 2.48

H'

3 2.66

H

1 0 2.70 6-OMe; 3.09 H 5 3.20 H' 2 3.10 to 3.30:

CH

2 3.55 H'5; 3.78 Hg E isomer; 3.87 HI1 3.88 H 2 4.29: H' 1 and H 5 4.87 and 4.98

OCH

2 1 5.02

H

13 7.15 to 7.30: phenyl and H 3 quinoline; 7.51 and 7.67: H 6 and H 7 -8.09 and 8.13: H 5 and H 8 quinoline; 8.78

H

2 EXAMPLE 2: 9(E) 9-oxime of 11,12-dideoxy-3-de[(2,6-dideoxy-3methyl-3-oxo-12,11-[oxycarbonyl [3-(4-quinolinyl)propyl] hydrazono] erythromycin A mixture of 1 g of product A, 25 cm 3 of ethanol and 311 mg of hydroxylamine hydrochloride is agitated for 6 weeks at 105 0 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 272 mg of sought product is obtained.

NMR CDC1 3 ppm 0.86 CH 3

-CH

2 1.06 (dl)-1.19 (d)-1.29 (d)-1.33 (d)-1.38 the CH 3 -CH's; 1.51 (s)-1.60 6 and 12-Me; 2.28 N(Me) 2 2.47 H' 3 2.73 H 1 0 2.84 CH 2

-NH;

2.89 6-OMe; 2.90 to 3.15: CH 2 -3.14 H 4 3.24

H'

2 3.58 H' 5 3.92 H 2 3.95 H 11 -3.95 Hg E isomer; -4.31: H' 1 and H 5 5.09

H

13 6.75 H 3 8.35 H 2 7.43 and 7.61: H 6 and H 7 -7.89 and 7.99: H 5 and H 8 quinoline; "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 2 ,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribohexopyranosyl)-oxy]-6-0-methyl-3-oxo-12,11- [oxycarbonyl[[3-(4quinolinyl)-propyl] hydrazono]] erythromycin 8 cm 3 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 cm 3 of ethanol. 1 g of product A in solution in 10 cm 3 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 cm 3 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 cm 3 of methanol and 53 mg of palladium on charcoal. Agitation is carried out under a hydrogen atmosphere for 5 hours, followed by filtering, rinsing with methanol and evaporating to dryness. Chromatography on silica is carried out eluting with a methylene chloridemethanol-ammonium hydroxide mixture 150 mg of product is obtained.

NMR CDC1 3 ppm localized; 0.73 (t)-0.76 CH 3

-CH

2 1.00 8-Me; 1.14 10-Me; 1.26 5'-Me; 1.30 4-Me; 1.36 2-Me; 1.42-1.47: 6 and 12-Me; 2.27 N(Me) 2 2.69- 2.71: 6-OMe; 2.45 H' 5 -2.71 (masked): H 10 3.08

H

4 3.19 H' 2 -2.79 CH 2 NHNC; 2.65 to 3.35: the

CH

2 N and CH 2 c's 3.55 H' 5 3.74 H 8 DE, does not seem to be in deficit; 3.82-3.98: O-CH=; 3.87 H 11 5.03 H 13 3.89 H 2 6.06-6.10: NH-NC=O; -7.31: H 3 8.77: H 2 -7.52 and 7.66: H 6 and H 7 8.09 and 8.12: H 5 and H 8 quinoline.

EXAMPLE 4: (9E) 9-[0-(4-piperidinyl) oxime] of 11,12-dideoxy- 3 -de[(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-Lribohexopyranosyl) oxy]-6-0-methyl-3-oxo-12,11- [oxycarbonyl (4-quinolinyl)propyl] hydrazono] erythromycin A solution containing 311 mg of product A, 10 cm 3 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 acetatetriethylamine mixture 170 mg of product is obtained.

A mixture of 105 mg of this product, 6 cm 3 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: 9-(O-2-bromoethyl) oxime of 11,12-dideoxy-3de[2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-Lribohexopyranosyl-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(CH 2 2 0NH 2 HBr is agitated under reflux for 14 days, followed by evaporating to dryness, taking 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 60 mg of sought product is obtained.

NMR CDC13 ppm 0.79 CH 3

-CH

2 1.02 (d)-1.13 (dd)-1.30 (d)-1.36 1.30 (d)-1.36 (d)-1.43-1.48: 6 and 12-Me; 2.27 N(Me) 2 2.45 H' 3 2.70 6-OMe; =3.08 H 4 3.19

H'

2 -3.19 H' 2 =3.27 H 1 0 2.4 3.0-3.27

CH

2 and CH 2 NH; 3.45 CH 2 Br; 3.54 H' 5 3.73 Hg E isomer; 3.88 H 11 3.88 H 2 4.1 to 4.3: 4.29: H' 1 and H 5 5.03

H

13 5.88 NHCH 2 7.29 H 3 7.53 and 7.68: H 6 and H 7 -8.09 and 8.13: H 5 and

H

8 -8.78: H 2 quinoline.

EXAMPLE 6: 9-[0-[2-[(4-phenylbutyl) amino] ethyl] oxime of 11,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-0-methylalpha-L-ribohexopyranosyl)-oxy]-6-0-methyl-3-oxo-12,11- [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 (96-4then it is purified for a second time with an ethyl acetate triethylamine mixture (95-5) 66 mg of product is obtained.

NDS2 CDCL 3 ppm 0.78 Ct) CH 3

-CE

2 0.99 CH 3 in position 8; 1.12 CE 3 in position 10; 1.24 CHI~ in position 1.30 CE 3 in position 4; 1.36 CHI in position 2; 1.40 and 1.46

CE

3 in position 6 and 12; 2.27 N(CE 3 2 2.69 Cs):

CH

3 0 in position 6; 2.46 H 3 1; -1.20 -1.70

CH

2 in position -1.40 Cm) -1.70 CE 2 in position 7; 1.60 -1.95 CE 2 in position 14; 1.50 2.10 central

CH

2 1 s of chains; 2.61 4H-2.70 3.30 the N-CH 2 's and j: 2 69 (masked) H 10 3 .07 H 4 3.19 (dd, J and 7.5) H 2 1; 3.54 Cm): H 5 3.67 Cm): H 8 3.86 H 1 1 3.87 H 2 3.92 to 4.08 Cm): O-CH 2

-CH

2 4.27 Cm): H 1

H

5 5.02 H 13 5.99 mobile 1Hi.

EXAMPLE 7: 9 [2 -(dimethylamino) ethyl] oxime] of ll,l 2 -dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-0-methyl-alpha- L-ribohexopyranosyl) -oxy] -6-O-methyl-3-oxo-12,11- Coxycarbonyl (4-quinolinyl) propyl] hydrazono]l erythromycin 250 mng of the product obtained in Example 5 in solution in 10 cm 3 of diinethylarnine with 33A EtOH is agitated for 1 hour at 75 0 C. Chromatography on silica is carried out eluting with a mnethylene chioride-methanol-amnionium 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 ammionium hydroxide, dried over magnesium sulphate and evaporated to dryness.. 190 mg of sought product is obtained.

NNR CDC1 3 ppm 0.78 Ct): CH 3

-CH

2 3.07 Cm): H 4 3.88 H 2 EXAMPLE 8: By operating as previously the 9-methyloxine of compound A was prepared, starting from compound A and CH 3

ONH

2 EXAMPLE 9: 9- (3-pyridinyl) -1H-imidazol-1-ylJ ethyl] oxime] of 11,12-dideoxy-3-de[ 6-dideoxy-3-C-methyl- 3 -O-methyl -alpha -L -ribo-hexopyranosyl) oxy] 6-O-methyl-3-oxo- 12,12- (oxycarbonyl- (4-quinolinyl) propyl] hydrazono] J erythromycin This product was prepared starting from the product of Example 5 by operating as in Example 6 using pyridinoimidazole.

EXAMPLE 10: 9-[O-piperidinyl] of 11,12-dideoxy-3-de[(2,6dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribo-hexopyranosyl) oxy] 6-0-methyl-3-oxo-12,11- oxycarbonyl-(hydrazono)] erythromycin.

Stage A: 9-[O-[l-[(phenylmethoxy) carbonyl] 3piperidinyl] oxime] of 11,12-dideoxy-3-de[(2,6-dideoxy-3-Coxy] methyl-3-oxo-12,11- [oxycarbonyl- (hydrazono)] erythromycin.

1.19 g of N-methyl benzyl 3-hydroxylamine piperidine and 0 1 g of ll,12-dideoxy-3-de[(2,6-dideoxy-3-C-methyl-3-O-methylalpha-L-ribo-hexopyranosyl) oxy] 6-O-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 1050C 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: CH 2 C12-MeOH-NH 4 0H 96-4- 1 g of expected product is obtained.

Stage B: 9-[0-3-piperidinyl] of 11,12-dideoxy-3-de[(2,6dideoxy-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:

CH

2 C12-MeOH-NH 4 OH 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 CDC1 3 ppm 0.85: CH 3

-CH

2 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: NMe 2 2.48:

H

3 2.68: H 1 0 2.70: 6-OMe; =2.70-2.83-3.08: the CH 2 -NH's; 3.08: H 4 3.19: H2'; 3.55: H 5 ~3.72: H 11 3.72 H 8

E

isomer; 3.85: H 2 3.92: O-CH 4.24: H 5 4.31: HI'; 5.06:

H

13 EXAMPLE 11: 9 -[O-3-piperidinyloxime] of 11,12-dideoxy-3de 2 ,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribohexopyranosyl) oxy] 6-0-methyl-3-oxo-12,11-[oxycarbonyl- (propyl-hydrazono)] erythromycin.

Stage A: 9 -[O-[1-[(phenylmethoxy) carbonyl] 3piperidinyl] oxime] of 11,12-dideoxy-3-de[(2,6-dideoxy-3-Cmethyl-3-O-methyl-alpha-L-ribo-hexopyranosyl) oxy] methyl-3-oxo-12,11-[oxycarbonyl-(propylhydrazono)] erythromycin.

250 mg of the product obtained in Stage A of Example in 5 ml of methanol is agitated for 24 hours at ambient temperature in the presence 50 tl 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: CH 2 Cl 2 -MeOH-NH40H 96-4and 262 mg of expected product is obtained.

Stage B: 9 -[O-3-piperidinyloxime] of 11,12-dideoxy-3-de 6 -dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribohexopyranosyl) oxy] 6-0-methyl-3-oxo-12,11-[oxycarbonyl- (propylhydrazono)] erythromycin The operation is carried out as in Stage B of Example 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 CDCl 3 ppm 0.86: H 15 0.97: CH 3 1.00: 8Me; 1.13: 10Me; 1.26: 1.3: 4Me; 1.36: 2Me; 1.39: H 7 1.42-1.47: 6Me and l2Me; 1.53:

CE

2 1.63: 4"1; 1.64-1.46: 5"1; 1.68-1.23: 1.97-1.56:

H

14 2.28: N~e; 2.47: 2.66: H1io; 2.68: CE 2 2.7-2.83: 6"1; 2.72: 6OMe; 3.07-2.78: 2"1; 3.09: H 4 3.19: 3.55: 3.74: H 8 3.87: H 11 3.88: H 2 3.9: 4.27: H 5 q; 4.29: 1'; 5.06: H 13 5.87: NH.

EXAMPLE 12: 9 -[O-3-piperidinyloximeJ of 11,12-dideoxy-3deE 6 -dideoxy-3-C-methyl-3-o-methyl-alpha-L-ribohexopyranosyl) oxy] 6-O-methyl-3-oxo-12,11- (oxycarbonyl- phenyipropyl) hydrazono)JJ erythromycin.

Stacre A: 9 -[O-(1-[(phenylmethoxy) carbonyll 3piperidinyl] oximel of 11,12-dideoxy-3-de[(2,6-dideoxy-3-Cmethyl-3-O-methyl-alpha-L-ribo.hexopyranosyl) oxy] methyl-3-oxo-12,11- foxycarbonyl- [(3-phenyipropyl) 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 phenyipropanaldehyde, 66 mg of acetic acid in 10 ml of methanol then 69 mg of sodium cyanoborohydride. After chromatography, 270 mg of expected product is obtained.

Stac~e B: 9 -[0-3-piperidinyloxime] of 11,12-dideoxy-3-de 6 -dideoxy-3-C-methyl-3-o-methyl-alpha-Lribo.

hexopyranosyl) oxy] 6-O-methyl-3-oxo-12, 11- (oxycarbonyl- phenylpropyl) hydrazono)]] erythromycin.

The operation is carried out as in Stage B of Example 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 CDC1 3 ppm 0.85: CH 3

-CH

2 1.00: 8Me; 1.12: lOMe; 1.22-1.68: CE 2 in position 1.26: 5'Me; 1.3: 4Me; 1.36: 2Me; 1.38-1.7: CH 2 in position 7; 1.39: H 7 1.41-1.47: 6Me and l2Me; 1.5 to 2: cycl. CH 2 C 1.57-1.95: CH 2

CH

3 1.83: central CE 2 2.28: NMe 2 2.45: 3' 2.67 to 2.87: H 1 0 and 6-OMe; 2.68: CE 2 3.1:

H

4 3.18: 3.55: 3.73: H 8 3.86: CH-OH; 3.87: H 11 3.88: H 2 3.9: 4.27: H 5 4.29: 5.07: H 13 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 370C, the growth inhibition is evaluated by transillumination, which allows the minimal inhibitory concentrations to be determined, expressed in 20 micrograms/cm micrograms/cm The following results were obtained Gram bacterial strains Products Example 3 Staphylococcus aureus 011UC4 0.3 Streptococcus pyogenes 0.08 group A 02A1UC1 Streptococcus agalactiae 0.08 group B 02B1HT1 Streptococcus faecalis 0.08 group D 02D2UC1 Streptococcus faecium 0.08 group D 02D3HT1 Streptococcus mitis 02mitCBl 0.04 Streptococcus agalactiae 0.08 group B 02B1SJ1 Streptococcus sanguis 0.08 Streptococcus pneumoniae s 0.02 032UC1 Streptococcus pneumoniae 0.04 030GR20 Streptococcus pneumoniae 0.08 030PW23c Streptococcus pneumoniae 0.08 030R01i 25 Streptococcus pneumoniae 0.15 030SJlc -2 la- Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to preclude the presence or addition of one or more other feature, integer, step, component or group thereof.

js1 0761 .comprise22/09/99,js 10761 .comprise,2

Claims

6-O-methyl-3-oxo-12,11- [oxycarbonyl-[[3-(4-quinolinyl) propyl] hydrazono]] erythromycin. 9) As medicaments, the compounds of formula as defined in any one of claims 1 to 7. As medicaments, the compound of formula as defined in claim 8. 11) The pharmaceutical compositions containing at least one medicament as defined in claim 9 or 10 as active ingredient. 12) Preparation process for the compound of formula as defined in claim 1, characterized in that a compound of formula (II): 0 H 3C 9 J" I I ICH3 B OCH 3 C 11111"'. A 6 1 1 1 0 3 3 III 11111111111111111111 0 S3 CH C 29 in which A, B and Z retain their previous meaning is subjected to the action of a compound of formula (III): in which R retains its previous meaning in order to obtain the corresponding compound of formula 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.