MACROLIDE DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF

The present invention relates to macrolide derivatives, and to the preparation and therapeutic use thereof. The compounds according to the present invention have substantial antimicrobial activity, mainly on gram-positive microorganisms, and also on mycobacteria, especially in the treatment of tuberculosis.

Due to the appearance of resistance, the development of novel antibacterial agents is necessary to make it possible to kill or to prevent the growth of mycobacteria, especially those which induce tuberculosis.

Tuberculosis is a disease which, at the present time, is still a worldwide health threat. Globally, a third of the human population is infected with Mycobacterium tuberculosis. Despite the fact that treatments exist and that the disease is curable, tuberculosis killed approximately 1.82 million people in 2008, and its global incidence increases by 1% per year, with an estimation in 2008 of 9.4 million annual new cases of declared disease. Added to this are the difficulties of correct prescription and of adherence to the treatment protocols, and also the emergence of multi-resistant strains of M. tuberculosis. Drug-drug interactions also interfere with the optimum treatment of AIDS and tuberculosis in the case of co-infected patients.

The common treatment protocols for combating sensitive strains of M. tuberculosis are mainly based on a combination of three or, more frequently, of four molecules: isoniazide (INH), rifampicin (RIF), pyrazinamide (PZA) and ethambutol (EMB). These drugs constitute the “first-line” treatment.

In recent decades, tuberculosis has become resistant to each of these molecules. Strains that are resistant at least to isoniazide and to rifampicin are referred to as “multi-resistant” (MDR-TB). Recently, novel strains have appeared which are resistant to a larger number of molecules: those that are resistant to isoniazide, to rifampicin, to fluoroquinolones and to at least one injectable second-line drug are defined as being “ultra-resistant” (XDR-TB).

According to an estimation made by the WHO in 2009, there were 0.5 million cases of MDR-TB in 2007. Other evaluations report a relative incidence of about 11% of multi-resistant strains among all new cases of tuberculosis.

Another therapeutic drawback in the treatment of tuberculosis is the interaction of rifampicin with treatments for combating HIV (human immunodeficiency virus), which represents an obstacle in the treatment of patients co-infected with tuberculosis and HIV. The current anti-HIV therapeutic recommendations favour, as a first-line treatment, an anti-retroviral triple therapy combining a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) with two nucleoside reverse transcriptase inhibitors (NRTI). PI and NNRTI are metabolized by CYP3A4. Metabolic interactions between anti-retrovirals (ATRV) and certain combined drugs have been demonstrated. Thus, rifampicin, which is a powerful inducer of intestinal and hepatic CYP3A4, reduces the concentrations of ATRV.

There is an urgent need to develop improved therapies for combating tuberculosis. These novel anti-tuberculosis treatments should be capable of satisfying one or more of the following criteria:

- shorten the treatment time to improve the adherence to the treatment protocols and reduce the appearance of resistant bacteria,
- be well tolerated, acting via novel mechanisms of action and thus effective against multi-resistant and/or ultra-resistant strains,
- be active against tuberculosis,
- have a shortened latent tuberculosis (asymptomatic first infection) treatment time, so as to address the problem of the biological reservoir of M. tuberculosis.

FR 2 126 108 and Arnoux et al. (Journal of the American Chemical Society 102(10), 1980, 3605) describe sequanamycin (A), having the following formula:

(3S,4S,5R,7S,9S,10S,11R,12S,13R)-12-[(4,5-dihydroxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy]-7-hydroxy-2-{1-[(5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy]propan-2-yl}-10-[(3-hydroxy-6-methyl-4-oxotetrahydro-2H-pyran-2-yl)oxy]-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl) 3-methylbutanoate.

embedded image

This compound is described therein as an antimicrobial agent and especially enables the treatment of tuberculosis. However, this compound may show instability, in particular in acidic or basic aqueous medium, and/or may also show metabolic instability, which makes it difficult to use as a drug.

It is therefore necessary to develop compounds with improved and/or more active pharmacokinetic properties, so as to enable their use as medicaments.

A subject of the present invention is in particular macrolide derivatives, which have bacteriostatic and/or bactericidal action, mainly on gram-positive microorganisms, and also on mycobacteria, especially against strains of sensitive Mycobacterium or Corynebacterium that are resistant to the first-line antibiotics, and the preparation and therapeutic uses thereof.

[Compounds]

The present invention relates to compounds corresponding to formula (I):

embedded image

in which:

- Y represents a hydrogen atom, a group —(C═O)—NR₂R₃or a group —(C═O)—O—R₁₈;
- Z represents:
  - a hydrogen atom,
  - a group —C_1-6-alkyl, which is unsubstituted or substituted with one or more groups R₄,
  - a group —C_3-7-cycloalkyl, which is unsubstituted or substituted with a group —NH—(C═O)—R₁₉or with a group —NH—SO₂—R₂₀,
  - a group —C_3-6-heterocycloalkyl,
  - a group —NH—(C═O)—R₅;
- R₁represents a hydrogen atom, a group —C_2-6-alkenyl, a group —C_2-6-alkynyl or a group —C_1-6-alkyl which is unsubstituted or substituted with a group —C_1-4-fluoroalkyl or with a heteroaryl group which is unsubstituted or substituted with a group 3-(3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-ylmethyl;
- R₂represents a hydrogen atom or a group —C_1-6-alkyl;
- R₃represents:
  - a group —C_3-7-cycloalkyl, which is unsubstituted or substituted with a group —C_1-3-alkyl substituted with a group —NH—SO₂—R₂₁,
  - a heteroaryl group,
  - a linear or branched group —C_1-6-alkyl, which is unsubstituted or substituted with a group chosen from:
    - a group —NH—R₆,
    - a group —NH—SO₂—R₇,
    - a group —NH—(C═O)—R₈,
    - a group —C_3-7-cycloalkyl, which is unsubstituted or substituted with a group —C_3-6-heterocycloalkyl,
    - a group —C_3-6-heterocycloalkyl,
    - an aryl group, which is unsubstituted or substituted with one or more groups chosen independently from a halogen atom and a group —C_1-4-fluoroalkyl,
    - a heteroaryl group, which is unsubstituted or substituted with a group —C_1-3-alkyl, a group —C_1-4-alkoxy, a group —C_1-4-fluoroalkyl or a group —C_3-6-heterocycloalkyl,
    - or alternatively with one or more groups —C_1-4-alkoxy;
- or alternatively R₂and R₃, together with the nitrogen atom to which they are attached, constitute a group —C_3-6-heterocycloalkyl chosen from: aziridine, azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine or piperazine; the said heterocycloalkyl group being unsubstituted or substituted with a heteroaryl group, the said heteroaryl group being unsubstituted or substituted with a group —C_1-4-fluoroalkyl;
- R₄independently represents a group chosen from:
  - a hydroxyl group,
  - a deuterium,
  - a halogen atom,
  - a group —C_3-7-cycloalkyl,
  - an aryl group, which is unsubstituted or substituted with one or more groups —R₉,
  - a heteroaryl group,
  - a group —C_3-6-heterocycloalkyl,
  - a group —C_1-4-alkoxy,
  - a group —(C═O)—NH—R₁₀,
  - a group —NH—R₁₁,
  - a group —NH—(C═O)—R₁₂,
  - or a group —NH(SO₂)—R₁₃;
- R₅represents a heteroaryl group;
- R₆represents a heteroaryl group, which is unsubstituted or substituted with one or more halogen atoms;
- R₇represents a group —C_1-4-fluoroalkyl, an aryl group or a heteroaryl group, the said aryl and heteroaryl groups being unsubstituted or substituted with one or more groups R_1′;
- R₈represents a heteroaryl group, which is unsubstituted or substituted with one or more groups R_2′;
- R₉represents a halogen atom, a group —C_1-4-alkoxy, a formyl group (CHO) or a group —C_1-4-alkyl, which is unsubstituted or substituted with a hydroxyl group;
- R₁₀represents a heteroaryl group, which is unsubstituted or substituted with a group —C_1-3-alkyl;
- R₁₁represents:
  - a group —C_3-10-heterocycloalkyl, which is unsubstituted or substituted with one or more oxide groups,
  - a heteroaryl group or an aryl-C_1-4-alkyl group, the said heteroaryl or aryl groups being unsubstituted or substituted with one or more groups independently chosen from a halogen atom, a hydroxyl group, a nitro group and a group —C_1-3-alkyl;
- R₁₂represents:
  - a group —C_1-4-alkoxy,
  - a group —C_1-4-alkyl, which is unsubstituted or substituted with a group —NR₁₄R₁₅or with a heteroaryl group, the said heteroaryl group being unsubstituted or substituted with a group —C_1-3-alkyl,
  - a heteroaryl group, which is unsubstituted or substituted with one or more groups chosen from a hydroxyl group and a group —C_1-3-alkyl;
- R₁₃represents:
  - a group —C_1-4-alkyl,
  - a group —C_1-4-fluoroalkyl,
  - an aryl group, which is unsubstituted or substituted with a nitro group,
  - or a heteroaryl group, which is unsubstituted or substituted with a group —NR₁₆R₁₇;
- R₁₄, R₁₅, R₁₆and R₁₇each independently represent:
  - a hydrogen atom,
  - or a group —C_1-4-alkyl;
- R₁₈represents a group —C_1-4-alkyl or a benzyl group;
- R₁₉represents an aryl group or a heteroaryl group;
- R₂₀represents a group —C_1-4-alkyl or an aryl group;
- R₂₁represents an aryl group;
- R_1′ represents:
  - a halogen atom,
  - a group —C_1-4-alkoxy,
  - a group —C_1-4-fluoroalkyl,
  - a group —OCF₃,
  - a nitro group,
  - a group —NH₂,
  - a group —NHCH₃;
- R_2′ represents:
  - a hydroxyl group,
  - a group —C_1-6-alkyl.

The compounds of general formula (I) may comprise one or more asymmetric carbons. They may therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the invention.

The compounds of formula (I) may exist in the form of bases or acid-addition salts. Such addition salts form part of the invention.

These salts are advantageously prepared with pharmaceutically acceptable acids, but salts of other acids, for example for purifying or isolating the compounds of general formula (I), also form part of the invention.

The compounds of formula (I) according to the present invention also comprise those in which one or more hydrogen, carbon or halogen atoms, especially chlorine or fluorine atoms, have been replaced with their radioactive isotopes, for example deuterium or tritium to replace hydrogen or carbon-14 to replace carbon-12. Such labelled compounds are useful in research, metabolism or pharmacokinetic studies, and also in biological and pharmacological tests as tools.

In the context of the present invention:

- alkyl represents a saturated, linear or branched aliphatic group; for example, a group C_1-3-alkyl represents a linear or branched carbon-based chain of 1 to 3 carbon atoms, especially a methyl, ethyl, propyl or isopropyl. Similarly, a group C_1-4-alkyl represents a linear or branched carbon-based chain of 1 to 4 carbon atoms, especially a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. Similarly, a group C_1-6alkyl represents a linear or branched carbon-based chain of 1 to 6 carbon atoms, especially a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl or isohexyl.
- alkenyl represents a linear or branched hydrocarbon-based aliphatic group comprising at least one unsaturation in the form of a double bond, and comprising from 2 to 6 carbon atoms. Examples that may be mentioned include the vinyl and allyl groups.
- alkynyl represents a linear or branched hydrocarbon-based aliphatic group comprising at least one unsaturation in the form of a triple bond, and comprising from 2 to 6 carbon atoms. Examples that may be mentioned include the ethynyl and 2-propynyl groups.
- cycloalkyl represents a saturated cyclic aliphatic group comprising from 3 to 7 carbon atoms. Examples that may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups.
- halogen represents a fluorine, chlorine, bromine or iodine atom.
- fluoroalkyl represents an alkyl group comprising from 1 to 4 carbon atoms, in which one or more hydrogen atoms are replaced with a fluorine atom. Examples of fluoroalkyl groups that may be mentioned include trifluoromethyl, difluoromethyl, 3,3,3-trifluoropropyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2,3,3-tetrafluoropropyl, 1,1-difluoroethyl and 3,3,3-trifluoro-2-(trifluoromethyl)propyl.
- heterocycloalkyl represents a saturated or partially saturated, monocyclic or polycyclic, optionally substituted 3- to 9-membered ring including one or more heteroatoms such as nitrogen, oxygen or sulfur atoms. The sulfur atoms may be in the form of sulfoxide or sulfone. By way of example, a heterocycloalkyl may be a pyrrolidine, a morpholine, a piperazine, a diazetidine, a dihydropyrrolidine, a piperidine, an azepane, an imidazolidine, a thiomorpholine, a tetrahydropyran, a tetrahydrothiophene, a tetrahydrothiopyran, a diazepane or an azabicyclooctane, a tropane, a 3,6-diazabicyclo[3.1.0]hexane, a tetrahydrofuran, a 3,7-diazabicyclo[3.3.1]nonane or a tetrahydrothiophene 1,1-dioxide.
- aryl represents a monocyclic or polycyclic, optionally substituted aromatic system comprising from 6 to 14 carbon atoms. According to one embodiment of the invention, the aryl group comprises 6 to 10 carbon atoms. When the system is polycyclic, at least one of the rings is aromatic. Examples of aryl groups that may be mentioned include phenyl, naphthyl, indanyl, tetrahydronaphthyl, anthracenyl and azulenyl.
- heteroaryl represents a monocyclic or polycyclic, optionally substituted 5- to 14-membered aromatic system. According to one embodiment of the invention, the heteroaryl is 5- to 10-membered and comprises one or more heteroatoms such as nitrogen, oxygen or sulfur atoms. When the system is polycyclic, at least one of the rings is aromatic. Examples of monocyclic heteroaryls that may be mentioned include thiazole, thiadiazole, thiophene, imidazole, triazole, tetrazole, pyridine, furan, oxazole, isoxazole, oxadiazole, pyrrole, pyrazole, pyrimidine, pyridazine and pyrazine. Examples of polycyclic heteroaryls that may be mentioned include indole, benzofuran, benzimidazole, benzothiophene, benzotriazole, benzothiazole, benzoxazole, quinoline, isoquinoline, indazole, quinazoline, phthalazine, quinoxaline, naphthyridine, 2,3-dihydro-1H-indole, 2,3-dihydrobenzofuran, tetrahydroquinoline, tetrahydroisoquinoline, tetrahydroisoquinazoline, furo[3,2-c]pyridine, 1H-pyrrolo[2,3-b]pyridine or tetrahydroquinazoline.
- alkoxy represents a group O-alkyl containing a saturated, linear or branched aliphatic chain comprising 1 to 4 carbon atoms. Examples of alkoxy groups that may be mentioned include methoxy and ethoxy.

According to the present invention, distinguished compounds are those of formula (I) in which Y represents a group —(C═O)—NR₂R₃, of formula:

embedded image

in which R₁, R₂, R₃and Z are as defined for the compounds of formula (I); in the form of bases or of acid-addition salts.

According to the present invention, distinguished compounds are also those of formula (I) in which Y represents a hydrogen atom, of formula:

embedded image

which R₁and Z are as defined for a compound of formula (I);

in the form of bases or of acid-addition salts.

According to a first variant of formula (IA). R₂represents a hydrogen atom and R₃represents a linear C_1-6-alkyl (Alk), which is unsubstituted or substituted with a group as defined for the compounds of formula (I), the compounds then having the formula (IC) below

embedded image

in which R₁and Z are as defined for the compounds of formula (I);

in the form of bases or of acid-addition salts.

Within the compounds of formula (IC), distinguished compounds are those of formula (ID) below in which Alk represents a methyl substituted with a phenyl group:

embedded image

and R₁and Z are as defined for a compound of formula (I);

in the form of bases or of acid-addition salts.

According to a second variant of formula (IA), distinguished compounds are those of formula (IE) in which R₂represents a hydrogen atom and R₃represents a branched C_1-6-alkyl (—C(CH₃)₂-Alk′), which is unsubstituted or substituted with a group as defined for the compounds of formula (I):

embedded image

and R₁and Z are as defined for the compounds of formula (I);

in the form of bases or of acid-addition salts.

Within the compounds of formula (IE), distinguished compounds are those of formula (IG) below in which Alk′ represents a [(phenylsulfonyl)amino]methyl group:

embedded image

and R₁and Z are as defined for the compounds of formula (I);

in the form of bases or of acid-addition salts.

According to a third variant of formula (IA). R₂and R₃represent an unsubstituted group —C_1-6-alkyl (Alk), the compounds then having the formula (IF) below:

embedded image

in which R₁and Z are as defined for a compound of formula (I);

in the form of bases or of acid-addition salts.

According to a fourth variant of formula (IA). R₂represents a hydrogen atom and R₃represents an unsubstituted group —C_3-7-cycloalkyl (cycloAlk), the compounds then having the formula (IH) below:

embedded image

in which R₁and Z are as defined for a compound of formula (I);

in the form of bases or of acid-addition salts.

According to the present invention, distinguished compounds are also those of formula (I) in which Y represents a group —(C═O)—OR₁₈, of formula:

embedded image

in which R₁, R₁₈and Z are as defined for a compound of formula (I);

in the form of bases or of acid-addition salts.

According to the present invention, distinguished compounds are those of formula (I) in which:

- Y represents a hydrogen atom, a group —(C═O)—NR₂R₃or a group —(C═O)—OMe;
- Z represents:
  - a hydrogen atom,
  - a group —C_1-6-alkyl, which is unsubstituted or substituted with one or more groups R₄,
  - a cyclopropyl group, a cyclobutyl group, a 3-(benzoylamino)cyclobutyl group, a 3-[(pyrazin-2-ylcarbonyl)amino]cyclobutyl group, a 3-[(methylsulfonyl)amino]cyclobutyl group, a 3-[(phenylsulfonyl)amino]cyclobutyl group, a cyclopentyl group, a cyclohexyl group,
  - a tetrahydro-2H-pyranyl group,
  - a group —NH—(C═O)—R₅;
- R₁represents a hydrogen atom, an ethyl group, a 2,2,2-trifluoroethyl group or a methyl group, which is unsubstituted or substituted with a 1,2,3-triazole group substituted with a 3-(3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-ylmethyl group;
- R₂represents a hydrogen atom or a methyl group;
- R₃represents:
  - a cyclohexyl group, a 1-{[(phenylsulfonyl)amino]methyl}cyclohexyl group or a 1-{[(phenylsulfonyl)amino]methyl}cyclopentyl group,
  - a 5,6,7,8-tetrahydroquinolin-5-yl group,
  - or a linear or branched group C_1-4-alkyl, which is unsubstituted or substituted with a group chosen from:
    - —NH—R₆,
    - —NH—SO₂—R₇,
    - —NH—(C═O)—R₈,
    - a 1-morpholin-4-ylcyclopentyl group,
    - a tetrahydro-2H-pyranyl group, a tetrahydrofuranyl group or a morpholin-4-yl group,
    - a phenyl group, which is unsubstituted or substituted with one or more groups chosen independently from a chlorine atom and a group —CF₃,
    - a 1H-pyrrolo[2,3-b]pyridinyl group, a 4-methyl-5,6,7,8-tetrahydroquinazolin-2-yl group, a 6-methoxy-1H-benzimidazol-2-yl group, a pyridinyl group, which is unsubstituted or substituted with a group —CF₃or with a morpholin-4-yl group,
    - or alternatively with one or more methoxy groups;
- or alternatively R₂and R₃, together with the nitrogen atom to which they are attached, constitute a —C_3-6-heterocycloalkyl group chosen from: azetidine, morpholine, 4-[5-(trifluoromethyl)pyridin-2-yl]piperazine;
- R₄independently represents a group chosen from:
  - a hydroxyl group,
  - a deuterium,
  - a fluorine atom,
  - a cyclopropyl group,
  - a phenyl group, which is unsubstituted or substituted with one or more groups chosen independently from a fluorine atom, a methoxy group, a —CH₂OH group and a —CHO group,
  - a pyridyl group,
  - a morpholinyl group, a tetrahydro-2H-pyranyl group,
  - a methoxy group,
  - a group —(C═O)—NH—R₁₀,
  - a group —NH—R₁₁,
  - a group —NH—(C═O)—R₁₂,
  - or a group —NH(SO₂)—R₁₃;
- R₅represents a pyridyl group;
- R₆represents a quinolyl group, the said quinolyl group being unsubstituted or substituted with a chlorine atom;
- R₇represents a —CF₃group, a phenyl, pyridyl, pyrazolyl, 1H-pyrrolo[2,3-b]pyridyl or indolyl group, the said phenyl, pyridyl, pyrazolyl, 1H-pyrrolo[2,3-b]pyridyl or indolyl groups being unsubstituted or substituted with one or more groups R_1′;
- R₈represents a pyrazinyl group, the said pyrazinyl group being unsubstituted or substituted with one or more groups R_2′;
- R₁₀represents a 1,8-naphthyridinyl group substituted with a methyl group;
- R₁₁represents a tetrahydrothiophene-1,1-dioxide, quinolyl, pyridyl or benzyl group, the said quinolyl, pyridyl or benzyl groups being unsubstituted or substituted with a chlorine atom, a hydroxyl group, a nitro group or a methyl group;
- R₁₂represents:
  - a tert-butoxy group,
  - a group —C_1-4-alkyl, which is unsubstituted or substituted with a group chosen from a group —NR₁₄R₁₅, pyridyl or pyrazolyl, the said pyridyl or pyrazolyl groups being unsubstituted or substituted with a methyl group,
  - a pyrazinyl or pyridyl, which is unsubstituted or substituted with one or more groups chosen from a hydroxyl group and a methyl group;
- R₁₃represents:
  - a group —CF₃,
  - a phenyl group, which is unsubstituted or substituted with a nitro group,
  - or a pyridyl group, which is unsubstituted or substituted with a group —NR₁₆R₁₇;
- R₁₄, R₁₅, R₁₆and R₁₇each independently represent:
  - a hydrogen atom,
  - a methyl group or an isopropyl group;
- R_1′ represents:
  - a fluorine atom, a chlorine atom,
  - a methoxy group,
  - a group —CF₃,
  - a group —OCF₃,
  - a nitro group,
  - a group —NH₂,
  - a group —NHCH₃;
- R_2′ represents:
  - a hydroxyl group,
  - a methyl group;
    
    in the form of bases or of acid-addition salts.

According to the present invention, distinguished compounds are those of formula (I) in which:

- Y represents a hydrogen atom or a group —(C═O)—NR₂R₃;
- Z represents:
  - a hydrogen atom,
  - a methyl group, an isopropyl group, a 2,2-dimethylpropyl group,
  - a group CD₃,
  - a 2-fluoroethyl group,
  - a cyclopropylmethyl group,
  - a 2-phenylethyl group,
  - a [(7-methyl-1,8-naphthyridin-2-yl)amino]-4-oxobutyl group,
  - a 2-{[(2-nitrophenyl)sulfonyl]amino}ethyl group,
  - a cyclopropyl group,
  - a tetrahydro-2H-pyranyl group;
- R₁represents a hydrogen atom, an ethyl group, a 2,2,2-trifluoroethyl group or a methyl group;
- R₂represents a hydrogen atom or a methyl group;
- R₃represents:
  - a methyl group,
  - a 2-{[(2,6-difluorophenyl)sulfonyl]amino}-1,1-dimethylethyl group,
  - a 1,1-dimethyl-2-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl group,
  - a 2-{[(2-fluorophenyl)sulfonyl]amino}-1,1-dimethylethyl group,
  - a 1,1-dimethyl-2-({[2-(trifluoromethoxy)phenyl]sulfonyl}amino)ethyl group,
  - a 1,1-dimethyl-2-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)ethyl group,
  - a 2-methyl-1-[(phenylsulfonyl)amino]propan-2-yl group,
  - a 2-methyl-1-{[(5-nitro-1H-pyrazol-4-yl)sulfonyl]amino}propan-2-yl group,
  - a 2-methyl-1-{[(trifluoromethyl)sulfonyl]amino}propan-2-yl group,
  - a 2-methyl-1-{[(2-nitrophenyl)sulfonyl]amino}propan-2-yl group,
  - a 1-{[(5-hydroxypyrazin-2-yl)carbonyl]amino}-2-methylpropan-2-yl group,
  - a 1,1-dimethyl-2-morpholin-4-ylethyl group,
  - a benzyl group,
  - a 2-(4-pyridyl)ethyl group;
    
    in the form of bases or of acid-addition salts.

Among the compounds according to the invention, mention may be made especially of the compounds below:

- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[(benzylcarbamoyl)oxy]-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-{[(2S,5S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[(benzylcarbamoyl)oxy]-2-(1{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-{[(2S,5R,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-12-{[(2S,7R)-4-cyclopropyl-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-7-{[(1-{[(5-hydroxypyrazin-2-yl)carbonyl]amino}-2-methylpropan-2-yl)carbamoyl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12-{[(2S,5R,7R)-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxo-7-({[2-(pyridin-4-yl)ethyl]carbamoyl}oxy)-12-{[(2S,5S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12-{[(2S,7R)-4-cyclopropyl-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12-{[(2S,7R)-2,5-dimethyl-4-(²H₃)methyl-1,4-oxazepan-7-yl]oxy}-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[(dimethylcarbamoyl)oxy]-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-{[(2S,5R,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12-{[(2S,7R)-2,5-dimethyl-4-(2-{[(2-nitrophenyl)sulfonyl]amino}ethyl)-1,4-oxazepan-7-yl]oxy}-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12-{[(2S,7R)-4-(2-fluoroethyl)-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12-{[(2S,7R)-2,5-dimethyl-4-{4-[(7-methyl-1,8-naphthyridin-2-yl)amino]-4-oxobutyl}-1,4-oxazepan-7-yl]oxy}-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[(benzylcarbamoyl)oxy]-12-{[(2S,7R)-4-(2,2-dimethylpropyl)-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-12-{[(2S,7R)-2,5-dimethyl-4-(2-phenylethyl)-1,4-oxazepan-7-yl]oxy}-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-7-{[(1-{[(5-hydroxypyrazin-2-yl)carbonyl]amino}-2-methylpropan-2-yl)carbamoyl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-7-{[(2-methyl-1-{[(5-nitro-1H-pyrazol-4-yl)sulfonyl]amino}propan-2-yl)carbamoyl]oxy}-6,14-dioxo-12-{[(2S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-hydroxy-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-{[(2S,5R,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-7-{[(2-methyl-1-{[(trifluoromethyl)sulfonyl]amino}propan-2-yl)carbamoyl]oxy}-6,14-dioxo-12-{[(2S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-12-{[(2S,7R)-2,5-dimethyl-4-(2-phenylethyl)-1,4-oxazepan-7-yl]oxy}-7-hydroxy-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-7-{[(2-methyl-1-{[(2-nitrophenyl)sulfonyl]amino}propan-2-yl)carbamoyl]oxy}-6,14-dioxo-12-{[(2S,5R,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-7-{[(2-methyl-1-{[(2-nitrophenyl)sulfonyl]amino}propan-2-yl)carbamoyl]oxy}-6,14-dioxo-12-{[(2S,5S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-7-[({2-methyl-1-[(phenylsulfonyl)amino]propan-2-yl}carbamoyl)oxy]-6,14-dioxo-12-{[(2S,5S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-2-(1-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}propan-2-yl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-7-[({2-methyl-1-[(phenylsulfonyl)amino]propan-2-yl}carbamoyl)oxy]-6,14-dioxo-12-{[(2S,5R,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[({1,1-dimethyl-2-[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-12-{[(2S,7R)-4-isopropyl-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-12-{[(2S,5R,7R)-4-(cyclopropylmethyl)-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-7-[({1,1-dimethyl-2-[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-12-{[(2S,7R)-4-(cyclopropylmethyl)-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-7-[({1,1-dimethyl-2-[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[({1,1-dimethyl-2-[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-12-{[(2S,7R)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-yl)-1,4-oxazepan-7-yl]oxy}-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-12-{[(2S,5S,7R)-4-(cyclopropylmethyl)-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-7-[({1,1-dimethyl-2-[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[({1,1-dimethyl-2-[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-12-{[(2S,5R,7R)-4-(2,2-dimethylpropyl)-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[({1,1-dimethyl-2-[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-12-{[(2S,7R)-4-(2,2-dimethylpropyl)-2,5-dimethyl-1,4-oxazepan-7-yl]oxy}-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-{[(1,1-dimethyl-2-morpholin-4-ylethyl)carbamoyl]oxy}-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-{[(2S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-{[(2-{[(2,6-difluorophenyl)sulfonyl]amino}-1,1-dimethylethyl)carbamoyl]oxy}-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-{[(2S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-({[1,1-dimethyl-2-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]carbamoyl}oxy)-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-{[(2S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-{[(2-{[(2-fluorophenyl)sulfonyl]amino}-1,1-dimethylethyl)carbamoyl]oxy}-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-{[(2S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-({[1,1-dimethyl-2-({[2-(trifluoromethoxy)phenyl]sulfonyl}amino)ethyl]carbamoyl}oxy)-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-{[(2S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-({[1,1-dimethyl-2-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)ethyl]carbamoyl}oxy)-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-{[(2S,3R,6R)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-{[(2S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[({1,1-dimethyl-2-[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-10-({(2S,3R,6R)-3-hydroxy-6-methyl-4-[(2,2,2-trifluoroethoxy)imino]tetrahydro-2H-pyran-2-yl}oxy)-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-{[(2S,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
- (2R,3S,4R,5R,7S,9S,10S,11R,12S,13R)-7-[({1,1-dimethyl-2-[(phenylsulfonyl)amino]ethyl}carbamoyl)oxy]-10-{[(2S,3R,6R)-4-(ethoxyimino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-2-(2-{[(2R,3R,4R,5R,6R)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-1-methylethyl)-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-{[(2S,5R,7R)-2,4,5-trimethyl-1,4-oxazepan-7-yl]oxy}oxacyclotetradecan-4-yl 3-methylbutanoate;
  
  in the form of bases or of acid-addition salts.

[Preparation]
[Nature of the Strain]

The strain described in FR 2 126 108 deposited at the Northern Regional Research Laboratory (NRRL) under the number NRRL 3892 may be used.

The strain named Allokutzneria albata deposited at the Deutsche Sammlung Von Mikroorganismen und Zellkulturen GmbH (DSMZ) by the group Sanofi-Aventis (Sanofi Aventis Deutschland GmbH, Industriepark Höchst H831, 65926 Frankfurt am Main) under the identification reference ST108942 may also be used.

[Fermentation and Purification to Isolate Sequanamycin of Formula (A)]

The fermentation and purification process described in FR 2 126 108 makes it possible to isolate sequanamycin of formula (A) from the strain Allokutzneria albata. This may be performed by application of the protocol below. This protocol is given as a non-limiting illustration: it may be adapted to other conditions.

Thus, the fermentation process described below was performed for 500 litres, but may be adapted for smaller or larger proportions.

The preculture medium (named “medium 5294”) used is typically the following:

Component
g/L

Glucose
4

Yeast extract
4

Malt extract
10

CaCO₃
2

The pH of the medium before sterilization is 7.2.

The main culture medium (named “medium 5254-Seq01”) used is typically the following:

Component
g/L

Glucose
15

Soybean meal
10

Corn maceration water
3

CaCO₃
1

NaCl
5

The fermentation process is typically as follows:

embedded image

The fermentation process described above was performed for 500 litres, but may be adapted for smaller or larger proportions. It was performed, for example, at a scale of 7000 litres as follows, using the same culture media:

Preculture 1=250 ml, inoculum: one vial of BCT.

Preculture 2=5 litres in flasks (2×2.5 litres), inoculum of 0.5% from preculture 1.

Preculture 3=400 litres of medium in a 600 litre bioreactor, seeding rate of 1.25% from preculture 2.

Main culture=7000 litres of medium in a 10 000 litre bioreactor, seeding rate of 5.7% from preculture 3.

The fermentation process is followed by the purification process below (performed on the 500 litre fermentation broth described above).

Once the fermentation was complete, the fermentation broth was separated into culture supernatant and mycelium using a cylindrical seed grader. The separation led to about 440 litres of culture supernatant.

In separate batches, 100-120 litres of culture supernatant comprising, inter alia, the macrolide (sequanamycin (A)) were placed on a column filled with adsorption resin (glass column filled with styrene-divinylbenzene copolymer, inside diameter of 200, length of about 180 mm, flow rate of 250 ml/min). The resin was then washed with 30% 2-propanol.

The sequanamycin (A) was isolated by eluting the column with the following elution gradient: 30-70% B over 45 minutes, 70% B over 10 minutes, 100% B over 25 min; with A=H₂O, B=2-propanol, modifier: 1 vol % NH₄Ac 50 g/L adjusted to pH 7).

The fractions comprising the sequanamycin (A) were combined and the 2-propanol was evaporated off. The pH of the solution obtained was adjusted to above 7.5 and the solution was then extracted twice with EtOAc. The organic phases were combined and the solvents were evaporated off. The oil obtained (about 10 g per 100 litres of culture supernatant) was purified on silica gel (column of 40 mm×260 mm), the column being eluted with an n-heptane to 30/70 n-heptane/EtOAc gradient over 45 minutes, followed by 30/70 n-heptane/EtOAc maintained for about 40 minutes (with a flow of 100 ml/minute). The monitoring of the purification may be performed by thin-layer chromatography, eluting with EtOAc and revealing the sequanamycins (in the form of blue spots) with a reagent such as vanillin.

According to the concentration of sequanamycin (A) in the individual 100 litre batches, about 2.5 to 3.5 g of sequanamycin (A) with a purity of 68-75% (determined by NMR) were obtained per batch.

If a higher purity is required, the sequanamycin (A) obtained may be repurified by reverse-phase chromatography on a WatersAtlantis machine with a 50×100 mm, 5μ column. An elution gradient of H₂O (A) and acetonitrile (B) and 1 vol % NH₄Ac 50 g/L adjusted to pH 7 was used (40-60% B over 30 minutes, flow rate of 140 ml/min). The chromatography was monitored by a light-scattering electrical signal. The fractions comprising the sequanamycin (A) were combined and lyophilized after having evaporated off the acetonitrile. The sequanamycin (A) yield after this final purification step was 57%, with an 85% pure compound according to the NMR analyses.

The compounds of formula (I) according to the invention are prepared from sequanamycin of formula (A).

[Processes for Preparing the Compounds of Formula (I) from Sequanamycin of Formula (A)]

In the steps described below, the usual organic chemistry reactions may be followed, especially those described in “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” by Richard C. Larock, published by John Wiley & Sons Inc.

In the text hereinbelow, the term “protecting group PG” means a group that can, firstly, protect a reactive function such as a hydroxyl or an amine during the synthesis and, secondly, regenerate the intact reactive function at the end of the synthesis. Examples of protecting groups and also protection and deprotection methods are given in Protective Groups in Organic Synthesis, Greene et al., 4th Edition (John Wiley & Sons, Inc., New York), 2007.

In the text hereinbelow, the term “leaving group LG” means a group that can be readily cleaved from a molecule by breaking a heterolytic bond, with loss of an electron pair. This group may thus be readily replaced with another group, for example during a substitution reaction. Such leaving groups are, for example, halogens or an activated hydroxyl group such as a methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate, etc. Examples of leaving groups and also references for their preparation are given in Advanced Organic Chemistry, M. B. Smith and J. March, 6th Edition, Wiley Interscience, 2007, pp. 496-501.

In accordance with the invention, the compounds of formula (I) in which Y represents a group —(C═O)—NR₂R₃may be prepared according to the process characterized in that:

a compound of formula (I), in which Y represents a hydrogen atom below:

embedded image

and R1 and Z are as defined for the compounds of formula (I), is reacted with a compound of formula (II) HNR2R3 in which R2 and R3 are as defined for the compounds of formula (I), in the presence of a carbonyl derivative and a base.

The introduction of a group Y representing a group —(C═O)—NR₂R₃into the compounds of formula (IB) typically comprises the following four successive steps:

- a-1) protection of the hydroxyl functions of the compound of formula (IB),
- a-2) formation of a carbonyl intermediate from the hydroxyl function in position 7 of the macrocycle,
- a-3) reaction of the carbonyl intermediate with a compound of formula (II) HNR₂R₃,
- a-4) deprotection of the hydroxyl functions.

In step a-1), the hydroxyl functions of the compound of formula (IB) are protected to form a compound of formula (III) below, the hydroxyl function in position 7 of the macrocycle (onto which the group Y will be introduced) remaining free:

embedded image

in which:

- R₁and Z are as defined for the compounds of formula (I);
- PG₁and PG₂independently represent a hydroxyl-function protecting group.

In step a-2), the hydroxyl function in position 7 of the macrocycle of the compound of formula (III) is used to form a carbonyl intermediate of formula (IV) below:

embedded image

in which:

- R₁and Z are as defined for the compounds of formula (I);
- LG represents a leaving group;
- PG₁and PG₂independently represent a hydroxyl-function protecting group.

In step a-3), the carbonyl intermediate of formula (IV) is reacted with a compound of formula (II) HNR₂R₃in which R₂and R₃are as defined for the compounds of formula (I).

Step a-3) is typically performed in a polar solvent, for instance dimethylformamide (DMF), generally for 10 to 48 hours and at room temperature.

In step a-4), the hydroxyl functions of the compound obtained in step a-3) are deprotected.

Step a-4) is typically performed according to the deprotection processes described in Protective Groups in Organic Chemistry, J. F. W. McOmie, Plenum Press, 1973 or in Greene's Protective Groups in Organic Synthesis, by Theodora W. Greene published by John Wiley & Sons Inc., 2006.

As regards step a-1), the hydroxyl functions of compound (IB) are protected, for example, with acetate functions. This protection reaction may be performed by placing the compound of formula (IB) in contact with acetic anhydride in the presence of a base, especially a nitrogenous base, for example pyridine, at room temperature, the hydroxyl function in position 7 of the macrocycle onto which the group Y will be introduced remaining free, to form a compound of formula (IIIα) below:

embedded image

in which:

- R₁and Z are as defined for the compounds of formula (I).

In a first embodiment of step a-2), a compound of formula (III) as defined above is reacted, for example, with 4-N,N-dimethylaminopyridine (DMAP) and trichloromethyl chloroformate, generally in the presence of a base, especially a nitrogenous base, for example pyridine, in an apolar aprotic solvent, for example dichloromethane, at a temperature between −20° C. and room temperature and for a time of between 5 and 30 hours, to form two carbonyl intermediates of formulae (IVα) and (IV_β) below:

embedded image

in which:

- R₁and Z are as defined for the compounds of formula (I);
- PG₁and PG₂independently represent a hydroxyl-function protecting group; or

embedded image

in which:

- R₁and Z are as defined for the compounds of formula (I);
- PG₁and PG₂independently represent a hydroxyl-function protecting group, for example an acetate function.

In a second embodiment of step a-2), a compound of formula (III) is reacted, for example, with imidazole and diphosgene to form a carbonyl intermediate of formula (IVγ) below:

embedded image

in which:

- R₁and Z are as defined for the compounds of formula (I);
- PG₁and PG₂independently represent a hydroxyl-function protecting group, for example an acetate function.

In a third embodiment of step a-2), a compound of formula (III) is reacted, for example, with diphosgene to form a carbonyl intermediate of formula (IVδ) below:

embedded image

in which:

- R₁and Z are as defined for the compounds of formula (I);
- PG₁and PG₂independently represent a hydroxyl-function protecting group, for example an acetate function.

In particular, steps a-1), a-2), a-3) and a-4) may be performed simultaneously or in reverse order. Thus, for example:

- a′-1) the hydroxyl functions of the compound of formula (IB) are protected, and a carbonyl intermediate is formed from the hydroxyl function in position 7 of the macrocycle by microwave heating of the compound of formula (IB) with, for example, N,N′-carbonyldiimidazole, in a solvent, for instance cyclohexane, and at a temperature of between 80° C. and 100° C., to obtain a compound of formula:

embedded image

in which Z and R₁are as defined for a compound of formula (I);

a′-2) the hydroxyl functions are deprotected by placing the compound of formula (XX) in contact with an acid, for instance hydrochloric acid, in a solvent, for instance tetrahydrofuran, to obtain a compound of formula:

embedded image

in which Z and R₁are as defined for a compound of formula (I);

a′-3), the compound of formula (XXI) is reacted with a compound of formula (II) HNR₂R₃in which R₂and R₃are as defined for the compounds of formula (I).

Step a′-3) is typically performed in a polar solvent, for instance dimethylformamide (DMF), in the presence of a base, for instance 1,8-diazabicyclo[5.4.0]undec-7-ene, generally for 10 to 48 hours and at room temperature.

In accordance with the invention, the compounds of formula (I) in which Y represents a group —(C═O)—NR₂R₃may also be prepared according to the process characterized in that:

b-1) a compound of formula (V):

embedded image

in which:

- R₁, R₂and R₃are as defined for the compounds of formula (I);
  
  is reacted with an oxidizing agent to obtain a compound of formula (VI):

embedded image

in which:

R₁, R₂and R₃are as defined for the compounds of formula (I);

b-2) the compound of formula (VI) thus obtained is reacted with a compound of formula (VII):

ZNH₂ (VII)

in which Z is as defined for compound (I), in the presence of a reducing agent, to obtain the expected compound of formula (I).

In step b-1), the oxidation of the compound of formula (V) is performed via the action of an oxidizing agent, for instance sodium periodate, in a polar solvent, for instance MeOH, and at a temperature of between 0 and 10° C.

In step b-2), the reaction of the compound of formula (VI) with a compound of formula (VII) takes place in the presence of a reducing agent, for instance sodium cyanoborohydride, in a slightly acidic medium, in a solvent such as MeOH.

In accordance with the invention, the compounds of formula (I) in which Y represents a hydrogen atom may be prepared according to the process characterized in that:

c-1) a compound of formula (VIII):

embedded image

in which:

- R₁is as defined for the compounds of formula (I);
  - is reacted with an oxidizing agent to obtain a compound of formula (IX):

embedded image

in which R₁is as defined for the compounds of formula (I);

c-2) the compound of formula (IX) thus obtained is reacted with a compound of formula (VII):

ZNH₂ (VII)

in which Z is as defined for compound (I), in the presence of a reducing agent, to obtain the expected compound of formula (I).

Steps c-1) and c-2) are performed under the same operating conditions as those described in steps b-1) and b-2) above.

In accordance with the invention, the compounds of formula (I) in which Y represents a group —(C═O)—O—R₁₈may be prepared according to the process characterized in that:

a compound of formula (XXI):

embedded image

in which Z and R₁are as defined for a compound of formula (I), is reacted with an alcohol of formula HO—R₁₈(XXII), in the presence of a base.

The reaction is performed in the presence of a mineral base, for instance potassium carbonate, at room temperature.

In particular, certain compounds of formula (I) may be prepared from other compounds of formula (I). Thus, for example, a compound of formula (I) in which Z═Me may be prepared from a compound of formula (I) in which Z═H, by reaction with formaldehyde in the presence of formic acid and in a solvent, for instance chloroform.

The compounds of formula (I) thus obtained may be subsequently separated from the reaction medium and purified according to standard methods, for example by crystallization or chromatography.

The compounds of formula (I) thus obtained are isolated in the form of the free base or of a salt, according to the standard techniques.

The compounds of formula (II) are commercial, known or prepared according to methods known to those skilled in the art.

The compounds of formula (V) in which Y represents a group —(C═O)NR₂R₃are prepared by reacting a compound of formula (VIII):

embedded image

in which R₁is as defined for the compounds of formula (I);

- with a compound of formula (II) HNR₂R₃in which R₂and R₃are as defined for the compounds of formula (I), in the presence of a carbonyl derivative, according to the four steps below:
  - d-1) protection of the hydroxyl functions of the compound of formula (VIII),
  - d-2) formation of an activated intermediate by activation of the hydroxyl function in position 7 of the macrocycle,
  - d-3) reaction of the activated intermediate with a compound of formula (II) HNR₂R₃,
  - d-4) optional deprotection of the hydroxyl functions.

In step d-1), the hydroxyl functions of the compound of formula (VIII) are protected to form a compound of formula (X) below (the hydroxyl function in position 7 of the macrocycle onto which the group Y will be introduced remaining free):

embedded image

in which:

- R₁is as defined for the compounds of formula (I);
- PG₁, PG₂, PG₃and PG₄independently represent a hydroxyl-function protecting group.

In step d-2), a carbonyl intermediate is formed from the hydroxyl function in position 7 of the macrocycle of the compound of formula (X), especially one or more of the carbonyl intermediates of formula (XI) below:

embedded image

in which:

- R₁is as defined for the compounds of formula (I);
- LG represents a leaving group;
- PG₁, PG₂PG₃and PG₄independently represent a hydroxyl-function protecting group.

In step d-3), the carbonyl intermediate obtained in step d-2) is reacted with a compound of formula (II) HNR₂R₃in which R₂and R₃are as defined for the compounds of formula (I).

Step d-3) is typically performed in a polar solvent, for instance dimethylformamide (DMF), generally for 10 to 48 hours and at room temperature.

In step d-4), the hydroxyl functions of the compound obtained in step d-3) are deprotected.

Step d-4) is typically performed according to the deprotection processes described in Protective Groups in Organic Chemistry, J. F. W. McOmie, Plenum Press, 1973 or in Greene's Protective Groups in Organic Synthesis, by Theodora W. Greene published by John Wiley & Sons Inc., 2006.

In a first embodiment of step d-1), the hydroxyl functions of compound (VIII) are protected, for example, with acetate functions. This protection reaction may be performed by placing the compound of formula (VIII) in contact with acetic anhydride in the presence of a base, especially a nitrogenous base, for example pyridine, at a temperature typically ranging from room temperature to 160° C., the hydroxyl function in position 7 of the macrocycle onto which the group Y will be introduced remaining free, to form a compound of formula (Xα) below:

embedded image