RU2353622C2 - Novel fusidic acid derivatives - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel fusidic acid derivatives of general formula

[I], where X represents halogen, trifluoromethyl, C₁-C₇alkyl, substituted with phenyl, C₂-C₉alkenyl, optionally substituted with C₁-C₇alkyl, halogen or phenyl, phenyl, optionally substituted with one or two similar or different substituents, selected from group consisting of halogen, C₁-C₇alkyl, C₂-C₉alkenyl, phenyl, C₁-C₆alkoxy, nitro, C₁-C₆alkyltio, trifluoromethyl and cyano; or X represents naphtyl; Y and Z both represent hydrogen or together with bond C-17/C-20 form double bond between C-17 and C-20 or together represent methylene and form cyclopropane ring in combination with C-17 and C-20; A represents O, S or S(O); B represents C_1-6alkyl, C_2-6alkenyl, C_1-6acyl, phenyl or benzoyl, where C_1-6alkyl is optionally substituted with one or more halogens, hydroxy, C_2-6alkenyl, phenyl, C_1-4heteroaryl or C_1-6alkoxy; Q₁ represents -(CHOH)-, or -(CHW)-, where W represents halogen or azido; Q₂ represents -(CHOH)-; to their pharmaceutically acceptable salts and easily hydrolysed esters and to pharmaceutical compositions, including said derivatives, as well as to their application in therapy.

EFFECT: application in therapy.

31 cl, 127 ex, 5 tbl

Description

FIELD OF THE INVENTION

The present invention relates to new derivatives of fusidic acid, pharmaceutical compositions containing these derivatives, as well as their use in therapy.

State of the art

Fusidic acid refers to fusidans, which are a small family of natural antibiotics.

Fusidans combines the presence of a tetracycline ring system with a unique “chair-boat-chair” conformation, which distinguishes them from steroids. In this regard, despite some structural similarities with steroids, namely: the presence of a tetracyclic system, fusidans do not show any hormonal activity. In addition, fusidans have the same side chain containing carboxylic acid, which is attached to the ring system in position C-17 due to a double bond, and an acetate group attached in position C-16. Fusidic acid as a fermentation product of Fusidium coccineum is the most powerful antibiotic among fusidan compounds and is the only fusidan that has found clinical use in the treatment of infectious diseases. Fusidic acid (Fucidin® (Fucidin®)) is used in clinical practice in the treatment of severe staphylococcal infections, in particular, infections of bones and joints in both acute and intractable forms of the disease ( The Use of Antibiotics , 5 ^th Ed., A. Kucers and N. Mck. Bennett (Eds.), Butterworth 1997, p. 580-587; and references cited therein). Despite the fact that fusidic acid is the most commonly used drug against staphylococci, it is also used as a means of combating some other gram-positive microorganisms. The clinical significance of fusidic acid is also determined by its effective distribution in various tissues, a low level of toxicity and allergic reactions, as well as the absence of cross-resistance with other clinically used antibiotics. Fusidic acid is widely used in local therapy of various skin and eye infections caused by staphylococci. It is mainly used in combination with traditional antibiotics such as penicillins, erythromycins or clindamycin. It is also used as an alternative to vancomycin to control C lostridium difficile .

Compared to staphylococci, some other gram-positive cocci often show less sensitivity to fusidic acid. For example, it can be noted that different types of sterptococci are generally up to 100 times less sensitive to fusidic acid than staphylococci [Kuchers et al., Supra ]. Other sensitive bacteria include gram-positive anaerobic cocci, such as Peptococcus and Peptostreptococcus spp, aerobic or anaerobic gram-positive bacteria, such as Corynebacterium diphtheriae, Clostridium tetani, Clostridium difficile and Clostridium perfringens . Gram-negative bacteria are resistant, with the exception of Neisseria spp. and Legionella pneumophila . This drug is particularly effective against both intracellular and extracellular M.leprae. The relationship between structure and activity (SAR) for fusidic acid has been extensively studied and many analogues have been obtained. However, only a few of these analogues have activity comparable to that of fusidic acid. Despite intensive and widespread SAR studies, the possibility of side chain modifications has not been studied extensively.

Compared to other antibiotics, the use of fusidic acid does not lead to the development of serious clinical problems associated with drug resistance [Turnidge, Int. J. Antimicro. Agents , 12, S35-S44, 1999]. However, as mentioned above, this substance itself has a rather limited spectrum of antibiotic activity, and, in this regard, it would be desirable to develop new analogues of fusidic acid that would have antibiotic activity against a wider range of pathogenic microorganisms and, in particular, streptococcus.

Previously, attempts were made to improve the therapeutic properties of fusidan by changing the structure of the side chain. Thus, document WO 02/070537 describes derivatives of fusidic acid in which the C17-C20 double bond was converted to a cyclopropane fragment by introducing a methylene group.

WO 01/29061 describes fusidic acid derivatives with a saturated C17-C20 double bond.

SUMMARY OF THE INVENTION

The authors of the present invention unexpectedly found that derivatives of fusidic acid, in which the position of C-24 is substituted, retain activity against staphylococci and significantly increase activity against streptococci. Thus, the present invention relates to compounds of the general formula I:

where X is halogen, trifluoromethyl, cyano, azido, alkyl, alkenyl or aryl, wherein said alkyl, alkenyl or aryl are optionally substituted with one or more, same or different, substituents selected from the group consisting of alkyl, alkenyl, aryl, alkoxy, nitro, alkylthio, halogen, azido, trifluoromethyl and cyano;

Y and Z both represent hydrogen or together with the C-17 / C-20 bond form a double bond between C-17 and C-20 or together represent methylene and form a cyclopropane ring in combination with C-17 and C-20;

A is a bond, O, S or S (O);

B is C _1-6 alkyl, C _2-6 alkenyl, C _1-6 acyl, C _3-7 cycloalkylcarbonyl or benzoyl, where all these groups are optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy , aryl, heteroaryl and azido, or, if A is a bond, then B can also be hydrogen;

Q ₁ and Q _{2 are} independently —CH ₂ -, —C (O) -, - (CHOH) -,

- (CHOR) -, - (CHSH) -, - (NH) -, - (CHNH ₂ ) - or - (CHW) -, where R is C _1-6 alkyl and W is halogen, cyano, azido or trifluoromethyl;

Q ₃ is —CH ₂ -, —C (O) - or —CHOH—;

G is hydrogen, OH or O — CO — CH ₃ ;

two bonds in the pentacyclic ring, shown by solid and broken lines, indicate that either of these two bonds can be a double bond, in which case Y is absent and Z is hydrogen;

the bond between C-1 and C-2 may be a single or double bond;

and pharmaceutically acceptable salts and readily hydrolyzable esters of these compounds.

In another aspect, the present invention relates to compounds of general formula I used in therapy, and more particularly, to a pharmaceutical composition comprising a compound of formula I together with a pharmaceutically acceptable excipient or carrier.

In another aspect, the present invention relates to a method for treating, preventing or ameliorating infection, wherein said method comprises administering an effective amount of compounds of formula I to a patient, if necessary.

In another aspect, the present invention relates to the use of a compound of formula I for the manufacture of a medicament for the prevention, treatment, amelioration, or prevention of infections.

In another aspect, the present invention relates to the use of a compound of formula I for regulating microbial growth and for preventing or preventing bacterial infections in breeding animals.

In another aspect, the present invention relates to a method for producing a compound of formula Ia

where X is bromo, Y and Z are both hydrogen or, together with the C-17 / C-20 bond, form a double bond between C-17 and C-20 or together represent methylene and form a cyclopropane ring in combination with C-17 and C-20; A is a bond, O, S or S (O); B is C _1-6 alkyl, C _2-6 alkenyl, C _1-6 acyl, C _3-7 cycloalkylcarbonyl or benzoyl, where all these groups may optionally be substituted with one or more substituents selected from the group consisting of halogen, hydroxy , C _1-6 alkoxy, aryl, heterocyclyl or azido, or, if A is a bond, then B can also be hydrogen; Q ₁ and Q ₂ independently represent —C (O) -, - (CHOH) -, - (CHSH) - or - (CHW) -, where W is halogen, cyano, azido and trifluoromethyl, including:

(a) dissolving fusidic acid or a suitable fusidic acid analogue in an appropriate organic solvent, followed by bromine treatment to give a 24.25-dibromic intermediate of general structure Ib:

where X and X 'are bromo, R is hydrogen, the bond between C-24 and C-25 is a single bond and Y, Z, A, B, Q ₁ and Q _{2 are as} defined above;

(b) treating a solution of the 24.25-dibromic intermediate in a suitable solvent in the presence of a suitable base to give a dehydrobrominated compound of formula Ia as a salt; and

(c) contacting the salt formed in step (b) with an acid to give a compound of formula Ia as a free acid.

In another aspect, the present invention relates to a compound of general structure Ib:

where X and X 'are bromo, R is hydrogen, the bond between C-24 and C-25 is a single bond, Y and Z are both hydrogen or together with C-17 / C-20 form a double bond between C -17 and C-20 or together represent methylene and form a cyclopropane ring in combination with C-17 and C-20; A is a bond, O, S or S (O); B is C _1-6 alkyl, C _2-6 alkenyl, C _1-6 acyl, C _3-7 cycloalkylcarbonyl or benzoyl, where all these groups are optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C _1-6 alkoxy, aryl, heterocyclyl and azido, or, if A is a bond, then B may also be hydrogen; Q ₁ and Q _{2 are} independently —C (O) -, - (CHOH) -, - (CHSH) - or - (CHW) -, where W is halogen, cyano, azido or trifluoromethyl.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

In the context of the present description, the term "alkyl" means a monovalent radical derived from alkane by removing a hydrogen atom from any carbon atom, and encompasses subclasses of primary, secondary and tertiary alkyl groups, including, for example, C ₁ -C ₁₂ alkyl, such as C _{1 -} C ₈ alkyl, such as C ₁ -C ₆ alkyl, such as C ₁ -C ₄ alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl , nonyl, dodecanyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclohexyl. Alkane refers to an acyclic or cyclic, branched or unbranched saturated hydrocarbon and, in this regard, is completely composed of hydrogen atoms and carbon atoms.

The term "alkenyl" in the context of the present description refers to a linear or branched acyclic hydrocarbon containing one or more carbon-carbon double bonds in the stereochemistry of E or Z, which is acceptable. The term includes, for example, C ₂ -C ₁₂ alkenyl, C ₂ -C ₈ alkenyl, C ₂ -C ₆ alkenyl, vinyl, allyl, 1-butenyl, 2-butenyl and 2-methyl-2-propenyl.

The term “acyl” as used herein refers to a radical of the formula —CO — R, where R is alkyl as defined above, for example, C ₁ -C ₆ acyl such as acyl, propionyl, butyryl or pivaloyl.

The term “alkoxy” as used herein means a radical of the formula —OR, where R is alkyl as defined above, for example, C ₁ -C ₅ alkoxy, C ₁ -C ₃ alkoxy, methoxy, n-propoxy, tert-butoxy, etc. P.

The term "halogen" means a representative of the seventh main group of the periodic system of elements, for example, fluorine, chlorine, bromine and iodine.

The term “cycloalkylcarbonyl” as used herein refers to a radical of the formula —C (O) —R ′, where R ′ is a cyclic radical as defined above.

The term “aryl” as used herein refers to a cyclic radical, an optionally fused bicyclic radical in which all ring atoms are carbon and in which the ring is aromatic, or in the case of a fused ring system, at least one ring is aromatic. Examples of aryl include phenyl, naphthyl and tetralinyl.

The term “alkylthio,” as used herein, refers to a radical of the formula —S — R ′, where R ′ is alkyl as defined above.

The term “heteroaryl” as used herein includes heterocyclic aromatic ring radicals that include 1-6 heteroatoms (selected from O, S, and N) and 1-20 carbon atoms, such as rings containing 1-5 heteroatoms and 1 -10 carbon atoms, such as rings containing 1-5 heteroatoms and 1-6 carbon atoms, such as rings containing 1-5 heteroatoms and 1-3 carbon atoms, in particular 5- or 6-membered rings with 1- 4 heteroatoms selected from O, S and N, or optionally fused bicyclic rings with 1-4 get roatomami, wherein at least one ring is aromatic, for example, furanyl, pyridyl, quinolyl, isoquinolyl, indolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thienyl, pyrazinyl, isothiazolyl, benzimidazolyl and benzofuranyl.

The term “readily hydrolyzable esters” as used herein refers to alkanoyloxyalkyl, aralkanoyloxyalkyl, aroyloxyalkyl, for example, acetoxymethyl, pivaloyloxymethyl, benzoyloxymethyl esters and their corresponding 1'-hydroxyethyl derivatives, and alkoxycarbonyloxyalkyl ethers, for example and their corresponding 1'-hydroxyethyl derivatives, or lactonyl esters, for example, phthalidyl esters or dialkylaminoalkyl esters, for example diethylaminoethyl esters. The expression "readily hydrolyzable esters" includes in vivo hydrolyzable esters of the compounds of the present invention. Such esters can be prepared using methods known to those skilled in the art, see GB Patent No. 1,490,852, incorporated herein by reference.

Preferred Variants of Compounds of Formula I

In a preferred embodiment, the present invention relates to compounds of General formula Ia

where X is halogen, trifluoromethyl, cyano, azido, C _1-7 alkyl, C _2-9 alkenyl or aryl, wherein said C _1-6 alkyl, C _2-9 alkenyl or aryl are optionally substituted with one or more identical or different substituents, selected from the group consisting of C _1-7 alkyl, C _2-9 alkenyl, aryl, C _1-6 alkoxy, nitro, alkylthio, halogen, azido, trifluoromethyl or cyano;

Y and Z both represent hydrogen or together with the C-17 / C-20 bond form a double bond between C-17 and C-20 or together represent methylene and form a cyclopropane ring in combination with C-17 and C-20;

A is a bond, O, S or S (O);

B is C _1-6 alkyl, C _2-6 alkenyl, C _1-6 acyl, C _3-7 cycloalkylcarbonyl or benzoyl, where all these groups are optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C _1-6 alkoxy, aryl, heteroaryl or azido, or, if A is a bond, then B can also be hydrogen;

Q ₁ and Q _{2 are} independently —C (O) -, - (CHOH) -, - (CHSH) - or - (CHW) -, where W is halogen, cyano, azido or trifluoromethyl;

and their pharmaceutically acceptable salts or readily hydrolyzable esters.

In a preferred embodiment of the compounds of formula I, Ia or Ib, Y and Z are both hydrogen and have a stereochemical configuration S both at C-17 and at C-20.

In another preferred embodiment of the compounds of formula I, Ia or Ib, Y and Z together represent methylene and form a cyclopropane ring in combination with C-17 and C-20, having a stereochemical configuration S both at C-17 and at C-20.

In another preferred embodiment of the compounds of formula I, Ia or Ib, Y and Z together with the C-17 / C-20 bond form a double bond between C-17 and C-20. The most preferred double bond configuration between C-17 and C-20 is the same as in fusidic acid.

In another preferred embodiment, X is chloro, bromo, iodo, fluoro, methyl, ethyl, propyl, phenyl, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, nonenyl, biphenyl or naphthyl, wherein said methyl, ethyl, propyl, phenyl , vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, nonenyl, biphenyl or naphthyl are optionally substituted with one or more identical or different substituents selected from the group consisting of fluoro, chloro, bromo, phenyl, vinyl, cyano, methoxy, trifluoromethyl, nitro, methylthio, butyl, methyl, ethyl, propyl, butyl, foam tyla, hexyl and heptyl.

In a particular preferred embodiment, X is fluoro, chloro, bromo, iodo, trifluoromethyl, phenyl, 4-bromophenyl, 4-chlorophenyl, 3,5-difluorophenyl, trans -1-hexen-1-yl, trans -1-butene-3, 3-dimethyl-1-yl, trans -1-nonen-1-yl, trans- 5-chloro-1-penten-1-yl, trans -2-phenyl-1-vinyl, 2-phenyl-1-ethyl, 4-n-propylphenyl, 4-vinylphenyl, 4- tert- butylphenyl, 4-cyanophenyl, 3-biphenyl, 4- (trifluoromethyl) phenyl, 4-methoxyphenyl, 3-cyanophenyl, 2-methoxyphenyl, 3-nitrophenyl, 3-bromophenyl , 4- (methylthio) phenyl, 2-naphthyl, 3,5- bis - (trifluoromethyl) phenyl, 3,4-dimethoxyphenyl or 3,5-dibromophenyl.

Q ₁ and Q ₂ can be successfully selected from the group consisting of - (CO) - and - (CHOH) -. Q ₁ can also successfully be CHF, CHCl, CHBr, CHI, CHN ₃ .

Another embodiment of the present invention relates to compounds of formula Ia, wherein Q ₁ and Q ₂ are both

- a (CHOH) group or one of Q ₁ and Q ₂ is - (CO) -, or Q ₁ is CHF, CHCl, CHBr, CHI or CHN ₃ ;

X is chloro, bromo, iodo, trifluoromethyl, azido or cyano;

Z and Y together with the C-17 / C-20 bond form a double bond between C-17 and C-20;

A is O, S or S (O);

B is a C _1-4 alkyl group optionally substituted with one or more substituents selected from the group consisting of azido, hydroxy, fluoro, chloro and bromo; or B is a C _1-4 acyl group or a benzoyl group, where both of these groups are optional substituted with one or more halogen atoms, such as, for example, fluorine and chlorine.

Specifically, in a preferred embodiment, A is O or S (O).

In yet another preferred embodiment, B is acyl, methyl, ethyl, propyl, butyl, pentyl, propenyl or cyclopentyl, where all of these groups are optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, fluorine, vinyl, hydroxy, phenyl, furfuryl and methoxy.

In a particular preferred embodiment, B is acetyl, isopropyl, ethyl, 2,2,2-trifluoroethyl, vinyl, 1-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, cyclopentyl, 2-hydroxyethyl, benzyl, furfuryl, phenyl, 2-fluoroethyl, 2-methoxyethyl, 2,2,2-trichloroethyl, 2-azidoethyl, 2-hydroxyethyl, propyl, tert -butyl, 1,3-difluoro-isopropyl, propionyl, chloroacetyl or trifluoroacetyl.

In a particular preferred embodiment, Q ₁ or Q _2, or both, and Q ₁ and Q ₂ are - (COH) -.

When Q ₁ and / or Q ₂ in the formulas I, Ia or Ib denote

- (COH) -, then the stereochemical configuration is preferably 3α and 11α, respectively.

Specific examples of the compounds of the present invention include the following compounds:

24-trifluoromethylfusidic acid sodium salt (compound 101),

24-trifluoromethylfusidic acid pivaloyloxymethyl ester (compound 102),

24-chlorofusidic acid (compound 103),

24-chlorofusidic acid pivaloyloxymethyl ester (compound 104),

24-chlorofusidic acid sodium salt (compound 105),

24-trifluoromethylfusidic acid (compound 106),

Acetoxymethyl ester of 24-bromofusidic acid (compound 107),

24-bromofusidic acid (compound 108),

24-bromfusidic acid sodium salt (compound 109),

24-bromofusidic acid pivaloyloxymethyl ester (compound 110),

24-Bromo-16-deacetoxy-16β-thioacetylfusidic acid acetoxymethyl ester (compound 111),

24-bromo-16-deacetoxy-16β-isopropylthiofusidic acid (compound 112),

24-bromo-16-deacetoxy-16β-isopropylsulfinylfusidic acid (compound 113),

24-bromo-16-deacetoxy-16β-thioacetylfusidic acid (compound 114),

24-bromo-17S, 20S-dihydrofusidic acid (compound 115),

24-bromo-16-deacetoxy-16β-ethoxyfusidic acid (compound 116),

24-Bromo-16-deacetoxy-16β-ethoxyfusidic acid acetoxymethyl ester (compound 117),

Acetoxymethyl ester 24-bromo-16-deacetoxy-16β- (2 ', 2', 2'-trifluoroethoxy) fusidic acid (compound 118),

24-bromo-16-deacetoxy-16β- (2 ', 2', 2'-trifluoroethoxy) fusidic acid (compound 119),

Acetoxymethyl ester 24-bromo-17S, 20S-fusidic acid (compound 120),

Acetoxymethyl ester 24-bromo-17S, 20S-methylenefusidic acid (compound 121),

24-bromo-17S, 20S-methylenefusidic acid (compound 122),

3-deoxy-3β, 24-dibromofusidic acid (compound 123),

3α-azido-24-bromo-3-deoxyfusidic acid (compound 124),

24-iodofusidic acid (compound 125),

Acetoxymethyl ester of 24-iodofusidic acid (compound 126),

24-iodofusidic acid pivaloyloxymethyl ester (compound 127),

24-phenylfusidic acid pivaloyloxymethyl ester (compound 136),

24-phenylfusidic acid (compound 137),

24- (4-bromophenyl) fusidic acid pivaloyloxymethyl ester (compound 138),

24- (4-bromophenyl) fusidic acid (compound 139),

24- (4-chlorophenyl) fusidic acid pivaloyloxymethyl ester (compound 140),

24- (4-chlorophenyl) fusidic acid (compound 141),

24- (3,5-difluorophenyl) fusidic acid pivaloyloxymethyl ester (compound 142),

24- (3,5-difluorophenyl) fusidic acid (compound 143),

3-Deoxy-3β, 24-dibromofusidic acid acetoxymethyl ester (compound 144),

24-bromo-16-deacetoxy-16β-ethylthiofusidic acid (compound 146),

24-bromo-16-deacetoxy-16β-ethylsulfinylfusidic acid (compound 147),

24-bromo-16-deacetoxy-16β-allyllthiofusidic acid (compound 148),

24-bromo-16-deacetoxy-16β- (1-pentylthio) fusidic acid (compound 149),

24-bromo-16-deacetoxy-16β- (1-pentylsulfinyl) fusidic acid (compound 150),

24-bromo-16-deacetoxy-16β- (2-methyl-1-butylthio) fusidic acid (compound 151),

24-bromo-16-deacetoxy-16β- (2-methyl-1-butylsulfinyl) fusidic acid (compound 152),

24-bromo-16-deacetoxy-16β- (3-methyl-1-butylthio) fusidic acid (compound 153),

24-bromo-16-deacetoxy-16β- (3-methyl-1-butylsulfinyl) fusidic acid (compound 154),

24-bromo-16-deacetoxy-16β-cyclopentylthiofusidic acid (compound 155),

24-bromo-16-deacetoxy-16β- (2,2,2-tritfortoethylthio) fusidic acid (compound 156),

24-bromo-16-deacetoxy-16β- (2-hydroxyethylthio) fusidic acid (compound 157),

24-bromo-16-deacetoxy-16β-benzylthiofusidic acid (compound 158),

24-bromo-16-deacetoxy-16β-benzylsulfinylfusidic acid (compound 159),

24-bromo-16-deacetoxy-16β- (2-furylmethylthio) fusidic acid (compound 160),

24-bromo-16-deacetoxy-16β-phenylthiofusidic acid (compound 161),

24-bromo-16-deacetoxy-16β-benzoylthiofusidic acid (compound 162),

24-bromo-16-deacetoxy-16β-isopropoxyfusidic acid (compound 163),

24-bromo-16-deacetoxy-16β- (2-fluoroethoxy) fusidic acid (compound 164),

24-bromo-16-deacetoxy-16β- (2-methoxyethoxy) fusidic acid (compound 165),

24- ( trans -1-hexen-1-yl) fusidic acid (compound 166),

24- ( trans -1-butene-3,3-dimethyl-1-yl) fusidic acid (compound 167),

24- ( trans -1-nonen-1-yl) fusidic acid (compound 168),

24- ( trans -5-chloro-1-penten-1-yl) fusidic acid (compound 169),

24- ( trans -2-phenyl-1-vinyl) fusidic acid (compound 170),

24- (2-phenyl-1-ethyl) fusidic acid (compound 171),

24- (4-n-propylphenyl) fusidic acid (compound 172),

24- (4-vinylphenyl) fusidic acid (compound 173),

24- (4- tert- butylphenyl) fusidic acid (compound 174),

24- (4-cyanophenyl) fusidic acid (compound 175),

24- (3-biphenyl) fusidic acid (compound 176),

24- (4- (trifluoromethyl) phenyl) fusidic acid (compound 177),

24- (4-methoxyphenyl) fusidic acid (compound 178),

24- (3-cyanophenyl) fusidic acid (compound 179),

24- (2-methoxyphenyl) fusidic acid (compound 180),

24- (3-nitrophenyl) fusidic acid (compound 181),

24- (3-bromophenyl) fusidic acid (compound 182),

24- (4- (methylthio) phenyl) fusidic acid (compound 183),

24- (2-naphthyl) fusidic acid (compound 184),

24- (3,5- bis - (trifluoromethyl) phenyl) fusidic acid (compound 185),

24- (3,4-dimethoxyphenyl) fusidic acid (compound 186),

24- (3,5-dibromophenyl) fusidic acid (compound 187),

Choline salt of 24-bromofusidic acid (compound 188),

L-arginine salt of 24-bromofusidic acid (compound 189),

2- (dimethylamino) ethanol salt of 24-bromofusidic acid (compound 190),

4- (2-hydroxyethyl) morpholine salt of 24-bromofusidic acid (compound 191),

L-lysine salt of 24-bromofusidic acid (compound 192),

N- (2-hydroxyethyl) pyrrolidine salt of 24-bromofusidic acid (compound 193),

Ethanolamine salt of 24-bromofusidic acid (compound 194),

Potassium salt of 24-bromofusidic acid (compound 195),

Tetrabutylammonium salt of 24-bromofusidic acid (compound 196),

Benzyltrimethylammonium salt of 24-bromofusidic acid (compound 197),

Cetyltrimethylammonium salt of 24-bromofusidic acid (compound 198),

Tetramethylammonium salt of 24-bromofusidic acid (compound 199),

Tetrapropylammonium salt of 24-bromofusidic acid (compound 300),

Tris (hydroxymethyl) aminomethane salt of 24-bromofusidic acid (compound 301),

N-methyl-D-glucamine salt of 24-bromofusidic acid (compound 302),

Silver salt of 24-bromofusidic acid (compound 303),

Benzetonium salt of 24-bromofusidic acid (compound 304),

Triethanolamine salt of 24-bromofusidic acid (compound 305),

24- ( trans -1-hexen-1-yl) fusidic acid pivaloyloxymethyl ester (compound 306),

24- ( trans -1-butene-3,3-dimethyl-1-yl) fusidic acid pivaloyloxymethyl ester (compound 307),

24- ( trans -1-nonen-1-yl) fusidic acid pivaloyloxymethyl ester (compound 308),

24- ( trans- 5-chloro-1-penten-1-yl) fusidic acid pivaloyloxymethyl ester (compound 309),

24- ( trans- 2-phenyl-1-vinyl) fusidic acid pivaloyloxymethyl ester (compound 310),

24- (2-phenyl-1-ethyl) fusidic acid pivaloyloxymethyl ester (compound 311),

24- (4-n-propylphenyl) fusidic acid pivaloyloxymethyl ester (compound 312),

24- (4-vinylphenyl) fusidic acid pivaloyloxymethyl ester (compound 313),

24- (4- tert- butylphenyl) fusidic acid pivaloyloxymethyl ester (compound 314),

24- (4-cyanophenyl) fusidic acid pivaloyloxymethyl ester (compound 315),

24- (3-biphenyl) fusidic acid pivaloyloxymethyl ester (compound 316),

24- (4- (trifluoromethyl) phenyl) fusidic acid pivaloyloxymethyl ester (compound 317),

24- (4-methoxyphenyl) fusidic acid pivaloyloxymethyl ester (compound 318),

24- (3-cyanophenyl) fusidic acid pivaloyloxymethyl ester (compound 319),

24- (2-methoxyphenyl) fusidic acid pivaloyloxymethyl ester (compound 320),

24- (3-nitrophenyl) fusidic acid pivaloyloxymethyl ester (compound 321),

24- (3-Bromophenyl) fusidic acid pivaloyloxymethyl ester (compound 322),

24- (4- (Methylthio) phenyl) fusidic acid pivaloyloxymethyl ester (compound 323),

24- (2-Naphthyl) fusidic acid pivaloyloxymethyl ester (compound 324),

24- (3,5- bis - (trifluoromethyl) phenyl) fusidic acid pivaloyloxymethyl ester (compound 325),

24- (3,4-Dimethoxyphenyl) fusidic acid pivaloyloxymethyl ester (compound 326),

24- (3,5-Dibromophenyl) fusidic acid pivaloyloxymethyl ester (compound 327).

The compounds of the present invention can be used as such either in the form of salts or readily hydrolyzable esters (as defined above). In particular, the salts of the compounds of the present invention are pharmaceutically acceptable salts, such as alkali metal salts and alkaline earth metal salts, for example, sodium, potassium, magnesium or calcium salts, as well as silver and base salts, such as ammonium salts or salts of suitable non-toxic amines, such as lower alkyl amines, for example triethylamine, hydroxy lower alkyl amines, for example 2-hydroxyethylamine, bis- (2-hydroxyethyl) amine, cycloalkylamines, for example dicyclohexylamine, il benzylamines, e.g., N, N'-dibenzylethylenediamine, and dibenzylamine. The silver salts of the present invention may be particularly useful for use in topical treatment.

In a preferred embodiment, the pharmaceutically acceptable salts of the compounds of general formula I or Ia are selected from the group consisting of sodium salts, choline salts, L-arginine salts, 2- (dimethylamino) ethanol salts, 4- (2-hydroxyethyl) morpholine salts, L-lysine salts, N- (2-hydroxyethyl) pyrrolidine salts, ethanolamine salts, potassium salts, tetrabutylammonium salts, benzyltrimethylammonium salts, cetyltrimethylammonium salts, tetramethylammonium salts, tetrapropylammonium salts of methyltrimethanes, Nomethanes (Tris) il-D-glucamine salts, silver salts, benzethonium salts and triethanolamine salts.

In a preferred embodiment of the preparation of a compound of formula Ia, the solvent used in step (a) for dissolving fusidic acid is acetic acid or a C _1-3 alkyl ester of C _1-4 carboxylic acid and is, in particular, ethyl acetate.

In a preferred embodiment of the preparation of a compound of formula Ia, the solvent used in step (b) for dissolving the 24.25-dibromic intermediate is a C _1-6 alcohol, such as methanol, ethanol, n-propanol, isopropanol or butanol, or water, or a mixture of these solvents.

In a preferred embodiment of the preparation of a compound of formula Ia, the base used in step (b) for dehydrobromination of the 24.25-dibromic intermediate is an alkali metal or alkaline earth metal salt and a weak acid such as carboxylic, phosphoric or boric acid, for example, potassium carbonate or sodium or a base, such as ammonia or a C _1-8 substituted ammonia, for example, ethylamine, diethylamine, triethylamine or piperidine, or an alkali hydroxide or alkaline earth metal such as dilute w roksid sodium hydroxide, calcium hydroxide or dilute potassium hydroxide.

The compounds of the present invention may include chiral carbon atom (s) and carbon-carbon double (s) bond (s), which determine the possibility of the appearance of stereoisomeric forms. The present invention relates to all such isomers, both in pure form and in the form of mixtures thereof. Pure stereoisomeric forms of the compounds of the present invention can be obtained using methods known in the art. Diastereomers can be separated using physical separation methods, such as selective crystallization and chromatography, for example, liquid chromatography using chiral stationary phases. Said pure stereoisomeric forms can also be obtained from the corresponding pure stereoisomeric forms of the corresponding starting materials, provided that the reaction is stereoselective or stereospecific. Preferably, if a particular stereoisomer of said compound is desired, the synthesis is carried out using stereoselective or stereospecific methods of preparation.

The compounds of the present invention are useful for the treatment, prevention or amelioration of infections in patients, including mammals, and in particular humans. More specifically, animals that can be treated using the compounds of the present invention include domestic animals such as horses, cows, pigs, sheep, poultry, fish, cats, dogs and zoo animals. The compounds of the present invention may be particularly useful in the treatment of bacterial infections, such as skin infections or secondary skin infections, or eye infections. In addition, the compounds of the present invention can be used in the treatment of simple abscesses, impetigo, boils, or cellulite. The compounds of the present invention, in particular, can be used in the treatment of, for example, topical treatment of contagious superficial skin infections, such as non-bullous impetigo (or contagious impetigo) or bullous impetigo. In this regard, the present invention relates to a method for treating, preventing or ameliorating bacterial infections, wherein the method comprises administering to a patient an effective amount of a compound of formula I, optionally together with another therapeutically active compound. Examples of such other therapeutically active compounds include antibiotics such as β-lactams, such as penicillins (phenoxymethylpenicillin, benzylpenicillin, dicloxacillin, ampicillin, amoxicillin, pivampicillin, fluxloxacillin, pipecephalipin, cefefilefin, cefefalipin, cefefalpecin, cefefalipin, cefefalipin, cephalphefalin, cephalphefalin, cefefalipin, cefefalipin, cefefalipin, cefefalipin, cephalphellin, cephalphellin, cephalphellin, cephalphefinol ceftriazone and cefuroxime), monobactams (aztreonam) and carbapenems (meropenem); macrolides (azithromycin, clarithromycin, erythromycin and roxithromycin); polymyxins (colistin); tetracyclines (tetracycline, doxycycline, oxytetracycline and limycycline); aminoglycosides (streptomycin, gentamicin, tobramycin and netilmicin); fluoroquinolones (norfloxacin, ofloxacin, ciprofloxacin and moxifloxacin); clindamycin, lincomycin, teicoplanin, vancomycin, oxazolidones (linezolid), rifamycin, metronidazole and fusidic acid. Other compounds that can be successfully combined with the compound of the present invention, especially for topical use, include, for example, corticosteroids such as hydrocortisone, betamethasone-17-valerate and triamcinolone acetonide. Compounds can be administered both simultaneously and in sequential mode.

The compounds of the present invention can also be used to prevent or prevent bacterial infections in animals and, in this regard, can be used in breeding domestic animals such as mammals, for example horses, cows, pigs, sheep, poultry, fish, cats, dogs , animals of the zoo.

For therapeutic use, the compounds of the present invention are taken in the form of a pharmaceutical composition. In this regard, the present invention relates to a pharmaceutical composition comprising compounds of formula I or Ia, optionally in combination with other pharmaceutically active compounds, as well as together with a pharmaceutically acceptable excipient or carrier. The excipient must be “acceptable” in the sense that it must be combined with the other ingredients of the composition and must not adversely affect the recipient.

Typically, the active ingredient comprises from 0.05 to 99.9% by weight of the total composition.

In the form of a standard dosage form, the compound can be administered once or several times a day at appropriate intervals and always depending on the condition of the patient, in accordance with the instructions of the attending physician. Typically, a unit dosage composition contains from 50 mg to 5000 mg, preferably from 200 mg to 1000 mg, of a compound of formula I or Ia.

In the context of topical application, the phrase “unit used” is more appropriate, which refers to a single dose that can be administered to a patient that is easy to manipulate and which, after packaging, is stored in the form of a physically and chemically stable unit dose, including the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers.

The term "unit used" in the context of topical application refers to a single, that is, a single dose that can be administered locally to a patient by applying from a dose of 0.1 mg to 10 mg per square centimeter of the affected surface, and preferably from 0.2 mg to 1 mg of the subject active ingredient.

It is also envisaged that in some treatment regimens, it is better to administer at longer intervals, for example, every other day, every week or at even longer intervals.

If the treatment regimen involves administering another therapeutically active compound, it is recommended that you consult the recommendations in the Goodman &Gilman's Pharmacological Basis of Therapeutics , 9 ^th Ed., JG Hardman and LE Limbird (Eds.), McGraw-Hill 1995 ), which shows the used doses of these compounds.

Contemplated compositions include, but are not limited to, those compositions which are in a form suitable for oral administration (including sustained or delayed release), rectal administration, parenteral administration (including subcutaneous, intraperitoneal, intramuscular, intraarticular and intravenous administration), transdermal, ophthalmic, local nasal or buccal administration.

In a convenient embodiment, the compositions can be presented in dosage form and can be manufactured using any methods known in pharmacy, such as those described in the Remington manual (Remington, The Science and Practice of Pharmacy , 20 ^th ed., 2000). All such methods include the step of contacting the active ingredient with a carrier, which is one or more accessory ingredients. In general, compositions are prepared by uniformly and thoroughly contacting the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product to the desired composition.

Compositions of the present invention suitable for oral administration may be in the form of discrete units, such as capsules, sachets, tablets or lozenges, each of which contains a predetermined amount of the active ingredient, may also be in the form of powder or granules, in the form of a solution or suspension in an aqueous liquid or in a non-aqueous liquid such as ethanol or glycerin; or may be in the form of an oil-in-water emulsion or a water-in-oil emulsion. Such oils may be edible oils, such as, for example, cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing agents or suspending agents, if used in aqueous suspensions, include synthetic or natural gums such as tragacanth, alginate, gum arabic, dextran, sodium carboxymethyl cellulose, gelatin, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose and polycarbyl cellulose. The active ingredients may also be administered as a bolus, electuary or paste.

Tablets may be made by compression or molding of the active ingredient, optionally with one or more accessory ingredients. Tablets can be prepared by compression in an appropriate apparatus where the active ingredient (s) are in free flowing form, such as powder or granules, optionally when mixed with a binder, such as, for example, lactose, glucose, starch, gelatin, gum arabic, tragacanth, sodium alginate, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, waxes or the like; with a sizing agent such as, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride or the like; with a decomposition aid such as, for example, starch, methylcellulose, agar, bentonite, croscarmellose sodium, starch glycolate, crospovidone or the like; or a dispersion aid, such as Polysorbate 80. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered active ingredient and a suitable carrier moistened with an inert liquid diluent.

Formulations for rectal administration may be in the form of a suppository in which the compound of the present invention is mixed with low melting water-soluble or water-insoluble solids, such as cocoa butter, hydrogenated vegetable oils, polyethylene glycol or esters of fatty acids and polyethylene glycols, wherein elixirs can be prepared by the use of myristyl palmitate.

Compositions suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredients, which is preferably isotonic for the blood of the recipient, based on, for example, isotonic saline, isotonic glucose or buffer solution. The composition can be suitably sterilized, for example, by filtration through a bacterial filter, by adding a sterilizing agent to the composition, by irradiating or heating the composition. Liposomal compositions described, for example, in the Encyclopedia of Pharmaceutical Technology (Encyclopedia of Pharmaceutical Technology, vol. 9, 1994) are also suitable for parenteral administration.

Alternatively, the compound of formula I can be presented in the form of a sterile solid preparation, for example, freeze-dried powder, which is readily soluble in a sterile solvent immediately before use.

Transdermal compositions may take the form of a patch or other form of small overlay areas of the respective material.

Compositions suitable for ophthalmic administration are presented as a sterile aqueous preparation of the active ingredients, which may be in the form of a microcrystalline product, for example, in the form of an aqueous microcrystalline suspension. Liposomal compositions or biodegradable polymer systems described, for example, in the Encyclopedia of Pharmaceutical Technology (Encyclopedia of Pharmaceutical Technology, vol. 2, 1989) can also be used with these active ingredients for ophthalmic administration.

Compositions suitable for topical or ophthalmic administration include liquid or semi-liquid preparations, such as liniment, lotions, gels, applications, oil-in-water or water-in-oil emulsions, such as creams, ointments or pastes ; or solutions or suspensions, such as drops.

Compositions suitable for nasal or buccal administration include powder, self-spraying and nebulizing compositions, such as aerosols and atomizers. Such compositions are described in sufficient detail in the literature (Modern Pharmaceutics, 2 ^nd ed., GS Banker and CT Rhodes (Eds.), P. 427-432, Marcel Dekker, New York; Modern Pharmaceutics, 3 ^th ed., GS Banker and CT Rhodes (Eds.), P. 618-619 and 718-721, Marcel Dekker, New York and Encyclopedia of Pharmaceutical Technology, vol. 10, Swarbrick and JC Boylan (Eds.), P. 191-221, Marcel Dekker, New York).

In addition to the above ingredients, the compositions of the compounds of the present invention of formula I or Ia may include one or more additional ingredients, such as diluents, buffers, flavors, colorants, surfactants, thickeners, preservatives, for example methyl hydroxybenzoate (including antioxidants), emulsifiers and the like

Parenteral compositions are useful, in particular, for treating conditions in which a quick response of the body to treatment is desired. In the case of continuous treatment of patients suffering from infectious diseases, the tablets or capsules used may be in the form of a pharmaceutical preparation having a prolonged effect achieved by the oral administration of the drug, in particular, these may be sustained-release tablets. When the active ingredient is administered in the form of salts of pharmaceutically acceptable non-toxic acids or bases, preferred salts are, for example, readily soluble in water or slightly soluble in water, selected for the purpose of achieving a certain state of absorption.

As noted above, the composition may contain other therapeutically active components that can be appropriately administered in combination with the compounds of the present invention in the treatment of infectious diseases, such as other suitable antibiotics, in particular antibiotics that can increase activity and / or inhibit development of resistance. Corticosteroids included in the compositions of the present invention may also be successfully used. In particular, the indicated other active component may include β-lactams, such as penicillins (phenoxymethylpenicillin, benzylpenicillin, dicloxacillin, ampicillin, amoxicillin, pivampicillin, fluxloxacillin, piperacillin and metsellinam), cephalefincetin, cefalefincetimonetz cefalefincetin cefalefinzimonetz cefalefincetin cefalefincetin cefalefincetin cefalefincetin cefalefinzimetin cefalefincetin cefalefinzimetin cefalefinzimetin cefalefinzimetin cefalefinzimetin cefalefin cytin cefatecimetin cefalefin tezimincetin cefalefincetin cefalefincetin cefalefincetim cefuroxime), monobactams (aztreonam) and carbapenems (meropenem); macrolides (azithromycin, clarithromycin, erythromycin and roxithromycin); polymyxins (colistin); tetracyclines (tetracycline, doxycycline, oxytetracycline and limycycline); aminoglycosides (streptomycin, gentamicin, tobramycin and netilmicin); fluoroquinolones (norfloxacin, ofloxacin, ciprofloxacin and moxifloxacin); clindamycin, lincomycin, teicoplanin, vancomycin, oxazolidones (linezolid), rifamycin, metronidazole and fusidic acid. Other compounds that can be successfully combined with the compounds of the present invention, especially for topical use, include, for example, corticosteroids such as hydrocortisone, betamethasone-17-valerate and triamcinolone acetonide.

Another therapeutically active compound may be in the same or in a separate container in the composition of the drug, adapted for the simultaneous or sequential administration of these therapeutically active compounds.

Treatment for infectious diseases often involves determining before treatment whether the disease is persistent or difficult to treat. As an example, it can be noted that samples containing an infectious microorganism can be taken from a patient, for example, blood or urine samples, after which this sample is cultured and exposed to the compound used for treatment in order to determine whether this infectious organism responds to the intended treatment. Accordingly, the present invention also relates to a method for identifying compounds effective against a microorganism, wherein the method comprises administering a compound of formula I or Ia, optionally in combination with other pharmaceutically active agents, into the microorganism and determining whether the compound or mixture of compounds is toxic or static effect on a given microorganism.

The compositions of the present invention are not limited to pharmaceutical preparations, but can be used in the field of non-therapeutic use for regulating microbial growth. For example, the compositions or compounds of the present invention may be useful as additives that inhibit microbial growth, used, for example, in fermentation processes. As an example, it can be noted that the selectivity inherent in these antimicrobial agents is useful for enhancing the growth of certain microorganisms due to other microorganisms in a culture that includes many types of microorganisms.

Biological activity

In vitro studies have demonstrated the high efficiency of the compounds of the present invention in relation to strains of both staphylococci and streptococci, which are among the most common pathogenic bacteria that cause various skin and eye infections. Biological tests showed the same or, in some cases, slightly increased antibacterial activity against staphylococci of the compounds of the present invention compared to fusidic acid and, more importantly, significantly higher antibacterial activity against streptococci, as can be seen from table 1, which shows the MIC values selected compounds of formula Ia in relation to both staphylococci and streptococci.

Connections

The fusidic acid analogs of the present invention and reference compounds 201 (fusidic acid (as sodium salt)), 207, 205, 203 and 206 (see notes to table A) are stored in powder form at a temperature of + 4 ° C. For use in these tests, they are dissolved in 95% EtOH (3.84 mg / ml) and stored for a maximum of one month at a temperature of -20 ° C before selection.

Bacterial strains used for biological assessment Bacterial strain Origin Staphylococcus aureus FDA486 Laboratory strain Staphylococcus aureus CJ12 Laboratory strain Staphylococcus aureus 8325-4 Laboratory strain Streptococcus pyogenes DA7121 Clinical isolate from infected human skin Streptococcus pyogenes DA7864 Clinical isolate from infected human skin

Wednesday

LB medium (per 1000 ml of ddH ₂ O: 10 g of bactotryptone, 5 g of yeast extract, 10 g of NaCl). THD Todd-Hewitt broth (SIGMA), product number: T1438 (per 1000 ml ddH ₂ O: 50 g infusion from the heart of a bull, 20 g casein peptone, 2 g dextrose, 2 g NaHCO ₃ , 2.5 g of NaCl; 0.4 g of Na ₂ HPO ₄ ). Cups are prepared using agar at a concentration of 1.5%. Blood agar Petri dishes contain an additional 5 vol. % defibrinated horse blood obtained from SLU (Swedish Agricultural University, Uppsala).

Determination of MIC (minimum inhibitory concentration)

The test for the determination of MIC compounds is carried out in 96-well microtiter plates (Thermo Labsystems). Bacteria in an amount of 4 × 10 ^{5 are} inoculated in 0.4 ml of growth media ( S. aureus - LB broth, S. pyogenes - TH broth) containing serial dilutions of the studied compounds, starting from 128 μg / ml (dilution factor 2, for example, 128 μg / ml, 64 μg / ml, ..., 0.016 μg / ml). The sensitivity criterion is the absence of visible growth after 24 hours under aerobic incubation conditions at a temperature of 37 ° C. Each compound was tested at least twice and in all cases, fusidic acid was included as an experimental control in the test.

Table a:
Antibacterial activity,
specific to selected compounds of the present invention. MIC / μg ml ^-1 Compound No. Staph.aureus FDA486 Staph.aureus CJ12 Staph.aureus 8325-4 Strep.pyogenes
DA7121 Strep.pyogenes
DA7864 108
Etal. conn. 201 (fusidic acid) 0.05
0.11 0,03
0.03 n.i.
0,03 0.8
3,5 0.8
3,5 113
Etal. conn. 207 0.22
0.22 0.11
0.05 n.i.
n.i. 0.4
1,6 0.4
1,6 115
Etal. conn. 205 0.88
0.44 0.06
0.06 0.11
0.11 1.8
fourteen 1.8
28 116
Etal. conn. 203 0.44
0.22 0.06
0.06 0.11
0.22 7
7 7
fourteen 122
Etal. conn. 206 0.88
0.22 0.22
0.06 0.88
0.11 7
> 32 7
28 Notes to table A:
The concentration of cells at time t = 0 corresponds to ~ 10 ⁶ / ml. Bacteria grow in the broth under aerobic conditions at 37 ° C.
n.i. = not investigated
Etal. conn. - reference connection

The reference compounds in Table A are known fusidic acid derivatives. Each reference compound refers to the compound of the present invention indicated above in the same column. The reference compounds are not substituted with C-24 and have a double bond between C-24 and C-25. All other structural characteristics of the reference compounds are identical to the corresponding compounds of the present invention, indicated above in the same column:

201 - Fusidic acid

207 - 16-deoxy-16β-isopropylsulfinylfusidic acid (von Daehne, W. et al., Adv. Appl. Microbiol ., 1979. vol. 25, p. 95-146)

205-17S, 20S-dihydrofusidic acid (Duvold, T. et al., J. Med. Chem. , 2001, Vol 44, p. 3125-3131)

203 - 16-deacetoxy-16β-ethoxyfusidic acid (von Daehne, W. et al., Adv. Appl. Microbiol. , 1979. vol. 25, p. 95-146)

206-17S, 20S-methylenefusidic acid (Duvold, T., et al., Bioorg. Med. Chem. Lett ., 2002, Vol. 12, p. 3569-3572)

The above data clearly show that the substitution of fusidic acid at position 24 leads to a significant increase in the activity of the compound against streptococci (2-15 times), while the activity against staphylococci remains essentially at the same level.

Abbreviations

The following are definitions of standard abbreviations used in this application:

AcOH = acetic acid

Ac ₂ O = Acetic Anhydride

Ac = Acetyl

aq. (aq) = water

Bu = n-butyl

^t Bu, tBu = tert-butyl

Comp. = connection

DBU = 1,8-diazabicyclo [5.4.0] undec-7-ene

DMF (DMF) = dimethylformamide

eq. (equiv.) = equivalent

Et = ethyl

Ether = diethyl ether

EtOAc = ethyl acetate

EtOH = Ethanol

Ex. (approx.) = example

FA = fusidic acid or an analogue of the ring substructures A, B, C, D

FCC = flash column chromatography

Fu = ring substructures A, B, C, D in fusidic acid

HMPA = hexamethylphosphoric triamide

HPLC (HPLC) = high performance liquid chromatography

iPr = Isopropyl

Me = methyl

MeOH = methanol

m.p. (Mp.) = Melting point

MRSA = methicillin-resistant Staphylococcus aureus

Pet.ether = petroleum ether

Ph = phenyl

Phenac = phenacyl

Piv = pivaloyl

Prep. (prep.) = drug

THF (THF) = tetrahydrofuran

TLC (TLC) = thin layer chromatography

rt (rt) = room temperature

sat. (sat.) NaCl = saturated aqueous solution of sodium chloride

TMS (TMS) = trimethylsilyl

v = volume

Obtaining compounds of the present invention

The compounds of formula I can be synthesized from known starting materials using various synthesis schemes, depending on the needs determined by each specific compound I, such as the availability of starting materials, the need for temporary protection of sensitive substituents, the level of purity and yield in the synthesis steps, and the selection of the preferred order following these reaction steps.

The following are illustrative, but not limiting methods and examples of the synthesis of various compounds of formula I or Ia. Various synthesis methods can be combined with each other, as it is deemed necessary by a person skilled in the art, to obtain the desired compounds of formula I or Ia with the desired substitution in ring A, C and D, at the 24 position of the side chain, and taking into account concerns their form: free acids, salts or easily hydrolyzable esters.

The basic method for the synthesis of 24-bromo compounds of general formula I with ring substructures A, B, C, D in FA (fusidic acid / fusidic acid analog) from starting materials 201-206 (with the same ring substructures A, B, C, D) is shown in diagram 1:

Examples of ring substructures A, B, C, D of fusidic acid and analogues of fusidic acid, FA :

Conditions: (a) ClCH ₂ O (CO) R ', Et ₃ N, DMF (R' = Me or C (CH ₃ ) ₃ ), qt .; (b) Br ₂ , CCl ₄ , 0 ° C; (c) DBU, CCl ₄ or CH ₃ CN, qt .; (d) DBU / aq. MeOH or K ₂ CO ₃ / MeOH, k.t.

Fusidic acid or an analogue of fusidic acid may be esterified, for example, with chloromethyl acetate or chloromethyl pivalate, using an appropriate solvent, such as dimethylformamide, in the presence of a suitable base such as triethylamine. The ester can then be brominated using bromine in a suitable solvent, such as carbon tetrachloride or acetonitrile. The resulting dibromide (which is usually a mixture of 24-diastereoisomers) can be dehydrobrominated by treatment with an appropriate base, such as DBU, in an appropriate solvent, such as carbon tetrachloride or acetonitrile, to form a predominantly 24-bromfusidic acid or ester analogue of fusidic acid. If desired, the ester can be used as a prodrug of the corresponding free acid I, for example, in the case of the presence of an easily hydrolyzable ester group. Alternatively, the ester can be hydrolyzed using a suitable base, such as DBU or K ₂ CO ₃ , in a suitable solvent, such as water containing methanol or ethanol, to give the desired compounds of general structure I (where X = bromo) as free acids or salts. In another embodiment of the present invention, the dibromide is subjected in one step to dehydrobromination and hydrolysis to obtain the desired compound I as a free acid or as salts, for example, using the methods described above. In another preferred embodiment, fusidic acid or an analogue of fusidic acid is directly brominated in accordance with the methods described above to give the corresponding dibromo acid (which is usually a mixture of 24-diastereoisomers). The dibromo acid is then subjected to dehydrobromination, for example, in accordance with the methods described above, to obtain the desired compounds of general structure I (where X = bromo) in the form of free acids and optionally in the form of salts.

The currently common method for preparing compounds of formula Ia, wherein Q ₁ , Q ₂ , A and B are indicated above, Y and Z together with the C-17 / C-20 bond form a double bond between C-17 and C-20, or together are methylene, or both are hydrogen, and X is bromo, illustrated in Scheme 1a by the corresponding reaction (where FA is ring substructures A, B, C, D-fusidic acid or fusidic acid analogue, as shown in scheme 1):

Fusidic acid or a fusidic acid analogue is dissolved in a suitable solvent such as acetic acid or a C _1-4 ester alkiovy C _1-4 carboxylic acid such as ethyl acetate, isopropyl acetate, tert-butyl acetate, and treated with bromine is preferably dissolved in the same solvent, at a temperature of −10 ° C. to 20 ° C., preferably at a temperature of 0 ° C. to 10 ° C., such as 5 ° C., to obtain a 24.25-dibromated intermediate. The 24.25-dibrominated intermediate may optionally be isolated after addition of an aqueous base and / or a reducing agent, such as Na ₂ SO ₃ , and the phases are separated by evaporation of the organic solvent. Then, the 24.25-dibrominated intermediate (optionally without performing isolation or purification steps) is subjected to dehydrobromination to give a compound of formula Ia by reacting a solution of the 24.25-dibromated intermediate in a suitable solvent, such as C _1-6 alcohol, for example methanol, ethanol, 1-propanol, isopropanol or butanol, or water, or a mixture of these solvents, with a suitable base, for example, at reflux temperature, or, for example, at a temperature of from 50 ° C to 120 ° C, such as in the range of 60 ° C-90 ° C, such as in the range of 70 ° C-80 ° C, to obtain the dehydrobrominated compound of formula Ia as a salt. The base used to prepare the dehydrobrominated compounds of formula Ia may be suitably selected from alkali metal or alkaline earth metal salts of a weak acid, such as carbonic, phosphoric or boric acid, for example, it may be potassium or sodium carbonate, or may be selected from bases such as ammonia or C _1-8 substituted ammonia, for example ethylamine, diethylamine, triethylamine or piperidine, or alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, calcium hydroxide or diluted potassium hydroxide. The compound of formula Ia in the form of a free acid can be further obtained from the salt by acidification with an appropriate acid, such as an aqueous solution of phosphoric acid or acetic acid. The compound of formula Ia can then be subjected to purification and recrystallization, for example, as described below in examples 8 and 45, to obtain pure compound Ia or conversion to an easily hydrolyzable ester, for example, as part of the procedure described in production method 1 and 2, or can be converted into a suitable salt, such as a sodium salt, for example, as described below in example 9.

The basic method used to convert the bromine substituent at the 24th position of the compound of general formula I (X = bromo) into 24-substituted compounds of general formula I (X = bromo) is shown by the example of the conversion of compound 108 in scheme 2:

Conditions: (a) ClCH ₂ O (CO) R ', Et ₃ N, DMF (R' = Me or C (CH ₃ ) ₃ ), qt .; (d) DBU / aq. MeOH or K ₂ CO ₃ / MeOH, rt .; (e) CuI, KI, HMPA, 120 ° C; (f) (R ′ = —CH ₂ COPh) BrCH ₂ COPh, KF, DMF, qt .; (g) CuI, CiCl, HMPA, 120 ° C; (h) CF ₃ Cu, HMPA, qt .; (i) ArB (OR ") ₂ *, Pd (PPh ₃ ) ₄ , K ₂ CO ₃ , EtOH + toluene, 90 ° C.

(Fu = ring substructures A, B, C, D-fusidic acid)

*cm. examples 36-43 illustrating procedures involving Ar and ArB (OR ”) ₂

Acetoxymethyl esters or pivaloyloxymethyl esters of 24-bromofusidic acid or an analogue of 24-bromofusidic acid or can be hydrolyzed to the corresponding free acids, for example, by treatment with methanol and an aqueous base. The bromic acids are further heated with copper (I) iodide and potassium iodide in HMPA at a temperature of 120 ° C. to give the corresponding 24-iodide acid of formula I. The acids can be further esterified to the corresponding phenacyl esters by treatment with phenacyl bromide and potassium fluoride in DMF. Phenacyl esters give the corresponding 24-trifluoromethyl esters, for example, by reaction with a solution of trifluoromethyl copper in HMPA. As a result, esters can be converted to the free 24-trifluoromethylfusidic acids (or fusidic acid analogues) of formula I by hydrolysis, for example, alkaline hydrolysis.

Alternatively, 24-iodoacids can be esterified to their acetoxymethyl esters or pivaloyloxymethyl esters as described above, and then converted to the corresponding 24-aryl or alkenyl esters and the like, during corresponding coupling reactions, for example, to in the framework of a coupling reaction of the Suzuki type with an arylboronic acid or ester, or substituted with an arylboronic acid or ester, as shown in Scheme 2. As a result, the corresponding free acids of the compounds are of the general form s I can be prepared by carrying out ester hydrolysis such as alkaline hydrolysis.

In another embodiment, acetoxymethyl esters or pivaloyloxymethyl esters of 24-bromofusidic acid or a 24-bromofusidic acid analogue are heated with copper (I) iodide and lithium chloride in HMPA to give the corresponding 24-chlorine ester. This ester gives free 24-chloroacids of the compounds of general formula I after hydrolysis, such as alkaline hydrolysis.

The main method for the synthesis of compounds I, including the modification in ring A during synthesis reactions, is illustrated in relation to the synthesis of compounds 123, 124 and 144 in scheme 3:

Conditions: (j) PhP ₃ P, CBr ₄ , benzene, qt .; (k) K ₂ CO ₃ , MeOH, qt .; (l) LiN ₃ , DMF, qt

A non-limiting example of a substitution modification in one of the rings of the ring substructures A, B, C, D of fusidic acid, for example, after the introduction of a 24-substituent, is shown in Scheme 3 as applied to the modification in ring A: for example, acetoxymethyl ester or pivaloyloxymethyl complex an ester of 24-bromofusidic acid or a 24-bromofusidic acid analogue may be brominated with triphenylphosphine and tetrabromomethane to form an inverse configuration corresponding to a 3-β-bromo-containing ester. The ester may optionally be hydrolyzed to the free acid of formula I. This acid may be further modified, for example, as shown by treatment with lithium azide to form another inverse configuration corresponding to the 3-α-azido ester of formula I.

The main method for the synthesis of compound I, including the modification in ring A and ring D during synthesis reactions, is illustrated in relation to the synthesis of compounds 112 and 113 in scheme 4:

Conditions: (m) Ac ₂ O, pyridine, qt .; (n) 1. 1 equiv. aq. NaOH, Meon, KT, 2. aq. NaHCO ₃ , 100 ° C; (o) 1. 1 equiv. aq. NaOH, MeOH, rt., 2. ClCH ₂ (CO) C (CH ₃ ) ₃ , DMF, rt .; (p) Cl (CO) OPh, NaBr, DMF, 0 ° C; (q) Br ₂ , CCl ₄ , qt .; (r) DBU, CH ₃ CN, reflux temperature; (s) 1. iPrSH, NaOH, DMF, qt, 2. aq. NaOH, 60 ° C; (t) 1.1 eq. aq. NaOH, MeOH, c .; 2. NaIO ₄ , MeOH, KT

The synthesis of compounds 112 and 113 from fusidic acid is illustrated by the following non-limiting procedure, in which the 16-substituent in ring D can be changed to an alkylthio or alkylsulfinyl group with 16-β-stereochemistry during the synthesis of compounds of general formula I. Temporary protection of the 3-hydroxy group and the carboxy group can be useful for this reaction, and the bromine at position 24 can be introduced at the corresponding synthesis stage: fusidic acid (201) can be acetylated at position C3 using acetic anhydride and pyridine to form compound (4) . The corresponding sodium salt of compound (4) is then heated with an aqueous solution of sodium bicarbonate to obtain the 16-α-hydroxy compound (5) (with the configuration inverted at position C16). The sodium salt of compound (5) can then be, for example, esterified with chloromethyl pivalate to form compound (6). Compound (6) can then be treated with phenylchloroformate, dimethylformamide and sodium bromide to form 16-α-bromo compound (11) (while maintaining the configuration at position C16). Compound (11) can be brominated to form 24.25-dibromic compound (12), which can be subjected to dehydrobromination, for example, using DBU to 24-bromo compound (13). Alkylation of sodium isopropylthiolate with compound (13) gives a 16-β-isopropylthio intermediate (with an inversion of configuration at position C16), which can be hydrolyzed, for example, with an aqueous base, to form 24-bromo-3-α-hydroxy-16-β isopropylthiocarboxylic acid (112) of the formula I. If desired, the compound (112) can be oxidized (for example, sodium periodate) to the corresponding sulfoxide (113).

METHODS FOR PRODUCING AND EXAMPLES

Basic information

All melting points are given in uncorrected form.

The values of the chemical shift in the spectra of nuclear magnetic resonance (NMR) for ¹ N (300 MHz) and ¹³ C (75.6 MHz) (δ) (ppm) relate, unless otherwise indicated, to solutions of deuterochloroform relative to internal standard tetramethylsilane (δ = 0.00) or deuterochloroform (δ = 76.81 for ¹³ C NMR). The value of the multiplet, either specific ((doublet (d), triplet (t), quartet (k)), or indefinite (m), is given at the corresponding midpoint if the range is not specified (c = singlet, w. - wide singlet The reaction mixtures are usually treated as follows: they are extracted with an organic solvent (as indicated), which is shaken with water and / or aqueous solutions of salts or acids (which is also indicated); organic solutions are usually dried over sodium or magnesium sulfate and concentrated under reduced pressure rotary ispa The chromatography is carried out on silica gel, usually using ethyl acetate and petroleum ether with a low boiling point as an eluent. The solvent ratio used is indicated in volumetric ratios / percent (volume: volume). The appropriate fractions are combined and concentrated, in some cases crystallizing or lyophilic drying. Solvents include: anhydrous solvents, which are usually prepared using stored solvents of analytical purity after sieving them through molecular sieve 4E for several days before use.

Obtaining intermediate compounds for the synthesis of compounds I

Intermediates of general formula Ib are listed in table 1:

Notes to Formula Ib and Table 1: Prep. = Drug; Rev. = the procedure is used to obtain other drugs and in other examples; Connection - Connection; Q ₂ = CH-OH (α);

X In the case of compounds that do not contain X ', the configuration around C24 and C25 is the same as in formula Ia, that is, C24 and C25 are connected by a double bond. For those compounds where X = X '= Br, both C24 and C25 are replaced by a bromine atom, C24 and C25 are connected by a single bond and the compounds are mixtures of two C24 diastereoisomers. R H = free acid; Na = sodium salt; CH ₂ OAc = acetoxymethyl ester; CH ₂ OPiv = pivaloyloxymethyl ether; fenats. = phenacyl ether; Y z Bd = carbon-carbon bond, i.e. C17 and C20 are linked by a double bond; H, H = 17S-H, 20S-H, that is, C17 and C20 are connected by a single bond;
-CH ₂ - = [Y, Z] -C17-C20 form a cyclopropane ring with the stereochemistry 17S, 20S-.

Production methods

Production Method 1 : Acetoxymethyl ester of fusidic acid (2a)

To a solution of fusidic acid (201) (128.6 g, 250 mmol) in DMF (375 ml) was added Et ₃ N (45 ml, 33 g, 320 mmol) and the mixture was stirred for 30 minutes at room temperature. After this, chloromethyl acetate (49 ml, 55 g, 500 mmol) was added and the reaction mixture was stirred overnight at room temperature and then washed (EtOAc, water) to obtain a crude product. The crude ester (2a) is recrystallized from isopropyl ether to give the pure compound as a colorless powder, mp. 103-105 ° C.

¹³ C NMR (CDCl ₃ ): 170.4, 169.6, 168.4, 150.6, 132.7, 129.3, 122.9, 79.4, 74.4, 71.4, 68, 2, 49.2, 48.7, 44.3, 39.5, 39.0, 37.1, 36.2, 36.2, 35.5, 32.4, 30.3, 30.0, 28.8, 28.3, 25.7, 24.2, 22.8, 20.9, 20.8, 20.7, 17.9, 17.7.15.

Production Method 2 : Pivaloyloxymethyl ester of fusidic acid (2b)

According to the procedure described for Production Method 1, by replacing chloromethyl acetate with chloromethyl pavalate, reacting at a temperature of 50 ° C. overnight, pivaloyloxymethyl ester of fusidic acid (2b) is obtained in the form of a colorless amorphous substance.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 168.1, 150.9, 132.6, 129.3, 123.0, 79.8, 74.3, 71.4, 68, 2, 49.3, 48.8, 44.3, 39.5, 39.0, 38.8, 37.0, 36.3, 36.1, 35.6, 32.3, 30.2, 30.0, 28.8, 28.3, 26.9, 25.7, 24.1, 22.9, 20.8, 17.9, 17.8, 15.9.

Production Method 3 : Acetoxymethyl ester 24R, S, 25-dibromofusidic acid (3a)

Fusidic acid acetoxymethyl ester (2a) (6 g, 10 mmol) was dissolved in CCl ₄ (40 ml) and a solution of bromine (0.56 ml, 1.76 g, 11 mmol) in CCl ₄ (40 ml) was added over a period of one hour with constant stirring and cooling in an ice bath. The resulting slightly yellow solution was used in the next step without further purification.

¹ H NMR (CDCl ₃ ): 5.91 (m, 1H), 5.78 (br s, 2H), 4.36 (br s, 1H), 4.20 (m, 1H), 3.75 (br s, 1H), 3.16 (m, 1H), 2.80-1.00 (m, 20H), 2.10 (s, 3H), 1.97 (br s 6H), 1.80 (s, 3H), 1.38 (s, 3H), 0.96 (s, 3H), 0.95 (s, 3H), 0.91 (d, 3H).

Production Method 4 : Pivaloyloxymethyl ester 24R, S, 25-dibromofusidic acid (3b)

According to the procedure described for production method 3, when substituting fusidic acid acetoxymethyl ester (2a) with fusidic acid pivaloyloxymethyl ester (2b), after concentrating the reaction mixture and purifying the product by flash column chromatography (hexane: EtOAc 50:50, as eluent) give the title compound 3b as a colorless foam.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 170.2, 167.7, 167.6, 153.0, 153.0, 127.7, 80.1, 80.0, 74, 3, 71.4, 68.5, 68.4, 68.2, 68.1, 66.2, 65.8, 60.4, 49.3, 49.2, 48.9, 48.9 44 5 39.5, 39.0 38.8, 37.0, 36.3, 36.1, 35.8, 35.2, 35.1, 32.3, 31.6, 30.2, 30 , 0, 28.5, 28.2, 28.2, 27.7, 26.9, 24.1, 24.1, 22.8, 22.7, 20.8, 20.8, 18.1 , 18.0, 16.0, 14.2.

The method of obtaining 5 : 3-acetylfusidic acid (4)

Fusidic acid (201) (74.3 g, 0.144 mol) was dissolved in pyridine (75 ml, 74 g, 0.93 mol) and acetic anhydride (75 ml, 81 g, 0.79 mol) and the resulting reaction mixture was stirred at room temperature for three hours, after which the reaction is complete. The acetylated product is precipitated by the addition of ice and water. Recrystallization from methanol / water gives the pure compound (4).

¹³ C NMR (CDCl ₃ ): 174.5, 171.0, 170.6, 151.1, 132.7, 129.7, 123.0, 74.4, 74.2, 68.3, 49, 1, 48.8, 44.3, 39.4, 39.0, 37.8, 37.0, 35.8, 34.8, 32.7, 31.1, 28.7, 28.4, 27.4, 25.7, 24.4, 22.6, 21.3, 20.6, 20.6, 18.1, 17.8, 15.5.

The method of obtaining 6 : 3-acetyl-16-deacetoxy-16α-hydroxyfusidic acid (5)

3-acetoxyfusidic acid (4) (9.95 g, 17.8 mmol) was dissolved in MeOH (250 ml) and neutralized with an equivalent amount of aqueous NaOH (about 9 ml, 2M). The solvents were evaporated and water (150 ml) was added to the residue. The mixture was heated to reflux and 20 ml of saturated aqueous NaHCO ₃ solution (about 1 M) was added over 30 minutes. The resulting clear solution is heated to a temperature of 100 ° C for eight hours, after which an insoluble by-product (corresponding lactone) is formed. The lactone was removed by filtration and the filtrate was acidified with HCl (20 ml, 4M) and extracted with EtOAc. The organic phase is washed with water, dried using MgSO ₄ and concentrated under reduced pressure to obtain the title compound (5), which is used in the next step without further purification.

¹³ C NMR (CDCl ₃ ): 174.2, 171.2, 164.7, 132.5, 127.6, 123.2, 74.2, 72.2, 68.4, 49.1, 47, 4, 43.9, 39.5, 39.2, 37.7, 36.9, 35.9, 34.9, 32.6, 31.0, 29.1, 28.4, 27.3, 25.7, 24.5, 22.7, 21.4, 20.7, 18.4, 17.9, 15.5.

Production Method 7 : 3-Acetyl-16-deacetoxy-16α-hydroxyfusidic acid pivaloyloxymethyl ester (6)

3-Acetyl-16-deacetoxy-16α-hydroxyfusidic acid (5) (39.7 g, 77 mmol) was dissolved in MeOH (250 ml) and neutralized with 1 equivalent. aqueous NaOH. The solvent was evaporated and the residue was redissolved in DMF (450 ml). Chloromethyl pivalate (13.4 ml, 13.9 g, 92 mmol) was added over 30 minutes with constant stirring and cooling with ice. The resulting mixture was stirred overnight at room temperature, after which it was washed (EtOAc, aq. CaCl ₂ , water, saturated with NaCl), dried using MgSO ₄ and concentrated under reduced pressure to obtain the title compound (6) as an oil which is used in the next step without further purification (production method 11).

¹³ C NMR (CDCl ₃ ): 177.2, 171.0, 168.6, 164.6, 132.6, 127.2, 123.1, 80.0, 74.1, 72.1, 68, 4, 49.1, 47.4, 43.7, 39.5, 39.4, 38.8, 37.7, 36.9, 36.0, 34.9, 32.6, 31.0, 28.9, 28.0, 27.4, 26.9, 25.7, 24.5, 22.6, 21.3, 20.7, 18.4, 17.8, 15.5.

Production Method 8 : Acetoxymethyl ester of 16-deacetoxy-16β-thioacetylfusidic acid (8)

According to the procedure described for production method 1, when replacing fusidic acid with 16-deacetoxy-16β-thioacetylfusidic acid (202) (von Daehne, W. et al., Adv. Appl. Microbiol. , 1979, vol. 25, p. 95 -146) and using 10 equiv. each of Et ₃ N and chloromethyl acetate, upon further purification of the crude product by flash column chromatography using petroleum ether: EtOAc (1: 1) as the eluent, the title compound (8) is obtained.

¹³ C NMR (CDCl ₃ ): 194.9, 169.5, 168.4, 151.3, 132.7, 129.5, 122.9, 80.0, 71.4, 68.3, 49, 2, 49.0, 45.7, 43.7, 41.4, 39.7, 37.2, 36.3, 35.9, 35.7, 32.7, 30.4, 30.0, 29.9, 29.3, 28.3, 25.7, 24.4, 22.4, 20.7, 20.6, 18.6, 17.7, 16.0.

Production Method 9 : Acetoxymethyl ester of 16-deacetoxy-16β-ethoxyfusidic acid (9)

According to the procedure described for production method 1, when fusidic acid is replaced with potassium salt of 16-deacetoxy-16β-ethoxyfusidic acid (203) (von Daehne, W. et al., Adv. Appl. Microbiol. , 1979, vol. 25, p . 95-146), without Et ₃ N, but using 10 equiv. chloromethyl acetate, upon further purification of the crude product by flash column chromatography using petroleum ether: EtOAc (1: 1) as the eluent, the title compound (9) is obtained.

¹³ C NMR (CDCl ₃ ): 169.7, 169.6, 151.2, 132.4, 128.6, 123.2, 79.6, 78.8, 71.4, 68.4, 65, 2, 49.2, 49.0, 43.3, 39.5, 37.0, 36.3, 36.2, 35.8, 35.5, 32.5, 30.2, 30.0, 28.8, 28.2, 25.7, 24.1, 22.8, 20.9, 20.8, 17.8, 17.7, 16.0, 15.3.

Production Method 10 : Acetoxymethyl ester of 16-deacetoxy-16β- (2 ', 2', 2'-trifluoroethoxy) fusidic acid (10)

According to the procedure described for the production method (1), when replacing fusidic acid with 16-deacetoxy-16β- (2 ', 2', 2'-trifluoroethoxy) fusidic acid (204) (von Daehne, W. et al., Adv. Appl. Microbiol ., 1979, vol. 25, p. 95-146) and using 10 eq. each of Et ₃ N and chloromethyl acetate, upon further purification of the crude product by flash column chromatography using petroleum ether: EtOAc (1: 1) as the eluent, the title compound (10) is obtained.

¹³ C NMR (CDCl ₃ ): 169.7, 169.1, 151.0, 132.6, 129.9, 123.7, 123.0, 80.1, 79.5, 71.4, 68, 3, 67.8, 49.1, 49.0, 43.8, 39.5, 37.1, 36.3, 36.2, 35.8, 35.5, 32.6, 30.3, 30.0, 28.6, 28.2, 25.7, 24.3, 22.7, 20.8, 20.7, 17.7, 17.6, 15.9.

Production Method 11 : 3-Acetyl-16α-bromo-16-deacetoxyfusidic acid pivaloyloxymethyl ester (11)

3-Acetyl-16-deacetoxy-16α-hydroxyfusidic acid pivaloyloxymethyl ester (6) (22.8 g, 36.1 mmol) was dissolved in DMF (200 ml) and cooled in an ice bath under argon atmosphere with constant stirring. Sodium bromide (18.6 g, 181 mmol) was added to the solution, and the resulting mixture was stirred for one hour. Phenylchloroformate (22.8 ml, 28.3 g, 181 mmol) is added over one hour at 0 ° C. and then stirred for 18 hours at room temperature. The reaction mixture was washed (EtOAc, aq. CaCl ₂ , water, sat. NaCl), dried using MgSO ₄ and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (10% -30% EtOAc in petroleum ether as eluent) to give the title compound (11) as an oil.

¹³ C NMR (CDCl ₃ ): 177.3, 171.0, 167.5, 154.8, 132.6, 129.5, 123.0, 79.8, 74.1, 68.2, 50, 6, 49.3, 48.8, 43.5, 42.0, 39.5, 38.9, 37.6, 36.9, 35.8, 35.0, 32.5, 30.9, 28.6, 28.3, 27.3, 27.0, 25.7, 24.3, 22.8, 21.3, 20.7, 17.8, 17.4, 15.5.

Production Method 12 : 3-Acetyl-16-deacetoxy-16α-24,25-tribromofusidic acid pivaloyloxymethyl ester (12)

According to the procedure described for production method (3), when substituting fusidic acid ester of acetoxymethyl ester (2a) with 3-acetyl-16α-bromo-16-deacetoxyfusidic acid pivaloyloxymethyl ester (11), the title compound (12) is obtained as a colorless foam.

¹³ H NMR (CDCl ₃ ): 5.87 (m, 2H), 5.64 (br, 1H), 4.93 (br, 1H), 4.35 (br, 1H), 4.14 (dd, 1H), 3.46 (bd, 1H), 2.80-1.00 (m, 20H), 2.07 (s, 3H), 1.97 ( s, 3H), 1.84 (s, 3H), 1.49 (s, 3H), 1.22 (s, 9H), 0.98 (s, 3H), 0.83 (d, 3H), 0.78 (s, 3H).

Production Method 13 : 3-Acetyl-16-deacetoxy-16α, 24-dibromofusidic acid pivaloyloxymethyl ester (13)

3-Acetyl-16-deacetoxy-16α-24.25-tribromofusidic acid pivaloyloxymethyl ester (12) (14.4 g, 16.4 mmol) and DBU (7.4 ml, 7.6 g, 49 mmol) are dissolved in acetonitrile (200 ml) and the resulting solution is heated for five hours at a temperature of 50 ° C in argon atmosphere with constant stirring. The reaction mixture was concentrated under reduced pressure and washed (EtOAc, water, sat. NaCl). The crude product was purified by flash column chromatography (10% -15% EtOAc in petroleum ether as eluent) to give the title compound (13) as a crystalline product.

¹ H NMR (CDCl ₃ ) 5.87 (d, 1H) 5.84 (d, 1H), 5.64 (bt, 1H), 4.94 (bt, 1H), 4.36 (br.s, 1H), 3.45 (br, 1H), 2.75-2.50 (m, 5H), 2.30-1.00 (m, 15H), 2.07 ( s, 3H), 1.85 (s, 3H), 1.78 (s, 3H), 1.46 (s, 3H), 1.23 (s, 9H), 0.98 (s, 3H) 0.83 (dd, 3H); 0.77 (s, 3H).

Production Method 14 : Acetoxymethyl ester 17S, 20S-dihydrofusidic acid (14)

According to the procedure described for the production method (1), when replacing fusidic acid 17S, 20S-dihydrofusidic acid (205) (von Duvold, T. et al., J. Med. Chem. , 2001, vol. 44, p. 3125 -3131) using 10 eq. each of Et ₃ N and chloromethyl acetate, upon further purification of the crude product by flash column chromatography using petroleum ether: EtOAc (1: 1) as the eluent, the title compound (14) is obtained.

¹³ C NMR (CDCl ₃ ): 173.8, 170.0, 169.8, 132.4, 123.3, 78.7, 76.5, 71.4, 68.8, 49.3, 45, 7, 44.1, 40.6, 38.3, 37.1, 36.3, 34.3, 32.7, 32.5, 30.3, 30.0, 25.7, 25.2, 23.7, 22.8, 21.0, 20.9, 20.7, 17.7, 17.2, 16.0.

Production Method 15 : Acetoxymethyl ester 17S, 20S-methylenefusidic acid (15)

According to the procedure described for the production method (1), when replacing fusidic acid 17S, 20S-methylenefusidic acid (206) (Duvold, T. et al., Bioorg. Med. Chem. Lett. , 2002, vol. 12, p. 3569-3572) using 10 eq. each of Et ₃ N and chloromethyl acetate, upon further purification of the crude product by flash column chromatography using petroleum ether: EtOAc (1: 1) as the eluent, the title compound (15) is obtained.

¹³ C NMR (CDCl ₃ ): 171.5, 170.1, 169.6, 132.2, 123.6, 79.1, 78.8, 71.4, 68.3, 49.7, 48, 5, 42.6, 40.1, 39.9, 38.6, 37.1, 36.4, 36.3, 36.1, 34.6, 32.3, 31.8, 30.3, 29.9, 26.0, 25.7, 24.1, 22.9, 20.7, 20.7, 18.9, 18.0, 17.6, 16.0.

Production Method 16 : 24-Iodfusidic Acid Phenacyl Ester (7)

A mixture of phenacyl bromide (0.42 g, 2.1 mmol), potassium fluoride (0.27 g, 4.6 mmol) and DMF (10 ml) was stirred for five minutes at a temperature of 90 ° C in an argon atmosphere. 24-Iodfusidic acid ( ¹²⁵ I) (1.35 g, 2.1 mmol) was added and the resulting mixture was stirred for one hour at a temperature of 90 ° C. The reaction mixture was treated (diethyl ether, water, sat. NaCl, MgSO ₄ ) and concentrated under reduced pressure to obtain the title compound (7) as an amorphous powder.

¹³ C NMR (CDCl ₃ ): 171.1, 170.5, 168.6, 152.3, 137.4, 134.3, 133.8, 128.9, 128.2, 127.8, 100, 3, 74.4, 71.4, 68.2, 65.8, 60.4, 49.3, 48.9, 44.7, 41.6, 39.5, 39.1, 37.0, 36.4, 36.1, 36.0, 32.2, 31.7, 30.2, 30.0, 28.9, 24.0, 22.9, 21.0, 20.9, 19, 4, 18.0, 16.0, 14.2.

Production Method 17 : 24-Trifluoromethylfusidic Acid Phenacyl Ester (16)

A solution of a complex compound of trifluoromethyl copper in HMPA (Kobayashi, Y. et al., Tetrahedron. Lett ., 1979, Vol. 42, p. 4071-4072) obtained from trifluoromethyl iodide (0.43 g, 2.2 mmol) and copper powder (0.32 g, 5 mg At) in HMPA (1.5 ml) was added to the 24-iodofusidic acid phenacyl ester (7) (190 mg, 0.25 mmol). The resulting mixture was stirred in a closed bottle for 3 days at room temperature in an argon atmosphere, then treated with EtOAc, water and a saturated solution of NaCl, dried and concentrated under reduced pressure. The crude product is purified by flash column chromatography (20-40% EtOAc in petroleum ether as eluent) and then preparative HPLC (Lichrospher®-100 RP18, in a gradient of 50% -0% 0.01 M aq. NH ₄ ⁺ HCOO ^- , mixed with 0.01 M NH ₄ ⁺ HCOO ^- , in a mixture of acetonitrile: water (9: 1) as eluent). The appropriate fractions were combined, concentrated under reduced pressure, extracted with EtOAc; concentration of the EtOAc solution under reduced pressure afforded the title compound (16) as an oil.

¹ H NMR (CDCl ₃ ): 7.88 (dd, 2H), 7.58 (t, 1H), 7.48 (t, 2H), 5.98 (d, 1H), 5.48 (d, 1H), 5.11 (d, 1H), 4.36 (s, 1H), 3.75 (br s, 1H), 3.10 (bd, 1H), 2.75-1 00 (m, 21H), 2.01 (s, 3H), 1.88 (, 3H), 1.83 (, 3H), 1.38 (s, 3H), 0.98 (s, 3H) 0.93 (s, 3H); 0.92 (d, 3H).

The method of obtaining 18 : 24,25-dibromofusidic acid (17)

A solution of bromine (16.0 g, 2.1 mol) in ethyl acetate (100 ml) was added to a mixed solution of fusidic acid (51.6 g, 0.1 mol) in ethyl acetate (1000 ml) over 75 minutes. The temperature is maintained at 5 ° C, cooling the mixture in an ice bath. KH ₂ PO ₄ (100 ml, 1M aq) and Na ₂ S ₂ O ₃ (50 ml, 1M aq) were added over several minutes. The EtOAc phase was separated and extracted with KH ₂ PO ₄ (200 ml, 0.5M aq) and water (100 ml), and then concentrated under reduced pressure to obtain a solid residue of compound (17), which was used in the next step without further purification ( Example 45).

¹ H NMR (CDCl ₃ ): 5.81 (d, 1H), 4.32 (m, 1H), 4.26 (t, 1H), 3.66 (m, 1H), 3.09 (m, 1H), 3.0-1.0 (m, 19H), 1.82 (s, 3H), 1.81 (s, 3H), 1.39 (s, 3H), 1.00 (s, 3H ), 0.99 (s, 3H), 0.94 (s, 3H), 0.89 (d, 3H).

Compounds I of the present invention

Table 2 lists examples of compounds of general formula I (compounds of general formula Ia, where Q ₂ = CH-OH (α)):

Note to table 2: The symbols in table 2, which are common to the symbols of table 1, have the same meanings. Ex. = Example; Ex. = procedure used in other examples.

Examples of readily hydrolyzable esters of compounds of general formula I are shown in table 3a (for acetoxymethyl esters) and table 3b (for pivaloyloxymethyl esters) (for esters of compounds of general formula Ia (Q ₂ = CH-OH (α)):

Note to tables 3a b 3b: The symbols in tables 3a and 3b, which are common to the symbols of table 1, have the same meanings. Ex. = Example; Ex. = procedure used in other examples.

Examples of salts of the compounds of general formula I are listed in table 4 (for salts of the general formula Ic (Q ₂ = CH-OH (α)):

Note to table 4: The symbols in tables 3a and 3b, which are common to the symbols of table 1, have the same meanings. Ex. = Example; Ex. = procedure used in other examples.

EXAMPLES

Example 1 : Sodium salt of 24-trifluoromethylfusidic acid (compound 101)

The title compound (101) can be obtained by the procedure of Example 9 by substituting 24-bromofusidic acid (108) for 24-trifluoromethylfusidic acid (106).

Example 2 : Pivaloyloxymethyl ester of 24-trifluoromethylfusidic acid (compound 102)

The title compound (102) can be obtained by the procedure described in Production Method 2 by replacing fusidic acid with 24-trifluoromethylfusidic acid (106) followed by freeze drying of the product.

Example 3 : 24-chlorofusidic acid (compound 103)

24-chlorofusidic acid pivaloyloxymethyl ester (104) (140 mg, 0.21 mmol) and K ₂ CO ₃ (60 mg, 0.43 mmol) were stirred in MeOH (2 ml) for 3 hours at room temperature. After flash column chromatography of the concentrated reaction mixture (petroleum ether: EtOAc: HCOOH, 90: 10: 1-10: 90: 1, as an eluent), the title compound 103 was obtained.

¹³ C NMR (CDCl ₃ ): 174.0, 170.6, 152.5, 128.5, 126.8, 74.5, 71.5, 68.2, 49.3, 48.8, 44, 6, 39.5, 39.0, 37.0, 36.3, 36.0, 35.6, 32.2, 30.2, 29.9, 27.3, 24.0, 22.9, 21.9, 20.8, 20.6, 20.3, 17.9, 15.9.

Example 4 : Pivaloyloxymethyl ester of 24-chlorofusidic acid (compound 104)

24-Bromofusidic acid pivaloyloxymethyl ester (10) (283 mg, 0.40 mmol), CuI (240 mg, 1.26 mmol), LiCl (30 mg, 0.7 mmol) and HMPA (1.2 ml) are shaken in a closed bottle for 3 hours at a temperature of 120 ° C. The reaction mixture was washed (EtOAc and sat. NaCl) to give a crude product. This product was then purified by flash column chromatography using petroleum ether: EtOAc (90: 10-10: 90) as an eluent to give the pure title compound 104.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 167.8, 152.8, 128.5, 128.0, 126.7, 80.0, 74.4, 71.4, 68, 2, 49.3, 48.8, 44.6, 39.5, 39.0, 38.8, 37.0, 36.4, 36.0, 35.5, 35.4, 32.2, 30.2, 29.9, 27.2, 26.9, 24.0, 22.9, 21.9, 20.8, 20.4, 17.9, 16.0, 14.2.

Example 5 : Sodium salt of 24-chlorofusidic acid (compound 105)

According to the procedure described in Example 9, by replacing 24-bromofusidic acid (108) with 24-chlorofusidic acid (103) followed by freeze drying of the product, the title compound (105) is obtained.

Example 6 : 24-trifluoromethylfusidic acid (compound 106)

24-trifluoromethylfusidic acid phenacyl ester (17) (15 mg, 0.021 mmol) and sodium thiophenolate (20 mg, 0.15 mmol) in dry DMF (0.5 ml) are stirred under argon at 100 ° C for five hours. EtOAc (15 ml) was added and the organic solution was extracted using: 3M aq. CaCl ₂ (10 ml) + 1 M aq. H ₃ PO ₄ (0.25 ml) and then (10 ml each) 3M aq. CaCl ₂ , water and sat. NaCl. After drying and concentration, the crude product is purified by flash column chromatography using petroleum ether: EtOAc: HCOOH (60: 40: 1/2) as eluent to give the title compound 106 as an amorphous powder after freeze drying.

¹ H NMR (CDCl ₃ ): 5.87 (d, 1H), 4.34 (s, 1H), 3.75 (s, 1H), 3.06 (bd, 1H), 2.70 -0.80 (m, 22H), 1.98 (s, 3H), 1.85 (q, 3H), 1.83 (q, 3H), 1.37 (m, 3H), 0, 97 (s, 3H), 0.91 (s, 3H), 0.90 (d, 3H).

Example 7: Acetoxymethyl ester of 24-bromofusidic acid (compound 107)

Acetoxymethyl ester 24-R, S, 25-dibromofusidic acid (3a) (obtained from 22.3 mmol of acetoxymethyl ester of fusidic acid) in CCl ₄ (280 ml) and DBU (6.64 ml, 6.77 g, 44 , 5 mmol) is refluxed for 16 hours. The reaction mixture in the form of a clay-like precipitate is filtered through a cotton filter and the filter is washed with a mixture of petroleum ether and EtOAc. The combined filtrate and washings were concentrated to afford the title compound 107 as a crude product (about 70% pure, according to NMR), which could be used without further purification to give compound 108 (Example 8). A pure sample was obtained using flash column chromatography (30-50% EtOAc in petroleum ether as eluent).

¹³ C NMR (CDCl ₃ ): 170.3, 169.6, 167.3, 152.6, 131.6, 127.9, 120.0, 79.5, 74.4, 71.4, 68, 2, 49.3, 48.8, 44.6, 39.5, 39.0, 37.8, 37.0, 36.3, 36.0, 35.6, 32.2, 30.2, 29.9, 27.8, 25.3, 24.0, 22.9, 20.8, 20.7, 20.4, 18.0, 16.0.

Example 8 : 24-bromfusidic acid (108)

The crude 24-bromofusidic acid acetoxymethyl ester (compound 107) or its pivaloyloxymethyl ester (110) (obtained from 44.4 mmol of acetoxymethyl ester (2a) or pivaloyloxymethyl ester (2b)) was dissolved in MeOH (250 ml) and added DBU (3 ml) to maintain an alkaline reaction. At room temperature, MeOH / water (1: 1) (300 ml) was added over two hours with stirring, which was continued for another two hours. A 1M solution of KH ₂ PO ₄ (100 ml) and, if necessary, also phosphoric acid are added to achieve a pH of about 4-5; the precipitate that forms is dissolved by double extraction with EtOAc. The organic phase is extracted with water and sat. NaCl, dried using MgSO ₄ and concentrated to obtain a crude product. This product was purified by flash column chromatography (50% EtOAc in petroleum ether + 0.5% HCOOH as eluent) and then recrystallized from EtOAc + toluene (partially evaporated) to give the pure title compound (108).

¹³ C NMR (CDCl ₃ ): 173.0, 170.5, 152.6, 131.5, 128.1, 120.1, 74.5, 71.4, 68.2, 49.2, 48, 8, 44.6, 39.5, 39.0, 37.8, 37.1, 36.2, 36.2, 35.7, 32.4, 30.2, 29.9, 28.0, 25.3, 24.1, 22.8, 20.8, 20.7, 20.4, 18.0, 15.9.

Example 9 : Sodium salt of 24-bromofusidic acid (compound 109)

24-bromofusidic acid (108) (2.38 g, 4.00 mmol) was dissolved in MeOH (30 ml). An equivalent amount of a 1N NaOH solution (4 ml) is gradually added until a pH of about 8.5 is reached when measured with a pH meter. The resulting solution was concentrated and the residue was dissolved in EtOH (15 ml). EtOAc (25 ml) was added, but crystallization did not occur until the solvents were evaporated, EtOH and EtOAc were added, and the solvents were again evaporated. The residue is crystallized from EtOH + EtOAc to give the title compound (109) as colorless crystals.

¹³ C NMR (CDCl ₃ ): 179.1, 173.5, 138.8, 138.2, 131.3, 122.6, 76.0, 72.5, 68.9, 50.8, 50, 0, 43.8, 40.7, 40.3, 38.5, 38.3, 37.8, 37.5, 36.9, 33.0, 31.1, 31.0, 30.2, 25.4, 23.8, 23.8, 22.5, 21.1, 20.5, 17.9, 16.5.

Example 10 : Pivaloyloxymethyl ester of 24-bromofusidic acid (compound 110)

When the procedure described in Example 7 was carried out with the substitution of 24R, S, 25-dibromofusidic acid acetoxymethyl ester with pivaloyloxymethyl ester 24R, S, 25-dibromofusidic acid (3b), the crude title compound (110) was obtained. This compound can be hydrolyzed without further purification to give compound 108. Flash column chromatography of a crude product sample using 30% -50% EtOAc in petroleum ether as eluent gives the pure title compound (110) as slightly yellow amorphous foam.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 167.8, 152.8, 131.5, 127.9, 120.1, 80.0, 74.4, 71.4, 68, 2, 49.3, 48.8, 44.6, 39.5, 39.0, 38.8, 37.7, 37.0, 36.3, 36.0, 35.7, 32.3, 30.2, 30.0, 27.8, 26.9, 25.3, 24.0, 22.9, 20.8, 20.4, 18.0, 16.0.

Example 11 : Acetoxymethyl ester of 24-bromo-16-deacetoxy-16β-thioacetylfusidic acid (compound 111)

A solution of bromine (45 μl, 140 mg, 0.88 mmol) in CCl ₄ (5 ml) was added to a solution of 16-deacetoxy-16β-thioacetylfusidic acid acetoxymethyl ester (8) (0.48 g, 0.8 mmol) in CCl ₄ (10 ml), adding over two hours in an argon atmosphere with stirring and cooling in an ice bath. Stirring is continued for 15 minutes in an ice bath and for another 15 minutes at room temperature. DBU (0.66 ml, 0.67 g, 4.4 mmol) was added and the mixture was refluxed for 12 hours. The reaction mixture was filtered through a filter device and concentrated in vacuo . The residue was purified by flash column chromatography using 0% -70% EtOAc in petroleum ether as the eluent to give the title compound (111).

¹³ C NMR (CDCl ₃ ): 194.8, 169.5, 168.0, 153.0, 131.7, 128.1, 120.0, 79.9, 71.4, 68.2, 49, 3, 49.0, 45.9, 43.8, 41.4, 39.7, 37.6, 37.2, 36.4, 35.9, 35.8, 32.8, 30.4, 30.1, 29.9, 28.3, 25.3, 24.5, 22.4, 20.7, 20.6, 20.4, 18.8, 16.0.

Example 12 : 24-bromo-16-deacetoxy-16β-isopropylthiofusidic acid (compound 112)

2-propanethiol (1.4 ml, 1.13 g, 15 mmol) was dissolved in dry DMF (12.5 ml) and sodium hydride (60% dispersion in oil, 0.6 g, about 15 mmol) was added and then pivaloyloxymethyl 3-acetyl-16-deacetoxy-16α-24-dibromofusidic acid ester (13) (0.45 g, 0.6 mmol), stirring at room temperature in an argon atmosphere. Stirring was continued for two hours, after which the reaction mixture was treated (EtOAc, water, aq. HCl (to about pH 4), water, sat. NaCl) and concentrated to give an oil. The specified oil was dissolved in EtOH (20 ml), 2N aq. NaOH (10 ml) and heat the mixture to a temperature of 60 ° C for two hours. The hydrolysis mixture is treated as described above, and the crude product is purified by flash column chromatography (10-20% EtOAc in petroleum ether + 1% AcOH as eluent) to give the title compound (112).

¹ H NMR (CDCl ₃ ): 4.30 (m, 1H), 4.15 (m, 1H), 3.75 (m, 1H), 3.10 (m, 1H), 1.82 (s, 3H), 1.75 (s, 3H), 1.35 (s, 3H), 1.24 (d, 3H, J = 6 Hz), 1.18 (d, 3H, J = 6 Hz), 0 99 (s, 3H), 0.98 (s, 3H), 0.88 (d, 3H, J = 6 Hz), 2.9-1.0 (m, 23H).

Example 13 : 24-bromo-16-deacetoxy-16β-isopropylsulfinylfusidic acid (compound 113)

To a solution of 24-bromo-16-deacetoxy-16β-isopropylthiofusidic acid (112) (0.29 g, 0.47 mmol) in MeOH (10 ml) was added 2N aq. NaOH (0.5 ml) and sodium periodate (0.23 g, 1.1 mmol) in water (40 ml). The mixture was stirred for one hour at room temperature and acidified with aq. HCl for precipitation of acid. The product is then filtered off, washed with water and recrystallized from EtOAc to give the title compound (113) as crystals, mp. 166-168 ° C.

¹³ C NMR (CDCl ₃ ): 173.7, 159.6, 131.3, 125.8, 120.2, 71.5, 68.3, 60.2, 51.8, 49.5, 48, 2, 47.5, 39.7, 38.2, 37 ^ 2, 36.3, 36.1, 35.6, 32.6, 30.4, 30.6, 28.0, 26.6, 25.3, 24.6, 22.7, 20.7, 20.4, 18.3, 17.8, 16.0, 13.5.

Example 14 : 24-bromo-16-deacetoxy-16β-thioacetylfusidic acid (114)

24-Bromo-16-deacetoxy-16β-thioacetylfusidic acid (111) acetoxymethyl ester (40 mg, 0.059 mmol) was dissolved in MeOH (2.5 ml), potassium carbonate (17 mg, 0.12 mmol) was added and the mixture was stirred within three hours (with the access of moisture from the air). Water (10 ml) was added and the mixture was acidified to approximately pH 4 using aq. HCl, which leads to the precipitation of acid. The mixture is treated with EtOAc, water, sat. NaCl, dried using Na ₂ SO ₄ and concentrated to give a crude product. This product was purified by flash column chromatography (0% -10% MeOH in dichloromethane as eluent) to give the title compound (114).

¹³ C NMR (CDCl ₃ ): 202.7, 175.6, 133.0, 131.6, 120.4, 71.4, 68.0, 54.5, 50.4, 48.5, 40, 8, 40.6, 37.1, 37.0, 36.7, 36.0, 35.2, 32.7, 31.7, 30.2, 29.9, 25.3, 23.4, 23.3, 21.0, 20.4, 19.5, 16.0.

Example 15 : 24-bromo-17S, 20S-dihydrofusidic acid (115)

According to the procedure described in Example 14, when replacing the 24-bromo-16-deacetoxy-16β-thioacetylfusidic acid (111) acetoxymethyl ester with 24-bromo-17S, 20S-dihydrofusidic acid (120) acetoxymethyl ester (120), the title compound ( 115).

¹³ C NMR (CDCl ₃ ): 180.7, 170.1, 130.9, 120.5, 76.3, 71.5, 68.8, 49.4, 49.4, 44.9, 44, 2, 40.6, 38.3, 37.2, 36.4, 36.2, 35.1, 34.3, 32.5, 31.3, 30.3, 29.9, 25.4, 23.8, 22.8, 21.0, 20.8, 20.3, 17.2, 15.9.

Example 16 : 24-bromo-16-deacetoxy-16β-ethoxyfusidic acid (116)

According to the procedure described in Example 14, when the 24-bromo-16-deacetoxy-16β-thioacetylfusidic acid (111) acetoxymethyl ester is replaced with the 24-bromo-16-deacetoxy-16β-ethoxyfusidic acid ester (117), the title compound is obtained compound (116).

¹³ C NMR (CDCl ₃ ): 171.0, 151.7, 132.6, 131.6, 120.2, 80.9, 71.5, 68.4, 64.8, 49.5, 49, 0, 44.2, 39.8, 37.6, 37.2, 36.5, 35.9, 35.9, 35.1, 32.8, 30.4, 30.1, 28.9, 25.3, 24.4, 22.3, 20.6, 20.5, 18.6, 16.0, 14.7.

Example 17 : Acetoxymethyl ester of 24-bromo-16-deacetoxy-16β-ethoxyfusidic acid (117)

By the procedure described in Example 11, when replacing the acetoxymethyl ester with 16-deacetoxy-16β-thioacetylfusidic acid (8) with acetoxymethyl ester of 16-deacetoxy-16β-ethoxyfusidic acid (9), the title compound (117) is obtained.

¹³ C NMR (CDCl ₃ ): 169.7, 152.8, 131.2, 127.3, 120.4, 79.6, 78.8, 71.4, 68.4, 65.3, 49, 2, 49.1, 43.4, 39.5, 37.7, 37.1, 36.3, 36.3, 35.8, 35.5, 32.5, 30.3, 30.0, 27.8, 25.3, 24.2, 22.8, 20.8, 20.9, 20.3, 17.9, 16.0, 15.3.

Example 18 : Acetoxymethyl ester 24-bromo-16-deacetoxy-16β- (2 ', 2', 2'-trifluoroethoxy) fusidic acid (compound 118)

According to the procedure described in example 11, when replacing the acetoxymethyl ester with 16-deacetoxy-16β-thioacetylfusidic acid (8) with acetoxymethyl ester of 16-deacetoxy-16β- (2 ', 2', 2'-trifluoroethoxy) fusidic acid (10) the title compound (118) is obtained.

¹³ C NMR (CDCl ₃ ): 169.6, 168.7, 152.6, 131.4, 128.5, 123.8, 120.2, 80.1, 79.4, 71.4, 68, 2, 67.8, 67.6, 49.1, 49.1, 44.0, 39.5, 37.6, 37.1, 36.2, 35.8, 35.6, 32.5, 30.3, 30.0, 27.6, 25.3, 24.2, 22.8, 20.7, 20.8, 20.3, 17.7, 16.0.

Example 19 : 24-bromo-16-deacetoxy-16β- (2 ', 2', 2'-trifluoroethoxy) fusidic acid

According to the procedure described in example 14, when replacing the acetoxymethyl ester of 24-bromo-16-deacetoxy-16β-thioacetylfusidic acid (111) with the acetoxymethyl ester of 24-bromo-16-deacetoxy-16β- (2 ', 2', 2 ' trifluoroethoxy) fusidic acid (118) affords the title compound (119).

¹³ C NMR (CDCl ₃ ): 175.3, 151.9, 131.4, 129.0, 123.6, 120.2, 80.5, 77.2, 71.5, 68.3, 67, 8, 49.1, 49.0, 43.9, 39.6, 37.7, 37.1, 36.2, 35.8, 35.6, 32.5, 30.3, 30.0, 28.0, 25.3, 24.2, 22.8, 20.2, 17.7, 16.0.

Example 20 : Acetoxymethyl ester 24-bromo-17S, 20S-dihydrofusidic acid (120)

By the procedure described in Example 11, when replacing the acetoxymethyl ester with 16-deacetoxy-16β-thioacetylfusidic acid (8) with acetoxymethyl ester 17S, 20S-dihydrofusidic acid (14), the title compound (120) is obtained.

¹³ C NMR (CDCl ₃ ): 173.6, 169.9, 169.7, 130.8, 120.4, 78.8, 76.5, 71.4, 68.8, 49.4, 49, 3, 45.4, 43.9, 40.6, 40.6, 38.3, 37.2, 36.4, 36.2, 35.0, 34.2, 32.6, 31.2, 30.4, 30.0, 25.3, 23.8, 22.7, 20.9, 20.9, 20.7, 20.3, 17.2, 16.0.

Example 21 : Acetoxymethyl ester 24-bromo-17S, 20S-methylenefusidic acid (compound 121)

By the procedure described in Example 11, when replacing the acetoxymethyl ester with 16-deacetoxy-16β-thioacetylfusidic acid (8) with acetoxymethyl ester 17S, 20S-methylenefusidic acid (15), the title compound (121) is obtained.

¹³ C NMR (CDCl ₃ ): 171.5, 169.9, 169.6, 130.9, 120.9, 79.2, 79.0, 71.4, 68.3, 49.6, 48, 5, 43.3, 40.4, 39.9, 39.2, 37.1, 36.3, 36.2, 35.9, 35.7, 34.6, 32.4, 30.3, 30.0, 29.5, 25.4, 24.2, 22.8, 21.1, 20.9, 20.7, 20.2, 19.4, 17.9, 15.9.

Example 22 : 24-bromo-17S, 20S-methylenefusidic acid (compound 122)

Following the procedure in Example 14, when the 24-bromo-16-deacetoxy-16β-thioacetylfusidic acid (111) acetoxymethyl ester is replaced with the 24-bromo-17S, 20S-methylenefusidic acid ester (compound 121), the title compound is obtained (122). (Flash column chromatography eluent was 50% EtOAc in petroleum ether + 1% HCOOH).

¹³ C NMR (CDCl ₃ ): 178.3, 170.0, 130.8, 120.9, 79.6, 71.5, 68.3, 49.3, 48.6, 44.5, 40, 8, 40.3, 39.8, 37.1, 36.2, 36.1, 35.9, 34.7, 32.5, 30.3, 29.9, 29.0, 25.3, 24.4, 22.7, 21.4, 20.8, 20.4, 20.2, 17.6, 15.9.

Example 23 : 3-deoxy-3β, 24-dibromofusidic acid (123)

According to the procedure described in Example 14, by replacing the 24-bromo-16-deacetoxy-16β-thioacetylfusidic acid (111) acetoxymethyl ester with 3-deoxy-3β, 24-dibromfusidic acid (144) acetoxymethyl ester, the title compound ( 123). (Flash column chromatography eluent is 10% EtOAc in petroleum ether + 1% HCOOH).

¹³ C NMR (CDCl ₃ ): 173.8, 170.4, 153.0, 131.7, 128.2, 120.0, 74.4, 68.2, 62.7, 49.0, 48, 8, 45.5, 44.5, 41.3, 39.4, 39.0, 37.7, 37.2, 36.8, 36.1, 35.1, 32.5, 27.9, 25.4, 23.9, 23.8, 22.0, 20.6, 20.4, 18.9, 17.9.

Example 24 : 3α-azido-24-bromo-3-deoxyfusidic acid (compound 124)

3-deoxy-3β, 24-dibromofusidic acid (123) (100 mg, 0.15 mmol) was dissolved in DMF (2.5 ml) and lithium azide (30 mg, 0.6 mmol) was added. The mixture was stirred at room temperature under argon for 11 days. EtOAc and water (5 ml each) are added and a slightly acidic pH is created with AcOH. Further processing (EtOAc, water, sat. NaCl), drying using Na ₂ SO ₄ and concentration gave the crude product, which was purified by flash column chromatography (eluent: 0-50% EtOAc in petroleum ether + 1% HCOOH) to give the indicated in the title compound (124).

¹³ C NMR (CDCl ₃ ): 174.1, 170.5, 153.1, 131.6, 128.2, 120.0, 74.5, 68.1, 65.4, 49.1, 48, 8, 44.6, 39.4, 39.0, 37.8, 37.4, 36.9, 35.9, 35.5, 32.4, 30.8, 27.9, 26.9, 25.4, 24.2, 23.0, 20.6, 20.5, 20.4, 18.1, 16.7.

Example 25 : 24-iodofusidic acid (compound 125)

24-bromfusidic acid (108) (17.0 g, 28.5 mmol), CuI (27.2 g, 143 mmol), KI (43.4 g, 285 mmol) and HMPA (100 ml) are heated in an oil bath for 20 hours in an argon atmosphere at a temperature of 120 ° C, with stirring and boiling under reflux using a partial condenser of hot irrigation. Water (400 ml) was added and the resulting viscous mixture was extracted four times with EtOAc (400 ml total). The organic phase is filtered through a filter device, which is washed with EtOAc. The combined organic phase is extracted with a 20% aqueous solution of Na ₂ S ₂ O ₅ , twice with water and sat. NaCl. After drying using MgSO _{4, the} solvent was evaporated and the residue was stirred with toluene (300 ml) for three hours. The precipitate was separated by filtration, washed with toluene and petroleum ether, and then dried to obtain substantially pure title compound 125 as beige colored crystals.

¹³ C NMR (CDCl ₃ ) 173.8, 170.6, 152.3, 137.4, 128.0, 99.9, 74.5, 71.5, 68.2, 60.4, 49.3 , 48.8, 44.5, 41.7, 39.5, 39.0, 37.0, 36.4, 36.0, 32.1, 31.6, 30.2, 29.9, 24 , 0, 23.0, 20.9, 20.7, 19.5, 17.9, 15.9, 14.2.

Example 26 : Acetoxymethyl ester of 24-iodofusidic acid (compound 126)

According to the procedure described in Example 25, when compound 108 was replaced with 24-bromofusidic acid acetoxymethyl ester (107), crude compound 126 was obtained. The product was purified by flash column chromatography using 40% EtOAc in petroleum ether as the eluent to give the title compound the title compound (126) as an amorphous substance.

¹³ C NMR (CDCl ₃ ): 170.3, 169.6, 168.0, 152.5, 137.5, 127.6, 99.8, 79.5, 74.4, 71.4, 68, 1, 49.4, 48.8, 44.6, 41.7, 39.5, 39.0, 36.9, 36.5, 35.8, 32.0, 31.6, 30.1, 29.9, 28.6, 23.9, 23.1, 20.9, 20.8, 20.8, 19.4, 17.9, 16.0, 14.2.

Example 27 : Pivaloyloxymethyl ester of 24-iodofusidic acid (compound 127)

24-iodo-fusidic acid (125) (0.84 g, 1.31 mmol) and triethylamine (0.19 ml, 0.14 g, 1.35 mmol) are dissolved in DMF (5 ml) and stirred for 20 minutes at room temperature. Chloromethyl pivalate (0.30 ml, 0.32 g, 2.1 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with 3M aq. CaCl ₂ , water and sat. NaCl, dried using MgSO ₄ and concentrated. The residue was purified by flash column chromatography using 40% EtOAc in petroleum ether as eluent to afford the title compound (127) as an amorphous substance.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 167.8, 152.8, 137.5, 127.7, 99.7, 80.1, 74.4, 71.4, 68, 2, 60.4, 49.3, 48.8, 44.6, 41.6, 39.5, 39.0, 38.8, 37.1, 36.3, 36.1, 36.0, 32.3, 31.6, 30.2, 30.0, 28.6, 26.9, 24.1, 22.8, 20.8, 20.8, 19.5, 18.0, 16, 0, 14.2.

Example 28 : Cream

24-bromfusidic acid sodium salt 1 g Petroleum jelly 7.5 g Liquid paraffin 7.5 g Spermaceti 2.5 g Sorbitan Monopalmitate 2.5 g Polyoxyethylene sorbitan monopalmitate 2.5 g Water 26.5 g 50 g

Vaseline, paraffin, spermaceti, sorbitan monopalmitate, polyoxyethylene sorbitan monopalmitate are heated to a temperature of 70 ° C and water is slowly added with constant stirring. Stirring is continued until the cream cools. Rub the sodium salt of 24-bromofusidic acid to obtain a cream base, which is homogenized in a roller mill. Fill the cream with aluminum soft tubes.

Example 29 : Ointment

24-bromfusidic acid sodium salt 1 g Liquid paraffin 6.9 g Cetanol 0.2 g Anhydrous Lanolin 2.3 g Petroleum jelly 39.6 g 50 g

Paraffin, cetanol, lanolin and petrolatum are melted at a temperature of 70 ° C. After cooling to a temperature below 40 ° C, the sodium salt of 24-bromofusidic acid is triturated. Fill ointment with varnished aluminum soft tubes.

Example 30 : Capsules

24-bromfusidic acid sodium salt 25 g Microcrystalline cellulose 14.5 g Magnesium stearate 0.5 g 40 g

Pass the ingredients through a 60 mesh sieve and mix the whole mass for 10 minutes. Hard gelatin capsules are filled with a mixture of 400 mg in capsules.

Example 31 : Tablets

24-bromfusidic acid sodium salt 25 g Avicel ^TM (Avicel ^TM ) 12 g STA-Rx 1500 12 g Magnesium stearate 1 g 50 g

The sodium salt of 16-Deacetoxy-16β- (2 ', 2', 2'-trifluoroethoxy) -17S, 20S-methanesulfonic acid Avicel ^TM (Avicel ^TM) and STA-Rx are mixed, sieved through a sieve with a pore size of 0.7 mm and then mixed with magnesium stearate. The mixture is compressed into tablets, each containing 500 mg.

Example 32 : Suspension

24-bromo-16-deacetoxy-16β-isopropylsulfinylfusidic acid sodium salt 1 g Lemon acid 0.09 g Sodium Monohydrogen Phosphate 0.14 g Sucrose 5 g Twin ^TM 80 (Tween ^TM 80) 0.01 g Potassium sorbate 0.04 g Sodium Carboxymethyl Cellulose 0.1 g Water suspension up to 100 ml

The crystals are micronized and suspended in a solution of citric acid, sodium monohydrogen phosphate, sucrose, potassium sorbate, and Tween ^TM 80 in 10 ml of water, if necessary, conducting mild heating. Sodium carboxymethyl cellulose is dissolved in 4 ml of boiling water. After cooling, it is added to other ingredients. The suspension is homogenized in a mixer and water is added at the end of the procedure to a final volume of 100 ml.

Example 33 : Ointment

A: Sodium salt of 24-bromo-16-deacetoxy-
16β- (2 ', 2', 2'-trifluoroethoxy) fusidic acid 1 g B: One of the compounds: hydrocortisone,
triamcinolone or fluocinolone 0.5 g Liquid paraffin 6.9 g Cetanol 0.2 g Anhydrous Lanolin 2.3 g Petroleum jelly 39.1 g 50 g

Paraffin, cetanol, lanolin and petrolatum are melted at a temperature of 70 ° C. After cooling to a temperature below 40 ° C, rub A and B. Fill the varnished aluminum soft tubes with ointment.

Example 34 : Ointment

A: 24-bromo-17S, 20S-dihydrofusidic acid 1.5 g B: tetracycline 1.5 g Liquid paraffin 13, 8 g Cetanol 0.4 g Anhydrous Lanolin 4.6 g Petroleum jelly 78.2 g 100 g

Paraffin, cetanol, lanolin and petrolatum are melted at a temperature of 70 ° C. After cooling to a temperature below 40 ° C, rub A and B. Fill the varnished aluminum soft tubes with ointment.

Example 35 : Eye Gel

24-bromo-16-deacetoxy-16β- (2 ', 2', 2'-trifluoroethoxy) fusidic acid 10 g Benzalkonium chloride 0.1 g Carbomer 5 g Mannitol 50 g Sodium edetate 0.5 g Sodium hydroxide q.s. Sterile water up to 100 g

Disodium edetate and mannitol are dissolved in water for injection in a stainless steel vessel equipped with a stirrer and an integrated homogenizer. Carbomer 934P is added, a vessel is taken and the dispersion is autoclaved with slow stirring and homogenization at high speed. Cool to a temperature of 70 ° C, stop mixing and homogenization. Micronized sterile 24-bromo-16-deacetoxy-16β- (2 ′, 2 ′, 2′-trifluoroethoxy) fusidic acid sodium salt was added, a vessel was selected and 24-bromo-16-deacetoxy-16β- (2 ′, 2 ′) was taken , 2'-trifluoroethoxy) fusidic acid precipitate with slow stirring. Homogenize at high speed for 10 minutes at 70 ° C. Cool to a temperature below 30 ° C with stirring and homogenization at a low speed. A sterile solution of benzalkonium chloride in water for injection is added with slow stirring. Neutralize Carbomer 934P by adding a sterile solution of sodium hydroxide (1,050 kg) in water for injection. Mix and homogenize at low speed for 5 minutes. Correct, if necessary, the pH value to 5.4-5.8. The ophthalmic gel is transferred to storage tanks under nitrogen pressure using a low-speed portable system for homogenization. Store at room temperature until filled. Eye gel is administered under aseptic conditions into sterile tubes, using 3.5 g of product to fill it.

Example 36 : Pivaloyloxymethyl ester of 24-phenylfusidic acid (compound 136)

Phenylboronic acid (50 mg, 0.4 mmol) and EtOAc (0.25 ml) are added to a solution of pivaloyloxymethyl ester of 24-iodofusidic acid (127) (150 mg, 0.2 mmol) in toluene (1.5 ml) and bubble the mixture with argon for 2 minutes. K ₂ CO ₃ (2M aq. Solution, 0.3 ml) and Pd (PPh ₃ ) ₄ (11.5 mg, 0.01 mmol) were added, after which the mixture was shaken at 90 ° C for 20 hours under argon atmosphere . The reaction mixture was treated with EtOAc, water and sat. NaCl, dried and concentrated. The resulting crude product was purified by flash column chromatography (20% EtOAc in petroleum ether as eluent) to give the pure title compound 136.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 167.7, 152.3, 144.1, 133.9, 129.6, 128.9, 128.4, 127.9, 125, 9, 80.0, 74.3, 71.4, 67.9, 48.9, 48.7, 44.4, 39.4, 39.0, 38.8, 36.9, 36.3, 36.1, 35.4, 35.0, 32.2, 30.0, 27.4, 26.9, 23.9, 22.7, 22.0, 20.8, 20.0, 17, 9, 15.9.

Example 37 : 24-phenylfusidic acid (compound 137)

According to the procedure described in example 3, when replacing pivaloyloxymethyl ester of 24-chlorofusidic acid (104) with pivaloyloxymethyl ester of 24-phenylfusidic acid (136) and when carrying out aqueous treatment before flash column chromatography (EtOAc, water + aq. HCl to pH about 2 and sat. NaCl) give the pure title compound (137).

¹³ C NMR (CDCl ₃ ): 173.9, 170.6, 151.7, 144.1, 134.0, 129.6, 129.5, 128.4, 127.9, 125.9, 74, 4, 71.5, 67.9, 48.9, 48.6, 44.3, 39.4, 39.0, 36.8, 36.3, 36.1, 35.4, 35.0, 32.2, 30.0, 30.0, 27.4, 23.8, 22.8, 22.0, 20.8, 20.7, 20.0, 17.9, 15.9.

Example 38 : 24- (4-Bromophenyl) fusidic acid pivaloyloxymethyl ester (compound 138)

According to the procedure described in Example 36, when the phenylboronic acid is replaced with [2- (4-bromophenyl) -5,5-dimethyl-1,3,2-dioxaborinan] ohm, the title compound (138) is obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 167.7, 152.5, 142.9, 132.9, 131.3, 131.1, 129.0, 128.6, 119, 9, 80.0, 74.3, 71.4, 68.0, 49.0, 48.6, 44.5, 39.4, 39.0, 38.8, 37.0, 36.2, 35.1, 35.0, 32.4, 30.1, 30.0, 27.4, 26.9, 24.1, 22.7, 22.0, 20.8, 20.7, 20, 0, 18.0, 15.9.

Example 39 : 24- (4-bromophenyl) fusidic acid (compound 139)

According to the procedure described in example 3, when replacing pivaloyloxymethyl ester of 24-chlorofusidic acid (104) with pivaloyloxymethyl ester of 24- (4-bromophenyl) fusidic acid (138) and when carrying out aqueous treatment before flash column chromatography (EtOAc, water + aq HCl to a pH of about 2 and sat. NaCl) give the pure title compound (139).

¹³ C NMR (CDCl ₃ ): 174.0, 170.6, 152.1, 142.9, 133.0, 131.3, 131.1, 129.1, 128.4, 119.8, 74, 3, 71.5, 68.0, 49.0, 48.6, 44.4, 39.4, 39.0, 37.0, 36.2, 35.1, 35.0, 32.3, 30.1, 30.0, 27.4, 24.0, 22.7, 22.1, 20.8, 20.6, 20.0, 17.9, 15.9.

Example 40 : Pivaloyloxymethyl ester of 24- (4-chlorophenyl) fusidic acid (compound 140)

Following the procedure in Example 36, when the phenylboronic acid [2- (4-chlorophenyl) -5,5-dimethyl-1,3,2-dioxaborinan] ohm is replaced, the title compound (140) is obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 167.8, 152.3, 142.4, 132.9, 131.8, 130.9, 129.1, 128.7, 128, 2, 80.0, 74.2, 71.4, 68.0, 49.0, 48.6, 44.5, 39.4, 39.0, 37.0, 36.2, 36.1, 35.1, 35.0, 32.3, 30.1, 30.0, 27.4, 26.9, 24.0, 22.7, 22.0, 21.3, 20.8, 20, 8, 20.0, 17.9, 15.9.

Example 41 : 24- (4-chlorophenyl) fusidic acid (compound 141)

According to the procedure described in example 3, when replacing pivaloyloxymethyl ester of 24-chlorofusidic acid (104) with pivaloyloxymethyl ester of 24- (4-chlorophenyl) fusidic acid (140) and when water treatment (EtOAc, water +) is carried out before flash column chromatography aq HCl to a pH of about 2 and sat. NaCl) give the pure title compound (141).

¹³ C NMR (CDCl ₃ ): 173.9, 170.6, 151.9, 142.4, 133.0, 131.8, 130.9, 129.2, 129.1, 128.1, 74, 3, 71.6, 71.5, 68.0, 49.0, 48.6, 44.4, 39.4, 39.0, 37.0, 36.2, 36.1, 35.0, 32.3, 30.0, 27.4, 24.0, 22.7, 22.1, 21.3, 20.8, 20.6, 20.0, 17.9, 15.9.

Example 42 : Pivaloyloxymethyl ester of 24- (3,5-difluorophenyl) fusidic acid (compound 142)

According to the procedure described in Example 36, when phenylboronic acid is replaced with [2- (3,5-difluorophenyl) -5,5-dimethyl-1,3,2-dioxaborinan] ohm, the title compound (142) is obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 167.8, 162.9, 162.7, 152.2, 147.2, 132.3, 130.1, 128.5, 112, 2, 112.0, 101.4, 80.1, 74.2, 71.4, 68.1, 49.1, 48.6, 44.5, 39.4, 39.0, 38.8, 37.0, 36.2, 35.3, 34.4, 32.4, 30.2, 30.0, 27.6, 26.9, 24.2, 22.6, 22.1, 20, 8, 20.7, 20.2, 18.0, 15.9.

Example 43 : 24- (3,5-difluorophenyl) fusidic acid (compound 143)

According to the procedure described in example 3, when replacing pivaloyloxymethyl ester of 24-chlorofusidic acid (104) with pivaloyloxymethyl ester of 24- (3,5-difluorophenyl) fusidic acid (142) and when water treatment (EtOAc, water + aq HCl to a pH of about 2 and sat. NaCl) give the pure title compound (143).

¹³ C NMR (CDCl ₃ ): 174.1, 170.6, 162.8, 162.7, 152.0, 147.2, 132.3, 130.2, 129.0, 112.2, 101, 4, 74.3, 71.5, 68.1, 49.1, 48.6, 44.4, 39.4, 39.0, 37.0, 36.2, 36.2, 35.3, 34.5, 32.4, 30.2, 29.9, 27.5, 24.1, 22.7, 22.1, 20.7, 20.6, 20.1, 17.9, 15, 9.

Example 44 : Acetoxymethyl 3-deoxy-3β, 24-dibromofusidic acid ester (compound 144)

Acetoxymethyl ester of 24-bromofusidic acid (107) (0.45 g, 0.67 mmol) was dissolved in dry benzene (10 ml) and stirred under argon. Triphenylphosphine (0.7 g, 2.7 mmol) and tetrabromomethane (1.1 g, 3.3 mmol) were added and the mixture was stirred at room temperature for one hour. Diethyl ether (50 ml) was added and the precipitated material was removed by filtration. The filtrate was concentrated, and the residue was purified by flash column chromatography (eluent: 0% -50% EtOAc in petroleum ether) to give the title compound (144).

¹³ C NMR (CDCl ₃ ): 170.3, 169.6, 167.8, 152.3, 131.8, 128.1, 119.9, 79.5.74.3, 68.1, 62, 7, 49.0, 48.8, 45.5, 44.4, 41.3, 39.4, 39.0, 37.7, 37.2, 36.8, 36.1, 35.1 _, 32.5, 27.8, 25.3, 23.9, 23.9, 22.0, 20.8, 20.7, 20.4, 18.9, 17.9.

Example 45 : 24-bromofusidic acid (compound 108)

24,25-dibromofusidic acid (17) (crude product obtained from 0.1 mol of fusidic acid) was dissolved in EtOH (900 ml) and water (25 ml) and K ₂ CO ₃ (30 g, 0.22 mol) was added. . The mixture was refluxed with continuous stirring for 30 minutes, cooled to room temperature and poured into water (4 liters). The alkaline potassium salt solution (108) is acidified by the addition of aq. H ₃ PO ₄ (350 ml, 1M) with continuous stirring to pH 4.0, a precipitate forms. The product was collected by filtration, washed with water and dried to obtain a crude product (108). The specified crude compound 108 can then be purified and crystallized, for example, according to the procedure described in example 8, to obtain pure compound 108, or can be converted into an easily hydrolyzable ester, for example, according to the procedure described in methods 1 and 2, or can be converted to a suitable salt, such as the sodium salt, as described in Example 9. The advantage of the sodium salt of compound 108 8 is that it is immediately possible to obtain a very pure crystalline sodium salt, so that there is no need to NOSTA to chromatographic purification. When free acid is released from a given sodium salt (for example, as described above with respect to the potassium salt), a product is obtained which can be directly crystallized (for example, from ethyl acetate and toluene) to give pure crystalline compound 108.

Example 46 : 24-bromo-16-deacetoxy-16β-ethylthiofusidic acid (compound 146)

According to the procedure described in Example 12, when replacing 2-propanethiol with ethanethiol, the title compound (146) was obtained.

¹³ C NMR (CDCl ₃ ): 176.3, 154.8, 131.3, 128.3, 120.4, 71.5, 68.4, 49.4, 48.9, 46.1, 45, 6, 41.0, 39.7, 37.9, 37.1, 36.4, 36.0, 35.8, 32.7, 30.4, 30.0, 29.6, 28.6, 25.3, 24.4, 22.5, 20.7, 20.4, 18.8, 16.0, 14.7.

Example 47 : 24-bromo-16-deacetoxy-16β-ethylsulfinylfusidic acid (compound 147)

Following the procedure in Example 13, by replacing 24-bromo-16-deacetoxy-16β-isopropylthiofusidic acid (112) with 24-bromo-16-deacetoxy-16β-ethylthiofusidic acid (compound 146), the title compound (147) was obtained.

¹ H NMR (CDCl 3): 4.40 (d, 1H), 4.37 (m, 1H), 3.76 (m, 1H), 3.18 (d, 1H), 2.90-2.40 (m, 5H), 2.25-1.0 (m, 19H), 1.84 (br.s, 3H), 1.77 (br.s, 3H), 1.45 (s, 3H) ), 1.25 (t, 3H), 0.97 (s, 3H), 0.93 (d, 3H), 0.79 (s, 3H).

Example 48 : 24-bromo-16-deacetoxy-16β-allylthiofusidic acid (compound 148)

According to the procedure described in Example 12, when replacing 2-propanethiol with allyl mercaptan, the title compound (148) was obtained.

¹³ C NMR (CDCl ₃ ): 175.5, 154.7, 134.4, 131.3, 128.4, 120.4, 117.0, 71.5, 68.4, 49.4, 48, 9, 45.6, 39.7, 37.9, 37.1, 36.4, 36.0, 34.7, 32.7, 30.9, 30.3, 30.0, 29.7, 29.0, 28.6, 25.4, 24.4, 22.5, 20.7, 20.4, 18.9, 16.0.

Example 49 : 24-bromo-16-deacetoxy-16β- (1-pentylthio) fusidic acid (compound 149)

According to the procedure described in Example 12, when replacing 2-propanethiol with 1-pentanethiol, the title compound (149) was obtained.

¹³ C NMR (CDCl ₃ ): 176.0, 155.0, 131.3, 128.3, 120.4, 71.5, 68.4, 49.4, 48.9, 46.6, 45, 6, 41.0, 39.7, 38.0, 37.1, 36.3, 36.0, 35.9, 35.9, 32.7, 31.4, 30.3, 30.0, 29.4, 28.7, 25.3, 24.3, 22.5, 22.3, 20.7, 20.4, 18.8, 16.0, 14.0.

Example 50 : 24-bromo-16-deacetoxy-16β- (1-pentylsulfonyl) fusidic acid (compound 150)

Following the procedure in Example 13, by replacing 24-bromo-16-deacetoxy-16β-isopropylthiofusidic acid (112) with 24-bromo-16-deacetoxy-16β- (1-pentylthio) fusidic acid (compound 149), the title was obtained compound (150).

¹³ C NMR (CDCl ₃ ): 173.6, 159.2, 131.3, 125.9, 120.2, 71.5, 68.3, 49.5, 48.2, 47.6, 39, 8, 38.1, 37.1, 36.2, 35.5, 32.5, 31.0, 30.3, 29.9, 27.9, 25.8, 25.3, 24.5, 22.8, 22.7, 22.4, 20.7, 20.4, 17.8, 16.0, 14.0.

Example 51 : 24-bromo-16-deacetoxy-16β- (2-methyl-1-butylthio) fusidic acid (compound 151)

Following the procedure described in Example 12, substituting 2-propanethiol with 2-methyl-1-butanethiol affords the title compound (151).

¹³ C NMR (CDCl ₃ ): 175.8, 155.0, 131.3, 128.3, 120.4, 71.6, 68.4, 49.4, 48.9, 47.2, 46, 8, 45.7, 45.6, 43.4, 42.9, 40.8, 40.4, 39.7, 38.0, 37.1, 36.4, 36.0, 35.9, 34.9, 34.6, 32.8, 30.4, 30.0, 29.3, 28.7, 25.3, 24.4, 22.5, 20.7, 20.4, 19, 3, 19.0, 18.9, 16.0, 11.3.

Example 52 : 24-bromo-16-deacetoxy-16β- (2-methyl-1-butylsulfinyl) fusidic acid (compound 152)

According to the procedure described in example 13, when replacing 24-bromo-16-deacetoxy-16β-isopropylthiofusidic acid (112) with 24-bromo-16-deacetoxy-16β- (2-methyl-1-butylthio) fusidic acid (compound 151) the title compound (152) is obtained.

¹³ C NMR (CDCl ₃ ): 173.9, 131.3, 126.0, 120.2, 71.5, 68.3, 49.6, 48.3, 47.8, 39.8, 38, 2, 37.1, 36.2, 36.1, 35.5, 32.4, 30.3, 29.9, 28.0, 27.9, 25.3, 24.5, 22.8, 20.8, 20.4, 19.5, 17.9, 16.0, 11.2.

Example 53 : 24-bromo-16-deacetoxy-16β- (3-methyl-1-butylthio) fusidic acid (compound 153)

Following the procedure described in Example 12, substituting 2-propanethiol with 3-methyl-1-butanethiol affords the title compound (153).

¹³ C NMR (CDCl ₃ ): 176.0, 155.0, 131.2, 128.3, 120.5, 71.6, 68.4, 49.4, 48.9, 46.6, 45, 7, 40.9, 39.7, 38.5, 38.0, 37.1, 36.3, 36.1, 35.9, 33.9, 32.6, 30.3, 30.0, 28.7, 27.7, 25.3, 24.3, 22.6, 22.4, 22.3, 20.8, 20.4, 18.8, 16.0.

Example 54 : 24-bromo-16-deacetoxy-16β- (3-methyl-1-butylsulfinyl) fusidic acid (compound 154)

According to the procedure described in example 13, when replacing 24-bromo-16-deacetoxy-16β-isopropylthiofusidic acid (112) with 24-bromo-16-deacetoxy-16β- (3-methyl-1-butylthio) fusidic acid (compound 153) the title compound (154) is obtained.

¹³ C NMR (CDCl ₃ ): 173.6, 131.3, 120.2, 71.5, 68.3, 49.5, 48.2, 39.8, 38.1, 37.1, 36, 2, 35.6, 32.5, 31.5, 30.3, 29.9, 27.8, 25.3, 24.5, 22.8, 22.6, 2.3, 20.8, 20.4, 17.8, 16.0.

Example 55 : 24-bromo-16-deacetoxy-16β-cyclopentylthiofusidic acid (compound 155)

A solution of bromine (12.0 mg, 0.150 mol) in ethyl acetate (0.6 ml) was added to a solution of 16-deacetoxy-16β-cyclopentylthiofusidic acid (von Daehne, W. et. Al., Adv. Appl. Microbiol ., 1979, vol 25, p. 95-146) (76.0 mg, 0.136 mmol) in ethyl acetate (4 ml) for 2 minutes with stirring and cooling in an ice bath. Then add 1M aq. KH ₂ PO ₄ (0.2 ml) and 1M aq. Na ₂ S ₂ O ₃ (0.1 ml), with stirring for 5 minutes. The EtOAc phase was separated, extracted with 0.5M aq. KH ₂ PO ₄ (0.5 ml) and water (0.5 ml) and concentrated to obtain an intermediate compound - analogue of 24.25-dibromofusidic acid in the form of an oil, which is used without further purification in the dehydrobromination reaction. An intermediate product, an analogue of 24.25-dibromofusidic acid, was dissolved in ethanol (3 ml), water (0.06 ml) and K ₂ CO ₃ (40 mg, 0.3 mmol) were added and the mixture was refluxed with stirring for Ѕ hours; cooled to room temperature and poured into water (15 ml). The alkaline solution (155) is acidified by adding 1M aq. H ₃ PO ₄ with stirring to pH 4.0 and treated (EtOAc, sat. NaCl) to obtain a crude product. Next, the crude product was purified by flash column chromatography (10-50% EtOAc in petroleum ether + 1% AcOH as eluent) to give the pure title compound (155).

¹³ C NMR (CDCl ₃ ): 175.3, 155.0, 131.3, 128.2, 120.4, 71.5, 68.4, 49.4, 48.8, 47.7, 46, 2, 45.6, 41.1, 39.7, 38.0, 37.2, 36.5, 35.9, 34.6, 32.9, 32.5, 30.4, 30.1, 28.8, 25.3, 24.8, 24.6, 24.5, 22.3, 20.7, 20.4, 19.0, 16.0.

Example 56 : 24-bromo-16-deacetoxy-16β- (2 ', 2', 2'-trifluoroethylthio) fusidic acid (compound 156)

According to the procedure described in Example 12, substituting 2-propanethiol with 2,2,2-trifluoroethanethiol afforded the title compound (156).

¹³ C NMR (CDCl ₃ ): 175.6, 155.6, 131.5, 128.9, 120.2, 71.5, 68.3, 49.1, 48.9, 45.9, 41, 2, 39.6, 38.9, 37.8, 37.1, 36.3, 36.0, 35.8, 32.7, 30.4, 30.0, 28.5, 25.3, 24.4, 22.5, 21.1, 20.6, 20.4, 18.9, 16.0.

Example 57 : 24-bromo-16-deacetoxy-16β- (2-hydroxyethithio) fusidic acid (compound 157)

According to the procedure described in example 55, when replacing 16-deacetoxy-16β-cyclopentylthiofusidic acid with 16-deacetoxy-16β- (2-hydroxyethylthio) fusidic acid (von Daehne, W. et. Al., Adv. Appl. Microbiol. , 1979 vol 25, p. 95-146), the title compound (157) is obtained.

¹³ C NMR (CDCl ₃ ): 174.4, 153.3, 131.3, 129.0, 120.5, 71.6, 68.3, 59.0, 49.4, 48.9, 45, 7, 43.9, 39.9, 39.8, 37.9, 37.1, 36.7, 36.3, 36.1, 35.8, 32.6, 30.3, 30.0, 28.5, 25.4, 24.3, 22.6, 20.7, 20.4, 18.9, 16.0.

Example 58 : 24-bromo-16-deacetoxy-16β-benzylthiofusidic acid (compound 158)

Following the procedure described in Example 12, when 2-propanethiol was replaced with benzyl mercaptan, the title compound (158) was obtained.

¹³ C NMR (CDCl ₃ ): 175.9, 155.0, 138.4, 131.3, 129.0, 128.4, 128.3, 126.8, 120.4, 71.6, 68, 4, 49.3, 48.9, 46.0, 45.7, 40.1, 39.9, 39.7, 38.0, 37.1, 36.3, 36.0, 35.8, 32.5, 30.3, 30.0, 28.7, 25.3, 24.2, 22.5, 20.7, 20.4, 18.9, 16.0.

Example 59 : 24-bromo-16-deacetoxy-16β-benzylsulfinylfusidic acid (compound 159)

Following the procedure in Example 13, by replacing 24-bromo-16-deacetoxy-16β-isopropylthiofusidic acid (112) with 24-bromo-16-deacetoxy-16β-benzylthiofusidic acid (158), the title compound (159) is obtained.

¹ H NMR (CDCl ₃ ): 7.30 (m, 5H), 4.54 (d, 1H), 4.35 (br s, 1H), 4.04 (d, 1H), 3.76 (m, 1H), 3, l5 (bd, 1H), 2.80-2.4 (m, 4H), 2.20-1.0 (m, 18H), 1.84 (b. s, 3H), 1.76 (bs, 3H), 1.38 (s, 3H), 0.96 (s, 3H), 0.92 (d, 3H), 0.75 (s , 3H).

Example 60 : 24-bromo-16-deacetoxy-16β- (2-furylmethylthio) fusidic acid (compound 160)

Following the procedure described in Example 12, when 2-propanethiol was replaced with furfuryl mercaptan, the title compound (160) was obtained.

¹³ C NMR (CDCl ₃ ): 175.6, 154.8, 151.9, 141.9, 131.3, 128.4, 120.4, 110.5, 107.5, 71.6, 68, 4, 60.4, 49.3, 48.9, 46.6, 45.6, 40.4, 39.7, 37.9, 37.0, 36.2, 36.1, 35.8, 32.4, 32.2, 30.3, 30.0, 25.3, 24.2, 22.6, 21.0, 20.7, 20.4, 18.7, 16.0.

Example 61 : 24-bromo-16-deacetoxy-16β-phenylthiofusidic acid (compound 161)

According to the procedure described in Example 12, when 2-propanethiol was replaced with thiophenol, the title compound (161) was obtained.

¹³ C NMR (CDCl ₃ ): 176.6, 175.2, 153.1, 138.3, 131.5, 129.1, 129.0, 128.8, 126.0, 120.2, 71, 6, 68.4, 49.5, 48.8, 48.5, 45.8, 39.8, 37.9, 37.1, 36.4, 35.9, 35.8, 32.8, 30.3, 30.0, 28.6, 25.3, 24.4, 22.4, 20.7, 20.4, 19.3, 16.0.

Example 62 : 24-bromo-16-deacetoxy-16β-benzoylthiofusidic acid (compound 162)

According to the procedure described in Example 55, when replacing 16-deacetoxy-16β-cyclopentylthiofusidic acid with 16-deacetoxy-16β-benzoylthiofusidic acid (von Daehne, W. et. Al., Adv. Appl. Microbiol. , 1979, vol 25, p . 95-146), the title compound (162) is obtained.

¹³ C NMR (CDCl ₃ ): 191.4, 173.6, 154.1, 137.0, 133.0, 131.5, 128.5, 128.3, 127.3, 120.2, 71, 5, 68.3, 49.3, 49.0, 46.1, 43.9, 41.5, 39.7, 37.8, 37.2, 36.4, 35.9, 32.7, 30.4, 30.0, 28.4, 25.3, 24.5, 22.4, 20.6, 20.4, 19.0, 16.0.

Example 63 : 24-bromo-16-deacetoxy-16β-isopropoxyfusidic acid (compound 163)

According to the procedure described in Example 55, when replacing 16-deacetoxy-16β-cyclopentylthiofusidic acid with 16-deacetoxy-16β-isopropoxyfusidic acid (von Daehne, W. et. Al., Adv. Appl. Microbiol. , 1979, vol 25, p . 95-146), the title compound (163) is obtained.

¹³ C NMR (CDCl ₃ ): 171.6, 151.7, 131.9, 131.5, 120.2, 71.5, 70.1, 68.4, 49.3, 49.0, 44, 2, 39.7, 37.6, 37.2, 36.4, 35.9, 35.3, 32.8, 30.3, 30.1, 28.9, 25.3, 24.3, 23.2, 22.4, 20.7, 20.5, 20.0, 18.4, 16.0.

Example 64 : 24-bromo-16-deacetoxy-16β- (2-fluoroethoxy) fusidic acid (compound 164)

According to the procedure described in example 55, when replacing 16-deacetoxy-16β-cyclopentylthiofusidic acid with 16-deacetoxy-16β- (2-fluoroethoxy) fusidic acid (von Daehne, W. et. Al., Adv. Appl. Microbiol. , 1979 vol 25, p. 95-146), the title compound (164) is obtained.

¹³ C NMR (CDCl ₃ ): 174.0, 151.8, 131.4, 129.6, 120.3, 82.5, 80.1, 71.5, 69.1, 68.4, 49, 2, 49.1, 43.8, 39.6, 37.7, 37.1, 36.3, 36.1, 35.7, 32.6, 30.3, 30.0, 28.3, 25.3, 24.3, 22.6, 20.8, 20.4, 18.0, 16.0.

Example 65 : 24-bromo-deacetoxy-16β- (2-methoxyethoxy) fusidic acid (compound 165)

According to the procedure described in Example 55, when replacing 16-deacetoxy-16β-cyclopentylthiofusidic acid with 16-deacetoxy-16β- (2-methoxyethoxy) fusidic acid (von Daehne, W. et. Al., Adv. Appl. Microbiol. , 1979 vol 25, p. 95-146) give the title compound (165).

¹³ C NMR (CDCl ₃ ): 172.1, 151.3, 131.4, 131.0, 120.3, 80.7, 71.6, 71.5, 68.8, 68.4, 59, 0, 49.4, 49.1, 43.9, 39.7, 37.6, 37.1, 36.3, 36.1, 35.8, 35.3, 32.6, 30.3, 30.1, 28.6, 25.3, 24.2, 22.6, 20.8, 20.4, 18.2, 16.0.

Example 66 : 24- ( trans -1-hexen-1-yl) fusidic acid (compound 166)

A suspension of pivaloyloxymethyl ester of 24- ( trans -1-hexen-1-yl) fusidic acid (306) (50 mg, 0.070 mmol) in MEOH (1 ml) was cooled in an ice bath and K ₂ CO ₃ (20 mg, 0 , 14 mmol). The mixture was stirred at room temperature for 3 hours and then treated (EtOAc, water + aq. HCl to a pH of about 2 and sat. NaCl) to give a crude product. Flash column chromatography of the crude product (petroleum ether: EtOAc: HCOOH (90: 10: 0-0: 99: 1, as eluent) gave the pure title compound (166).

¹³ C NMR (CDCl _3): 174.1, 170.6, 149.9 _r 129.9, 129.8, 129.7, 128.5, 127.9, 74.5, 71.5, 68, 2, 49.2, 48.7, 44.2, 39.5, 39.0, 37.0, 36.2, 36.2, 35.7, 33.2, 32.4, 32.1, 30.3, 29.9, 28.0, 27.8, 24.2, 22.8, 22.3, 21.5, 20.8, 20.6, 20.4, 17.8, 15, 9, 14.0.

Example 67 : 24- ( trans- butene-3,3-dimethyl-1-yl) fusidic acid (compound 167)

According to the procedure described in example 66, when replacing pivaloyloxymethyl ester of 24- ( trans -1-hexen-1-yl) fusidic acid (306) with pivaloyloxymethyl ester of 24- ( trans -1-butene-3,3-dimethyl-1 -yl) fusidic acid (307), the title compound (167) is obtained.

¹³ C NMR (CDCl ₃ ): 171.1, 139.2, 130.0, 129.9, 122.5, 74.5, 71.5, 68.2, 49.2, 48.7, 44, 1, 39.4, 39.0, 37.0, 36.3, 36.2, 35.7, 33.4, 32.4, 30.2, 30.0, 27.9, 24.2, 22.8, 21.6, 20.8, 20.5, 17.8 15.9.

Example 68: 24- ( trans -1-nonen-1-yl) fusidic acid (compound 168)

According to the procedure described in example 66, when replacing pivaloyloxymethyl ester of 24- ( trans -1-hexen-1-yl) fusidic acid (306) with pivaloyloxymethyl ester of 24- ( trans -1-nonen-1-yl) fusidic acid ( 308), the title compound (168) is obtained.

¹³ C NMR (CDCl ₃ ): 173.8, 170.6, 149.9, 129.9, 129.8, 129.7, 128.5, 127.9, 74.5, 71.4, 68, 3, 49.2, 48.7, 44.2, 39.5, 39.0, 37.1, 36.2, 35.7, 33.6, 32.4, 31.9, 30.3, 30.0, 29.9, 29.3, 28.0, 27.8, 24.2, 22.7, 21.5, 20.8, 20.6, 20.4, 17.8, 15, 9, 14.1.

Example 69 : 24- ( trans- 5-chloro-1-penten-1-yl) fusidic acid (compound 169)

According to the procedure described in example 66, when replacing pivaloyloxymethyl ester of 24- ( trans- 1-hexen-1-yl) fusidic acid (306) with pivaloyloxymethyl ester of 24- ( trans- 5-chloro-1-penten-1-yl ) fusidic acid (309), the title compound (169) is obtained.

¹³ C NMR (CDCl ₃ ): 174.1, 170.6, 150.2, 130.6, 129.6, 129.3, 125.9, 74.5, 71.5, 68.2, 49, 2, 48.7, 44.6, 44.3, 39.5, 39.0, 37.1, 36.2, 35.7, 32.6, 32.4, 30.5, 30.3, 29.9, 27.9, 27.8, 24.2, 22.8, 21.5, 20.8, 20.6, 20.4, 17.8, 15.9.

Example 70 : 24- ( trans -2-phenyl-1-vinyl) fusidic acid (compound 170)

According to the procedure described in example 66, when replacing pivaloyloxymethyl ester of 24- ( trans- 1-hexen-1-yl) fusidic acid (306) with pivaloyloxymethyl ester of 24- ( trans- 2-phenyl-1-vinyl) fusidic acid ( 310) receive the title compound (170).

¹³ C NMR (CDCl ₃ ): 174.4, 170.6, 150.6, 138.5, 133.6, 130.4, 129.5, 128.6, 127.2, 126.9, 126, 3, 126.1, 74.5, 71.5, 68.1, 49.2, 48.7, 44.3, 39.4, 39.0, 37.0, 36.3, 36.1, 35.9, 32.3, 30.1, 29.9, 27.9, 24.0, 22.8, 21.9, 20.8, 20.7, 20.6, 17.8, 15, 9.

Example 71 : 24- (2-phenyl-1-ethyl) fusidic acid (compound 171)

According to the procedure described in Example 66, when replacing pivaloyloxymethyl ester of 24- ( trans- 1-hexen-1-yl) fusidic acid (306) with pivaloyloxymethyl ester of 24- (2-phenyl-1-ethyl) fusidic acid (311) the title compound (171) is obtained.

¹³ C NMR (CD ₃ OD): 174.5, 172.6, 147.8, 144.2, 144.1, 132.8, 129.4, 129.4, 129.3, 126.6, 75 7, 72.4, 68.5, 50.7, 44.8, 44.3, 40.7, 40.0, 38.2, 37.8, 37.4, 37.3, 36.7 , 35.0, 34.8, 33.7, 33.3, 32.8, 31.6, 31.6, 31.0, 30.9, 30.3, 30.2, 28.1, 23 , 9, 23.8, 22.4, 20.7, 19.7, 19.7, 19.5, 19.4, 18.0, 16.5.

Example 72 : 24- (4-n-propylphenyl) fusidic acid (compound 172)

According to the procedure described in example 66, when replacing pivaloyloxymethyl ester of 24- ( trans- 1-hexen-1-yl) fusidic acid (306) with pivaloyloxymethyl ester of 24- (4-n-propylphenyl) fusidic acid (312), the indicated in the title compound (172).

¹³ C NMR (CDCl ₃ ): 173.3, 170.6, 152.0, 141.4, 140.5, 133.9, 129.4, 128.2, 127.8, 74.5, 71, 5, 67.9, 48.9, 48.7, 44.3, 39.4, 39.0, 37.7, 36.9, 36.3, 36.1, 35.5, 35.0, 32.2, 30.1, 30.0, 27.5, 24.7, 23.8, 22.7, 22.1, 20.8, 20.7, 19.9, 18.0, 15, 9, 14.0.

Example 73 : 24- (4-vinylphenyl) fusidic acid (compound 173)

According to the procedure described in example 66, when replacing pivaloyloxymethyl ester of 24- ( trans- 1-hexen-1-yl) fusidic acid (306) with pivaloyloxymethyl ester of 24- (4-vinylphenyl) fusidic acid (313), the title is obtained compound (173).

¹³ C NMR (CDCl ₃ ): 173.5, 170.5, 152.5, 143.8, 136.4, 135.4, 133.7, 129.9, 129.0, 128.5, 125, 8, 113.5, 74.4, 71.5, 67.8, 48.9, 48.6, 44.4, 39.4, 39.0, 36.9, 36.3, 36.0, 35.3, 35.1, 32.1, 30.0, 27.4, 23.8, 22.7, 22.1, 20.8, 20.7, 19.9, 17.9, 15, 9.

Example 74 : 24- (4- tert- butylphenyl) fusidic acid (compound 174)

According to the procedure described in example 66, when replacing pivaloyloxymethyl ester of 24- ( trans- 1-hexen-1-yl) fusidic acid (306) with pivaloyloxymethyl ester of 24- (4- tert- butylphenyl) fusidic acid (314), the indicated in the title compound (174).

¹³ C NMR (CDCl ₃ ): 173.6, 170.6, 151.8, 149.0, 141.0, 133.8, 129.6, 129.1, 128.3, 124.6, 74, 5, 71.5, 67.9, 48.9, 48.8, 44.2, 39.4, 39.0, 36.9, 36.2, 36.1, 35.5, 34.9, 34.5, 32.3, 31.5, 30.3, 29.9, 27.6, 23.9, 22.7, 22.1, 20.8, 20.7, 19.9, 18, 0, 15.9.

Example 75 : 24- (4-cyanophenyl) fusidic acid (compound 175)

According to the procedure described in Example 66, when replacing pivaloyloxymethyl ester of 24- ( trans- 1-hexen-1-yl) fusidic acid (306) with pivaloyloxymethyl ester of 24- (4-cyanophenyl) fusidic acid (315), the title is obtained compound (175).

¹³ C NMR (CDCl ₃ ): 173.4, 170.6, 151.6, 148.9, 132.9, 131.9, 130.4, 130.2, 129.2, 119.0, 109, 8, 74.3, 71.4, 68.2, 49.1, 48.7, 44.4, 39.4, 39.0, 37.1, 36.3, 36.1, 35.0, 34.4, 32.6, 30.3, 30.0, 27.6, 24.3, 22.6, 22.2, 20.7, 20.2, 18.0, 15.9.

Example 76 : 24- (3-biphenyl) fusidic acid (compound 176)

According to the procedure described in Example 66, when replacing pivaloyloxymethyl ester of 24- ( trans- 1-hexen-1-yl) fusidic acid (306) with pivaloyloxymethyl ester of 24- (3-biphenyl) fusidic acid (316), the title is obtained compound (176).

¹³ C NMR (CDCl ₃ ): 173.8, 170.5, 152.2, 144.4, 140.9, 140.7, 134.0, 129.1, 128.9, 128.7, 128, 6, 128.5, 128.0, 127.4, 126.9, 124.5, 74.4, 71.5, 67.9, 48.8, 48.6, 44.4, 39.3, 39.0, 36.8, 36.2, 36.0, 35.5, 34.9, 32.2, 29.9, 27.6, 23.9, 22.6, 22.2, 20, 8, 20.6, 20.0, 17.9, 15.9.

Example 77 : 24- (4-trifluoromethyl) phenyl) fusidic acid (compound 177)

According to the procedure described in example 66, when replacing pivaloyloxymethyl ester of 24- ( trans -1-hexen-1-yl) fusidic acid (306) with pivaloyloxymethyl ester of 24- (4- (trifluoromethyl) phenyl) fusidic acid (317), the title compound (177).

¹³ C NMR (CDCl ₃ ): 173.5, 170.6, 152.3, 147.8, 133.0, 129.8, 129.7, 129.0, 125.0, 74.3, 71, 4, 67.9, 49.0, 48.6, 44.4, 39.4, 39.0, 37.0, 36.2, 36.1, 35.0, 34.9, 32.5, 30.0, 27.5, 24.2, 22.5, 22.1, 20.6, 20.0, 18.0, 15.9.

Example 78 : 24- (4-methoxyphenyl) fusidic acid (compound 178)

According to the procedure described in Example 66, when replacing pivaloyloxymethyl ester of 24- ( trans- 1-hexen-1-yl) fusidic acid (306) with pivaloyloxymethyl ester of 24- (4-methoxyphenyl) fusidic acid (318), the title is obtained compound (178).

¹³ C NMR (CDCl ₃ ): 173.6, 170.7, 157.9, 151.3, 136.4, 133.5, 130.6, 129.7, 128.2, 113.2, 74, 4, 71.5, 68.0, 55.2, 49.0, 48.6, 44.2, 39.4, 39.0, 36.9, 36.3, 36.0, 35.3, 35.1, 32.1, 30.0, 27.4, 23.8, 22.8, 22.1, 20.8, 20.7, 20.0, 17.9, 15.9.

Example 79 : 24- (3-cyanophenyl) fusidic acid (compound 179)

According to the procedure described in example 66, when replacing pivaloyloxymethyl ester of 24- ( trans- 1-hexen-1-yl) fusidic acid (306) with pivaloyloxymethyl ester of 24- (3-cyanophenyl) fusidic acid (319), the title is obtained compound (179).

¹³ C NMR (CDCl ₃ ): 173.2, 170.5, 152.3, 144.9, 134.0, 132.9, 132.2, 130.6, 129.7, 128.9, 128, 8, 119.0, 112.1, 74.3, 71.4, 68.1, 49.1, 48.7, 44.5, 39.4, 39.0, 37.1, 36.3, 36.1, 35.2, 34.4, 32.5, 30.3, 30.0, 27.5, 24.3, 22.6, 22.1, 20.7, 20.2, 18, 0, 15.9.

Example 80 : 24- (2-methoxyphenyl) fusidic acid (compound 180)

According to the procedure described in Example 66, when replacing pivaloyloxymethyl ester of 24- ( trans- 1-hexen-1-yl) fusidic acid (306) with pivaloyloxymethyl ester of 24- (2-methoxyphenyl) fusidic acid (320), the title is obtained compound (180).

¹ H NMR (CDCl ₃ ): 7.23 (m, 1H), 6.95 (m, 3H), 5.83 (d, 1H), 3.81 (br s, 1H), 3.79 (s, 3H), 3.74 (br s, 1H), 2.81 (dd, 1H), 2.65-0.95 (m, 22H), 1.95 (s, 3H), 1 84 (br.s., 3H), 1.50 (br.s, 3H), 1.27 (s, 3H), 0.92 (br.s, 3H), 0.92 (d, 3H), 0.81 (br s, 3H).

Example 81 : 24- (3-nitrophenyl) fusidic acid (compound 181)

According to the procedure described in Example 66, when replacing pivaloyloxymethyl ester of 24- ( trans- 1-hexen-1-yl) fusidic acid (306) with pivaloyloxymethyl ester of 24- (3-nitrophenyl) fusidic acid (321), the title is obtained compound (181).

¹³ C NMR (CDCl ₃ ): 173.1, 170.5, 152.5, 148.2, 145.3, 135.8, 132.1, 130.9, 128.9, 128.6, 124, 1, 121.1, 74.3, 71.4, 68.1, 49.1, 48.6, 44.5, 39.4, 38.9, 37.0, 36.2, 36.1, 35.2, 34.4, 32.5, 30.2, 30.0, 27.5, 24.2, 22.6, 22.2, 20.6, 20.3, 18.0, 15, 9.

Example 82 : 24- (3-bromophenyl) fusidic acid (compound 182)

According to the procedure described in example 66, when replacing pivaloyloxymethyl ester of 24- ( trans- 1-hexen-1-yl) fusidic acid (306) with pivaloyloxymethyl ester of 24- (3-bromophenyl) fusidic acid (322), the title is obtained compound (182).

¹³ C NMR (CDCl ₃ ): 173.8, 170.7, 151.7, 146.1, 132.9, 132.2, 129.6, 129.5, 129.3, 129.0, 128, 4, 122.0, 74.3, 71.5, 68.1, 49.0, 48.6, 44.4, 39.4, 39.0, 36.9, 36.3, 36.1, 35.5, 34.8, 32.2, 30.0, 27.6, 24.0, 22.8, 22.1, 20.8, 20.7, 20.0, 17.9, 15, 9.

Example 83 : 24- (4- (methylthio) phenyl) fusidic acid (compound 183)

According to the procedure described in example 66, when replacing pivaloyloxymethyl ester of 24- ( trans- 1-hexen-1-yl) fusidic acid (306) with pivaloyloxymethyl ester of 24- (4- (methylthio) phenyl) fusidic acid (323), the title compound (183).

¹³ C NMR (CDCl ₃ ): 173.6, 170.7, 151.5, 140.9, 135.9, 133.5, 130.1, 129.5, 128.5, 126.0, 74, 4, 71.5, 68.0, 49.0, 48.6, 44.3, 39.4, 39.0, 36.9, 36.3, 36.1, 35.3, 35.0, 32.2, 30.0, 27.4, 23.9, 22.8, 22.1, 20.8, 20.7, 19.9, 17.9, 15.9, 15.7.

Example 84 : 24- (2-naphthyl) fusidic acid (compound 184)

According to the procedure described in Example 66, when replacing pivaloyloxymethyl ester of 24- ( trans- 1-hexen-1-yl) fusidic acid (306) with pivaloyloxymethyl ester of 24- (2-naphthyl) fusidic acid (324), the title is obtained compound (184).

¹³ C NMR (CDCl ₃ ): 174.4, 170.8, 151.6, 141.7, 134.0, 133.4, 131.9, 129.6, 128.7, 128.6, 127, 8, 127.6, 127.4, 126.2, 125.6, 74.3, 71.5, 67.5, 48.7, 48.4, 44.2, 39.3, 38.9, 36.6, 36.3, 35.8, 35.2, 35.1, 31.9, 29.9, 29.7, 27.4, 23.6, 22.7, 22.2, 20, 8, 20.6, 19.9, 17.8, 15.9.

Example 85 : 24- (3,5- bis - (trifluoromethyl) phenyl) fusidic acid (compound 185)

According to the procedure described in Example 66, when replacing pivaloyloxymethyl ester of 24- ( trans- 1-hexen-1-yl) fusidic acid (306) with pivaloyloxymethyl ester of 24- (3,5- bis - (trifluoromethyl) phenyl) fusidic acid (325) receive the title compound (185).

¹³ C NMR (CDCl ₃ ): 173.1, 170.5, 152.9, 145.9, 131.7, 131.4, 129.5, 128.4, 125.3, 121.7, 120, 0, 74.3, 71.4, 67.9, 49.0, 48.6, 44.6, 39.4, 38.9, 37.0, 36.2, 36.1, 35.3, 34.6, 32.5, 30.2, 30.0, 27.6, 24.2, 22.4, 22.1, 20.6, 20.2, 18.0, 15.9.

Example 86 : 24- (3,4-dimethoxyphenyl) fusidic acid (compound 186)

According to the procedure described in example 66, when replacing pivaloyloxymethyl ester of 24- ( trans- 1-hexen-1-yl) fusidic acid (306) with pivaloyloxymethyl ester of 24- (3,4-dimethoxyphenyl) fusidic acid (326), the above in the title compound (186).

¹³ C NMR (CDCl ₃ ): 173.4, 170.5, 152.2, 148.5, 147.3, 136.6, 133.7, 129.1, 128.2, 121.7, 113, 1, 110.6, 74.4, 71.5, 68.0, 56.1, 55.9, 49.0, 48.6, 44.4, 39.4, 39.0, 36.9, 36.3, 36.1, 35.2, 35.0, 32.2, 30.0, 27.5, 23.9, 22.7, 22.2, 20.8, 20.6, 20, 0, 17.9, 15.9.

Example 87 : 24- (3,5-dibromophenyl) fusidic acid (compound 187)

According to the procedure described in example 66, when replacing pivaloyloxymethyl ester of 24- ( trans -1-hexen-1-yl) fusidic acid (306) with pivaloyloxymethyl ester of 24- (3,5-dibromophenyl) fusidic acid (327), the above in the title compound (187).

¹³ C NMR (CDCl ₃ ): 173.3, 170.5, 152.9, 147.4, 131.8, 131.5, 131.2, 130.7, 128.5, 122.4, 74, 4, 71.5, 68.1, 49.1, 48.6, 44.6, 39.4, 39.0, 37.0, 36.2, 36.1, 35.6, 34.6, 32.3, 30.2, 30.0, 27.6, 24.1, 22.8, 22.2, 20.8, 20.7, 20.1, 18.0, 15.9.

Example 88 : Choline salt of 24-bromofusidic acid (compound 188)

A solution of choline hydroxide in methanol (45%, 0.4 ml, 0.18 g, 1.5 mmol) is gradually added with stirring to a solution of 24-bromofusidic acid (108) (893 mg, 1.5 mmol) in ethanol ( 10 ml). The resulting solution was concentrated under reduced pressure, and the residue was crystallized from diethyl ether. The title compound (188) was collected by filtration.

¹³ C NMR (CD ₃ OD): 179.1, 173.3, 138.5, 138.3, 131.3, 122.6, 76.0, 72.5, 69.1, 68.9, 57 , 1, 54.7, 50.8, 50.0, 43.7, 40.7, 40.3, 38.5, 38.3, 37.8, 37.5, 36.9, 33.0 , 31.1, 31.0, 30.3, 25.4, 23.8, 22.5, 21.1, 20.5, 17.9, 16.5.

Example 89 : L-arginine salt of 24-bromofusidic acid (compound 189)

Following the procedure in Example 88, when choline hydroxide was replaced with L-arginine (261 mg, 1.5 mmol, in water (10 ml)), the title compound (189) (from ethyl acetate) was obtained as an amorphous powder.

¹³ C NMR (CD ₃ OD): 179.2, 174.7, 173.3, 158.9, 139.9, 137.6, 131.5, 122.4, 75.9, 72.5, 68 , 8, 55.6, 50.8, 50.0, 43.9, 41.9, 40.7, 40.2, 38.6, 38.3, 37.9, 37.5, 36.9 , 33.0, 31.1, 31.0, 30.1, 29.5, 25.8, 25.4, 23.8, 22.5, 21.1, 20.5, 17.9, 16 ,5.

Example 90 : 2- (dimethylamino) ethanol salt of 24-bromofusidic acid (compound 190)

Following the procedure in Example 88, when choline hydroxide was replaced with 2- (dimethylamino) ethanol (151 μl, 134 mg, 1.5 mmol), the title compound (190) (from diethyl ether) was obtained in the form of crystals.

¹³ C NMR (CD ₃ OD): 178.1, 173.1, 141.6, 136.4, 131.6, 122.3, 75.9, 72.5, 68.8, 66.9, 60 , 9, 57.5, 50.8, 50.0, 44.1, 40.7, 40.2, 38.7, 38.3, 37.9, 37.5, 36.9, 33.0 , 31.1, 31.0, 30.0, 25.4, 23.8, 22.5, 21.1, 20.5, 17.9, 16.5, 15.5.

Example 91 : 4- (2-hydroxyethyl) morpholine salt of 24-bromofusidic acid (compound 191)

Following the procedure in Example 88, when choline hydroxide was replaced with 4- (2-hydroxyethyl) morpholine (184 μl, 197 mg, 1.5 mmol), the title compound (191) (from diisopropyl ether) was obtained as an amorphous powder.

¹³ C NMR (CD ₃ OD): 175.0, 172.7, 147.7, 132.4, 132.2, 121.7, 75.8, 72.5, 68.6, 66.9, 61 , 3, 58.7, 54.6, 50.7, 49.9, 44.9, 40.7, 40.1, 38.8, 38.2, 37.8, 37.4, 36.8 , 32.9, 31.1, 31.0, 29.3, 25.5, 23.9, 23.1, 22.4, 20.8, 20.6, 18.0, 16.5.

Example 92 : L-lysine salt of 24-bromofusidic acid (compound 192)

Following the procedure in Example 88, when choline hydroxide was replaced with L-lysine (219 mg, 1.5 mmol, in water (5 ml)), the title compound (192) (from ethyl acetate) was obtained as crystals.

¹³ C NMR (CD ₃ OD): 179.1, 175.1, 173.2, 139.4, 137.9, 131.4, 122.5, 75.9, 72.5, 68.8, 55 , 9, 50.8, 50.0, 43.9, 40.7, 40.4, 40.3, 38.6, 38.3, 37.9, 37.5, 36.9, 33.0 , 32.0, 31.1, 31.0, 30.2, 28.5, 25.4, 23.8, 23.2, 22.5, 21.2, 20.6, 17.9, 16 ,5.

Example 93 : N- (2-hydroxyethyl) pyrrolidine salt of 24-bromofusidic acid (compound 193)

Following the procedure in Example 88, by replacing the choline hydroxide with N- (2-hydroxyethyl) pyrrolidine (177 μl, 173 mg, 1.5 mmol), the title compound (193) (from diisopropyl ether) was obtained as crystals.

¹³ C NMR (CD ₃ OD): 178.5, 173.1, 140.7, 137.0, 131.5, 122.4, 75.9, 72.5, 70.1, 68.8, 58 , 3, 55.2, 50.8, 50.0, 44.0, 40.7, 40.2, 38.6, 38.3, 37.8, 37.5, 36.9, 33.0 , 31.1, 31.0, 30.1, 25.4, 24.0, 23.8, 23.1, 22.5, 21.1, 20.5, 17.9, 16.5.

Example 94 : Ethanolamine salt of 24-bromofusidic acid (compound 194)

Following the procedure in Example 88, when replacing choline hydroxide with ethanolamine (90 μl, 92 mg, 1.5 mmol), the title compound (194) (from diethyl ether) was obtained as an amorphous powder.

¹³ C NMR (CD ₃ OD): 178.9, 173.3, 139.7, 137.6, 131.4, 122.5, 75.9, 72.5, 68.8, 59.4, 50 , 8, 50.0, 43.9, 43.0, 40.7, 40.2, 38.6, 38.3, 37.8, 37.5, 36.9, 33.0, 31.1 , 31.0, 30.1, 25.4, 23.8, 22.5, 21.1, 20.5, 17.9, 16.5.

Example 95 : Potassium salt of 24-bromofusidic acid (compound 195)

An aqueous solution of potassium hydroxide (0.82 M, 1.8 ml, 1.5 mmol) is added gradually to a solution of 24-bromofusidic acid (108) (893 mg, 1.5 mmol) in ethanol (10 ml) and water (2 5 ml). The pH of the solution is monitored using a pH meter. Some more water (7.5 ml) was added to a pH of about 7. The resulting solution (with a final pH of 10) was concentrated under reduced pressure and the residue was crystallized from acetone. The title compound (195) was collected by filtration.

¹³ C NMR (CD ₃ OD): 179.2, 173.4, 138.6, 138.4, 131.3, 122.6, 75.9, 72.5, 68.9, 50.8, 50 , 0, 43.7, 40.7, 40.3, 38.5, 38.3, 37.8, 37.5, 36.9, 33.0, 31.1, 31.0, 30.3 , 25.4, 23.8, 22.5, 21.2, 20.5, 17.9, 16.5, 8.1.

Example 96 : Tetrabutylammonium salt of 24-bromofusidic acid (compound 196)

According to the procedure described in example 95, when replacing potassium hydroxide aq. tetrabutylammonium hydroxide (about 25%, 1.8 ml, 1.5 mmol, final pH 9) gave the title compound (196) (from diethyl ether) as crystals.

¹³ C NMR, (CD ₃ OD): 178.3, 173.2, 140.3, 137.1, 131.4, 122.5, 76.0, 72.5, 68.8, 59.5, 50.8, 50.0, 43.9, 40.7, 40.2, 38.6, 38.3, 37: 8, 37.5, 36.8, 32.9, 31.1, 31, 0, 30.0, 25.4, 24.8, 23.8, 22.5, 21.1, 20.7, 20.5, 17.9, 16.5, 14.0.

Example 97 : Benzyltrimethylammonium salt of 24-bromofusidic acid (compound 197)

According to the procedure described in Example 95, when replacing potassium hydroxide with benzyltrimethylammonium hydroxide (about 40% in methanol, with a final pH of 9), the title compound (197) (from acetone) was obtained in the form of crystals.

¹ H NMR (CD ₃ OD): 7.55 (m, 5H) 5.74 (d, 1H), 4.53 (s, 2H), 4.30 (br s, 1H), 3.64 (br.s., 1H), 3.10 (s, 9H), 3.00 (d, 1H), 2.8-2.0 (m, 8H), 1.99 (s, 3H), 1 91-1.40 (m, 7H), 1.83 (s, 3H), 1.80 (s, 3H), 1.38 (s, 3H), 1.2-1.0 (m, 3H) ), 0.99 (s, 3H), 0.95 (s, 3H), 0.89 (d, 3H).

Example 98 : Cetyltrimethylammonium salt of 24-bromofusidic acid (compound 198)

According to the procedure described in Example 95, when replacing potassium hydroxide with cetyltrimethylammonium hydroxide (about 10% in water, with a final pH of 10), the title compound (198) (from methyl ethyl ketone) was obtained in the form of crystals.

¹³ C NMR (CD ₃ OD): 179.2, 173.3, 138.4, 138.3, 131.2, 122.6, 76.0, 72.5, 68.9, 67.9, 53 5, 50.8, 50.0, 43.7, 40.7, 40.3, 38.5, 38.3, 37.8, 37.5, 36.8, 33.1, 32.9 , 31.1, 31.0, 30.8, 30.7, 30.6, 30.5, 30.3, 27.4, 25.4, 24.0, 23.9, 23.8, 22 5, 21.1, 20.5, 17.9, 16.5, 14.5.

Example 99 : Tetramethylammonium salt of 24-bromofusidic acid (compound 199)

According to the procedure described in Example 95, when replacing potassium hydroxide with tetramethylammonium hydroxide (approximately 10% in water, with a final pH of 10), the title compound (199) (from acetone / diethyl ether) was obtained in the form of crystals.

¹³ C NMR (CD ₃ OD): 179.2, 173.3, 138.4, 138.3, 131.2, 122.6, 76.0, 72.5, 68.9, 55.9, 50 , 8, 50.0, 43.7, 40.7, 40, -3, 38.5, 38.3, 37.8, 37.5, 36.8, 32.9, 31.1, 31, 0, 30.3, 25.4, 23.8, 23.8, 22.5, 21.1, 20.5, 17.9, 16.5.

Example 100 : Tetrapropylammonium salt of 24-bromofusidic acid (compound 300)

Following the procedure in Example 95, when the potassium hydroxide was replaced with tetrapropylammonium hydroxide (about 10% in water, with a final pH of 9.5), the title compound (300) (from acetone / diethyl ether) was obtained in the form of crystals.

¹³ C NMR (CD ₃ OD): 179.2, 173.3, 138.4, 138.3, 131.2, 122.7, 76.0, 72.5, 68.9, 61.3, 50 , 8, 50.0, 43.7, 40.7, 40.3, 38.5, 38.3, 37.8, 37.5, 36.9, 33.0, 31.1, 31.0 , 30.3, 25.4, 23.8, 23.8, 22.5, 21.1, 20.5, 17.9, 16.5, 16.4, 10.9.

Example 101 : Tris (hydroxymethyl) aminomethane salt of 24-bromofusidic acid (compound 301)

By the procedure of Example 88, by replacing potassium hydroxide with tris (hydroxymethyl) aminomethane (82 mg, 1.5 mmol) dissolved in ethanol (12 ml) and water (8 ml), the title compound (301) ( from diethyl ether) as an amorphous powder.

¹³ C NMR (CD ₃ OD): 178.8, 173.3, 140.1, 137.4, 131.4, 122.4, 76.0, 72.5, 70.1, 68.8, 61 , 8, 50.8, 50.0, 43.9, 40.7, 40.2, 38.6, 38.3, 37.8, 37.5, 36.9, 32.9, 31.1 , 31.0, 30.1, 25.4, 23.8, 23.1, 22.5, 21.1, 20.5, 17.9, 16.5.

Example 102 : N-methyl-D-glucamine salt of 24-bromofusidic acid (compound 302)

Following the procedure in Example 88, by replacing potassium hydroxide with N-methyl-D-glucamine (293 mg, 1.5 mmol) dissolved in ethanol (5 ml) and water (5 ml), the title compound (302) was obtained. ) (from diethyl ether) as an amorphous powder.

¹³ C NMR (CD ₃ OD): 179.2, 173.3, 139.5, 137.8, 131.4, 122.5, 75.9, 73.0, 72.5, 72.2, 70 , 1, 68.8, 64.8, 61.6, 53.0, 50.8, 50.0, 43.9, 40.7, 40.3, 38.6, 38.3, 37.8 , 37.5, 36.9, 34.2, 33.0, 31.0, 30.2, 25.4, 23.8, 22.5, 21.2, 20.9, 20.6, 17 9, 16.5, 14.5.

Example 103 : Silver salt of 24-bromofusidic acid (compound 303)

A solution of 24-bromfusidic acid sodium salt (109) (926 mg, 1.5 mmol) in water (10 ml) is added to a solution of silver acetate (250 mg, 1.5 mmol) in water (30 ml). Ethanol (25 ml) was added and after one hour a fine precipitate was collected by filtration (through a fine-pore glass filter), washed with water and dried in vacuum over silica gel in the dark for several days. Silver salt (303) is a slightly gray amorphous powder.

¹ H NMR (DMSO): 5.68 (d, 1H), 4.14 (br, 1H), 4.00 (m, 2H), 3.51 (br, 1H), 2.9-0 93 (m, 20H), 1.90 (s, 3H), 1.79 (s, 3H), 1.78 (s, 3H), 1.27 (s, 3H), 0.89 (s, 3H), 0.82 (s, 3H), 0.79 (d, 3H).

Example 104 : Benzetonium salt of 24-bromofusidic acid (compound 304)

A solution of benzethonium chloride (672 mg, 1.5 mmol) in water (5 ml) is added to a solution of 24-bromofusidic acid sodium salt (109) (926 mg, 1.5 mmol) in water (10 ml), and a sticky precipitate of benzethonium salt. The aqueous phase is decanted and the precipitate is washed with water with decantation. The precipitate was dissolved in acetone, concentrated and evaporated using ethyl acetate (3 times) to remove water. After treatment with diethyl ether, the salt remains as a sticky mass, which is filtered off and left overnight to afford the title compound (304) as a brittle amorphous powder.

¹³ C NMR (CD ₃ OD): 179.0, 173.3, 157.8, 143.6, 138.7, 138.2, 134.4, 132.0, 131.3, 130.4, 128 9, 128.4, 122.6, 114.8, 76.0, 72.5, 71.0, 70.4, 68.9, 68.3, 66.9, 65.9, 64.7 , 58.0, 51.4, 50.8, 50.0, 43.7, 40.7, 40.3, 38.9, 38.5, 38.3, 37.8, 37.5, 36 , 8, 33.1, 32.9, 32.4, 32.3, 31.1, 31.0, 30.3, 25.4, 23.8, 23.8, 22.5, 21.1 , 20.5, 17.9, 16.5, 15.5.

Example 105 : Triethanolamine salt of 24-bromofusidic acid (compound 305)

Following the procedure in Example 88, when replacing choline hydroxide with triethanolamine (209 μl, 234 mg, 1.5 mmol, pure), the title compound (305) (from ethanol / diethyl ether) was obtained as a crystalline powder.

¹³ C NMR (CD ₃ OD): 176.4, 172.9, 144.7, 134.3, 131.9, 122.0, 75.8, 72.5, 68.7, 58.7, 57 , 6, 50.8, 50.0, 44.5, 40.7, 40.1, 38.7, 38.2, 37.8, 37.5, 36.8, 32.9, 31.0 , 29.6, 25.5, 23.8, 22.4, 20.9, 20.5, 18.0, 16.5.

Example 106 : Pivaloyloxymethyl ester 24- ( trans -1-hexen-1-yl) fusidic acid (compound 306)

Following the procedure in Example 36, by replacing phenylboronic acid with trans -1-hexen-1-ylboronic acid, the title compound (306) was obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.3, 168.4, 149.9, 129.8, 129.7, 129.6, 128.4, 127.8, 80.0, 74, 4, 71.4, 68.2, 49.2, 48.7, 44.2, 39.4, 39.0, 38.8, 37.1, 36.2, 36.2, 35.7, 33.2, 32.5, 32.1, 30.3, 30.0, 27.8, 27.6, 26.9, 24.3, 22.7, 22.4, 21.5, 20, 8, 20.7, 20.4, 17.9, 15.9, 14.0.

Example 107 : Pivaloyloxymethyl ester 24- ( trans -1-butene-3,3-dimethyl-1-yl) fusidic acid (compound 307)

Following the procedure in Example 36, when substituting phenylboronic acid for trans -1-butene-3,3-dimethyl-1-ylboronic acid, the title compound (307) is obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.3, 168.5, 149.9, 139.2, 130.1, 129.7, 129.5, 122.5, 80.0, 74, 4, 71.4, 68.2, 49.2, 48.7, 44.2, 39.4, 39.0, 38.8, 37.1, 36.2, 36.2, 35.6, 33.4, 32.5, 30.3, 30.0, 29.0, 27.8, 27.7, 26.9, 24.3, 22.7, 21.6, 20.8, 20, 7, 20.4, 17.8, 15.9.

Example 108 : Pivaloyloxymethyl ester 24- ( trans -1-nonen-1-yl) fusidic acid (compound 308)

Following the procedure in Example 36, when phenylboronic acid is replaced with trans -1-nonen-1-ylboronic acid, the title compound (308) is obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.3, 168.4, 149.9, 129.8, 129.7, 129.6, 128.5, 127.8, 80.0, 74, 4, 71.4, 68.2, 49.2, 48.7, 44.2, 39.4, 39.0, 38.8, 37.1, 36.3, 36.1, 35.7, 33.6, 32.5, 31.9, 30.3, 30.0, 30.0, 29.4, 29.3, 27.8, 27.6, 26.9, 24.3, 22, 7, 22.7, 21.5, 20.8, 20.7, 20.4, 17.9, 15.9, 14.1.

Example 109 : 24- ( trans- 5-chloro-1-penten-1-yl) fusidic acid pivaloyloxymethyl ester (compound 309)

Following the procedure in Example 36, when replacing phenylboronic acid with trans- 5-chloro-1-penten-1-ylboronic acid, the title compound (309) is obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 168.4, 149.9, 130.7, 129.6, 129.5, 129.3, 125.9, 80.0, 74, 4, 71.4, 68.2, 49.2, 48.7, 44.6, 44.2, 39.4, 39.0, 38.8, 37.1, 36.3, 36.1, 35.7, 32.6, 30.5, 30.3, 30.0, 27.8, 27.6, 26.9, 24.3, 22.6, 21.5, 20.8, 20, 7, 20.4, 17.9, 15.9.

Example 110 : Pivaloyloxymethyl ester 24- ( trans -2-phenyl-1-vinyl-1-yl) fusidic acid (compound 310)

According to the procedure described in Example 36, when replacing phenylboronic acid with trans -2-phenyl-1-vinylboronic acid, the title compound (310) is obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 168.4, 150.4, 138.4, 133.6, 130.3, 129.3, 128.6, 127.1, 126, 9, 126.3, 126.1, 80.1, 74.4, 71.4, 68.1, 49.2, 48.7, 44.3, 39.4, 39.0, 38.8, 37.0, 36.2, 36.1, 35.9, 32.4, 30.2, 29.9, 27.9, 27.6, 26.9, 24.1, 22.7, 21, 9, 20.8, 20.8, 20.7, 17.8, 15.9.

Example 111 : 24- (2-Phenyl-1-ethyl) fusidic acid pivaloyloxymethyl ester (compound 311)

24- ( trans -2-phenyl-1-vinyl) fusidic acid pivaloyloxymethyl ester (310) (230 mg, 0.3 mmol) was dissolved in ethanol (5 ml) and palladium on charcoal (25 mg, 5%) was added. The flask was removed, a cylinder containing hydrogen gas was attached to it, and stirred overnight on a magnetic stirrer. The catalyst was filtered through a filter device and the filtrate was concentrated. The crude product was purified by flash column chromatography (eluent: petroleum ether: EtOAc, 90: 10-50: 50) to give the pure title compound (311).

¹³ C NMR (CD ₃ OD): 178.2, 172.1, 169.7, 152.1, 152.1, 144.1, 143.9, 130.9, 130.8, 129.4, 129 , 3, 126.6, 81.0, 75.6, 72.3, 68.4, 50.6, 45.5, 44.8, 44.4, 40.6, 40.0, 39.7 , 38.1, 37.8, 37.4, 37.3, 36.7, 35.0, 34.8, 33.6, 33.3, 32.8, 31.9, 31.0, 30 , 2, 28.2, 27.3, 23.9, 23.0, 22.3, 20.9, 19.6, 19.5, 18.2, 16.5.

Example 112 : 24- (4-n-propylphenyl) fusidic acid pivaloyloxymethyl ester (compound 312)

Following the procedure in Example 36, when the phenylboronic acid is replaced with 4-n-propylphenylboronic acid, the title compound (312) is obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 167.6, 152.5, 141.4, 140.5, 133.8, 129.5, 129.0, 128.2, 127, 8, 80.0, 74.4, 71.4, 67.9, 48.9, 48.7, 44.4, 39.4, 39.0, 38.8, 37.7, 36.9, 36.3, 36.1, 35.5, 35.0, 32.2, 30.1, 30.0, 27.4, 26.9, 24.7, 23.8, 22.7, 22, 1, 20.9, 20.8, 19.9, 18.0, 15.9, 14.0.

Example 113 : Pivaloyloxymethyl ester of 24- (4-vinylphenyl) fusidic acid (compound 313)

Following the procedure in Example 36, when the phenylboronic acid is replaced with 4-vinylphenylboronic acid, the title compound (313) is obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 167.7, 152.6, 143.8, 136.4, 135.4, 133.7, 129.9, 128.8, 128, 5, 125.8, 113.6, 80.0, 74.3, 71.4, 67.8, 48.9, 48.6, 44.4, 39.4, 39.0, 38.8, 36.9, 36.3, 36.0, 35.3, 35.0, 32.2, 30.0, 27.3, 26.9, 23.9, 22.7, 22.1, 20, 8, 20.8, 19.9, 17.9, 15.9.

Example 114 : Pivaloyloxymethyl ester of 24- (4- tert- butylphenyl) fusidic acid (compound 314)

By the procedure of Example 36, when the phenylboronic acid is replaced with 4- tert- butylphenylboronic acid, the title compound (314) is obtained.

¹³ C NMR (CDCl ₃ ) 177.0, 170.2, 167.6, 152.5, 149.0, 140.9, 133.7, 129.1, 129.0, 128.3, 124.6 , 80.0, 74.4, 71.4, 67.9, 48.9, 48.8, 44.3, 39.4, 39.0, 38.8, 36.9, 36.2, 36 , 1, 35.5, 34.8, 34.5, 32.3, 31.5, 30.3, 30.0, 27.5, 26.9, 23.9, 22.6, 22.1 , 20.9, 20.7, 20.0, 18.1, 15.9.

Example 115 : Pivaloyloxymethyl ester of 24- (4-cyanophenyl) fusidic acid (compound 315)

Following the procedure in Example 36, when the phenylboronic acid is replaced with 4-cyanophenyl boronic acid, the title compound (315) is obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.1, 167.7, 152.2, 148.9, 132.8, 131.9, 130.5, 130.2, 128.5, 119, 0, 109.9, 80.0, 74.2, 71.3, 68.1, 49.1, 48.6, 44.5, 39.4, 39.0, 38.8, 37.1, 36.3, 36.0, 34.9, 34.4, 32.6, 30.3, 30.0, 27.5, 26.9, 24.3, 22.6, 22.2, 20, 8, 20.6, 20.2, 18.0, 15.9.

Example 116 : 24- (3-Biphenyl) fusidic acid pivaloyloxymethyl ester (compound 316)

Following the procedure in Example 36, when the phenylboronic acid is replaced with 3-biphenylboronic acid, the title compound (316) is obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 167.8, 152.3, 144.4, 140.9, 140.7, 133.9, 128.9, 128.8, 128, 6, 128.6, 128.5, 128.0, 127.5, 126.9, 124.5, 80.0, 74.3, 71.4, 67.8, 48.8, 48.6, 44.4, 39.3, 39.0, 38.8, 36.8, 36.2, 36.1, 35.5, 34.8, 32.2, 30.0, 27.6, 26, 9, 23.9, 22.5, 22.2, 20.8, 20.7, 20.0, 18.0, 15.9.

Example 117 : Pivaloyloxymethyl ester 24- (4- (trifluoromethyl) phenyl) fusidic acid (compound 317)

Following the procedure in Example 36, when the phenylboronic acid is replaced with 4- (trifluoromethyl) phenylboronic acid, the title compound (317) is obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 167.7, 152.6, 147.8, 133.0, 129.8, 129.7, 128.5, 125.0, 124, 9, 80.0, 74.2, 71.4, 67.9, 49.0, 48.6, 44.5, 39.3, 39.0, 3878, 37.0, 36.2, 36, 1, 34.9, 34.8, 32.5, 30.0, 27.4, 26.9, 24.2, 22.4, 22.1, 20.8, 20.6, 20.0, 18.0, 15.9.

Example 118 : Pivaloyloxymethyl ester of 24- (4-methoxyphenyl) fusidic acid (compound 318)

Following the procedure in Example 36, when the phenylboronic acid is replaced with 4-methoxyphenylboronic acid, the title compound (318) is obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 167.7, 157.9, 152.2, 136.3, 133.4, 130.6, 129.0, 128.2, 113, 2, 80.0, 74.3, 71.4, 67.9, 55.2, 49.0, 48.6, 44.4, 39.4, 39.0, 38.8, 36.9, 36.3, 36.0, 35.3, 35.1, 32.1, 30.0, 27.3, 26.9, 23.8, 22.8, 22.0, 20.8, 20, 0, 17.9, 15.9.

Example 119 : Pivaloyloxymethyl ester 24- (3-cyanophenyl) fusidic acid (compound 319)

Following the procedure in Example 36, when the phenylboronic acid is replaced with 3-cyanophenylboronic acid, the title compound (319) is obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 167.7, 152.3, 144.9, 134.0, 132.9, 132.2, 130.6, 129.7, 128, 9, 128.5, 119.0, 112.2, 80.0, 74.2, 71.3, 68.1, 49.1, 48.7, 44.5, 39.4, 39.0, 38.8, 37.1, 36.3, 36.1, 35.2, 34.4, 32.6, 30.3, 30.0, 27.5, 26.9, 24.3, 22, 5, 22.1, 20.8, 20.6, 20.2, 18.0, 15.9.

Example 120 : Pivaloyloxymethyl ester of 24- (2-methoxyphenyl) fusidic acid (compound 320)

According to the procedure described in Example 36, when the phenylboronic acid is replaced with 2-methoxyphenylboronic acid, the title compound (320) is obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 167.8, 157.2, 152.2, 132.7, 131.9, 130.9, 130.3, 129.1, 127, 5, 120.3, 111.0, 79.9, 74.4, 71.5, 68.0, 55.9, 55.4, 48.9, 48.7, 44.4, 39.4, 39.0, 38.8, 36.8, 36.4, 36.0, 35.4, 34.4, 33.2, 32.1, 30.0, 27.2, 26.9, 23, 8, 22.8, 22.0, 20.9, 19.7, 17.9, 15.9.

Example 121 : Pivaloyloxymethyl ester of 24- (3-nitrophenyl) fusidic acid (compound 321)

According to the procedure described in Example 36, when replacing phenylboronic acid with 3-nitrophenylboronic acid, the title compound (321) was obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 167.7, 152.3, 148.3, 145.3, 135.7, 132.1, 130.9, 129.0, 128, 4, 124.1, 121, l, 80.0, 74.2, 71.3, 68.1, 49.0, 48.6, 44.5, 39.4, 39.0, 38.8, 37.0, 36.3, 36.1, 35.2, 34.3, 32.6, 30.3, 30.0, 27.6, 26.9, 24.3, 22.5, 22, 2, 20.8, 20.6, 20.3, 18.0, 15.9.

Example 122 : Pivaloyloxymethyl ester 24- (3-bromophenyl) fusidic acid (compound 322)

According to the procedure described in Example 36, when replacing phenylboronic acid with 3-bromophenylboronic acid, the title compound (322) was obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 167.7, 152.5, 146.1, 132.8, 132.2, 129.6, 129.5, 129.0, 128, 5, 128.4, 122.0, 80.0, 74.3, 71.4, 68.0, 49.0, 48.6, 44.5, 39.4, 39.0, 38.8, 36.9, 36.3, 36.1, 35.5, 34.8, 32.2, 30.1, 30.0, 27.5, 26.9, 24.0, 22.7.

Example 123 : 24- (4- (Methylthio) phenyl) fusidic acid pivaloyloxymethyl ester (compound 323)

Following the procedure in Example 36, when the phenylboronic acid is replaced with 4- (methylthio) phenylboronic acid, the title compound (323) is obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 167.7, 152.5, 140.8, 135.9, 133.3, 130.1, 128.7, 128.5, 125, 9, 79.9, 74.3, 71.4, 67.9, 48.9, 48.6, 44.4, 39.4, 39.0, 38.8, 36.9, 36.3, 36.0, 35.2, 35.0, 32.1, 30.0, 29.9, 27.3, 26.9, 23.9, 22.8, 22.0, 20.8, 20, 8, 19.9, 17.9, 15.9, 15.6.

Example 124 : Pivaloyloxymethyl ester of 24- (2-naphthyl) fusidic acid (compound 324)

According to the procedure described in Example 36, when replacing phenylboronic acid with 2-naphthylboronic acid, the title compound (324) was obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 167.7, 152.7, 141.7, 133.9, 133.3, 131.9, 128.7, 128.6, 128, 6, 127.8, 127.6, 127.4, 126.2, 125.6, 80.0, 74.3, 71.4, 67.4, 48.6, 48.4, 44.4, 39.3, 39.0, 38.8, 36.6, 36.3, 35.8, 35.2, 35.1, 32.0, 29.9, 29.6, 27.4, 26, 9, 23.7, 22.6, 22.2, 20.8, 20.8, 19.9, 17.8, 15.9.

Example 125 : Pivaloyloxymethyl ester 24- (3,5- bis - (trifluoromethyl) phenyl) fusidic acid (compound 325)

By the procedure described in Example 36, when replacing phenylboronic acid with 3,5- bis - (trifluoromethyl) phenylboronic acid, the title compound (325) is obtained.

¹³ C NMR (CDCl ₃ ): 176.9, 170.2, 167.6, 152.7, 145.9, 131.7, 131.7, 131.4, 129.4, 128.2, 123, 5, 120.0, 80.1, 74.2, 71.3, 67.9, 60.4, 49.0, 48.6, 44.6, 39.4, 39.0, 38.8, 37.0, 36.2, 36.1, 35.3, 34.6, 32.5, 30.2, 30.0, 27.6, 26.9, 24.3, 22.4, 22, 1, 20.8, 20.6, 20.2, 18.0, 15.9, 14.2.

Example 126 : Pivaloyloxymethyl ester of 24- (3,4-dimethoxyphenyl) fusidic acid (compound 326)

Following the procedure in Example 36, when the phenylboronic acid is replaced with 3,4-dimethoxyphenylboronic acid, the title compound (326) is obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 167.8, 152.1, 148.5, 147.3, 136.6, 133.7, 128.9, 128.2, 121, 7, 113.1, 110.6, 80.0, 74.3, 71.4, 67.9, 56.1, 55.8, 49.0, 48.6, 44.4, 39.4, 39.0, 38.8, 36.9, 36.3, 36.0, 35.2, 35.0, 32.2, 30.0, 27.5, 26.9, 23.9, 22, 7, 22.1, 20.8, 20.8, 20.0, 17.9, 15.9, 14.2.

Example 127 : Pivaloyloxymethyl ester of 24- (3,5-dibromophenyl) fusidic acid (compound 327)

According to the procedure described in Example 36, when replacing phenylboronic acid with 3,5-dibromophenylboronic acid, the title compound (327) was obtained.

¹³ C NMR (CDCl ₃ ): 177.0, 170.2, 167.7, 152.7, 147.4, 131.8, 131.5, 131.2, 130.7, 128.3, 122, 5, 80.0, 74.2, 71.4, 68.1, 49.1, 48.6, 44.6, 39.4, 39.0, 38.8, 36.9, 36.3, 36.1, 35.6, 34.6, 32.3, 30.2, 30.0, 27.5, 26.9, 24.1, 22.7, 22.2, 20.8, 20, 8, 20.1, 18.0, 15.9.

Claims (31)

1. Derivatives of fusidic acid of General formula I

wherein X is halogen, trifluoromethyl, C _1- C ₇ alkyl substituted by phenyl, C ₂ -C ₉ alkenyl, optionally substituted C ₁ -C ₇ alkyl, halogen or phenyl, phenyl optionally substituted with one or two identical or different substituents selected from the group consisting of halogen, C ₁ -C ₇ alkyl, C ₂ -C ₉ alkenyl, phenyl, C ₁ -C ₆ alkoxy, nitro, C ₁ -C ₆ alkylthio, trifluoromethyl and cyano; or X is naphthyl;
Y and Z are both hydrogen or, together with the C-17 / C-20 bond, form a double bond between C-17 and C-20 or together represent methylene and form a cyclopropane ring in combination with C-17 and C-20;
A is O, S or S (O);
B is C _1-6 alkyl, C _2-6 alkenyl, C _1-6 acyl, phenyl or benzoyl, where C _{1-6 is} optionally substituted with one or more halogens, hydroxy, C _2-6 alkenyl, phenyl, C _1-4 heteroaryl or C _1-6 alkoxy;
Q ₁ is - (CHOH) -, or - (CHW) -, where W is halogen or azido;
Q ₂ is - (CHOH) -;
and its pharmaceutically acceptable salts and hydrolyzable esters. 2. The compound according to claim 1, where Y and Z are both hydrogen and the stereochemical configuration corresponds to S, both at C-17 and at C-20. 3. The compound according to claim 1, where Y and Z together represent methylene and form a cyclopropane ring in combination with C-17 and C-20 and the stereochemical configuration corresponds to S both at C-17 and C-20. 4. The compound according to claim 1, where Y and Z together with the bond C-17 / C-20 form a double bond between C-17 and C-20. 5. The compound according to claim 4, in which the double bond C-17 / C-20 has the same configuration as fusidic acid. 6. The compound of claim 1, wherein X is chloro, bromo, iodo, trifluoromethyl, ethyl substituted with phenyl, vinyl substituted with phenyl, butenyl substituted with two methyl groups, pentenyl substituted with chlorine, hexenyl, nonenyl, phenyl optionally substituted one or two identical or different substituents selected from the group consisting of bromine, chlorine, fluorine, propyl, vinyl, phenyl, cyano, methoxy, trifluoromethyl, nitro, methylthio, tert-butyl or naphthyl. 7. The compound according to claim 1, in which X represents chlorine, bromine, iodine, trifluoromethyl, phenyl, 4-bromophenyl, 4-chlorophenyl, 3,5-difluorophenyl, trans-1-hexen-1-yl, trans-1- butene-3,3-dimethyl-1-yl, trans-1-nonen-1-yl, trans-5-chloro-1-penten-1-yl, trans-2-phenyl-1-vinyl, 2-phenyl- 1-ethyl, 4-n-propylphenyl, 4-vinylphenyl, 4-tert-butylphenyl, 4-cyanophenyl, 3-biphenyl, 4- (trifluoromethyl) phenyl, 4-methoxyphenyl, 3-cyanophenyl, 2-methoxyphenyl, 3-nitrophenyl , 3-bromophenyl, 4- (methylthio) phenyl, 2-naphthyl, 3,5-bis- (trifluoromethyl) phenyl, 3,4-dimethoxyphenyl or 3,5-dibromophenyl. 8. The compound according to claim 1, in which Q ₁ denotes - (CHOH) -. 9. The compound according to claim 1, in which Q ₁ denotes CHBr or CHN ₃ . 10. The compound according to claim 1, in which Q ₁ and Q ₂ both denote a - (CHOH) group or Q ₁ denotes CHBr, or CHN ₃ ,
X is chloro, bromo, iodo, trifluoromethyl;
Z and Y together with the C-17 / C-20 bond form a double bond between C-17 and C-20;
A is O, S or S (O);
B is a C _1-4 alkyl group optionally substituted with one or more substituents selected from the range consisting of hydroxy or fluorine, or B is a C _1-4 acyl group or benzoyl group. 11. The compound according to claim 1, in which a denotes O or S (O). 12. The compound according to claim 1, wherein B is C ₁ -C ₄ acyl, methyl substituted with vinyl or phenyl, ethyl optionally substituted with one or more substituents selected from fluorine, hydroxy, methyl or methoxy, butyl substituted with methyl, pentyl, propenyl or cyclopentyl. 13. The compound according to claim 1, in which B represents acetyl, isopropyl, ethyl, 2,2,2-trifluoroethyl, 1-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, cyclopentyl, 2- hydroxyethyl, benzyl, furfuryl, phenyl, 2-fluoroethyl, or 2-methoxyethyl. 14. The compound according to claim 1, in which Q ₁ and Q ₂ denote - (CHOH) - and the stereochemical configuration corresponds to both at C-3 and C-11. 15. The compound according to claim 1, where the easy-hydrolyzable ester is pivaloyloxymethyl ester or acetoxymethyl ester. 16. A pharmaceutically acceptable salt of a compound according to any one of claims 1 to 13, wherein the salts are selected from the group consisting of sodium salts, choline salts, L-arginine salts, 2- (dimethylamino) ethanol salts, 4- (2-hydroxyethyl) morpholine salts, L-lysine salts, N- (2-hydroxyethyl) pyrrolidine salts, ethanolamine salts, potassium salts, tetrabutylammonium salts, benzyltrimethylammonium salts, cetyltrimethylammonium salts, tetramethylammonium ammonium, tetrapropylmethylamine glucose s, silver salts, and triethanolamine salts benzetonievyh salts. 17. The compound according to claim 1, which is selected from the group consisting of such compounds as
24-trifluoromethylfusidic acid sodium salt (compound 101),
pivaloyloxymethyl ester of 24-trifluoromethylfusidic acid (compound 102),
24-chlorofusidic acid (compound 103),
pivaloyloxymethyl ester of 24-chlorofusidic acid (compound 104),
24-chlorofusidic acid sodium salt (compound 105), 24-trifluoromethylfusidic acid (compound 106),
acetoxymethyl ester of 24-bromofusidic acid (compound 107),
24-bromofusidic acid (compound 108),
24-bromofusidic acid sodium salt (compound 109),
pivaloyloxymethyl ester of 24-bromofusidic acid (compound 110),
24-bromo-16-deacetoxy-16β thioacetylfusidic acid acetoxymethyl ester (compound 111),
24-bromo-16-deacetoxy-16β-isopropylthiofusidic acid (compound 112),
24-bromo-16-deacetoxy-16β-isopropylsulfinylfusidic acid (compound 113),
24-bromo-16-deacetoxy-16β-thioacetylfusidic acid (compound 114),
24-bromo-17S, 20S-dihydrofusidic acid (compound 115), 24-bromo-16-deacetoxy-16β-ethoxyfusidic acid (compound 116),
24-bromo-16-deacetoxy-16β-ethoxyfusidic acid acetoxymethyl ester (compound 117),
24-bromo-16-deacetoxy-16β- (2 ', 2', 2'-trifluoroethoxy) fusidic acid acetoxymethyl ester (compound 118),
24-bromo-16-deacetoxy-16β- (2 ', 2', 2'-trifluoroethoxy) fusidic acid (compound 119),
acetoxymethyl ester 24-bromo-17S, 20S-fusidic acid (compound 120),
acetoxymethyl ester 24-bromo-17S, 20S-methylenefusidic acid (compound 121),
24-bromo-17S, 20S-methylenefusidic acid (compound 122),
3-deoxy-3β, 24-dibromofusidic acid (compound 123),
3α-azido-24-bromo-3-deoxyfusidic acid (compound 124),
24-iodofusidic acid (compound 125),
24-iodofusidic acid acetoxymethyl ester (compound 126),
pivaloyloxymethyl ester of 24-iodofusidic acid (compound 127),
pivaloyloxymethyl ester of 24-phenylfusidic acid (compound 136),
24-phenylfusidic acid (compound 137),
pivaloyloxymethyl ester 24- (4-bromophenyl) fusidic acid (compound 138),
24- (4-bromophenyl) fusidic acid (compound 139),
24- (4-chlorophenyl) fusidic acid pivaloyloxymethyl ester (compound 140),
24- (4-chlorophenyl) fusidic acid (compound 141),
24- (3,5-difluorophenyl) fusidic acid pivaloyloxymethyl ester (compound 142),
24- (3,5-difluorophenyl) fusidic acid (compound 143),
3-deoxy-3β, 24-dibromofusidic acid acetoxymethyl ester (compound 144),
24-bromo-16-deacetoxy-16β-ethylthiofusidic acid (compound 146),
24-bromo-16-deacetoxy-16β-ethylsulfinylfusidic acid (compound 147),
24-bromo-16-deacetoxy-16β-allyllthiofusidic acid (compound 148),
24-bromo-16-deacetoxy-16β- (1-pentylthio) fusidic acid (compound 149),
24-bromo-16-deacetoxy-16β- (1-pentylsulfinyl) fusidic acid (compound 150),
24-bromo-16-deacetoxy-16β- (2-methyl-1-butylthio) fusidic acid (compound 151),
24-bromo-16-deacetoxy-16β- (2-methyl-1-butylsulfinyl) fusidic acid (compound 152),
24-bromo-16-deacetoxy-16β- (3-methyl-1-butylthio) fusidic acid (compound 153),
24-bromo-16-deacetoxy-16β- (3-methyl-1-butylsulfinyl) fusidic acid (compound 154),
24-bromo-16-deacetoxy-16β-cyclopentylthiofusidic acid (compound 155),
24-bromo-16-deacetoxy-16β- (2,2,2-tritfortoethylthio) fusidic acid (compound 156),
24-bromo-16-deacetoxy-16β- (2-hydroxyethylthio) fusidic acid (compound 157),
24-bromo-16-deacetoxy-16β-benzylthiofusidic acid (compound 158),
24-bromo-16-deacetoxy-16β-benzylsulfinylfusidic acid (compound 159),
24-bromo-16-deacetoxy-16β- (2-furylmethylthio) fusidic acid (compound 160),
24-bromo-16-deacetoxy-16β-phenylthiofusidic acid (compound 161),
24-bromo-16-deacetoxy-16β-benzoylthiofusidic acid (compound 162),
24-bromo-16-deacetoxy-16β-isopropoxyfusidic acid (compound 163),
24-bromo-16-deacetoxy-16β- (2-fluoroethoxy) fusidic acid (compound 164),
24-bromo-16-deacetoxy-16β- (2-methoxyethoxy) fusidic acid (compound 165),
24- (trans-1-hexen-1-yl) fusidic acid (compound 166),
24- (trans-1-butene-3,3-dimethyl-1-yl) fusidic acid (compound 167),
24- (trans-1-nonen-1-yl) fusidic acid (compound 168),
24- (trans-5-chloro-1-penten-1-yl) fusidic acid (compound 169),
24- (trans-2-phenyl-1-vinyl) fusidic acid (compound 170),
24- (2-phenyl-1-ethyl) fusidic acid (compound 171),
24- (4-n-propylphenyl) fusidic acid (compound 172),
24- (4-vinylphenyl) fusidic acid (compound 173),
24- (4-tert-butylphenyl) fusidic acid (compound 174),
24- (4-cyanophenyl) fusidic acid (compound 175),
24- (3-biphenyl) fusidic acid (compound 176),
24- (4- (trifluoromethyl) phenyl) fusidic acid (compound 177),
24- (4-methoxyphenyl) fusidic acid (compound 178),
24- (3-cyanophenyl) fusidic acid (compound 179),
24- (2-methoxyphenyl) fusidic acid (compound 180),
24- (3-nitrophenyl) fusidic acid (compound 181),
24- (3-bromophenyl) fusidic acid (compound 182),
24- (4- (methylthio) phenyl) fusidic acid (compound 183),
24- (2-naphthyl) fusidic acid (compound 184),
24- (3,5-bis- (trifluoromethyl) phenyl) fusidic acid (compound 185),
24- (3,4-dimethoxyphenyl) fusidic acid (compound 186),
24- (3,5-dibromophenyl) fusidic acid (compound 187),
24-bromofusidic acid choline salt (compound 188),
L-arginine salt of 24-bromofusidic acid (compound 189),
2- (dimethylamino) ethanol salt of 24-bromofusidic acid (compound 190),
4- (2-hydroxyethyl) morpholine salt of 24-bromofusidic acid (compound 191),
L-lysine salt of 24-bromofusidic acid (compound 192),
N- (2-hydroxyethyl) pyrrolidine salt of 24-bromofusidic acid (compound 193),
ethanolamine salt of 24-bromofusidic acid (compound 194),
potassium salt of 24-bromofusidic acid (compound 195),
tetrabutylammonium salt of 24-bromofusidic acid (compound 196),
benzyltrimethylammonium salt of 24-bromofusidic acid (compound 197),
cetyltrimethylammonium salt of 24-bromofusidic acid (compound 198),
tetramethylammonium salt of 24-bromofusidic acid (compound 199),
tetrapropylammonium salt of 24-bromofusidic acid (compound 300),
tris (hydroxymethyl) aminomethane salt of 24-bromofusidic acid (compound 301),
N-methyl-D-glucamine salt of 24-bromofusidic acid (compound 302),
silver salt of 24-bromofusidic acid (compound 303),
benzethonium salt of 24-bromofusidic acid (compound 304),
triethanolamine salt of 24-bromofusidic acid (compound 305),
pivaloyloxymethyl ester 24- (trans-1-hexen-1-yl) fusidic acid (compound 306),
24- (trans-1-buten-3,3-dimethyl-1-yl) fusidic acid pivaloyloxymethyl ester (compound 307),
pivaloyloxymethyl ester 24- (trans-1-nonen-1-yl) fusidic acid (compound 308),
24- (trans-5-chloro-1-penten-1-yl) fusidic acid pivaloyloxymethyl ester (compound 309),
pivaloyloxymethyl ester 24- (trans-2-phenyl-1-vinyl) fusidic acid (compound 310),
pivaloyloxymethyl ester of 24- (2-phenyl-1-ethyl) fusidic acid (compound 311),
24- (4-n-propylphenyl) fusidic acid pivaloyloxymethyl ester (compound 312),
24- (4-vinylphenyl) fusidic acid pivaloyloxymethyl ester (compound 313),
24- (4-tert-butylphenyl) fusidic acid pivaloyloxymethyl ester (compound 314),
24- (4-cyanophenyl) fusidic acid pivaloyloxymethyl ester (compound 315),
pivaloyloxymethyl ester 24- (3-biphenyl) fusidic acid (compound 316),
24- (4- (trifluoromethyl) phenyl) fusidic acid pivaloyloxymethyl ester (compound 317),
24- (4-methoxyphenyl) fusidic acid pivaloyloxymethyl ester (compound 318),
24- (3-cyanophenyl) fusidic acid pivaloyloxymethyl ester (compound 319),
24- (2-methoxyphenyl) fusidic acid pivaloyloxymethyl ester (compound 320),
pivaloyloxymethyl ester 24- (3-nitrophenyl) fusidic acid (compound 321),
pivaloyloxymethyl ester 24- (3-bromophenyl) fusidic acid (compound 322),
24- (4- (methylthio) phenyl) fusidic acid pivaloyloxymethyl ester (compound 323),
pivaloyloxymethyl ester of 24- (2-naphthyl) fusidic acid (compound 324),
24- (3,5-bis- (trifluoromethyl) phenyl) fusidic acid pivaloyloxymethyl ester (compound 325),
24- (3,4-dimethoxyphenyl) fusidic acid pivaloyloxymethyl ester (compound 326) and
pivaloyloxymethyl ester of 24- (3,5-dibromophenyl) fusidic acid (compound 327). 18. The compound according to any one of claims 1 to 17 for use in antibacterial therapy. 19. An antibacterial pharmaceutical composition comprising a compound according to any one of claims 1-17, together with a pharmaceutically acceptable excipient or carrier. 20. The antibacterial pharmaceutical composition according to claim 19, further comprising another therapeutically active compound selected from the group consisting of antibiotics and corticosteroids. 21. The antibacterial pharmaceutical composition according to claim 20, in which the specified other therapeutically active compound is selected from the group consisting of penicillins (phenoxymethylpenicillin, benzylpenicillin, dicloxacillin, ampicillin, amoxicillin, pivampicillin, fluloxacillin, piperacillin cefepime, cefotaxime, ceftazidime, ceftriazone and cefuroxime), monobactams (aztreonam) and carbapenems (meropenem); macrolides (azithromycin, clarithromycin, erythromycin and roxithromycin); polymyxins (colistin); tetracyclines (tetracycline, doxycycline, oxytetracycline and limycycline); aminoglycosides (streptomycin, gentamicin, tobramycin and netilmicin); fluoroquinolones (norfloxacin, ofloxacin, ciprofloxacin and moxifloxacin); clindamycin, lincomycin, teicoplanin, vancomycin, oxazolidones (linezolid), rifamycin, metronidazole, fusidic acid, hydrocortisone, betamethasone-17-valerate and triamcinolone acetonide. 22. A method of treating, preventing, or attenuating bacterial infections in a patient, comprising administering to said patient an effective amount of a compound according to any one of claims 1-17, and optionally further comprising simultaneously or sequentially administering one or more other therapeutically active compounds. 23. The method of claim 22, wherein said other therapeutically active compound is selected from the group consisting of antibiotics and corticosteroids. 24. The method according to p. 22, characterized in that the specified other therapeutically active compound is selected from the group consisting of penicillins (phenoxymethylpenicillin, benzylpenicillin, dicloxacillin, ampicillin, amoxicillin, pivampicillin, fluxloxacillin, piperacillin and mecefalfelexpene, cecelefalinospelin, cecelefalinospelin, cecelefalinospalin, cecelefalinospalin, cecelfalinospelin, celecefaloxalin, celecefaloxalm, celecefaloxalin, cecelefalinospalin, celecefaloxalin, cecelefalamin, cefepime, cefotaxime, ceftazidime, ceftriazone and cefuroxime), monobactams (aztreonam) and carbapenems (meropenem); macrolides (azithromycin, clarithromycin, erythromycin and roxithromycin); polymyxins (colistin); tetracyclines (tetracycline, doxycycline, oxytetracycline and limycycline); aminoglycosides (streptomycin, gentamicin, tobramycin and netilmicin); fluoroquinolones (norfloxacin, ofloxacin, ciprofloxacin and moxifloxacin); clindamycin, lincomycin, teicoplanin, vancomycin, oxazolidones (linezolid), rifamycin, metronidazole, fusidic acid, hydrocortisone, betamethasone-17-valerate and triamcinolone acetonide. 25. The use of a compound according to any one of claims 1-17 for the manufacture of a medicament for the treatment, attenuation or prevention of bacterial infections. 26. The use of claim 25, wherein said drug also comprises another therapeutically active compound, in the same or in separate containers, adapted for simultaneous or sequential administration of said therapeutically active compounds. 27. The application of claim 25, wherein said other drug compound is selected from the group consisting of penicillins (phenoxymethylpenicillin, benzylpenicillin, dicloxacillin, ampicillin, amoxicillin, povampicillin, fluloxacillin, piperacillin and metsellin), cefalefexin ceftazidime, ceftriazone and cefuroxime), monobactams (aztreonam) and carbapenems (meropenem); macrolides (azithromycin, clarithromycin, erythromycin and roxithromycin); polymyxins (colistin); tetracyclines (tetracycline, doxycycline, oxytetracycline and limycycline); aminoglycosides (streptomycin, gentamicin, tobramycin and netilmicin); fluoroquinolones (norfloxacin, ofloxacin, ciprofloxacin and moxifloxacin); clindamycin, lincomycin, teicoplanin, vancomycin, oxazolidones (linezolid), rifamycin, metronidazole, fusidic acid, hydrocortisone, betamethasone-17-valerate and triamcinolone acetonide. 28. The use according to any one of claims 1 to 17 for the fight against bacterial infection. 29. The use of a compound according to any one of claims 1-17 for the prevention or prevention of bacterial infections in animal breeding. 30. A method of obtaining a compound of formula Ia

where X is bromo, Y and Z are both hydrogen or, together with the C-17 / C-20 bond, form a double bond between C-17 and C-20 or together represent methylene and form a cyclopropane ring in combination with C-17 and C-20; A is O, S or S (O);
B is C _1-6 alkyl optionally substituted with one or more halogens or hydroxy, C _2-6 alkenyl, phenyl, C ₁ -C ₄ heteroaryl or C _1-6 alkoxy, C _2-6 alkenyl, C _1-6 acyl, phenyl or benzoyl;
Q ₁ is - (CHOH) -, or - (CHW) -, where W is halogen or azido;
Q ₂ is - (CHOH) -;
including:
(a) dissolving fusidic acid or a suitable fusidic acid analog in a suitable organic solvent, followed by bromine treatment to give a 24.25-dibromic intermediate of general structure Ib:

where X and X 'are bromo, R is hydrogen, the bond between C-24 and C-25 is a single bond and Y, Z, A, B, Q ₁ and Q _{2 are as} defined above;
(b) treating a solution of the 24.25-dibromo intermediate in a suitable solvent in the presence of a suitable base to give a dehydrobrominated compound of formula Ia as a salt; and
(c) contacting the salt formed in step (b) with an acid to give a compound of formula Ia as a free acid. 31. The compound of General structure Ib;

where X and X 'are bromo, R is hydrogen, the bond between C-24 and C-25 is a single bond, Y and Z together with the C-17 / C-20 bond form a double bond between C-17 and C-20 ; A is O; B is C _1-6 acyl; Q ₁ and Q ₂ independently represent - (CHOH) -.