KR20060091290A - Novel fusidic acid derivatives - Google Patents

Abstract

The present Invention relates to novel fusidic acid derivatives of general formula (I) wherein X represents halogen, trifluoromethyl, cyano, azido, alkyl, alkenyl or aryl, wherein. said alkyl, alkenyl or aryl are optionally substituted by 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 are methylene and form a cyclopropane ring in combination with C-17 and C-20; A represents a bond,. O, S or S(O); B represents C1-6 alkyl, C2-6 alkenyl, CI-6 acyl, C3-7cycloalkylcarbonyl or benzoyl, all of which are optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, aryl, heteroaryl and azido, or, if A represents a bond, B may also represent hydrogen; Q1 and 'Q2 independently represent. -CH2-, - C(O)-, -(CHOR)-, -(CHOR)-, -(CHSH)-, - (NH)-, -(CHNH2)- or -(CHW)-., wherein R represents CI-6alkyl and W represents halogen, cyano, azido or trifluoromethyi; Q3 represents -CH2-, -C(O)- or -CHOH-; G represents hydrogen, OH or O-CO-CH3; two bonds in the pentacyclic ring being depicted with full and dotted lines to indicate that either of the two bonds may be a double bond, in which case Y is absent and Z represents hydrogen; the bond between C-1 and C-2 being either a single or a double bond; and pharmaceutically acceptable salts and easily hydrolysable esters thereof, to pharmaceutical compositions comprising said derivatives, as well as to their use in therapy.

Description

Novel fusidic acid derivatives

Field of invention

The present invention relates to novel fusidic acid derivatives, pharmaceutical compositions containing them and their use in therapy.

Background of the Invention

Fusidic acid belongs to the fusidan, a small group of natural antibiotics.

Pushed acid

The push end typically has a tetracyclic ring system with a unique chair-fold-chair configuration. Thus, despite some structural similarities with steroids, the push end does not exhibit hormonal activity. In addition, the push end typically has a carboxylic acid having a side chain bonded to the ring system at C-17 via a double bond and an acetate group bonded at C-16. Pushed acid, a fermentation product of Fucidium coccineum, is the most antibiotically active compound of the push end and the only push step used clinically in the treatment of infectious diseases. Fusidic acid [Fucidin ^R ] is used clinically to treat severe staphylococci infections in both acute and malignant forms of the disease, especially in bone and joint infections (see literature; The Use of Antibiotics, 5th Ed., A. Kucers and N. McK. Bennett (Eds.), Butterworth 1997, pp. 580-587, and references cited therein]. Although fusidic acid is most commonly used for Staphylococcus, it is also used for several other Gram-positive strains. The clinical value of fusidic acid is also due to its effective distribution in various tissues, low toxicity levels and allergic reactions, and lack of mutual resistance to other clinically used antibiotics. Fusidic acid is widely used for topical treatment of many skin and ocular infections caused by Staphylococcus. It is generally provided in combination with conventional antibiotics such as penicillin, erythromycin or clindamycin. It is also used as a substitute for vancomycin to inhibit Clostridium difficile. Compared to Staphylococcus, several other Gram-positive cocci are often less susceptible to fusdin. By way of example, Streptococci strains are generally up to 100 times less sensitive to fusidic acid than Staphylococcus. Kuchers et al; supra]. Other susceptible bacteria include Gram-positive basic cocci, such as peptococcus and peptostreptococcus strains, aerobic or anaerobic Gram-positive bacteria, such as Corynebacterium diphtheriae, Clostridium Testoni (Clostridium tetani), Clostridium difficile and Clostridium perfringens. Gram-negative bacteria are resistant except for Neisseria spp. And Legionella pneumophila. Drugs are very effective against both intracellular and extracellular M. leprae. The structure-activity relationship (SAR) of fusidic acid has been extensively studied and many analogs have been prepared. However, only a few of these analogs showed comparable activity to fusidic acid. Despite extensive SAR studies, the possibility of side chain modifications has not been extensively investigated.

Compared to other antibiotics, fusidic acid has so far not revealed serious clinical problems due to drug resistance [see literature; Turnidge, Int. J. Antimicro. Agents, 12, S35-S44, 1999]. However, as discussed above, since the components themselves have a fairly limited antibiotic spectrum, it may be desirable to develop new analogues based on pusheds that have antibiotic activity against a wide range of pathogenic microorganisms, particularly Streptococcus.

Attempts have been made to improve the therapeutic properties of the push end by manipulating side chains. Accordingly, WO 02/070537 describes fusidic acid derivatives in which a C17-C20 double bond is converted to a cyclopropane residue by a methylene group.

WO 01/29061 describes a fudic acid derivative in which a C17-C20 double bond is saturated.

The gist of the invention

The inventors have surprisingly found that the Cd-24-substituted pushed acid derivative retains activity against Staphylococcus and significantly increases activity against Staphylococcus. Accordingly, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof and easily hydrolyzable esters thereof.

In Formula I above,

X is halogen, trifluoromethyl, cyano, azido, alkyl, alkenyl or aryl, wherein alkyl, alkenyl or aryl is alkyl, alkenyl, aryl, alkoxy, nitro, alkylthio, halogen, azido, Optionally substituted with one or more identical or different substituents selected from the group consisting of trifluoromethyl and cyano),

Y and Z are both hydrogen, or form a double bond between C-17 and C-20 with a C-17 / C-20 bond, or methylene together, or a cyclopropane ring with C-17 and C-20 Form the

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, all of which are halogen, hydroxy, alkoxy, aryl, heteroaryl and a Optionally substituted with one or more substituents selected from the group consisting of a map), or when A is a bond, B may 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, 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 ,

The two bonds of the pentacyclic ring represented by the solid and dashed lines indicate that when Y is absent and Z is hydrogen, one of the two bonds may be a double bond,

The bond between C-1 and C-2 is a single bond or a double bond.

In a further aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) for use in therapy, and in particular, a compound of formula (I) together with a pharmaceutically acceptable excipient or adjuvant.

In a further aspect, the present invention relates to a method of treating, preventing or alleviating an infection comprising administering an effective amount of a compound of formula (I) to an infected patient.

In a further aspect, the invention relates to the use of a compound of formula (I) for the manufacture of a medicament for the prevention, treatment, alleviation or prevention of infection.

In a further aspect, the invention relates to the use of a compound of formula (I) for inhibiting microbial growth and for preventing or preventing bacterial infections during animal breeding.

In a further aspect, the present invention provides a process for the preparation of a 24,25-dibromo intermediate of formula (Ib) by dissolving a fusidic acid or a suitable fusidic acid analog in a suitable organic solvent, followed by bromine (a),

(B) treating a solution of 24,25-dibromo intermediate in a suitable solvent in the presence of a suitable base to obtain the dehydrobrominated compound of formula (Ia) in salt form, and

A process for the preparation of a compound of formula (Ia) comprising the step of (c) acidifying the salt produced in step (b) to obtain the compound of formula (Ia) in free acid form.

In Formula Ia above,

X is bromo,

Y and Z are both hydrogen, or form a double bond between C-17 and C-20 with a C-17 / C-20 bond, or methylene together, or a cyclopropane ring with C-17 and C-20 Form the

A is a bond, 0, S or S (O),

B is C _1-6 alkyl, C _2-6 alkenyl, C _1-6 acyl, C _3-7 cycloalkylcarbonyl or benzoyl, all of which are halogen, hydroxy, C _1-6 alkoxy, aryl, Optionally substituted with one or more substituents selected from the group consisting of heterocyclyl and azido, or when A is a bond, B may also be hydrogen,

Q ₁ and Q ₂ are independently —C (0) —, — (CHOH) —, — (CHSH) — or — (CHW) —, where W is halogen, cyano, azido or trifluoromethyl )to be.

In Formula Ib above,

X and X 'are bromo,

R is hydrogen,

The bond between C-24 and C-25 is a single bond,

Y, Z, A, B, Q ₁ and Q ₂ are as defined above.

In a further aspect, the invention relates to compounds of formula (lb).

Formula Ib

In Formula Ib above,

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 form a double bond between C-17 and C-20 with a C-17 / C-20 bond, or methylene together, or a cyclopropane ring with C-17 and C-20 Form the

A is a bond, 0, S or S (O),

B is C _1-6 alkyl, C _2-6 alkenyl, C _1-6 acyl, C _3-7 cycloalkylcarbonyl or benzoyl, all of which are halogen, hydroxy, C _1-6 alkoxy, aryl, Optionally substituted with one or more substituents selected from the group consisting of heterocyclyl and azido, or when A is a bond, B may also be hydrogen,

Q ₁ and Q ₂ are independently —C (0) —, — (CHOH) —, — (CHSH) — or — (CHW) —, where W is halogen, cyano, azido or trifluoromethyl )to be.

Justice

As used herein, the term "alkyl" refers to monovalent radicals derived from alkanes by removing hydrogen atoms from carbon atoms and includes subclasses of primary, secondary and tertiary alkyl groups, for example C _1- C ₁₂ alkyl, for example C ₁ -C ₈ alkyl, for example C ₁ -C ₆ alkyl, for example C ₁ -C ₄ alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, tert-butyl, pentyl, hexyl, nonyl, dodecanyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclohexyl. Alkanes represent acyclic or cyclic branched or unbranched saturated hydrocarbons and therefore all consist solely of hydrogen and carbon atoms.

The term "alkenyl", when available, refers to a straight or branched chain bicyclic hydrocarbon having one or more carbon-carbon double bonds of E or Z stereochemistry. The terms are, 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" refers to a radical of the formula -CO-R, wherein R is alkyl as defined above, for example C ₁ -C ₆ acyl, eg propionyl, butyryl or p It is Kaloil.

The term "alkoxy" refers to 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, t-butoxy and the like.

The term "halogen" denotes a member of the Group 7 elements of the periodic table, namely fluoro, chloro, bromo and iodo.

The term "cycloalkylcarbonyl" refers to a radical of the formula -C (O) -R 'wherein R' represents cyclic alkyl as defined above.

The term "aryl" refers to a cyclic, optionally fused bicyclic radical, where all ring elements are carbon and the ring is aromatic, or in the case of a fused ring system, one or more rings are aromatic. Examples of aryl include phenyl, naphthyl and tetralinyl.

The term "alkylthio" refers to a radical of the formula -S-R 'wherein R' is alkyl as defined above.

The term "heteroaryl" refers to 1 to 6 heteroatoms (selected from O, S and N) and 1 to 20 carbon atoms, such as 1 to 5 heteroatoms and 1 to 10 carbon atoms, e.g. For example selected from radicals of heterocyclic aromatic rings comprising in particular 1 to 5 heteroatoms and 1 to 6 carbon atoms, for example 1 to 5 heteroatoms and 1 to 3 carbon atoms, in particular O, S and N 5 or 6 membered rings having 1 to 4 heteroatoms or optionally fused bicyclic rings having 1 to 4 heteroatoms, wherein at least one ring is aromatic, for example furanyl, pyridyl, Includes quinolyl, isoquinolyl, indolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazoli, thienyl, pyrazinyl, isothiazolyl, benzimidazolyl and benzofuranyl do.

The term “easily hydrolyzable ester” is used herein to refer to alkanoyloxyalkyl, aralkanoyloxyalkyl, aroyloxyalkyl, such as acetoxymethyl, pivaloyloxymethyl, benzoyloxymethyl esters and corresponding 1'-oxyethyl derivatives or alkoxycarbonyloxyalkyl esters such as methoxycarbonyloxymethyl esters and ethoxycarbonyloxymethyl esters and the corresponding 1'-oxyethyl derivatives or lactonyl esters such as Phthalidyl esters, or dialkylaminoalkyl esters, for example diethylaminoethyl ester. The expression “easy hydrolyzable ester” includes esters that are hydrolyzable in vivo of the compounds of the present invention. Such esters are known to those skilled in the art and can be prepared using the method of British Patent No. 1 490 852, which is incorporated herein by reference.

Preferred Embodiments of Compounds of Formula (I)

In a preferred embodiment, the present invention relates to compounds of formula (Ia) and pharmaceutically acceptable salts thereof and easily hydrolyzable esters thereof.

Formula Ia

In Formula Ia above,

X is halogen, trifluoromethyl, cyano, azido, C _1-7 alkyl, C _2-9 alkenyl or aryl, where C _1-6 alkyl, C _2-6 alkenyl or aryl is C _{1- Is} optionally substituted with one or more identical or different substituents selected from the group consisting of ₇ alkyl, C _2-9 alkenyl, aryl, C _1-6 alkoxy, nitro, alkylthio, halogen, azido, trifluoromethyl and cyano) ego,

Y and Z are both hydrogen, or form a double bond between C-17 and C-20 with a C-17 / C-20 bond, or methylene together, or a cyclopropane ring with C-17 and C-20 Form the

A is a bond, 0, S or S (O),

B is C _1-6 alkyl, C _2-6 alkenyl, C _1-6 acyl, C _3-7 cycloalkylcarbonyl or benzoyl, all of which are halogen, hydroxy, C _1-6 alkoxy, aryl, Optionally substituted with one or more substituents selected from the group consisting of heterocyclyl and azido, or when A is a bond, B may also be hydrogen,

Q ₁ and Q ₂ are independently —C (0) —, — (CHOH) —, — (CHSH) — or — (CHW) —, where W is halogen, cyano, azido or trifluoromethyl )to be.

In a preferred embodiment of the compounds of Formula (I), (Ia) or (Ib), Y and Z are both hydrogen and the stereochemical configuration is S in both C-17 and C-20.

In a preferred embodiment of the compound of Formula (I), (Ia) or (Ib), Y and Z together are methylene and together with C-17 and C-20 form a cyclopropane ring, the stereochemical coordination is both C-17 and C-20 Is S.

In a preferred embodiment of the compounds of formula (I), (la) or (lb), Y and Z together with C-17 / C-20 bonds form a double bond between C-17 and C-20. Most preferably, the coordination of the double bonds between C-17 and C-20 is the same as in the fumed 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 (where methyl, ethyl, propyl, phenyl, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, nonenyl, biphenyl or naphthyl is fluoro, chloro, bromo, phenyl, vinyl , Cyano, methoxy, trifluoromethyl, nitro, methylthio, butyl, methyl, ethyl, propyl, butyl, pentyl, hexyl and heptyl, optionally substituted with one or more identical or different substituents).

In a particularly preferred embodiment, X is fluoro, chloro, bromo, iodo, trifluoromethyl, phenyl, 4-bromophenyl, 4-chlorophenyl, 3,5-difluorophenyl, trans-1-hexene -1-yl, trans-1-buten-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- (trifluoro Methyl) 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 may advantageously be selected from the group consisting of — (CO) — and — (CHOH) —. Q ₁ may also be advantageously CHF, CHCl, CHBr, CHI, CHN ₃ .

Further aspects of the invention

Q ₁ and Q ₂ are both — (CHOH) — groups, either Q ₁ or 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 0, S or S (O),

B is a C _1-4 alkyl group wherein these groups are 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 Provided are compounds of formula (Ia) that are benzoyl groups, both of which are optionally substituted with one or more halogen atoms, such as fluoro and chloro.

In a particularly preferred embodiment, A is 0 or S (O).

In another preferred embodiment, B is acyl, methyl, ethyl, propyl, butyl, pentyl, propenyl or cyclopentyl, all of which are methyl, ethyl, propyl, butyl, fluoro, vinyl, hydroxy, phenyl, furfuryl And one or more substituents selected from the group consisting of methoxy.

In a particularly 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, 3 Tert-butyl, 1,3-difluoro-isopropyl, propionyl, chloroacetyl or trifluoroacetyl.

In a particularly preferred embodiment, Q ₁ or Q ₂ or both Q ₁ and Q _{2 are} — (COH) —.

When Q ₁ and / or Q ₂ in formula (I), (Ia) or (Ib) is — (COH) —, the stereochemical configuration is preferably 3α and 11α, respectively.

Specific examples of the compounds of the present invention are as follows:

24-trifluoromethyl sodium fusiate (compound 101),

24-trifluoromethyl pushed acid pivaloyloxymethyl ester (Compound 102),

24-chloro-fusidic acid (compound 103),

24-chloro-fusidic pivaloyloxymethyl ester (compound 104),

24-chloro-fusidic acid sodium salt (compound 105),

24-trifluoromethyl fusidic acid (compound 106),

24-bromo-fusidic acid acetoxymethyl ester (compound 107), '

24-bromo-fusidic acid (compound 108),

24-bromo-fusidic acid sodium salt (Compound 109),

24-bromo-fusidic pivaloyloxymethyl ester (Compound 110),

24-bromo-16-deacetoxy-16β-thioacetyl-fusidic acid acetoxymethyl ester (Compound 111),

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

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

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

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

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

24-bromo-16-deacetoxy-16β-ethoxy-fusidic 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),

24-bromo-17S, 20S-fusidic acetoxymethyl ester (Compound 120),

24-bromo-17S, 20S-methylene-fusidic acid acetoxymethyl ester (Compound 121),

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

3-deoxy-3β, 24-dibromo-fusidic acid (compound 123),

3α-azido-24-bromo-3-deoxy-fusidic acid (Compound 124),

24-iodo-fusidic acid (compound 125),

24-iodo-fusidic acetoxymethyl ester (Compound 126),

24-iodo-fusidic pivaloyloxymethyl ester (Compound 127),

24-phenyl-fusidic pivaloyloxymethyl ester (Compound 136),

24-phenyl-fusidic acid (compound 137),

24- (4-bromophenyl) -fusidic pivaloyloxymethyl ester (Compound 138),

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

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

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

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

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

3-deoxy-3β, 24-dibromo-fusidic acid acetoxymethyl ester (Compound 144),

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

24-bromo-16-deacetoxy-16β-ethylsulfinyl-fusidic acid (Compound 147),

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

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

24-bromo-16-deacetoxy-16β- (l-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-cyclopentylthio-fusidic acid (compound 155),

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

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

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

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

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

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

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

24-bromo-16-deacetoxy-16β-isopropoxy-fusidic 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),

24-bromofusidic acid, L-arginine salt (Compound 189),

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

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

24-bromofusidic acid, L-lysine salt (Compound 192),

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

24-bromofusidic acid, ethanolamine salt (Compound 194),

24-bromofusidic acid, potassium salt (Compound 195),

24-bromofusidic acid, tetrabutylammonium salt (Compound 196),

24-bromofusidic acid, benzyltrimethylammonium salt (Compound 197),

24-bromofusidic acid, cetyltrimethylammonium salt (Compound 198),

24-bromofusidic acid, tetramethylammonium salt (Compound 199),

24-bromofusidic acid, tetrapropylammonium salt (Compound 300),

24-bromofusidic acid, tris (hydroxymethyl) aminomethane salt (Compound 301),

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

24-bromofusidic acid, silver salt (Compound 303),

24-bromofusidic acid, benzethonium salt (compound 304),

24-bromofusidic acid, triethanolamine salt (Compound 305),

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

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

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

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

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

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

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

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

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

24- (4-cyanophenyl) -fusidic pivaloyloxymethyl ester (Compound 315),

24- (3-biphenyl) -fusidic pivaloyloxymethyl ester (Compound 316),

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

24- (4-methoxyphenyl) -fusidic pivaloyloxymethyl ester (Compound 318),

24- (3-cyanophenyl) -fusidic pivaloyloxymethyl ester (Compound 319),

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

24- (3-nitrophenyl) -fusidic pivaloyloxymethyl ester (Compound 321),

24- (3-bromophenyl) -fusidic pivaloyloxymethyl ester (Compound 322),

24- (4- (methylthio) phenyl) -fusidic pivaloyloxymethyl ester (Compound 323),

24- (2-naphthyl) -fusidic pivaloyloxymethyl ester (Compound 324),

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

24- (3,4-dimethoxyphenyl) -fusidic pivaloyloxymethyl ester (Compound 326) and

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

The compounds of the present invention can be used on their own or in the form of salts or easily hydrolyzable esters (as defined above). In particular, the salts of the compounds of the present invention are pharmaceutically acceptable salts such as alkali metal and alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts as well as silver salts and bases (eg Ammonia or a suitable non-toxic amine such as lower alkylamines such as triethylamine, hydroxy-lower alkylamines such as 2-hydroxyethylamine, bis- (2-hydroxyethyl) -Amines, cycloalkylamines such as dicyclohexylamine or benzylamine such as N, N'-dibenzylethylenediamine and dibenzylamine). Silver salts of compounds may be particularly useful for topical treatment.

In a preferred embodiment of the invention, pharmaceutically acceptable salts of the compounds according to formula (I) or formula (I ') are sodium salts, choline salts, L-arginine salts, 2- (dimethylamino) -ethanol salts, 4- (2-hydroxy Ethyl) -morpholine salt, L-lysine salt, N- (2-hydroxyethyl) -pyrrolidine salt, ethanolamine salt, potassium salt, tetrabutylammonium salt, benzyltrimethylammonium salt, cetyltrimethylammonium salt, tetra Methylammonium salt, tetrapropylammonium salt, tris (hydroxymethyl) aminomethane salt, N-methyl-D-glucamine salt, silver salt, benzetonium salt and triethanolamine salt.

In a preferred embodiment of the preparation of compounds of formula (la), the solvent used in step (a) to dissolve the _fudic acid is acetic acid or C _1-3 alkyl esters of C _1-4 carboxylic acids, in particular ethyl acetate.

In a preferred embodiment of the preparation of the compound of formula (la), the solvent used in step (b) to dissolve the 24,25-dibromo intermediate is C _1-6 alcohols 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 the compound of formula (la), the base used in step (b) for dehydrobromination of the 24,25-dibromo intermediate is an alkali metal salt of a weak acid (e.g., carboxylic acid, phosphoric acid or boric acid). Or an alkaline earth metal salt, for example potassium carbonate or sodium carbonate, or a base such as ammonia or C _1-8 substituted ammonia, for example ethylamine, diethylamine, triethylamine or piperidine, or dilute hydroxide Alkali or alkaline earth metal hydroxides such as sodium, calcium hydroxide or diluted potassium hydroxide.

The compounds of the present invention may comprise chiral carbon atom (s) and carbon-carbon double bond (s), resulting in stereoisomeric forms. The present invention relates to all of the aforementioned isomers in pure form and as mixtures. Pure stereoisomeric forms of the compounds of the present invention can be obtained by applying procedures known in the art. Diastereomers may be separated by selective crystallization and chromatographic techniques, for example by physical separation methods such as liquid chromatography using chiral stationary phases. Pure stereoisomeric forms may be derived from the corresponding pure stereoisomeric forms of the appropriate starting materials, so long as the reaction occurs stereoselectively or stereospecifically. Preferably, for the purpose of specific stereoisomers, the compounds will be synthesized by stereoselective or stereospecific methods of preparation.

The compounds of the present invention are useful for treating, preventing or alleviating infections in patients, including mammals, in particular human patients. Animals that can be treated with the compounds of the present invention more specifically include livestock such as horses, cattle, pigs, sheep, poultry, fish, cats, dogs, and zoo animals. The compounds of the present invention may be particularly useful for treating bacterial infections, such as skin infections or secondary skin infections or ocular infections. In addition, the compounds of the present invention may be useful for the treatment of simple abscesses, impetigo lesions, nodules or cellulite. The compounds of the present invention may be particularly useful for topical treatment of infectious epidermal infections of the skin, such as, for example, non-vesicular impetigo (or infectious impetigo) or bullous impetigo. As a result, the present invention provides a method of treating, preventing or alleviating a bacterial infection, comprising administering to a patient an effective amount of a compound of formula (I), optionally with another therapeutically active compound. Examples of such other therapeutically active compounds include antibiotics, for example β-lactams, for example penicillin (phenoxymethyl penicillin, benzyl penicillin, dicloxacillin, ampicillin, amoxicillin, pibampicillin, flucloxacillin Lean, piperacillin and meselinam), cephalosporin (cephalexin, cephalotin, cefepime, cephataxime, ceftazidime, ceftriazone and cepuroxime), monobactam (aztreonam) and carbapenem (Merofenene), macrolides (azitimycin, clarithromycin, erythromycin and oxythromycin), polymycin (colistin), tetracycline (tetracycline, doxycycline, oxytetracycline and limecycline), aminoglycoins Said (streptomycin, gentamycin, tobramycin and netylmycin), fluoroquinolone (norproxacin, opfloxacin, ciprofloxacin and moxifloxacin), clindamycin, linco Who, teicoplanin, and vancomycin-containing acid, oxazolidone (linezolid), rifamycin, metronidazole and Pu oxide. Other compounds that can be advantageously combined with the compounds of the invention, particularly for topical treatment, include, for example, corticosteroids such as hydrocortisone, betamethasone-17-valerate and triamcinolone acetonide. The compounds may be administered simultaneously or sequentially.

The compounds of the present invention are also useful for preventing or preventing bacterial infections in animals and are therefore useful in mammals such as domestic animals such as horses, cattle, pigs, sheep, poultry, fish, cats, dogs, and zoo animals. It is also useful for breeding.

For use in therapy, the compounds of the present invention are typically present in the form of pharmaceutical compositions. Accordingly, the present invention relates to pharmaceutical compositions comprising a compound of formula (I) or formula (I '), optionally in combination with other therapeutically active compounds, pharmaceutically acceptable excipients or adjuvants. Excipients should be "acceptable" in the sense of being compatible with the other ingredients of the composition and not harmful to the recipient thereof.

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

In dosage unit form, the compound may be administered one or more times a day at appropriate intervals, but depending on the condition of the patient and the prescription made by the attending physician. Typically, the dosage unit of the formulation contains 50 to 5000 mg, preferably 200 to 1000 mg of the compound of formula (I) or formula (I '). In the case of topical treatment, it may be more appropriate to refer to "unit of use", which refers to a single dose that can be administered to a patient and can be easily handled and packaged, which contains the active substance as such or is solid or liquid pharmaceutical. Physically and chemically stable unit dosages included as a mixture with a diluent or carrier.

The term “unit of use” in connection with topical use refers to one, ie single dose, which can be administered locally to a patient when 0.1 to 10 mg, preferably 0.2 to 1 mg of the active ingredient is applied per cm ^{2 of the} area of infection. Means.

It is also contemplated that for certain therapeutic regimens it may be advantageous to administer at longer intervals, eg, every other day, weekly, or longer.

If the treatment involves the administration of another therapeutically active compound, for useful administration of the compound see literature; Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Ed., J. G. Hardman and L. E. Limbird (Eds.), McGraw-Hill 1995.

The formulations are suitable for, for example, oral (including sustained or delayed release), rectal, parenteral (including subcutaneous, intraperitoneal, intramuscular, intraarterial and intravenous), transdermal, ophthalmic, topical, nasal or oral administration. Include form.

The formulations may conventionally be in dosage unit form and are described, for example, in literature; Remington, The Science and Practice of Pharmacy, 20th ed., 2000, can be prepared by methods well known in the art of pharmacy. All methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more additional ingredients. In general, formulations are prepared by uniformly and intimately bonding the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administration are in the form of discrete units, such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of active ingredient, in the form of powders or granules, aqueous liquids or non-aqueous liquids, for example It may be present in the form of a liquid or suspension in ethanol or glycerol or in the form of an oil-in-water emulsion or a water-in-oil emulsion. Such oils may be edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspending agents for aqueous suspensions are synthetic or natural gums such as tragacanth, alginate, acacia, dextrin, sodium carboxymethylcellulose, gelatin, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, Carbomer and polyvinylpyrrolidone. The active ingredient may also be administered in the form of concentrates, soft pills, and pastes.

Tablets may be made by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets may contain the active ingredient (s) in weaning form, eg, in powder or granule form, in a suitable device, optionally in the form of a binder, for example, lactose, glucose, starch, gelatin, acacia gum, tragacanth gum. Sodium alginate, carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, wax and the like, lubricants such as sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride And disintegrating agents such as starch, methylcellulose, agar, bentonite, croscarmellose sodium, sodium starch glycolate, crospovidone and the like, or by mixing with a dispersing agent such as polysorbate 80 and compressing. Can be. Molded tablets may be prepared by molding a mixture of the powdered active ingredient with a suitable carrier moistened with an inert liquid diluent in a suitable device.

Rectal formulations may be in the form of suppositories in which the compounds of the invention are mixed with low melting water soluble or insoluble solids, such as cocoa butter, hydrogenated vegetable oils, polyethylene glycols or fatty acid esters of polyethylene glycols, while elixirs It can be prepared using myristyl palmitate.

Formulations suitable for parenteral administration typically include sterile oily or aqueous preparations of the active ingredient, eg, isotonic saline, isotonic glucose solutions or buffered solutions, which are isotonic with the blood of the recipient. The formulation can typically be sterilized, for example, by filtration through a bacterial retention filter, by adding a sterilant to the formulation, by irradiating the formulation or by heating the formulation. Literature references; Encyclopedia of Pharmaceutical Technology, vol. 9, 1994 are also suitable for parenteral administration.

Alternatively, the compounds of formula (I) may be present as sterile solid preparations, for example lyophilized powders, which are readily dissolved in sterile solvent immediately before use.

Transdermal formulations may be in the form of plaster or patches.

Formulations suitable for ophthalmic administration may be in the form of sterile aqueous preparations of the active ingredient, which may be in the form of microcrystalline forms, for example, aqueous microcrystalline suspensions. See, eg, literature; Encyclopedia of Pharmaceutical Tehcnology, vol. 2, 1989, liposome formulations or biodegradable polymer systems can also be used to represent the active ingredient for ophthalmic administration.

Formulations suitable for topical or ophthalmic administration include liquid or semi-liquid preparations such as liniments, lotions, gels, applicators, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes. Or solutions or suspensions such as drops.

Formulations suitable for nasal or oral administration include powder, self-propelled and nebulized formulations such as aerosols and atomizers. Such formulations are described, for example, in literature; Modern Pharmaceutics, 2nd ed., G. S. Banker and C. T. Rhodes (Eds.), Pages 427-432, Marcel Dekker, New York; Modern Pharmaceutics, 3 th ed., G. S. Banker and C. T. Rhodes (Eds.), Page 618-619 and 718-721, Marcel Dekker, New York and Encyclopedia of Pharmaceutical Technology vol. 10, J Swarbrick and J. C. Boylan (Eds), page 191-221, Marcel Dekker, New York.

Formulations of the compounds of formula (I) or formula (I ') include, in addition to the components mentioned above, ones such as diluents, buffers, fragrances, colorants, surfactants, thickeners, preservatives, for example methyl hydroxybenzoate (including antioxidants), emulsifiers, It may contain the above additional components.

Parenteral formulations are particularly useful for treating diseases aimed at rapid response to treatment. In continuous therapy in patients suffering from infectious diseases, the tablets or capsules may be suitable forms of pharmaceutical preparations, due to the prolonged effect obtained when the drug is given orally, especially in the form of sustained release tablets. When the active ingredient is administered in the form of salts with pharmaceutically acceptable non-toxic acids or bases, in order to obtain a special and suitable absorption rate, preferred salts are, for example, readily water soluble or slightly soluble in water.

As previously indicated, the compositions may be used to treat other therapeutically active ingredients, such as other suitable antibiotics, in particular to enhance activity and / or develop resistance, which may be appropriately administered with a compound of the present invention in the treatment of an infectious disease. It may contain antibiotics that can prevent this. Corticosteroids may also be advantageously included in the compositions of the present invention. In particular, other active ingredients include β-lactams such as penicillin (phenoxymethyl penicillin, benzyl penicillin, dicloxacillin, ampicillin, amoxicillin, pibampicillin, flucloxacillin, piperacillin and mecelyl Male), cephalosporins (cephalexin, cephalotin, cefepime, cephataxime, ceftazidime, cefriazone and cepuroxime), monobactam (aztreonam) and carbapenem (meropenem); Macrolides (azithromycin, clarithromycin, erythromycin and roxytromycin); Polymycin (colistin); Tetracyclines (tetracycline, doxycycline, oxytetracycline and limecycline); Aminoglycosides (streptomycin, gentamicin, tobramycin and netylmycin); Fluoroquinolones (norfloxacin, opfloxacin, ciprofloxacin and moxifloxacin); Clindamycin, lincomycin, teicoplanin, vancomycin, oxazolidone (linezolide), rifamycin, metronidazole and fusidic acid. Other compounds that may be advantageously combined with the compounds of the invention, particularly for topical treatment, include, for example, corticosteroids such as hydrocortisone, betamethasone-17-valerate and triamcinolone acetonide.

Other therapeutically active compounds may be in the same or separate containers suitable for simultaneous or continuous administration of the therapeutically active compounds described above.

Treatment of an infectious disease often involves determining whether the disease is resistant to treatment or immune before initiating treatment. For example, a sample containing infectious microorganisms can be extracted from a patient (eg, blood or urine) and then cultured and exposed to treatment to determine whether the infected organism responds to the treatment. Accordingly, the present invention also provides a method of identifying a compound effective for a microorganism, including the administration of a compound of Formula (I) or (Ia) to the microorganism, optionally in combination with other therapeutically active agents, such that the compound or mixture thereof has a toxic or static effect on that microorganism. It provides a method comprising determining whether having.

The compositions of the present invention are not limited to medicaments and may also be used to inhibit microbial growth in non-medical situations. For example, the compositions or compounds of the present invention may be useful as additives, for example, to inhibit microbial growth during the fermentation process. For example, due to the selectivity of antimicrobial agents, they are useful for enhancing the growth of certain microorganisms at the expense of others in multi species culture.

Biological activity

In vitro investigations have demonstrated high efficacy of the compounds of the invention against both Staphylococcus and Streptococcus strains among the most relevant pathogenic bacteria involved in various skin and eye infections. In biological tests, the antibacterial against Staphylococcus of the compounds of the present invention, as compared to the fusidic acid, as apparent from Table 1 showing the MIC values of selected compounds of Formula Ia for both Staphylococcus and Streptococcus The activity has been shown to be the same or in some cases slightly enhanced, and more importantly, significantly improved antibacterial activity against Streptococcus.

compound

Fused acid analogs of the invention and standard compound 201 (fusidic acid) (as sodium salt), 207, 205, 203 and 206 (see note in Table A) were stored in powder form at + 4 ° C. When used for pumice, they were dissolved in 95% EtOH (3.84 mg / ml) and stored at −20 ° C. for up to 1 month before discarding.

Bacterial Strains Used for Biological Evaluation

Bacterial strain origin

Staphylococcus aureus FDA486 Laboratory Strains

Staphylococcus aureus FDA486 Laboratory Strains

Staphylococcus aureus CJ12 laboratory strain

Staphylococcus aureus 8325-4 laboratory strain

Clinical Isolates from Streptococcus Piogenes DA7121 Human Skin Infections

Clinical Isolates from Streptococcus Piogenes DA7864 Human Skin Infections

badge

LB medium (per 1000 ml ddH ₂ O: 10 g Bacto-tryptone, 5 g yeast extract, 10 g NaCl).

Todd-Hewitt Broth (THB) medium, SIGMA, Article No .: T1438 (1000 g ddH ₂ O: 50 g, Beef-Heart infusion, 20 g casein peptone, 2 g dextrose, 2 g NaHCO ₃ , 2.5 g NaCl 0.4 g Na ₂ HPO ₄ ). Plates were prepared using agar concentrations of 1.5%. Blood-agar plates contained an additional 5% (v / v) defibrated hose blood [purchaser; SLU (Swedish Agricultural University), Uppsala].

Minimum Inhibitory Concentration (MIC) Measurement

MIC testing of the compounds was performed in 96 well microtiter plates (Thermo Labsystems). 0.4 ml growth medium (S) containing serial dilutions of the compound to be tested starting from 128 μg / ml (dilution rate 2, eg 128 μg / ml, 64 μg / ml, .., 0.016 μg / ml) Aureus, LB broth, S. piogenes-TH broth) were inoculated with 4 × 10 ⁵ bacteria. The criterion for sensitivity was that growth was not visually observed after aerobic incubation at 37 ° C. for 24 hours. Each compound was tested at least twice and fusidic acid was always included as a test control.

Antibacterial activity (MIC / μg.ml ⁻¹ ) measured for selected compounds of the invention Compound number Staphylococcus aureus FDA486 Staphylococcus aureos cj12 Staphylococcus aureos 8325-4 Streptococcus piogenes DA7121 Streptococcus fiogenes DA7864 108 Standard Compound 201 (Fusidic Acid) 0.05 0.11 0.03 0.03 n.t. 0.03 0.8 3.5 0.8 3.5 113 Standard Compound 207 0.22 0.22 0.11 0.05 n.t. n.t. 0.4 1.6 0.4 1.6 115 Standard Compound 205 0.88 0.44 0.06 0.06 0.11 0.11 1.8 14 1.8 28 116 Standard Compound 203 0.44 0.22 0.06 0.06 0.11 0.22 7 7 7 14 122 Standard Compound 206 0.88 0.22 0.22 0.06 0.88 0.11 7> 32 7 28

Comments on Table A

cell concentration at t = 0: ˜10 ⁶ / ml. Bacteria grow aerobic at 37 ° C broth

n.t. = Not measurable

The standard compounds in Table A are known fudic acid derivatives. Each standard compound represents the corresponding compound of the invention described above in the same column.

The standard compound is not substituted at C-24 and there is a double bond between C24 and C25. All other structural features of the standard compounds are identical to the corresponding compounds of the invention described above in the same column.

201 pushed acid

207 16-Deacetoxy-16β-isopropylsulfinyl-fusidic acid (see literature; von Daehne, W. et al., Adv. Appl. Microbiol., 1979, vol. 25, p. 95-146)

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

203 16-Deacetoxy-16β-ethoxy-fusidic acid (see literature; von Daehne, W. et al., Adv. Appl. Microbiol., 1979, vol. 25, p. 95-146)

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

The data clearly shows that substitution of the 24 position of the fusidic acid significantly increases the activity against Streptococcus (2-15 fold) while essentially maintaining the activity against Staphylococcus.

Abbreviation

The following standard abbreviations are used throughout this specification:

AcOH = acetic acid

Ac ₂ O = acetic anhydride

Ac = acetyl

aq. = Aqueous

Bu = n-butyl

^t Bu, tBu = tertiary butyl

Comp. = Compound

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

DMF = dimethylformamide

eq. = Equivalent

Et = ethyl

Ether = diethyl ether

EtOAc = ethyl acetate

EtOH = ethanol

Ex. Example

FA = Fused Acid or Fused Acid Analog Ring-A, B, C, D Substructure

FCC = scintillation column chromatography

Fu = Fused Acid Ring-A, B, C, D Substructure

HMPA = hexamethyl phosphate triamide

HPLC = high performance liquid chromatography

iPr = Isopropyl

Me = methyl

MeOH = Methanol

m. p. = Melting point

MRSA = methicillin resistant Staphylococcus aureus

Pet. ether = petroleum ether

Ph = phenyl

Phenac = penacyl

Piv = pivaloyl

Prep. = Manufacturing

THF = tetrahydrofuran

TLC = thin layer chromatography

rt = room temperature

sat. NaCl = saturated aqueous sodium chloride solution

TMS = trimethylsilyl

v = volume

Preparation of Compounds of the Invention

Compounds of formula (I) can be formulated according to the requirements indicated for each compound of formula (I), e.g., availability of starting materials, temporary protection of sensitive substituents, purity and yield in the synthetic steps and the desired sequence of these steps. It can be synthesized from known starting materials by different synthetic routes.

Exemplary but non-limiting methods and examples for the synthesis of different compounds of formula (I) or formula (I ') are provided below. As commonly judged by those skilled in the art, various synthetic methods may be combined with one another to provide the desired compounds and formulas of Formula (I) or (Ia) having the desired substituents on rings A, C, and D at the 24 position of the side chain. Acids, salts or easily hydrolyzable esters can be obtained.

24 of Formula I having FA (fusidic acid / fusidic acid analog) ring-A, B, C, D substructure from starting materials 201 to 206 (having the same ring-A, B, C, D substructure) A general method for the synthesis of bromo compounds is shown in Scheme 1.

Compound 201 = fud acid

Exemplary Pushed Acid and Pushed Acid Analog Rings-A, B, C, D Substructures, FA:

Conditions: (a) ClCH ₂ 0 (CO) R ′, Et ₃ N, DMF (R ′ = Me or C (CH ₃ ) ₃ ), rt; (b) Br ₂ , CCl ₄ , 0 ° C .; (c) DBU, CCl ₄ or CH ₃ CN, rt; (d) DBU / aq. MeOH or K ₂ CO ₃ / MeOH, rt

Fusidic acid or fusidic acid analogs can be esterified using chloromethyl acetate or chloromethyl pivalate in a suitable solvent (eg dimethylformamide) in the presence of a suitable base (eg triethylamine). have. The ester can then be brominated with bromine in a suitable solvent (eg carbon tetrachloride or acetonitrile). The obtained dibromide (which is usually a mixture of 24-side diastereomers) is dehydrobrominated by treatment with a suitable base (eg DBU) in a suitable solvent (eg carbon tetrachloride or acetonitrile) to give a predominantly 24 Bromo-fusidic acid or pushed acid analogue-esters can be obtained. If desired, esters can be used, for example, as prodrugs of the corresponding free acid I, if they have an easily hydrolyzable ester group. Alternatively, the ester is hydrolyzed in a suitable solvent (eg methanol or ethanol containing water) with a suitable base (eg DBU or K ₂ CO ₃ ) to give the desired compound of formula (I) wherein X is bromo ) Can be obtained as a free acid or salt. In another embodiment of the present invention, the dibromide is dehydrobrominated and hydrolyzed in one step, for example by using the method described above, to obtain the desired compound of formula (I) as a free acid or salt. In another preferred embodiment, the pushed acid or pushed acid analog is directly brominated using the method as described above to obtain the corresponding dibromo acid, which is typically a mixture of 24-diastereomers. The dibromo acid is then dehydrobrominated, for example, in the manner described above to afford the desired compound of formula I, wherein X is bromo, as a free acid, optionally as a salt.

Q ₁ , Q ₂ , A and B are as defined above, Y and Z together with a C-17 / C-20 bond form a double bond between C-17 and C-20, or together are methylene, Preferred methods for the preparation of compounds of formula (Ia), wherein both are hydrogen and X is bromo, are described in Scheme 1a, wherein FA is a pushed acid or pushed acid analogue ring as shown in Scheme 1 -A, B, C, D Exemplified by the reaction shown in FIG.

Fu acid seed or seed Fu acid analogs dissolved in a suitable solvent and (for example, C _1-4 alkyl esters of acetic acid or a C _1-4 carboxylic acid such as ethyl acetate, isopropyl acetate, tert-butyl acetate) The bromine, preferably dissolved in bromine, preferably in the same solvent at −10 to 20 ° C., preferably 0 to 10 ° C., for example 5 ° C., affords a 24,25-dibromo intermediate. The 24,25-dibromo intermediate may be isolated after phase separation, optionally by addition of an aqueous base and / or reducing agent such as Na ₂ SO ₃ and evaporation of the organic solvent. Next, the 24,25-dibromo intermediate in a suitable solvent (e.g., C _1-6 alcohol, such as methanol, ethanol, 1-propano, isopropanol or butanol, or water or a mixture of these solvents). The solution is reacted with a suitable base at, for example, a reflux temperature, for example 50 to 120 ° C., for example 60 to 90 ° C., for example 70 to 90 ° C., to give a 24,25-dibromo intermediate. The dehydrobrominated compound of formula (Ia) is obtained in the form of a salt by dehydrobromination with a compound of formula (Ia) (optionally without isolation or purification steps). Bases used to prepare the dehydrobrominated compounds of formula (Ia) are alkali metal or alkaline earth metal salts of weak acids (e.g. carbonic acid, phosphoric acid or boric acid), e.g. sodium carbonate or potassium carbonate, or ammonia or C _{1- 8} bases such as substituted ammonia, for example ethylamine, diethylamine, triethylamine or piperidine, or alkali metal or alkaline earth metal hydroxides such as diluted sodium hydroxide, calcium hydroxide or diluted potassium hydroxide You can choose to. Compounds of formula (Ia) in free acid form can be obtained from salts by acidifying with a suitable acid (eg aqueous phosphoric acid or acetic acid). The compound of formula (Ia) is then purified and recrystallized, for example, as described in Examples 8 and 45 below to obtain pure compound of formula (Ia), or, for example, using the procedures described in preparations 1 and 2. It can be converted to an easily hydrolyzable ester or, for example, to a suitable salt, for example sodium salt, as described in Example 9 below.

A general method for converting a 24-bromo substituent of a compound of Formula (X = Bromo) to a 24-substituted compound of Formula (I = Bromo), as exemplified by the conversion of Compound 108, is It is shown in Scheme 2:

Conditions: (a) ClCH ₂ 0 (CO) R ′, Et ₃ N, DMF (R ′ = Me or C (CH ₃ ) ₃ ), rt; (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, rt; (g) CuI, LiCl, HMPA, 120 ° C .; (h) CF ₃ Cu, HMPA, rt; (i) ArB (OR ") ₂ *, Pd (PPh ₃ ) ₄ , K ₂ CO ₃ , EtOH + toluene, 90 ° C.

(Fu = Fused Acid Rings A, B, C, D Substructure)

* See Examples 36 to 43 for Ar and ArB (OR ") ₂ ;

24-bromo-fusidic acid- or 24-bromo-fusidic acid analogue-acetoxymethyl ester or -pivaloyloxymethylester can be treated with, for example, methanol and an aqueous base to the corresponding free acid. May be hydrolyzed. The bromo-acid can be heated at 120 ° C. with copper (I) iodide and potassium iodide in HMPA to afford the corresponding 24-iodo acid of formula (I). Acids can be treated with phenacylbromide and potassium fluoride in DMF to esterify with the corresponding phenacyl esters. The phenacyl esters produce the corresponding 24-trifluoromethyl esters, for example when reacted with a solution of trifluoromethyl copper in HMPA. Finally, the ester can be converted to the free 24-trifluoromethyl fusidic acid (or fusidic acid analog) upon hydrolysis, eg alkali hydrolysis.

Alternatively, 24-iodo acid can be esterified with acetoxymethyl ester or pivaloyloxymethyl ester as described above, and these can be reacted with a suitable coupling reaction, such as aryl boron, as shown in Scheme 2. Suzuki-type coupling with acids or esters or substituted aryl boronic acids or esters can be used to convert to the corresponding 24-aryl or alkenyl esters and the like. Finally, the corresponding free acid of the compound of formula I can be obtained by hydrolysis of the ester, for example alkali hydrolysis.

In another embodiment, 24-bromo-fusidic acid- or 24-bromo-fusidic acid analogue-acetoxymethyl ester or pivaloyloxymethylester is heated with copper iodide (I) and lithium chloride in HMPA To afford the corresponding 24-chloro ester. These esters give free 24-chloro acids of the compounds of formula (I) after hydrolysis, for example alkali hydrolysis.

A general method for the synthesis of compounds of formula (I), including modifications in ring A during the reaction sequence, illustrated for the synthesis of compounds 123, 124 and 144, is shown in Scheme 3:

Conditions: (j) Ph ₃ P, CBr ₄ , benzene, rt; (k) K ₂ CO ₃ , MeOH, rt; (l) LiNg, DMF, rt

For example, a non-limiting example of modifying a substituent in one of the rings of the fusidic acid ring-A, B, C, D substructure after introducing a 24-substituent is illustrated in Scheme 3 for modification in ring A. For example, 24-bromo-fusidic acid- or 24-bromo-fusidic acid analogue-acetoxymethyl ester or -pivaloyloxymethylester is converted into triphenylphosphine and tetrabromomethane The corresponding 3-β-bromo ester can be obtained by bromination followed by inversion of coordination. The ester can optionally be hydrolyzed with the free acid of formula (I). Such acids can be further modified, for example, by treatment with lithium azide, as shown, to invert coordination to obtain the corresponding 3-α-azido esters of formula (I).

A general method for the synthesis of compounds of formula (I) including modifications in rings A and D during the reaction sequence, illustrated for the synthesis of compounds 112 and 113, is shown in Scheme 4:

Conditions: (m) Ac ₂ O, pyridine, rt; (n) 1. 1 eq. aq. NaOH, MeOH, rt, 2. aq. NaHCO ₃ , 100 ° C.; (o) 1. 1 eq. 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 , rt; (r) DBU, CH ₃ CN, reflux; (s) 1. iPrSH, NaOH, DMF, rt, 2. aq. NaOH, 60 ° C .; (t) 1. 1 eq. aq. NaOH, MeOH, rt, 2. NaIO ₄ , MeOH, rt.

Synthesis of compounds 112 and 113 starting with fusidic acid illustrates a non-limiting process wherein the 16-substituent of ring D is alkylthio having 16-β-stereochemistry during synthesis of the compound of formula (I). Or an alkylsulfinyl- group. Temporary protection of 3-hydroxy groups and carboxy groups can be advantageously used and bromine at position 24 can be introduced at the appropriate stage of the synthetic sequence: acetylated fusidic acid 201 to acetic anhydride and pyridine at C3 Compound (4) can be obtained. The corresponding sodium salt of compound (4) can then be heated with aqueous sodium hydrogen carbonate to produce 16-α-hydroxy compound 5 (coordination reversal at C16). The sodium salt of compound (5) is esterified with, for example, chloromethyl pivalate to give compound (6). Compound 6 can be treated with phenyl chloroformate, dimethylformamide and sodium bromide to afford 16-α-bromo compound 11 (coordination maintenance at C16). Compound 911) can be brominated to afford 24,25-dibromo compound (12), which can be dehydrobrominated to 24-bromo compound (13) using, for example, DBU. Sodium isopropylthiolate can be alkylated with compound (13) to afford 16-β-isopropylthio intermediate (coordination reversal in C16), for example, with an aqueous base of Hydrolysis with bromo-3-α-hydroxy-16-β-isopropylthio carboxylic acid 112. If desired, compound 112 may be oxidized to the corresponding sulfoxide 113 (eg, using sodium periodate).

Preparation and Examples

General principles

All melting points are uncorrected. ^{For 1} H (300 MHz) and ¹³ C (75.6 MHz) nuclear magnetic resonance (NMR) spectra, internal tetramethylsilane (δ = 0.00) or deuteriochloroform (δ for ¹³ C NMR) unless otherwise noted = 76.81), the chemical shift value (δ) (in ppm) for deuteriochloroform solution. Values for the polyline (defined as doublet (d), triplet (t), quartet (q)) or none (m) are given as the approximate midpoint, unless the range is quoted otherwise (s = Single line, b = wide area). The reaction mixture was typically post-treated by shaking with an aqueous solution of water and / or (shown) salts or acids, extracted with an (shown) organic solvent, and the organic solution was typically dried over sodium sulfate or magnesium sulfate and reduced pressure in a rotary evaporator under reduced pressure. Concentrated. Chromatography was typically performed on silica gel using ethyl acetate and low boiling petroleum ether as eluent. The solvent ratio used is expressed as volume ratio /% (v / v). Appropriate fractions were combined and concentrated and, in some cases, recrystallized or lyophilized. Solvent: Anhydrous solvents were conventionally prepared by storing an analysis grade solvent in a 4mm molecular sieve a few days before use.

Preparation of Intermediates for Synthesizing Compounds of Formula (I)

Intermediates of Formula (Ib) are listed in Table 1:

Formula Ib

Annotation to Formula Ib and Table 1

Prep. = Manufacturing; Prep. = Process is used in other preparations or examples.

Comp. = Compound; Comm. Proced. = Usual procedure; Q ₂ = CH-OH (α);

For compounds that do not contain X X ', the coordination around C # 24 and C # 25 is the same as in Formula Ia, ie C24 and C25 are linked by a double bond. For compounds where X = X '= Br, both C24 and C25 are substituted with bromine atoms, C24 and C25 are linked by a single bond, and the compound is a mixture of two C24 diastereomers.

RH = free acid; Na = sodium salt; CH ₂ OAc = acetoxymethyl ester

CH ₂ OPiv = pivaloyloxymethyl ester; phenac = phenacyl ester

Y, Z Bd = carbon-carbon bond, ie C17 and C20 are connected 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 forms a cyclopropane ring with 17S, 20S-stereochemistry.

Produce

Preparation 1: Fused Acid Acetoxymethyl Ester (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 at room temperature for 30 minutes. Chloromethyl acetate (49 ml; 55 g; 500 mmol) was added and the reaction mixture was stirred at rt overnight and then worked up (EtOAc, water) to afford the crude product. Crude ester (2a) was crystallized from isopropyl ether to give pure compound (2a) as a colorless powder. Melting point 103-105 캜. 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, 15.9

Preparation 2: Fused Acid Pivaloyloxymethyl Ester (2b)

Following the procedure provided in Preparation 1, replacing chloromethyl acetate with chloromethyl pivalate, and the reaction was carried out at 50 ° C. overnight, the fusidic pivaloyloxymethyl ester (2b) was obtained as a colorless amorphous powder. 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.

Preparation 3: 24R, S, 25-dibromofusidic acid acetoxymethyl ester (3a)

Solution of (11mmol;; 1.76g 0.56ml); Fu seed acid acetoxymethyl ester (2a) (6g 10mmol) of CCl ₄ (40ml) of bromine in CCl ₄ (40ml) was dissolved, with cooling in an ice bath and continuous stirred in Was added for 1 hour. The resulting pale yellow solid was used in the next step without further purification. ¹ H NMR, (CDCl ₃ ): 5.91 (m, 1H), 5.78 (bs, 2H), 4.36 (bs, 1H), 4.20 (m, 1H), 3.75 (bs, 1H), 3.16 (m, 1H) , 2.80-1.00 (m, 20H), 2.10 (s, 3H), 1.97 (bs, 6H), 1.80 (s, 3H), 1.38 (s, 3H), 0.96 (s, 3H), 0.95 (s, 3H ), 0.91 (d, 3H).

Preparation 4: 24R, S, 25-dibromofuside acid pivaloyloxymethyl ester (3b)

Following the procedure provided in Preparation 3, replacing the fusidic acetoxymethyl ester (2a) with the fudic acid pivaloyloxymethyl ester (2b), and after concentrating the reaction mixture, the crude product was subjected to FCC (eluent). By hexane: EtOAc 50:50) to 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.

Preparation 5: 3-acetyl-fusidic acid (4)

Fusidic acid 201 (74.3 g; 0.144 mol) is 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 is stirred at room temperature for 3 hours. After the reaction was completed. The acetylated product was precipitated by addition of ice and water. Recrystallization from methanol / water gave 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.

Preparation 6: 3-acetyl-16-deacetoxy-16α-hydroxy fudic acid (5)

3-acetoxy-fusidic 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 solvent was evaporated and water (150 ml) was added to the residue. The mixture was heated to reflux and 20 ml of saturated aqueous solution of NaHCO ₃ (ca. 1M) was added over 30 minutes. The resulting clear solution is heated to 100 ° C. for 8 hours, after which an insoluble byproduct (corresponding lactone) is produced. The lactone was filtered off and the filtrate was acidified with HCl (20 ml, 4M) and extracted with EtOAc. The organic phase was washed with water, dried over MgSO ₄ and concentrated under reduced pressure to afford the title compound (5) which was 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.

Preparation 7: 3-Acetyl-16-deacetoxy-16α-hydroxy pushed acid pivaloyloxymethyl ester (6)

3-Acetyl-16-deacetoxy-16a-hydroxy fudic acid (5) (39.7 g; 77 mmol) was dissolved in MeOH (250 ml) and neutralized with 1 equivalent of aqueous NaOH. The solvent was evaporated and the residue was redissolved in DMF (450 ml). Chloromethylpivalate (13.4 ml; 13.9 g; 92 mmol) was added over 30 minutes with continuous stirring and ice cooling. The resulting mixture was stirred overnight at room temperature and then worked up (EtOAc, aqueous CaCl ₂ , water, saturated NaCl), dried over MgSO ₄ and concentrated under reduced pressure to afford the title compound (6) as an oil, which was further Used in the next step without purification (Preparation 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.

Preparation 8: 16-Deacetoxy-16β-thioacetyl-fusidic acid acetoxymethyl ester (8)

Following the procedure provided in preparation (1), the fudic acid was converted to 16-deacetoxy-16β-thioacetyl-fusidic acid 202 (see literature; von Daehne, W. et al., Adv. Appl. Microbiol. , 1979, vol. 25, p. 95-146), using 10 equivalents of Et ₃ N and chloromethyl acetate each, and the crude product to FCC using petroleum ether: EtOAc (1: 1) as eluent. Purification by the title gave the title compound (8). 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.

Preparation 9: 16-Deacetoxy-16β-ethoxy-fusidic acid acetoxymethyl ester (9)

Following the procedure provided in Preparation 1, the fudic acid was added to potassium salt 203 of 16-deacetoxy-16β-ethoxy-fusidic acid (see von Daehne, W. et al., Adv. Appl. Microbiol). , 1979, vol. 25, p. 95-146), without using 10 equivalents of Et ₃ N and chloromethyl acetate, and using the crude product as eluent as petroleum ether: EtOAc (1: 1). Purification by gave the title compound (9). 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.

Preparation 10: 16-Deacetoxy-16β- (2 ', 2', 2'-trifluoroethoxy) -fusidic acid acetoxymethyl ester (10)

Following the procedure provided in preparation (1), the fumed acid was converted to 16-deacetoxy-16β- (2 ', 2', 2'-trifluoroethoxy) -fusidic acid 204 (see literature; von Daehne, W et al., Adv. Appl. Microbiol., 1979, vol. 25, p. 95-146), each using 10 equivalents of Et ₃ N and chloromethyl acetate, and the crude product as eluent. Purification by FCC with petroleum ether: EtOAc (1: 1) afforded the title compound (10). 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.

Preparation 11: 3-acetyl-16α-bromo-16-deacetoxy-fusidic acid pivaloyloxymethyl ester (11)

3-Acetyl-16-deacetoxy-16α-hydroxy fudic acid pivaloyloxymethyl ester (6) (22.8 g; 36.2 mmol) was dissolved in DMF (200 ml) and placed in an ice bath with continuous stirring under an argon dash. Cooled in. Sodium bromide (18.6 g; 181 mmol) was added to the solution and the resulting mixture was stirred for 1 hour. Phenyl chloroformate (22,8 ml; 28.3 g; 181 mmol) was added at 0 ° C. over 1 h and then stirred at rt for 18 h. The reaction mixture was worked up (EtOAc, aqueous CaCl ₂ , water, saturated NaCl), dried over MgSO ₄ and concentrated under reduced pressure to afford the crude product. The crude product was purified by FCC (10% to 30% EtOAc in petroleum ether as eluent) to afford pure title compound 11 as 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.

Preparation 12: 3-Acetyl-16-deacetoxy-16α-24,25-tribromo fusidic acid pivaloyloxymethyl ester (12)

By following the procedure given in Preparation 3, by replacing the fusidic acetoxymethyl ester (2a) with 3-acetyl-16α-bromo-16-deacetoxy-fusidic pivaloyloxymethyl ester (11), The title compound (12) was obtained as a colorless foam. ¹ H NMR, (CDCl ₃ ): 5.87 (m, 2H), 5.64 (bt, lH), 4.93 (bs, lH), 4.35 (bs, lH), 4.14 (dd, lH), 3.46 (bd, lH) , 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).

Preparation 13: 3-Acetyl-16-deacetoxy-16α, 24-dibromo pushed acid pivaloyloxymethyl ester (13)

3-Acetyl-16-deacetoxy-16α-24,25-tribromo fudic acid pivaloyloxymethyl ester (12) (14.4 g; 16.4 mmol) and DBU (7.4 ml; 7.6 g; 49 mmol) The resulting solution, dissolved in acetonitrile (200 ml), was heated at 50 ° C. for 5 hours with continuous stirring under argon. The reaction mixture was concentrated under reduced pressure and worked up (EtOAc, water, saturated NaCl). The crude product was purified by FCC (10% to 15% EtOAc in petroleum ether as eluent) to afford the title compound (13) as crystalline product. ¹ H NMR, (CDCl ₃ ): 5.87 (d, lH), 5.84 (d, lH), 5.64 (bt, lH), 4.94 (bs, lH), 4.36 (bs, lH), 3.45 (bd, lH) , 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).

Preparation 14: 17S, 20S-dihydrofusidic acid acetoxymethyl ester (14)

According to the procedure provided in Preparation (1), the fusid acid was converted to 17S, 20S-dihydrofusidic acid 205 (see literature; Duvold, T. et al., J. Med. Chem., 2001, Vol 44, p. 3125-3131), using 10 equivalents of Et ₃ N and chloromethyl acetate, respectively, and the crude product was purified by FCC with petroleum ether: EtOAc (1: 1) as eluent. 14) was 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.

Preparation 15: 17S, 20S-methylene- fusidic acid acetoxymethyl ester (15)

Following the procedure provided in Preparation (1), the fumed acid was converted to 17S, 20S-methylene-fusidic acid (206) (see Duvold T., et al., Bioorg. Med. Chem. Lett., 2002, Vol. 12, p. 3569-3572), using 10 equivalents of Et ₃ N and chloromethyl acetate each, and the crude product was purified by FCC with petroleum ether: EtOAc (1: 1) as eluent, The title compound (15) was 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.

Preparation 16: 24-iodo-fusidic acid penacyl ester (7)

A mixture of phenacylbromide (0.42 g; 2.1 mmol), potassium fluoride (0.27 g; 4.6 mmol) and DMF (10 ml) was stirred at 90 ° C. for 5 minutes under an argon atmosphere. 24-iodo-fusidic acid (125,) (1.35 g; 2. lmmol) was added and the resulting mixture was stirred at 90 ° C. for 1 hour. The reaction was worked up (ether, water, saturated NaCl, MgSO ₄ ) and concentrated under reduced pressure to afford 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.

Preparation 17: 24-trifluoromethyl-fusidic acid phenacyl ester (16)

Solution of trifluoromethyl copper complex in HMPA (see literature; Kobayashi, prepared from trifluoromethyl iodide (0.43 g, 2.2 mmol) and copper powder (0.32 g, 5 mgAt) in HMPA (1.5 ml) Y. et al., Tetrahedron. Lett., 1979, Vol. 42, p. 4071-4072) were added to 24-iodo-fusidic acid phenacyl ester (7) (190 mg, 0.25 mmol). The resulting mixture was stirred for 3 days at room temperature in a sealed vial under argon atmosphere, then worked up with EtOAc, water and saturated NaCl, dried and concentrated under reduced pressure. The crude product was purified by FCC (20% to 40% EtOAc in petroleum ether as eluent) followed by preparative HPLC (Lichrospher ^R- 100 RP18, acetonitrile: water (9: 1) as eluent. 0.01M NH ₄ ⁺ HCOO ^- with a mixed aqueous 0.01M NH ₄ ⁺ HCOO ^- 50% to 0% gradient] was performed. The appropriate fractions were combined and concentrated under reduced pressure and extracted with EtOAc, EtOAc solution was concentrated under reduced pressure to give the title compound (16) as an oil. ¹ H NMR, (CDCl ₃ ): 7.88 (dd, 2H), 7.58 (t, lH), 7.48 (t, 2H), 5.98 (d, lH), 5.48 (d, lH), 5.11 (d, lH) , 4.36 (s, lH), 3.75 (bs, lH), 3.10 (bd, lH), 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).

Preparation 18: 24, 25-dibromo-fusidic acid (17)

A solution of bromine (16.0 g, 0.1 mol) in ethyl acetate (100 ml) was added over 75 minutes to a stirred solution of fusidic acid (51.6 g, 0.1 mol) in ethyl acetate (1000 ml). The temperature was kept at 5 ° C. by cooling in an ice bath. KH ₂ PO ₄ (100 ml, 1M aqueous) and Na ₂ S ₂ 0 ₃ (50 ml, 1M aqueous) were added for several minutes. The EtOAc phase was separated, extracted with KH ₂ PO ₄ (200 ml, 0.5 M aqueous) and water (100 ml), then concentrated under reduced pressure to give the title residue (17) which was used in the next step without further purification. (Example 45). ¹ H NMR (CDCl ₃ ): 5.81 (d, lH), 4.32 (m, lH), 4.26 (t, lH), 3.66 (m, lH), 3.09 (m, lH), 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 of Formula (I) of the Invention

Exemplary compounds of Formula (I) are listed in Table 2 (for compounds of Formula (Ia) wherein Q ₂ is CH—OH (α)):

Formula Ia

Notes on Table 2: The symbols in Table 2, which are common to Table 1, have the same meaning. Ex. = Example; Ex. = Procedure is used in another embodiment.

Easily hydrolyzable esters of the compounds of formula (I) illustrated are listed in Tables 3a (for acetoxymethyl esters) and 3b (for pivaloyloxymethyl esters) (Q ₂ is CH-OH (α). For esters of compounds of formula la)

Notes on Tables 3a and 3b: The symbols in Tables 3a and 3b which are common to Table 1 have the same meaning. Ex. = Example; Ex. = Procedure is used in another embodiment.

Exemplary salts of the compounds of formula I are listed in Table 4 (for salts of formula Ic where Q ₂ is CH—OH (α)):

Formula Ic

Notes on Table 4: The symbols in Table 2, which are common to Table 1, have the same meaning. Ex. = Example; Ex. = Procedure is used in another embodiment.

Example 1: 24-trifluoromethyl-sodium fusid acid salt (Compound 101)

The title compound 101 can be obtained by following the procedure of Example 9 and replacing 24-bromo-fusidic acid 108 with 24-trifluoromethyl fusidic acid 106.

Example 2: 24-trifluoromethyl-fusidic pivaloyloxymethyl ester (Compound 102)

The title compound 102 can be obtained by following the procedure of Preparation 2 and replacing fusidic acid with 24-trifluoromethyl fudic acid 106 and lyophilizing the product.

Example 3: 24-chloro-fusidic acid (compound 103)

24-chloro-fusidic pivaloyloxymethyl ester 104 (140 mg, 0.21 mmol) and K ₂ CO ₃ (60 mg, 0.43 mmol) were stirred in MeOH (2 ml) at room temperature for 3 hours. FCC of the concentrated reaction mixture (petroleum ether: EtOAc: HCOOH as eluent, 90: 10: 1 to 10: 90: 1) afforded the title compound 103 as pure. 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: 24-chloro-fusidic pivaloyloxymethyl ester (Compound 104)

24-bromo-fusidic 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) in a sealed vial Shaken at 120 ° C. for 3 hours. The reaction mixture was worked up (EtOAc and saturated NaCl) to afford crude product. This was purified by FCC using petroleum ether: EtOAc (90:10 to 10:90) as eluent to afford 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: 24-chloro-fusidic acid sodium salt (Compound 105)

Following the procedure of Example 9 and replacing 24-bromo-fusidic acid 108 with 24-chlorofusidic acid 103 and lyophilizing the product, the title compound 105 was obtained.

Example 6: 24-trifluoromethyl fusidic acid (compound 106)

24-trifluoromethyl-fusidic acid phenacyl ester (17) (15 mg, 0.021 mmol) and sodium thiophenolate (20 mg, 0.15 mmol) in anhydrous DMF (0.5 ml) were stirred at 100 ° C. for 5 hours under argon. It was. EtOAc (15 ml) was added and the organic solution was extracted with 3M aqueous CaCl ₂ (10 ml) + 1M aqueous H ₃ PO ₄ (0.25 ml) and 3M aqueous CaCl ₂ , water and saturated NaCl (10 ml each). After drying and concentration, the crude product was purified by FCC with petroleum ether: EtOAc: HCOOH (60: 40: 1/2) as eluent to freeze-dry and then the title compound 106 was obtained as an amorphous powder. . ¹ H NMR, (CDCl ₃ ): 5.87 (d, lH), 4.34 (s, lH), 3.75 (s, lH), 3.06 (bd, lH), 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: 24-bromo-fusidic acid acetoxymethyl ester (compound 107)

24-R, S, 25-dibromofusidic acetoxymethyl ester (3a) from CCl ₄ (280 ml) and DBU (6.64 ml; 6.77 g; 44.5 mmol) (from fusidic acetoxymethyl ester 22.3 mmol) Was refluxed for 16 h. The reaction mixture was filtered from a clay precipitate through a cotton wool filter, the filtrate was washed with petroleum ether and EtOAc, the combined filtrates and washes were concentrated to give the title compound (107) as crude product (pH 70 by NMR). %) Was obtained, which could be used for the preparation of compound 108 (Example 8) without further purification. Pure samples were obtained by FCC (30% to 50% EtOAc in petroleum ether as eluent). ¹³ C NMR, (CDCl ₃ ): 170.3, 169.6, 167.9, 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-bromo-fusidic acid (compound 108)

From crude 24-bromo-fusidic acetoxymethyl ester (107) or pivaloyloxymethyl ester (110) (fusidic acetoxymethyl ester (2a) or pivaloyloxymethyl ester (2b) 44.4 mmol ) Was dissolved in MeOH (250 ml), and DBU (3 ml) was added to reliably basal the reaction. MeOH: water (1: 1) (300 ml) was added at room temperature for 2 hours while stirring was continued for a further 2 hours. 1 M KH ₂ PO ₄ -solution (100 ml) was added and, if necessary, phosphoric acid was added to bring the pH to about 4-5, and the precipitate formed was extracted twice with EtOAc and dissolved. The organic phase was extracted with water and saturated NaCl, dried over MgSO ₄ and concentrated to give crude product. It was purified by FCC (50% EtOAc in petroleum ether as eluent + 0.5% HCOOH as eluent) followed by recrystallization from EtOAc + toluene (partial evaporation) to give 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: 24-bromo-fusidic acid sodium salt (Compound 109)

24-bromofusidic acid 108 (2.38 g; 4.00 mmol) was dissolved in MeOH (30 ml). An equal amount of 1N NaOH-solution (4 ml) was added slowly until the pH was about 8.5 as measured by 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 solvent was evaporated and the solvent was evaporated again with EtOH and EtOAc. The residue was then crystallized from EtOH + EtOAc to afford 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 24-bromo-fusidic pivaloyloxymethyl ester (Compound 110)

By following the procedure set forth in Example 7, by replacing 24R, S, 25-dibromofusidic acetoxymethyl ester with 24R, S, 25-dibromofusidic pivaloyloxymethyl ester (3b) , Crude title compound (110) was obtained. If hydrolyzed without further purification, compound 108 can be obtained. Samples of the crude product were FCC using 30% to 50% EtOAc in petroleum ether as eluent to afford pure title compound 110 as a pale 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: 24-Bromo-16-deacetoxy-16β-thioacetyl-fusidic acid acetoxymethyl ester (Compound 111)

A solution of bromine (45 μl; 140 mg; 0.88 mmol) in CCl ₄ (5 ml) was added to 16-deacetoxy-16β-thioacetyl-fusidic acid acetoxymethyl ester in CCl ₄ (10 ml) for 2 hours under argon. ) (0.48 g; 0.8 mmol) was added, stirred in an ice bath and cooled. Stirring was continued for 15 minutes in an ice bath and then further for 15 minutes at room temperature. DBU (0.66 ml; 0.67 g; 4.4 mmol) was added and the mixture was boiled under reflux for 12 h. The reaction mixture was filtered through a filter aid and concentrated in vacuo. The residue was purified by FCC with 0% to 70% EtOAc in petroleum ether as eluent to afford 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-isopropylthio-fusidic acid (Compound 112)

2-propanethiol (1.4 ml; 1.13 g; 15 mmol) was dissolved in anhydrous DMF (12.5 ml), sodium hydride (60% dispersion in oil; 0.6 g; about 15 mmol) was added, followed by stirring at room temperature under argon. Acetyl-16-deacetoxy-16α, 24-dibromo fusidic acid pivaloyloxymethyl ester (13) (0.45 g; 0.6 mmol) was added. Stirring was continued for 2 hours and the reaction mixture was worked up (EtOAc, water, aqueous HCl (to about pH 4), water, saturated NaCl) and concentrated to an oil. It was dissolved in EtOH (20 ml) and 2N aqueous NaOH (10 ml) was added and the mixture was heated to 60 ° C. for 2 hours. The hydrolysis-mixture was worked up as described above and the crude product was FCC (10% to 20% EtOAc + 1% AcOH in petroleum ether as eluent) to afford 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-isopropylsulfinyl-fusidic acid (Compound 113)

To a solution of 24-bromo-16-deacetoxy-16β-isopropylthio-fusidic acid 112 (0.29 g; 0.47 mmol) in MeOH (10 ml) 2N aqueous NaOH (0.5 ml) in water (40 ml) And sodium periodate (0.23 g; 1.1 mmol) were added. The mixture was stirred at rt for 1 h and acidified with aqueous HCl to precipitate the acid. It was filtered off, washed with water and then recrystallized from EtOAc to give the title compound (113) as crystals. Melting point 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, 30.0 , 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-thioacetyl-fusidic acid (Compound 114)

24-Bromo-16-deacetoxy-16β-thioacetyl-fusidic acid acetoxymethyl ester (111) (40 mg; 0.059 mmol) was dissolved in MeOH (2.5 ml) and potassium carbonate (17 mg; 0.12 mmol) Was added and the mixture was stirred for 3 hours (with air passing through). Water (10 ml) was added and the mixture was acidified to pH about 4 with aqueous HCl, whereby acid precipitated. The mixture was worked up with EtOAc, water and saturated NaCl, dried over Na ₂ SO ₄ and concentrated to give the crude product. This was FCC (0-10% MeOH in dichloromethane as eluent) to afford 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 (Compound 115)

24-bromo-16-deacetoxy-16β-thioacetyl-fusidic acid acetoxymethylester (111) was followed by the procedure provided in Example 14 to 24-bromo-17S, 20S-dihydro-fusidic acid. Substitution with acetoxymethyl ester (Compound 120) gave 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-ethoxy-fusidic acid (Compound 116)

Follow the procedure provided in Example 14 and replace 24-bromo-16-deacetoxy-16β-thioacetyl-fusidic acid acetoxymethylester (111) with 24-bromo-16-deacetoxy-16β-ethoxy Substitution with fusidic acetoxymethyl ester (Compound 117) gave the title 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 24-Bromo-16-deacetoxy-16β-ethoxy-fusidic acid acetoxymethyl ester (Compound 117)

16-Deacetoxy-16β-thioacetyl-fusidic acid acetoxymethyl ester (8) was followed by the procedure provided in Example 11 and 16-deacetoxy-16β-ethoxy-fusidic acid acetoxymethyl ester (9 ), The title compound (117) was 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 24-Bromo-16-deacetoxy-16β- (2 ', 2', 2'-trifluoroethoxy) -fusidic acid acetoxymethyl ester (Compound 118)

16-Deacetoxy-16β-thioacetyl-fusidic acid acetoxymethyl ester (8) was followed by the procedure provided in Example 11, and 16-deacetoxy-16β- (2 ', 2', 2'-trifluoro Substitution with loethoxy) -fusidic acid acetoxymethyl ester (10) gave the title compound (118). 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 (Compound 119)

Follow the procedure provided in Example 14 and replace 24-bromo-16-deacetoxy-16β-thioacetyl-fusidic acid acetoxymethylester (111) with 24-bromo-16-deacetoxy-16β- (2 Substitution of ', 2', 2'-trifluoroethoxy) pushed acid acetoxymethyl ester (118) gave 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, 20.8, 20.2, 17.7, 16.0.

Example 20 24-bromo-17S, 20S-dihydro-fusidic acid acetoxymethyl ester (Compound 120)

By following the procedure provided in Example 11 and replacing 16-deacetoxy-16β-thioacetyl-fusidic acetoxymethylester (8) with 17S, 20S-dihydro-fusidic acetoxymethyl ester (14) The title compound (120) was 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 24-Bromo-17S, 20S-methylene-fusidic acid acetoxymethyl ester (Compound 121)

By following the procedure provided in Example 11 and replacing 16-deacetoxy-16β-thioacetyl-fusidic acetoxymethylester (8) with 17S, 20S-methylene-fusidic acid acetoxymethyl ester (15), The title compound (121) was 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-methylene-fusidic acid (Compound 122)

24-bromo-16-deacetoxy-16β-thioacetyl-fusidic acid acetoxymethylester (111) was followed by the procedure provided in Example 14 to 24-bromo-17S, 20S-methylene-fusidic acid Substitution with oxymethyl ester (Compound 121) gave the title compound 122. (FCC-eluate was 50% EtOAc + 1% HCOOH in petroleum ether). 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-dibromo-fusidic acid (Compound 123)

Follow the procedure provided in Example 14 and follow 24-bromo-16-deacetoxy-16β-thioacetyl-fusidic acid acetoxymethylester (111) to 3-deoxy 3β, 24-dibromo-fusidic acid. Substitution with acetoxymethyl ester (Compound 144) gave the title compound (123). (FCC-eluate was 10% EtOAc + 1% HCOOH in petroleum ether). 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-deoxy-fusidic acid (Compound 124)

3-deoxy-3β, 24-dibromo-fusidic 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 for 11 days at room temperature under argon. EtOAc and water (5 ml each) are added with AcOH to give a slightly acidic pH. Post-treatment (EtOAc, water, saturated NaCl), dried over Na ₂ SO ₄ and concentrated to afford the crude product, which was obtained with FCC (eluent: 0% to 50% EtOAc + 1% HCOOH in petroleum ether). Purification gave 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-iodo-fusidic acid (Compound 125)

24-bromofusidic acid 108 (17.Og; 28.5mmol), CuI (27.2g; 143mmol), KI (43.4g; 285mmol) and HMPA (100ml) were stirred using a reflux condenser under an oil bath under argon. Heated at 120 ° C. for 20 hours. Water (400 ml) was added and the resulting viscous mixture was extracted four times (400 ml total) with EtOAc. The organic phase was filtered through a filter aid, which was washed with EtOAc. The combined organic phases were extracted with 20% aqueous Na ₂ S ₂ 0 ₅ , twice with water and with saturated NaCl. After drying over MgSO ₄ , the solvent was evaporated and the residue was stirred with toluene (300 ml) for 3 hours. The precipitate was separated by filtration, washed with toluene and petroleum ether and dried to give the nearly pure title compound 125 as beige 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 24-iodo-fusidic acid acetoxymethyl ester (Compound 126)

The crude compound 126 was obtained by following the procedure provided in Example 25 and replacing compound 108 with 24-bromofusidic acid acetoxyl methyl ester 107. It was purified by FCC using 40% EtOAc in petroleum ether as eluent to afford the title compound 126 as an amorphous material. 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 24-iodo-fusidic pivaloyloxymethyl ester (Compound 127)

24-iodo-fusidic acid 125 (0.84 g; 1.31 mmol) and triethylamine (0.19 ml; 0,14 g; 1.35 mmol) were dissolved in DMF (5 ml) and stirred at room temperature for 20 minutes. Chloromethyl pivalate (0.30 ml; 0.32 g; 2.1 mmol) was added and the mixture was stirred at rt overnight. The reaction mixture was extracted with 3M aqueous CaCl ₂ , water and saturated NaCl and worked up, then dried over MgSO ₄ and concentrated. The residue was purified by FCC 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

1 g of 24-bromo-fusidic acid sodium salt

7.5 g of petroleum jelly

7.5 g of liquid paraffin

2.5g

Sorbitan Monopalmitate 2.5g

2.5 g of polyoxyethylene sorbitan monopalmitate

26.5 g of water

                                          50 g

Vaseline, paraffin, spermatozoon, sorbitan monopalmitate and polyoxyethylene sorbitan monopalmitate are heated to 70 ° C. and water is slowly added under continuous stirring. Stir continuously until the cream cools. The 24-bromo-fusidic acid sodium salt is ground to a cream base and homogenized using a roller mill. The cream is filled into an aluminum prefabricated tube.

Example 29: Ointment

1 g of 24-bromo-fusidic acid sodium salt

6.9 g of liquid paraffin

0.2 g of cetanol

2.3g anhydrous lanolin

Vaseline 39.6 g

                                          50 g

 Paraffin, cetanol, lanolin and petrolatum are melted at 70 ° C. After cooling to below 40 ° C., 24-bromo-fusidic acid sodium salt is triturated. The ointment is filled into a prefabricated aluminum tube that is lacquered.

Example 30 Capsules

25 g of 24-chloro-fusidic acid sodium salt

Microcrystalline Cellulose 14.5g

0.5 g magnesium stearate

                                          40 g

Pass the ingredients through a 60 mesh sieve and mix for 10 minutes. The mixture is filled into hard gelatin capsules using a 400 mg capsule fill weight.

Example 31 Tablet

25 g 24-bromo-fusidic acid sodium salt

Avicel ^TM 12g

STA-Rx 1500 12g

1 g magnesium stearate

                                          50 g

16-Deacetoxy-16β- (2 ', 2', 2'-trifluoroethoxy) -17S, 20S-methanofusidic acid, sodium salt, Avicel ^TM and STA-Rxfmf mixed together, 0.7 mm sieve Sieve through, then mix with magnesium stearate. The mixture is compressed into tablets 500 mg each.

Example 32: Suspension

24-Bromo-16-deacetoxy-16β-isopropylsulfinyl-fusidic acid

1 g of sodium salt

Citric acid 0.09 g

Sodium monohydrogenphosphate 0.14 g

Sucrose 5g

Tween ^TM 80 0.01 g

Potassium Sorbate 0.04g

Carboxymethylcellulose-Na 0.1 g

Amount to make the water suspension 100 ml

The crystals are ground 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, with a slight warming. Carboxymethylcellulose-Na is dissolved in 4 ml of boiling water. After cooling, other ingredients are added thereto. The suspension is homogenized in a blender and finally water is added to bring the total volume to 100 ml.

Example 33: Ointment

A: 24-bromo-16- deacetoxy-16β- (2 ', 2', 2'-trifluoroethoxy)-

   1 g of fusidic acid sodium salt

B: hydrocortisone, triamcinolone or fluorsinolone

   0.5 g of one of the compounds

6.9 g of liquid paraffin

0.2 g of cetanol

2.3g anhydrous lanolin

Vaseline 39.1 g

                                          50 g

Paraffin, cetanol, lanolin and petrolatum are melted at 70 ° C. After cooling to below 40 ° C., A and B are milled. The ointment is filled into a prefabricated aluminum tube that is lacquered.

Example 34 Ointment

A: 1.5 g of 24-bromo-17S, 20S-dihydrofusidic acid

B: 1.5 g tetracycline

13.8 g of liquid paraffin

Cetanol 0.4 g

4.6 g of anhydrous lanolin

Vaseline 78.2 g

                                          100 g

Paraffin, cetanol, lanolin and petrolatum are melted at 70 ° C. After cooling to below 40 ° C., A and B are milled. The ointment is filled into a prefabricated aluminum tube with lacquer.

Example 35 Eye Gel

24-bromo-16-deacetoxy-16β- (2 ', 2', 2'-trifluoroethoxy)-

10 g of fusidic acid

Benzalkonium chloride 0.1g

5g carbomer

Mannitol 50g

0.5 g Sodium Edetite

Sufficient amount of sodium hydroxide

To 100g of sterile water

Disodium edetate and mannitol are dissolved in water for injection in a stainless steel vessel equipped with a stirring device and a built-in homogenizer. Carbomer 934P is added, the vessel is evacuated, and then autoclaved the dispersion with slow stirring and high speed homogenization. Cool to 70 ° C. and stop the stirrer and homogenizer. Finely divided 24-bromo-16-deacetoxy-16β- (2 ', 2', 2'-trifluoroethoxy) -fusidic acid, sodium salt is added and the vessel is sterilized-exhausted, then slowly 4-Bromo-16-deacetoxy-16β- (2 ', 2', 2'-trifluoroethoxy) -fusidic acid is allowed to settle while stirring. Homogenize at 70 ° C. for 10 min at high speed. Cool to below 30 ° C. during stirring and low speed homogenization. Sterilized solution of benzalkonium chloride in water for injection is added with gentle stirring. A sterile solution of 1.050 kg sodium hydroxide in water for injection is added to neutralize Carbomer 934P. Stir and homogenize for 5 minutes at low speed. If necessary, the pH is adjusted to 5.4 to 5.8. Eye gels are transferred to storage tanks using nitrogen pressure and a low speed homogenization delivery system. Store at room temperature until charged. Eye gel is aseptically filled into sterile tubes using a 3.5 g fill weight.

Example 36 24-phenyl-fusidic pivaloyloxymethyl ester (Compound 136)

Phenylboronic acid (50 mg, 0.4 mmol) and EtOH (0.25 ml) were added to a solution of 24-iodo-fusidic pivaloyloxymethylester (127) (150 mg, 0.2 mmol) in toluene (1.5 ml), Argon was bubbled through the mixture for 2 minutes. K ₂ CO ₃ (2M aqueous solution, 0.3 ml) and Pd (PPh ₃ ) ₄ (11.5 mg, 0.01 mmol) were added and the mixture was shaken at 90 ° C. for 20 hours under argon. The reaction mixture was worked up with EtOAc, water and saturated NaCl, dried and concentrated. The resulting crude product was purified by FCC (20% EtOAc in petroleum ether as eluent) to afford 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, 20.8, 20.0, 17.9, 15.9.

Example 37: 24-phenyl-fusidic acid (compound 137)

Following the procedure of Example 3, replacing 24-chloro-fusidic pivaloyloxymethyl ester 104 with 24-phenyl-fusidic pivaloyloxymethyl ester 136 and after aqueous prior to FCC The pure title compound 137 was obtained by inserting treatment (EtOAc, water + aqueous HCl (pH to about 2) and saturated NaCl). 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 pivaloyloxymethylester (Compound 138)

Following the procedure of Example 36 and replacing the phenylboronic acid with [2- (4-bromophenyl) -5,5-dimethyl-1,3,2-dioxaborinane] to give the title compound 138. It was. 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)

Following the procedure of Example 3, replacing 24-chloro-fusidic pivaloyloxymethyl ester (104) with 24- (4-bromophenyl) -fusidic pivaloyloxymethyl ester (138) The pure title compound 139 was obtained by inserting an aqueous aftertreatment procedure (EtOAc, water + aqueous HCl (pH to about 2) and saturated NaCl) prior to FCC. 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 24- (4-chlorophenyl) -fusidic pivaloyloxymethylester (Compound 140)

Following the procedure of Example 36 and replacing phenylboronic acid with [2- (4-chlorophenyl) -5,5-dimethyl-1,3,2-dioxaborinane] the title compound 140 was 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)

Following the procedure of Example 3 and replacing 24-chloro-fusidic pivaloyloxymethyl ester 104 with 24- (4-chlorophenyl) -fusidic pivaloyloxymethyl ester 140, The pure title compound 141 was obtained by inserting an aqueous aftertreatment procedure (EtOAc, water + aqueous HCl (pH to about 2) and saturated NaCl) prior to FCC. 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: 24- (3,5-difluorophenyl) -fusidic pivaloyloxymethyl ester (Compound 142)

By following the procedure of Example 36 and replacing phenylboronic acid with [2- (3,5-difluorophenyl) -5,5-dimethyl-1,3,2-dioxaborinane], the title compound (142) ) Was 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)

Following the procedure of Example 3, 24-chloro-fusidic pivaloyloxymethyl ester 104 was replaced with 24- (3,5-difluorophenyl) -fusidic pivaloyloxymethyl ester 142 The pure title compound 143 was obtained by inserting an aqueous aftertreatment procedure (EtOAc, water + aqueous HCl (pH to about 2) and saturated NaCl) prior to FCC. 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 3-deoxy-3β, 24-dibromo-fusidic acid acetoxymethyl ester (Compound 144)

24-bromo-fusidic acetoxymethyl ester 107 (0.45 g; 0.67 mmol) was dissolved in anhydrous benzene (10 ml) and stirred at room temperature 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 1 hour. Ether (50 ml) was added and the precipitated material was removed by filtration. The filtrate was concentrated and the residue was purified by FCC (eluent: 0% to 50% EtOAc in petroleum ether) to afford 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-Bromo-fusidic acid (Compound 108)

24,25-Dibromo-fusidic acid (17) (crude product 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) These mixtures were refluxed with continuous stirring for 30 minutes, then cooled to room temperature and poured into water (4 L). The alkaline solution of potassium salt of compound 108 was acidified by addition of aqueous H ₃ PO ₄ (350 ml, 1M) under continuous stirring to give a pH 4.0, whereby a precipitate formed. The product was collected by filtration, washed with water and dried to give crude product 108. The crude compound 108 is then purified and recrystallized, for example, as described in Example 8, to obtain pure compound 108, or easily, for example, using the procedures described in Preparations 1 and 2. It may be converted to a hydrolyzable ester or, for example, to a suitable salt (eg sodium salt) as described in Example 9. An advantage of preparing the sodium salt of compound 108 is that the pure crystalline sodium salt is formed directly, without the need for purification by chromatography. By freeing the free acid from this sodium salt (in the same manner as described above for the potassium salt), the product is obtained, which is crystallized directly (eg from ethyl acetate and toluene) to give pure crystalline compound 108 Can be obtained.

Example 46: 24-Bromo-16-deacetoxy-16β-ethylthio-fusidic acid (Compound 146)

The title compound 146 was obtained by following the procedure described in Example 12 and replacing 2-propanethiol with ethanethiol. 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-ethylsulfinyl-fusidic acid (Compound 147)

Follow the procedure provided in Example 13 and replace 24-bromo-16-deacetoxy-16β-isopropylthio-fusidic acid 112 with 24-bromo-16- deacetoxy-16β-ethylthio-fusid By replacing with acid (compound 146), the title compound (147) was obtained. ¹ H NMR (CDCl ₃ ): 4.40 (d, lH), 4.37 (m, lH), 3.76 (m, lH), 3.18 (d, lH), 2.90-2.40 (m, 5H), 2.25-1.0 (m , 19H), 1.84 (bs, 3H), 1.77 (bs, 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-allylthio-fusidic acid (Compound 148)

The title compound 148 was obtained by following the procedure provided in Example 12 and replacing 2-propanethiol with allyl mercaptan. 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)

The title compound 146 was obtained by following the procedure provided in Example 12 and replacing 2-propanediol with 1-pentanethiol. 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-pentylsulfinyl) -fusidic acid (compound 150)

Follow the procedure provided in Example 13 and replace 24-bromo-16-deacetoxy-16β-isopropylthio-fusidic acid 112 with 24-bromo-16- deacetoxy-16β- (1-pentylthio Substitution of) -fusidic acid (compound 149) gave the title 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)

The title compound 151 was obtained by following the procedure given in Example 12 and replacing 2-propanediol with 2-methyl-1-butanethiol. 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)

Follow the procedure provided in Example 13 and replace 24-bromo-16- deacetoxy-16β-isopropylthio-fusidic acid 112 with 24-bromo-16- deacetoxy-16β- (2-methyl- Substitution with 1-butylthio) -fusidic acid (Compound 151) gave the title compound (152). 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)

The title compound 153 was obtained by following the procedure given in Example 12 and replacing 2-propanethiol with 3-methyl-1-butanethiol. 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)

Follow the procedure provided in Example 13 and replace 24-bromo-16- deacetoxy-16β-isopropylthio-fusidic acid 112 with 24-bromo-16- deacetoxy-16β- (3-methyl- Substitution with 1-butylthio) -fusidic acid (compound 153) gave the title compound (154). 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-cyclopentylthio-fusidic acid (Compound 155)

A solution of bromine (12.0 mg, 0.150 mol) in ethyl acetate (0.6 ml) was cooled in an agitation and ice bath for 16 minutes with 16-deacetoxy-16β-cyclopentylthio-fusidic acid in literature (4 ml). Von Daehne, W. et al., Adv. Appl. Microbiol., 1979, vol. 25, p. 95-146) (76.0 mg, 0.136 mmol). 1M aqueous KH ₂ PO ₄ (0.2 ml) and 1M aqueous Na ₂ S ₂ 0 ₃ (0.1 ml) were added with stirring for 5 minutes. The EtOAc phase was separated, extracted with 0.5 M aqueous KH ₂ PO ₄ (0.5 ml) and water (0.5 ml) to give the intermediate 24,25-dibromo fudic acid analog as an oil, which was not further purified. Used for dehydrobromination. Intermediate 24,25-dibromo fusidic acid analog 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 1/2 hour, cooled to room temperature and poured into water (15 ml). The alkaline solution of compound 155 was acidified by addition of 1M aqueous H ₃ PO ₄ with stirring to give a pH 4.0 which was worked up (EtOAc, saturated NaCl) to give the crude product. The crude product was purified by FCC (10% to 50% EtOAc + 1% AcOH in petroleum ether as eluent) to afford 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)

The title compound 156 was obtained by following the procedure given in Example 12 and replacing 2-propanethiol with 2,2,2-trifluoroethanethiol. 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-hydroxyethylthio) -fusidic acid (compound 157)

16-Deacetoxy-16β-cyclopentylthio-fusidic acid was followed by the procedure provided in Example 55 and 16-deacetoxy-16β- (2-hydroxyethylthio) -fusidic acid (see literature; von Daehne) , W. et al., Adv. Appl. Microbiol., 1979, vol. 25, p. 95-146) to give the title compound (157). 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-benzylthio-fusidic acid (compound 158)

The title compound 158 was obtained by following the procedure given in Example 12 and replacing 2-propanethiol with benzyl mercaptan. 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-benzylsulfinyl-fusidic acid (Compound 159)

Follow the procedure provided in Example 13 and replace 24-bromo-16- deacetoxy-16β-isopropylthio-fusidic acid 112 with 24-bromo-16- deacetoxy-16β-benzylthio-fusid By replacing with acid (compound 158), the title compound (159) was obtained. ¹ H NMR (CDCl ₃ ): 7.30 (m, 5H), 4.54 (d, lH), 4.35 (bs, lH), 4.04 (d, lH), 3.76 (d, lH), 3.76 (m, lH), 3.15 (bd, lH), 2.80-2.4 (m, 4H), 2.20-1.0 (m, 18H), 1.84 (bs, 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)

The title compound 160 was obtained by following the procedure given in Example 12 and replacing 2-propanethiol with furfuryl mercaptan. 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-phenylthio-fusidic acid (Compound 161)

The title compound 161 was obtained by following the procedure given in Example 12 and replacing 2-propanethiol with thiophenol. 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-benzoylthio-fusidic acid (compound 162)

16-Deacetoxy-16β-cyclopentylthio-fusidic acid was followed by the procedure provided in Example 55 and 16-deacetoxy-16β-benzoylthio-fusidic acid (see von Daehne, W. et al. , Adv. Appl. Microbiol., 1979, vol-25, p. 95-146) to give the title compound 162. 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-isopropoxy-fusidic acid (Compound 163)

16-Deacetoxy-16β-cyclopentylthio-fusidic acid was followed by the procedure provided in Example 55 and 16-deacetoxy-16β-isopropoxy-fusidic acid (see von Daehne, W. et al. , Adv. Appl. Microbiol., 1979, vol. 25, p. 95-146) to give the title compound 163. 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)

16-Deacetoxy-16β-cyclopentylthio-fusidic acid was followed by the procedure provided in Example 55 and 16-deacetoxy-16β- (2-fluoroethoxy) -fusidic acid (see literature; von Daehne) , W. et al., Adv. Appl. Microbiol., 1979, vol. 25, p. 95-146) to give the title compound 164. 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-16-deacetoxy-16β- (2-methoxyethoxy) -fusidic acid (compound 165)

16-Deacetoxy-16β-cyclopentylthio-fusidic acid was followed by the procedure provided in Example 55 and 16-deacetoxy-16β- (2-methoxyethoxy) -fusidic acid (see literature; von Daehne) , W. et al., Adv. Appl. Microbiol., 1979, vol. 25, p. 95-146) to 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 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester 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) was added. The mixture was stirred at rt for 3 h and then worked up (EtOAc, water + aqueous HCl (pH to about 2) and saturated NaCl) to afford the crude product. The crude product was purified by FCC (petroleum ether: EtOAc: HCOOH as eluent, 90: 10: 0 to 0: 99: 1) to afford pure title compound 166. ¹³ C NMR, (CDCl ₃ ): 174.1, 170.6, 149.9, 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-1-butene-3,3-dimethyl-1-yl) -fusidic acid (compound 167)

Follow the procedure provided in Example 66 and apply 24- (trans-1-hexen-1-yl) -fud acid pivaloyloxymethyl ester 306 to 24- (trans-1-butene-3,3-dimethyl- Substitution with 1-yl) -fusidic pivaloyloxymethyl ester (307) gave the title compound (167). 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)

Follow the procedure provided in Example 66 and replace 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester 306 with 24- (trans-1-nonen-1-yl) -fu Substitution with the seed acid pivaloyloxymethyl ester 308 afforded the title compound 168. 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)

Follow the procedure provided in Example 66 and replace 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester 306 with 24- (trans-5-chloro-1-pentene-1- The title compound 169 was obtained by replacement with yl) -fusidic pivaloyloxymethyl ester 309. 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)

Follow the procedure provided in Example 66 and replace 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester 306 with 24- (trans-2-phenyl-1-vinyl) -fusid Substitution with the acid pivaloyloxymethyl ester 310 afforded 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)

Follow the procedure provided in Example 66 and replace 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester 306 with 24- (2-phenyl-1-ethyl) -fusidic acid. Substitution with pivaloyloxymethyl ester (311) afforded the title compound (171). ¹³ C NMR, (CD ₃ 0D): 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)

Follow the procedure provided in Example 66 and replace 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester 306 with 24- (4-n-propyl-phenyl) -fusidic acid. Substitution with pivaloyloxymethyl ester 312 gave the title compound 171. 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)

Follow the procedure provided in Example 66 and replace 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester 306 with 24- (4-vinyl-phenyl) -fusidic pival Substitution with iloxymethyl ester 313 afforded the title 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)

Follow the procedure provided in Example 66 and apply 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester 306 to 24- (4-tert-butylphenyl) -fusidic acid. Substitution with pivaloyloxymethyl ester 314 yielded 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)

Follow the procedure provided in Example 66 and replace 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester 306 with 24- (4-cyanophenyl) -fusidic pival Substitution with iloxymethyl ester 315 gave the title 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)

Follow the procedure provided in Example 66 and replace 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester 306 with 24- (3-biphenyl) -fusidic pivaloyl Substitution with oxymethyl ester 316 gave the title 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)

Follow the procedure provided in Example 66 and replace 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester 306 with 24- (4- (trifluoromethyl) phenyl) -fu Substitution with the seed acid pivaloyloxymethyl ester (317) gave 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)

Follow the procedure provided in Example 66 and replace 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester 306 with 24- (4- (methoxyphenyl) -fusidic acid Substitution with baloyloxymethyl ester 318 gave the title 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)

Follow the procedure provided in Example 66 and replace 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester 306 with 24- (3-cyanophenyl) -fusidic pivaloyl Substitution with oxymethyl ester 319 afforded the title 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)

Follow the procedure provided in Example 66 and replace 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester 306 with 24- (2-methoxyphenyl) -fusidic acid pival Substitution with iloxymethyl ester 320 gave the title compound 180. ¹ H NMR (CDCl ₃ ): 7.23 (m, lH), 6.95 (m, 3H), 5.83 (d, lH), 3.81 (bs, lH), 3.79 (s, 3H), 3.74 (bs, lH), 2.81 (dd, lH), 2.65-0.95 (m, 22H), 1.95 (s, 3H), 1.84 (bs, 3H), 1.50 (bs, 3H), 1.27 (s, 3H), 0.92 (bs, 3H) , 0.92 (d, 3H), 0.81 (bs, 3H).

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

Follow the procedure provided in Example 66 and replace 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester 306 with 24- (3-nitrophenyl) -fusidic pivaloyl Substitution with oxymethyl ester 321 gave the title 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)

Follow the procedure provided in Example 66 and replace 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester 306 with 24- (3-bromophenyl) -fusidic pival Substitution with iloxymethyl ester 322 gave the title 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)

Follow the procedure provided in Example 66 and replace 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester 306 with 24- (4- (methylthio) phenyl) -fusidic acid. Substitution with pivaloyloxymethyl ester 323 afforded 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)

Follow the procedure provided in Example 66 and replace 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester 306 with 24- (2-naphthyl) -fusidic pivaloyl Substitution with oxymethyl ester 324 gave the title 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)

Follow the procedure provided in Example 66 and replace 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester 306 with 24- (3,5-bis- (trifluoromethyl) Phenyl) -fusidic pivaloyloxymethyl ester 325 gave 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)

Follow the procedure provided in Example 66 and replace 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester 306 with 24- (3,4-dimethoxyphenyl) -fusidic acid. Substitution with pivaloyloxymethyl ester 326 afforded 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)

Follow the procedure provided in Example 66 and apply 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester 306 to 24- (3,5-dibromophenyl) -fusid Substitution with the acid pivaloyloxymethyl ester 327 gave 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 24-bromofusidic acid, choline salt (Compound 188)

A solution of choline hydroxide in methanol (45%, 0.4 ml, 0.18 g, 1.5 mmol) was added slowly to a solution of 24-bromofusidic acid 108 (893 mg, 1.5 mmol) in ethanol (10 ml) with stirring. The resulting solution was concentrated under reduced pressure and the residue was crystallized from ether. The title compound (188) was collected by filtration. ¹³ C NMR, (CD ₃ 0D): 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 24-bromofusidic acid, L-arginine salt (Compound 189)

By following the procedure provided in Example 88 and replacing choline hydroxide with L-arginine (261 mg, 1.5 mmol; in water (10 ml)), the title compound 189 was obtained (from ethyl acetate) as an amorphous powder. ¹³ C NMR, (CD ₃ 0D): 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 24-bromofusidic acid, 2- (dimethylamino) -ethanol salt (compound 190)

The title compound 190 was obtained (from ether) crystals by following the procedure provided in Example 88 and replacing choline hydroxide with 2- (dimethylamino) -ethanol (151 μl, 134 mg, 1.5 mmol). ¹³ C NMR, (CD ₃ 0D): 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 24-bromofusidic acid, 4- (2-hydroxyethyl) -morpholine salt (Compound 191)

Following the procedure provided in Example 88 and replacing the choline hydroxide with 4- (2-hydroxyethyl) -wh morpholine (184 μl, 197 mg, 1.5 mmol), the title compound 191 was removed from (di-isopropylether ) As an amorphous powder. ¹³ C NMR, (CD ₃ 0D): 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 24-bromofusidic acid, L-lysine salt (Compound 192)

The title compound 192 was obtained (from ethyl acetate) by following the procedure provided in Example 88 and replacing choline hydroxide with L-lysine (219 mg, 1.5 mmol; in water (5 ml)). ¹³ C NMR, (CD ₃ 0D): 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 24-bromofusidic acid, N- (2-hydroxyethyl) -pyrrolidine salt (Compound 193)

Following the procedure provided in Example 88 and replacing the choline hydroxide with N- (2-hydroxyethyl) -ppyrrolidine (177 μl, 173 mg, 1.5 mmol), the title compound (193) was converted to (di-isopropylether From) as a crystal. ¹³ C NMR, (CD ₃ 0D): 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 24-bromofusidic acid, ethanolamine salt (Compound 194)

By following the procedure provided in Example 88 and replacing choline hydroxide with ethanolamine (90 μl, 92 mg, 1.5 mmol), the title compound 194 was obtained as an amorphous powder (from ether). ¹³ C NMR, (CD ₃ 0D _): 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 24-bromofusidic acid, potassium salt (Compound 195)

An aqueous solution of potassium hydroxide (0.82 M; 1.8 ml, 1.5 mmol) was added slowly 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 was monitored by a pH meter. At about pH 7, more water (7.5 ml) was added. The resulting solution (final-pH 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 0D): 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 24-bromofusidic acid, tetrabutylammonium salt (Compound 196)

The title compound 196 is determined (from ether) by following the procedure provided in Example 95 and replacing potassium hydroxide with aqueous tetrabutylammonium hydroxide (about 25%, 1.8 ml, 1.5 mmol; final-pH = 9). Obtained as. ¹³ C NMR, (CD ₃ 0D): 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, 30.1, 25.4, 24.8, 23.8, 22.5, 21.1, 20.7, 20.5, 17.9, 16.5, 14.0.

Example 97 24-bromofusidic acid, benzyltrimethylammonium salt (Compound 197)

The title compound 197 was obtained as crystals (from acetone) by following the procedure provided in Example 95 and replacing potassium hydroxide with benzyltrimethylammonium hydroxide (about 40% in methanol; final-pH = 9). ¹ H NMR, (CD ₃ 0D): 7.55 (m, 5H), 5.74 (d, lH), 4.53 (s, 2H), 4.30 (br, lH), 3.64 (br, lH), 3.10 (s, 9H ), 3.00 (d, lH), 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 24-bromofusidic acid, cetyltrimethylammonium salt (Compound 198)

The title compound 198 was obtained as crystals (from methyl ethyl ketone) by following the procedure provided in Example 95 and replacing potassium hydroxide with cetyltrimethylammonium hydroxide (about l0% in water; final-pH = 10). . ¹³ C NMR, (CD ₃ 0D): 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 24-bromofusidic acid, tetramethylammonium salt (Compound 199)

The title compound (199) was obtained as crystals (from acetone / ether) by following the procedure provided in Example 95 and replacing potassium hydroxide with tetramethylammonium hydroxide (about 10% in water; final-pH = 10). . ¹³ C NMR, (CD ₃ 0D): 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 24-bromofusidic acid, tetrapropylammonium salt (Compound 300)

The title compound 300 was obtained as crystals (from acetone / ether) by following the procedure provided in Example 95 and replacing potassium hydroxide with tetrapropylammonium hydroxide (about 10% in water; final-pH = 9.5). . ¹³ C NMR, (CD ₃ 0D): 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 24-bromofusidic acid, tris (hydroxymethyl) aminomethane salt (Compound 301)

Following the procedure provided in Example 88 and substituting tris (hydroxymethyl) aminomethane (82 mg, 1.5 mmol) dissolved in ethanol (12 ml) and water (8 ml), the title compound 301 was removed from (ether ) As an amorphous powder. ¹³ C NMR, (CD ₃ 0D): 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 24-bromofusidic acid, N-methyl-D-glucamine salt (Compound 302)

Following the procedure given in Example 88 and 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 (from ether ) As an amorphous powder. ¹³ C NMR, (CD ₃ 0D): 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 24-bromofusidic acid, silver salt (Compound 303)

A solution of 24-bromo fusidic acid salt 109 (926 mg, 1.5 mmol) in water (10 ml) was added to a solution of silver acetate (250 mg, 1.5 mmol) in water (30 ml). Ethanol (25 ml) was added and after 1 hour the particulate precipitate was collected by filtration (via a small pore glass filter), washed with water and vacuum dried over silica gel in the dark for several days. Silver salt 303 was a light gray amorphous powder. ¹ H NMR, (DMSO): 5.68 (d, lH), 4.14 (br, lH), 4.00 (m, 2H), 3.51 (br, lH), 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 24-bromofusidic acid, benzetonium salt (compound 304)

A solution of benzethonium chloride (672 mg, 1.5 mmol) in water (5 ml) was added to a solution of 24-bromo fusidate salt 109 (926 mg, 1.5 mmol) in water (10 ml) to form a viscous precipitate of benzethonium salt. Formed. The aqueous phase was decanted and the precipitate was washed with water by decantation. The precipitate was dissolved in acetone, concentrated and extracted with ethyl acetate (three times) to remove water. The salt remains as a viscous material upon treatment with ether, which is filtered and left in air overnight to give the title compound 304 as a brittle amorphous powder. ¹³ C NMR, (CD ₃ 0D): 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 24-bromofusidic acid, triethanolamine salt (Compound 305)

The title compound 305 was obtained as a crystalline powder (from ethanol / ether) by following the procedure provided in Example 88 and replacing choline hydroxide with triethanolamine (209 μl, 234 mg, 1.5 mmol; pure). ¹³ C NMR, (CD ₃ 0D): 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: 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethylester (Compound 306)

The title compound 306 was obtained by following the procedure given in Example 36 and replacing phenylboronic acid with trans-1-hexen-1-ylboronic acid. 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: 24- (trans-1-butene-3,3-dimethyl-1-yl) -fusidic pivaloyloxymethyl ester (Compound 307)

The title compound 307 was obtained by following the procedure given in Example 36 and replacing phenylboronic acid with trans-1-butene-3,3-dimethyl-1-ylboronic acid. 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: 24- (trans-1-nonen-1-yl) -fusidic pivaloyloxymethyl ester (Compound 308)

The title compound 308 was obtained by following the procedure given in Example 36 and replacing phenylboronic acid with trans-1-nonen-1-ylboronic acid. 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 pivaloyloxymethyl ester (Compound 309)

The title compound 309 was obtained by following the procedure provided in Example 36 and replacing phenylboronic acid with trans-5-chloro-1-pentene-1-ylboronic acid. 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: 24- (trans-2-phenyl-1-vinyl) -fusidic pivaloyloxymethyl ester (compound 310)

The title compound 310 was obtained by following the procedure given in Example 36 and replacing phenylboronic acid with trans-2-phenyl-1-vinylboronic acid. 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 pivaloyloxymethyl ester (Compound 311)

24- (trans-2-phenyl-1-vinyl) -fusidic pivaloyloxymethyl ester (310) (230 mg, 0.3 mmol) is dissolved in ethanol (5 ml) and palladium on carbon (25 mg, 5%) Was added. The flask was evacuated and a balloon containing hydrogen gas was fitted to the flask and left overnight with magnetic stirring. The catalyst was filtered through a filter aid and the filtrate was concentrated. The crude product was purified by FCC (eluant: petroleum ether: EtOAc, 90:10 to 50:50) to afford pure title compound 311. ¹³ C NMR, (CD ₃ 0D): 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 pivaloyloxymethyl ester (Compound 312)

The title compound 312 was obtained by following the procedure provided in Example 36 and replacing phenylboronic acid with 4-n-propylphenylboronic acid. 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: 24- (4-vinylphenyl) -fusidic pivaloyloxymethyl ester (Compound 313)

The title compound 313 was obtained by following the procedure given in Example 36 and replacing phenylboronic acid with 4-vinylphenylboronic acid. 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: 24- (4-tert-butylphenyl) -fusidic pivaloyloxymethyl ester (Compound 314)

The title compound 314 was obtained by following the procedure given in Example 36 and replacing phenylboronic acid with 4-tert-butylphenylboronic acid. 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: 24- (4-cyanophenyl) -fusidic pivaloyloxymethyl ester (Compound 315)

The title compound 315 was obtained by following the procedure given in Example 36 and replacing phenylboronic acid with 4-cyanophenylboronic acid. 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 pivaloyloxymethyl ester (Compound 316)

The title compound 316 was obtained by following the procedure given in Example 36 and replacing phenylboronic acid with 3-biphenylboronic acid. 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 24- (4- (trifluoromethyl) phenyl) -fusidic pivaloyloxymethyl ester (Compound 317)

The title compound 317 was obtained by following the procedure given in Example 36 and replacing phenylboronic acid with 4- (trifluoromethyl) phenyl boronic acid. 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, 38.8 , 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 24- (4-methoxyphenyl) -fusidic pivaloyloxymethyl ester (Compound 318)

The title compound 318 was obtained by following the procedure provided in Example 36 and replacing phenylboronic acid with 4-methoxyphenylboronic acid. 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 24- (3-cyanophenyl) -fusidic pivaloyloxymethyl ester (Compound 319)

The title compound 319 was obtained by following the procedure provided in Example 36 and replacing phenylboronic acid with 3-cyanophenylboronic acid. 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 24- (2-methoxyphenyl) -fusidic pivaloyloxymethyl ester (Compound 320)

The title compound 320 was obtained by following the procedure provided in Example 36 and replacing phenylboronic acid with 2-methoxyphenylboronic acid. 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 24- (3-nitrophenyl) -fusidic pivaloyloxymethyl ester (Compound 321)

The title compound 321 was obtained by following the procedure given in Example 36 and replacing phenylboronic acid with 3-nitrophenylphenylboronic acid. 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, 121.1, 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: 24- (3-Bromophenyl) -fusidic pivaloyloxymethyl ester (Compound 322)

The title compound 322 was obtained by following the procedure provided in Example 36 and replacing phenylboronic acid with 3-bromophenylboronic acid. 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 pivaloyloxymethyl ester (Compound 323)

The title compound 323 was obtained by following the procedure given in Example 36 and replacing phenylboronic acid with 4- (methylthio) phenylboronic acid. 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 24- (2-naphthyl) -fusidic pivaloyloxymethyl ester (Compound 324)

The title compound 324 was obtained by following the procedure given in Example 36 and replacing phenylboronic acid with 2-naphthylboronic acid. 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 24- (3,5-bis- (trifluoromethyl) phenyl) -fusidic pivaloyloxymethyl ester (Compound 325)

The title compound 325 was obtained by following the procedure given in Example 36 and replacing phenylboronic acid with 3,5-bis- (trifluoromethyl) phenylboronic acid. 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: 24- (3,4-dimethoxyphenyl) -fusidic pivaloyloxymethyl ester (Compound 326)

The title compound 326 was obtained by following the procedure provided in Example 36 and replacing phenylboronic acid with 3,4-dimethoxyphenylboronic acid. 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: 24- (3,5-Dibromophenyl) -fusidic pivaloyloxymethyl ester (Compound 327)

The title compound 327 was obtained by following the procedure provided in Example 36 and replacing phenylboronic acid with 3,5-dibromophenylboronic acid. 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 (35)

Compounds of formula (I) and pharmaceutically acceptable salts thereof and easily hydrolyzable esters thereof. Formula I

In Formula I above, X is halogen, trifluoromethyl, cyano, azido, alkyl, alkenyl or aryl, wherein alkyl, alkenyl or aryl is alkyl, alkenyl, aryl, alkoxy, nitro, alkylthio, halogen, azido, Optionally substituted with one or more identical or different substituents selected from the group consisting of trifluoromethyl and cyano), Y and Z are both hydrogen, or form a double bond between C-17 and C-20 with a C-17 / C-20 bond, or methylene together, or a cyclopropane ring with C-17 and C-20 Form the 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 of these are halogen, hydroxy, alkoxy, aryl, heteroaryl and acyl Optionally substituted with one or more substituents selected from the group consisting of a map), or when A is a bond, B may 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, 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 , The two bonds of the pentacyclic ring represented by the solid and dashed lines indicate that when Y is absent and Z is hydrogen, one of the two bonds may be a double bond, The bond between C-1 and C-2 is a single bond or a double bond. The compound of formula Ia and a pharmaceutically acceptable salt thereof and an easily hydrolyzable ester thereof. Formula Ia

In Formula Ia above, X is halogen, trifluoromethyl, cyano, azido, C _1-7 alkyl, C _2-9 alkenyl or aryl, where C _1-6 alkyl, C _2-6 alkenyl or aryl is C _{1- Is} optionally substituted with one or more identical or different substituents selected from the group consisting of ₇ alkyl, C _2-9 alkenyl, aryl, C _1-6 alkoxy, nitro, alkylthio, halogen, azido, trifluoromethyl and cyano) ego, Y and Z are both hydrogen, or form a double bond between C-17 and C-20 with a C-17 / C-20 bond, or methylene together, or a cyclopropane ring with C-17 and C-20 Form the A is a bond, 0, S or S (O), B is C _1-6 alkyl, C _2-6 alkenyl, C _1-6 acyl, C _3-7 cycloalkylcarbonyl or benzoyl, all of which are halogen, hydroxy, C _1-6 alkoxy, aryl, Optionally substituted with one or more substituents selected from the group consisting of heteroaryl and azido, or when A is a bond, B may also be hydrogen, Q ₁ and Q ₂ are independently —C (0) —, — (CHOH) —, — (CHSH) — or — (CHW) —, where W is halogen, cyano, azido or trifluoromethyl )to be. The compound of claim 1 or 2, wherein Y and Z are both hydrogen and the stereochemical configuration is S at both C-17 and C-20. 3. The compound of claim 1, wherein Y and Z together are methylene, together with C-17 and C-20 form a cyclopropane ring, and the stereochemical configuration is S at both C-17 and C-20 compound. The compound of claim 1 or 2, wherein Y and Z together with a C-17 / C-20 bond form a double bond between C-17 and C-20. 6. A compound according to claim 5, wherein the C-17 / C-20 double bond has the same configuration as in fusidic acid. The compound of claim 1, wherein X is chloro, bromo, iodo, fluoro, methyl, ethyl, propyl, phenyl, vinyl, propenyl, butenyl, pentenyl, hexenyl, hep Tenyl, nonenyl, biphenyl or naphthyl, wherein methyl, ethyl, propyl, phenyl, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, nonenyl, biphenyl or naphthyl are fluoro One or more of the same or selected from the group consisting of chloro, bromo, phenyl, vinyl, cyano, methoxy, trifluoromethyl, nitro, methylthio, butyl, methyl, ethyl, propyl, butyl, pentyl, hexyl and heptyl Optionally substituted with a different substituent). 8. The compound of claim 1, wherein X is fluoro, chloro, bromo, iodo, trifluoromethyl, phenyl, 4-bromophenyl, 4-chlorophenyl, 3,5-di Fluorophenyl, trans-1-hexen-1-yl, trans-1-buten-3,3-dimethyl-1-yl, trans-1-nonen-1-yl, trans-5-chloro-1-pentene- 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. The compound of claim 1, wherein Q ₁ and Q ₂ are independently —C (O) — or — (CHOH) —. The compound of claim 1, wherein Q ₁ is CHF, CHCl, CHBr, CHI or CHN ₃ . The method of claim 2, Q ₁ and Q ₂ are both — (CHOH) — groups, either Q ₁ or 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, wherein these groups Are both optionally substituted with one or more halogen atoms. 12. The compound of claim 11, wherein the halogen atom, optionally substituted for B, is fluoro or chloro. The compound of any one of claims 1-12, wherein A is O or S (O). 14. A compound according to any one of claims 1 to 13, wherein B is acyl, methyl, ethyl, propyl, butyl, pentyl, propenyl or cyclopentyl, wherein all of them are methyl, ethyl, propyl, butyl, fluoro, Optionally substituted with one or more substituents selected from the group consisting of vinyl, hydroxy, phenyl, furfuryl and methoxy. The compound of claim 1, wherein 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, tertiary butyl, 1,3-difluoro-isopropyl, propionyl, chloroacetyl or trifluoroacetyl. 3. The compound of claim 1, wherein Q ₁ or Q ₂ or both Q ₁ and Q _{2 are} — (COH) — and the stereochemical configuration is α in both C-3 and C-11. 4. The compound according to any one of claims 1 to 16, wherein the easily hydrolyzable ester is pivaloyloxymethyl ester or acetoxymethyl ester. Sodium salt, choline salt, L-arginine salt, 2- (dimethylamino) -ethanol salt, 4- (2-hydroxyethyl) -morpholine salt, L-lysine salt, N- (2-hydroxyethyl)- Pyrrolidine salt, ethanolamine salt, potassium salt, tetrabutylammonium salt, benzyltrimethylammonium salt, cetyltrimethylammonium salt, tetramethylammonium salt, tetrapropylammonium salt, tris (hydroxymethyl) aminomethane salt, N- 16. A pharmaceutically acceptable salt of a compound according to any one of claims 1 to 15, selected from the group consisting of methyl-D-glucamine salt, silver salt, benzetonium salt and triethanolamine salt. The method of claim 1, 24-trifluoromethyl sodium fudate salt (Compound 101), 24-trifluoromethyl pushed acid pivaloyloxymethyl ester (Compound 102), 24-chloro-fusidic acid (compound 103), 24-chloro-fusidic pivaloyloxymethyl ester (compound 104), 24-chloro-sodium fusidate salt (Compound 105), 24-trifluoromethyl fusidic acid (compound 106), 24-bromo-fusidic acid acetoxymethyl ester (compound 107), ' 24-bromo-fusidic acid (compound 108), 24-bromo-sodium fusidate salt (Compound 109), 24-bromo-fusidic pivaloyloxymethyl ester (Compound 110), 24-bromo-16-deacetoxy-16β-thioacetyl-fusidic acid acetoxymethyl ester (Compound 111), 24-bromo-16-deacetoxy-16β-isopropylthio-fusidic acid (compound 112), 24-bromo-16-deacetoxy-16β-isopropylsulfinyl-fusidic acid (compound 113), 24-bromo-16-deacetoxy-16β-thioacetyl-fusidic acid (compound 114), 24-bromo-17S, 20S-dihydrofusidic acid (compound 115), 24-bromo-16-deacetoxy-16β-ethoxy-fusidic acid (compound 116), 24-bromo-16-deacetoxy-16β-ethoxy-fusidic 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), 24-bromo-17S, 20S-fusidic acetoxymethyl ester (Compound 120), 24-bromo-17S, 20S-methylene-fusidic acid acetoxymethyl ester (Compound 121), 24-bromo-17S, 20S-methylene-fusidic acid (compound 122), 3-deoxy-3β, 24-dibromo-fusidic acid (compound 123), 3α-azido-24-bromo-3-deoxy-fusidic acid (Compound 124), 24-iodo-fusidic acid (compound 125), 24-iodo-fusidic acetoxymethyl ester (Compound 126), 24-iodo-fusidic pivaloyloxymethyl ester (Compound 127), 24-phenyl-fusidic pivaloyloxymethyl ester (Compound 136), 24-phenyl-fusidic acid (compound 137), 24- (4-bromophenyl) -fusidic pivaloyloxymethyl ester (Compound 138), 24- (4-bromophenyl) -fusidic acid (compound 139), 24- (4-chlorophenyl) -fusidic pivaloyloxymethyl ester (compound 140), 24- (4-chlorophenyl) -fusidic acid (compound 141), 24- (3,5-difluorophenyl) -fusidic pivaloyloxymethyl ester (Compound 142), 24- (3,5-difluorophenyl) -fusidic acid (compound 143), 3-deoxy-3β, 24-dibromo-fusidic acid acetoxymethyl ester (Compound 144), 24-bromo-16-deacetoxy-16β-ethylthio-fusidic acid (compound 146), 24-bromo-16-deacetoxy-16β-ethylsulfinyl-fusidic acid (Compound 147), 24-bromo-16-deacetoxy-16β-allylthio-fusidic acid (compound 148), 24-bromo-16-deacetoxy-16β- (1-pentylthio) -fusidic acid (compound 149), 24-bromo-16-deacetoxy-16β- (l-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-cyclopentylthio-fusidic acid (compound 155), 24-bromo-16-deacetoxy-16β- (2,2,2-trifluoroethylthio) -fusidic acid (compound 156), 24-bromo-16-deacetoxy-16β- (2-hydroxyethylthio) -fusidic acid (compound 157), 24-bromo-16-deacetoxy-16β-benzylthio-fusidic acid (compound 158), 24-bromo-16-deacetoxy-16β-benzylsulfinyl-fusidic acid (compound 159), 24-bromo-16-deacetoxy-16β- (2-furylmethylthio) -fusidic acid (compound 160), 24-bromo-16-deacetoxy-16β-phenylthio-fusidic acid (compound 161), 24-bromo-16-deacetoxy-16β-benzoylthio-fusidic acid (compound 162), 24-bromo-16-deacetoxy-16β-isopropoxy-fusidic 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), 24-bromofusidic acid, L-arginine salt (Compound 189), 24-bromofusidic acid, 2- (dimethylamino) -ethanol salt (compound 190), 24-bromofusidic acid, 4- (2-hydroxyethyl) -morpholine salt (Compound 191), 24-bromofusidic acid, L-lysine salt (Compound 192), 24-bromofusidic acid, N- (2-hydroxyethyl) -pyrrolidine salt (Compound 193), 24-bromofusidic acid, ethanolamine salt (Compound 194), 24-bromofusidic acid, potassium salt (Compound 195), 24-bromofusidic acid, tetrabutylammonium salt (Compound 196), 24-bromofusidic acid, benzyltrimethylammonium salt (Compound 197), 24-bromofusidic acid, cetyltrimethylammonium salt (Compound 198), 24-bromofusidic acid, tetramethylammonium salt (Compound 199), 24-bromofusidic acid, tetrapropylammonium salt (Compound 300), 24-bromofusidic acid, tris (hydroxymethyl) aminomethane salt (Compound 301), 24-bromofusidic acid, N-methyl-D-glucamine salt (Compound 302), 24-bromofusidic acid, silver salt (Compound 303), 24-bromofusidic acid, benzethonium salt (compound 304), 24-bromofusidic acid, triethanolamine salt (Compound 305), 24- (trans-1-hexen-1-yl) -fusidic pivaloyloxymethyl ester (Compound 306), 24- (trans-1-butene-3,3-dimethyl-1-yl) -fusidic pivaloyloxymethyl ester (Compound 307), 24- (trans-1-nonen-1-yl) -fusidic pivaloyloxymethyl ester (Compound 308), 24- (trans-5-chloro-1-penten-1-yl) -fusidic pivaloyloxymethyl ester (Compound 309), 24- (trans-2-phenyl-1-vinyl) -fusidic pivaloyloxymethyl ester (compound 310), 24- (2-phenyl-1-ethyl) -fusidic pivaloyloxymethyl ester (compound 311), 24- (4-n-propylphenyl) -fusidic pivaloyloxymethyl ester (Compound 312), 24- (4-vinylphenyl) -fusidic pivaloyloxymethyl ester (compound 313), 24- (4-tert-butylphenyl) -fusidic pivaloyloxymethyl ester (Compound 314), 24- (4-cyanophenyl) -fusidic pivaloyloxymethyl ester (Compound 315), 24- (3-biphenyl) -fusidic pivaloyloxymethyl ester (Compound 316), 24- (4- (trifluoromethyl) phenyl) -fusidic pivaloyloxymethyl ester (Compound 317), 24- (4-methoxyphenyl) -fusidic pivaloyloxymethyl ester (Compound 318), 24- (3-cyanophenyl) -fusidic pivaloyloxymethyl ester (Compound 319), 24- (2-methoxyphenyl) -fusidic pivaloyloxymethyl ester (compound 320), 24- (3-nitrophenyl) -fusidic pivaloyloxymethyl ester (Compound 321), 24- (3-bromophenyl) -fusidic pivaloyloxymethyl ester (Compound 322), 24- (4- (methylthio) phenyl) -fusidic pivaloyloxymethyl ester (Compound 323), 24- (2-naphthyl) -fusidic pivaloyloxymethyl ester (Compound 324), 24- (3,5-bis- (trifluoromethyl) phenyl) -fusidic pivaloyloxymethyl ester (Compound 325), 24- (3,4-dimethoxyphenyl) -fusidic pivaloyloxymethyl ester (Compound 326) and A compound selected from the group consisting of 24- (3,5-dibromophenyl) -fusidic pivaloyloxymethyl ester (Compound 327). 20. A compound according to any one of claims 1 to 19 for use in therapy. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 together with a pharmaceutically acceptable excipient or adjuvant. The pharmaceutical composition of claim 21, further comprising another therapeutically active compound selected from the group consisting of antibiotics and corticosteroids. 23. The method of claim 22, wherein the other therapeutically active compounds are penicillin (phenoxymethyl penicillin, benzyl penicillin, dicloxacillin, ampicillin, amoxicillin, pibampicillin, flucloxacillin, piperacillin and mecelinin), three Palosporin (cephalexin, cephalotin, cefepime, cefotaxime, ceftazidime, ceftriazone and cepuroxime), monobactam (aztreonam) and carbapenem (meropenenen), macrolide (aziromycin) , Clarithromycin, erythromycin and oxytromycin), polymycin (colistin), tetracycline (tetracycline, doxycycline, oxytetracycline and limecycline), aminoglycosides (streptomycin, gentamicin, tobramycin and Netylmycin), fluoroquinolones (norproxacin, opfloxacin, ciprofloxacin and moxifloxacin), clindamycin, lincomycin, teicoplanin, vancomycin, Four Jolly money (linezolid), rifamycin, metronidazole, fumaric acid seed, hydrocortisone, betamethasone 17-valerate and triamcinolone pharmaceutical composition is selected from a group made eojin acetonide. 20. An infection in a patient comprising administering an effective amount of a compound according to any one of claims 1 to 19 to the infected patient, and optionally further comprising simultaneously or sequentially administering one or more other therapeutically active compounds. How to treat, prevent or alleviate. The method of claim 24, wherein the other therapeutically active compound is selected from the group consisting of antibiotics and corticosteroids. 25. The method of claim 24, wherein the other therapeutically active compounds are penicillin (phenoxymethyl penicillin, benzyl penicillin, dicloxacillin, ampicillin, amoxicillin, pibampicillin, flucloxacillin, piperacillin and mecelinin), three Palosporin (cephalexin, cephalotin, cefepime, cefotaxime, ceftazidime, ceftriazone and cepuroxime), monobactam (aztreonam) and carbapenem (meropenenen), macrolide (aziromycin) , Clarithromycin, erythromycin and oxytromycin), polymycin (colistin), tetracycline (tetracycline, doxycycline, oxytetracycline and limecycline), aminoglycosides (streptomycin, gentamicin, tobramycin and Netylmycin), fluoroquinolones (norproxacin, opfloxacin, ciprofloxacin and moxifloxacin), clindamycin, lincomycin, teicoplanin, vancomycin, Four Jolly money (linezolid), rifamycin, metronidazole, fumaric acid seed, hydrocortisone, betamethasone 17-valerate and triamcinolone is selected from the group consisting of acetonide. 27. The method of any one of claims 24 to 26 wherein the infection is a bacterial infection. Use of a compound according to any one of claims 1 to 19 for the manufacture of a medicament for the treatment, alleviation or prevention of an infection. The use of claim 28, wherein the medicament further comprises the other therapeutically active compound in the same or separate container suitable for simultaneous or continuous administration of the therapeutically active compound. 30. The method of claim 29, wherein the other therapeutically active compounds are penicillin (phenoxymethyl penicillin, benzyl penicillin, dicloxacillin, ampicillin, amoxicillin, pibampicillin, flucloxacillin, piperacillin and mecelinin), three Palosporin (cephalexin, cephalotin, cefepime, cefotaxime, ceftazidime, ceftriazone and cepuroxime), monobactam (aztreonam) and carbapenem (meropenenen), macrolide (aziromycin) , Clarithromycin, erythromycin and oxytromycin), polymycin (colistin), tetracycline (tetracycline, doxycycline, oxytetracycline and limecycline), aminoglycosides (streptomycin, gentamicin, tobramycin) And netylmycin), fluoroquinolones (norproxacin, opfloxacin, ciprofloxacin and moxifloxacin), clindamycin, lincomycin, teicoplanin, vancomycin, Purpose is selected from the four Jolly money (linezolid), rifamycin, metronidazole, fumaric acid seed, hydrocortisone, betamethasone 17-valerate, and the group consisting of triamcinolone acetonide. 31. The use of any of claims 28-30, wherein the infection is a bacterial infection. Use of a compound according to any one of claims 1 to 19 for inhibiting microbial growth. Use of a compound according to any one of claims 1 to 19 for preventing or preventing bacterial infections during animal breeding. Dissolving the fusidic acid or a suitable fusidic acid analog in a suitable organic solvent and then treating with bromine to obtain a 24,25-dibromo intermediate of formula (Ib), (B) treating a solution of 24,25-dibromo intermediate in a suitable solvent in the presence of a suitable base to obtain the dehydrobrominated compound of formula (Ia) in salt form, and Acidifying the salt produced in step (b) to obtain a compound of formula (Ia) in free acid form. Formula Ia

In Formula Ia above, X is bromo, Y and Z are both hydrogen, or form a double bond between C-17 and C-20 with a C-17 / C-20 bond, or methylene together, or a cyclopropane ring with C-17 and C-20 Form the A is a bond, 0, S or S (O), B is C _1-6 alkyl, C _2-6 alkenyl, C _1-6 acyl, C _3-7 cycloalkylcarbonyl or benzoyl, all of which are halogen, hydroxy, C _1-6 alkoxy, aryl, Optionally substituted with one or more substituents selected from the group consisting of heterocyclyl and azido, or when A is a bond, B may also be hydrogen, Q ₁ and Q ₂ are independently -C (0)-,-(CHOH)-,-(CHSH)-or-(CHW)-, where W is halogen, cyano, azido or trifluoromethyl )to be. Formula Ib

In Formula Ib above, X and X 'are bromo, R is hydrogen, The bond between C-24 and C-25 is a single bond, Y, Z, A, B, Q ₁ and Q ₂ are as defined above. Compound of formula (lb). Formula Ib

In Formula Ib above, 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 form a double bond between C-17 and C-20 with a C-17 / C-20 bond, or methylene together, or a cyclopropane ring with C-17 and C-20 Form the A is a bond, 0, S or S (O), B is C _1-6 alkyl, C _2-6 alkenyl, C _1-6 acyl, C _3-7 cycloalkylcarbonyl or benzoyl, all of which are halogen, hydroxy, C _1-6 alkoxy, aryl, Optionally substituted with one or more substituents selected from the group consisting of heterocyclyl and azido, or when A is a bond, B may also be hydrogen, Q ₁ and Q ₂ are independently -C (0)-,-(CHOH)-,-(CHSH)-or-(CHW)-, where W is halogen, cyano, azido or trifluoromethyl )to be.