Novel fusidic acid derivatives

FIELD: chemistry.

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

EFFECT: application in therapy.

31 cl, 127 ex, 5 tbl

 

The technical field to which the invention relates

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

The level of technology

Fozilova acid refers to posidonas, which constitute a small family of natural antibiotics.

Fusetani unites the presence of the tetracycline ring system with a unique conformation type "chair-boat-chair", which distinguishes them from steroids. In this regard, despite some structural similarities with steroids, namely the presence of the tetracyclic system, fusetani not demonstrate any hormonal activity. In addition, fusetani have the same side chain containing a carboxylic acid that is attached to the ring system in position C-17 due to the double bond, and an acetate group attached at position C-16. Fozilova acid as a fermentation productFusidium coccineumis the most powerful antibiotic among musicanova compounds and is the only Fusiderm that has found clinical application in the treatment of infectious diseases. Fozilova acid (Fucidin® (Fucidin®)is used in clinical practice in the treatment of severe article is filatochev infections, in particular, infections of bones and joints as in case of acute and intractable form of the disease (The Use of Antibiotics, 5thEd., A. Kucers and N. Mck. Bennett (Eds.), Butterworth 1997, p. 580-587; and is contained in the link operation). Although fozilova acid is a commonly used drug against staphylococci, it is also used as a means of dealing with some other gram-positive microorganisms. The clinical significance of fusidic acid is also determined by its effective distribution in various tissues, low toxicity and allergic reactions, and lack of cross-resistance to other clinically used antibiotics. Fozilova acid is widely used in local therapy of various skin and eye infections caused by Staphylococcus. Basically, it is used in combination with conventional antibiotics, such as penicillins, eritromicina or clindamycin. It is also used as an alternative to vancomycin for control Clostridium difficile.

In comparison with staphylococci and some other gram-positive cocci are often less sensitive to fusidic acid. For example, it can be noted that different types of streptococcal up to 100 times less sensitive to fusidic acid than staphylococci [Kuchers et al.,supraPeptococcusandPeptostreptococcus spp,aerobic or anaerobic gram-positive bacteria, such asCorynebacterium diphtheriae, Clostridium tetani, Clostridium difficileandClostridium perfringens. Gram-negative bacteria are characterized by their resistance, exceptNeisseria spp.andLegionella pneumophila. This medicine is especially effective against intracellular and extracellularM.leprae.The relationship of the structure-activity (SAR) to fusidic acid was widely studied and received many analogies. However, only a few of these analogues have activity comparable with the activity of fusidic acid. Despite intensive and extensive SAR studies, the possible modifications of the side chain was studied not so widely.

In comparison with other antibiotics, the use of fusidic acid does not lead to the development of serious clinical problems associated with drug resistance [Turnidge,Int. J. Antimicro. Agents, 12, S35-S44, 1999]. However, as mentioned above, the substance itself has a fairly limited spectrum antibiotic activity, and, in this regard, it would be desirable to develop new analogs of fusidic acid, which would possess antibiotic activity on the wearing of a broader spectrum of pathogens and, in particular, Streptococcus spp.

There have been previous attempts to improve therapeutic properties of fusidin due to changes in the structure of the side chain. So, in document WO 02/070537 describes derivatives of fusidic acid in which the double bond C17-C20 was transformed into tsiklopropanovy fragment by introduction of a methylene group.

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

A brief description of the invention

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

where X denotes halogen, trifluoromethyl, cyano, azido, alkyl, alkenyl or aryl, where these alkyl, alkenyl or aryl optionally substituted by one or more, same or different, substituents selected from the group consisting of alkyl, alkenyl, aryl, alkoxy, nitro, alkylthio, halogen, azido, trifloromethyl and cyano;

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

And denotes a bond, O, S, or S(O);

B represents C1-6alkyl, C2-6alkenyl, C1-6acyl, C3-7cycloalkylcarbonyl or benzoyl, where all these groups are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, aryl, heteroaryl, azido, or, if a denotes a bond, can also denote hydrogen;

Q1and Q2independently represent-CH2-, -C(O)-, -(CHOH)-,

-(CHOR)-, -(CHSH)-, -(NH)-, -(CHNH2)- or -(CHW)-, where R is a C1-6alkyl, and W represents halogen, cyano, azido or trifluoromethyl;

Q3denotes-CH2-, -C(O)- or-CHOH-;

G denotes hydrogen, OH, or O-CO-CH3;

two communication Pyh ring, shown in solid and broken lines indicate that any of these two links can be a double bond, and in this case, Y is absent, and Z denotes hydrogen;

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

and to pharmaceutically acceptable salts and easily hydrolyzable esters of these compounds.

In another aspect, the present invention relates to compounds of General formula I used in therapy, and, particularly, to pharmaceutical compositions comprising a compound of formula I together with pharmaceutically acceptable excipients or n what Cetelem.

In another aspect, the present invention relates to a method of treating, preventing or reducing infection, where the method includes introducing an effective amount of compounds of formula I to a patient in need of such administration.

In another aspect the present invention relates to the use of compounds of formula I for the production of drugs to prevent, treat, mitigate or prevent infections.

In another aspect the present invention relates to the use of compounds of formula I for the regulation of microbial growth and to prevent or prevention of bacterial infections in animal breeding.

In another aspect the present invention relates to a method for obtaining compounds of formula Ia

where X denotes bromine, Y, and Z both represent hydrogen or together with the linking C-17/C-20 form a double bond between C-17 and C-20 or together represent a methylene to form cyclopropane ring in combination with the C-17 and C-20; And denotes a bond, O, S, or S(O); B represents C1-6alkyl, C2-6alkenyl, C1-6acyl, C3-7cycloalkylcarbonyl or benzoyl, where all these groups may be optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C1-6alkoxy, aryl, who heterocyclyl or azido, or, if a denotes a bond, can also denote hydrogen; Q1and Q2independently represent-C(O)-, -(CHOH)-, -(CHSH)- or -(CHW)-, where W denotes halogen, cyano, azido and trifluoromethyl, including:

(a) the dissolution of fusidic acid or a suitable analog of fusidic acid in an appropriate organic solvent, followed by treatment with bromine to obtain 24,25-dibromo intermediate compounds of General structure Ib:

where X and X' denote bromine, R is hydrogen, the bond between C-24 and C-25 is a single bond and Y, Z, A, B, Q1and Q2defined above;

(b) treatment of a solution of 24.25-dibromo intermediate compounds in a suitable solvent in the presence of a suitable base to obtain dehydrobrominated the compounds of formula Ia in the form of a salt and

(C) contacting the salt formed in stage (b)with an acid to obtain the compounds of formula Ia in the form of the free acid.

In another aspect the present invention relates to the compound of General structure Ib:

where X and X' denote bromine, R is hydrogen, the bond between C-24 and C-25 is a single bond, Y and Z both represent hydrogen or together with the linking C-17/C-20 form a double bond between C-17 and C-20 or together represent a methylene and the will is formed cyclopropane ring in combination with the C-17 and C-20; And denotes a bond, O, S, or S(O); B represents C1-6alkyl, C2-6alkenyl, C1-6acyl, C3-7cycloalkylcarbonyl or benzoyl, where all these groups are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C1-6alkoxy, aryl, heterocyclyl, azido, or, if a denotes a bond, can also denote hydrogen; Q1and Q2independently represent-C(O)-, -(CHOH)-, -(CHSH)- or -(CHW)-, where W denotes halogen, cyano, azido or trifluoromethyl.

Detailed description of the invention

Definitions

In the context of the present description, the term "alkyl" denotes a monovalent radical derived from an alkane when removing a hydrogen atom from any carbon atom, and includes the subclasses of primary, secondary and tertiary alkyl groups, including, for example, With1-C12alkyl, such as C1-With8alkyl, such as1-C6alkyl, such as1-C4alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, nonyl, dodecanol, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclohexyl. Alkane refers to acyclic or cyclic, branched or unbranched saturated hydrocarbon and, in this connection, consists entirely of hydrogen atoms and carbon atoms

The term "alkenyl" in the context of the present description denotes a linear or branched acyclic hydrocarbon containing one or more double carbon-carbon bonds in stereochemistry E or Z, that is acceptable. This term includes, for example, With2-C12alkenyl,2-C8alkenyl,2-C6alkenyl, vinyl, allyl, 1-butenyl, 2-butenyl and 2-methyl-2-propenyl.

The term "acyl" in the context of the present description refers to a radical of the formula-CO-R, where R is alkyl, as defined above, for example, With1-C6acyl, such as acyl, propionyl, butyryl or pivaloyl.

The term "alkoxy" in the context of the present description refers to a radical of the formula-O-R, where R is alkyl, as defined above, for example, With1-C5alkoxy, C1-C3alkoxy, methoxy, n-propoxy, tert-butoxy etc.

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

The term "cycloalkylcarbonyl" in the context of the present description refers to a radical of the formula-C(O)-R', where R' denotes a cyclic radical, as defined above.

The term "aryl" in the context of the present description denotes a cyclic radical, optionally condensed bicyclic radical, in which all ring atoms are carbon and in to the m ring is aromatic, or in the case of a condensed ring system at least one ring is aromatic. Examples of aryl include phenyl, naphthyl and tetralinyl.

The term "alkylthio" in the context of the present description refers to a radical of the formula-S-R', where R' denotes an alkyl, as defined above.

The term "heteroaryl" in the context of the present description includes radicals, which represents a heterocyclic aromatic ring which includes 1 to 6 heteroatoms (selected from O, S and N) and 1-20 carbon atoms, such as rings, including 1-5 heteroatoms and 1-10 carbon atoms, such as rings, including 1-5 heteroatoms and 1-6 carbon atoms, such as rings, including 1-5 heteroatoms and 1 to 3 carbon atoms, in particular 5 - or 6-membered rings with 1-4 heteroatoms, selected from O, S and N, or optionally condensed bicyclic rings with 1-4 heteroatoms, where at least one ring is aromatic, for example, furanyl, pyridyl, hinely, ethanolic, indolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thienyl, pyrazinyl, isothiazolin, benzimidazolyl and benzofuranyl.

The expression "easily hydrolyzable esters" in the context of the present description denotes alkanolamine, arachnological, urologically, for example, acetoxymethyl, pivaloyloxymethyl, b is solarenergie esters and the corresponding 1'-oxyethyl derivatives, or alkoxycarbonylmethyl esters, for example, methoxycarbonylmethylene esters and ethoxycarbonylmethylene esters and the corresponding 1'-oxyethyl derivatives, or lastonline esters, for example, phthalidyl esters or dialkylaminoalkyl esters, for example, diethylaminoethyl esters. The expression "easily hydrolyzable esters" includes hydrolyzablein vivoesters of the compounds of the present invention. Such esters can be obtained using methods known to experts in this field, see patent GB No. 1 490 852, included in the description by reference.

Preferred variants of the compounds of formula I

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

where X denotes a halogen, trifluoromethyl, cyano, azido, C1-7alkyl, C2-9alkenyl or aryl, where these C1-6alkyl, C2-9alkenyl or aryl optionally substituted by one or more identical or different substituents selected from the group consisting of C1-7of alkyl, C2-9alkenyl, aryl, C1-6alkoxy, nitro, alkylthio, halogen, azido, trifloromethyl or cyano;

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

And denotes a bond, O, S, or S(O);

B represents C1-6alkyl, C2-6alkenyl, C1-6acyl, C3-7cycloalkylcarbonyl or benzoyl, where all these groups are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C1-6alkoxy, aryl, heteroaryl or azido, or, if a denotes a bond, can also denote hydrogen;

Q1and Q2independently represent-C(O)-, -(CHOH)-, -(CHSH)- or -(CHW)-, where W denotes halogen, cyano, azido or trifluoromethyl;

and their pharmaceutically acceptable salts or easily hydrolyzable esters.

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

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

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

In another preferred embodiment, X represents chlorine, bromine, iodine, fluorine, methyl, ethyl, PR is drank, phenyl, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, nonanal, biphenyl or naphthyl, where these methyl, ethyl, propyl, phenyl, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, nonanal, biphenyl or naphthyl optionally substituted by one or more identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, phenyl, vinyl, cyano, methoxy, trifloromethyl, nitro, methylthio, butyl, methyl, ethyl, propyl, butyl, penttila, hexyl and heptyl.

In a particular preferred embodiment, X represents fluorine, chlorine, bromine, iodine, trifluoromethyl, phenyl, 4-bromophenyl, 4-chlorophenyl, 3,5-differenl,TRANS-1-HEXEN-1-yl,TRANS-1-butene-3,3-dimethyl-1-Il,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-vinylphenol, 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-acid or 3,5-dibromophenyl.

Q1and Q2can be successfully selected from the group consisting of -(CO)- and -(CHOH)-. Q1can also be represented as CHF, CHCl, CHBr, CHI, CHN3.

Another variant implementation of the present invention relates to compounds of formula Ia, where Q1and Q2both designation shall indicate the

-(CHOH)-group or one of Q1and Q2represents -(CO)-, or Q1denotes CHF, CHCl, CHBr, CHI, or CHN3;

X denotes chlorine, bromine, iodine, trifluoromethyl, azido or cyano;

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

And denotes O, S or S(O);

B represents C1-4alkyl group, optionally substituted by one or more substituents selected from the group consisting of azido, hydroxy, fluorine, chlorine and bromine, or represents C1-4acyl group or benzoyloxy group, where both of these groups optionally substituted by one or more halogen atoms, such as, for example, fluorine and chlorine.

Specifically, in the preferred embodiment, And denotes O or S(O).

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

In a particular preferred embodiment, In denotes acetyl, isopropyl, ethyl, 2,2,2-triptorelin, vinyl, 1-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, cyclopentyl, 2-hydroxyethyl, benzyl, furfuryl, phenyl, 2-foretel, 2-methoxyethyl, 2,2,2-trichloroethyl, 2-azidoethyl, 2-hydroxyethyl, propyl,tert-butyl, 1,3-debtor and propyl, propionyl, chloroacetyl or TRIFLUOROACETYL.

In a particular preferred embodiment, Q1or Q2or both, and Q1and Q2represent -(SON)-.

When Q1and/or Q2in formulas I, Ia or Ib denote

-(SON)-stereochemical configuration is a preferred 3α and 11α, respectively.

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

Sodium salt 24-triftormetilfosfinov acid (compound 101),

Pivaloyloxymethyl ester 24-triftormetilfosfinov acid (compound 102),

24-Chloropidae acid (compound 103),

Pivaloyloxymethyl ester 24-CHLOROSILANES acid (compound 104),

Sodium salt 24-CHLOROSILANES acid (compound 105),

24-triftormetilfosfinov acid (compound 106),

Acetoxymethyl ester 24-pomposity acid (compound 107),

24-pomposity acid (compound 108),

Sodium salt 24-pomposity acid (compound 109),

Pivaloyloxymethyl ester 24-pomposity acid (compound 110),

Acetoxymethyl ester 24-bromo-16-deacetoxy-16β-thioacetimidate acid (compound 111),

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

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

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

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

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

Acetoxymethyl ester 24-bromo-16-deacetoxy-16β-ethoxyphenol acid (compound 117),

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

24-bromo-16-deacetoxy-16β-(2',2',2'-triptoreline)fozilova acid (compound 119),

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

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

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

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

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

24-yadhunatha acid (compound 125),

Acetoxymethyl ester 24-hotfusion acid (compound 126),

Pivaloyloxymethyl ester 24-hotfusion acid (compound 127),

Pivaloyloxymethyl ester 24-vanilloideae acid (compound 136),

24-vanilloideae acid (compound 137),

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

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

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

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

Pivaloyloxymethyl ester 24-(3,5-differenl)fusidic acid (compound 142),

24-(3,5-differenl)fozilova acid (compound 143),

Acetoxymethyl ester 3-deoxy-3β,24-dibromothiophene acid (compound 144),

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

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

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

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

24-bromo-16-deacetoxy-16β-(1-pentasulfide)fozilova acid (compound 150),

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

24-bromo-16-deacetoxy-16β-(2-methyl-1-butylsulfonyl)fozilova acid (compound 152),

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

24-bromo-16-deacetoxy-16β-(3-methyl-1-butylsulfonyl)fozilova acid (compound 154),

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

24-bromo-16-deacetoxy-16β-(2,2,2-twitteratti)fozilova acid (compound 156),

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

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

24-bromo-16-deacetoxy-16 is-benzilgalogenidov acid (compound 159),

24-bromo-16-deacetoxy-16β-(2-fullerto)fozilova acid (compound 160),

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

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

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

24-bromo-16-deacetoxy-16β-(2-floratone)fozilova acid (compound 164),

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

24-(TRANS-1-HEXEN-1-yl)fozilova acid (compound 166),

24-(TRANS-1-butene-3,3-dimethyl-1-yl)fozilova acid (compound 167),

24-(TRANS-1 nonen-1-yl)fozilova acid (compound 168),

24-(TRANS-5-chloro-1-penten-1-yl)fozilova acid (compound 169),

24-(TRANS-2-phenyl-1-vinyl)fozilova acid (compound 170),

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

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

24-(4-vinylphenol)fozilova acid (compound 173),

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

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

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

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

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

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

24-(2-methoxyphenyl)fozilova acid (Obedinenie 180),

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

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

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

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

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

24-(3,4-acid)fozilova acid (compound 186),

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

Kalinova Sol 24-pomposity acid (compound 188),

L-arginine salt 24-pomposity acid (compound 189),

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

4-(2-hydroxyethyl)Martinova Sol 24-pomposity acid (compound 191),

L-lysine salt 24-pomposity acid (compound 192),

N-(2-hydroxyethyl)pyrolidine Sol 24-pomposity acid (compound 193),

Ethanolamine Sol 24-pomposity acid (compound 194),

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

Tetrabutylammonium Sol 24-pomposity acid (compound 196),

Benzyltrimethylammonium Sol 24-pomposity acid (compound 197),

Cetyltrimethylammonium Sol 24-pomposity acid (compound 198),

Tetramethylammonium Sol 24-pomposity acid (compound 199),

Tetrapropylammonium Sol 24-pomposity acid (compound 300),

Tr is C(hydroxymethyl)aminobutanova Sol 24-pomposity acid (compound 301),

N-methyl-D-glucagonoma Sol 24-pomposity acid (compound 302),

Silver Sol 24-pomposity acid (compound 303),

Bentonia Sol 24-pomposity acid (compound 304),

Triethanolamine Sol 24-pomposity acid (compound 305),

Pivaloyloxymethyl ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (compound 306),

Pivaloyloxymethyl ester 24-(TRANS-1-butene-3,3-dimethyl-1-yl)fusidic acid (compound 307),

Pivaloyloxymethyl ester 24-(TRANS-1 nonen-1-yl)fusidic acid (compound 308),

Pivaloyloxymethyl ester 24-(TRANS-5-chloro-1-penten-1-yl)fusidic acid (compound 309),

Pivaloyloxymethyl ester 24-(TRANS-2-phenyl-1-vinyl)fusidic acid (compound 310),

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

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

Pivaloyloxymethyl ester 24-(4-vinylphenol)fusidic acid (compound 313),

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

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

Pivaloyloxymethyl ester 24-(3-biphenyl)fusidic acid (Obedinenie 316),

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

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

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

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

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

Pivaloyloxymethyl ester 24-(3-bromophenyl)fusidic acid (compound 322),

Pivaloyloxymethyl ester 24-(4-(methylthio)phenyl)fusidic acid (compound 323),

Pivaloyloxymethyl ester 24-(2-naphthyl)fusidic acid (compound 324),

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

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

Pivaloyloxymethyl ester 24-(3,5-dibromophenyl)fusidic acid (compound 327).

Compounds of the present invention can be used as such 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 salts of alkaline m is the metal and salts of alkaline earth metals, for example, salts of sodium, potassium, magnesium or calcium, and salt and silver salt obtained using bases such as ammonium salts or salts of suitable non-toxic amines, such as lower alkylamines followed, for example, triethylamine, hydroxy-lower alkylamines followed, for example, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, cycloalkylation, for example, dicyclohexylamine, or benzylamines, for example, N,N'-dibenziletilendiaminom and dibenzylamine. Of silver salts of the present invention can be particularly useful for use in the local treatment.

In a preferred embodiment, pharmaceutically acceptable salts of the compounds of General formula I or Ia are selected from the group consisting of sodium salts, Kalinovich salts, L-arginine salts, 2-(dimethylamino)ethanol salt of 4-(2-hydroxyethyl)Martinovich salt, L-lysine salt of N-(2-hydroxyethyl)pyrrolidinium salts, ethanolamine salts, potassium salts, tetrabutylammonium salts, benzyltrimethylammonium salts, cetyltrimethylammonium salts, Tetramethylammonium salts, tetrapropylammonium salts, Tris(hydroxymethyl)aminomethane salts, N-methyl-D-glucamine salts, salts silver, benzethonium salts and triethanolamine salts.

In a preferred embodiment, obtaining the compounds of formula Ia, the solvent used in stage (a) for dissolution fusedav the acid, represents acetic acid or With1-3alkilany ester With1-4carboxylic acid and is, in particular, ethyl acetate.

In a preferred embodiment, obtaining the compounds of formula Ia, the solvent used in stage (b) for dissolution of 24.25-dibromo intermediate compounds, represents a C1-6alcohol, such as methanol, ethanol, n-propanol, isopropanol or butanol, or water, or a mixture of these solvents.

In a preferred embodiment, obtaining the compounds of formula Ia base used in stage (b) for dehydrobrominated 24,25-dibromo intermediate compound is a salt of an alkali metal or seachnasaigh metal and a weak acid, such as carboxylic, phosphoric or boric acid, for example, potassium carbonate or sodium, or bases, such as ammonia or1-8substituted ammonia, for example, ethylamine, diethylamine, triethylamine or piperidine, or hydroxide of alkali or alkaline earth metal, such as dilute sodium hydroxide, calcium hydroxide or dilute potassium hydroxide.

Compounds of the present invention may include chiral(s) atom(s) of carbon and double(s) carbon-carbon(s) relationship(s)that define the appearance of stereoisomeric forms. The present invention relates to the SEM such isomers both in pure form, and mixtures thereof. Pure stereoisomeric forms of the compounds of the present invention can be obtained using known in the field of methods. The diastereomers can be separated using physical methods of separation, such as selective crystallization and chromatography, for example, liquid chromatography using chiral stationary phases. These pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric forms of the appropriate starting materials, provided that the reaction is carried out stereoselective or stereospecific. Preferably, if desired specific stereoisomer of the compounds to the synthesis was carried out using stereoselective or stereospecific methods of receipt.

Compounds of the present invention are useful to treat, prevent or ameliorate infections in patients, including mammals and in particular humans. More specifically, the animals in respect of which can be treated using compounds of the present invention, include domestic animals such as horses, cows, pigs, sheep, poultry, fish, cats, dogs and zoo animals. Compounds of the present invention can be particularly useful when cured and bacterial infections, such as skin infections or secondary skin infections or eye infections. In addition, the compounds of the present invention can be used in the treatment of simple abscesses, impetigo, boils, or cellulite. Compounds of the present invention, in particular, can be used in the treatment of, for example, in the local treatment contagious superficial skin infections such as nebulize impetigo (or contagious impetigo) or bullous impetigo. In this regard, the present invention relates to a method for treatment, prevention or attenuation of bacterial infections, where the method comprises the administration to the patient an effective amount of the compounds of formula I, optionally together with another therapeutically active compound. Examples of such other therapeutically active compounds include antibiotics, such as β-lactams, such as penicillins (phenoxymethylpenicillin penicillin, dicloxacillin, ampicillin, amoxicillin, pivampicillin, Flucloxacillin, piperacillin and mecillinam), cephalosporins (cephalexin, cephalothin, cefepime, Cefotaxime, ceftazidime, Ceftriazone and cefuroxime), carbapenems (aztreonam) and carbapenems (Meropenem); macrolides (azithromycin, clarithromycin, erythromycin and roxithromycin); polymyxins (colistin); tetracyclines (tetracycline, doxycycline, oxytetracycline and imacillin); aminoglycosides (streptomycin, gentamicin, tobramycin and netilmicin); fluoroquinolone (norfloxacin, ofloxacin, ciprofloxacin and moxifloxacin); clindamycin, lincomycin, teicoplanin, vancomycin, oxazolidone (linezolid), rifamycin, metronidazole and fozilova acid. Other compounds that can be successfully combined with the compound of the present invention, particularly for topical application include, for example, corticosteroids, such as hydrocortisone, betamethasone-17-valerate and triamcinolone acetonide. The compounds can be administered either simultaneously or in sequential mode.

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

For therapeutic use the compounds of the present invention take the form of pharmaceutical compositions. In this regard, the present invention relates to pharmaceutical compositions comprising the compounds of formula I or Ia, optionally in combination with other pharmaceutically active compounds together with pharmaceutically acceptable excipients or nose is Telem. Excipient must be "acceptable" in the sense that it must be combined with the other ingredients of the composition and must not have a harmful influence on the recipient.

Usually the active ingredient comprises from 0.05 to 99.9 wt.% the weight of the entire composition.

Standard dosage forms, the compound may be administered once or several times a day at appropriate intervals, and always depending on the condition of the patient, in accordance with the prescriptions of the doctor. Usually the standard dosage unit composition contains from 50 mg to 5000 mg, preferably from 200 mg to 1000 mg of the compounds of formula I or Ia.

In the context of the use in the local treatment is more suitable expression "common unit", which denotes a single dose, which you can enter the patient, which is easy to manipulate and which after packaging is maintained in the form of a physically and chemically stable standard dose, including the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers.

The term "common unit" in the context of local application refers to a unit, i.e. a single dose which you can enter in local mode the patient by drawing on a square centimeter of the surface of the affected from 0.1 mg to 10 mg, and preferably from 0.2 is g to 1 mg considered an active ingredient.

It is also envisaged that in some modes of treatment is best done introduction with longer intervals, such as every other day, every week or even longer intervals.

If the treatment involves the introduction of another therapeutically active compounds, it is recommended to check with the recommendations in the manual Goodman and Gilman (Goodman & Gilman''s The Pharmacological Basis of Therapeutics, 9thEd., J.G. Hardman and Limbird LE (Eds.), McGraw-Hill 1995), which are used doses of these compounds.

Consider compositions include, in particular, to such compositions which have a form acceptable for oral administration (including prolonged or delayed release), rectal administration, parenteral administration (including subcutaneous, intraperitoneal, intramuscular, intra-articular and intravenous), transdermal, ophthalmic, local, or nasal transbukkalno introduction.

In a convenient embodiment, the composition may be presented in a unit dosage form and may be fabricated using any known pharmaceutical methods, such as, for example, which is described in the manual Remington (Remington,The Science and Practice of Pharmacy, 20thed., 2000). All such methods include the stage of bringing into contact of the active ingredient with the carrier which is the Wallpaper one or more accessory ingredients. In General, the compositions obtained by the implementation of a uniform and thorough contact of the active ingredient with a liquid carrier or a finely ground solid carrier, or both of them and then, if necessary, by giving the product to form the desired composition.

The compositions of the present invention suitable for oral administration may be in the form of discrete units such as capsules, sachets, tablets or lozenges, each of which contains a defined amount of the active ingredient may also be in the form of powder or granules, a solution or suspension in an aqueous liquid or non-aqueous liquid, such as ethanol or glycerol; or can be in the form of an emulsion of the type oil-in-water or emulsion of the type water-in-oil". Such oils can be an edible oil, such as cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing means or a means of facilitating suspendirovanie, when used in aqueous suspensions include synthetic and natural gums, such as tragakant, alginate, Arabic gum, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, hypromellose, hydroxypropylcellulose, carbomer and polyvinylpyrrolidone. The active ingredients may also be entered in VI is E. boles, electuary or paste.

Tablets can be manufactured by molding or forming of the active ingredient optionally in the presence of one or more accessory ingredients. Tablets can be obtained by pressing the corresponding device, where the active(s) ingredient(s) is(are) in free-flowing form such as powder or granules, optionally mixing with a binder, such as, for example, lactose, glucose, starch, gelatin, Arabic gum, tragakant, sodium alginate, carboxymethylcellulose, methylcellulose, hypromellose, polyethylene glycol, waxes or the like; a lubricant, such as, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, or so; with means to decomposition, such as, for example, starch, methylcellulose, agar, bentonite, sodium croscarmellose, sodium chromalveolata, crosspovidone, or the like; or a means of contributing to the dispersion, such as Polysorbate 80. Molded tablets can be obtained by molding the respective machine powder mixture of the active ingredient and a suitable carrier, moistened with an inert liquid diluent.

Compositions for rectal injection can be in the form of suppositories in which the compound present is Adamu invention is mixed with low-melting water-soluble or water-insoluble solids, such as cocoa butter, hydrogenated vegetable oil, polyethylene glycol or esters of fatty acids and glycols, and the elixirs can be obtained when using myristoleate.

Compositions suitable for parenteral administration, in a convenient embodiment, include sterile oil or aqueous preparation of the active ingredients, which is preferably isotonic to the blood of the recipient, based on, for example, isotonic saline, isotonic glucose solution or buffer solution. The composition may be appropriately sterilized, for example, by filtration through a bacterial filter, adding sterilizing agent to the composition, by irradiation or heating of the composition. Liposomal compositions, described, for example, in Encyclopedia of pharmaceutical technology (Encyclopedia of Pharmaceutical Technology, vol. 9, 1994), is also acceptable for parenteral administration.

Alternatively, the compound of the formula I can be represented in the form of sterile solid preparation, for example, lyophilized powder which is easily dissolved in sterile solvent immediately before use.

Percutaneous composition can be in the form of plaster or other small imposed by sections of the material.

Com is osili, suitable for ophthalmic administration, presented in the form of a sterile aqueous preparation of the active ingredients, which may take the form of a microcrystalline product, for example, an aqueous microcrystalline suspension. Liposomal compositions or biodegradable polymer systems described, for example, in Encyclopedia of pharmaceutical technology (Encyclopedia of Pharmaceutical Technology, vol. 2, 1989), may also be used with data of the active ingredients in the ophthalmic introduction.

Compositions suitable for local or ophthalmic administration, include liquid or semi-liquid preparations such as liniments, lotions, gels, wraps, emulsions of the type oil-in-water or water-in-oil", such as creams, ointments or pastes; or solutions or suspensions such as drops.

Compositions suitable for nasal or transbukkalno introduction, include powder, kumarapalayam and sprayable compositions, such as sprays and atomizers. Such compositions are described in enough detail in the literature (Modern Pharmaceutics, 2nded., G.S. Banker and C.T. Rhodes (Eds.), p. 427-432, Marcel Dekker, New York; Modern Pharmaceutics, 3thed., G.S. Banker and C.T. Rhodes (Eds.), p. 618-619 and 718-721, Marcel Dekker, New York and Encyclopedia of Pharmaceutical Technology, vol. 10, Swarbrick and J.C. Boylan (Eds.), p. 191-221, Marcel Dekker, New York).

In addition to the above ingredients, the compositions of the compounds according to the present image is the shadow of formula I or Ia may include one or more additional ingredients, such as diluents, buffers, flavoring agents, dyes, surfactants, thickeners, preservatives, for example, methylhydroxybenzoate (including anti-oxidants), emulsifying agents and the like,

Parenteral compositions are particularly useful for treating conditions in which the desired quick response to therapy. In the case of treatment in a continuous mode of patients suffering from infectious diseases, used tablets or capsules can be in the form of a pharmaceutical preparation, have a prolonged effect, achieved by oral administration of a medicinal product, in particular, it can be tablets with prolonged-release. In the case when the active ingredient is introduced in the form of salts of pharmaceutically acceptable non-toxic acids or bases, preferred salts are, for example, easily soluble in water or slightly soluble in water, salt, selected for the purpose of achieving a specific, corresponding to the degree of absorption.

As noted above, the composition may contain other therapeutically active components, which can be appropriately introduced in combination with the compounds of the present invention in the treatment of infectious diseases, such as other suitable antibiotics, in particular, such antibi the Tiki, which can increase the activity and/or inhibit the development of resistance. Can also be used with success corticosteroids included in the compositions of the present invention. In particular, the other active ingredient may include β-lactams, such as penicillins (phenoxymethylpenicillin penicillin, dicloxacillin, ampicillin, amoxicillin, pivampicillin, Flucloxacillin, piperacillin and mecillinam), cephalosporins (cephalexin, cephalothin, cefepime, Cefotaxime, ceftazidime, Ceftriazone and cefuroxime), carbapenems (aztreonam) and carbapenems (Meropenem); macrolides (azithromycin, clarithromycin, erythromycin and roxithromycin); polymyxins (colistin); tetracyclines (tetracycline, doxycycline, oxytetracycline and lymecycline); aminoglycosides (streptomycin, gentamicin, tobramycin and netilmicin); fluoroquinolone (norfloxacin, ofloxacin, ciprofloxacin and moxifloxacin); clindamycin, lincomycin, teicoplanin, vancomycin, oxazolidone (linezolid), rifamycin, metronidazole and fozilova acid. Other compounds that can be successfully combined with the compounds of the present invention, particularly for topical application include, for example, corticosteroids, such as hydrocortisone, betamethasone-17-valerate and triamcinolone acetonide.

Other therapeutically active link which may be in the same or in a separate container in the composition of the drug, adapted to conduct simultaneous or sequential introduction of these therapeutically active compounds.

The treatment of infectious diseases often involves the determination before the beginning of treatment whether the disease is stable or difficult this treatment. As an example, it can be noted that the patient can be taken samples containing infectious organism, such as samples of blood or urine, and then this sample is cultured and exposed to treatment for connection to determine whether this infecting organism to the proposed treatment. Accordingly, the present invention also relates to a method of identifying compounds that are effective against the microorganism, where the method includes the introduction of the compounds of formula I or Ia, optionally in combination with other pharmaceutically active agents, in the microorganism and determining, does this compound or mixture of compounds toxic or static effect on the organism.

The compositions of the present invention is not limited to pharmaceuticals, but can be used in the field is not therapeutic applications to control microbial growth. For example, compositions or compounds according to the present izaberete the Oia can be useful as additives which inhibit microbial growth that may be used, for example, in fermentation processes. As an example, it can be noted that inherent in these antimicrobial agents selectivity is useful to enhance the growth of certain microorganisms at the expense of other microorganisms in the culture, including many species of microorganisms.

Biological activity

Researchin vitrodemonstrated high efficiency of the compounds of the present invention against strains as Staphylococcus and Streptococcus, which are among the most frequent pathogenic bacteria that cause various skin and eye infections. Biological tests showed the same or in some cases a higher antibacterial activity against Staphylococcus compounds of the present invention in comparison with fusidic acid and, more importantly, significantly higher antibacterial activity against streptococci, as is evident from table 1, which shows the values of MIC of selected compounds of the formula Ia in respect and staphylococci, and streptococci.

Connections

Analogs of fusidic acid of the present invention and reference compounds 201 (fozilova acid (as sodium salt)), 207, 205, 203 and 206 (see notes to table And stored in powder form at a temperature which e +4°C. For use in these tests, they are dissolved in 95% EtOH (3,84 mg/ml) and stored for a maximum period of one month at -20°C before selection.

Bacterial strains used for biological assessment
Bacterial strainOrigin
Staphylococcus aureus FDA486Laboratory strain
Staphylococcus aureus CJ12Laboratory strain
Staphylococcus aureus 8325-4Laboratory strain
Streptococcus pyogenes DA7121Clinical isolate from an infected human skin
Streptococcus pyogenes DA7864Clinical isolate from an infected human skin

Environment

LB medium (1000 ml ddH2O: 10 g bacteriophora, 5 g yeast extract, 10 g NaCl). THB broth Todd-Hewitt (Todd-Hewitt) (SIGMA), product number: T (1000 ml ddH2O: 50g infusion from the heart of a bull, 20 g of casein peptone, 2 g dextrose, 2 g NaHCO3, 2.5 g NaCl, 0.4 g Na2HPO4). Cups are prepared with agar at a concentration of 1.5%. A Petri dish filled with blood agar contain complement the flax 5 about. % defibrination horse blood obtained from SLU (Swedish Agricultural University, Uppsala).

Determination of MIC (minimum inhibitory concentration)

The test to determine the MIC of the compounds is carried out in 96-well microtiter plates (Thermo Labsystems). Bacteria in the number C5inoculant in 0.4 ml of growth medium (S. aureus- LB broth,S. pyogenes -TH broth)containing serial dilutions of the compounds under study, ranging from 128 μg/ml (dilution factor 2, for example, 128 μg/ml to 64 μg/ml, ..., to 0.016 μg/ml). The criterion of sensitivity is the absence of visible growth after 24 hours under conditions of aerobic incubation at 37°C. Each compound is tested at least two times, and in all cases in the test include guideway acid as an experimental control.

Table a:
Antibacterial activity,
defined for selected compounds of the present invention. MICK/µg ml-1
Connection No.Staph.aureusFDA486Staph.aureus CJ12Staph.aureus 8325-4Strep.pyogenes
DA7121
Strep.pyogenes
DA7864
108
Etal. Conn. 201 (fozilova acid)
0,05
0,11
0,03
0.03
n
0,03
0,8
3,5
0,8
3,5
113
Etal. Conn. 207
0,22
0,22
0,11
0,05
n
Ni
0,4
1,6
0,4
1,6
115
Etal. Conn. 205
0,88
0,44
0,06
0,06
0,11
0,11
1,8
14
1,8
28
116
Etal. Conn. 203
0,44
0,22
0,06
0,06
0,11
0,22
7
7
7
14
122
Etal. Conn. 206
0,88
0,22
0,22
0,06
0,88
0,11
7
>32
7
28
Notes to table:
The cell concentration at time t=0 corresponds to ~106/ml Bacteria grow in broth under aerobic conditions at 37°C.
Ni = not investigated
Etal. Conn. - Etalon the e connection

The reference compounds in the table And are known derivatives of fusidic acid. Each reference compound refers to the compound of the present invention, the above in the same column. Reference compound is not substituted With-24 and have a double bond between C-24 and C-25. All other structural characteristics of the reference compounds identical to those of the compounds of the present invention, the above in the same column:

201 - Fozilova acid

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

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

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

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

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

Reduction

Below are definitions for common abbreviations used in this application:

AcOH = acetic acid

Ac2O = acetic anhydride

Ac = acetyl

aq. (aq.) = water

Bu n-butyl

tBu, tBu = tert-butyl

Comp. = connection

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

DMF (DMF = dimethylformamide

eq. (equiv.) = equivalent

Et = ethyl

Ether = diethyl ether

EtOAc = ethyl acetate

EtOH = ethanol

Ex. (approx.) = example

FA = fozilova acid or similar circular substructures A,B,C,D

FCC = column flash chromatography

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

HMPA = triamide hexamethylphosphoric acid

HPLC (HPLC)= high performance liquid chromatography

iPr = isopropyl

Me = methyl

MeOH = methanol

m.p. (TPL) = melting point

MRSA = methicillin-resistant Staphylococcus aureus

Pet.ether = petroleum ether

Ph = phenyl

Phenac = pencil

Piv = pivaloyl

Prep. (prep.) = drug

THF (THF= tetrahydrofuran

TLC (TLC) = thin-layer chromatography

rt (K.T.)= room temperature

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

TMS (TMS = trimethylsilyl)

v = volume

Obtaining the compounds of the present invention

The compounds of formula I can be synthesized from known starting materials using different methods of synthesis, depending on the needs determined by each individual compound I, such as the availability of source materials, the need for temporary protection of sensitive deputies, the net is you and exit at the stages of synthesis and selection of the preferred data sequence reaction stages.

Below is illustrative, but not limiting the methods and examples of the synthesis of various compounds of the formula I or Ia. Different synthesis methods can be combined with each other, as it deems necessary specialist in this field, to obtain the desired compounds of formula I or Ia with the desired substitution in ring A, C and D, 24 position side chain, and with regard to their form: free acids, salts or easily hydrolyzable esters.

The main method for the synthesis of 24-bromoethylene General formula I with a circular substructures A,B,C,D in FA (fozilova acid analog of fusidic acid) from the source materials 201-206 (with the same ring substructures A,B,C,D) shown in figure 1:

Examples of the ring substructures A,B,C,D fusidic acid and analogs of fusidic acidFA:

Conditions: (a) ClCH2O(CO)R', Et3N, DMF (R' = Me or C(CH3)3), K.T.; (b) Br2, CCl4, 0°C; (c) DBU, CCl4or CH3CN, K.T.; (d) DBU/aq. MeOH or K2CO3/MeOH, K.T.

Fozilova acid or the analog of fusidic acid may be tarifitsirovana, for example, chloromethylation or climaterealists, using an appropriate solvent, such as dimethylformamide, in the presence of a suitable base, such as triethylamine. Ester can then be subjected to bromirovanii using bromine in a suitable solvent, such as carbon tetrachloride or acetonitrile. The resulting dibromide (which is usually a mixture of 24-diastereoisomers) may be subjected to dehydrobrominated by treatment with an appropriate base, such as DBU, in an appropriate solvent such as carbon tetrachloride or acetonitrile, with the formation of predominantly 24-pomposity acid or ester analog of fusidic acid. If desired, the ester may be used as prodrugs of the corresponding free acid I, for example, in the case of easily hydrolyzable ester groups. Alternatively, the ester can be hydrolyzed using a suitable base, such as DBU or K2CO3, in a suitable solvent, such as water containing methanol or ethanol, to obtain the desired compounds of General structure I (where X = bromine) in the form of free acids or salts. In another embodiment, the present invention dibromide is subjected to one stage dehydrobrominated and hydrolysis to give the desired compound I in the form of the free acid or in the form of salts, for example, using methods described above. In another preferred embodiment, fusicology acid or the analog of fusidic acid is subjected to direct bromirovanii in accordance with the method of the mi, described above, to obtain the corresponding dibranchiata (which is usually a mixture of 24-diastereoisomers). Next, dibranchiata are dehydrobrominated, for example, in accordance with the methods described above, to obtain the desired compounds of General structure I (where X = bromine) in the form of free acids, and optionally in the form of salts.

Common in the present method of preparing compounds of formula Ia, where Q1, Q2, A and b above, Y and Z together with the linking C-17/C-20 form a double bond between C-17 and C-20, or together represent a methylene or both represent hydrogen, and X denotes bromine, illustrated in scheme 1a corresponding reaction (where FA denotes the ring substructures A,B,C,D-fusidic acid or analog of fusidic acid as shown in scheme 1):

Guideway acid or the analog of fusidic acid is dissolved in a suitable solvent, such as acetic acid or With1-4alcovy ester With1-4carboxylic acids, such as ethyl acetate, isopropylacetate, tert-butyl acetate, and treated with bromine, preferably dissolved in the same solvent, at a temperature of -10°C-20°C, preferably at a temperature of 0°C.-10°C., such as 5°C, with the receipt of 24.25-dibromononane intermediate compounds. 24,25-dibromononane intermediate the connection can be allocated, optional, after adding water base and/or a reducing agent such as Na2SO3and carry out the separation of the phases by evaporation of the organic solvent. Then 24,25-dibromononane intermediate connection (optional without implementation stages of the selection or purification) are dehydrobrominated with obtaining the compounds of formula Ia in the interaction of a solution of 24.25-dibromononane intermediate compounds in a suitable solvent, such as1-6alcohol, for example methanol, ethanol, 1-propanol, isopropanol or butanol, or water, or a mixture of these solvents, with a suitable base, for example, at the boiling point under reflux, or, for example, at a temperature from 50°C to 120°C, such as in the range 60°C-90°C, such as in the range of 70°C-80°C, obtaining dehydrobrominated the compounds of formula Ia in the form of a salt. The basis used to obtain dehydrobrominated compounds of formula Ia, can be appropriately selected from salts of alkali metal or alkaline earth metal on the basis of weak acids such as carbonic, phosphoric or boric acid, for example, it may be a carbonate of potassium or sodium, or may be selected from bases such as ammonia or1-8substituted ammonia, for example, ethylamine, diethylamine, triethylamine or Pieper the Dean, or hydroxides of alkali metal or alkaline earth metal, such as sodium hydroxide, calcium hydroxide or dilute potassium hydroxide. The compound of formula Ia in the form of the free acid can be further obtained from the salt by acidification of the corresponding acid, such as aqueous solution of phosphoric acid or acetic acid. The compound of formula Ia can then be subjected to purification and recrystallization, for example, as described below in examples 8 and 45, to obtain the pure compounds Ia or transformation in an easily hydrolyzable ester, for example, in the procedure described in the method of obtaining 1 and 2, or may be converted into a suitable salt such as sodium salt, for example, as described below in example 9.

The primary method used to convert the bromine substituent in the 24-th position of the compounds of General formula I (X = bromine), 24-substituted compounds of General formula I (X = bromine) shown in the example of converting a compound 108 figure 2:

Conditions: (a) ClCH2O(CO)R', Et3N, DMF (R' = Me or C(CH3)3), K.T.; (d) DBU/aq. MeOH or K2CO3/MeOH, K.T.; (e) CuI, KI, HMPA, 120°C; (f) (R'= -CH2COPh) BrCH2COPh, KF, DMF, K.T.; (g) CuI, CiCl, HMPA, 120°C; (h) CF3Cu, HMPA, K.T.; (i) ArB(OR”)2*, Pd(PPh3)4, K2CO3, EtOH+toluene, 90°C.

(Fu = ring substructures A,B,CD fusidic acid)

*see examples 36-43 illustrating procedures with the inclusion of Ar and ArB(OR”)2

Acetoxymethyl esters or pivaloyloxymethyl esters 24-pomposity acid or analogue 24-pomposity acid or can be hydrolyzed to the corresponding free acids, for example, by treatment with methanol and water base. Bracelet then heated with copper iodide (I) and potassium iodide in HMPA at a temperature of 120°C to obtain the corresponding 24-godcity formula I. the Acids may be further tarifitsirovana to the appropriate peacelove esters handling penacerrada and potassium fluoride in DMF. Peacelove esters to give the corresponding 24-cryptomelane esters, for example, when interacting with the solution tricornered in HMPA. In the end, esters can be converted into the free 24-triftormetilfosfinov acid (or analogs of fusidic acid) of the formula I when carrying out the hydrolysis, for example, alkaline hydrolysis.

Alternatively, 24-etkileri can be subjected to esterification to its acetoxymethyl esters or pivaloyloxymethyl esters, as described above, and then converted to the corresponding 24-aryl or alkeneamine esters and the like, in the course of the reaction mixture, for example, in the framework of combination reaction type is Suzuki with arylboronic acid or a complex ester, or replaced arylboronic acid or a complex ester as shown in scheme 2. In the end, the corresponding free acids of the compounds of General formula I can be obtained by conducting hydrolysis of ester, such as alkaline hydrolysis.

In another embodiment, acetoxymethyl esters or pivaloyloxymethyl esters 24-pomposity acid or analogue 24-pomposity acid is heated with copper iodide (I) and lithium chloride in HMPA to obtain the corresponding 24-chlorine complex ester. This broadcast provides free 24-horkesley compounds of General formula I after hydrolysis, such as alkaline hydrolysis.

The main method of synthesis of compounds I, including modifications in the ring And in the fusion reaction, is illustrated as applied to the synthesis of compounds 123, 124 and 144 figure 3:

Conditions: (j) PhP3P, CBr4benzene , K.T.; (k) K2CO3, MeOH, K.T.; (l) LiN3, DMF, K.T.

Non-limiting modification example on the type of substitution in one of the rings ring substructures A,B,C,D, fusidic acid, for example, after the introduction of the 24-substituent, shown in figure 3 as applied to the modification in the ring: for example, acetoxymethyl ester or pivaloyloxymethyl ester 24-pomposity acid or analogue 24-pomposity acid may be under ergot bromirovanii with triphenylphosphine and tetrabromomethane with the formation of inverted configuration, the corresponding 3-β-prosteradlo of ester. Ester may be optionally subjected to hydrolysis to the free acid of formula I. this acid may be further subjected to modification, for example, as shown, by treatment with lithium azide with the formation of another inverted configuration, the corresponding 3-α-azidoethyl formula I.

The main method of synthesis of compound I, including modification of ring a and ring D in the fusion reaction, is illustrated as applied to the synthesis of compounds 112 and 113 in figure 4:

Conditions: (m) Ac2O, pyridine, K.T.; (n) 1. 1 EQ. aq. NaOH, Meon, K.T., 2. aq. NaHCO3100°C; (o) 1. 1 EQ. aq. NaOH, MeOH, K.T., 2. ClCH2(CO)C(CH3)3, DMF, K.T.; (p) Cl(CO)OPh, NaBr, DMF, 0°C; (q) Br2, CCl4, K.T.; (r) DBU, CH3CN, the boiling point under reflux; (s) 1. iPrSH, NaOH, DMF, K.T., 2. aq. NaOH, 60°C; (t) 1. 1 EQ. aq. NaOH, MeOH, K.T.; 2. NaIO4, MeOH, K.T.

The synthesis of compounds 112 and 113 of fusidic acid to illustrate a non-limiting procedure in which 16-substituent in ring D may be in the course of the synthesis of compounds of General formula I changed to alkylthio or alkylsulphonyl group with 16-β-stereochemistry. Temporary protection 3-hydroxy-group and carboxypropyl can be useful for this reaction, and bromine in position 24 can be entered is as appropriate stage of synthesis: fozilova acid (201) can be azetilirovanna in position C3 when using acetic anhydride and pyridine to form compound (4). The corresponding sodium salt of the compound (4) is further heated with an aqueous solution of sodium bicarbonate to obtain a 16-α-hydroxycodone (5) (with inversion of configuration at position C16). Sodium salt of compound (5) can be, for example, subjected to esterification by climaterealists with the formation of compound (6). The compound (6) can then be processed by phenylcarbamates, dimethylformamide and sodium bromide with formation of 16-α-bromoaniline (11) (when saving configuration in position C16). The compound (11) may be subject to bromirovanii with the formation of 24,25-dibromo connection (12), which can be subjected to dehydrobrominated, for example, using DBU to 24-bromoaniline (13). Alkylation of isopropylmalate sodium compound (13) gives 16-β-isopropylthio intermediate connection (with inversion of configuration at position C16), which can be subjected to hydrolysis, for example, water base, with the formation of 24-bromo-3-α-hydroxy-16-β-isopropylcarbonate acid (112) of formula I. If desired, the compound (112) can be oxidized (for example, periodates sodium) to the corresponding sulfoxide (113).

METHODS of preparation AND EXAMPLES

Basic information

All values of the melting points given in unadjusted form.

The values of chemical shift spectra in nuclear-m is gitogo resonance (NMR) for 1H (300 MHz) and13(Of 75.6 MHz) (δ) (in ppm) are, unless specifically provided otherwise, the solutions deuterochloroform relative to the internal standard tetramethylsilane (δ=0,00) or deuterochloroform (δ=76,81 for13WITH NMR). The value of a multiplet, either definite ((doublet (doctor), triplet (t), Quartet (K)), or indeterminate (m), the corresponding average point given, if you do not specify the range (s = singlet, sh. - broad singlet). The reaction mixture is usually treated as follows: the extraction is carried out with an organic solvent (as indicated), which is shaken out with water and/or aqueous solutions of salts or acids (also indicated); the organic solutions are usually dried over sodium sulfate or magnesium and concentrated under reduced pressure on a rotary evaporator. Chromatography is performed on silica gel, usually using ethyl acetate and petroleum ether with a low boiling point as eluent. Used the ratio of the solvents indicated in volume ratios/percentages (volume:volume). The appropriate fractions are combined and concentrated, holding in some cases, crystallization or freeze drying. Solvents include anhydrous solvents, which are usually prepared using the stored solvents of analytical purity after sifting through molecular the sieve 4E for several days before using.

The production of intermediate compounds for the synthesis of compounds I

Intermediate compounds of General formula Ib are listed in table 1:

Notes to formula Ib and table 1: the Ven. = Drug;Rev. =procedure upon receipt of other drugs and other examples; Conn. Connection; Q2= CH-OH(α);

XIn the case of those compounds that do not contain X'configuration around C24 and C25 is the same as in formula Ia, i.e. C24 and C25 are connected by a double bond. For those compounds where X=X'= Br, both C24 and C25 are substituted by bromine atom, C24 and C25 are connected by a single bond and the compounds are mixtures of two of C24 diastereoisomers.
RN = the free acid; Na = sodium salt; CH2OAc = acetoxymethyl esters;
CH2OPiv = pivaloyloxymethyl ether; fenac. = finacialy ether;
Y, ZBd = the carbon-carbon bond, that is, C17 and C20 are connected by a double bond;
H,H = 17S-H, 20-H, that is, C17 and C20 are connected by a single bond;
-CH2- = [Y,Z]-C17-C20 form yclopropane ring with stereochemistry 17S, 20S.

Ways to get

The method of obtaining 1: Acetoxymethyl ester fusidic acid (2A)

To a solution of fusidic acid (201) (of 128.6 g, 250 mmol) in DMF (375 ml) add Et3N (45 ml, 33 g, 320 mmol) and the mixture is stirred for 30 minutes at room temperature. After that add chloromethylated (49 ml, 55 g, 500 mmol) and the reaction mixture was stirred over night at room temperature, then washed (EtOAc, water) to obtain the crude product. The crude ester (2A) will recrystallized from isopropyl ether to obtain the pure compound as a colourless powder, TPL 103-105°C.

13C NMR (CDCl3): 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.

The method of obtaining 2: Pivaloyloxymethyl ester fusidic acid (2b)

The procedure for a method of obtaining 1, with the substitution of chlormethiazole chlormethiazole, conducting the reaction at a temperature of 50°C during the night, get pivaloyloxymethyl ester fusidic acid (2b) as a colorless amorphous substance.

13C NMR (CDCl3): 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.

The method of obtaining 3: ACET ximately ester 24R,S,25-dibromothiophene acid (3A)

Acetoxymethyl ester fusidic acid (2A) (6 g, 10 mmol) dissolved in CCl4(40 ml) and add a solution of bromine (of 0.56 ml of 1.76 g, 11 mmol) in CCl4(40 ml) for one hour with constant stirring and cooling in an ice bath. Obtained slightly yellow solution used in the next stage without further purification.

1H NMR (CDCl3): 5,91 (m, 1H), 5,78 (Sh.S., 2H), 4,36 (Sh.S., 1H), 4,20 (m, 1H), 3,75 (Sh.S., 1H), and 3.16 (m, 1H), 2,80 of 1.00 (m, 20H), 2,10 (s, 3H), 1,97 (sh, 6H), of 1.80 (s, 3H), of 1.38 (s, 3H), of 0.96 (s, 3H), of 0.95 (s, 3H), of 0.91 (d, 3H).

The method of obtaining 4: Pivaloyloxymethyl ester 24R,S,25-dibromothiophene acid (3b)

The procedure for a method of obtaining 3, with the substitution acetoxymethyl of ester fusidic acid (2A) pivaloyloxymethyl complex air fusidic acid (2b), after concentration of the reaction mixture and purification of the product by the method column flash chromatography (hexane:EtOAc 50:50 as eluent) get mentioned in the title compound 3b as a colorless foam.

13C NMR (CDCl3): 177,0, 170,2, 170,2, 167,7, 167,6, 153,0, 153,0, 127,7, 80,1, 80,0, 74,3, 71,4, 68,5, 68,4, 68,2, 68,1, 66,2, 65,8, 60,4, 49,3, 49,2, 48,9, 48,9 44,5 39,5, 39,0 38,8, 37,0, 36,3, 36,1, 35,8, 35,2, 35,1, 32,3, 31,6, 30,2, 30,0, 28,5, 28,2, 28,2, 27,7, 26,9, 24,1, 24,1, 22,8, 22,7, 20,8, 20,8, 18,1, 18,0, 16,0, 14,2.

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

Guideway acid (201) (74,3 g, 0.144 mol) is dissolved in pyridine (75 ml, 74 g, 0.93 in mo is ü) and acetic anhydride (75 ml 81 g of 0.79 mol) and the resulting reaction mixture was stirred at room temperature for three hours, after which the reaction is finished. Acetylated product is precipitated by adding ice and water. Recrystallization from methanol/water gives pure compound (4).

13C NMR (CDCl3): 174,5, 171,0, 170,6, 151,1, 132,7, 129,7, 123,0, 74,4, 74,2, 68,3, 49,1, 48,8, 44,3, 39,4, 39,0, 37,8, 37,0, 35,8, 34,8, 32,7, 31,1, 28,7, 28,4, 27,4, 25,7, 24,4, 22,6, 21,3, 20,6, 20,6, 18,1, 17,8, 15,5.

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

3-acetoxypropionyl acid (4) (9.95 g, 17.8 mmol) was dissolved in MeOH (250 ml) and neutralized by an equivalent amount of aqueous NaOH (about 9 ml, 2M). The solvent is evaporated and to the residue is added water (150 ml). The mixture is heated to the boiling temperature under reflux and added dropwise within 30 minutes, 20 ml of a saturated aqueous solution of NaHCO3(approximately 1 M). The obtained clear solution is heated to a temperature of 100°C for eight hours, after which the insoluble by-product (corresponding lactone). The lactone is removed by filtration and the filtrate is acidified with HCl (20 ml, 4M) and extracted with EtOAc. The organic phase is washed with water, dried using MgSO4and concentrate under reduced pressure to obtain specified in the connection header (5), which is used in the next stage without [daln] is ISA cleanup.

13C NMR (CDCl3): 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.

The method of obtaining 7: Pivaloyloxymethyl ester 3-acetyl-16-deacetoxy-16α-hydroxypyridones acid (6)

3-acetyl-16-deacetoxy-16α-hydroxyquinolyl acid (5) (39,7 g, 77 mmol) was dissolved in MeOH (250 ml) and neutralized with 1 EQ. aqueous NaOH. The solvent is evaporated and the residue pererastayut in DMF (450 ml). Add chlorocyphidae (13.4 ml, 13,9 g, 92 mmol) over 30 minutes under stirring and ice cooling. The resulting mixture is stirred over night at room temperature, after which it is washed (EtOAc, aq. CaCl2, water, saturated NaCl), dried using MgSO4and concentrate under reduced pressure to obtain specified in the header of the compound (6) in the form of oils, which are used in the next stage without further purification (method of obtaining 11).

13C NMR (CDCl3): 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.

The way to obtain 8: Acetoxymethyl ester 16 deacetoxy-16β-thioacetimidate acid (8)

The procedure for a method of obtaining 1, when replacing fusidic acid 16 deacetoxy-16β-thioacetimidate acid (202) (von Daehne, . et al.,Adv. Appl. Environ., 1979, vol. 25, p. 95-146) and using 10 EQ. each of Et3N and chlormethiazole, if further purification of the crude product column flash chromatography using as eluent a mixture of petroleum ether:EtOAc (1:1) get the specified header connection (8).

13C NMR (CDCl3): 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.

The method of obtaining 9: Acetoxymethyl ester 16 deacetoxy-16β-ethoxyphenol acid (9)

The procedure for a method of obtaining 1, when replacing fusidic acid potassium salt 16 deacetoxy-16β-ethoxyphenol acid (203) (von Daehne, W.et al., Adv. Appl. Environ., 1979, vol.25, p. 95-146), without Et3N, but using 10 EQ. chlormethiazole, if further purification of the crude product column flash chromatography using as eluent a mixture of petroleum ether:EtOAc (1:1) get the specified header connection (9).

13C NMR (CDCl3): 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.

The method of obtaining 10: Acetoxymethyl ester 16 deacetoxy-16β-(2',2',2'-triptoreline)fusidic acid (10)

The procedure for a method of obtaining (1), if replacement is fusidic acid 16 deacetoxy-16β-(2',2',2'-triptoreline)fusidic acid (204) (von Daehne, W.et al., Adv. Appl. Environ., 1979, vol.25, p. 95-146) and using 10 EQ. each of Et3N and chlormethiazole, if further purification of the crude product column flash chromatography using as eluent a mixture of petroleum ether:EtOAc (1:1) get the specified header connection (10).

13C NMR (CDCl3): 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.

The method of obtaining 11: Pivaloyloxymethyl ester 3-acetyl-16α-bromo-16-diacetoxybenzoic acid (11)

Pivaloyloxymethyl ester 3-acetyl-16-deacetoxy-16α-hydroxypyridones acid (6) (22,8 g, 36,1 mmol) dissolved in DMF (200 ml) and cooled in an ice bath in an argon atmosphere with constant stirring. To the solution was added sodium bromide (18.6 g, 181 mmol) and the resulting mixture is stirred for one hour. Add phenylcarbamate (22,8 ml, 28,3 g, 181 mmol) in one hour at a temperature of 0°C and then stirred for 18 hours at room temperature. The reaction mixture was washed (EtOAc, aq. CaCl2water, feast upon. NaCl), dried using MgSO4and concentrate under reduced pressure to get crude product. The crude product is purified column flash chromatography (10%-30% EtOAc in petroleum ether as alue the TA) obtaining specified in the header of the compound (11) in the form of oil.

13C NMR (CDCl3): 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.

The method of obtaining 12: Pivaloyloxymethyl ester 3-acetyl-16-deacetoxy-16α-24,25-tribromoethanol acid (12)

The procedure for a method of obtaining (3), with the substitution acetoxymethyl of ester fusidic acid (2A) pivaloyloxymethyl complex ester of 3-acetyl-16α-bromo-16-diacetoxybenzoic acid (11) receive specified in the header of the compound (12) as a colourless foam.

13H NMR (CDCl3): by 5.87 (m, 2H), 5,64 (St, 1H), 4,93 (Sh.S., 1H), 4,35 (Sh.S., 1H), 4,14 (DD, 1H), 3.46 in (SD, 1H), 2,80 of 1.00 (m, 20H), 2,07 (s, 3H), of 1.97 (s, 3H), of 1.84 (s, 3H), 1,49 (s, 3H), 1,22 (s, 9H), and 0.98 (s, 3H), or 0.83 (d, 3H), to 0.78 (s, 3H).

The method of obtaining 13: Pivaloyloxymethyl ester 3-acetyl-16-deacetoxy-16α,24-dibromothiophene acid (13)

Pivaloyloxymethyl ester 3-acetyl-16-deacetoxy-16α-24,25-tribromoethanol acid (12) (14.4 g, 16.4 mmol) and DBU (7,4 ml, 7.6 g, 49 mmol) was dissolved in acetonitrile (200 ml) and the resulting solution was heated for five hours at a temperature of 50°C in argon atmosphere with constant stirring. The reaction mixture was concentrated under reduced pressure and washed (EtOAc, water, feast upon. NaCl). The crude product is purified column flash chromatography (10%-15% EtOAc in petroleum ether, in which the quality of eluent) to obtain specified in the header of the compound (13) in the form of a crystalline product.

1H NMR (CDCl3) by 5.87 (d, 1H) of 5.84 (d, 1H), 5,64 (St 1H), 4,94 (Sh.S., 1H), 4,36 (sh, 1H), 3.45 points (SD, 1H), 2,75-of 2.50 (m, 5H), 2,30 of 1.00 (m, 15H), 2,07 (s, 3H), of 1.85 (s, 3H), 1,78 (C., 3H), of 1.46 (s, 3H), of 1.23 (s, 9H), and 0.98 (s, 3H), or 0.83 (DD, 3H), of 0.77 (s, 3H).

The method of obtaining 14: Acetoxymethyl ester 17S,20S-digidrofolievoy acid (14)

The procedure for a method of obtaining (1), when replacing fusidic acid 17S,20S-digidrofolievoy acid (205) (von Duvold, T.et al., J. Med. Chem., 2001, vol. 44, p. 3125-3131), using 10 EQ. each of Et3N and chlormethiazole, if further purification of the crude product column flash chromatography using as eluent a mixture of petroleum ether:EtOAc (1:1) get the specified header connection (14).

13C NMR (CDCl3): 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.

The method of obtaining 15: Acetoxymethyl ester 17S,20S-medienfestival acid (15)

The procedure for a method of obtaining (1), when replacing fusidic acid 17S,20S-medienfestival acid (206) (Duvold, T.et al., Bioorg. Med. Chem.Lett., 2002, vol. 12, p. 3569-3572), using 10 EQ. each of Et3N and chlormethiazole, if further purification of the crude product column flash chromatography using as eluent a mixture of petroleum ether:EtOAc (1:1) get specified the second header connection (15).

13C NMR (CDCl3): 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.

The method of obtaining 16: Finacialy ester 24-imputados acid (7)

A mixture of pencilvania (0,42 g, 2.1 mmol), potassium fluoride (0.27 g, 4.6 mmol) and DMF (10 ml) is stirred for five minutes at a temperature of 90°C in argon atmosphere. Add 24-infosidor acid (125I) (1.35 g, 2.1 mmol) and the resulting mixture is stirred for one hour at a temperature of 90°C. the Reaction mixture was treated with (diethyl ether, water, feast upon. NaCl, MgSO4) and concentrated under reduced pressure, obtaining specified in the header of the compound (7) in the form of amorphous powder.

13C NMR (CDCl3): 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.

The method of obtaining 17: Finacialy ester 24-triftormetilfosfinov acid (16)

The solution of complex compounds tricornered in HMPA (Kobayashi, Y.et al., Tetrahedron. Lett., 1979, Vol. 42, p. 4071-4072)obtained from triptoreline (of 0.43 g, 2.2 mmol) and copper powder (0.32 g, 5 mg At) in HMPA (1.5 ml), added to pencilbeam complex ether 24-imputados acid (7) (190 mg, 0.25 mmol). The resulting mixture is stirred in a closed vial for 3 days at room temp is the temperature in argon atmosphere, then treated with EtOAc, water and saturated NaCl solution, dried and concentrated under reduced pressure. The crude product is purified column flash chromatography (20-40% EtOAc in petroleum ether as eluent) and then spend preparative HPLC (Lichrospher®-100 RP18, gradient 50%-0% 0.01 M aq. NH4+HCOO-mixed with 0.01 M NH4+HCOO-in a mixture of acetonitrile:water (9:1) as eluent). The appropriate fractions are combined to a concentrated under reduced pressure, extracted with EtOAc; the concentration of the EtOAc solution under reduced pressure gives specified in the header of the compound (16) in the form of oil.

1H NMR (CDCl3): 7,88 (DD, 2H), 7,58 (t, 1H), of 7.48 (t, 2H), 5,98 (d, 1H), 5,48 (d, 1H), 5,11 (d, 1H), 4,36 (s, 1H), 3,75 (Sh.S., 1H), 3,10 (SD, 1H), to 2.75 to 1.00 (m, 21H), a 2.01 (s, 3H), 1,88 (, 3H), 1,83 (, 3H), of 1.38 (s, 3H), and 0.98 (s, 3H), of 0.93 (s, 3H), of 0.92 (d, 3H).

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

A solution of bromine (16.0 g, 2.1 mol) in ethyl acetate (100 ml) is added to the mixed solution fusidic acid (51,6 g, 0.1 mol) in ethyl acetate (1000 ml) for 75 minutes. The temperature is maintained at 5°C, cooling the mixture in an ice bath. Add KH2PO4(100 ml, 1M aq.) and Na2S2O3(50 ml, 1M aq.) within a few minutes. The EtOAc phase was separated and extracted with KH2PO4(200 ml, 0.5 m aq.) and water (100 ml), then concentrated in on igenom pressure to obtain solid residue of the compound (17), which is used in the next stage without further purification (example 45).

1H NMR (CDCl3): of 5.81 (d, 1H), 4,32 (m, 1H), 4.26 deaths (t, 1H), 3,66 (m, 1H),3,09 (m, 1H), 3,0-1,0 (m, 19H), is 1.82 (s, 3H), of 1.81 (s, 3H), of 1.39 (s, 3H), and 1.00 (s, 3H), 0,99 (s, 3H), were 0.94 (s, 3H), of 0.89 (d, 3H).

The compounds I according to the present invention

Table 2 lists examples of compounds of General formula I (compounds of General formula Ia, where Q2= CH-OH (α)):

Note to table 2: Symbols in table 2 that are common to characters in table 1, have the same values. Ex.= example;Ex.= the procedure used in other examples.

Examples of easily hydrolyzable esters of compounds of General formula I are given in table 3A (for acetoxymethyl esters) and table 3b (for pivaloyloxymethyl esters) (for esters of compounds of General formula Ia (Q2=CH-OH (α)):

Note to tables 3A b 3b: Symbols in tables 3a and 3b, which are common for characters in table 1, have the same values. Ex.= p the emer; Ex.= the procedure used in other examples.

Examples of salts of compounds of General formula I are listed in table 4 (for salts of the General formula Ic (Q2= CH-OH (α)):

Note to table 4: Symbols in tables 3a and 3b, which are common for characters in table 1, have the same values. Ex.= example;Ex.= the procedure used in other examples.

EXAMPLES

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

Specified in the title compound (101) can be obtained by the procedure of example 9 when replacing the 24-pomposity acid (108) 24-triftormetilfosfinov acid (106).

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

Specified in the title compound (102) can be obtained by the procedure described in the production method of 2, when replacing fusidic acid, 24-triftormetilfosfinov acid (106) with subsequent freeze-drying of the product.

Example 3: 24-Chloropidae acid (compound 103)

Pivaloyloxymethyl ester 24-CHLOROSILANES acid (104) (140 mg, 0.21 mmol) and K2CO3(60 mg, 0.43 mmol) was stirred in MeOH (2 ml) for 3 hours at room temperature. After conducting column flash chrome is adopted, the concentrated reaction mixture (petroleum ether:EtOAc:HCOOH, 90:10:1 to 10:90:1 as eluent) get the specified header connection 103.

13C NMR (CDCl3): 174,0, 170,6, 152,5, 128,5, 126,8, 74,5, 71,5, 68,2, 49,3, 48,8, 44,6, 39,5, 39,0, 37,0, 36,3, 36,0, 35,6, 32,2, 30,2, 29,9, 27,3, 24,0, 22,9, 21,9, 20,8, 20,6, 20,3, 17,9, 15,9.

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

Pivaloyloxymethyl ester 24-pomposity acid (10) (283 mg, 0.40 mmol), CuI (240 mg, of 1.26 mmol), LiCl (30 mg, 0.7 mmol) and HMPA (1.2 ml) is shaken in a closed vial for 3 hours at a temperature of 120°C. the Reaction mixture was washed (EtOAc and feast upon. NaCl) to obtain the crude product. Further, this product cleans column flash chromatography using a mixture of petroleum ether:EtOAc (90:10-10:90) as eluent and get clean, specified in the header connection 104.

13C NMR (CDCl3): 177,0, 170,2, 167,8, 152,8, 128,5, 128,0, 126,7, 80,0, 74,4, 71,4, 68,2, 49,3, 48,8, 44,6, 39,5, 39,0, 38,8, 37,0, 36,4, 36,0, 35,5, 35,4, 32,2, 30,2, 29,9, 27,2, 26,9, 24,0, 22,9, 21,9, 20,8, 20,4, 17,9, 16,0, 14,2.

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

According to the procedure described in example 9, replacing the 24-pomposity acid (108) 24-CHLOROSILANES acid (103) with subsequent freeze drying product get mentioned in the title compound (105).

Example 6: 24-triftormetilfosfinov acid (compound 106)

Finacialy ester 24-triftormetilfosfinov acid 17) (15 mg, 0,021 mmol) and thiophenol sodium (20 mg, 0.15 mmol) in dry DMF (0.5 ml) is stirred in an argon atmosphere at a temperature of 100°C for five hours. Add EtOAc (15 ml) and the organic solution is extracted using: 3M aq. CaCl2(10 ml) + 1 M aq. H3PO4(0.25 ml) and then (10 ml each) 3M aq. CaCl2water , and to feast upon. NaCl. After drying and concentrating, the crude product is purified column flash chromatography using as eluent a mixture of petroleum ether:EtOAc:HCOOH (60:40:1/2) and get after freeze drying specified in the header connection 106 in the form of amorphous powder.

1H NMR (CDCl3): by 5.87 (d, 1H), 4,34 (s, 1H), 3,75 (s, 1H), 3,06 (SD, 1H), 2,70-0,80 (m, 22H), to 1.98 (s, 3H), 1,85 (square, 3H), 1,83 (square, 3H), of 1.37 (m, 3H), of 0.97 (s, 3H), of 0.91 (s, 3H), of 0.90 (d, 3H).

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

Acetoxymethyl ester 24-R,S,25-dibromothiophene acid (3A) (obtained from 22,3 mmol acetoxymethyl of ester fusidic acid) in CCl4(280 ml) and DBU (6,64 ml, 6,77 g of 44.5 mmol) is refluxed for 16 hours. The reaction mixture is in the form of a clay-like sludge is filtered through a cotton filter and wash the filter with a mixture of petroleum ether and EtOAc. The combined filtrate and wash water concentrate with obtaining specified in the connection header 107 in the form of n is the pure product (approximately 70% purity, according to NMR), which can be used without further purification when the connection 108 (example 8). A pure sample is obtained using a column flash chromatography (30-50% EtOAc in petroleum ether as eluent).

13C NMR (CDCl3): 170,3, 169,6, 167,3, 152,6, 131,6, 127,9, 120,0, 79,5, 74,4, 71,4, 68,2, 49,3, 48,8, 44,6, 39,5, 39,0, 37,8, 37,0, 36,3, 36,0, 35,6, 32,2, 30,2, 29,9, 27,8, 25,3, 24,0, 22,9, 20,8, 20,7, 20,4, 18,0, 16,0.

Example 8: 24-pomposity acid (108)

Untreated acetoxymethyl ester 24-pomposity acid (compound 107) or pivaloyloxymethyl ester (110) (obtained from 44.4 mmol acetoxymethyl of ester (2A) or pivaloyloxymethyl of ester (2b)) is dissolved in MeOH (250 ml) and added dropwise DBU (3 ml) to maintain an alkaline reaction. At room temperature for two hours, add a mixture of MeOH/water (1:1) (300 ml) under stirring, which will continue for another two hours. Add a 1M solution KH2PO4(100 ml) and, if necessary, also phosphoric acid to achieve a pH approximately 4-5; the precipitate which is formed is dissolved in a double extraction with EtOAc. The organic phase is extracted with water and feast upon. NaCl, dried using MgSO4and concentrate to obtain the crude product. This product cleans column flash chromatography (50% EtOAc in petroleum ether to + 0.5% HCOOH, as eluent is) and then spend recrystallization from a mixture of EtOAc + toluene (partial evaporation) to obtain the net specified in the connection header (108).

13C NMR (CDCl3): 173,0, 170,5, 152,6, 131,5, 128,1, 120,1, 74,5, 71,4, 68,2, 49,2, 48,8, 44,6, 39,5, 39,0, 37,8, 37,1, 36,2, 36,2, 35,7, 32,4, 30,2, 29,9, 28,0, 25,3, 24,1, 22,8, 20,8, 20,7, 20,4, 18,0, 15,9.

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

24-pomposity acid (108) (2.38 g, 4.00 mmol) dissolved in MeOH (30 ml). Add gradually equivalent amount of 1N NaOH solution (4 ml) to achieve a pH of about 8.5 in the measurement of pH-meter. The resulting solution was concentrated and the residue is dissolved in EtOH (15 ml). Add EtOAc (25 ml), but the crystallization does not occur until evaporation of the solvent, add EtOH and EtOAc and the solvent again evaporated. When this residue is crystallized from EtOH+EtOAc education specified in the connection header (109) in the form of colorless crystals.

13C NMR (CDCl3): 179,1, 173,5, 138,8, 138,2, 131,3, 122,6, 76,0, 72,5, 68,9, 50,8, 50,0, 43,8, 40,7, 40,3, 38,5, 38,3, 37,8, 37,5, 36,9, 33,0, 31,1, 31,0, 30,2, 25,4, 23,8, 23,8, 22,5, 21,1, 20,5, 17,9, 16,5.

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

During the procedure described in example 7, replacing acetoxymethyl of ester 24R,S,25-dibromothiophene acid pivaloyloxymethyl complex air 24R,S,25-dibromothiophene acid (3b) receive untreated specified in the title compound (110). This connection can be subjected to hydrolysis without further purification getting connection 108. Colonoscopy because it allows the Naya flash chromatography of a sample of the crude product, conducted using as eluent 30%-50% EtOAc in petroleum ether gives pure indicated in the title compound (110) in the form of a slightly yellow amorphous foam.

13C NMR (CDCl3): 177,0, 170,2, 167,8, 152,8, 131,5, 127,9, 120,1, 80,0, 74,4, 71,4, 68,2, 49,3, 48,8, 44,6, 39,5, 39,0, 38,8, 37,7, 37,0, 36,3, 36,0, 35,7, 32,3, 30,2, 30,0, 27,8, 26,9, 25,3, 24,0, 22,9, 20,8, 20,4, 18,0, 16,0.

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

A solution of bromine (45 μl, 140 mg, 0.88 mmol) in CCl4(5 ml) are added to a solution acetoxymethyl of ester 16 deacetoxy-16β-thioacetimidate acid (8) (0,48 g, 0.8 mmol) in CCl4(10 ml), by adding for two hours in an argon atmosphere with stirring and cooling in an ice bath. Stirring is continued for 15 minutes in an ice bath and for a further 15 minutes at room temperature. Add DBU (0,66 ml of 0.67 g, 4.4 mmol) and the mixture refluxed for 12 hours. The reaction mixture is filtered through a filter device and concentratein the vacuum. The residue is purified column flash chromatography using as eluent 0%-70% EtOAc in petroleum ether, getting mentioned in the title compound (111).

13C NMR (CDCl3): 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-isopropylthiazole acid (compound 112)

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

1H NMR (CDCl3): 4,30 (m, 1H), 4,15 (m, 1H, in), 3.75 (m, 1H), 3,10 (m, 1H), equal to 1.82 (s, 3H), of 1.75 (s, 3H), of 1.35 (s, 3H), of 1.24 (d, 3H, J=6 Hz), of 1.18 (d, 3H, J=6 Hz), 0,99 (s, 3H), and 0.98 (s, 3H), from 0.88 (d, 3H, J=6 Hz), 2,9-1,0 (m, 23H).

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

To a solution of 24-bromo-16-deacetoxy-16β-isopropylthiazole acid (112) (0,29 g, 0.47 mmol) in MeOH (10 ml) is added 2N aq. NaOH (0.5 ml) and periodate is the atrium (0,23 g, 1.1 mmol) in water (40 ml). The mixture is stirred for one hour at room temperature and acidified with aq. HCl to precipitate the acid. The product is then filtered off, washed with water and recrystallized from EtOAc to obtain specified in the connection header (113) in the form of crystals, TPL 166-168°C.

13C NMR (CDCl3): 173,7, 159,6, 131,3, 125,8, 120,2, 71,5, 68,3, 60,2, 51,8, 49,5, 48,2, 47,5, 39,7, 38,2, 37^2, 36,3, 36,1, 35,6, 32,6, 30,4, 30,6, 28,0, 26,6, 25,3, 24,6, 22,7, 20,7, 20,4, 18,3, 17,8, 16,0, 13,5.

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

Acetoxymethyl ester 24-bromo-16-deacetoxy-16β-thioacetimidate acid (111) (40 mg, 0,059 mmol) dissolved in MeOH (2.5 ml), add potassium carbonate (17 mg, 0.12 mmol) and the mixture is stirred for three hours (at the access of moisture from the air). Add water (10 ml) and the mixture is acidified to about pH 4 using aq. HCl, which leads to acid deposition. The mixture was treated with EtOAc, water, feast upon. NaCl, dried using Na2SO4and concentrate to obtain the crude product. This product cleans column flash chromatography (0%-10% MeOH in dichloromethane as eluent) to obtain specified in the connection header (114).

13C NMR (CDCl3): 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-digidrofolieva to the slot (115)

According to the procedure described in example 14, when replacing acetoxymethyl of ester 24-bromo-16-deacetoxy-16β-thioacetimidate acid (111) acetoxymethyl complex air 24-bromo-17S,20S-digidrofolievoy acid (120) receive specified in the title compound (115).

13C NMR (CDCl3): 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-toxipedia acid (116)

According to the procedure described in example 14, when replacing acetoxymethyl of ester 24-bromo-16-deacetoxy-16β-thioacetimidate acid (111) acetoxymethyl complex air 24-bromo-16-deacetoxy-16β-ethoxyphenol acid (117) get the specified header connection (116).

13C NMR (CDCl3): 171,0, 151,7, 132,6, 131,6, 120,2, 80,9, 71,5, 68,4, 64,8, 49,5, 49,0, 44,2, 39,8, 37,6, 37,2, 36,5, 35,9, 35,9, 35,1, 32,8, 30,4, 30,1, 28,9, 25,3, 24,4, 22,3, 20,6, 20,5, 18,6, 16,0, 14,7.

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

The procedure in example 11, replacing acetoxymethyl of ester 16 deacetoxy-16β-thioacetimidate acid (8) acetoxymethyl complex air 16 deacetoxy-16β-ethoxyphenol acid (9) receive specified in the title compound (117).

13C NMR (CDCl3): 169,7, 152,8, 131,2, 127,3, 120,4, 79,6, 78,8, 71,4, 68,4, 65,3, 49,2, 49,1, 43,4, 39,5,37,7, 37,1, 36,3, 36,3, 35,8, 35,5, 32,5, 30,3, 30,0, 27,8, 25,3, 24,2, 22,8, 20,8, 20,9, 20,3, 17,9, 16,0, 15,3.

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

The procedure in example 11, replacing acetoxymethyl of ester 16 deacetoxy-16β-thioacetimidate acid (8) acetoxymethyl complex air 16 deacetoxy-16β-(2',2',2'-triptoreline)fusidic acid (10) receive specified in the header connection (118).

13C NMR (CDCl3): 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'-triptoreline)fozilova acid

According to the procedure described in example 14, when replacing acetoxymethyl of ester 24-bromo-16-deacetoxy-16β-thioacetimidate acid (111) acetoxymethyl complex air 24-bromo-16-deacetoxy-16β-(2',2',2'-triptoreline)fusidic acid (118) get mentioned in the title compound (119).

13C NMR (CDCl3): 175,3, 151,9, 131,4, 129,0, 123,6, 120,2, 80,5, 77,2, 71,5, 68,3, 67,8, 49,1, 49,0, 43,9, 39,6, 37,7, 37,1, 36,2, 35,8, 35,6, 32,5, 30,3, 30,0, 28,0, 25,3, 24,2, 22,8, 20,2, 17,7, 16,0.

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

The procedure in example 11, replacing acetoxymethyl of ester 16 deacetoxy-16β-thioacetal asadovoy acid (8) acetoxymethyl complex air 17S,20S-digidrofolievoy acid (14) receive specified in the header connection (120).

13C NMR (CDCl3): 173,6, 169,9, 169,7, 130,8, 120,4, 78,8, 76,5, 71,4, 68,8, 49,4, 49,3, 45,4, 43,9, 40,6, 40,6, 38,3, 37,2, 36,4, 36,2, 35,0, 34,2, 32,6, 31,2, 30,4, 30,0, 25,3, 23,8, 22,7, 20,9, 20,9, 20,7, 20,3, 17,2, 16,0.

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

The procedure in example 11, replacing acetoxymethyl of ester 16 deacetoxy-16β-thioacetimidate acid (8) acetoxymethyl complex air 17S,20S-medienfestival acid (15) get mentioned in the title compound (121).

13C NMR (CDCl3): 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-medienfestival acid (compound 122)

According to the procedure described in example 14, when replacing acetoxymethyl of ester 24-bromo-16-deacetoxy-16β-thioacetimidate acid (111) acetoxymethyl complex air 24-bromo-17S,20S-medienfestival acid (compound 121) receive specified in the header connection (122). (Eluent for column flash chromatography represents 50% EtOAc in petroleum ether + 1% HCOOH).

13C NMR (CDCl3): 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-dibromoethane acid (123)

According to the procedure given in p is the iMER 14, when replacing acetoxymethyl of ester 24-bromo-16-deacetoxy-16β-thioacetimidate acid (111) acetoxymethyl complex ester of 3-deoxy-3β,24-dibromothiophene acid (144) receive specified in the title compound (123). (Eluent for column flash chromatography represents 10% EtOAc in petroleum ether + 1% HCOOH).

13C NMR (CDCl3): 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-detoxifica acid (compound 124)

3-deoxy-3β,24-dibromoethyl acid (123) (100 mg, 0.15 mmol) dissolved in DMF (2.5 ml) and add lithium azide (30 mg, 0.6 mmol). The mixture is stirred at room temperature in an argon atmosphere for 11 days. Add EtOAc and water (5 ml each) and together with AcOH create a slightly acidic pH. Further processing (EtOAc, water, feast upon. NaCl), dried using Na2SO4and concentration gives the crude product, which was purified flash column-chromatography (eluent: 0-50% EtOAc in petroleum ether + 1% HCOOH) to obtain specified in the header connection (124).

13C NMR (CDCl3): 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-infosida acid (compound 125)

24-pomposity acid (108) (17.0 g, 28.5 m is ol), CuI (27,2 g, 143 mmol), KI (43,4 g, 285 mmol) and HMPA (100 ml) is heated on an oil bath for 20 hours in an argon atmosphere at a temperature of 120°C, under stirring and boiling under reflux using a partial condenser hot irrigation. Add water (400 ml) and the resulting viscous mixture is extracted four times with EtOAc (400 ml). The organic phase is filtered through a filter device, which was washed with EtOAc. The combined organic phase is extracted with 20% aqueous solution of Na2S2O5twice with water and feast upon. NaCl. After drying using MgSO4the solvent is evaporated and the residue is stirred with toluene (300 ml) for three hours. The precipitate was separated by filtration, washed with toluene and petroleum ether and then dried to obtain almost pure specified in the connection header 125 in the form of painted beige crystals.

13C NMR (CDCl3) 173,8, 170,6, 152,3, 137,4, 128,0, 99,9, 74,5, 71,5, 68,2, 60,4, 49,3, 48,8, 44,5, 41,7, 39,5, 39,0, 37,0, 36,4, 36,0, 32,1, 31,6, 30,2, 29,9, 24,0, 23,0, 20,9, 20,7, 19,5, 17,9, 15,9, 14,2.

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

According to the procedure described in example 25, replacing connection 108 acetoxymethyl complex air 24-pomposity acid (107) get the crude compound 126. The specified product is distilled column flash chromatography the th, using as eluent 40% EtOAc in petroleum ether, and get mentioned in the title compound (126) as an amorphous substance.

13C NMR (CDCl3): 170,3, 169,6, 168,0, 152,5, 137,5, 127,6, 99,8, 79,5, 74,4, 71,4, 68,1, 49,4, 48,8, 44,6, 41,7, 39,5, 39,0, 36,9, 36,5, 35,8, 32,0, 31,6, 30,1, 29,9, 28,6, 23,9, 23,1, 20,9, 20,8, 20,8, 19,4, 17,9, 16,0, 14,2.

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

24-infosidor acid (125) (0.84 g, 1,31 mmol) and triethylamine (0,19 ml, 0.14 g, 1.35 mmol) dissolved in DMF (5 ml) and stirred for 20 minutes at room temperature. Add chlorocyphidae (0,30 ml, 0.32 g, 2.1 mmol) and the mixture is stirred over night at room temperature. The reaction mixture was extracted with 3M aq. CaCl2, water and feast upon. NaCl, dried using MgSO4and concentrate. The residue is purified column flash chromatography, using as eluent 40% EtOAc in petroleum ether, to obtain specified in the connection header (127) as an amorphous substance.

13C NMR (CDCl3): 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

7.5 g
Sodium salt 24-pomposity acid1 g
Vaseline
Liquid paraffin7.5 g
Spermaceti2.5 g
Monopalmitate sorbitan2.5 g
Monopalmitate of polyoxyethylenesorbitan2.5 g
Water26,5 g
50 g

Heat the petrolatum, paraffin, spermaceti, monopalmitate sorbitan, monopalmitate of polyoxyethylenesorbitan to a temperature of 70°C and slowly add water with constant stirring. Continue stirring until cooling cream. Pound sodium salt 24-pomposity acid to obtain a cream base, which is homogenized in a roller mill. Fill with cream aluminum soft tubes.

Example 29: Ointment

Sodium salt 24-pomposity acid1 g
Liquid paraffin6,9 g
Cetanol0.2 g
Anhydrous lanolin2.3 g
Vaseline39,6 g
50 g

Melt paraffin, cetanol, lanolin and petrolatum at a temperature of 70°C. After cooling to a temperature below 40°C pound sodium salt 24-pomposity acid. Fill ointment lacquered aluminum soft tubes.

Example 30Capsules

Sodium salt 24-pomposity acid25 g
Microcrystalline cellulose14, 5 g
Magnesium stearate0.5 g
40 g

Pass the ingredients through a sieve of 60 mesh and mix the whole lot in for 10 minutes. Fill with a mixture of hard gelatin capsules with the introduction of capsules quantities equal to 400 mg

Example 31: Tablets

Sodium salt 24-pomposity acid25 g
AvicelTM(AvicelTM)12 g
STA-Rx 1500
Magnesium stearate1 g
50 g

Sodium salt of 16-deacetoxy-16β-(2',2',2'-triptoreline)-17S,20S-methanesulfonic acid, AvicelTM(AvicelTMand STA-Rx mixed, sieved through a sieve with a pore size of 0.7 mm and then mixed with magnesium stearate. The mixture is pressed into tablets, each containing 500 mg.

Example 32: Suspension

Sodium salt 24-bromo-16-deacetoxy-16β-isopropylacetanilide acid1 g
Citric acid0.09 g
Monohydratefast sodium0.14 g
Sucrose5 g
TwinTM80 (TweenTM80)0.01 g
Potassium sorbate0.04 g
Sodium-carboximetilceluloza0.1 g
Water suspensionto 100 ml

Crystals micronizer and suspisious in solution limo is Noah acid, monohydrogenphosphate sodium, sucrose, potassium sorbate and twinTM80 in 10 ml of water, if necessary, conducting low heat. Sodium carboxymethylcellulose are dissolved in 4 ml of boiling water. After cooling, it is added to other ingredients. The suspension is homogenized in the mixer and at the end, add water to a final volume of 100 ml

Example 33: Ointment

A: Sodium salt of 24-bromo-16-deacetoxy-
16β-(2',2',2'-triptoreline)fusidic acid
1 g
B: One of the compounds: hydrocortisone,
triamcinolone or fluotsinolon
0.5 g
Liquid paraffin6,9 g
Cetanol0.2 g
Anhydrous lanolin2.3 g
Vaseline39,1 g
50 g

Melt paraffin, cetanol, lanolin and petrolatum at a temperature of 70°C. After cooling to a temperature below 40°C is ground A and B. Fill ointment lacquered aluminum soft tubes.

Example 34: Ointment

A: 24-bromo-17S,20S-digidrofolieva acid1.5 g
B: Tetracycline1.5 g
Liquid paraffin13, 8 g
Cetanol0.4 g
Anhydrous lanolin4.6 g
Vaseline78,2 g
100 g

Melt paraffin, cetanol, lanolin and petrolatum at a temperature of 70°C. After cooling to a temperature below 40°C is ground A and B. Fill ointment lacquered aluminum soft tubes.

Example 35: Eye gel

24-bromo-16-deacetoxy-16β-(2',2',2'-triptoreline)fozilova acid10 g
Benzalkonium chloride0.1 g
Carbomer5 g
Mannitol50 g
Edetate sodium0.5 g
Sodium hydroxide q.s.
Water sterileto 100 g

Dissolve edetate disodium and mannitol in water for injection in a vessel of stainless steel, provided with a device for mixing and built-in homogenizer. Add Carbomer R selected vessel and autoclave variance with slow stirring and homogenize at high speed. Cooled to a temperature of 70°C, stop stirring and homogenization. Add sterile micronized sodium salt 24-bromo-16-deacetoxy-16β-(2',2',2'-triptoreline)fusidic acid is selected vessel and give 24-bromo-16-deacetoxy-16β-(2',2',2'-triptoreline)fusidic acid to settle with slow stirring. Homogenize at high speed for 10 minutes at 70°C. is Cooled to a temperature below 30°C under stirring and homogenization with a low speed. Add sterile solution of benzalkonium chloride in water for injection with slow stirring. Neutralize Carbomer R adding sterile solution of sodium hydroxide (1,050 kg) in water for injection. Mixed and homogenized at low speed for 5 minutes. Adjust, if necessary, the pH to 5.4 to 5.8. Carry eye gel storage tanks under nitrogen pressure using a low-speed portable system on the I homogenization. Store at room temperature until completion. Eye gel is injected under aseptic conditions in sterile tubes using to populate the product in the amount of 3.5 g

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

Phenylboronic acid (50 mg, 0.4 mmol) and EtOAc (0.25 ml) are added to a solution pivaloyloxymethyl of ester 24-imputados acid (127) (150 mg, 0.2 mmol) in toluene (1.5 ml) and the mixture bubbled with argon for 2 minutes. Add K2CO3(2M aq. the solution, 0.3 ml) and Pd(PPh3)4in (11.5 mg, 0.01 mmol), after which the mixture is shaken at 90°C for 20 hours in an argon atmosphere. The reaction mixture was treated with EtOAc, water and feast upon. NaCl, dried and concentrated. The crude product was then purified column flash chromatography (20% EtOAc in petroleum ether as eluent) to obtain the net specified in the connection header 136.

13C NMR (CDCl3): 177,0, 170,2, 167,7, 152,3, 144,1, 133,9, 129,6, 128,9, 128,4, 127,9, 125,9, 80,0, 74,3, 71,4, 67,9, 48,9, 48,7, 44,4, 39,4, 39,0, 38,8, 36,9, 36,3, 36,1, 35,4, 35,0, 32,2, 30,0, 27,4, 26,9, 23,9, 22,7, 22,0, 20,8, 20,0, 17,9, 15,9.

Example 37: 24-vanilloideae acid (compound 137)

According to the procedure described in example 3, replacing pivaloyloxymethyl of ester 24-CHLOROSILANES acid (104) pivaloyloxymethyl complex air 24-vanilloideae acid (136) and held at the before and column flash chromatography water treatment (EtOAc, water + aq. HCl to pH of about 2 and feast upon. NaCl) receive a net specified in the title compound (137).

13C NMR (CDCl3): 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: Pivaloyloxymethyl ester 24-(4-bromophenyl)fusidic acid (compound 138)

According to the procedure described in example 36, when replacing phenylboronic acid [2-(4-bromophenyl)-5,5-dimethyl-1,3,2-dioxaborinane]om get mentioned in the title compound (138).

13C NMR (CDCl3): 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)fozilova acid (compound 139)

According to the procedure described in example 3, replacing pivaloyloxymethyl of ester 24-CHLOROSILANES acid (104) pivaloyloxymethyl complex air 24-(4-bromophenyl)fusidic acid (138) and when performing in front of a column flash chromatography water treatment (EtOAc, water + aq. HCl to pH of about 2 and feast upon. NaCl) receive a net specified in the title compound (139).

13C NMR (CDCl3): 174,0, 170,6, 152,1, 142,9, 133,0, 131,3, 131,1, 129,1, 128,4, 119,8, 74,3, 71,5, 68,0, 49,0, 48,6, 44,4, 39,4, 39,0, 37,0, 36,2, 35,1, 35,0, 32,3, 30,1, 30,0, 27,4, 24,0, 22,7, 22,1, 20,8, 20,6, 20,0, 17,9, 15,9.

Example 40: Pivaloyloxymethyl ester 24-(4-shall lorgeril)fusidic acid (compound 140)

According to the procedure described in example 36, when replacing phenylboronic acid [2-(4-chlorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane]om get mentioned in the title compound (140).

13C NMR (CDCl3): 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)fozilova acid (compound 141)

According to the procedure described in example 3, replacing pivaloyloxymethyl of ester 24-CHLOROSILANES acid (104) pivaloyloxymethyl complex air 24-(4-chlorophenyl)fusidic acid (140) and when performing in front of a column flash chromatography water treatment (EtOAc, water + aq. HCl to pH of about 2 and feast upon. NaCl) receive a net specified in the title compound (141).

13C NMR (CDCl3): 173,9, 170,6, 151,9, 142,4, 133,0, 131,8, 130,9, 129,2, 129,1, 128,1, 74,3, 71,6, 71,5, 68,0, 49,0, 48,6, 44,4, 39,4, 39,0, 37,0, 36,2, 36,1, 35,0, 32,3, 30,0, 27,4, 24,0, 22,7, 22,1, 21,3, 20,8, 20,6, 20,0, 17,9, 15,9.

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

According to the procedure described in example 36, when replacing phenylboronic acid [2-(3,5-differenl)-5,5-dimethyl-1,3,2-dioxaborinane]om get mentioned in the title compound (142).

13C NMR (CDCl3): 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, 3,3, 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-differenl)fozilova acid (compound 143)

According to the procedure described in example 3, replacing pivaloyloxymethyl of ester 24-CHLOROSILANES acid (104) pivaloyloxymethyl complex air 24-(3,5-differenl)fusidic acid (142) and when performing in front of a column flash chromatography water treatment (EtOAc, water + aq. HCl to pH of about 2 and feast upon. NaCl) receive a net specified in the title compound (143).

13C NMR (CDCl3): 174,1, 170,6, 162,8, 162,7, 152,0, 147,2, 132,3, 130,2, 129,0, 112,2, 101,4, 74,3, 71,5, 68,1, 49,1, 48,6, 44,4, 39,4, 39,0, 37,0, 36,2, 36,2, 35,3, 34,5, 32,4, 30,2, 29,9, 27,5, 24,1, 22,7, 22,1, 20,7, 20,6, 20,1, 17,9, 15,9.

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

Acetoxymethyl ester 24-pomposity acid (107) (0.45 g, 0.67 mmol) dissolved in dry benzene (10 ml) and stirred in an argon atmosphere. Add triphenylphosphine (0.7 g, 2.7 mmol) and tetrabromomethane (1.1 g, 3.3 mmol) and the mixture is stirred at room temperature for one hour. Add diethyl ether (50 ml) and the precipitated material is removed by filtration. The filtrate is concentrated and the residue purified flash column-chromatography (eluent: 0%-50% EtOAc in petroleum ether)to give specified in the title compound (144).

13C NMR (CDCl3): 170,3, 169,6, 167,8, 152,3, 11,8, 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-pomposity acid (compound 108)

24,25-dibromoethyl acid (17) (crude product obtained from 0.1 mol fusidic acid) is dissolved in EtOH (900 ml) and water (25 ml) and add K2CO3(30 g, 0.22 mol). The mixture is refluxed with continuous stirring for 30 minutes, cooled to room temperature and poured into water (4 liters). The alkaline solution of potassium salt (108) is acidified by adding aq. H3PO4(350 ml, 1M) with continuous stirring until a pH of 4.0, with a precipitate. The product is collected by filtration, washed with water and dried to obtain the crude product (108). Specified raw connection 108 can then be purified and crystallized, for example, by the procedure described in example 8, to obtain the pure compounds 108, or can be converted into an easily hydrolyzable ester, for example, by the procedure described in the methods of obtaining 1 and 2, or can be converted into a suitable salt such as sodium salt, as described in example 9. The advantage of the sodium salt of compound 108 8 is that it is immediately possible to obtain very pure crystalline sodium salt, so there is no need to chromatograph the standard treatment. With the release of the free acid from the sodium salt (for example, as described above with respect to potassium salt) receive the product, which can be directly subjected to crystallization (for example, ethyl acetate and toluene) with the formation of pure crystalline compound 108.

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

According to the procedure given in example 12, replacing 2-propandiol atention get mentioned in the title compound (146).

13C NMR (CDCl3): 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-ethylsulfinylmethyl acid (compound 147)

The procedure in example 13, replacing the 24-bromo-16-deacetoxy-16β-isopropylthiazole acid (112) 24-bromo-16-deacetoxy-16β-aterciopelados acid (compound 146) get mentioned in the title compound (147).

1H NMR (CDCl): 4,40 (d, 1H), 4,37 (m, 1H), 3,76 (m, 1H), 3,18 (d, 1H), 2,90-to 2.40 (m, 5H), of 2.25 to 1.0 (m, 19H), 1,84 (Sh.S., 3H), 1.77 in (Sh.S., 3H), 1,45 (s, 3H), 1,25 (t, 3H), of 0.97 (s, 3H), of 0.93 (d, 3H), of 0.79 (s, 3H).

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

According to the procedure given in example 12, replacing 2-propandiol allylmercaptan get mentioned in the title compound (148).

13C 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)fozilova acid (compound 149)

According to the procedure given in example 12, replacing 2-propanethiol 1-potentiala get mentioned in the title compound (149).

13C NMR (CDCl3): 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-intercoupling)fozilova acid (compound 150)

The procedure in example 13, replacing the 24-bromo-16-deacetoxy-16β-isopropylthiazole acid (112) 24-bromo-16-deacetoxy-16β-(1-pentylthio)fusidic acid (compound 149) get mentioned in the title compound (150).

13C NMR (CDCl3): 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)fozilova acid (compound 151)

According to the procedure given in example 12, replacing 2-propanethiol 2-methyl-1-butandiol get mentioned in the title compound (151).

13C NMR (CDCl3): 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-butylsulfonyl)fozilova acid (compound 152)

The procedure in example 13, replacing the 24-bromo-16-deacetoxy-16β-isopropylthiazole acid (112) 24-bromo-16-deacetoxy-16β-(2-methyl-1-butylthio)fusidic acid (compound 151) get mentioned in the title compound (152).

13C NMR (CDCl3): 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)fozilova acid (compound 153)

According to the procedure given in example 12, replacing 2-propanethiol 3-methyl-1-butandiol get mentioned in the title compound (153).

13C NMR (CDCl3): 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-butylsulfonyl)fozilova acid (compound 154)

The procedure in example 13, replacing the 24-bromo-16-deacetoxy-16β-isopropylthiazole acid (112) 24-bromo-16-deacetoxy-16β-(3-methyl-1-butylthio)fusidic acid (compound 153) get mentioned in the title compound (154).

13C NMR (CDCl3): 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-dear the toxi-16β-cyclopentylpropionate acid (compound 155)

A solution of bromine (12.0 mg, 0,150 mol) in ethyl acetate (0.6 ml) are added to a solution of 16-deacetoxy-16β-cyclopentylpropionic acid (von Daehne, W.et. al., Adv. Appl. Environ., 1979, vol 25, p. 95-146) (76,0 mg, 0,136 mmol) in ethyl acetate (4 ml) for 2 minutes under stirring and cooling in an ice bath. Next, add 1M aq. KH2PO4(0.2 ml) and 1M aq. Na2S2O3(0.1 ml), under stirring for 5 minutes. EtOAc phase was separated, extracted with 0.5m aq. KH2PO4(0.5 ml) and water (0.5 ml) and concentrate to obtain the intermediate analog 24,25-dibromothiophene acid in the form of oil, which is used without further purification in the reaction of dihydrobromide. The intermediate product is similar to 24.25-dibromothiophene acid dissolved in ethanol (3 ml), add water (0.06 ml) and K2CO3(40 mg, 0.3 mmol) and the mixture refluxed with stirring for ½ hour; cooled to room temperature and poured into water (15 ml). Alkaline solution (155) is acidified by addition of 1M aq. H3PO4under stirring until pH 4.0 and process (EtOAc, feast upon. NaCl) to obtain the crude product. Below the crude product is purified column flash chromatography (10-50% EtOAc in petroleum ether + 1% AcOH as eluent) to obtain the net specified in the connection header (155).

13C 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'-triptoreline) fozilova acid (compound 156)

According to the procedure given in example 12, replacing 2-propandiol 2,2,2-cryptomaterial get mentioned in the title compound (156).

13C NMR (CDCl3): 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)fozilova acid (compound 157)

According to the procedure described in example 55, when replacing a 16-deacetoxy-16β-cyclopentylpropionic acid 16 deacetoxy-16β-(2-hydroxyethylthio)fusidic acid (von Daehne, W.et. al., Adv. Appl. Environ., 1979, vol 25, p. 95-146) get mentioned in the title compound (157).

13C NMR (CDCl3): 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-sensitivedata acid (compound 158)

According to the procedure given in example 12, replacing 2-propandiol benzylmercaptan get mentioned in the title compound (158).

13C NMR (CDCl3): 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, 8,9, 16,0.

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

The procedure in example 13, replacing the 24-bromo-16-deacetoxy-16β-isopropylthiazole acid (112) 24-bromo-16-deacetoxy-16β-benzylcyanide acid (158) get mentioned in the title compound (159).

1H NMR (CDCl3): 7,30 (m, 5H), of 4.54 (d, 1H), 4,35 (Sh.S., 1H), Android 4.04 (d, 1H), 3,76 (m, 1H), 3,l5 (SD, 1H), 2,80-2,4 (m, 4H), 2,20-1,0 (m, 18H), 1,84 (Sh.S., 3H), 1,76 (Sh.S., 3H), of 1.38 (s, 3H), of 0.96 (s, 3H), of 0.92 (d, 3H), 0.75 in (s, 3H).

Example 60: 24-bromo-16-deacetoxy-16β-(2-fullerto)fozilova acid (compound 160)

According to the procedure given in example 12, replacing 2-propandiol furfurylmercaptan get mentioned in the title compound (160).

13C NMR (CDCl3): 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-phenylthiourea acid (compound 161)

According to the procedure given in example 12, replacing 2-propandiol thiophenols get mentioned in the title compound (161).

13C NMR (CDCl3): 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-benzoylthiourea acid (compound 162)

The procedure in PR is least 55, when replacing a 16-deacetoxy-16β-cyclopentylpropionic acid 16 deacetoxy-16β-benzoylthiophene acid (von Daehne, W.et. al., Adv. Appl. Environ., 1979, vol 25, p. 95-146) get mentioned in the title compound (162).

13C NMR (CDCl3): 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-isopropoxypyridine acid (compound 163)

According to the procedure described in example 55, when replacing a 16-deacetoxy-16β-cyclopentylpropionic acid 16 deacetoxy-16β-isopropoxybenzoic acid (von Daehne, W.et. al., Adv. Appl. Environ., 1979, vol 25, p. 95-146) get mentioned in the title compound (163).

13C NMR (CDCl3): 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-floratone)fozilova acid (compound 164)

According to the procedure described in example 55, when replacing a 16-deacetoxy-16β-cyclopentylpropionic acid 16 deacetoxy-16β-(2-floratone)fusidic acid (von Daehne, W.et. al., Adv. Appl. Environ., 1979, vol 25, p. 95-146) get the specified header connection (164).

13C NMR (CDCl3): 174,0, 151,8, 131,4, 129,6, 120,3, 82,5, 80,1, 71,5, 69,1, 68,4, 49,2, 49,1, 43,8, 39,6, 37,7, 37,1, 36,3, 36,1, 35,7, 32,6, 30,3, 30,0, 28,3, 25,3, 24,3, 22,6, 20,8, 20,4, 18,0, 16,0.

Example 65: 24-bromo-deacetoxy-16β-(2-metoxi is hydroxy)fozilova acid (compound 165)

According to the procedure described in example 55, when replacing a 16-deacetoxy-16β-cyclopentylpropionic acid 16 deacetoxy-16β-(2-methoxyethoxy)fusidic acid (von Daehne, W.et. al., Adv. Appl. Environ., 1979, vol 25, p. 95-146) get mentioned in the title compound (165).

13C NMR (CDCl3): 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)fozilova acid (compound 166)

Suspension pivaloyloxymethyl of ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (306) (50 mg, 0,070 mmol) in MEOH (1 ml) cooled in an ice bath and add K2CO3(20 mg, 0.14 mmol). The mixture is stirred at room temperature for 3 hours and then treated (EtOAc, water + aq. HCl to pH of about 2 and feast upon. NaCl) to obtain the crude product. After column flash chromatography of the crude product (petroleum ether:EtOAc:HCOOH (90:10:0-0:99:1 as eluent) to get the net specified in the title compound (166).

13C NMR (CDCl3): 174,1, 170,6, 149,9r129,9, 129,8, 129,7, 128,5, 127,9, 74,5, 71,5, 68,2, 49,2, 48,7, 44,2, 39,5, 39,0, 37,0, 36,2, 36,2, 35,7, 33,2, 32,4, 32,1, 30,3, 29,9, 28,0, 27,8, 24,2, 22,8, 22,3, 21,5, 20,8, 20,6, 20,4, 17,8, 15,9, 14,0.

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

The procedure in example 66, when replacing pivaloyloxy the methyl ether complex 24-( TRANS-1-HEXEN-1-yl)fusidic acid (306) pivaloyloxymethyl complex air 24-(TRANS-1-butene-3,3-dimethyl-1-yl) fusidic acid (307) get mentioned in the title compound (167).

13C NMR (CDCl3): 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)fozilova acid (compound 168)

The procedure in example 66, when replacing pivaloyloxymethyl of ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (306) pivaloyloxymethyl complex air 24-(TRANS-1 nonen-1-yl) fusidic acid (308) get mentioned in the title compound (168).

13C NMR (CDCl3): 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)fozilova acid (compound 169)

The procedure in example 66, when replacing pivaloyloxymethyl of ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (306) pivaloyloxymethyl complex air 24-(TRANS-5-chloro-1-penten-1-yl)fusidic acid (309) get mentioned in the title compound (169).

13C NMR (CDCl3): 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,, 20,4, 17,8, 15,9.

Example 70: 24-(TRANS-2-phenyl-1-vinyl)fozilova acid (compound 170)

The procedure in example 66, when replacing pivaloyloxymethyl of ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (306) pivaloyloxymethyl complex air 24-(TRANS-2-phenyl-1-vinyl)fusidic acid (310) get mentioned in the title compound (170).

13C NMR (CDCl3): 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)fozilova acid (compound 171)

The procedure in example 66, when replacing pivaloyloxymethyl of ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (306) pivaloyloxymethyl complex air 24-(2-phenyl-1-ethyl)fusidic acid (311) get mentioned in the title compound (171).

13C NMR (CD3OD): 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)fozilova acid (compound 172)

The procedure in example 66, when replacing pivaloyloxymethyl of ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (306) pivaloyloxymethyl complex air 24-(4-n-propylphenyl)fusidic KIS is the notes (312) get mentioned in the title compound (172).

13C NMR (CDCl3): 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-vinylphenol)fozilova acid (compound 173)

The procedure in example 66, when replacing pivaloyloxymethyl of ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (306) pivaloyloxymethyl complex air 24-(4-vinylphenol)fusidic acid (313) get mentioned in the title compound (173).

13C NMR (CDCl3): 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)fozilova acid (compound 174)

The procedure in example 66, when replacing pivaloyloxymethyl of ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (306) pivaloyloxymethyl complex air 24-(4-tert-butylphenyl)fusidic acid (314) get mentioned in the title compound (174).

13C NMR (CDCl3): 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)fozilova acid (compound 175)

The procedure in example 66, when replacing pivaloyloxymethyl of ester 24-(tra is -1-HEXEN-1-yl)fusidic acid (306) pivaloyloxymethyl complex air 24-(4-cyanophenyl)fusidic acid (315) get mentioned in the title compound (175).

13C NMR (CDCl3): 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)fozilova acid (compound 176)

The procedure in example 66, when replacing pivaloyloxymethyl of ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (306) pivaloyloxymethyl complex air 24-(3-biphenyl)fusidic acid (316) get mentioned in the title compound (176).

13C NMR (CDCl3): 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)fozilova acid (compound 177)

The procedure in example 66, when replacing pivaloyloxymethyl of ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (306) pivaloyloxymethyl complex air 24-(4-(trifluoromethyl)phenyl)fusidic acid (317) get mentioned in the title compound (177).

13C NMR (CDCl3): 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-meth is xifei)fozilova acid (compound 178)

The procedure in example 66, when replacing pivaloyloxymethyl of ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (306) pivaloyloxymethyl complex air 24-(4-methoxyphenyl)fusidic acid (318) get mentioned in the title compound (178).

13C NMR (CDCl3): 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)fozilova acid (compound 179)

The procedure in example 66, when replacing pivaloyloxymethyl of ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (306) pivaloyloxymethyl complex air 24-(3-cyanophenyl)fusidic acid (319) get mentioned in the title compound (179).

13C NMR (CDCl3): 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)fozilova acid (compound 180)

The procedure in example 66, when replacing pivaloyloxymethyl of ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (306) pivaloyloxymethyl complex air 24-(2-methoxyphenyl)fusidic acid (320) get mentioned in the title compound (180).

1H NMR (CDCl3): of 7.23 (m, 1H), 6,95 (m, 3H), of 5.83 (d, 1H), 3,81 (Sh.S., 1H), 3,79 (s, 3H), 3,74 (W.the., 1H), 2,81 (DD, 1H), 2,65-of 0.95 (m, 22H), of 1.95 (s, 3H), 1,84 (Sh.S., 3H), 1,50 (Sh.S., 3H), of 1.27 (s, 3H), 0,92 (Sh.S., 3H), of 0.92 (d, 3H), 0,81 (Sh.S., 3H).

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

The procedure in example 66, when replacing pivaloyloxymethyl of ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (306) pivaloyloxymethyl complex air 24-(3-nitrophenyl)fusidic acid (321) get mentioned in the title compound (181).

13C NMR (CDCl3): 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)fozilova acid (compound 182)

The procedure in example 66, when replacing pivaloyloxymethyl of ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (306) pivaloyloxymethyl complex air 24-(3-bromophenyl)fusidic acid (322) get mentioned in the title compound (182).

13C NMR (CDCl3): 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)fozilova acid (compound 183)

The procedure in example 66, when replacing pivaloyloxymethyl of ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (306) pivaloyloxymethyl complex air 24-(4-(IU is ylthio)phenyl)fusidic acid (323) get mentioned in the title compound (183).

13C NMR (CDCl3): 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)fozilova acid (compound 184)

The procedure in example 66, when replacing pivaloyloxymethyl of ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (306) pivaloyloxymethyl complex air 24-(2-naphthyl)fusidic acid (324) get mentioned in the title compound (184).

13C NMR (CDCl3): 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)fozilova acid (compound 185)

The procedure in example 66, when replacing pivaloyloxymethyl of ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (306) pivaloyloxymethyl complex air 24-(3,5-bis-(trifluoromethyl)phenyl)fusidic acid (325) get mentioned in the title compound (185).

13C NMR (CDCl3): 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-acid)fozilova acid (compound 186)

The procedure in example 66, when replacing pivaloyloxymethyl difficult what about the ether 24-( TRANS-1-HEXEN-1-yl)fusidic acid (306) pivaloyloxymethyl complex air 24-(3,4-acid)fusidic acid (326) get mentioned in the title compound (186).

13C NMR (CDCl3): 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)fozilova acid (compound 187)

The procedure in example 66, when replacing pivaloyloxymethyl of ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (306) pivaloyloxymethyl complex air 24-(3,5-dibromophenyl)fusidic acid (327) get mentioned in the title compound (187).

13C NMR (CDCl3): 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: Kalinova Sol 24-pomposity acid (compound 188)

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

13C NMR (CD3OD): 179,1, 173,3, 138,5, 138,3, 131,3, 122,6, 76,0, 72,5, 69,1, 68,9, 57,1, 54,7, 50,8, 50,0, 43,7,40,7, 40,3, 38,5, 38,3, 37,8, 37,5, 36,9, 33,0, 31,1, 31,0, 30,3, 25,4, 23,8, 22,5, 21,1, 20,5, 17,9, 16,5.

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

According to the procedure described in example 88, with the replacement of choline hydroxide L-arginine (261 mg, 1.5 mmol, in water (10 ml) receive specified in the title compound (189) (from ethyl acetate) in the form of amorphous powder.

13C NMR (CD3OD): 179,2, 174,7, 173,3, 158,9, 139,9, 137,6, 131,5, 122,4, 75,9, 72,5, 68,8, 55,6, 50,8, 50,0, 43,9, 41,9, 40,7, 40,2, 38,6, 38,3, 37,9, 37,5, 36,9, 33,0, 31,1, 31,0, 30,1, 29,5, 25,8, 25,4, 23,8, 22,5, 21,1, 20,5, 17,9, 16,5.

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

According to the procedure described in example 88, with the replacement of choline hydroxide 2-(dimethylamino)ethanol (151 μl, 134 mg, 1.5 mmol) get mentioned in the title compound (190) (from diethyl ether) in the form of crystals.

13C NMR (CD3OD): 178,1, 173,1, 141,6, 136,4, 131,6, 122,3, 75,9, 72,5, 68,8, 66,9, 60,9, 57,5, 50,8, 50,0, 44,1, 40,7, 40,2, 38,7, 38,3, 37,9, 37,5, 36,9, 33,0, 31,1, 31,0, 30,0, 25,4, 23,8, 22,5, 21,1, 20,5, 17,9, 16,5, 15,5.

Example 91: 4-(2-hydroxyethyl)Martinova Sol 24-pomposity acid (compound 191)

According to the procedure described in example 88, with the replacement of choline hydroxide 4-(2-hydroxyethyl)morpholine (184 μl, 197 mg, 1.5 mmol) get mentioned in the title compound (191) (from diisopropyl ether) as amorphous powder.

13C NMR (CD3OD): 175,0, 172,7, 147,7, 132,4, 132,2, 121,7, 75,8, 72,5, 68,6, 66,9, 61,3, 58,7, 54,6 50,7, 49,9, 44,9, 40,7, 40,1, 38,8, 38,2, 37,8, 37,4, 36,8, 32,9, 31,1, 31,0, 29,3, 25,5, 23,9, 23,1, 22,4, 20,8, 20,6, 18,0, 16,5.

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

According to the procedure described in example 88, with the replacement of choline hydroxide L-lysine (219 mg, 1.5 mmol, in water (5 ml)) get mentioned in the title compound (192) (from ethyl acetate) in the form of crystals.

13C NMR (CD3OD): 179,1, 175,1, 173,2, 139,4, 137,9, 131,4, 122,5, 75,9, 72,5, 68,8, 55,9, 50,8, 50,0, 43,9, 40,7, 40,4, 40,3, 38,6, 38,3, 37,9, 37,5, 36,9, 33,0, 32,0, 31,1, 31,0, 30,2, 28,5, 25,4, 23,8, 23,2, 22,5, 21,2, 20,6, 17,9, 16,5.

Example 93: N-(2-hydroxyethyl)pyrolidine Sol 24-pomposity acid (compound 193)

According to the procedure described in example 88, with the replacement of choline hydroxide N-(2-hydroxyethyl)pyrrolidine (177 μl, 173 mg, 1.5 mmol) get mentioned in the title compound (193) (from diisopropyl ether) in the form of crystals.

13C NMR (CD3OD): 178,5, 173,1, 140,7, 137,0, 131,5, 122,4, 75,9, 72,5, 70,1, 68,8, 58,3, 55,2, 50,8, 50,0, 44,0, 40,7, 40,2, 38,6, 38,3, 37,8, 37,5, 36,9, 33,0, 31,1, 31,0, 30,1, 25,4, 24,0, 23,8, 23,1, 22,5, 21,1, 20,5, 17,9, 16,5.

Example 94: Ethanolamine Sol 24-pomposity acid (compound 194)

According to the procedure described in example 88, with the replacement of choline hydroxide by ethanolamine (90 μl, 92 mg, 1.5 mmol) get mentioned in the title compound (194) (from diethyl ether) as amorphous powder.

13C NMR (CD3OD): 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, 3,3, 37,8, 37,5, 36,9, 33,0, 31,1, 31,0, 30,1, 25,4, 23,8, 22,5, 21,1, 20,5, 17,9, 16,5.

Example 95: Potassium salt of 24-pomposity acid (compound No. 195)

An aqueous solution of potassium hydroxide (0,82 M, 1.8 ml, 1.5 mmol) is added gradually to a solution of 24-pomposity acid (108) (893 mg, 1.5 mmol) in ethanol (10 ml) and water (2.5 ml). the pH of the solution is followed by means of a pH meter. Add some more water (7.5 ml) to pH about 7. The resulting solution (final pH 10) concentrate under reduced pressure and the residue crystallized from acetone. Specified in the title compound (195) collected by filtration.

13C NMR (CD3OD): 179,2, 173,4, 138,6, 138,4, 131,3, 122,6, 75,9, 72,5, 68,9, 50,8, 50,0, 43,7, 40,7, 40,3, 38,5, 38,3, 37,8, 37,5, 36,9, 33,0, 31,1, 31,0, 30,3, 25,4, 23,8, 22,5, 21,2, 20,5, 17,9, 16,5, 8,1.

Example 96: Tetrabutylammonium Sol 24-pomposity acid (compound 196)

According to the procedure described in example 95, the replacement of potassium hydroxide aq. tetrabutylammonium hydroxide (about 25%, 1.8 ml, 1.5 mmol, final pH 9) get mentioned in the title compound (196) (from diethyl ether) in the form of crystals.

13C NMR, (CD3OD): 178,3, 173,2, 140,3, 137,1, 131,4, 122,5, 76,0, 72,5, 68,8, 59,5, 50,8, 50,0, 43,9, 40,7, 40,2, 38,6, 38,3, 37:8, 37,5, 36,8, 32,9, 31,1, 31,0, 30,0, 25,4, 24,8, 23,8, 22,5, 21,1, 20,7, 20,5, 17,9, 16,5, 14,0.

Example 97: Benzyltrimethylammonium Sol 24-pomposity acid (compound 197)

According to the procedure described in example 95, the replacement of hydroxide feces what I hydroxide designed (about 40% in methanol, with a final pH 9) get mentioned in the title compound (197) (from acetone) in the form of crystals.

1H NMR (CD3OD): at 7.55 (m, 5H) 5,74 (d, 1H), 4.53-in (s, 2H), 4,30 (Sh.S., 1H), 3,64 (Sh.S., 1H), 3,10 (s, 9H), 3.00 and (d, 1H), 2.8 to 2.0 (m, 8H), of 1.99 (s, 3H), 1,91-of 1.40 (m, 7H)and 1.83 (s, 3H), of 1.80 (s, 3H), of 1.38 (s, 3H), 1,2-1,0 (m, 3H), 0,99 (s, 3H), of 0.95 (s, 3H), of 0.89 (d, 3H).

Example 98: Cetyltrimethylammonium Sol 24-pomposity acid (compound 198)

According to the procedure described in example 95, the replacement of hydroxide, potassium hydroxide, cetyltrimethylammonium (approximately 10% in water with a final pH 10) get mentioned in the title compound (198) (methyl ethyl ketone) in the form of crystals.

13C NMR (CD3OD): 179,2, 173,3, 138,4, 138,3, 131,2, 122,6, 76,0, 72,5, 68,9, 67,9, 53,5, 50,8, 50,0, 43,7, 40,7, 40,3, 38,5, 38,3, 37,8, 37,5, 36,8, 33,1, 32,9, 31,1, 31,0, 30,8, 30,7, 30,6, 30,5, 30,3, 27,4, 25,4, 24,0, 23,9, 23,8, 22,5, 21,1, 20,5, 17,9, 16,5, 14,5.

Example 99: Tetramethylammonium Sol 24-pomposity acid (compound 199)

According to the procedure described in example 95, the replacement of potassium hydroxide hydroxide of Tetramethylammonium (approximately 10% in water with a final pH 10) get mentioned in the title compound (199) (from acetone/diethyl ether) in the form of crystals.

13C NMR (CD3OD): 179,2, 173,3, 138,4, 138,3, 131,2, 122,6, 76,0, 72,5, 68,9, 55,9, 50,8, 50,0, 43,7, 40,7, 40,-3, 38,5, 38,3, 37,8, 37,5, 36,8, 32,9, 31,1, 31,0, 30,3, 25,4, 23,8, 23,8, 22,5, 21,1, 20,5, 17,9, 16,5.

Example 100: Tetrapropylammonium Sol 24-pomposity acid (compound 300)

The procedure is shown in example 95, when replacing potassium hydroxide hydroxide of tetrapropylammonium (approximately 10% in water with a final pH of 9.5) get mentioned in the title compound (300) (from acetone/diethyl ether) in the form of crystals.

13C NMR (CD3OD): 179,2, 173,3, 138,4, 138,3, 131,2, 122,7, 76,0, 72,5, 68,9, 61,3, 50,8, 50,0, 43,7, 40,7, 40,3, 38,5, 38,3, 37,8, 37,5, 36,9, 33,0, 31,1, 31,0, 30,3, 25,4, 23,8, 23,8, 22,5, 21,1, 20,5, 17,9, 16,5, 16,4, 10,9.

Example 101: Tris(hydroxymethyl)aminobutanova Sol 24-pomposity acid (compound 301)

According to the procedure described in example 88, with the replacement of potassium hydroxide Tris(hydroxymethyl)aminomethane (82 mg, 1.5 mmol)dissolved in ethanol (12 ml) and water (8 ml), get mentioned in the title compound (301) (from diethyl ether) as amorphous powder.

13C NMR (CD3OD): 178,8, 173,3, 140,1, 137,4, 131,4, 122,4, 76,0, 72,5, 70,1, 68,8, 61,8, 50,8, 50,0, 43,9, 40,7, 40,2, 38,6, 38,3, 37,8, 37,5, 36,9, 32,9, 31,1, 31,0, 30,1, 25,4, 23,8, 23,1, 22,5, 21,1, 20,5, 17,9, 16,5.

Example 102: N-methyl-D-glucagonoma Sol 24-pomposity acid (compound 302)

According to the procedure described in example 88, with the replacement of hydroxide potassium N-methyl-D-glucamine (293 mg, 1.5 mmol)dissolved in ethanol (5 ml) and water (5 ml), get mentioned in the title compound (302) (from diethyl ether) as amorphous powder.

13C NMR (CD3OD): 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, 145.

Example 103: Silver Sol 24-pomposity acid (compound 303)

The solution of sodium salt of 24-pomposity acid (109) (926 mg, 1.5 mmol) in water (10 ml) are added to a solution of silver acetate (250 mg, 1.5 mmol) in water (30 ml). Add ethanol (25 ml) and after one hour of finely dispersed precipitate is collected by filtration through a fine glass Frit), washed with water and driedin the vacuumover silica gel in the dark for several days. Silver Sol (303) is a slightly grey amorphous powder.

1H NMR (DMSO): of 5.68 (d, 1H), 4,14 (W.,1H), 4.00 points (m, 2H), 3,51 (W., 1H), 2,9-0,93 (m, 20H), 1,90 (s, 3H), 1,79 (s, 3H), of 1.78 (s, 3H), of 1.27 (s, 3H), 0,89 (s, 3H), of 0.82 (s, 3H), of 0.79 (d, 3H).

Example 104: Benzethonium Sol 24-pomposity acid (compound 304)

The chloride solution benzene (672 mg, 1.5 mmol) in water (5 ml) are added to a solution of sodium salt 24-pomposity acid (109) (926 mg, 1.5 mmol) in water (10 ml), forming a sticky residue benzethonium salt. The aqueous phase is decanted and the precipitate washed with water by decantation. The residue is dissolved in acetone, concentrated and evaporated using ethyl acetate (3 times) to remove the water. After processing diethyl ether salt remains as a sticky mass, which is filtered off and leave for the night, getting mentioned in the title compound (304) in the form of brittle amorphous powder.

13C NMR (CD3 OD): 179,0, 173,3, 157,8, 143,6, 138,7, 138,2, 134,4, 132,0, 131,3, 130,4, 128,9, 128,4, 122,6, 114,8, 76,0, 72,5, 71,0, 70,4, 68,9, 68,3, 66,9, 65,9, 64,7, 58,0, 51,4, 50,8, 50,0, 43,7, 40,7, 40,3, 38,9, 38,5, 38,3, 37,8, 37,5, 36,8, 33,1, 32,9, 32,4, 32,3, 31,1, 31,0, 30,3, 25,4, 23,8, 23,8, 22,5, 21,1, 20,5, 17,9, 16,5, 15,5.

Example 105: Triethanolamine Sol 24-pomposity acid (compound 305)

According to the procedure described in example 88, with the replacement of choline hydroxide-triethanolamine (209 μl, 234 mg, 1.5 mmol, pure substance) get mentioned in the title compound (305) (from ethanol/diethyl ether) in the form of crystalline powder.

13C NMR (CD3OD): 176,4, 172,9, 144,7, 134,3, 131,9, 122,0, 75,8, 72,5, 68,7, 58,7, 57,6, 50,8, 50,0, 44,5, 40,7, 40,1, 38,7, 38,2, 37,8, 37,5, 36,8, 32,9, 31,0, 29,6, 25,5, 23,8, 22,4, 20,9, 20,5, 18,0, 16,5.

Example 106: Pivaloyloxymethyl ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (compound 306)

According to the procedure described in example 36, when replacing phenylboronic acidTRANS-1-HEXEN-1-ylboronic acid get mentioned in the title compound (306).

13C NMR (CDCl3): 177,0, 170,3, 168,4, 149,9, 129,8, 129,7, 129,6, 128,4, 127,8, 80,0, 74,4, 71,4, 68,2, 49,2, 48,7, 44,2, 39,4, 39,0, 38,8, 37,1, 36,2, 36,2, 35,7, 33,2, 32,5, 32,1, 30,3, 30,0, 27,8, 27,6, 26,9, 24,3, 22,7, 22,4, 21,5, 20,8, 20,7, 20,4, 17,9, 15,9, 14,0.

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

According to the procedure described in example 36, when replacing phenylboronic acidTRANS-1-butene-3,3-dimethyl--Voronovo acid get mentioned in the title compound (307).

13C NMR (CDCl3): 177,0, 170,3, 168,5, 149,9, 139,2, 130,1, 129,7, 129,5, 122,5, 80,0, 74,4, 71,4, 68,2, 49,2, 48,7, 44,2, 39,4, 39,0, 38,8, 37,1, 36,2, 36,2, 35,6, 33,4, 32,5, 30,3, 30,0, 29,0, 27,8, 27,7, 26,9, 24,3, 22,7, 21,6, 20,8, 20,7, 20,4, 17,8, 15,9.

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

According to the procedure described in example 36, when replacing phenylboronic acidTRANS-1 nonen-1-Voronovo acid get mentioned in the title compound (308).

13C NMR (CDCl3): 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: Pivaloyloxymethyl ester 24-(TRANS-5-chloro-1-penten-1-yl)fusidic acid (compound 309)

According to the procedure described in example 36, when replacing phenylboronic acidTRANS-5-chloro-1-penten-1-Voronovo acid get mentioned in the title compound (309).

13C NMR (CDCl3): 177,0, 170,2, 168,4, 149,9, 130,7, 129,6, 129,5, 129,3, 125,9, 80,0, 74,4, 71,4, 68,2, 49,2, 48,7, 44,6, 44,2, 39,4, 39,0, 38,8, 37,1, 36,3, 36,1, 35,7, 32,6, 30,5, 30,3, 30,0, 27,8, 27,6, 26,9, 24,3, 22,6, 21,5, 20,8, 20,7, 20,4, 17,9, 15,9.

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

According to the procedure described in example 36, when replacing phenylboronic acidTRANS-2-phenyl-1-vinylboronic acids the th receive specified in the title compound (310).

13C NMR (CDCl3): 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: Pivaloyloxymethyl ester 24-(2-phenyl-1-ethyl)fusidic acid (compound 311)

Pivaloyloxymethyl ester 24-(TRANS-2-phenyl-1-vinyl)fusidic acid (310) (230 mg, 0.3 mmol) dissolved in ethanol (5 ml) and added palladium on coal (25 mg, 5%). The flask is selected, attach it to the balloon containing hydrogen gas, and stirred overnight on a magnetic stirrer. The catalyst is filtered off through filter device and the filtrate concentrated. The crude product is purified column flash chromatography (eluent: petroleum ether:EtOAc, 90:10-50:50) to obtain the net specified in the connection header (311).

13C NMR (CD3OD): 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: Pivaloyloxymethyl ester 24-(4-n-propylphenyl)fusidic acid (compound 312)

According to the procedure described in example 36, when replacing phenylboronic acid 4-n-propylpentanoic acid get mentioned in the title compound (312).

13C NMR (CDCl3): 177,0, 170,2, 167,6, 152,5, 141,4, 140,5 133,8, 129,5, 129,0, 128,2, 127,8, 80,0, 74,4, 71,4, 67,9, 48,9, 48,7, 44,4, 39,4, 39,0, 38,8, 37,7, 36,9, 36,3, 36,1, 35,5, 35,0, 32,2, 30,1, 30,0, 27,4, 26,9, 24,7, 23,8, 22,7, 22,1, 20,9, 20,8, 19,9, 18,0, 15,9, 14,0.

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

According to the procedure described in example 36, when replacing phenylboronic acid 4-vinylephenylamino acid get mentioned in the title compound (313).

13C NMR (CDCl3): 177,0, 170,2, 167,7, 152,6, 143,8, 136,4, 135,4, 133,7, 129,9, 128,8, 128,5, 125,8, 113,6, 80,0, 74,3, 71,4, 67,8, 48,9, 48,6, 44,4, 39,4, 39,0, 38,8, 36,9, 36,3, 36,0, 35,3, 35,0, 32,2, 30,0, 27,3, 26,9, 23,9, 22,7, 22,1, 20,8, 20,8, 19,9, 17,9, 15,9.

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

According to the procedure described in example 36, when replacing phenylboronic acid 4-tertbutylferrocene acid get mentioned in the title compound (314).

13C NMR (CDCl3) 177,0, 170,2, 167,6, 152,5, 149,0, 140,9, 133,7, 129,1, 129,0, 128,3, 124,6, 80,0, 74,4, 71,4, 67,9, 48,9, 48,8, 44,3, 39,4, 39,0, 38,8, 36,9, 36,2, 36,1, 35,5, 34,8, 34,5, 32,3, 31,5, 30,3, 30,0, 27,5, 26,9, 23,9, 22,6, 22,1, 20,9, 20,7, 20,0, 18,1, 15,9.

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

According to the procedure described in example 36, when replacing phenylboronic acid 4-cyanobenzeneboronic acid get mentioned in the title compound (315).

13C NMR (CDCl3): 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: Pivaloyloxymethyl ester 24-(3-biphenyl)fusidic acid (compound 316)

According to the procedure described in example 36, when replacing phenylboronic acid 3-biphenylmethanol acid get mentioned in the title compound (316).

13C NMR (CDCl3): 177,0, 170,2, 167,8, 152,3, 144,4, 140,9, 140,7, 133,9, 128,9, 128,8, 128,6, 128,6, 128,5, 128,0, 127,5, 126,9, 124,5, 80,0, 74,3, 71,4, 67,8, 48,8, 48,6, 44,4, 39,3, 39,0, 38,8, 36,8, 36,2, 36,1, 35,5, 34,8, 32,2, 30,0, 27,6, 26,9, 23,9, 22,5, 22,2, 20,8, 20,7, 20,0, 18,0, 15,9.

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

According to the procedure described in example 36, when replacing phenylboronic acid 4-(trifluoromethyl)phenylboronic acid get mentioned in the title compound (317).

13C NMR (CDCl3): 177,0, 170,2, 167,7, 152,6, 147,8, 133,0, 129,8, 129,7, 128,5, 125,0, 124,9, 80,0, 74,2, 71,4, 67,9, 49,0, 48,6, 44,5, 39,3, 39,0, 3878, 37,0, 36,2, 36,1, 34,9, 34,8, 32,5, 30,0, 27,4, 26,9, 24,2, 22,4, 22,1, 20,8, 20,6, 20,0, 18,0, 15,9.

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

According to the procedure described in example 36, when replacing phenylboronic acid 4-methoxyphenylacetic acid get mentioned in the title compound (318).

13C NMR (CDCl3): 177,0, 170,2, 167,7, 157,9, 152,2, 136,3, 133,4, 130,6, 129,0, 1282, 113,2, 80,0, 74,3, 71,4, 67,9, 55,2, 49,0, 48,6, 44,4, 39,4, 39,0, 38,8, 36,9, 36,3, 36,0, 35,3, 35,1, 32,1, 30,0, 27,3, 26,9, 23,8, 22,8, 22,0, 20,8, 20,0, 17,9, 15,9.

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

According to the procedure described in example 36, when replacing phenylboronic acid 3-cyanophenylacetic acid get mentioned in the title compound (319).

13C NMR (CDCl3): 177,0, 170,2, 167,7, 152,3, 144,9, 134,0, 132,9, 132,2, 130,6, 129,7, 128,9, 128,5, 119,0, 112,2, 80,0, 74,2, 71,3, 68,1, 49,1, 48,7, 44,5, 39,4, 39,0, 38,8, 37,1, 36,3, 36,1, 35,2, 34,4, 32,6, 30,3, 30,0, 27,5, 26,9, 24,3, 22,5, 22,1, 20,8, 20,6, 20,2, 18,0, 15,9.

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

According to the procedure described in example 36, when replacing phenylboronic acid 2-methoxyphenylacetic acid get mentioned in the title compound (320).

13C NMR (CDCl3): 177,0, 170,2, 167,8, 157,2, 152,2, 132,7, 131,9, 130,9, 130,3, 129,1, 127,5, 120,3, 111,0, 79,9, 74,4, 71,5, 68,0, 55,9, 55,4, 48,9, 48,7, 44,4, 39,4, 39,0, 38,8, 36,8, 36,4, 36,0, 35,4, 34,4, 33,2, 32,1, 30,0, 27,2, 26,9, 23,8, 22,8, 22,0, 20,9, 19,7, 17,9, 15,9.

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

According to the procedure described in example 36, when replacing phenylboronic acid 3-nitrophenylarsonic acid get mentioned in the title compound (321).

13C NMR (CDCl3): 177,0, 170,2, 167,7, 152,3, 148,3, 145,3, 135,7, 132,1, 130,9, 129,0, 128,4, 124,1, 121,l, 80,0, 74,2,71,3, 68,1, 49,0, 48,6, 44,5, 39,4, 39,0, 38,8, 37,0, 36,3, 36,1, 35,2, 34,3, 32,6, 30,3, 30,0, 27,6, 26,9, 24,3, 22,5, 22,2, 20,8, 20,6, 20,3, 18,0, 15,9.

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

According to the procedure described in example 36, when replacing phenylboronic acid 3-brompheniramine acid get mentioned in the title compound (322).

13C NMR (CDCl3): 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: Pivaloyloxymethyl ester 24-(4-(methylthio)phenyl)fusidic acid (compound 323)

According to the procedure described in example 36, when replacing phenylboronic acid 4-(methylthio)phenylboronic acid get mentioned in the title compound (323).

13C NMR (CDCl3): 177,0, 170,2, 167,7, 152,5, 140,8, 135,9, 133,3, 130,1, 128,7, 128,5, 125,9, 79,9, 74,3, 71,4, 67,9, 48,9, 48,6, 44,4, 39,4, 39,0, 38,8, 36,9, 36,3, 36,0, 35,2, 35,0, 32,1, 30,0, 29,9, 27,3, 26,9, 23,9, 22,8, 22,0, 20,8, 20,8, 19,9, 17,9, 15,9, 15,6.

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

According to the procedure described in example 36, when replacing phenylboronic acid 2-NativeWindow acid get mentioned in the title compound (324).

13C NMR (CDCl3): 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, 5,2, 35,1, 32,0, 29,9, 29,6, 27,4, 26,9, 23,7, 22,6, 22,2, 20,8, 20,8, 19,9, 17,8, 15,9.

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

According to the procedure described in example 36, when replacing phenylboronic acid 3,5-bis-(trifluoromethyl)phenylboronic acid get mentioned in the title compound (325).

13C NMR (CDCl3): 176,9, 170,2, 167,6, 152,7, 145,9, 131,7, 131,7, 131,4, 129,4, 128,2, 123,5, 120,0, 80,1, 74,2, 71,3, 67,9, 60,4, 49,0, 48,6, 44,6, 39,4, 39,0, 38,8, 37,0, 36,2, 36,1, 35,3, 34,6, 32,5, 30,2, 30,0, 27,6, 26,9, 24,3, 22,4, 22,1, 20,8, 20,6, 20,2, 18,0, 15,9, 14,2.

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

According to the procedure described in example 36, when replacing phenylboronic acid 3,4-dimethoxyphenylacetic acid get mentioned in the title compound (326).

13C NMR (CDCl3): 177,0, 170,2, 167,8, 152,1, 148,5, 147,3, 136,6, 133,7, 128,9, 128,2, 121,7, 113,1, 110,6, 80,0, 74,3, 71,4, 67,9, 56,1, 55,8, 49,0, 48,6, 44,4, 39,4, 39,0, 38,8, 36,9, 36,3, 36,0, 35,2, 35,0, 32,2, 30,0, 27,5, 26,9, 23,9, 22,7, 22,1, 20,8, 20,8, 20,0, 17,9, 15,9, 14,2.

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

According to the procedure described in example 36, when replacing phenylboronic acid 3,5-dibromopropanol acid get mentioned in the title compound (327).

13C NMR (CDCl3): 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, 8,1, 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.

1. Derivatives of fusidic acid of General formula I

where X denotes a halogen, trifluoromethyl, C1-With7alkyl, substituted phenyl, C2-C9alkenyl, optionally substituted C1-C7by alkyl, halogen or phenyl, phenyl, optionally substituted by one or two identical or different substituents selected from the group consisting of halogen, C1-C7of alkyl, C2-C9alkenyl, phenyl, C1-C6alkoxy, nitro, C1-C6alkylthio, trifloromethyl and cyano; or X represents naphthyl;
Y and Z both represent hydrogen or together with the linking C-17/C-20 form a double bond between C-17 and C-20 or together represent a methylene to form cyclopropane ring in combination with the C-17 and C-20;
And denotes O, S or S(O);
In stands With1-6alkyl, C2-6alkenyl,1-6acyl, phenyl or benzoyl, where C1-6optionally substituted by one or more halogen, hydroxy, C2-6alkenyl, phenyl, C1-4heteroaryl or1-6alkoxy;
Q1means -(NON)-, or -(CHW)-, where W represents halogen or azido;
Q2means -(NON)-;
and its pharmaceutically acceptable salts and easy-hydrolyzed esters.

2. Soy is inania according to claim 1, where Y and Z both represent hydrogen and the stereochemical configuration corresponds to S, as at C-17 and C-20.

3. The compound according to claim 1, where Y and Z together represent a methylene to form cyclopropane ring in combination with the C-17 and C-20 and the stereochemical configuration corresponds to S as in C-17 and C-20.

4. The compound according to claim 1, where Y and Z together with the linking C-17/C-20 form a double bond between C-17 and C-20.

5. The compound according to claim 4, in which the double bond C-17/C-20 has the same configuration as fozilova acid.

6. The compound according to claim 1, in which X denotes chlorine, bromine, iodine, trifluoromethyl, ethyl, substituted by phenyl, vinyl, substituted phenyl, butenyl, substituted by two methyl groups, pentenyl substituted by chlorine, hexenyl, nonanal, phenyl, optionally substituted by one or two identical or different substituents selected from the group consisting of bromine, chlorine, fluorine, propyl, vinyl, phenyl, cyano, methoxy, trifloromethyl, nitro, methylthio, tertbutyl or naphthyl.

7. The compound according to claim 1, in which X denotes chlorine, bromine, iodine, trifluoromethyl, phenyl, 4-bromophenyl, 4-chlorophenyl, 3,5-differenl, TRANS-1-HEXEN-1-yl, TRANS-1-butene-3,3-dimethyl-1-yl, TRANS-1-nonen-1-yl, TRANS-5-chloro-1-penten-1-yl, TRANS-2-phenyl-1-vinyl, 2-phenyl-1-ethyl, 4-n-propylphenyl, 4-vinylphenol, 4-tert-butylphenyl, 4-cyanophenyl, 3-biphenyl, 4-(trifluoromethyl)phenyl, 4-methoxy who enil, 3-cyanophenyl, 2-methoxyphenyl, 3-nitrophenyl, 3-bromophenyl, 4-(methylthio)phenyl, 2-naphthyl, 3,5-bis(trifluoromethyl)phenyl, 3,4-acid or 3,5-dibromophenyl.

8. The compound according to claim 1, in which Q1means -(NON)-.

9. The compound according to claim 1, in which Q1means CHBr or CHN3.

10. The compound according to claim 1, in which Q1and Q2both represent -(NON)-group, or Q1means CHBr, or CHN3,
X denotes chlorine, bromine, iodine, trifluoromethyl;
Z and Y together with communication C-17/C-20 form a double bond between C-17 and C-20;
And denotes O, S or S(O);
In stands With1-4alkyl group, optionally substituted by one or more substituents selected from the series consisting of hydroxy, or fluorine, or represents C1-4acyl group or benzoyloxy group.

11. The compound according to claim 1, where And denotes O or S(O).

12. The compound according to claim 1, in which means1-C4acyl, methyl, substituted vinyl, or phenyl, ethyl, optionally substituted by one or more substituents selected from fluorine, hydroxy, methyl or methoxy, butyl, substituted stands, pencil, propenyl or cyclopentyl.

13. The compound according to claim 1, where In denotes acetyl, isopropyl, ethyl, 2,2,2-triptorelin, 1 pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, cyclopentyl, 2-hydroxyethyl, benzyl, furfuryl, phenyl, 2-foretel, or 2-methoxyethyl.

14. The compound according to claim 1, in which Q1and Q2denote -(SNON)and the stereochemical configuration is as in C-3 and C-11.

15. The compound according to claim 1, where easy-hydrolyzed ester is pivaloyloxymethyl ester or acetoxymethyl ester.

16. Pharmaceutically acceptable salt of the compound according to any one of claims 1 to 13, where the salt is chosen from the group consisting of sodium salts, Kalinovich salts, L-arginine salts, 2-(dimethylamino)ethanol salt of 4-(2-hydroxyethyl)Martinovich salt, L-lysine salt of N-(2-hydroxyethyl)pyrrolidinium salts, ethanolamine salts, potassium salts, tetrabutylammonium salts, benzyltrimethylammonium salts, cetyltrimethylammonium salts, Tetramethylammonium salts, tetrapropylammonium salts, Tris(hydroxymethyl)aminomethane salts, N-methyl-D-glucamine salts, silver salts, benzethonium salts and triethanolamine salts.

17. The compound according to claim 1, which is chosen from the group consisting of these compounds, as
sodium salt 24-triftormetilfosfinov acid (compound 101),
pivaloyloxymethyl ester 24-triftormetilfosfinov acid (compound 102),
24-Chloropidae acid (compound 103),
pivaloyloxymethyl ester 24-CHLOROSILANES acid (compound 104),
sodium salt 24-CHLOROSILANES KIS is the notes (compound 105), 24-triftormetilfosfinov acid (compound 106),
acetoxymethyl ester 24-pomposity acid (compound 107),
24-pomposity acid (compound 108),
sodium salt 24-pomposity acid (compound 109),
pivaloyloxymethyl ester 24-pomposity acid (compound 110),
acetoxymethyl ester 24-bromo-16-deacetoxy-16β thioacetimidate acid (compound 111),
24-bromo-16-deacetoxy-16β-isopropylthiazole acid (compound 112),
24-bromo-16-deacetoxy-16β-isopropylacetanilide acid (compound 113),
24-bromo-16-deacetoxy-16β-thioacetimidate acid (compound 114),
24-bromo-17S,20S-digidrofolieva acid (compound 115), 24-bromo-16-deacetoxy-16β-toxipedia acid (compound 116),
acetoxymethyl ester 24-bromo-16-deacetoxy-16β-ethoxyphenol acid (compound 117),
acetoxymethyl ester 24-bromo-16-deacetoxy-16β-(2',2',2'-triptoreline)fusidic acid (compound 118),
24-bromo-16-deacetoxy-16β-(2',2',2'-triptoreline)fozilova acid (compound 119),
acetoxymethyl ester 24-bromo-17S,20S-fusidic acid (compound 120),
acetoxymethyl ester 24-bromo-17S,20S-medienfestival acid (compound 121),
24-bromo-17S,20S-medienfestival acid (compound 122),
3-deoxy-3β,24-dibromoethane acid (compound 123),
3α-azido-24-bromo-3-detoxifica acid (compound 124),
24-yadhunatha acid (compound 125),
acetoxymethyl ester 24-hotfusion acid (compound 126),
pivaloyloxymethyl ester 24-hotfusion acid (compound 127),
pivaloyloxymethyl ester 24-vanilloideae acid (compound 136),
24-vanilloideae acid (compound 137),
pivaloyloxymethyl ester 24-(4-bromophenyl)fusidic acid (compound 138),
24-(4-bromophenyl)fozilova acid (compound 139),
pivaloyloxymethyl ester 24-(4-chlorophenyl)fusidic acid (compound 140),
24-(4-chlorophenyl)fozilova acid (compound 141),
pivaloyloxymethyl ester 24-(3,5-differenl)fusidic acid (compound 142),
24-(3,5-differenl)fozilova acid (compound 143),
acetoxymethyl ester 3-deoxy-3β,24-dibromothiophene acid (compound 144),
24-bromo-16-deacetoxy-16β-ethylthiourea acid (compound 146),
24-bromo-16-deacetoxy-16β-ethylsulfinylmethyl acid (compound 147),
24-bromo-16-deacetoxy-16β-allylthiourea acid (compound 148),
24-bromo-16-deacetoxy-16β-(1-pentylthio)fozilova acid (compound 149),
24-bromo-16-deacetoxy-16β-(1-pentasulfide)fozilova acid (compound 150),
24-bromo-16-deacetoxy-16β-(2-methyl-1-butylthio)fozilova acid (compound 151),
24-bromo-16-deacetoxy-16β-(2-methyl-1-butylsulfonyl)fused the Wai acid (compound 152),
24-bromo-16-deacetoxy-16β-(3-methyl-1-butylthio)fozilova acid (compound 153),
24-bromo-16-deacetoxy-16β-(3-methyl-1-butylsulfonyl)fozilova acid (compound 154),
24-bromo-16-deacetoxy-16β-cyclopentylpropionate acid (compound 155),
24-bromo-16-deacetoxy-16β-(2,2,2-twitteratti)fozilova acid (compound 156),
24-bromo-16-deacetoxy-16β-(2-hydroxyethylthio)fozilova acid (compound 157),
24-bromo-16-deacetoxy-16β-sensitivedata acid (compound 158),
24-bromo-16-deacetoxy-16β-benzilgalogenidov acid (compound 159),
24-bromo-16-deacetoxy-16β-(2-fullerto)fozilova acid (compound 160),
24-bromo-16-deacetoxy-16β-phenylthiourea acid (compound 161),
24-bromo-16-deacetoxy-16β-benzoylthiourea acid (compound 162),
24-bromo-16-deacetoxy-16β-isopropoxypyridine acid (compound 163),
24-bromo-16-deacetoxy-16β-(2-floratone)fozilova acid (compound 164),
24-bromo-16-deacetoxy-16β-(2-methoxyethoxy)fozilova acid (compound 165),
24-(TRANS-1-HEXEN-1-yl)fozilova acid (compound 166),
24-(TRANS-1-butene-3,3-dimethyl-1-yl)fozilova acid (compound 167),
24-(TRANS-1-nonen-1-yl)fozilova acid (compound 168),
24-(TRANS-5-chloro-1-penten-1-yl)fozilova acid (compound 169),
24-(TRANS-2-phenyl-1-vinyl)fozilova acid (compound 170),
24-(2-phenyl-1-ethyl)fozilova acid (link is 171),
24-(4-n-propylphenyl)fozilova acid (compound 172),
24-(4-vinylphenol)fozilova acid (compound 173),
24-(4-tert-butylphenyl)fozilova acid (compound 174),
24-(4-cyanophenyl)fozilova acid (compound 175),
24-(3-biphenyl)fozilova acid (compound 176),
24-(4-(trifluoromethyl)phenyl)fozilova acid (compound 177),
24-(4-methoxyphenyl)fozilova acid (compound 178),
24-(3-cyanophenyl)fozilova acid (compound 179),
24-(2-methoxyphenyl)fozilova acid (compound 180),
24-(3-nitrophenyl)fozilova acid (compound 181),
24-(3-bromophenyl)fozilova acid (compound 182),
24-(4-(methylthio)phenyl)fozilova acid (compound 183),
24-(2-naphthyl)fozilova acid (compound 184),
24-(3,5-bis(trifluoromethyl)phenyl)fozilova acid (compound 185),
24-(3,4-acid)fozilova acid (compound 186),
24-(3,5-dibromophenyl)fozilova acid (compound 187),
Kalinova Sol 24-pomposity acid (compound 188),
L-arginine salt 24-pomposity acid (compound 189),
2-(dimethylamino)ethanol salt 24-pomposity acid (compound 190),
4-(2-hydroxyethyl)Martinova Sol 24-pomposity acid (compound 191),
L-lysine salt 24-pomposity acid (compound 192),
N-(2-hydroxyethyl)pyrolidine Sol 24-pomposity acid (compound 193),
ethanolamine Sol 24-pomposity sour is you (compound 194),
potassium salt of 24-pomposity acid (compound 195),
tetrabutylammonium Sol 24-pomposity acid (compound 196),
benzyltrimethylammonium Sol 24-pomposity acid (compound 197),
cetyltrimethylammonium Sol 24-pomposity acid (compound 198),
Tetramethylammonium Sol 24-pomposity acid (compound 199),
tetrapropylammonium Sol 24-pomposity acid (compound 300),
Tris(hydroxymethyl)aminobutanova Sol 24-pomposity acid (compound 301),
N-methyl-D-glucagonoma Sol 24-pomposity acid (compound 302),
silver Sol 24-pomposity acid (compound 303),
Bentonia Sol 24-pomposity acid (compound 304),
triethanolamine Sol 24-pomposity acid (compound 305),
pivaloyloxymethyl ester 24-(TRANS-1-HEXEN-1-yl)fusidic acid (compound 306),
pivaloyloxymethyl ester 24-(TRANS-1-butene-3,3-dimethyl-1-yl)fusidic acid (compound 307),
pivaloyloxymethyl ester 24-(TRANS-1-nonen-1-yl)fusidic acid (compound 308),
pivaloyloxymethyl ester 24-(TRANS-5-chloro-1-penten-1-yl)fusidic acid (compound 309),
pivaloyloxymethyl ester 24-(TRANS-2-phenyl-1-vinyl)fusidic acid (compound 310),
pivaloyloxymethyl ester 24-(2-phenyl-1-ethyl)fusidic acid (Obedinenie 311),
pivaloyloxymethyl ester 24-(4-n-propylphenyl)fusidic acid (compound 312),
pivaloyloxymethyl ester 24-(4-vinylphenol)fusidic acid (compound 313),
pivaloyloxymethyl ester 24-(4-tert-butylphenyl)fusidic acid (compound 314),
pivaloyloxymethyl ester 24-(4-cyanophenyl)fusidic acid (compound 315),
pivaloyloxymethyl ester 24-(3-biphenyl)fusidic acid (compound 316),
pivaloyloxymethyl ester 24-(4-(trifluoromethyl)phenyl)fusidic acid (compound 317),
pivaloyloxymethyl ester 24-(4-methoxyphenyl)fusidic acid (compound 318),
pivaloyloxymethyl ester 24-(3-cyanophenyl)fusidic acid (compound 319),
pivaloyloxymethyl ester 24-(2-methoxyphenyl)fusidic acid (compound 320),
pivaloyloxymethyl ester 24-(3-nitrophenyl)fusidic acid (compound 321),
pivaloyloxymethyl ester 24-(3-bromophenyl)fusidic acid (compound 322),
pivaloyloxymethyl ester 24-(4-(methylthio)phenyl)fusidic acid (compound 323),
pivaloyloxymethyl ester 24-(2-naphthyl)fusidic acid (compound 324),
pivaloyloxymethyl ester 24-(3,5-bis(trifluoromethyl)phenyl)fusidic acid (compound 325),
pivaloyloxymethyl ester 24-(3,4-Dimitar iphenyl)fusidic acid (compound 326) and
pivaloyloxymethyl ester 24-(3,5-dibromophenyl)fusidic acid (compound 327).

18. The compound according to any one of claims 1 to 17 for use in antibacterial therapy.

19. Antibacterial pharmaceutical composition comprising a compound according to any one of claims 1 to 17, together with a pharmaceutically acceptable excipient or the media.

20. Antibacterial pharmaceutical composition according to claim 19, further comprising another therapeutically active compound selected from the group consisting of antibiotics and corticosteroids.

21. Antibacterial pharmaceutical composition according to claim 20, in which the specified another therapeutically active compound selected from the group consisting of penicillins (dentists, dental, dicloxacillin, ampicillin, amoxicillin, pivampicillin, Flucloxacillin, piperazillina and mecillinam), cephalosporins (cephalexin, tsefalotina, cefepime, Cefotaxime, ceftazidime, Ceftriazone and cefuroxime), carbapenems (aztreonam) and carbapenems (Meropenem); macrolides (azithromycin, clarithromycin, erythromycin and roxithromycin); polymyxins (colistin); tetracyclines (tetracycline, doxycycline, oxytetracycline and lymecycline); aminoglycosides (streptomycin, gentamicin, tobramycin and netilmicin); fluoroquinolones (norfloxacin, oflox is of CIN, ciprofloxacin and moxifloxacin); clindamycin, lincomycin, teicoplanin, vancomycin, oxazolidones (linezolid), rifamycin, metronidazole, fusidic acid, hydrocortisone, betamethasone-17-valerate and triamcinolone acetonide.

22. A method of treating, preventing or reducing bacterial infections in a patient, comprising the introduction of a specified patient an effective amount of a compound according to any one of claims 1 to 17, and optionally additionally comprising the simultaneous or sequential addition of one or more other therapeutically active compounds.

23. The method according to item 22, which specified another therapeutically active compound selected from the group consisting of antibiotics and corticosteroids.

24. The method according to item 22, characterized in that the said other therapeutically active compound selected from the group consisting of penicillins (dentists, dental, dicloxacillin, ampicillin, amoxicillin, pivampicillin, Flucloxacillin, piperazillina and mecillinam), cephalosporins (cephalexin, tsefalotina, cefepime, Cefotaxime, ceftazidime, Ceftriazone and cefuroxime), carbapenems (aztreonam) and carbapenems (Meropenem); macrolides (azithromycin, clarithromycin, erythromycin and roxithromycin); polymyxins (colistin); tetracyclines (tetracycline, to whom Sicilia, oxytetracycline and lymecycline); aminoglycosides (streptomycin, gentamicin, tobramycin and netilmicin); fluoroquinolones (norfloxacin, ofloxacin, ciprofloxacin and moxifloxacin); clindamycin, lincomycin, teicoplanin, vancomycin, oxazolidones (linezolid), rifamycin, metronidazole, fusidic acid, hydrocortisone, betamethasone-17-valerate and triamcinolone acetonide.

25. The use of compounds according to any one of claims 1 to 17 for the manufacture of a medicinal product for the treatment, attenuation or prevention of bacterial infections.

26. Use A.25, which specified the drug also includes another therapeutically active compound in the same or in separate containers, adapted for simultaneous or sequential introduction of these therapeutically active compounds.

27. Use A.25 where other specified medicinal compound selected from the group consisting of penicillins (dentists, dental, dicloxacillin, ampicillin, amoxicillin, pivampicillin, Flucloxacillin, piperazillina and mecillinam), cephalosporins (cephalexin, tsefalotina, cefepime, Cefotaxime, ceftazidime, Ceftriazone and cefuroxime), carbapenems (aztreonam) and carbapenems (Meropenem); macrolides (azithromycin, clarithromycin is a, erythromycin and roxithromycin); polymyxins (colistin); tetracyclines (tetracycline, doxycycline, oxytetracycline and lymecycline); aminoglycosides (streptomycin, gentamicin, tobramycin and netilmicin); fluoroquinolones (norfloxacin, ofloxacin, ciprofloxacin and moxifloxacin); clindamycin, lincomycin, teicoplanin, vancomycin, oxazolidones (linezolid), rifamycin, metronidazole, fusidic acid, hydrocortisone, betamethasone-17-valerate and triamcinolone acetonide.

28. The use according to any one of claims 1 to 17 for combating bacterial infection.

29. The use of compounds according to any one of claims 1 to 17 for the prevention, or prevention of bacterial infections in animal breeding.

30. The method of obtaining the compounds of formula Ia

where X is bromine, Y, and Z both represent hydrogen or together with the linking C-17/C-20 form a double bond between C-17 and C-20 or together represent a methylene to form cyclopropane ring in combination with the C-17 and C-20; And denotes O, S or S(O);
In stands With1-6alkyl, optionally substituted by one or more halogen or hydroxy, C2-6alkenyl, phenyl, C1-C4heteroaryl or C1-6alkoxy, C2-6alkenyl,1-6acyl, phenyl or benzoyl;
Q1means -(NON)-, or -(CHW)-, where W denotes halogen Il is azido;
Q2means -(NON)-;
including:
(a) the dissolution of fusidic acid or a suitable analog of fusidic acid in a suitable organic solvent, followed by treatment with bromine to obtain 24,25-dibromo intermediate compounds of General structure Ib:

where X and X' denote bromine, R is hydrogen, the bond between C-24 and C-25 is a single bond and Y, Z, a, b, Q1and Q2defined above;
(b) treatment of a solution of 24.25-dibromo intermediate compounds in a suitable solvent in the presence of a suitable base to obtain dehydrobrominated the compounds of formula Ia in the form of a salt; and
(c) contacting the salt formed in stage (b)with an acid to obtain the compounds of formula Ia in the form of the free acid.

31. The compound of General structure Ib;

where X and X' denote bromine, R is hydrogen, the bond between C-24 and C-25 is a single bond, Y and Z together with the linking C-17/C-20 form a double bond between C-17 and C-20; And indicates On; In stands With1-6acyl; Q1and Q2independently represent -(NON)-.



 

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EFFECT: method is highly selective and single-stage.

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19 cl, 38 ex, 12 tbl

FIELD: chemistry.

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27 cl, 31 ex, 1 tbl, 2 dwg

FIELD: medicinal industry, sterols.

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EFFECT: improved producing method.

2 cl, 3 ex

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2 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

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22 cl, 7 tbl, 41 ex

FIELD: organic chemistry, steroids, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds, improved method for treatment.

38 cl, 1 tbl, 18 ex

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l,m, n- 0,1; L - (C1-C6)-alkyl, AA1, AA2independently amino acid residue, may be one - or multi-substituted amino group

The invention relates to substituted phenylalkylamines, their pharmaceutically acceptable salts and physiologically functional derivatives

FIELD: chemistry.

SUBSTANCE: polyaminosteroid branched derivatives of general formula I are described, where R1 is saturated or unsaturated C2-C10alkyl (conjugated or branched) or methyl, R2 is COOH or branched polyamine fragments, R3 is H, OR19, where R19 is H or C1-6acyl, R4 is H, R5 is H, CH3, R6 is H, CH3, R7=R8=R9=H, R10 is H, CH3, R11 is OH,-OSO3, - O-acyl, -(Z)n-(NR-Z)p-N(R)2, Z is linear hydrocarbon diradical, n=0, 1, p=1, R-H, C1-6alkyl, C1-6aminoalkyl, possibly substituted by C1-6alkyl, R12=R13=R15=H, R16 is H, OH, R17 is H, R18 is H, CH3, possible double bond. Compounds possess bactericidal activity and can be used for prevention of bacterial infections.

EFFECT: production of polyaminosteroid derivatives, possessing bactericidal activity which can be used for prevention of bacterial infections.

27 cl, 31 ex, 1 tbl, 2 dwg

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to improved method for production of 4,17(20)-E-pregnadiene-3,16-dione (E-guggulsterone) of formula III and 4,17(20)-Z-pregnadiene-3,16-dione (Z-guggulsterone) of formula IV including oxidation of compound of formula II , wherein C-OH or =O; ----- is optional double bond with pyridinium chlorochromate, pyridinium dichromate etc to produce 4,17(20)-E-pregnadiene-3,16-dione of formula III followed by conversion thereof by photochemical, thermochemical reaction or reaction in presence of acidic catalyst. Compounds of formulae III and IV effectively decrease increased low density lipoprotein levels and high cholesterol levels.

EFFECT: improved method for production of 4,17(20)-Z-pregnadiene-3,16-dione.

8 cl, 46 ex, 9 dwg

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention describes novel halogen- and pseudohalogen-substituted 17-methylene-4-azasteroids of the general formula (I) wherein each R20 and R20a means independently fluorine, chlorine, bromine atom, (C1-C4)-alkyl, hydrogen atom (H), cyano-group; R4 and R10 mean hydrogen atom or methyl group; both R1 and R2 represent hydrogen atom and form an additional bond. Compounds are inhibitors of 5α-reductase and can be used in treatment of diseases caused by the enhanced blood and tissue testosterone and dihydrotestosterone level.

EFFECT: valuable medicinal and biochemical properties of compounds.

9 cl, 5 dwg, 1 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention represents new derivatives of 17,20-dihydrofusidic acid of the formula (Ia)

wherein Q1 and Q2 are similar or different and mean -CO-, -CHOH-, -CHRO- wherein R means (C1-C4)-alkyl; Q3 means -CH2-; Y means hydrogen atom (H); A means -O- or -S-; R1 means (C1-C4)-alkyl, (C2-C4)-olefin, (C1-C6)-acyl, (C3-C7)-cycloalkylcarbonyl, benzoyl. These derivatives are used in pharmaceutical compositions for treatment of infectious diseases, in particular, in composition for topical applying for treatment of infectious diseases of skin and eyes.

EFFECT: valuable medicinal properties of compounds.

22 cl, 7 tbl, 41 ex

The invention relates to 17-deformation-estratriene, to a method for their production and to their use for pharmaceutical products (medicines)

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to disinfectants. The composition is applied for disinfection and antiseptic preparation, including human and animal skin. The liposome biocide composition contains quaternary ammonium compound that is didecyldimethylammonium halogenide as urea clathrate, and lipid.

EFFECT: invention ensures high biocide activity and does not irritate the skin.

12 cl, 2 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: present invention concerns area of medical products, in particular, pharmaceutical composition, suitable for treatment or the prevention of the bacteriemic infection containing dalbavancin and the stabiliser, with pH from 3 to 5; thus the stabiliser inhibits decomposing of one or more components of dalbavacin to less active or inactive substances. Besides, the invention concerns the method of dalbavancin drying, and to formula bonds and formulas .

EFFECT: dalbavancin stability improvement in the composition.

7 cl, 34 dwg, 44 tbl, 40 ex

FIELD: veterinary science.

SUBSTANCE: medication contains dimethyl sulphoxide, sulphadimine, erythromycin or chloramphenicol, silver sulphadiazine salt, camomile extract and hydrophilic base in ratio, wt %: sulphadimine 6.0-10.0, erythromycin or chloramphenicol 0.1-1.0, silver sulphadiazine salt 0.05-1.0, camomile extract 0.05-1.0, dimethyl sulphoxide 1.0-10.0 and hydrophilic base to 100.

EFFECT: medication allows for treatments time reduced by 1-2 days and complications lower by 10-15%.

1 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention refers to method of producing 3-fluorine-containing quinolines of general formula (I): where R1, R2, R3 and R4, being identical or different, represent: - hydrogen; - fluorine atom; - group OR6 where R6 represents hydrogen atom, or linear or branched alkyl radical, characterised that compound of general formula (IV): where R1, R2, R3 and R4 possess values specified above, is exposed to Hofmann degradation enabled with sodium hydroxide and bromine, and pyridine in water at temperature about 60°C to produce compound of general formula (III): where R1, R2, R3 and R4 possess values specified above, processed by alkali salt or alkyl ester of nitrous acid and fluoroboric acid or complex boron trifluoride and ethyl ether in appropriate solvent medium at temperature within 15°C to 20°C, reduced in producing diazonium salt of general formula (II): where R1, R2, R3 and R4 possess values specified above, heated up in inert organic solvent medium at temperature within 35°C to 120°C to produce compound of formula (I). Additionally, the invention refers to compounds of general formula (II).

EFFECT: new method of producing compounds of formula (I) being intermediates in producing compounds with antibacterial activity.

8 cl, 4 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to field of biotechnology, namely to obtaining vaccine strains, and can be used in veterinary. Bacterium Actinobacillus pleuropneumoniae is modified by introducing deletion, of at least one segment of gene apxIA and, optionally, segment of gene apxIIA, which code transmembrane domain of haemolytic and cytolytic exotoxins Apx. Obtained bacterium is used for production of vaccine against pig pleuropneumonia.

EFFECT: invention allows obtaining attenuated live vaccine against pig pleuropneumonia based on immunogenic non-haemolytic strain of bacterium Actinobacillus pleuropneumoniae.

11 cl, 6 dwg, 3 tbl, 1 ex

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