Derivative of fusidic acid, stereoisomer, pharmaceutical compositions, compounds

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 present invention relates to a new series of derivatives of 17,20-digidrofolievoy acid, their salts and easily hydrolyzable esters, to obtain these compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds in medicine. In particular, these compounds find antimicrobial activity, and, thus, they are useful for the treatment of infectious diseases. Compounds of the present invention can be used as a systemic treatment of infectious diseases, and for local treatment of infections affecting the skin and eyes.

BACKGROUND of INVENTION

Antibacterial properties of fusidic acid is well known. It is also known that structural changes can cause a significant or complete loss of the activity (cf. Godtfredsen et al., J. Med. Chem., Vol.9, p.15-22, 1966). Still generally considered that the double bond between carbons C-17 and C-20 attaching a side chain to the tetracyclic ring system, required for the manifestation of any antibacterial activity. The restoration of the double bond between C-24 and C-25 fusidic acid to simple communication has a significant impact on the antibacterial activity of the molecule at a time, as additional recovery of a double bond between C-17 and C-20, leading to tetrahydropyrido sour is e, causes almost complete loss of activity. Previously by catalytic hydrogenation of fusidic acid or its isomer lymphoidei acid obtained two epimer in a row tetrahydrophthalic acids having the configuration of 17(R), 20(S) and 17(R), 20(R), respectively (cf. von Daehne et al., Adv. Appl. Environ., 25, p.95-146, 1979, and listed in the references).

SUMMARY of the INVENTION

The aim of the invention are synthetic analogs of fusidic acid, which has antimicrobial activity. The above purpose is achieved by using the compounds of the present invention, belong to the series dihydro - tetrahydrophthalic acid binding configuration 17(S), 20(S)showing the in vitro high antimicrobial activity and good stability and pharmacokinetic properties, making compounds of the invention can be used in the treatment of infectious diseases in humans and animals.

The present invention relates to compounds of General formula Ia:

where

Q1, Q2and Q3are the same or different and represent, independently, a group -(CO)-; a group -(NON)-; a group -(CHOR)-; a group -(CHSH)-; a group-NH-; a group -(CHNH2)- or a group -(CHNHR)-, where R represents an alkyl radical with 1-4 carbon atoms or acyl radical with 1-4 carbon atoms; and where Q2 and O3can also represent, independently, a group -(CH2)-;

Y represents hydrogen, hydroxy, alkyl radical with 1-4 carbon atoms or acyl radical with 1-4 carbon atoms; a represents an oxygen atom or sulfur;

R1represents an alkyl radical with 1-4 carbon atoms, olefin group with 2-4 carbon atoms, (C1-C6)-acyl group, (C2-C7)-cycloalkylcarbonyl group or benzoyloxy group, and R1optionally substituted by one or more halogen atoms and/or hydroxy-, alkoxy - or sidegroups;

and their pharmaceutically acceptable salts and easily hydrolyzable esters.

In the formula Ia and subsequent formulae given in the description, the dotted line between C-1 and C-2 and/or C-24 and C-25 show that these atoms are connected or a double bond, or a simple link.

DETAILED description of the INVENTION

Preferred compounds of the invention are the compounds of formula I

where

Q1and Q2are the same or different and both represent the group -(NON)-, a group -(CO)- or a group -(CHSH)-;

A represents an oxygen atom or sulfur;

R1represents an alkyl radical with 1-4 carbon atoms, olefin group with 2-4 carbon atoms, (C1-C6)-acyl group, (C3With 7)-cycloalkylcarbonyl group or benzoyloxy group, and R1optionally substituted by one or more halogen atoms and/or hydroxy-, alkoxy - or sidegroups;

and

their pharmaceutically acceptable salts and easily hydrolyzable esters.

Preferably, Q1and Q2selected from the group consisting of -(CO)- and -(NON)-.

More preferred compounds of the invention are the compounds of formula I, where Q1and Q2both represent the groupor one of Q1and Q2represents -(CO)-; a is oxygen; R1is (C1-C4)-alkyl group, optionally substituted by one or more substituents selected from the group consisting of azido, hydroxy and halogen selected from fluorine, chlorine and bromine, or R1is acyl group with 1-4 carbon atoms or benzoyloxy group, both optionally substituted by one or more halogen atoms, preferably selected from the group consisting of fluorine and chlorine. R1preferably selected from the group consisting of ethyl, 2,2,2-triptoreline, 2,2,2-trichloroethyl, 2-azidoethyl, 2-hydroxyethyl, propyl and isopropyl, 1,3-diporiphora, acetyl, propionyl, chloroacetyl or TRIFLUOROACETYL, or R1selected from the preferred group consisting of ethyl, 2,2,2-three is loretel, 2-azidoethyl, isopropyl, tert-butyl and acetyl. Also preferred are the compounds of formula I and formula Ia, where the bond between C-24 and C-25 is a double bond.

Examples of compounds of the invention, which can be obtained by the methods described below, are:

17(S),20(S)-digidrofolieva acid,

17(S),20(S), 24,25-tetragidrofolieva acid,

11 dehydro-17(S),20(S)-digidrofolieva acid,

3-degidro-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-propionyloxy-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-(3'-chloropropionate)-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-(2'-methylpropyloxy)-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-cyclopropylmethoxy-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-chloroacetoxy-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-bromoacetate-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-benzoyloxy-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-(4'-perbenzoate)-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-cyclohexyloxycarbonyloxy-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-acryloyloxy-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-isopropylthio-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-ethylthio-17(S),20(S)-d is gidroshikapa acid,

16 diacetoxy-16β-(2',2',2'-trichloromethylthio)-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16βtert-butylthio-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-methoxymethyl-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-isopropylthio-17(S),20(S),24,25-tetragidrofolieva acid,

16 diacetoxy-16β-acetylthio-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-benzylthio-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-ethoxy-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-(2',2',2'-triptoreline)-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-propoxy-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-isopropoxy-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-(1',3'-deferasirox)-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-methoxyethoxy-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-(2',2',2'-trichlorethane)-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-(2'-azidoethoxy)-17(S),20(S)-digidrofolieva acid,

16 diacetoxy-16β-(2'-hydroxyethoxy)-17(S),20(S)-digidrofolieva acid,

and their pharmaceutically acceptable salts and easily hydrolyzable esters.

Unlike natural fusidic acid (1), where C-17 and C-20 are connected by a double bond, all described herein the compounds of formula I and formula I which have a simple relationship between C-17 and C-20. Configuration consider two asymmetric carbon atoms is 17(S) - and 20(S). This epimer is one of the four possible epimeres, which differ only in the configuration of the C-17 and C-20; and biological tests show that this is the only epimer detecting strong activity.

Compounds of the invention can be used as such or in the form of salts or easily hydrolyzable esters (as described below). Salts of the compounds are, in particular, pharmaceutically acceptable salts, such as alkali metal salts and salts of alkaline earth metals, e.g. sodium, potassium, magnesium or calcium salts, and also salts and silver salts of bases, such as ammonia or suitable non-toxic amines, such as lower alkylamines followed, for example, triethylamine, lower hydroxyethylamine, for example, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, cyclooctylamine, for example, dicyclohexylamine, or benzylamines, for example, N,N'-dibenziletilendiaminom and dibenzylamine. Of silver salts of compounds particularly useful for local treatment.

The expression "easily hydrolyzable esters" in this description is used to denote alkanoyloxy, arachnological, urologically esters, for example, acetoxymethyl, pivaloyloxymethyl, benzoyloxymethyl esters and the corresponding 1'-oxyethyl roizvodnykh, or alkoxycarbonylmethyl esters, for example, methoxycarbonylmethyl esters and ethoxycarbonylmethylene esters and the corresponding 1'-anxietyprovoking, or victoriavi esters, for example, palidrome esters, or dialkylaminoalkyl esters, for example, diethylaminoethyl esters. The expression "easily hydrolyzable esters" includes esters of the compounds of the invention, hydrolyzable in vivo. Such esters can be obtained using methods known to experts in the art, cf. patent GB No. 1490852 included in the present description by reference.

Used in the description of the following terms, unless otherwise indicated, have the meanings listed below, cf. also the recommendation of IUPAC, 1994, http://www.chem.qmw..uk/iupac/class/.

"Alkyl" refers to any univalent group formed from an alkane by removing a hydrogen atom from any carbon atom, and includes subclasses of normal alkyl (n-alkyl) and primary, secondary and tertiary alkyl groups, respectively, with a certain number of carbon atoms, including, for example, (C1-C4)-alkyl, (C1-C3)-alkyl, (C1-C2)-alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Alkanol is called acyclic branched or unbranched hydrocarbons with the General formula Cn H2n+2where n is an integer, and, therefore, composed entirely of hydrogen atoms and saturated carbon atoms.

The term "olefinic group" refers to linear or branched acyclic hydrocarbon with one or more carbon-carbon double bonds E - or Z stereochemistry where appropriate, with a certain number of carbon atoms. The term includes, for example, (C2-C4)-olefinic group, preferably, (C2-C4)-alkenyl; and (C2-C3)-olefinic group, preferably, (C2-C3)-alkenyl; vinyl; allyl; 1-butenyl; 2-butenyl and 2-methyl-2-propenyl. In addition, the term "olefinic group" refers to linear or branched alkenylphenol group containing at least one triple bond. This term would include, for example, crotyl and propargyl. Olefinic group containing only one carbon-carbon double bond, called here alkenylamine, are preferred.

The term "aryl" refers to groups derived from monocyclic and polycyclic aromatic hydrocarbon by removal of a hydrogen atom from the carbon atom of the ring, for example, tollu, phenyl, naphthyl. The number of carbon atoms in the aryl group, as a rule, 6, 7, 8, 9, or 10.

The term "acyl" refers broadly to a radical is ormula R-CO-, where R is an alkyl having the above values, for example, (C1-C6)-acyl.

The term "alkoxy" refers broadly to a radical of the formula-OR, where R is an alkyl having the above values, for example, (C1-C5)-alkoxy, (C1-C3)-alkoxy, methoxy, n-propoxy, tert-butoxy etc.

"Halogen" means identical or different fluorine, chlorine, bromine and iodine; and in the compounds of the present invention more useful fluorine, chlorine and bromine.

The term "alkanoyl" refers broadly to a radical of the formula R-CO-, where R represents alkyl having the above values, for example, (C1-C8-alkanoyl, acetyl, propionyl, Isopropenyl, butyryl. The term "arkanoid" refers broadly to a radical of the formula R(CH2)n-CO-, where R is an aryl having the values indicated above, and n represents an integer selected, preferably, from 1, 2, 3 and 4. The term "aroyl" refers broadly to a radical of the formula R-CO-, where R represents an aryl group having the above values.

The term "alkanoyloxy" or "urologically" refers broadly to a radical of the formula-CH2-O-CO-R, where R represents a C1-C6)-alkyl group or (C6-C8)-aryl group. Aryl and alkyl have the meanings specified above.

Ter the ins "alkoxycarbonyl-and aryloxyalkyl-" refers to the group-CO-OR, or acyloxy-" refers to the group R-CO-O-, where R is alkyl or aryl, with the values specified above.

In the compounds according to the invention there are several chiral centers because of the presence of asymmetric carbon atoms. The presence of several asymmetric carbon atoms leads to a number of stereoisomers of R - or S-configuration at each chiral center. The General formulas I and Ia and (unless specified otherwise) all other formulae in this specification should be understood as encompassing all such stereoisomers in pure form and as mixtures (e.g., mixtures of stereoisomers), except in those cases when the configuration is specified specially.

In the compounds of formulas I and Ia preferred stereochemical configuration, as a rule, is as follows: when Q1and Q2belong to the groupthe configuration at C-3 and C-11 in the compounds of formula I and Ia is 3α and 11α, respectively. Atom C-16, is attached to the group And has the (S)-configuration, hereinafter referred to 16β. In formulas in the description of simple lines denote communication approximately in the plane of the drawing; connection with the atoms above the plane shown in bold wedge-shaped line, the narrow end of which comes Atacama in the plane of the drawing; and communication with the atoms below the plane shown short parallel (wedge) lines. Mixing Italy above the plane denoted β and specifies bold wedge-shaped line, the deputies of the lower plane are denoted αand indicates the line of the short parallel lines (in the form of a wedge).

Biological activity

In vitro studies have shown a high efficacy of the compounds of the invention against some bacteria, including staphylococci, streptococci, corynebacteria and mycobacteria. Biological tests show that the antibacterial activity of 17(S),20(S)-digidrofolievoy acid (10) (compound 101) is comparable with the activity of fusidic acid (1), as can be seen from table 1, showing MIC values of these two compounds against a number of bacteria. Biological tests carried out on titration microplate using a liquid medium containing broth.

Table 1
Name of bacteria/strainExplanationThe MIC values (concentration in μg/ml required for 90%inhibition)
Connection 101Fozilova acid (1)
S. aureus/l Aus-peFusS. MRSA11
S. aureus/ATSC 29213FusS, MSSA 11
S. aureus/22 DKFusS. MSSAI0,5
S.aureus/54USA-brFusR, MSSA88
E.faecalis/V583 P. Cour.VanR1616
C. diphteria/62001 0,0630,063
Streptococcus - gr. A/67011 6416
Streptococcus - gr. B/61 >6432
Streptococcus - gr. C/68 42
Streptococcus - gr. G/59 84
Staphylococcus/291-2*FusS11
Staphylococcus/379-2*FusR6464
P. acnes/1060 0,50,125
N. gonorrhoea/C1 41
N. meningitidis/K1 10,25
M. tuberculosis/R 498 16>16

FusS = sensitive to fusidic acid; FusR = resistant to fusidic acid; MRSA = methicillinsensitive Staphylococcus aureus; MSSA = methicillinsensitive-AUX Staphylococcus aureus; VanR = vancome inwestycyjny. * Coagulasepositive.

Other compounds of the invention also show high in vitro activity against some bacteria. Antibacterial activity of some of these compounds relative to fusidic acid is seen from table 2, showing MIC values of the compounds of the invention.

Used the method recommended Europan Pharmacopoeia, 3rd Ed. (1977), to test the effectiveness of antibiotics. It is a method of diffusion in agar, where the deepening of agar add equal volumes of the test solution. Zone of inhibition is a function of the concentration of the used analog of fusidic acid. All tests conducted with fusidic acid (1) as a standard substance. The results in table 2 differ from the results in table 1 due to the use of different experimental methods.

Table 2
 The MIC values (concentration in μg/ml required for 90%inhibition)
StrainFozilova acid (1)101102105113123128
S-aureus0,0130,0020,0160,22160,020,26
ATSR       
S. aureus*0,0120,0030,120,24160,005>64
Leo id. CJ232       
S. aureus**0,010,0010,0090,063160,007>64
LeoidCJ234(R)       
S. aureus0,010,0010,020,19160,020,19
ATCC2977       
Strep. epidermis0,010,0010,015008>640,50,5
A. ATCC12228      Strep. faccalisa 4.93,7MIC>64>64>641616
ATCC10541       
Strep. faecium***2,71,2a 3.9a 3.9>641616
Leo id.E119(P)       
Strep. sp. Gr.Ba 4.93,53,4>6441616
Leo id.EF6       
*MRSA, **MRSA and rifampinusual, ***Penitsillinoustoychivyh

In addition, the compounds of the invention have certain advantages, compared with the corresponding compounds containing a double bond 17, 20, such as fozilova acid.

The compounds of formulas I and Ia are chemically more stable, probably due to the lower activity of the intense connection 17, 20, and the lack of pairing of carbon is th acid with a carbon-carbon double bond.

The compounds of formulas I and Ia are less easily decomposed under the action of sunlight.

The compounds of formulas I and Ia are more stable in solution. A solution of the compounds of formula 10 below, in ethanol, stored at 0°within 1 month, stores >80% of the initial activity at a time as the appropriate solution fusidic acid retains only 70% of the initial activity.

The compounds of formulas I and Ia are more lipophilic and, therefore, more suitable for products for local use.

Being synthetic, the compounds of formulas I and Ia can be obtained from relatively crude source fusidic acid, which in this case is not suitable for the purposes of medicine.

In this description uses the following standard abbreviations.

Asón = acetic acid

AU2O = acetic anhydride

AC = acetyl

BU = n-butyl

tVI, tBu = tert-butyl

Et = ethyl

Ether = diethyl ether

Me = methyl

MOM = methoxymethyl

MOMO = methoxymethyl-O

Ph = phenyl

TBAF = Tetra fluoride-n-butylamine

TBS = tert-butyldimethylsilyl

TBSCl = tert-butyldimethylsilyloxy

THF = tetrahydrofuran

TLC = thin layer chromatography

TMS = trimethylsilyl

Obtaining compounds of the invention

17S,20S-digidrofolievoy acid (10) can be derived from occurring is the nature of fusidic acid, sequentially according to scheme 1 below. First guideway acid (1) is transformed into the lactone (2) by deacetylation and subsequent acidification. The double bond between C-17 and C-20 (2) restore NaBH4in aqueous methanol with Cys-attack α-side of the molecule with the formation of the lactone (3). Inversion at C-20 get with quantitative yield by heating a lactone (3) in the presence of 28% aqueous sodium hydroxide solution. Then protect the hydroxy-group at C-3 and C-11 lactone (4) as a simple methoxymethyl (MOM) ethers. Restoring containing protective group of the lactone (5) LiAlH4gives the diol (6), which first selectively protect papervine the hydroxy-group at C-21 diphenylmethylsilane group, and then acetimidoyl the hydroxy-group at C-16. After desirelove (7) using a fluoride tetrabutylammonium (TBA+F), buffered with acetic acid, the free hydroxyl group in (8) can be first to oxidize the aldehyde periodinane (periodinane) dess-Martin, and then to carboxylic acid (9) with sodium chlorite. The compound (10) are obtained at the final stage by removal of the IOM-groups in (9) by treatment with trimethylsilylpropyne (TMSBr) in anhydrous dichloromethane.

The compound of formula 10 is a compound of the invention (compound 101) and the common source connection for analogues, with testwuide the formula I, as described later.

Scheme 1

a) aq. aq NaOH, EtOH, boiling under reflux; Asón b) aq. R-R NaBH4in the Meon; Asón; (C) aq. aq NaOH (28%), EtOH, boiling under reflux; (d) diisopropylethylamine, MOMCl, CH2CL2, boiling under reflux; (e) LiAlH4, THF, boiling under reflux; (f) (i) Ph2MeSiCl, Et3N, CH2Cl2, 0°C;

(ii) AU2O/pyridine; (g) TBA+F-The asón, THF, boiling under reflux; (h) (i) periodinane dess-Martin, CH2CL2/pyridine;

(ii) NaClO2, tert-BuOH; i) TMSBr, CH2Cl2.

Compound 101 can be obtained by another method using TBS protective group for masking functional 3-hydroxy-group in compound 4, leaving 11-hydroxy-group unprotected. Then the connection 11 with TBS-protecting group (scheme 2) the appropriate method reacts, as shown in figure 1. The final removal of the TBS group reach by treating compound 16 diluted hydrofluoric acid with the formation of the compounds of formula 10 (compound 101).

Scheme 2

a) imidazol, TBSCl, CH2Cl2; (b) LiAlH4, THF, boiling under reflux; (C) Ph2MeSiCl, Et3N, CH2Cl2, 0°C; d) Ac2O/pyridine; (e) TBA+F-, AcOH, THF, boiling under reflux; (f) (i) periodinane dess-Martin, CH2CL2/pyridine; (ii) NaClO2, tert-BuOH; (g) aq. HF, acetonitrile/THF.

Compounds of General formula I can be obtained by a process comprising a first stage in which the compounds of General formula II is converted into 16-bromoethylene formula III, as described below.

In the above formulas, Q'1and Q'2represent the group -(CO)-,

groupor group,

and R3is a conventional protective group such as alkanoyl, arkanoid, alkanoyloxy or aroyl, or tizamidine silyl radical, substituted alkyl, oxyalkyl, aryl or axially groups; R2represents a linear or branched alkyl radical with 1-6 carbon atoms, e.g. methyl, ethyl, tert-butyl, unsubstituted or substituted Uralkaliy radical, for example, benzyl, nitrobenzyl, alkanolamines or araymetrey radical, for example, acetonyl or pencil, alkanoyloxy or urologically the second radical, for example, acetoxymethyl, pivaloyloxymethyl or benzoyl-oxymethyl, alkoxymethyl radical or cyanomethylene radical, a silyl radical, a substituted groups from among alkyl, alkenyl, oxyalkyl, oxyalkyl, aryl or oxyaryl, for example, triethylsilyl, triisopropylsilyl, diphenylmethylsilane, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tert-butoxyphenyl; the dotted line between C-24 and C-25 have the meanings specified above.

The transformation is realized by the interaction of the compounds of formula II with tetrabromomethane/triphenylphosphine or with N,N-dimethylformamide in an inert solvent, such as ether, tetrahydrofuran or dimethylformamide, at room or lower temperatures (cf. von Daehne, W., and Rasmussen, P. (1975), the United Kingdom patent No. 1523803).

The compounds of formula II receive, based on the compounds listed in figure 1, by methods known from the literature (cf. patent of great Britain No. 1490852 and the United Kingdom patent No. 1523803), or similar methods. For example, the starting compounds of formula III can be obtained from compounds of formula 10, or, more conveniently, from compounds of formula 9, as shown in figure 3.

Scheme 3

a) N,N-dimethylformamide-bis-tert-butyl acetate, benzene, boiling under reflux; b) 2 N. aqueous solution of NaOH, EOH; boiling under reflux; (C) CBr4, PPh3CH2Cl2.

In the next stage of the intermediate compounds of formula III is introduced into reaction with compounds of the formula IV with education, with inversion of configuration at C-16, compounds of the formula V:

where in the above formulas, Q1', Q2', A, R1, R2and the dotted line between C-24 and C-25 have the values specified above. Transformation is carried out according to methods known from the literature (cf. von Daehne, W., and Rasmussen, P. (1975), the United Kingdom patent No. 1523803). When a in the formula V is oxygen, and R1differs from acyl, interacting compounds of formula IV is used, preferably, as solvents, and the reaction is carried out in the presence of silver salts or mercury, for example, silver carbonate, triptoreline silver or acetate of mercury, or base, for example potassium carbonate, sodium bicarbonate or (C1-C5)-sodium alcoholate, preferably, sodium methylate or ethylate sodium, and at room or slightly higher temperature. If a in formula V is sulfur, and R1differs from acyl, the reaction is carried out in an inert organic solvent, preferably ethanol or dimethylformamide, in the presence of a base, in the example, potassium hydroxide or sodium hydride, at room or slightly higher temperature.

When a in the formula V is oxygen, and R1is acyl, the reaction is carried out in the presence of the corresponding silver salts of compounds of formula IV in an inert solvent, e.g. benzene, at room or slightly higher temperature. When a in the formula V is sulfur, and R1represents acyl, interacting compounds of formula IV are used, preferably in the form of their potassium or sodium salts, and the reaction is carried out in an inert solvent, for example dimethylformamide, at room temperature.

The compounds of formula V where a is oxygen, and R1is (C1-C6)-acyl group or benzoyloxy group, can be obtained from compounds of formula II by reaction with a reactive derivative of carboxylic acid of the formula IV, for example, acid chloride or anhydride. The reaction is carried out in the presence of a base, preferably pyridine, in an inert solvent, for example dimethylformamide or pyridine, and at temperatures below room temperature.

At the final stage of the compounds of formula V can be converted into compounds of formula I by hydrolysis or in the presence of a base such as a hydroxide or carbonate of sodium or potassium hydroxide in aqueous methanol or ethane is Le, or in the presence of acid, such as hydrochloric acid or p-toluensulfonate acid in aqueous tetrahydrofuran, depending on the nature of Q1', Q2', R1and R2.

The compounds of formula V where Q1' and Q2' represent a group

or -(CO)-, and R2represents the residue is easily hydrolyzable ester, are the compounds of the invention without further transformation.

The compounds of formula V where Q1' and/or Q2' represent a group

or -(CO)-, and R3is albanology, alkoxyalkyl, arachnology or oreilly radical, can be converted into compounds of the invention by hydrolysis in aqueous methanol, ethanol or THF in the presence of acid, such as hydrochloric acid, acetic acid and p-toluensulfonate acid, or in an anhydrous aprotic organic solvents, for example dichloromethane, in the presence of a Lewis acid, for example, trimethylsilylpropyne. If R3represents an alkoxy radical or aryloxy, the compounds of formula V can be converted into compounds of the invention by hydrolysis in aqueous methanol or ethanol and in the presence of a base such as a hydroxide or carbonate of sodium or potassium.

The compounds of formula V, where each of Q1' and Q2' represent a group

or -(CO)-, and R2represents unsubstituted or substituted benzyl radical, cyanomethyl, alcoholmeter or areilly, also can be transformed into compounds of formula I of the restoration. If R2represents benzyl or cyanomethylene radical, preferably catalytic hydrogenation, while if R2is acetanilide, finally or trichlorethylene radical, you can use the recovery zinc in acetic acid. When R2represents a substituted silyl radical, you can use acid hydrolysis using dilute acids, such as hydrochloric acid, acetic acid or toluensulfonate acid, or cleavage with fluoride, for example, hydrogen fluoride in acetonitrile or tetrabutylammonium fluoride in THF.

Compounds of General formula I where a is oxygen, can be obtained through alternative means, including a first stage in which the compounds of General formula VI is converted into 16-acyloxy - or 16-O-alkylamine formula VII, as described below.

where in the formulas, Q1', Q2', R1and the dotted line between C-24 and C-25 have the values specified above; and R4is a conventional protective group such as alkanoyl, arkanoid, alkanoyloxy or aroyl,or tizamidine silyl radical, substituted alkyl, oxyalkylene, aryl or oxyuridine groups.

R4preferably represents a silyl protective group, such as diphenylmethylene or tert-butoxyphenyl, or acyl protective group such as acetyl or pivaloyl.

In the case of compounds of formula VII, where R1represents an alkyl radical, as described above, the transformation is realized by the interaction of the compounds of formula VI with alkylhalogenide or alkylacrylate, according to the General methods of obtaining ethers, well-known specialists in this field of technology.

In the case of compounds of formula VII, where R1represents the acyl group, the transformation is realized by the interaction of the compounds of formula VI with an acid chloride or the corresponding anhydrides in the presence of a weak base, according to the General methods of acylation, well-known specialists in this field of technology. The compounds of formula VII can be converted into compounds of the formula I, removing the first protective group, R4known methods and then through interaction in the same reaction stages f and g, described in scheme 2, or related methods.

The compounds of formula I, where Q1and/or Q2represents -(CO)-, can also be obtained from corresponding compounds of formula I, where Q1and Q2both represent g is the SCP

methods of oxidation, known to specialists in this field of technology.

The invention also relates to a method for obtaining compounds of formula I, in which heating of the specified lactone of formula 3 in the presence of concentrated sodium hydroxide solution to reach quantitative inversion of the C-20.

Easily hydrolyzable esters of compounds of formulas I and Ia can be obtained by methods known from the literature.

Compounds of the invention, where C-24 and C-25 is connected by a simple relationship can be obtained from the corresponding unsaturated analogues recovery, for example, catalytic hydrogenation using catalysts such as palladium or platinum. Compounds such as helvola acid and cephalosporin P1can be used as starting substances in obtaining other compounds of General formula Ia.

The compounds of formula II receive, based on the compounds listed in figure 1, by methods known from the literature (cf. patent of great Britain No. 1490852 and the United Kingdom patent No. 1523803), or similar methods. The initial compounds of formula III can be obtained, for example, from compounds of formula 10, or, more conveniently, from compounds of formula 9, as shown in figure 3.

Another objective of the present invention are pharmaceutical compositions useful in the treatment infe the ment of diseases in humans and in veterinary practice.

Excluding this purpose, the composition of the invention contains as an active ingredient at least one compound selected from the group consisting of compounds of formula I and formula Ia (hereinafter referred to as active ingredient), including acceptable salts and easily hydrolyzable esters, together with pharmaceutically acceptable carriers and/or diluents.

In this composition, the proportion of therapeutically active substances, and substances of the carrier may vary by up to 0.5 to 95 wt.%. The composition can be obtained in various pharmaceutical forms, such as granules, tablets, pills, pills, suppositories, capsules, tablets, delayed release, suspensions, injections, and they can fill the bottles or tubes or suitable containers. To obtain compositions containing compounds of the present invention, it is possible to use a pharmaceutical organic or inorganic solid or liquid carriers and/or diluents suitable for oral, enteral, parenteral or local administration, such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal oils and fats, benzyl alcohol, gum, polyalkyleneglycol, vaseline, cocoa butter, lanolin and other emulsifiers, as auxiliary substances can be used salts to change the osmotic pressure is I or buffering agents to provide a suitable pH of the composition.

In addition, the composition may contain other therapeutically active components, respectively, can be entered together with the compounds of the invention in the treatment of infectious diseases, such as other suitable antibiotics, in particular, such antibiotics, which can enhance the activity and/or to prevent the development of resistance. Such antibiotics include penicillins, cephalosporins, tetracyclines, rifamycins, eritromicina, lincomycin, clindamycin, and fluoroquinolones. Other compounds which can advantageously be combined with the compounds of the invention, in particular for topical application include, for example, corticosteroids such as hydrocortisone or triamcinolone. On the other hand, (s) other(s) active(s) component(s) can be entered with a composition of the invention as a side(s) tool(s) (simultaneously or consecutively).

In the case of granules, tablets, capsules or pills pharmaceutical composition of the invention contains, respectively, from 25% to 98% of the active substance of the invention, and in suspensions for oral administration the appropriate amount of the active ingredient is, respectively, from 2% to 20%.

When the compound is administered in the form of salts of pharmaceutically acceptable non-toxic bases, preferred salts are, for example, with the Lee, easily soluble in water or slightly soluble in water, in order to obtain a certain and appropriate rate of absorption.

As mentioned above, the compounds of formulas I and Ia and their salts can be entered in the pharmaceutical form of suspensions, ointments and creams. Pharmaceutical preparation for oral treatment may also be in the form of suspension of the active ingredient as such or in the form of sparingly soluble in water, pharmaceutically acceptable salts, and the product contains from 20 to 100 mg of active substance per ml of media. Pharmaceutical preparation for topical treatment can be in the form of ointment or cream containing the active ingredient in an amount of from 0.5 to 50% by weight of the preparation. The preparations for the local introduction of favorable due to resistance to sunlight and relatively lipophilic nature of the compounds of the present invention.

Another aim of the invention is the selection of the dose of the compounds of the invention, which can be entered in order to achieve the desired activity without concomitant side effects. In systemic therapy of people compounds and their salts convenient to introduce (adults) in dosage units containing not less than 50 mg up to 1000 mg, preferably from 200 to 750 mg per compound of formula I.

The term "dosage unit" refers to UNITA is Naya, i.e. a single dose which you can enter the patient and which can be easily handled and to pack it, keeping both physically and chemically stable in the standard form, containing or active substance as such, or its mixture with a solid or liquid pharmaceutical diluents or carriers.

In the form of dosage units connection, you can enter one or more times a day at appropriate intervals, however, also dependent on the patient's condition and in accordance with the prescriptions of the doctor.

Thus, systemic treatment the daily dosage will preferably be from 0.5 to 3 g of the active ingredient.

The term "used unit in communication with the local application meant a unitary, i.e. a single dose which you can enter the patient topically applied per square centimeter of the infected area from 0.1 mg to 10 mg, preferably from 0.2 mg to 1 mg of the desired active ingredient.

If the composition is administered by injection, as a standard dose may be sealed ampoule, vial or similar container containing a parenterally acceptable aqueous or oily solution or dispersion of the active substance for injection.

Preparations for parenteral administration are especially useful in the treatment of conditions in which the desired fast the th response to treatment. In long-term treatment of patients suffering from infectious diseases, tablets or capsules can be an appropriate form of pharmaceutical drug due to prolonged effect, obtained by oral administration of a medicinal product, in particular in the form of tablets with delayed release.

In the treatment of infectious diseases such tablets may contain, which is beneficial, other active ingredients listed in the description above.

Another aim of the invention is a method of treating patients suffering from infectious diseases, including the introduction of the patient from 0.03 g to 0.7 g per kg of body weight per day in 1-3 doses, preferably from 0.5 g to 3 g per day of the compounds of formula I or Ia, or an equivalent amount of salt, as mentioned above, the compounds of formula I or Ia. Preferably, the active ingredient is administered in the form of dosage units, as described above.

Hereinafter the invention will be described in the preparative examples and examples.

PREPARATIVE EXAMPLES AND EXAMPLES

General provisions

All melting points are uncorrected. For spectra (75,6 MHz)13Nuclear magnetic resonance (NMR) magnitude of chemical shift (δ) (in ppm) is estimated if there are no other instructions, for solutions in deuterochloroform regarding internal with whom andarta tetramethylsilane (δ =0,00) or deuterochloroform (δ=76,81 for13WITH NMR). Chromatography carried out on silica gel using ethyl acetate and low-boiling petroleum ether as eluent. Anhydrous solvents is obtained by storing analytically pure solvent over molecular sievesfor several days before use.

PREPARATIVE EXAMPLES

Preparative example 1: the lactone 16-deazetil-17(S),20(S)-digidrofolievoy acid (4)

The lactone (3) (20.2 g, 44 mmol) is dissolved in 100 ml of ethanol and added dropwise to 28% aqueous sodium hydroxide solution (100 ml). The obtained yellow solution is heated at 60°C for 1 hour. The reaction mixture was left to reach room temperature and the mixture is acidified to pH 4 with concentrated acetic acid, resulting in the almost colorless solution. Add water gradually (approximately 100 ml) with continuous stirring until precipitation of colorless crystalline substance.

Stirring is continued overnight at room temperature, the crystals are collected by filtration, receiving of 20.0 g of lactone 16-deazetil-17(S),20(S)-digidrofolievoy acid (4). Recrystallization from methanol/water gives of 18.5 g of substance TPL 167-169°C.

13With NMR (CDCl3): 181,0, 132,9, 122,9, 84,2, 71,4, 68,7, 49,7, 48,7, 46,8, 42,4, 41,4, 40,0, 38,8, 37,4, 36,6, 36,1, 339, 33,0, 32,9, 30,4, 30,0, 25,7, 25,7, 23,8, 22,6, 21,0, 17,8, 17,5, 16,0.

Preparative example 2: the lactone 3,11-bis-O-methoxymethyl-16-deazetil-17(S),20(S)-digidrofolievoy acid (5)

The lactone (4) (34.4 g, 75 mmol) dissolved in anhydrous dichloromethane (350 ml) in an argon atmosphere in dried in a drying Cabinet dvuhhodovoy round bottom flask, equipped with reflux condenser. Add N,N-diisopropylethylamine (52,3 ml, 300 mmol) and the resulting solution was stirred for 5 min at room temperature before adding methoxyethylamine (22,8 ml, 300 mmol), which is added gradually by syringe. The reaction mixture was stirred for 15 min at room temperature and then refluxed until the reaction is controlled by TLC (approximately 4 hours). The reaction mixture was left to reach room temperature and transferred into a separating funnel with 650 ml of dichloromethane. The organic solution is successively washed with water (500 ml), saturated sodium bicarbonate solution (500 ml), twice with water (2×200 ml) and twice with brine (2×500 ml). The organic solution is dried over anhydrous sodium sulfate, concentrated in vacuo, receiving a yellow oil that crystallized upon standing. Crystalline material is recrystallized from methanol (200 ml). Colorless crystals are collected by filtration, getting to 31.5 g of the lactone 3,11-bis-O-ethoxymethyl-16-deazetil-17(S),20(S)-digidrofolievoy acid (5), TPL 123-125°C. the Crystallization mother liquor still gives 6.5 g of the same compound, TPL 119-121°C.

13With NMR (CDCl3): 180,9, 132,8, 123,0, 97,6, 95,3, 84,3, 77,7, 77,2, 55,8, 55,4, 50,1, 48,5, 47,1, 42,6, 41,6, 40,0, 39,4, 37,1, 36,9, 36,4, 34,0, 32,3, 30,2, 30,1, 26,8, 25,9, 25,7, 23,3, 23,1, 21,3, 17,8, 17,7, 16,1.

Preparative example 3: 16β,21-diol (6)

Alumoweld lithium (3.8 g, 100 mmol) suspended in anhydrous THF (175 ml) in an argon atmosphere in dried in a drying Cabinet dvuhhodovoy round bottom flask, equipped with reflux condenser. To the suspension was added with stirring a solution of lactone (5) (26.7 g, for 48.9 mmol) in anhydrous THF (150 ml) with such speed that causes a low boil. The reaction mixture is refluxed with vigorous stirring for 3 hours and then left to reach room temperature. The excess lithium aluminum hydride destroy with ethyl acetate (125 ml) and then gradually add water (125 ml). The resulting suspension is acidified with diluted hydrochloric acid to pH 5.

The suspension is transferred into a separating funnel with ethyl acetate (1000 ml) and water (750 ml). Both layers are thoroughly shaken and then separated. The aqueous layer was extracted with ethyl acetate (1000 ml) and the combined organic layers are washed twice with brine (2×500 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo, getting to 26.6 g of beings is pure named in the title diol (6) in the form of colorless powder. Analytically pure sample is obtained by recrystallization from methanol, TPL 120-131°C.

13With NMR (CDCl3): 131,5, 124,5, 97,3, 95,3, 78,0, 77,3, 74,7, 64,8, 55,7, 55,4, 50,5, 49,1, 48,5, 43,5, 41,3, 40,5, 39,5, 36,9, 36,6, 32,0, 31,8, 31,4, 30,0, 26,8, 25,9, 25,7, 23,5, 22,9, 21,5, 18,6, 17,7, 16,1.

Preparative example 4: 16β,21-diol with a protective 21-diphenylmethylsilane group (7)

Diol (6) (5.5 g, 10 mmol) dissolved in anhydrous dichloromethane (50 ml) and triethylamine (2.8 ml, 20 mmol) in an argon atmosphere in dried in a drying Cabinet dvuhhodovoy round bottom flask and cooled to -10°C. To the cooled solution for 15 minutes, add a solution of diphenyldichlorosilane (2.3 ml, 11 mmol) in anhydrous dichloromethane (20 ml) so that the temperature did not exceed 0°and continue stirring for 15 minutes the Reaction mixture was transferred into a separating funnel and diluted with 100 ml of dichloromethane. The organic solution is successively washed with saturated sodium bicarbonate solution (100 ml), water (100 ml) and brine (100 ml). The organic solution is dried over anhydrous sodium sulfate and evaporated the solvent under reduced pressure, obtaining 9 g of colorless syrup. The crude mixture without purification will acetimidoyl, dissolving it in pyridine (15 ml) and acetic anhydride (15 ml). The resulting mixture is stirred over night at room temperature in a stoppered flask. At the end of this time the offer was concentrated in vacuo, receiving a pale yellow oil. Essentially pure named the title compound (7), 6.2 g, obtained as a colorless syrup after column chromatography using as eluent a mixture of ethyl acetate and low-boiling petroleum ether.

13With NMR (CDCl3): 170,1, 134,2, 129,5, 127,6, 124,6, 97,1, 95,0, 77,6, 77,1, 77,0, 64,9, 55,5, 55,1, 50,0, 48,3, 42,5, 40,9, 40,6, 38,9, 36,7, 36,3, 36,2, 31,7, 31,2, 30,3, 29,8, 26,6, 25,6, 25,5, 23,1, 22,8, 21,2, 21,1, 17,8, 17,5, 15,9, 14,0, -3,3.

Preparative example 5: 16-acetate 16β,21-diol (8)

16β,21-diol with a protective 21-diphenylmethylsilane group (7) (6.2 g, 7.9 mmol) was dissolved in tetrahydrofuran (100 ml) and glacial acetic acid (0.75 ml). To the resulting solution add hydrate Tetramethylammonium (4 g, 15.8 mmol) and the reaction mixture was stirred at room temperature for 10 min. Then the reaction mixture was transferred into a separating funnel with 200 ml of ethyl acetate. The organic solution is washed twice with water (2×100 ml) and brine (100 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo, obtaining a colorless syrup. Net named the title compound (8), 4.3 g, obtained as a colorless syrup after chromatography using as eluent a mixture of ethyl acetate and low-boiling petroleum ether.

13With NMR (CDCl3): 170,3, 131,7, 124,4, 97,4, 95,3, 77,9, 77,3, 64,9, 55,8, 55,4, 50,4, 48,6, 43,7, 41,3, 40,, 39,1, 37,0, 36,6, 36,5, 31,9, 31,6, 30,9, 30,1, 26,8, 25,9, 25,7, 23,4, 23,1, 21,6, 21,3, 18,3, 17,8, 16,1.

Preparative example 6: 3,11-bis-O-methoxymethyl-17(S),20(S}-digidrofolieva acid (9)

Periodinane dess-Martin (3.7 g, 8,7 mmol)dissolved in anhydrous dichloromethane (60 ml), added to a solution of 16-acetate 16β,21-diol (8) (4 g, 6.7 mmol) in dichloromethane (50 ml) at room temperature. The reaction mixture is stirred for 15 minutes after the specified time, the reaction mixture is poured onto 1 n sodium bicarbonate solution (50 ml) and 1 n sodium thiosulfate solution (50 ml), and two layers vigorously stirred for 10 minutes resulting two layers transferred into a separating funnel with ethyl acetate (100 ml). The layers are separated and the organic layer washed with saturated sodium bicarbonate solution (100 ml) and brine (100 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo, gaining 3.7 g of colorless syrup. The crude aldehyde (3.7 g, 6.2 mmol) without purification was dissolved in tert-butanol (50 ml). To the resulting solution was added 2-methyl-2-butene (1,48 ml of 16.8 mmol), 1 n solution of sodium dihydrophosphate (16 ml) and sodium chlorite (1.44 g, 16 mmol) in water (20 ml) and the reaction mixture is vigorously stirred for approximately 3 hours at room temperature. The reaction mixture is acidified to pH 4 with acetic acid and transferred into a separating funnel is by ethyl acetate (200 ml). Two layers shaken and separated. The aqueous layer was re-extracted with ethyl acetate (2×100 ml). The combined organic extracts washed twice with brine (2×100 ml), dried over anhydrous sodium sulfate and concentrated in vacuo, obtaining 3.4 g of a pale yellow foam. Purification of column chromatography using as eluent a mixture of ethyl acetate, low-boiling petroleum ether and trace amounts of formic acid gives 2.9 g of pure named in the connection header acid 9 in the form of a semi-crystalline substance.

13With NMR (CDCl3): 182,2, 170,1, 132,4, 123,2, 97,6, 95,3, 77,9, 77,3, 76,4, 55,8, 55,4, 49,9, 49,1, 45,2, 44,5, 40,9, 40,6, 38,8, 36,9, 36,6, 36,5, 32,6, 31,9, 31,5, 30,1, 26,8, 25,7, 25,2, 23,4, 23,2, 21,2, 20,6, 17,7, 17,6, 16,1.

Preparative example 7: tert-butyl ether 3,11-bis-O-methoxymethyl-17(S),20(S)-digidrofolievoy acid (17)

3,11-bis-O-methoxymethyl-17(S),20(S)-digidrofolievoy acid (9) (6.2 g, the 10.8 mmol) is dissolved in anhydrous benzene (40 ml). The solution is refluxed and within 4 hours add tert-butyl acetate N,N-dimethylformamide (10.4 ml, 43.2 mmol), dissolved in anhydrous benzene (20 ml). The reaction mixture is refluxed for 1 hour, cooled, transferred into a separating funnel and diluted with ethyl acetate (150 ml). The organic solution was washed with water (30 ml), saturated aqueous bicarbonate soda is I (30 ml) and brine (30 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo, obtaining a colorless foam, which is purified column chromatography on silica gel, getting called in the header tert-butyl ester 17 in the form of a colorless foamy substance.

13With NMR (CDCl3): 174,3, 170,5, 131,9, 123,8, 97,6, 95,3, 79,8, 77,9, 77,3, 77,2, 55,8, 55,4, 49,7, 49,2, 47,3, 43,8, 40,9, 40,7, 39,0, 36,9, 36,7, 36,3, 32,5, 32,0, 31,5, 30,1, 28,0, 26,8, 25,7, 25,2, 23,4, 23,2, 21,5, 21,2, 17,8, 17,7, 16,1.

Preparative example 8: tert-butyl ether 3,11-bis-O-methoxymethyl-16-deazetil-17(S),20(S)-digidrofolievoy acid (18)

tert-butyl ether 17 (4 g, 6.8 mmol) is dissolved in ethanol (10 ml), and 4 N. aqueous sodium hydroxide solution (10 ml). The resulting mixture was refluxed for 1 hour, cooled and acidified to pH 4 with hydrochloric acid. Add water (50 ml) and ethyl acetate (50 ml) and the mixture is transferred into a separating funnel. Separated the layers and the aqueous layer was re-extracted with ethyl acetate (3×50 ml). The combined organic layers dried over anhydrous sodium sulfate and concentrated in vacuo, getting called in the header tert-butyl ether (18).

Preparative example 9: tert-butyl ether 3,11-bis-O-methoxymethyl-16-deacetoxy-16α-bromo-17(S),20(S)-digidrofolievoy acid (19)

tert-butyl ester (18) (2 g, 3.4 mmol) and Tetra-bromatan (1,32 g, 4 mmol) dissolved in dichloromethane (50 ml) and cooling the t to 0° C. To the cooled solution was added in small portions of solid triphenylphosphine (of 1.05 g, 4 mmol). After 1 hour the reaction is quenched by adding triethylamine (3 ml). Add diethyl ether (50 ml) to precipitate triphenylphosphine, which is then filtered. The organic solution is transferred into a separating funnel and washed with water (20 ml), saturated sodium bicarbonate solution (20 ml) and brine (20 ml). The organic solution is dried over anhydrous sodium sulfate, concentrated in vacuo, getting called in the header tert-butyl ester (19).

Preparative example 10: the lactone 3-O-S-16-deazetil-17(S),20(S)-digidrofolievoy acid (11)

The lactone (4) (15,25 g, a 33.2 mmol) dissolved in anhydrous DMF (75 ml) in an argon atmosphere in dried in a drying Cabinet dvuhhodovoy round bottom flask. To the solution add imidazole (4.5 g, to 66.4 mmol) and then TBSCl (10 g, to 66.4 mmol). The obtained pale yellow reaction mixture is stirred over night at room temperature. The reaction mixture was diluted with ethyl acetate and sequentially washed with water and brine. The organic solution is dried over anhydrous sodium sulfate and concentrated in vacuo, receiving a yellow oil that crystallized upon standing. Crystalline material is recrystallized from methanol (100 ml). Colorless crystals are collected by filtration, receiving of 14.7 g of the lactone of 3-O-S-16-DEA is ethyl-17(S),20(S)-dihydropyrido-howl acid (11), TPL on 138.5-140°C.

Preparative example 11: 16β,21-diol (12)

Alumoweld lithium (2.5 g, 65 mmol) suspended in anhydrous THF (125 ml) in an argon atmosphere in dried in a drying Cabinet dvuhhodovoy round bottom flask, equipped with reflux condenser. To the suspension was added with stirring a solution of lactone 11 (18,4 g, 32.1 mmol) in anhydrous THF (75 ml) with such speed that causes a low boil. The reaction mixture is refluxed with vigorous stirring for 4 hours and then left to reach room temperature. The excess lithium aluminum hydride destroy with ethyl acetate (125 ml) and then gradually add water (125 ml). The resulting suspension is acidified with diluted hydrochloric acid to pH 5. The suspension is transferred into a separating funnel with ethyl acetate (500 ml) and water (400 ml). Both layers are thoroughly shaken and then separated. The aqueous layer was extracted with ethyl acetate (500 ml) and the combined organic layers washed twice with brine (2×500 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo, receiving 19 g of almost pure named in the title diol (12) in the form of colorless powder. Diol crystallized from methanol/water and collected by filtration colorless crystalline substance, after receiving the freeze-drying of 14.7 g of diol (12), TPL 122-124°C.

Preparative example 12: 16β,21-diol with a protective 21-diphenylmethylsilane group (13)

Diol (12) (14,05 g, 24.4 mmol) dissolved in anhydrous dichloromethane (125 ml) and triethylamine (6.8 ml, 48.8 mmol) in an argon atmosphere in dried in a drying Cabinet dvuhhodovoy round bottom flask and cooled to -20°C. To the cooled solution over 1 hour add a solution of diphenyldichlorosilane (25,7 ml, 26.8 mmol) in anhydrous dichloromethane (50 ml). Continue stirring for 15 minutes the Reaction mixture was transferred into a separating funnel and diluted with 500 ml of dichloromethane. The organic solution is successively washed with saturated sodium bicarbonate solution (250 ml), water (250 ml) and brine (250 ml). The organic solution is dried over anhydrous sodium sulfate, evaporated the solvent under reduced pressure, getting 17 g of colorless syrup. The crude pale yellow syrup cleanse column chromatography using as eluent a mixture of ethyl acetate and low boiling petroleum ether, receiving 14,7 g 16β, 21-diol with a protective 21-diphenylmethylsilane group (13) as a colourless foam.

Preparative example 13: compound 14

16β,21-diol with a protective 21-diphenylmethylsilane group (13) (9 g, 11.0 mmol) acetimidoyl, dissolving in pyridine (30 ml) and acetic anhydride (15 ml). The resulting mixture is stirred for 20 hours at whom atoi temperature in a stoppered flask. After a specified time, the reaction mixture was concentrated in vacuo, receiving 11 g of pale yellow oil. Column chromatography using as eluent a mixture of ethyl acetate and low-boiling petroleum ether gives 7.9 g of pure acetylated compound (14).

Preparative example 14: 16-acetate 16β, 21-diol (15)

Compound 14 (7.5 g, 9.2 mmol) is dissolved in 100 ml of THF. To the solution was added acetic acid (3.2 ml) and TBAF (4,69 g, 18.4 mmol) and the resulting reaction mixture is stirred for 5 min at room temperature. After a specified time, add water (100 ml) and ethyl acetate (200 ml) and both layers are transferred into a separating funnel. The layers are separated and the aqueous layer was again extracted with EtOAc (200 ml). The combined organic layers are washed twice with water (2×100 ml) and brine (100 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo, obtaining a colorless syrup. Net named the title compound (15), 5.7 g, obtained as a colorless syrup after column chromatography using as eluent a mixture of ethyl acetate and low-boiling petroleum ether.

Preparative example 15: 3-O-TBS-17(S),20(S)-digidrofolieva acid (16)

A. To a solution of 16-acetate 16β,21-diol (15) (5,4 g of 8.75 mmol) in anhydrous THF (125 ml), cooled to 0°With, in small portions during 1 hour add periodinane dess-Martin (and 3.72 g, is 8.75 mmol). The reaction mixture is stirred for 3 hours at 0°C. after the specified time, the reaction mixture is poured onto 1 n sodium bicarbonate solution (90 ml) and 1 n sodium thiosulfate solution (90 ml) and two layers vigorously stirred for 10 minutes, Both layers are transferred into a separating funnel with dichloromethane (400 ml). The layers are separated and the organic layer washed with saturated sodium bicarbonate solution (200 ml) and water (200 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo, obtaining of 5.4 g of syrup. Pure aldehyde, 5.0 g, obtained as a colorless syrup after column chromatography using as eluent a mixture of ethyl acetate and low-boiling petroleum ether.

C. the Aldehyde from preparative example 15A (5,18 g, 8.4 mmol) without purification was dissolved in tert-butanol (50 ml). To the resulting solution was added 2-methyl-2-butene (3.55 ml, 33.6 mmol), 1 n solution of sodium dihydrophosphate (34 ml) and sodium chlorite (3,84 g, 34 mmol) in water (20 ml) and the reaction mixture is vigorously stirred over night at room temperature. The reaction mixture is acidified to pH 4 with acetic acid and transferred into a separating funnel with ethyl acetate (200 ml). Two layers shaken and separated. The aqueous layer was re-extracted twice with ethyl acetate (2×200 ml). The combined organic extrac the s twice washed with brine (2× 100 ml), dried over anhydrous sodium sulfate and concentrated in vacuo, receiving 6 g of a pale yellow foam. Purification of column chromatography using as eluent a mixture of ethyl acetate, low-boiling petroleum ether and trace amounts of formic acid yields of 4.2 g of pure named in the title acid (16) in the form of a semi-crystalline substance.

Examples

Example 1: 17(S),20(S)-digidrofolieva acid (10) (compound 101)

The compound of formula 9 (2 g, 3.3 mmol) dissolved in anhydrous dichloromethane (50 ml) in an argon atmosphere in dried in a drying Cabinet dvuhhodovoy round bottom flask and cooled to -20°C. To the solution was added molecular sieves (6 g), and gradually with continuous stirring enter trimethylborazine (2.7 ml, 20 mmol). The reaction mixture is stirred until completion of the reaction (approximately 5 hours). Then the reaction mixture was transferred into a separating funnel with ethyl acetate and water, the two layers are shaken and separated. The aqueous layer was extracted three times with ethyl acetate (3×20 ml) and the combined organic layers washed with brine (30 ml). The organic solution is dried over anhydrous sodium sulfate and concentrated in vacuo, gaining 1.4 g of compound 101 in the form of a colorless solid. Recrystallization from methanol/water gives 1.2 g of colorless Crist is lifescope substances. TPL 195-195,5°C.

13With NMR (CD3OD): 173,1, 131,8, 126,2, 78,3, 72,6, 69,4, 50,8, 50,6, 46,6, 41,9, 41,8, 39,6, 38,2, 38,0, 37,1, 36,2, 35,2, 33,1, 31,1, 27,2, 25,9, 23,7, 23,6, 22,6, 21,2, 17,9, 16,5.

Example 1A: Alternative method of obtaining 17(S),20(S)-digidrofolievoy acid (10) (compound 101)

The compound of formula 16 (3.6 g, 5.7 mmol) dissolved in THF (15 ml) and 40% aqueous solution of hydrogen fluoride (10 ml) in a round bottom Teflon flask. The resulting reaction mixture was stirred at room temperature for two days. Then the reaction mixture was neutralized to pH 8 27% sodium hydroxide solution and finally bring the pH to 4 with acetic acid. Then the reaction mixture was transferred into a separating funnel with ethyl acetate and water, the two layers are shaken and separated. The aqueous layer was extracted three times with ethyl acetate (3×50 ml) and the combined organic layers washed with brine (50 ml). The organic solution is dried over anhydrous sodium sulfate and concentrated in vacuo, receiving 4 g of compound 101 in the form of a colorless solid. Purification of column chromatography using as eluent a mixture of ethyl acetate, the low-boiling petroleum ether and trace amounts of formic acid gives 3.1 g of pure named in title 17(S),20(S)-digidrofolievoy acid (10) (compound 101) in the form of a crystalline substance. Recrystallization from methanol/water Mae is 2.9 g of a colorless crystalline substance. TPL 195-196°C.

13With NMR (CD3OD): 173,1, 131,8, 126,2, 78,3, 72,6, 69,4, 50,8, 50,6, 46,6, 41,9, 41,8, 39,6, 38,2, 38,0, 37,1, 36,2, 35,2, 33,1, 31,1, 27,2, 25,9, 23,7, 23,6, 22,6, 21,2, 17,9, 16,5.

Example 2: 17(S),20(S),24,25-tetragidrofolieva acid (compound 102)

A solution of compound 101 (280 mg, 0.54 mmol) in ethanol (3 ml) hydronaut when the hydrogen pressure of 1 ATM in the presence of 5% palladium on calcium carbonate (30 mg). The reaction mixture was vigorously stirred until the absorption of theoretically calculated amount of hydrogen and removing the catalyst by filtration. To the filtrate is added dropwise water, receiving 255 mg of crystalline 17 (S),20 (S),24,25-tetrahydropyrido acid. TPL on 138.5-140°C.

13With NMR (DMSO-d6): 210,7, 176,6, 169,1, 131,2, 123,7, 75,3, 69,0, 57,7, 48,9, 43,8, 43,6, 43,3, 41,8, 41,7, 37,7, 37,2, 34,4, 32,6, 30,1, 27,9, 25,3, 24,8, 22,7, 20,6, 20,4, 20,1, 17,4, 16,3, 16,0.

Example 3: 11-degidro-17(S),20(S)-digidrofolieva acid (compound 103)

A. 3-O-formyl-17(S),20(S)-digidrofolieva acid

17(S),20(S)-digidrofolievoy acid (260 mg, 0.5 mmol) is dissolved in a solution of mixed anhydrides derived from acetic anhydride and formic acid (2:1, vol/about.) at 5°→50°containing formic anhydride, dichloromethane (4.4 ml) and dimethylaminopyridine (30 mg), and stirred at room temperature for 20 hours. The mixture was concentrated in vacuo, the oily residue is dissolved in ethyl acetate (25 ml) and the solution is washed in the Oh (10 ml) and brine (10 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo, receiving 250 mg of 3-O-formyl-17(S),20(S)-digidrofolievoy acid in the form of oily substance which crystallizes upon standing.

Century 3-O-formyl-11-degidro-17(S),20(S)-digidrofolieva acid

To the crude 3-O-formyl-17(S),20(S}-digidrofolievoy acid from the stage And dissolved in acetic acid (2.5 ml)add a solution of chromic acid (65 mg, of 0.65 mmol) in water (0,65 ml) and the resulting green reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was diluted with diethyl ether (40 ml), washed with water (20 ml) and twice with brine (2×10 ml), dried over anhydrous sodium sulfate and concentrated in vacuo, getting 255 mg of 3-O-formyl-11-degidro-17(S),20(S)-digidrofolievoy acid as a colourless oil.

S. 11-degidro-17(S),20(S)-digidrofolieva acid

To a solution of crude 3-O-formyl-11-degidro-17(S),20(S)-digidrofolievoy acid from the stage In methanol (3 ml), cooled to 0°add solid potassium carbonate (130 mg) and the resulting suspension is vigorously stirred for 1 hour. The reaction mixture is acidified to pH 3 2 N. hydrochloric acid, diluted with ethyl acetate (40 ml), transferred into a separating funnel and washed with water (15 ml) and twice with brine (2×10 ml). The organic layer is dried over anhydrous sulfate n the Tria and was concentrated in vacuo, receiving a pale yellow oily reaction product, which is purified column chromatography using as eluent mixtures of low-boiling petroleum ether, ethyl acetate and trace amounts of formic acid. Of methanol and water get semicrystalline 11 dehydro-17(S),20(S)-dihydro-guideway acid.

13With NMR (CD3OD): 180,5, 172,1, 77,9, 72,5, 69,2, 50,8, 50,6, 47,2, 46,2, 41,8, 40,2, 39,6, 38,2, 38,0, 37,0, 36,0, 34,5, 33,0, 31,1, 29,1, 25,7, 23,7, 23,6, 23,1, 23,0, 22,6, 20,8, 17,7, 16,5.

Example 4: 3-degidro-17(S),20(S)-digidrofolieva acid (compound 104)

17(S),20(S)-digidrofolievoy acid (260 mg, 0.5 mmol) dissolved in tetrahydrofuran (10 ml) and cooled to 0°C. Add small portions of solid periodinane dess-Martin (250 mg, 0.59 mmol) and the reaction mixture is stirred for 5 hours. The reaction mixture was diluted with ethyl acetate (40 ml) and transferred into a separating funnel. The organic solution was vigorously shaken with 10% aqueous sodium thiosulfate solution (15 ml), washed with water (10 ml) and brine (10 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo, obtaining a colorless syrup. Purification of column chromatography using as eluent mixtures of petroleum ether, ethyl acetate and formic acid to give 215 mg of 3-dehydro-17(S),20(S)-digidrofolievoy acid.

Example 5: 16 diacetoxy-16β-PR is pinelake-17(S),20(S)-digidrofolieva acid (compound 105)

A. 3,11-bis-O-methoxymethyl-16-deacetoxy-16β-propionyl oxy-17(S),20(S)-digidrofolieva acid

Compound 18 (288 mg, 0.5 mmol) dissolved in a mixture of dichloromethane (2 ml), propionic anhydride (2 ml) and pyridine (2 ml) and stirred over night at room temperature. The solvent is evaporated in vacuum, obtaining a colorless oil is essentially pure 3,11-bis-O-methoxymethyl-16-deacetoxy-16β-propionyloxy-17(S),20(S)-digidrofolievoy acid.

Century 16 diacetoxy-16β-propionyloxy-17(S),20(S)-digidrofolieva acid

To a solution of tert-butyl ester from step a in tetrahydrofuran (5 ml) add 2 N. hydrochloric acid (5 ml) and stirred at room temperature overnight. Then the reaction mixture was diluted with ethyl acetate (25 ml) and transferred into a separating funnel. The layers are separated and the organic layer washed twice with water (2×5 ml) and twice with brine (2×5 ml). The organic layer is dried over sodium sulfate and concentrated in vacuo, receiving 16 diacetoxy-16β-propionyloxy-17(S),20(S)-digidrofolievoy acid.

13With NMR (CDCl3): 180,9, 173,4, 132,4, 123,3, 76,2, 71,4, 68,8, 49,4, 45,2, 44,3, 40,7, 40,6, 38,3, 37,2, 36,4, 36,2, 34,4, 32,8, 32,6, 30,4, 30,0, 27,4, 25,7, 25,4, 23,9, 22,6, 20,9, 17,7, 17,3, 15,9, 8,9.

Example 6: 16 diacetoxy-16β-(3'-chloropropionate)-17(S),20(S)-digidrofolieva acid (compound 106)

A. tert-butyl ester of 3,11-bis-O-methoxymethyl-16-deace the hydroxy-16β -(3'-chloropropionate)-17(S),20(S)-digidrofolievoy acid

To compound 18 (588 mg, 1 mmol)dissolved in pyridine (3 ml), add 3-chloropropionitrile (0,29 ml, 3 mmol)and the mixture is stirred over night at room temperature. The solvent is evaporated in vacuum, obtaining a colorless oil is essentially pure tert-butyl ester of 3,11-bis-O-methoxymethyl-16-deacetoxy-16β-(3'-chloropropionate)-17(S),20(S)-digidrofolievoy acid.

Century 16 diacetoxy-16β-(3'-chloropropionate)-17(S),20(S)-digidrofolieva acid

To a solution of tert-butyl ester from step a in tetrahydrofuran (5 ml) add 2 N. hydrochloric acid (5 ml) and stirred at room temperature overnight. Then the reaction mixture was diluted with ethyl acetate (25 ml) and transferred into a separating funnel. The layers separated, and the organic layer washed twice with water (2 × 5 ml) and twice with brine (2 × 5 ml). The organic layer is dried over sodium sulfate and concentrated in vacuo, receiving 16 diacetoxy-16β-(3'-chloropropionate)-17(S),20(S)-digidrofolievoy acid.

Examples 7-14: 16 diacetoxy-16β-acyloxy-17(S),20(S)-digidrofolieva acid (compound 107-114)

A. 16β-acetoxypropionyl tert-butyl ester of 3,11-bis-O-methoxymethyl-16-deacetoxy-17(S),20(S)-digidrofolievoy acid

Following the methodology described in example 6A, substituting 3-propionyl the ID anhydrides, listed in table 3, receive 16β-allocryptopine tert-butyl ester of 3,11-bis-O-methoxymethyl-16-deacetoxy-17(S),20(S)-digidrofolievoy acids listed in table 3.

Table 3

ExampleThe acid chlorideRecip. connection, R
7A2'-methylpropionylCH(CH3)2
8AcyclopropanecarbonitrileWith3H5
9AchlorocatecholCH2Cl
10AbromocatecholCH2VG
11athe benzoyl chlorideWith6H5
12A4-perbenzoateWith6H4F
13AcyclohexylcarbonylWith6H11
14AakriloilkhloridaCH=CH2

Century 16β-allocryptopine 16 diacetoxy-17(S),20(S)-digidrofolievoy acid

Following the methodology described in example 6B, substituting tert-butyl ester of 3,11-bis-O-methoxymethyl-16-deacetoxy-16β-(3'-chloropropionate)-17(S),20(S)-digidrofolievoy acid 16#x003B2; -allactivity 3,11-bis-O-methoxymethyl-16-deace-hydroxy-17(S),20(S)-digidrofolievoy acid listed in table 2, receive 16-deacetoxy-16β-acyloxy-17(S),20(S)-dihydroquinoline acid listed in table 4.

Table 4

ExampleThe compound obtained
No.R
7B1072'-methylpropionyl
8B108cyclopropanecarbonyl
9V109chloroacetyl
10V110bromacetyl
11B111benzoyl
12V1124'-perbenzoic
13B113cyclohexylcarbonyl
14V114acryloyl

Data13C NMR for compounds 107-113

Connection 107,13With NMR (CD3OD): 180,7, 175,9, 132,3, 123,4, 76,3, 71,4, 68,8, 49,4, 45,2, 44,0, 40,8, 40,6, 38,3, 37,2, 36,4, 36,2, 34,5, 33,6, 32,7, 32,6, 30,4, 30,0, 25,7, 25,3, 23,9, 22,7, 20,9, 19,1, 18,1, 17,8, 17,5, 15,9.

The connection 108,13With NMR (l3): 180,3, 173,9, 132,3, 123,4, 76,4, 71,4, 68,9, 49,4, 45,2, 44,3, 40,7, 40,6, 38,3, 37,2, 36,4, 36,2, 34,5, 32,7, 32,6, 30,4, 30,0, 25,7, 25,4, 23,9, 22,7, 21,0, 17,7, 17,4, 15,9, 12,7, 8,0.

Connection 109 13With NMR (CO3CD): 180,1, 168,0, 133,2, 124,7, 79,9, 72,5, 69,1, 50,8, 50,7, 46,7, 46,2, 41,8, 41,7, 41,6, 39,7, 38,1, 38,0, 37,1, 35,9, 34,4, 33,1, 31,1, 26,4, 25,9, 23,7, 23,6, 22,5, 17,8, 17,7, 16,5.

The connection 110,13With NMR (l3): 180,5, 166,4, 154,3, 132,4, 123,3, 78,7, 71,5, 68,8, 49,5, 49,3, 45,2, 44,5, 40,7, 40,6, 38,4, 37,2, 36,4, 36,2, 34,3, 32,7, 32,5, 30,4, 29,9, 25,7, 25,4, 23,8, 22,7, 20,9, 17,7, 17,4, 15,9.

Connection 111,13With NMR (CD3OD): 179,8, 167,2, 134,1, 133,1, 131,6, 131,0, 129,4, 124,9, 78,7, 72,5, 69,2, 50,8, 50,7, 46,7, 45,9, 42,2, 41,9, 39,8, 38,1, 38,0, 37,1, 36,1, 34,4, 33,1, 31,1, 26,3, 25,9, 23,7, 23,6, 22,5, 18,1, 17,8, 16,5.

The connection 112,13With NMR (CD3OD): 179,8, 166,2, 167,3, 133,8, 133,1, 128,0, 124,8, 116,3, 78,9, 72,5, 69,2, 50,8, 50,7, 46,7, 46,0, 42,1, 41,9, 39,8, 38,1, 38,0, 37,1, 36,1, 34,4, 33,1, 31,1, 26,4, 25,9, 23,7, 23,6, 22,5, 18,2, 17,8, 16,5.

Connection 113,13With NMR (l3): 180,0, 174,9, 132,3, 123,4, 76,1, 71,4, 68,8, 49,4, 49,3, 45,2, 44,0, 42,7, 40,9, 40,5, 38,4, 37,2, 36,4, 36,1, 34,5, 32,7, 30,4, 30,0, 29,1, 28,1, 25,8, 25,7, 25,3, 25,1, 23,9, 22,6, 20,9, 17,8, 17,5, 15,9.

Example 15: 16 diacetoxy-16β-isopropylthio-17(S),20(S)-digidrofolieva acid (compound 115)

A. tert-butyl ester of 3,11-bis-O-methoxymethyl-6-diacetoxy-16β-isopropylthio-17(S),20(S)-digidrofolievoy acid

To a solution of potassium hydroxide (250 mg) and isopropylparaben (0.75 ml, 8 mmol) in ethanol (25 ml) is added tert-butyl ester of 3,11-bis-O-methoxymethyl-16-deacetoxy-16α-bromo-17(S),20(S)-digidrofolievoy acid (19) (700 mg, 1 mmol) and the suspension is stirred for four days. After a specified time add water (approximately 10 ml) to complete the OCA is Denia connection. The precipitation is filtered off, washed with cold mixture of ethanol and water (2:1) and dried, obtaining tert-butyl ester of 3,11-bis-O-methoxymethyl-16-deacetoxy-16β-isopropylthio-17(S),20(S)-digidrofolievoy acid.

Century 16 diacetoxy-16β-isopropylthio-17(S),20(S)-digidrofolieva acid

To a solution of the above tert-butyl ester in tetrahydrofuran (5 ml) add 2 N. hydrochloric acid (5 ml) and stirred over night at room temperature. The reaction mixture was diluted with ethyl acetate (25 ml) and transferred into a separating funnel. The layers are separated and the organic layer washed twice with water (2×5 ml) and twice with brine (2×5 ml). The organic layer is dried over sodium sulfate and concentrated in vacuo, receiving 16 diacetoxy-16β-isopropylthio-17(S),20(S)-digidrofolievoy acid.

Examples 16-19: 16β-thioethers 16 diacetoxy-17(S),20(S)-digidrofolievoy acid (compound 116 to 119)

A. Tert-butyl ester 16β-thioesters 3,11-bis-O-methoxymethyl-16-deacetoxy-17(S),20(S)-digidrofolievoy acid

Following the methodology described in example 15A, and replacing isopropylmalate on the mercaptans listed in table 5, receive tert-butyl ester 16β-thioesters 3,11-bis-O-methoxymethyl-16-deacetoxy-17(S),20(S)-digidrofolievoy acids listed in table 5.

Table 5
ExampleMercaptanRecip. connection, R
16Athe ethyl mercaptanCH2CH3
17A2,2,2-trichloromethylmercaptoCH2CCl3
18Atert-butylmercaptanC(CH3)3
19AmethoxyethylmercuryCH2Och3

Century 16β-thioethers 16 diacetoxy-17(S),20(S)-digidrofolievoy acid

Following the methodology described in example 15V, and replacing tert-butyl ester of 3,11-bis-O-methoxymethyl-16-deacetoxy-16β-isopropylthio-17(S),20(S)-digidrofolievoy acid tert-butyl ester 16β-thioesters 3,11-bis-O-methoxymethyl-16-deacetoxy-17(S),20(S)-digidrofolievoy acids listed in table 5, receive 16-deacetoxy-16β-alkylthio-17(S),20(S)-dihydroquinoline acids listed in table 6.

Table 6
ExampleThe compound obtained
No.R
16B116 CH2CH3
17V117CH2CCl3
18V118C(CH3)3
19C119CH2Och3

Example 20: 16 diacetoxy-16β-isopropylthio-17(S),20(S),24,25-tetragidrofolieva acid (compound 120)

Following the methodology described in example 2, and substituting 17(S),20(S)-digidrofolievoy acid 16-deacetoxy-16β-isopropylthio-17(S),20(S)-digidrofolievoy acid, receive 16-deacetoxy-16β-isopropylthio-17(S),20(S),24,25-tetrahydrophthalate acid.

Example 21: 16 diacetoxy-16β-acetylthio-17(S),20(S)-digidrofolieva acid (compound 121)

A. tert-butyl ester of 3,11-bis-O-methoxymethyl-16-deazetil-16β-acetylthio-17(S),20(S)-digidrofolievoy acid

To a solution of tert-butyl methyl ether 3,11-bis-O-methoxymethyl-16-deacetoxy-16α-bromo-17 (S), 20 (S)-digidrofolievoy acid (19) (700 mg, 1 mmol) in dimethylformamide (6 ml) is added solid thioacetate potassium (228 mg, 2 mmol) and the reaction mixture was stirred at room temperature for 20 hours. After a specified time, the reaction mixture was diluted with diethyl ether (50 ml), transferred into a separating funnel and washed twice with water (2×10 ml) and brine (10 ml). The organic layer is dried over anhydrous sodium sulfate and will centerour in vacuum, getting tert-butyl ester of 3,11-bis-O-methoxymethyl-16-deazetil-16β-acetylthio-17(S),20(S)-digidrofolievoy acid.

Century 16 diacetoxy-16β-acetylthio-17(S),20(S)-digidrofolieva acid

To a solution of tert-butyl ester from step a in tetrahydrofuran (5 ml) add 2 N. hydrochloric acid (5 ml) and vigorously stirred at 60°C for four hours. The reaction mixture was left to reach room temperature, diluted with ethyl acetate (25 ml) and transferred into a separating funnel. The layers are separated and the organic layer washed twice with water (2×5 ml) and twice with brine (2×5 ml). The organic layer is dried over sodium sulfate and concentrated in vacuo, receiving 16 diacetoxy-16β-acetylthio-17(S),20(S)-digidrofolievoy acid as colorless foam.

Example 22: 16 diacetoxy-16β-benzylthio-17(S),20(S)-digidrofolieva acid (compound 122)

A. tert-butyl ester of 3,11-bis-O-methoxymethyl-16-deacetoxy-16β-benzylthio-17(S),20(S)-digidrofolievoy acid

Following the methodology described in example 17A, but replacing thioacetate potassium on thiobenzoate potassium receive tert-butyl ester of 3,11-bis-O-methoxymethyl-16-deacetoxy-16β-benzylthio-17(S),20(S)-digidrofolievoy acid.

Century 16 diacetoxy-16β-benzylthio-17(S),20(S)-digidrofolieva acid

Following the methodology described in example 17B, but replacing tert-butyl EPE is 3,11-bis-O-methoxymethyl-16-deacetoxy-16β -acetylthio-17(S),20 (S)-digidrofolievoy acid tert-butyl ester of 3,11-bis-O-methoxymethyl-16-deacetoxy-16β-benzylthio-17(S),20(S)-digidrofolievoy acid, receive 16-deacetoxy-16β-benzylthio-17(S),20(S)-digidrofolievoy acid.

Example 23: 16 diacetoxy-16β-ethoxy-17(S),20(S)-digidrofolieva acid (compound 123)

To a suspension ventilago ether 3,11-bis-O-methoxymethyl-16-deacetoxy-16α-bromo-17(S),20(S)-digidrofolievoy acid (750 mg, 1 mmol) in ethanol (10 ml) is added silver carbonate (550 mg, 2 mmol) and, after protection from light, the reaction mixture was stirred at room temperature for 18 hours. The insoluble substance is filtered off and washed twice with ethanol (2×2 ml). To the combined filtrate and proryvnym liquids add 5 N. aqueous sodium hydroxide solution (4 ml) and the mixture refluxed for 2 hours. The reaction mixture was left to reach room temperature and acidified with 4 N. hydrochloric acid. The major part of the ethanol is removed in vacuo and to the residue is added ethyl acetate (50 ml) and water (20 ml). Both layers are vigorously stirred for 30 min, transferred into a separating funnel and separated. The aqueous layer was extracted with ethyl acetate (50 ml). The combined organic extracts washed with water (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate and concentrated in HAC the mind, getting oily residue. The crude reaction product is dissolved in anhydrous dichloromethane in an argon atmosphere and cooled to 0°C. To the cooled mixture is added molecular sieves(1 g) and trimethylamine (1.1 ml, 1.8 mmol) and the resulting mixture is stirred for 5 hours. After a specified time, the mixture is diluted with ethyl acetate (50 ml) and water (20 ml) and transferred into a separating funnel. Both layers are shaken and separated. The aqueous layer was extracted with ethyl acetate (50 ml) and the combined organic extracts washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated in vacuo, receiving 16 diacetoxy-16β-ethoxy-17(S),20(S)-digidrofolievoy acid.

13With NMR (CD3OD): 181,2, 132,8, 125,1, 82,9, 72,5, 69,4, 66,4, 50,8, 47,5, 46,6, 41,9, 39,3, 39,1, 38,2, 37,9, 37,1, 36,1, 34,4, 33,1, 31,1, 26,5, 25,9, 23,8, 23,6, 22,7, 17,8, 17,3, 16,5, 15,2.

Examples 24-29: 16 diacetoxy-16β-alkyloxy-17 (S),20(S)-dihydroquinoline acid (compound 124-129)

Replacing ethanol in the method described in example 21, the alcohols listed in table 6, receive 16-deacetoxy-16β-alkyloxy-17 (S), 20(S)-dihydroquinoline acids listed in table 7.

Table 7
Example AlcoholThe compound obtained
No.R
242,2,2-triptoreline124CH2CF3
25propanol125CH2CH2CH3
26isopropanol126CH(CH3)2
271,3-diftorhinolonom127CH(CH2F)2
28methoxymethanol128CH2Och3
292,2,2-trichloroethanol129CH2CCl3

Compound 126:13With NMR (CD3D): 181,1, 132,9, 125,0, 99,3, 83,6, 72,5, 69,4, 56,3, 50,9, 50,6, 47,7, 46,7, 41,9, 41,3, 39,3, 38,2, 37,9, 37,0, 36,2, 34,2, 33,1, 31,1, 26,5, 25,9, 23,8, 23,5, 22,7, 17,8, 17,3, 16,5.

Example 30: 16 diacetoxy-16β-(2'-azidoethoxy)-17(S),20(S)-digidrofolieva acid (compound 130)

A. tert-Butyl ester of 3,11-bis-O-methoxymethyl-16-deacetoxy-16β-(2'-hydroxyethoxy)-17(S),20(S)-digidrofolievoy acid

To a solution of tert-butyl methyl ether 3,11-bis-O-methoxymethyl-16-deacetoxy-16α-bromo-17(S),20(S)-digidrofolievoy acid (19) (1400 mg, 2 mmol) in a mixture of mono - and gazetterepella (1:1, 8 ml) is added silver carbonate (1.1 g, 4 mmol). A mixture of f the t from the light and then stirred for three days at room temperature. After removal of the solvents under reduced pressure liquid residue is diluted with methanol (40 ml), add potassium carbonate and the mixture is stirred at room temperature for 30 minutes the Mixture was concentrated in vacuo, the obtained oily residue is dissolved in diethyl ether (40 ml) and water (40 ml) and the solution neutralized with diluted hydrochloric acid. The layers are separated and the aqueous layer was re-extracted with diethyl ether (20 ml). The combined organic layers washed with water (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude reaction product is purified column chromatography using as an eluent of ethyl acetate and low-boiling petroleum ether, receiving tert-butyl ester of 3,11-bis-O-methoxymethyl-16-deacetoxy-16β-(2'-hydroxyethoxy)-17(S),20(S)-digidrofolievoy acid.

C. tert-butyl ester of 3,11-bis-O-methoxymethyl-16-deacetoxy-16β-(2'-bromoethoxy)-17(S),20(S)-digidrofolievoy acid

To a solution of tert-butyl methyl ether 3,11-bis-O-methoxymethyl-16-deacetoxy-16β-(2'-hydroxyethoxy)-17(S),20(S)-digidrofolievoy acid (670 mg) from the stage And add phenyl-N,N-dimethylformamide (740 mg, 3.2 mmol) and the resulting mixture is stirred for 16 hours at room temperature. After dilution with diethyl ether (30 ml) the mixture is transferred into a separating is oroku and washed three times with water (3× 10 ml) and brine (10 ml), the organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. Pale pink residue purified column chromatography using as an eluent of ethyl acetate and low-boiling petroleum ether, receiving tert-butyl ester of 3,11-bis-O-methoxymethyl-16-deacetoxy-16β-(2'-bromoethoxy)-17(S),20(S)-digidrofolievoy acid.

C. tert-butyl ester of 3,11-bis-O-methoxymethyl-16-deacetoxy-16β-(2'-azidoethoxy)-17(S),20(S)-digidrofolievoy acid

A solution of tert-butyl methyl ether 3,11-bis-O-methoxymethyl-16-deacetoxy-16β-(2'-bromoethoxy)-17(S),20(S)-digidrofolievoy acid from step B (370 mg, 0.5 mmol) and lithium azide (125 mg, 2.5 mmol) in dimethylformamide (8 ml) is stirred for 18 hours at room temperature. Then the solution was diluted with diethyl ether (40 ml) and washed three times with water (3×10 ml) and brine (10 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo, obtaining tert-butyl ester of 3,11-bis-O-methoxymethyl-16-deacetoxy-16β-(2'-azidoethoxy)-17(S),20(S)-digidrofolievoy acid.

D. 16-deacetoxy-16β-(2'-azidoethoxy)-17(S),20(S)-digidrofolieva acid

To a solution of tert-butyl methyl ether 3,11-bis-O-methoxymethyl-16-deacetoxy-16β-(2'-azidoethoxy)-17(S),20(S)-digidrofolievoy acid (300 mg, 0.4 mmol) in Tetra-hydrofuran (5 ml) add 2 N. hydrochloric to the slot (5 ml) and the mixture is heated at 60° With over four hours. The reaction mixture was left to reach room temperature, diluted with ethyl acetate (25 ml) and transferred into a separating funnel. The layers are separated and the organic layer washed twice with water (2×5 ml) and twice with brine (2×5 ml). The organic layer is dried over sodium sulfate and concentrated in vacuo, receiving 16 diacetoxy-16β-(2'-azidoethoxy)-17(S),20(S)-digidrofolievoy acid.

Example 31: 16 diacetoxy-16β-(2'-hydroxyethoxy)-17(S),20(S)-digidrofolieva acid (compound 131)

Following the methodology described in example 30D, and replacing tert-butyl ester of 3,11-bis-O-methoxymethyl-16-deacetoxy-16β-(2'-azidoethoxy)-17(S),20(S)-digidrofolievoy acid tert-butyl ester of 3,11-bis-O-methoxymethyl-16-deacetoxy-16β-(2'-hydroxyethoxy)-17(S),20(S)-digidrofolievoy acid from example 30A, receive 16-deacetoxy-16β-(2'-hydroxyethoxy)-17(S),20(S)-digidrofolievoy acid.

Example 32: sodium salt of 17(S),20(S)-digidrofolievoy acid

17(S),20(S)-digidrofolievoy acid (400 mg, 0.77 mmol) dissolved in methanol (0.4 ml) and acetone (1.2 ml) and neutralized 4 N. solution of sodium hydroxide. Gradually add diethyl ether until precipitation of colorless crystals. Colorless crystals (350 mg), filtered and dried in air.

13With NMR (CD3OD), 173,1, 131,8, 126,2, 78,3, 72,6, 69,4, 50,8, 50,6, 46,6, 41,9, 41,8, 39,6, 38,2 38,0, 37,1, 36,2, 35,2, 33,1, 31,1, 27,2, 25,9, 23,7, 23,6, 22,6, 21,2, 17,9, 16,5.

Example 33: diethanolamine Sol 17(S),20(S)-digidrofolievoy acid

17(S),20(S)-digidrofolievoy acid (450 mg, 0.87 mmol) dissolved in acetone (1 ml) and diethanolamine (0.1 ml, 1 mmol) and left at room temperature for 24 hours. After a specified time gradually add diethyl ether and the resulting solution is kept at 2°for a few days, getting 380 mg semi-crystalline substance.

Example 34: cream

Sodium salt of 16-deacetoxy-16β-ethoxy-17(S),20(S)-digidrofolievoy acid 1 g

Petrolatum 7.5 g

Vaseline oil 7.5 g

Spermaceti 2.5 g

Monopalmitate sorbitan 2.5 g

Monopalmitate of polyoxyethylenesorbitan 2.5 g

Water 26,5 g

A total of 50 g

Heated petrolatum, paraffin, spermaceti, monopalmitate sorbitan and monopalmitate of polyoxyethylenesorbitan up to 70°and gradually under continuous stirring the water. Stirring is continued until, until the cream cools. Sodium salt of 16-deacetoxy-16β-ethoxy-17(S),20(S)-digidrofolievoy acid rubbed with cream Foundation and homogenized using a ball mill. Cream filled soft aluminum tubes.

Example 35: ointment

Sodium salt of 16-deacetoxy-16β-ethoxy

-17(S),20(S)-digidrofolievoy acid 1 g

Vaseline oil 6,9 g

Cetanol 0.2 g/p>

Anhydrous lanolin 2.3 g

Petrolatum 39,6 g

A total of 50 g

Melted at 70°paraffin, cetanol, lanolin and petrolatum. After cooling to a temperature below 40°With powdered sodium salt of 16-deacetoxy-16β-ethoxy-17(S),20(S)-digidrofolievoy acid. The ointment filled soft lacquered aluminium tubes.

Example 36: capsules

Sodium salt of 16-deacetoxy-16β-acetylthio-

17(S),20(S)-digidrofolievoy acid 25 g

Microcrystalline cellulose 14.5 g

Magnesium stearate 0.5 g

A total of 40 g

The ingredients are sieved through a sieve of 60 mesh and mixed for 10 minutes with a Mixture of fill hard gelatin capsules using a capsule fill weight 400 mg

Example 37: tablets

Sodium salt of 16-deacetoxy-

16β-(2',2',2'-triptoreline)-

17(S),20(S)-digidrofolievoy acid 25 g

Avicel™ 12 g

STA-Rx 1500 12 g

Magnesium stearate 1 g

A total of 50 g

Sodium salt of 16-deacetoxy-16β-(2', 2',2'-triptoreline)-17(S),20(S)-digidrofolievoy acid, Avicel™ and STA-Rx 1500 mixed, sieved through sieve 0.7 mm and then mixed with magnesium stearate. The mixture is pressed into tablets weighing 500 mg

Example 38: suspension

Sodium salt of 16-deacetoxy-16β-acetylthio-

17(S),20(S)-digidrofolievoy acid 1 g

Citric acid 0.09 g

Monohydratefast sodium 0.14 g

Sucrose 5 g

Tween™ 80 0.01 g

The sorbate is Aliya 0.04 g

Na-carboxymethylcellulose 0.1 g

Water qs to 100 ml suspension

Crystalline substances micronizer and suspended in a solution of citric acid, monohydrogenphosphate sodium, sucrose, potassium sorbate and Tween™ 80 in 10 ml of water, if necessary, with a mild heat. Dissolve Na-carboxymethyl cellulose in 4 ml of boiling water. After cooling, the resulting solution is added to other ingredients. The suspension is homogenized in a mixer and, finally, add water to a total volume of 100 ml.

Example 39: ointment

A: sodium salt of 16-deacetoxy-

16β-(2',2',2'-triptoreline)-

17(S),20(S)-digidrofolievoy acid 1 g

Q: one connection from a number of hydrocortisone,

triamcinolone or ftorhinolona 0.5 g

Vaseline oil 6,9 g

Cetanol 0.2 g

Anhydrous lanolin 2.3 g

Petrolatum 39,1 g

A total of 50 g

Melted at 70°paraffin, cetanol, lanolin and petrolatum. After cooling to a temperature below 40°pound a and B. the Ointment filled soft lacquered aluminium tubes.

Example 40; ointment

A: sodium salt of 16-deacetoxy-

16β-(2',2',2'-triptoreline)-

17(S),20(S)-digidrofolievoy acid 1.5 g

In: tetracycline 1.5 g

Vaseline oil 13.8 g

Cetanol 0.4 g

Anhydrous lanolin 4.6 g

Petrolatum 78,2 g

A total of 100 g

Melted at 70°paraffin, cetanol, lanolin and petrolatum. Polioksidony to a temperature below 40° To grind a and B. the Ointment filled soft lacquered aluminium tubes.

Example 41: eye gel

17(S),20(S)-digidrofolieva acid 10 g

Benzylaniline 0.1 g

Carbomer 5 g

Mannitol 50 g

Edetate sodium 0.5 g

Sodium hydroxide q.s.

Sterile water to 100 ml

Dissolve edetate sodium 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, vacuum vessel and autoclave dispersion with weak stirring and homogenize at high speed.

Cooled to 70°With, stop the mixer and homogenizer. Add micronized 17(S),20(S)-digidrofolievoy acid, sterile - vacuum vessel and permit 17(S),20(S)-digidrofolievoy acid immersed in the dispersion with weak stirring. The mixture is homogenized at high speed for 10 minutes at 70°C. is Cooled to a temperature below 30°under stirring and spend homogenization at low speed. Add sterile solution of benzylaniline in water for injection with weak stirring. Neutralize carbomer R by adding sterile solution 1,050 kg of sodium hydroxide in water for injection. Carry out the mixing and homogenization at low speed for 5 minutes. If necessary, adjusted pH to 54-5,8. Pumped eye gel for storage in the tank using pressure nitrogen and systems for pumping low speed homogenization. The gel is stored at room temperature before packaging. The eye gel is filled under aseptic conditions with sterile tubes for fill weight of 3.5 g

1. Derivative of fusidic acid of General formula Ia

where Q1and Q2are the same or different and independently represent a group -(CO)-; a group -(NON)- or a group -(CHOR)-, where R represents an alkyl radical with 1-4 carbon atoms;

Q3represents a group -(CH2)-;

Y represents hydrogen;

A represents an oxygen atom or sulfur;

R1represents an alkyl radical with 1-4 carbon atoms, olefin group with 2-4 carbon atoms, (C1-C6)-acyl group, (C3-C7)-cycloalkylcarbonyl group or benzoyloxy group, and R1optionally substituted by one or more halogen atoms and/or hydroxy-, (C1-C5)-alkoxy or sidegroups;

where the dotted line between C-1 and C-2 and/or C-24 and C-25 indicates that these atoms connected by a double or single bond,

and its pharmaceutically acceptable salts.

2. The compound according to claim 1 of General formula I

where Q1and Q2are the same or different and both represent the group -(NON)- or a group -(CO)-;

A represents an oxygen atom or sulfur;

R1represents an alkyl radical with 1-4 carbon atoms, (C1-C6)-acyl group, (C3-C6)-cycloalkylcarbonyl group or benzoyloxy group, and R1optionally substituted by one or more halogen atoms and/or hydroxy-, methoxy - or sidegroups;

where the dotted line between C-1 and C-2 and/or C-24 and C-25 indicates that these atoms connected by a double or single bond,

and its pharmaceutically acceptable salts.

3. The compound according to claim 1 or 2, where Q1and Q2both represent the group.

4. The compound according to any one of the preceding paragraphs, where the stereochemistry when Q1and Q2belong to the groupatoms C-3 and C-11 is a 3αHE and 11α-OH, respectively, and the atom-16, is attached to the group And has the configuration(S), denoted 16β.

5. The compound according to any one of the preceding paragraphs, where one of Q1or Q2represents -(CO)-.

6. The compound according to any one of the preceding paragraphs, where a represents oxygen.

7. The compound according to any one of the preceding paragraphs, where 1is (C1-C4)-alkyl group, optionally substituted by one or more substituents selected from the group consisting of azido, hydroxy and halogen, and halogen selected from fluorine, chlorine and bromine.

8. The compound according to any one of the preceding paragraphs, where R1is (C1-C4)-alkyl group substituted by one or more galactography selected from fluorine and chlorine.

9. The compound according to any one of the preceding paragraphs, where R1selected from the group consisting of ethyl, 2,2,2-triptoreline, 2,2,2-trichloroethyl, 2-azidoethyl, 2-hydroxyethyl, propyl and isopropyl, 1,3-diporiphora, tert-butyl, acetyl, propionyl, chloroacetyl or TRIFLUOROACETYL.

10. The compound according to any one of the preceding paragraphs, where R1selected from the group consisting of ethyl, 2,2,2-trichloroethyl, 2-azidoethyl, isopropyl, tert-butyl and acetyl.

11. The compound according to any one of the preceding paragraphs, where the bond between C-24 and C-25 is a double bond.

12. The compound of formula I, selected from the group comprising 17(S),20(S)-digidrofolieva acid (compound 101),

17(S),20(S),24,25-tetragidrofolieva acid (compound 102),

11 dehydro-17(S),20(S)-digidrofolieva acid (compound 103),

3-degidro-17(S),20(S)-digidrofolieva acid (compound 104),

16 diacetoxy-16β-Pro is ynyloxy-17(S),20(S)-digidrofolieva acid (compound 105),

16 diacetoxy-16β-(3'-chloropropionate)-17(S),20(S)-digidrofolieva acid (compound 106),

16 diacetoxy-16β-(2'-methylpropyloxy)-17(S),20(S)-digidrofolieva acid (compound 107),

16 diacetoxy-16β-cyclopropylmethoxy-17(S),20(S)-digidrofolieva acid (compound 108),

16 diacetoxy-16β-chloroacetoxy-17(S),20(S)-digidrofolieva acid (compound 109),

16 diacetoxy-16β-bromoacetate-17(S),20(S)-digidrofolieva acid (compound 110),

16 diacetoxy-16β-benzoyloxy-17(S),20(S)-digidrofolieva acid (compound 111),

16 diacetoxy-16β-(4'-perbenzoate)-17(S),20(S)-digidrofolieva acid (compound 112),

16 diacetoxy-16β-cyclohexyloxycarbonyloxy-17(S),20(S)-digidrofolieva acid (compound 113),

16 diacetoxy-16β-acryloyloxy-17(S),20(S)-digidrofolieva acid (compound 114),

16 diacetoxy-16β-isopropylthio-17(S),20(S)-digidrofolieva acid (compound 115),

16 diacetoxy-16β-ethylthio-17(S),20(S)-digidrofolieva acid (compound 116),

16 diacetoxy-16β-(2',2’,2'-trichloromethylthio)-17(S),20(S)-digidrofolieva acid (compound 117),

16 diacetoxy-16βtert-butylthio-17(S),20(S)-digidrofolieva acid (compound 118),

16 diacetoxy-16β-methoxymethyl-17(S),20(S)-digidrofolieva acid is one (compound 119),

16 diacetoxy-16β-isopropylthio-17(S),20(S),24,25-Tetra-gidroshikapa acid (compound 120),

16 diacetoxy-16β-acetylthio-17(S),20(S)-digidrofolieva acid (compound 121),

16 diacetoxy-16β-benzylthio-17(S),20(S)-digidrofolieva acid (compound 122),

16 diacetoxy-16β-ethoxy-17(S),20(S)-digidrofolieva acid (compound 123),

16 diacetoxy-16β-(2',2',2'-triptoreline)-17(S),20(S)-digidrofolieva acid (compound 124),

16 diacetoxy-16β-propoxy-17(S),20(S)-digidrofolieva acid (compound 125),

16 diacetoxy-16β-isopropoxy-17(S),20(S)-digidrofolieva acid (compound 126),

16 diacetoxy-16β-(1’,3'-deferasirox)-17(S),20(S)-digidrofolieva acid (compound 127),

16 diacetoxy-16β-methoxyethoxy-17(S),20(S)-digidrofolieva acid (compound 128),

16 diacetoxy-16β-(2',2',2'-trichlorethane)-17(S),20(S)-digidrofolieva acid (compound 129),

16 diacetoxy-16β-(2'-azidoethoxy)-17(S),20(S)-digidrofolieva acid (compound 130),

16 diacetoxy-16β-(2'-hydroxyethoxy)-17(S),20(S)-digidrofolieva acid (compound 131),

and their pharmaceutically acceptable salts.

13. The connection section 12, selected from the group consisting of sodium salts of 17(S),20(S)-digidrofolievoy acid and diethanolamine salt 17(S),20(S)-digitop sidaway acid.

14. Stereoisomer of the compounds of formula I or Ia in a pure form or a mixture of such stereoisomers.

15. Pharmaceutical composition for treating microbial diseases containing a compound according to any one of claims 1 to 14 or together with a pharmaceutically acceptable non-toxic carrier and/or auxiliary substance and, optionally, together with one or more other therapeutically active components.

16. Pharmaceutical composition for treating microbial diseases, containing 17(S),20(S)-digidrofolievoy acid of formula Ia, one or together with a pharmaceutically acceptable non-toxic carrier and/or auxiliary substance, alone or together with pharmaceutically acceptable non-toxic carriers and/or excipients and, optionally, together with one or more therapeutically active components.

17. The pharmaceutical composition according to item 15 or 16 in the form of a product for local use.

18. The pharmaceutical composition according to 17 in the form of ointment.

19. The compound according to any one of claims 1 to 14, which is useful for the manufacture of drugs for systemic treatment of microbial diseases.

20. The compound according to any one of claims 1 to 14, which is useful for the manufacture of drugs for the local treatment of microbial diseases of the skin and/or eyes.

21. Connection claim 20, where the medication also contains one or several other those who piticescu active components.

22. Connection claim 20 or 21, where the medication is intended for associated with one or more other therapeutically active components.



 

Same patents:

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention relates to 3-methylene-steroid derivative of the general formula (1):

wherein R1 means hydrogen atom (H), or in common with R3 it forms β-epoxide; or R1 is absent in the presence of 5-10-double bond; R2 means (C1-C5)-alkyl; R3 means βH, βCH3 or in common with R1 it forms β-epoxide; either R3 is absent in the presence of 5-10-double bond; R4 means hydrogen atom, lower alkyl; Y represents [H, H], [OH, H], [OH, (C2-C5)-alkenyl], [OH, (C2-C5)-alkynyl] or (C1-C6)-alkylidene, or =NOR5 wherein R5 means hydrogen atom (H), lower alkyl; dotted lines represent optional double bond. Compound can relate also to its prodrug used for treatment of arthritis and/or autoimmune diseases.

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

38 cl, 1 tbl, 18 ex

The invention relates to substituted derivatives of propanolamine with bile acids of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives, where GS is a group of the bile acid of the formula II, R1connection with X, HE, R2connection with X, HE, -O-(C1-C6)alkyl, -NH-(C2-C6)-alkyl-SO3N, -NH-(C1-C6)-alkyl-COOH, R1and R2at the same time does not mean the relationship with X, X -

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

The invention relates to an improved method of direct esterification of Stanlow/sterols interaction of stanol/sterols and acid taken in stoichiometric ratio, in the presence of a sufficient amount of catalyst, which can be acidic or basic, and in the presence of a sufficient amount of decolorizing agent, preferably activated carbon

The invention relates to the field of biologically active substances from plant material, in particular to a method of simultaneously receiving 20-hydroxyecdysone but also of inokosterone, ecdysone, magisteria And having the following structural formula:

20-hydroxyecdysone - R1=OH, R2=H, R3=OH, R4=H

The invention relates to a method for producing water-dispersible compositions of oryzanol in which the Sterol is easily applied in the form of

The invention relates to steroids Sterol number of General formula I, where R1and R2independently selected from the group comprising hydrogen and unbranched or branched C1-C6-alkyl; R3selected from the group including hydrogen, methylene, hydroxy, oxo, =NOR26where R26represents hydrogen and hydroxy and C1-C4-alkyl, related to the same carbon atom of the Sterol skeleton, or R3together with R9or R14designate an additional bond between the carbon atoms that are associated with R3and R9or R14; R4selected from the group comprising hydrogen and oxo, or R4together with R13designate an additional bond between the carbon atoms that are associated with R4and R13; R5selected from the group comprising hydrogen and hydroxy, or R5together with R6designate an additional bond between the carbon atoms that are associated with R5and R6; R6represents hydrogen or R6together with R5designate an additional bond between the carbon atoms that are associated with R6and R5or R14; R9represents hydrogen or R9together with R3or R10denote dobavlaet hydrogen or R10together with R9designate an additional bond between the carbon atoms that are associated with R10and R9; R11selected from the group comprising hydroxy, acyloxy, oxo, = NOR28where R28represents hydrogen, halogen, or R11together with R12designate an additional bond between the carbon atoms that are associated with R11and R12; R12represents hydrogen or R12together with R11designate an additional bond between the carbon atoms that are associated with R12and R11; R13represents hydrogen or R13together with R4or R14designate an additional bond between the carbon atoms that are associated with R13and R4or R14; R14represents hydrogen or R14together with R3, R6or R13designates an additional bond between the carbon atoms that are associated with R14and R3or R6or R13; R15is hydrogen; R16selected from the group comprising hydrogen, hydroxy, oxo or16together with R17designate an additional bond between the carbon atoms that are associated with R16and R17; R17represents hydrogen or hydroxy, or R1716; R18and R19represent hydrogen; R25selected from the group including hydrogen, and C1-C4-alkyl; a represents a carbon atom or a nitrogen atom; when a represents a carbon atom, R7selected from the group including hydrogen, hydroxy and fluorine, and8selected from the group including hydrogen, C1-C4-alkyl, methylene, and halogen, or R7together with R8designate an additional bond between the carbon atoms that are associated with R7and R8; R20is1-C4-alkyl; R21selected from the group including1-C4-alkyl, C1-C4-hydroxyalkyl,1-C4-halogenated containing up to three halogen atoms; when a represents a nitrogen atom, R7denotes a lone pair of electrons, and R8selected from the group comprising hydrogen and oxo; R20and R21are1-C4-alkyl with the proviso that the compound of General formula (I) does not have any cumulated double bonds and with the additional condition that the connection is not one of the known compounds cholestenone

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

FIELD: organic chemistry, natural compounds, pharmacy.

SUBSTANCE: method involves mixing ergot derivative or its mixture with pharmaceutically acceptable hydrophilic swelling substance or its mixture and with one or some pharmaceutically acceptable vehicles. Derivative of ergot has the following formula: wherein R1 means hydrogen or halogen atom; R2 means hydrogen atom or (C1-C4)-alkyl; R3 represents isopropyl, sec.-butyl, isobutyl or benzyl; R4 represents methyl, ethyl or isopropyl; R5 means hydrogen atom; R6 means hydrogen atom or methoxy-group, or R5 and R6 in common correspond to the additional bond. The ratio of ergot derivative to swelling agent = (1-0.5):(1-10). Pharmaceutical composition containing the substance prepared by above indicated method comprises from 5 to 80 mg of ergot derivative in its ratio to swelling agent from 1:0.5 to 1:10. Invention provides realization the indicated designation.

EFFECT: improved methods for preparing, valuable properties of compositions.

6 cl, 6 tbl, 1 dwg, 8 ex

FIELD: medicine, toxicology, pharmacy.

SUBSTANCE: according with the first variant the composition contains neutral lipid and therapeutically effective amount of cholanic acid or cholanic acid salt and phospholipid. Neutral lipid presents in the amount from 3% to 50% by mass relatively to the total amount of lipid. According with the second variant the composition contains from 3% to 30% by mass of bile acid or bile acid salt, from 3% to 50% by mass of neutral lipid and from 10% to 95% by mass of phospholipid. Composition is designated for treatment in poisoning with endotoxins. Composition no containing peptides and proteins but containing the combination of phospholipid with cholanic acid proves effective relief or prophylaxis of endotoxemia.

EFFECT: enhanced effectiveness and valuable medicinal properties of composition.

23 cl, 10 dwg, 2 tbl, 10 ex

FIELD: medicine, hepatology.

SUBSTANCE: at achieving alkaline phosphatase of 580 U and more one should introduce ursodesoxycholic acid at the dosage of 15-20 mg/kg and orlistate at the dosage of 90-100 mg twice or thrice daily for patients with steatohepatitis. According to normalization of clinical and biochemical values of blood analyses it is possible to conclude upon successfulness of therapy performed. The method provides clinic-laboratory remission of the disease.

EFFECT: higher efficiency of therapy.

3 ex

The invention relates to substituted derivatives of propanolamine with bile acids of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives, where GS is a group of the bile acid of the formula II, R1connection with X, HE, R2connection with X, HE, -O-(C1-C6)alkyl, -NH-(C2-C6)-alkyl-SO3N, -NH-(C1-C6)-alkyl-COOH, R1and R2at the same time does not mean the relationship with X, X -

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

The invention relates to the field of biologically active substances from plant material, in particular to a method of simultaneously receiving 20-hydroxyecdysone but also of inokosterone, ecdysone, magisteria And having the following structural formula:

20-hydroxyecdysone - R1=OH, R2=H, R3=OH, R4=H

The invention relates to the creation of hepatoprotective tools
Up!