Bicyclic oxazin or thiazin-oxazolidinone or their pharmaceutically acceptable salts, and methods of treating microbial infections

 

(57) Abstract:

Disclosed are the compounds of formula I and formula II, where X represents O, S, SO2, SO; R1is independently H, F; R2represents hydrogen, C1-C8-alkyl, possibly substituted by one or more Deputy selected from the group comprising F, CL, hydroxy, C1-C8-alkoxy; a = 0-3; b = 0-2; C = 0-2 ( provided that b and c can be both 0); d = 0-2 & e = 0-2 ( provided that d and e cannot be both 0), or their pharmaceutically acceptable salts, and methods of treating microbial infections based on them. The invention can be used in medicine, it is useful against a number of pathogens of humans and animals, including gram-positive aerobic bacteria and anaerobic organisms. 4 c. and 11 C.p. f-crystals, 1 table.

This invention discloses a new and useful compounds of phenyloxazolidine, characterized in that they have a bicyclic casinoby or occasinaly Deputy. The compounds are useful antimicrobial agents, effective against a number of pathogens of human and animal pathogens, including gram-positive aerobic bacteria such as multi-resistant staphylococci, streptococci and enterococci, as well as

Information

These compounds are related because of their structure phenyloxazolidine ring, the compounds disclosed in the publications below, except that the compounds of the invention have either a bicyclic casinoby or oxazin phenyl Deputy. The considered compounds are useful antibacterial activity.

PCT/US 94/08904 application discloses oxazolidinone antibacterial compounds having either morpholinyl or thiomorpholine Deputy.

PCT/US 93/03570 application discloses oxazolidinone containing substituted casinobuy part and their use as antimicrobial agents.

PCT/US 92/08267 application discloses substituted aryl - and heteroaryl-phenyl-oxazolidinones as antibacterial agents.

PCT/US 89/03548 application discloses 5 indolyl-5 - aminoethylethanolamine, 3-(condensed-ring substituted)phenyl-5 - aminoethylethanolamine, and 3-(asutamiseni)phenyl-5 - aminoethylethanolamine, which are used as antibacterial agents.

Other references disclosing various oxazolidinone include U.S. Pat. USA 4 801 600, 4 921 869, Gregory W. A., et al., J. Med. Chem., 32, 1673-81 (1989); Gregory W. A., et al., J. 781 discloses phenyl and pyridylamine phenyl oxazolidinone.

Heb. Pat. publication 316 594 discloses 3-substituted of still oxazolidinone.

Heb. Pat. publication 312 000 reveals phenylmethyl and pyridylmethylamine phenyl oxazolidinone.

The invention

In one aspect the subject invention is a compound of the formula I

< / BR>
More preferred compounds of subclass of compounds described by structural formula I, represented by structural formula II

< / BR>
or their pharmaceutically acceptable salt,

where X is (a) O (b) S (c) SO (d) SO2;

R1is independently H, F, Cl or OMe;

R2represents (a) hydrogen, (b) C1-C8-alkyl, possibly substituted by one or more Deputy selected from: F, Cl, hydroxy, C1-C8-alkoxy, C1-C8-acyloxy, (c) C3-C6- cycloalkyl, (d) amino, (e) C1-C8-alkylamino, (f) C1-C8-dialkylamino, (g) C1-C8-alkoxy,

a = 0-3;

b = 0-2;,

c = 0-2, (provided that b and c cannot be both 0);

d = 0-2; and

e = 0-2, (provided that d u e cannot be both 0).

In another aspect of the subject invention is a method of treating microbial infections in humans or other warm-blooded animals purely I or II. The connection can be entered in the pharmaceutical composition or oral, parenteral or locally. Preferably, the compound is administered in an amount of from about 0.1 to about 100 mg/kg body weight/day, more preferably, from about 3.0 to about 50 mg/kg body weight/day.

A detailed description of the invention

This invention discloses new substituted bicyclic oxazine or diazinylarylacetonitriles the above structural formulas I and II. The compounds are useful as antimicrobial agents, effective against a number of pathogens of human and animal pathogens, in particular, aerobic gram-positive bacteria including multi-resistant staphylococci and streptococci, as well as anaerobic organisms such as bacteroids and Clostridia species, and acid-fast organisms such as Mycobacterium tuberculosis and other mycobacterial species.

"Alkyl" means a chain of carbon atoms, having the specified number of carbon atoms, which may be either unbranched or branched.

"Alkoxy" means the group having the specified number of carbon atoms connected with oxygen, such a group as methoxy (-OCH3), ethoxy, butoxy etc. and its isomeric form.

"And akuu as acetyl, CH3CO-; benzoyl, C6H5CO.

"Cycloalkyl" means a group with the specified number of carbon atoms forming cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., and its isomeric form.

"Amino" means NH, alkylamino" means a group where one of the positions of the hydrogen is replaced by alkyl, and dialkylamino" means a group in which both hydrogen substituted alkyl group.

The term "Pharmaceutically acceptable salt" means a salt accession acid, which can be obtained by any known in this field by the way. Typical salts accession acid include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, malate, succinate, tartrate, cyclohexylsulfamate, methansulfonate, econsultancy, bansilalpet, toluensulfonate, fumarate and other pharmaceutically acceptable counterions for amines.

Preferably, X is S.

R1substituents are preferably both fluorine and, more preferably, fluorine and hydrogen.

R2the Deputy is, preferably, hydrogen, methyl, dichloromethyl, hydroxymethyl or methoxy. More preferably, R2is water the absolute configuration at C-5 oxazolidinone ring of the claimed compounds of this invention is the configuration, represented in the structures of formulas I and II. This absolute configuration is referred to as (S) according to Cahn-Ingold-Prelog system of nomenclature. This (S)-enantiomer, which is pharmacologically active. The racemic mixture is used the same way and for the same purpose as pure (S)-enantiomer; the difference is that to get the same bactericidal action, you must apply twice racemic substance. Specialist in this field should be obvious that when the additional chiral center (s) present in the bicyclic oxazinium or casinova fragment compounds of structural formulas I and II, it is possible diastereoisomer. These diastereoisomer in racemic and enantiomeric forms, are also within the scope of compounds of formulas I and II of the invention.

Preferred compounds of formula I are

(S)-H-[[3-[3-fluoro-4-((1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane - 5-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide (Example 1);

(S)-N-[[3-[3-fluoro-4-[(1S, 4S)-2-thia-5-azabicyclo[2.2.1] heptane-5 - yl] phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide (Example 2);

(S)-N-[[3-[3-fluoro-4-[(1S, 4S)-2-thia-2,2-dioxo-5-azabicyclo[2.2.1] heptane-5-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide (Example 3);

(S)-N-[[3[3-[3-fluoro-4-(tetrahydro-1H-thieno[3,4-C] pyrrol-5(3H)-yl)phenyl] -2-oxo-5-oxazolidinyl]methyl]l, S-oxide (Example 5) ;

(S)-N-[[3-[3-fluoro-4-(tetrahydro-1H-thieno[3,4-C] pyrrol-5(3H)-yl) phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide, S,S-dioxide (Example 6);

CIS-(S)-N-[[3-[3-fluoro-4-[3-oxa-7-azabicyclo[3.3.0] Octan-7-yl] - phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide (Example 7);

(S)-N-{ [3-[3-fluoro-4-[(1R, 4R)-2-thia-5-azabicyclo[2.2.1] heptane-5 - yl] phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(2-thia-6-azabicyclo[3.2.0] heptane-6-yl)phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(3-thia-6-azabicyclo[3.2.0] heptane-6-yl)phenyl] -2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(3-thia-7-azabicyclo[3.3.1] nonan-7-yl)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-( 3-thia-9-azabicyclo[3.3.1]nonan-9-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-[[3-[3-fluoro-4-(2-thia-6-azabicyclo[3.2.1] Octan-6-yl)phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(2-thia-6-azabicyclo[3.3.1] nonan-6-yl)phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide;

(S)-[[3-[3-fluoro-4-(7-thia-3-azabicyclo[4.2.1] nonan-3-yl)phenyl]-2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(9-thia-3-azabicyclo[3.3.1] nonan-3-eleniel]-2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(3-oxa-6-azabicyclo[3.2.0]heptane-6-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]as the R> (S)-N-[[3-[3-fluoro-4-(3-oxa-7-azabicyclo[3.3.1] nonan-7-yl)phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

(S)-N-[(3-[3-fluoro-4-(3-oxa-9-azabicyclo[3.3.1] nonan-9-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(9-oxa-3-azabicyclo[3.3.1] nonan-3-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(2-oxa-5-azabicyclo[2.2.2] Octan-5-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(2-oxa-6-azabicyclo[3.2.1] Octan-6-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(3-oxa-7-azabicyclo[4.2.0] Octan-7-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(3-oxa-8-azabicyclo[3.2.1] Octan-8-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(6-oxa-2-azabicyclo[3.2.1] Octan-2-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(S)-N-[[3-[3-fluoro-4-(8-oxa-3-azabicyclo[3.2.1] Octan-3-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide; and

(S)-N-[[3-[3-fluoro-4-[(1R, 4R)-2-oxa-5-azabicyclo[2.2.1] heptane-5-yl] phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide.

The most preferred compound is (S)-N-[[3-[3-fluoro-4-[(1S, 4S)-2-thia-5-azabicyclo[2.2.1] heptane-5-yl] phenyl] -2 - oxo-5-oxazolidinyl] methyl]ndimethylacetamide (Example 2).

(S)-N-[[3-[3-fluoro-4-(tetrahydro-1H-thieno[3,4-C] pyrrol-5(3H)- yl)phenyl] -2-enyl] -2-oxo-5-oxazolidinyl]methyl]acetamide", she S,S-dioxide (Example 6).

The pharmaceutical compositions of this invention can be obtained by mixing (combining) compounds of the formula I or II of this invention with a solid or liquid pharmaceutically acceptable carrier, and optionally, with pharmaceutically acceptable adjuvants and eccipienti, using standard technology. The compositions in solid form include powders, tablets, dispersible granules, capsules, sachets and suppositories. A solid carrier can be at least one substance, which can also function as a diluent, flavoring agent, a solubilizer, lubricant, suspendisse agent, a binder, tablet - dezintegriruetsja means and the encapsulating means. Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulose substances, low melting wax, cocoa butter, etc., Compositions in liquid form include solutions, suspensions and emulsions. For example, you can develop the solutions of compounds of the present invention dissolved in water and water-glycol and water-glycol, optionally containing suitable conventional coloring means is aerobatic, using standard technology for unit dosage forms containing effective or appropriate quantities of the active ingredient, i.e. the compound of formula I according to this invention.

The number of active component that is a compound of formula I or II according to this invention, in the pharmaceutical compositions and dosage single dosage form can vary or be adjusted over a wide range depending on the particular application, the effectiveness of specific compounds, the desired concentration. In General, the number of active component is typically in the range from 0.5 to 90% by weight of the composition.

In therapeutic use for the treatment of bacterial infections or bacterial infections in warm-blooded animals, the compounds or pharmaceutical compositions are usually administered orally and/or parenterally at dose required for obtaining or maintaining concentration, i.e. the number and / or blood levels of the active component in the animal being treated, which usually antibiotic effective. In General, such an antibacterial effective amount of dosage of active compel/day. It should be borne in mind that the dose may vary depending on the needs of the patient, the severity of the bacterial infection to be treated, and specific to be used for the connection. In addition, it should be borne in mind that the initial injected dose can be increased beyond the above upper level in order to quickly reach the desired level in the blood, or the initial dose may be less than optimum, and the daily dose can progressively increase during the course of treatment depending on the specific situation. If necessary, the daily dose can also be divided into multiple doses for administration, for example, from two to four times a day.

The compounds of formula I or II according to this invention is administered parenterally, i.e., by injection, for example, intravenous injection, or by other parenteral routes of administration. Pharmaceutical compositions for parenteral administration typically contain a pharmaceutically acceptable amount of the compounds of formula I or II in the form of soluble salts (salt accession acid base or salt) dissolved in a pharmaceutically acceptable liquid carrier, such as, for example, water for injection or buffer to ensure podhodam, include trinitry the orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and (L)+-arginine, not calling other representative examples of buffer substances. The compound of formula I is usually dissolved in the carrier in a quantity sufficient to provide pharmaceutically acceptable injectable concentration in the range from about 1 mg/ml to 400 mg/ml. The liquid pharmaceutical composition is typically administered in such a way as to ensure the dose corresponding to the above-mentioned antibacterial effective amount.

The preferred method of obtaining oxazolidinones formula I or II in enantiomerically pure form described in Schemes I-IV.

As shown in Scheme 1, bicyclic oxazine and triazine (commercially available or known in the literature), such as (1S,4S)-2-oxa-5-azabicyclo[2.2.1] heptane (X= 0) and (1S,4S)-2-thia-5-azabicyclo [2.2.1]heptane (X=S) structure 1, is subjected to the influence of functionalized with a nitrobenzene 2 (Y= halogen or triftorbyenzola) in the presence of a suitable base, such as N,N-diisopropylethylamine, and in a suitable solvent, such as acetonitrile, tetrahydrofuran (THF, THF) or ethyl acetate at ambient temperature to those who by hydrogenation in the presence of a suitable catalyst, such as 10% palladium on coal or W-2 Raney Nickel, in a suitable solvent, such as ethyl acetate, tetrahydrofuran, water, tetrahydrofuran, methanol and mixtures thereof, receiving anilines 4. In the case when X=S, a nitrogroup 3 can be restored by the action of hydrosulfite sodium in aqueous tetrahydrofuran at ambient temperature up to 55oC, receiving anilines 4. Alternatively, the restoration of the nitro group 3 (X=S) can be performed by catalytic hydrogenation in the presence of a suitable catalyst, such as platinum on sulfide carbon or W-2 Raney Nickel, and in the corresponding system-solvent, e.g. aqueous tetrahydrofuran. The latter, in particular, is used in the case when the reaction mixture is just filtered through Celiteor similar to remove the catalyst, and the filtrate containing aniline 4, directly used in the next stage. Finally, anilines 4 turn in their benzyl (R3CH2Ph) or methyl (R3=CH3) urethane derivatives 5, using standard Schotten-Baumann conditions, or variations, known to specialists in this field. Then urethanes 5 deprotonized a suitable base, such as n-utility, lithium diisopropylamide, or lithium bis(timetemperature, such as from -78 to -60oC, receiving literaturnyi intermediate product which is then treated with commercially available (-)-(R)-glycidyl by butyrate. Then heated to ambient temperature directly gives 5-(hydroxymethyl)oxazolidinone 6 in enantiomerically enriched form. Then the connection 6 is transformed into the corresponding mesilate 7 (R4=methanesulfonyl) or aryl sulfonate 7 (R4= ArSO2for example, p-toluensulfonyl) by activity, for example, methansulfonate/pyridine or methansulfonate/triethylamine/ dichloromethane or n-toluensulfonate/pyridine.

As shown in Scheme II, then the sulfate derivative of 7 is subjected to interaction with azide source such as sodium azide or potassium, in an aprotic solvent such as N,N-dimethylformamide (DMF), DMF) or 1-methyl-2-pyrrolidinone, possibly in the presence of a catalyst such as 18-crown-6 at a temperature of 50-90oC, to obtain the azide 8. Then azide restore by hydrogenation using a palladium catalyst with coal or platinum catalyst in an appropriate solvent, such as ethyl acetate or methanol, receiving the appropriate amine 9. Alternatively, and preferably, in lifehistory, in an appropriate solvent, such as tetrahydrofuran, followed by addition of water. Alternatively, mesilato or arylsulfonate group of compounds 7 can be replaced by phthalimide potassium in acetonitrile at the boiling temperature of phlegmy obtaining intermediate phthalimide 10. Then phthalimid 10 deprotonated by treatment with aqueous methylamine in boiling ethanol, getting Amin 9. In yet another alternative embodiment mesilate 7 is subjected to interaction with ammonium hydroxide in hot isopropanol or isopropanol/tetrahydrofuran, preferably in a sealed reaction vessel, receiving Amin 9. Then Amin 9 acelerou using reactions known to specialists in this field, receiving oxazolidinone structure 11. For example, the amine may be subjected to interaction with the acid chloride or anhydride in a basic solvent such as pyridine, at a temperature in the range from -30oC to 30oC, to obtain the acylated compound 11 (R2= arbitrarily substituted alkyl). For specialists in this area it is obvious that other acyl groups, are not beyond the scope of this invention, can be easily introduced in the amine 9 using standard acylation techniques, e.g. the examples 11. Connection patterns 11 are examples of antibacterial agents-bicyclic oxazin and trainsleeve of oxazolidinones formula II, which are the subject of this invention. As shown in Scheme III, oxazolidinone 11, in themselves, examples of antibacterial agents of formula II can be further converted into further compounds of formula II. In particular, 11 (X=S) can be oxidized to the corresponding sulfoxide(s) 12 (X=SO) using metaperiodate sodium in a mixture of water and methanol. Specialists in this field obviously possible as endo-and accountkey, and that both isomeric forms and mixtures of them, are included in the scope of this invention. In addition, compounds 11 or 12 can be oxidized to the corresponding sulfones 13 (X=SO2) by treating 4-methylmorpholine N-oxide and catalytic amounts of osmium tetroxide in aqueous acetone. For specialists in this area it is obvious that well-known alternative conditions for the oxidation of 11 (X=S) 12 or 13, for example, those who lit March, J. "Advanced Organic Chemistry", 4th ed.; John Wiley & Sons: New York, 1992; p. 1201-1202.

As shown in Scheme IV, the synthesis of compounds that include cyanopyrrolidine, begins with the recovery of diapir 14 diol 15, IP is at 16 by reaction with methanesulfonanilide and trialkylamine base. The cyclization of 16 in cyanopyrrolidine 17 is carried out by interaction with the sodium sulfide and the connection 17 dibenzyline in thienopyrrole 18 by reaction with hydrogen in the presence of a suitable catalyst, such as palladium on coal. Then get a connection example 4 of 18, following the methods described in General terms in Schemes I and II (except for the substitution of 1 to 18). The compounds of examples 5 and 6 are obtained by oxidation of the compound of example 4, using the same methodology described in Scheme III.

Antimicrobial activity experience in vivo using the method of analysis in mice (Murine Assay). Groups of mice female mice injected intraperitoneally bacteria that thawed immediately before use and suspended in brain heart extract with 4% brewer's yeast UC9213 (Staphylococcus aureus) or in brain heart extract (Streptococcus species). Treatment antibiotic at six dose levels of the drug spend one hour and five hours after infection, either orally or subcutaneously. For survival observed daily for six days. ED50values, based on mortality, determine, using Pro bit analysis. The compounds of this invention are compared with well-known antimicrobial agent (Vancomycin, Vancomicin) quality is blasti obviously, as described synthetic methods are only illustrative and that the use of alternative bicyclic oxazine and triazines, known from the patent literature and open to the public, allows you to receive additional examples of the structural formula 1.

Example 1: (S)-N-[[3-[4-[(1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl] -3 - forfinal] -2-oxo-5-oxazolidinyl] methyl] ndimethylacetamide stage 1: 4-[(1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl]-3-ftorirovannom

A mixture of commercially available (1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (0,200 g of 1.47 mmol), the acid dicale phosphate (1,030 g 5,90 mmol) and 3,4-deformirovannoe (of € 0.195 ml, 1.77 mmol) in dimethyl sulfoxide (6 ml) was stirred at ambient temperature in an atmosphere of N2. TLC analysis (5% MeOH/CHCl3after 3 hours discovers that the source nitrobenzene is absorbed. The reaction mixture was diluted with H2O (60 ml) and extracted with CHCl3. The combined organic extracts washed with H2O and brine, dried over Na2SO4filter and concentrate under reduced pressure, obtaining a yellow solid. Chromatography on silica gel (60 g), elwira gradient 0-2% MeOH/CHCl3gives, after concentration of appropriate fractions, 0,3 stage 2: N-(carbobenzoxy)-4-[(1S, 4S)-2-oxa-5-azabicyclo- [2.2.1] heptane-5-yl]-3-ftoranila

A solution of 4-[(1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl]-3-peritrabecular (0,160 g, 0,672 mmol) in a mixture of 3:1 TRF/BUT (4 ml) is treated with acetic acid (0,115 ml) and then 10% palladium/charcoal (0,020 g) current N2. The atmosphere replaces the H2(balloons), repeating the evacuation and filling, and the mixture was stirred at ambient temperature. After 2 hours, TLC analysis (6% CH3CN/CHCl3) showed that the restoration was completed. The reaction mixture was filtered through Celiteand the filtrate is immediately placed in an atmosphere of N2process K2CO3(0,464 g, to 3.36 mmol) and then benzyl-chloroformate (0,117 ml, 0,864 mmol). TLC analysis (6% CH3CN/CHCl3) after 0.5 hours showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure and chromatographic on silica gel (20 g), elwira gradient 1-5% CH3CN/CHCl3. Concentration of the appropriate fractions gives 0,226 g (98%) of the titled compound as white solids with so pl. 120-121oC and MS (EI) 342 (M+).

Stage 3: (R)-[3-[4-[(1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5 - yl]-3-forfinal]-2-oxo-5-oxazolidinyl]methanol

A solution of N-(carbobenzoxy)-4-[(1S, 4S)-2-oxa-5-azabicyclo[2. the eat subjected to interaction with n-butyllithium (0,312 ml of 1.6 M solution in hexane, 0,499 mmol). After stirring for 10 minutes at -78oC, the reaction mixture was treated with (R)-glycidyl by butyrate (0,070 ml, 0,499 mmol). Upon completion of the addition the cooling bath removed and the mixture allowed to mix at ambient temperature overnight, and during this time appears whitish precipitate. TCS analysis (5% MeOH/CHCl3) showed that the reaction was completed. The reaction mixture is treated with approx. 5 drops of saturated aqueous NH4Cl, which leads to the formation of a homogeneous solution. The reaction mixture was concentrated under reduced pressure, obtaining a whitish solid. Chromatography on silica gel, elwira gradient of 1-5% MeOH/CHCl3gives, after concentration of appropriate fractions, 0,116 g (84%) of the titled compound as white solids with so pl. 138-140oC and MS (EI) 308 (M+). Additionally, 0,018 g (10%) of the second component, identified as: ester of butyrate these compounds using1H NMR analysis, get in the form of oil color amber.

Stage 4: (R)-[[3-{4-(1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5 - yl]-3-forfinal-2-oxo-5-oxazolidinyl]methyl]methanesulfonate

The solution (R-[3-4-[(1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl]-forfinal] -2-OK, the atmosphere and treated with Et3N (0,518 ml, 3.73 mmol), and then methanesulfonyl chloride (0,202 ml, 2,61 mmol). TCS analysis (5% MeOH/CHCl3) after 0.5 hours showed that the reaction was completed. The reaction mixture was washed with H2O and brine, dried over Na2SO4, filtered and concentrated in vacuo, getting 0,992 g (approximately 100%) of the titled compound as a yellowish brown solid. An analytical sample obtained by recrystallization from 5% CH2Cl2/U-D. This sample had so pl. 124,5-126oC and MS (EI) 386 (M+).

Stage 5: (R)-[[3-[4-[(1S, 4S)-2-oxa-5-azabicyclo [2.2.1]heptane-5-yl] -3-forfinal]-2-oxo-5-oxazolidinyl]methyl]azide

A solution of (R)-[[3-[4-[(1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl] -3-forfinal] -2-oxo-5-oxazolidinyl] methyl] methansulfonate (0,869 g, 2.25 mmol) in dry DMF (DMF) (10 ml) is treated with solid NaN3(0,732 g, 11.3 mmol) at ambient temperature in an atmosphere of N2. The mixture is then heated to 65oC and the progress of the reaction is controlled by using TLC. After 7.5 h at this temperature, TLC analysis (5% MeOH/CHCl3indicates the completion of the reaction. The reaction mixture was diluted with EtOAc (100 ml), washed with H2O (3 x 15 ml) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure, getting 0,692 the recrystallization from 1: 1 EtOAc/hexane in the form of a whitish solid with so pl. 101-102,5oC and MS (EI) 333 (M+).

Stage 6: (S)-N-[[3-[4-[(1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl] -3-forfinal]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

A solution of (R)-[[3-[4-[(1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl] -3-forfinal]-2-oxo-5-oxazolidinyl]methyl] - azide (0,652 g, a 1.96 mmol) in MeOH (20 ml) and CH2Cl2(10 ml) is treated with 10% palladium/charcoal (0,095 g) in a stream of N2. Then the atmosphere replaced with H2(balloons), repeating the evacuation and filling, and the mixture was stirred at ambient temperature under H2. After 3 h, TLC analysis (5% MeOH/CHCl3indicates the completion of the reaction. The reaction mixture was filtered through Celiteand the filtrate concentrated under reduced pressure. The crude 5-(aminomethyl)oxazolidinone was dissolved in CH2Cl2(20 ml) and treated with pyridine (0,190 ml of 2.35 mmol) and then acetic anhydride (0,222 ml of 2.35 mmol). After 0.5 h, TLC analysis (5% MeOH/CHCl3indicates the completion of the acetylation reaction. The reaction mixture was washed with H2O and brine, dried over Na2SO4, filtered and concentrated in vacuo, getting a whitish solid. Chromatography on silica gel (70 g), elwira gradient 1-3% MeOH/CHCl3gives, after concentration of appropriate fracc is with so pl. 60-65oC and MS (EI) 349 (M+).

Example 2: (S)-N-[[3-[3-fluoro-4-[(1S, 4S)-2-thia-5-azabicyclo[2.2.1] heptane-5-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

Stage 1: 4-[(1S, 4S)-2-thia-5-azabicyclo[2.2.1]heptane-5-yl]-3 - ftorirovannom

A mixture of commercially available (15,43)-2-thia-5-azabicyclo[2.2.1] heptane (0,500 g, 3,30 mmol), diisopropylethylamine (1,434 ml, 8,24 mmol) and 3,4-deformirovannoe (0,437 ml of 3.96 mmol) in dry acetonitrile (15 ml) is heated at the boiling temperature of phlegmy in N2atmosphere for 1 h and then cooled to ambient temperature over night. The reaction mixture was concentrated under reduced pressure, obtaining a yellow syrup. Chromatography on silica gel (50 g), elution with chloroform gives, after concentration of appropriate fractions, 0,700 g (84%) of the named compound as a yellow solid with so pl. 97-98oC and MS (EI) 254 (M+).

Stage 2: N-(carbobenzoxy)-4-[(1S, 4S)-2-thia-5-azabicyclo[2.2.1] heptane-5-yl]-3-ftoranila

A solution of 4-[(1S, 4S)-2-thia-5 - azabicyclo[2.2.1]heptane-5-yl]-3-peritrabecular (1.64 g, 6,46 mmol) in a mixture of 20% H2O/THF (50 ml) is treated with platinum on sulfide carbon (0,200 g) in N2current. The atmosphere replace H2(balloons), repeating the evacuation and filling. Through the ü is transferred into a Parr apparatus and shaken under 3,164 kg/cm (45 psi) H2. After 2 h, TLC analysis shows that there is still some amount of the original substance. The reaction mixture was filtered through Celiteand the filtrate containing a mixture of the desired aniline intermediate and source derived nitrobenzene, cooled to 0oC and treated with NaHCO3(2,170 g for 25.8 mmol) and benzyl-chloroformate (of 1.02 ml, 7,10 mmol). After 0.5 h, the reaction mixture was concentrated under reduced pressure to a yellow/green syrup. This substance is dissolved in CHCl3, washed with H2O and brine, dried over Na2SO4, filtered and concentrated in vacuo. Filtration through a silica gel gasket, when the elution 20-30% EtOAc/hexane to give, after concentration of appropriate fractions, a mixture of the original derived nitrobenzene and named connection. Substance absorb 20% H2O/THF (50 ml) and treated with W-2 Raney Nickel (approx. 0.400 g). The reaction mixture was shaken in a Parr apparatus at 3,164 kg/cm2(45 psi) H2. After 3 h, the reaction mixture was filtered through Celiteand the filtrate is cooled to 0oand treated with NaHCO3(2.00 g, to 23.8 mmol) and then benzyl-chloroformate (0,600 ml, 4,19 mmol). After 0.5 h, the reaction mixture was concentrated under reduced yeah the appropriate fractions, 2.20 g (95%) of the named compound as a yellow solid with so pl. 91-93oC and MS (EI) 358 (M+).

Stage 3: (R)-[3-[4-[(1S, 4S)-2-thia-5-azabicyclo[2.2.1]heptane-5-yl]-3 - forfinal]-2-oxo-5-oxazolidinyl]methanol

A solution of N-(carbobenzoxy)-4-[(1S, 4S)-2-thia-5-azabicyclo[2.2.1]heptane-5-yl]-3-foronline (0,359 g, 1.00 mmol) in dry THF (4 ml) in N2cooled to -78oC and then treated with n-butyllithium (0,633 ml, 1.6 M solution in hexane, 1.01 mmol). The reaction mixture was stirred at - 78oC for 15 minutes and then treated with (R)-glycidyl by butyrate (0,151 ml, 1.00 mmol). Upon completion of the addition, the cooling bath removed and the reaction mixture is allowed to warm to ambient temperature overnight. TCS analysis (5% MeOH/CHCl3) showed that the reaction was completed, but there are a number of complex ester butyrate these compounds. Add 5 drops of a 25 weight% solution of NaOMe/MeOH, followed by stirring for 20 min at room temperature, effectively for the conversion of this intermediate to the named connection. The reaction mixture was treated with saturated aqueous NH4CI (10 drops) and then concentrated under reduced pressure to an oil. This substance was dissolved in CH2Cl2and prinny product. Chromatography on silica gel (50 g), elution with a gradient of 1-3% MeOH/CHCl3gives, after concentration of appropriate fractions, 0,132 g (41%) of the titled compound as oil. Rubbing with EtOAc get a precipitate, which is isolated and dried in vacuum, obtaining a whitish solid with so pl. 156-157oC and MS (EI) 324 (M+).

Stage 4 : (R)-[[3-[4-[(1S, 4S)-2-thia-5-azabicyclo[2.2.1]heptane-5-yl-] -3-forfinal]-2-oxo-5-oxazolidinyl]methyl]methanesulfonate

A solution of (R)-[3-[4-[(1S, 4S)-2-thia-5-azabicyclo[2.2.1]heptane-5-yl]-3-forfinal]-2-oxo-5-oxazolidinyl]methanol (1, 68 g, 5,19 mmol) in dry CH2Cl2(100 ml) in N2cooled to 0oC and treated with Et3N (0,793 ml, 5,70 mmol), and then methanesulfonyl chloride (0,442 ml, 5,70 mmol). After 0.5 h at this temperature, TCS analysis (5% MeOH/CHCl3) showed that the reaction was completed. The mixture was washed with H2O, saturated aqueous NaHCO3and brine, dried over Na2SO4, filtered and concentrated in vacuo, obtaining of 1.65 g (79%) of the titled compound as white solids with so pl. 139-142oC and MS (EI) 402 (M+).

Stage 5: (R)-[[3-[4-[(1S, 4S)-2-thia-5-azabicyclo[2.2.1]heptane-5-yl] -phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

A solution of (R)-[[3-[4-[(1S, 4S)-2-thia-5-azabicyclo[2.2.1]heptane-5 - heated to 95oC in a sealed tube for 14 hours and then cooled to ambient temperature. TLC analysis (5% MeOH/CHCl3indicates the completion of the reaction. The mixture was diluted with CH2Cl2(75 ml), washed with saturated NaHCO3(15 ml) and brine (15 ml), dried over Na2SO4filter and concentrate under reduced pressure, obtaining a syrup. The crude intermediate 5-(aminomethyl)oxazolidinone was dissolved in CH2Cl2(75 ml) and treated with pyridine (0,345 ml, 4,27 mmol) and acetic anhydride (0,403 ml, 4,27 mmol) at ambient temperature. After 1 hour, TLC analysis (5% MeOH/CHCl3indicates the completion of the acylation reaction. The reaction mixture was washed with H2O and brine, dried over Na2SO4filter and concentrate under reduced pressure to a solid amber color. Chromatography on silica gel (125 g), elution 1-3% MeOH/CHCl3receive, after concentration of appropriate fractions, of 1.23 g (87%) of the named oxazolidinone-antibacterial agent in the form of a solid substance with so pl. 90-95oC and MS (EI) 365 (M+).

Example 3: (S)-N-[[3-[3-fluoro-4-[(1S, 4S)-2-thia-2,2-dioxo-5-azabicyclo [2.2.1]heptane-5-yl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]ndimethylacetamide

A solution of (S)-N-[[3-[art 25% H2O/acetone (16 ml) is treated at ambient temperature 4-methylmorpholin-N-oxide (in 0.288 g, 2,47 mmol), followed by osmium tetroxide (is 0.102 ml, 2.5 weight% solution in tert-butanol, 0,008 mmol). After 18 h, TLC analysis (10% MeOH/CHCl3indicates the completion of the oxidation reaction. The reaction mixture was treated with saturated aqueous NaHSO3then extracted with CHCl3. The combined organic extracts washed with brine, dried over Na2SO4filter and concentrate under reduced pressure. The remainder chromatographic on silica gel (10 g), elwira 1-3% MeOH/CHCl3getting after concentration of appropriate fractions, 0,321 g (98%) of the named oxazolidinone-microbicides in the form of a white solid with so pl. 95-105oC.

Example 4: (S)-N-[[3-[3-fluoro-4-(tetrahydro-1H-thieno[3,4-c] pyrrole -5(3H)-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

Step 1: CIS-1-(Phenylmethyl)-3,4-pyrrolidineethanol

Complex dimethyl ether (CIS)-1-(phenylmethyl)-3,4-pyrrolidinecarbonyl acid get according to the procedure of Y. Terao, et al. (Chem. Pharm. Bull., 1985, 33, 2762-66). To a stirred solution of this complex diapir (12,14 g that 43.8 mmol) in dry THF (175 ml) in an atmosphere of N2cooled to 0oC, is added dropwise RA is>C for 1 h, then at RT for 18 h, the Reaction mixture was cooled to 0oC and quenched with successive addition of H2O (3.2 ml), 5 N NaOH (3.2 ml) and H2O (11.7 ml). The reaction mixture becomes very thick and mixed with difficulty. The reaction mixture was diluted with ether (500 ml) and filtered through a small layer of celite. The precipitate on the filter is washed with ether (250 ml). The filtrate was washed with H2O (1 x 300 ml), and the organic filtrate is dried (MgSO4), filtered and concentrated, gaining 9.3 g (41,8 mmol, 96%) of the desired diol and a thick yellow oil. Used without additional purification. VRMS (HRMC) (THE BELARUSIAN LIBRARY ASSOCIATION. FAB) calculated for C13H19NO2+H 222, 1494, found 222, 1490.

Step 2: CIS-1-(Phenylmethyl)-3,4-di(methylsulfonyl)-methylpyrrolidine

To a stirred solution of CIS-1-(phenylmethyl)-3,4-pyrrolidineethanol (9.2 grams, to 41.6 mmol) in CH2Cl2(240 ml), cooled to 0oC, add triethylamine (29 ml, 208,1 mmol), and then methanesulfonyl chloride (8.1 ml, 104,0 mmol). The reaction mixture was stirred at 0oC for 15 min, then at room temperature (RT, RT) for 1.5 hours, the Reaction mixture was poured into H2O (240 ml) and the phases are separated. The aqueous phase is extracted with CH2Cl2(1 x 100 ml). Joint using ethyl acetate as eluent, and getting 14.2 g (37.5 mmol, 90%) of the desired bis-nelfinavir in the form of a thick yellow oil. VRMS (HRMC) (EI) calculated for C15H23NO6S2377, 0967, found 377, 0958.

Stage 3: Hexahydro-5-(phenylmethyl)-1H-thieno[3,4-c]pyrrol

To a stirred solution of CIS-1-(phenylmethyl)-3,4-di (methylsulfonyl) methylpyrrolidine (9,2 g, mmol) in dry DMSO (DMSO) (48 ml) is added anhydrous sodium sulfide (5.7 g, 73,3 mmol). The dark reaction mixture is heated at 120oC for 18 h the Cooled reaction mixture was poured into ice-cold H2O (150 ml). The resulting mixture is extracted with ether (3 x 200 ml). The combined organic phases are dried (MgSO4), filtered and concentrated. The resulting residue is purified flash chromatography using ethyl acetate as eluent and receiving of 4.2 g (19,1 mmol, 78%) of the desired product as a thick yellow oil. VRMS (HRMC) (EI) calculated for C13H17NS 219, 1082, found 219, 1080. Anal. Calculated for C17H17NS: C, 71,19; H, 7,81; N, 6,39. Found: C, 70,82; H, 7,83; N, 6,35.

Stage 4: Hexahydro-1H-thieno[3,4-c]pyrrole, hydrochloride

To a stirred solution of hexahydro-5-(phenylmethyl)-1H-thieno [3,4-c] pyrrole (1.2 g, 5.3 mmol) in CH2CI2(21 ml), cooled to 0oC add PE 20 minutes then at RT for 90 minutes. The reaction mixture was concentrated. The resulting residue is purified flash chromatography using 25% ethyl acetate in hexane as the eluent, getting 611,3 mg (2.6 mmol, 49%) of 1-chlorocinnamate. Then the column was washed with 20% methanolic ammonia in CHCl3getting 160,5 mg (1,24 mmol, 23%) of the desired amine as the free base. 1-chlorethylene (611,3 mg, 2.6 mmol) dissolved in methanol (15 ml) and refluxed for 90 minutes. The cooled reaction mixture is concentrated, receiving 408,0 (2.5 mol, 47%) of the desired amine as an HCl salt per chlorocarbonate). So pl. 149-151oC; VRMS (HRMC) (EI) calculated for C6H11NS 129, 0612, found 129, 0614. Anal. Calculated for C6H12ClNS: C, 43,50; H, 7,30;, 21,39; N, 8,45; S, 19,35. Found: C, 43,39; H, 7.23 Percent; N, 8,24; Cl, 21,08; S, 19,12.

Stage 5: 5-(2-fluoro-4-nitrophenyl)-hexahydro-1H-thieno[3,4-C] pyrrol

To a stirred solution of 5-hexahydro-1H-thieno[3,4-C]pyrrole, hydrochloride (147,3 mg, 0.89 mmol) in acetonitrile (5 ml) is added 3,4-ftorirovannom (of 0.11 ml, 0.98 mmol), then diisopropylate Amin (0,36 ml, 2.05 mmol). The homogeneous reaction mixture is refluxed for 18 hours the Cooled reaction mixture is concentrated. The resulting OSL). The combined organic phases are washed with saturated NaHCO3(1 x 40 ml), brine (1 x 40 ml), dried (MgSO4), filtered and concentrated. The residue is purified on a flash chromatography using 20% EtOAc in hexane as eluent and receiving 202,5 g (0.75 mmol, 89%) of the desired nitro compounds in the form of a light yellow solid. So pl. 107-109oC. Anal. Calculated for C12H13FN2O2S: 53,72; H 4,88; N, 10,44; S 11,95. Found: C, 53,38; H, To 5.03; N, 10,34, S, 11,89.

Step 6: 3-[3-fluoro-4-(tetrahydro-1H-thieno[3,4-c]pyrrol-5(3H)-yl) phenylcarbamoyl acid, fenilmetilovy ester

To a stirred solution of 5-(2-fluoro-4-nitrophenyl)hexahydro-1H-thieno [3,4-c] pyrrole (1.44 g, 5.4 mmol) in ethanol (70 ml) is added 2 M CuSO4(2,9 ml). This mixture is cooled to 0oC and portions add sodium borohydride (1.10 g, 26.8 mmol). (Note: the reaction is highly exothermic). Then the dark reaction mixture was refluxed for 2 h, the cooled reaction mixture was distributed between EtOAc and H2O. the Phases are separated. The aqueous phase is extracted with EtOAc (3 x 100 ml). The combined organic phases are dried (MgSO4), filtered and concentrated. The resulting solid residue dissolved in a mixture of acetone/H2O (2:1, 60 ml). This peregremesaout at 0oC for 15 min, then at RT for 2 h, the Reaction mixture was quenched by careful addition of 10% aqueous NaHSO4(30 ml). The reaction mixture was poured into EtOAc (250 ml) and the phases are separated. The aqueous layer was extracted with EtOAc (1 x 100 ml). The combined organic layers are dried (MgSO4), filtered and concentrated. The residue is purified on a flash chromatography using 20% EtOAc in hexane, obtaining 1.6 g (4.3 mmol, 81%) of the desired carbamate: so pl. 101-102oC. Anal. Calculated for C20H21FN2O2S: C, 64,50; H, OF 5.68; N, 7,52; S, 8,61. Found: C, 64,33; H, To 5.56; N, 7,53; S, 8,61.

Stage 7: (5R)-3-[3-fluoro-4-(tetrahydro-1H-thieno[3,4-C] pyrrol-5 (3H)-yl)phenyl]-5-(hydroxymethyl)-2-oxazolidinone

To mix the solution phenylmethylene ester 3-[3-fluoro-4-(tetrahydro-1H-thieno[3,4-C] pyrrol-5(3H)-yl) phenylcarbamate acid (1,36 g, 3.6 mmol) in dry THF (14 ml) in an atmosphere of N2cooled to -78oC add n-utility (1.6 M in hexane, 2.4 ml, 3.8 mmol). The reaction mixture was stirred at -78oC for 35 min and then add R-(-)-glycidylether (0.54 ml, 3.8 mmol). The reaction mixture was stirred at -78oC for 30 min, then at RT over night. Forms a thick sludge. The reaction mixture was quenched with saturated aqueous NH4CI (14 ml), and you (1 x 30 ml), dried (MgSO4), filtered and concentrated. The residue is purified on a flash chromatography using EtOAc as eluent, getting 801,6 mg (2.4 mmol, 65%) of the desired product: so pl. 165-167oC. Anal. Calculated for C16H19FN2O3S: C, 56,79; H, TO 5.66; N, 8,28; S, 9,48. Found: C, A 56.88; H, 5,74; N,8,21; S, Was 9.33.

Stage 8: (5R)-3-[3-fluoro-4-(tetrahydro-1H-thieno[3,4-C] pyrrol-5 (3H)-yl)phenyl]-5-[[(methylsulphonyl)oxy]methyl]-2-oxazolidinone

To a stirred solution of (5R)-3-[3-fluoro-4-(tetrahydro-1H-thieno[3,4-c] pyrrol-5(3H)-yl)phenyl-5- (hydroxymethyl)-2-oxazolidinone (656,5 mg, 1.9 mmol) in CH2Cl2(20 ml), cooled to 0oC, add triethylamine (of 0.41 ml, 2.9 mmol), and then methanesulfonanilide (of 0.18 ml, 2.3 mmol). The reaction mixture was stirred at 0oC for 15 min, then at RT for 18 h, the Reaction mixture was poured into H2O (20 ml). The phases are separated. The aqueous layer was extracted with CH2Cl2(1 x 50 ml). The combined organic layers are dried (MgSO4), filtered and concentrated. The residue is triturated with a mixture of ether/hexane, and the solid is separated by filtration and dried, obtaining 773,9 mg (1.9 mmol, 96%) of the desired nelfinavir. So pl. 148-150oC. Anal. Calculated for C17H21FN2O5S2: C 49,03; H, to 5.08; N, 6.73 X; S, 1o[3.4-C] pyrrol - 5(3H)-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

Stir a suspension of (5R)-3-[3-fluoro-4-(tetrahydro-1H-thieno[3,4-C] pyrrol-5(3H)-yl)phenyl] -5- [methylsulphonyl) oxy] -methyl]-2-oxazolidinone (208,5 mg, 0.5 mmol) in THF (3 ml) and methanolic ammonia (3 ml) is heated in a sealed tube at 100oC for 48 hours, the Reaction mixture becomes homogeneous at about 80oC). The cooled reaction mixture is concentrated and the resulting residue was dissolved in CH2Cl2(5 ml) and cooled to 0oC. To this stirred suspension is added pyridine (of 0.12 ml, 1.5 mmol) and then acetic anhydride (60 μl, 0.6 mmol). The homogeneous reaction mixture is stirred at 0oC for 15 min, then at RT for 1 h, then concentrated. The residue is purified using flash chromatography using 7% methanol in EtOAc as eluent, getting 148,2 mg (0.4 mmol, 78%) of the desired ndimethylacetamide. So pl. 143-144oC; KF-H2O: 0,52%. Anal. Calculated for C18H22FN3O3S plus 0,52% H2O: C, 56,68; H, BY 5.87; N, BR11.01; S, 8,40. Found: C, 56,31; H, 5,90; N, A 10.74; S, 8,30.

Example 5: (S)-N-[[3-[3-fluoro-4-(tetrahydro-1H-thieno[3,4-C] pyrrol-5(3H)-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide, S-oxide

To a stirred solution of (S)-N-[[3-[3-fluoro-4-(Tetra-hydro-1H-thieno [3,4-c] pyrrol-5(3H)-yl)phenyl]-2-oxo-5-Oxley metaperiodate sodium (RUR 134.4 mg, to 0.63 mmol). The reaction mixture was stirred at 0oC for 1 h, then at RT for 18 hours Solid precipitate is removed by filtration. The solid is washed with CHCl3(50 ml). The filtrate was washed with H2O (1 x 30 ml). The aqueous layer was extracted with CHCl2(2 x 25 ml). The combined organic layers are dried (MgSO4), filtered and concentrated. The residue is purified using flash chromatography using 7% methanol in CH2Cl2as eluent, getting 195,7 mg (0.5 mmol, 87%) of the desired sulfoxide. so pl. 162-164oC; VRMS (HRMC) (EI) calculated for C18H22FN3O4S 395, 1315, found 395, 1309. KF-H2O: 2,87%. Anal. Calculated for C18H22FN3O4S plus 2.87% of H2O: C, 53,09; H, USD 5.76; N, 10,32; S 7,87. Found: C, 53,07; H, 6,01; N, 10,20; S 7,87.

Example 6: (S)-N-[[3-[3-fluoro-4-(tetrahydro-1H-thieno[3,4-c] pyrrol-5(3H)-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide, S,S-dioxide

To a stirred solution of (S)-N-[[3-[L-fluoro-4-(tetrahydro-1H-thieno[3,4-c] pyrrol-5(3H)-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] ndimethylacetamide (213,9 mg of 0.56 mmol) in a mixture of 25% acetone/H2O (8 ml) is added N-methylmorpholine-N-oxide (198,1 mg, 1.7 mmol), and then osmium tetroxide in tert-butanol (2.5 per cent by weight) (30 μl, 0.08 mmol). The reaction mixture was stirred at RT in SUB>2Cl2(50 ml), the phases are separated. The aqueous phase is extracted with CH2Cl2(2 x 25 ml). The combined organic layers washed with brine (1 x 30 ml), dried (MgSO4), filtered and concentrated. The residue is purified using flash chromatography using 7% methanol in CHCl3as eluent, obtaining for 194.3 mg (0.47 mmol, 84%) of the desired sulfone. So pl. 135-137oC; VRMS (HRMC) (EI) calculated for C18H22FN3O5S 411, 1264, found 411, 1263. KF-H2O: 1,10%. Anal. Calculated for C18H22FN3O5S plus 1,10% H2O: C, 51,96; H, THE 5.45; N, 10,10; S, 7,71. Found: C, 51,73; H, 5,62; N, 9,96; S 7,75.

Example 7: CIS-(S)-N-[[3-[3-fluoro-4-[3-oxa-7-azabicyclo[3.3.0] Octan-7-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

Following the General method of example 2 and making minor changes, but substituting (1S, 4S)-2-thia-5-azabicyclo[2.2.1] -heptane at hexahydro-1H-fluoro-(3,4-c)pyrrole (Miller, A. D. U. S. Patent 3 975 532 1976) (2,33 g, 20,66 mmol), get a named connection, so pl. 124-126oC.

1. Bicyclic oxazin or thiazin-oxazolidinone structural formula I

< / BR>
and their pharmaceutically acceptable salts,

where X is (a) O (b) S (c) SO (d) SO2;

R1is independently H, F;

R2represents (a) hydrogen is F, Cl, hydroxy, (g) C1-C8-alkoxy;

a = 0 - 3;

b = 0 - 2;

c = 0 - 2 (provided that b and c cannot be both 0);

d = 0 - 2;

e = 0 - 2 (provided that d and e cannot be both 0).

2. Connection on p. 1, in which X is S.

3. Connection on p. 1, in which each R1independently is H or F.

4. Connection on p. 3, in which each R1is F.

5. Connection on p. 1, in which R2represents hydrogen, C1-C8-alkoxy or C1-C8-alkyl, possibly substituted by one or more Cl or OH.

6. Connection on p. 1, in which R2represents methyl, dichloromethyl, hydroxymethyl or methoxy.

7. Connection on p. 1 representing:

a) (S)-N-[[3-[3-fluoro-4-[(1S, 4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl] phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide", she

b) (S)-N-[[3-[3-fluoro-4-[(1S, 4S)-2-thia-5-azabicyclo[2.2.1] heptane-5-yl] phenyl]-2-oxo-5-oxazolidinyl]methyl]-ndimethylacetamide, or

c) (S)-N-[[3-[3-fluoro-4-[(1S, 4S)-2-thia-2,2-dioxo-5-azabicyclo[2.2.1] heptane-5-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-ndimethylacetamide.

8. Connection under item 1 in the form of S-enantiomer.

9. Connection on p. 1, in which c and b are both equal to 1.

10. Connection on p. 9, in which d and e both patients those in need of such treatment, wherein the administered effective amount of compounds of formula I.

13. Bicyclic oxazin or thiazin-oxazolidinedione structural formulas II

< / BR>
or their pharmaceutically acceptable salt,

where X is (a) O (b) S (c) SO (d) SO2;

R1is independently H, F;

R2represents (a) hydrogen, (b) C1-C8-alkyl, possibly substituted by one or more Deputy selected from F, Cl, hydroxy, (g) C1-C8-alkoxy.

14. Connection on p. 13 in the form of S-enantiomer.

15. A method of treating microbial infections in warm-blooded animals, characterized in that it is administered to a patient in need, an effective amount of the compounds of formula II.

 

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The invention relates to a derivative of oxazolidinone formula (I)

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

FIELD: organic chemistry, biochemistry, medicine, endocrinology.

SUBSTANCE: invention relates to a trans-olefinic activator of glucokinase representing compound taken among the group consisting of olefinic amide of the formula (I): wherein R1 and R2 mean independently of one another hydrogen, halogen atom, nitro-group, perfluoro-(lower)-alkyl, (lower)-alkylsulfonyl or (lower)-alkylsulfonylmethyl; R means -(CH2)m-R3 or lower alkyl comprising from 2 to 4 carbon atoms; R3 means cycloalkyl comprising from 3 to 8 carbon atoms; R4 means the group: or unsubstituted, or monosubstituted five- or six-membered heteroaromatic ring linked by ring carbon atom with indicated amino-group wherein this five- or six-membered heteroaromatic ring comprises from 1 to 2 heteroatoms taken among the group consisting of sulfur or nitrogen atom wherein one heteroatom being as nitrogen atom is arranged near with binding ring carbon atom, and wherein indicated monosubstituted heteroaromatic ring is substituted at ring carbon atom not adjacent with mentioned binding carbon atom with a substitute taken among the group consisting of halogen atom and group of the formula: m = 0 or 1; n = 0, 1, 2, 3 or 4; R7 means hydrogen atom or lower alkyl; Δ means trans-configuration relatively to a double bond; or its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition, method for prophylactic or therapeutic treatment of diabetes mellitus of type II and to methods for preparing compounds of the formula (I). Invention provides preparing activators of glucokinase that enhance insulin secretion in treatment of diabetes mellitus of type II.

EFFECT: valuable medicinal properties of compounds.

25 cl, 29 ex

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