Derived oxazolidinone or its pharmaceutically acceptable salt, a method of treating microbial infections in warm-blooded animals

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds exhibiting antimicrobial activity. The inventive derivative oxazolidinone formula I

< / BR>
or its pharmaceutically acceptable salt, where n = 1; A - pieperazinove ring; Y represents: - C1-6-alkyl; -C(O)-C1-6-alkyl; -C(O)-)-C1-6-alkyl; benzoyl; 2-benzyloxycarbonyl, 1,4-dioxaphetyl; N(C1-4)2piperidyl, morpholinyl, a group of the formula

< / BR>
X and Z independently represents a C1-6is alkyl or hydrogen; and in each case the specified C1-6the alkyl may be substituted by one or more substituents selected from F, Cl, Br, CN or or1where R1represents hydrogen or C1-4-alkyl; U, V and W independently represent F or hydrogen; R is lower alkyl; q is 0-4, inclusive. A method of treating microbial infections in warm-blooded animals by injection of 0.1-100 mg/kg of body weight per day (preferably from 3.0 to 50 mg/kg of body weight per day) of compounds of formula I. 2 C. and 11 C.p. f-crystals, 1 table.

The invention relates to oxazolidinone derivative having substituted casinobuy part associated with the N-aryl ring. These compounds possess what I multiresistant staphylococci and streptococci, as well as anaerobic organisms such as bacteroids and Clostridium, and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium. These compounds are particularly effective against the last of these microorganisms, which are known to be responsible for infection in individuals with AIDS.

In the application PCT/US 89/03548 disclosed 5 indolinyl-5-aminoethylethanolamine; 3-(substituted in condensed nuclei) phenyl-5-aminoethylethanolamine; and 3-(asutamiseni)phenyl-5-aminoethylethanolamine that can be used as antibacterial agents.

Various oxazolidinone described in other works, including, U.S. patent N 5801600, U.S. patent N 4921869, Gregoty W. A., And others J. Med. Chem., 32, 1673-81 (1989); C. Wang, and other Tetrahedron, 45, 1323-26 (1989); and Brittelli, etc. J. Med. Chem., 35 (1992).

In the publication of Europatent N 352781 disclosed phenyl - and pyridyl-substituted phenyloxazolidine.

In the publication of Europatent N 316594 disclosed 3-substituted sterilisation.

In the publication of Europatent N312000 reveal phenylmethyl and pyridinylmethyl-substituted phenyloxazolidine.

In one of its variants the present invention relates to a structural connection od;

b) -C1-6-alkyl or-aryl;

c) -OH, -O-C1-6-alkyl, -O-vinyl, -O-phenyl, -O-C(O)-C1-6-alkyl, -O-C(O)-phenyl (the phenyl may be substituted by 1-3 groups selected from F, Cl, -OCH3, -OH, NH2or C1-4-alkyl); or-O-C(O)-O-CH3;

d) -S-C1-6-alkyl;

e) -SO2-C1-6-alkyl, -SO2-N(R3)2(where R3independently represents hydrogen, C1-4-alkyl, or phenyl which may be substituted by 1-3 groups selected from F, Cl, OCH3, OH, NH2or-C1-4-alkyl);

f) -C(O)-C1-6-alkyl, -C(O)-O-C1-6-alkyl, -C(O)-N(R3)2, -C(O)-CH(R4)N(R3)2or-C(O)-CH(R4)NH-C(NH)-NH2(where R4represents the side chain of amino acids);

g) -N(R3)2, -N(CH2)m(where m = 2-6 and forms a cyclic structure together with the nitrogen atom and one or more carbon atoms can be replaced by S, O or NR3), or

,

(where R5represents OH, OCH3CH2OH, CH2OCH3, CO2CH3or CO2C2H5);

h) -C(CH3)=N-OR;

i) (where R6is CH3or hydrogen);

j) (where R7is CH2or C(O), and R8is-H or = O);

k) ;

l) (where p=1 or 2)
3or NCO2CH3);

moreover, in each case specified C1-6the alkyl may be substituted by one or more substituents selected from F, Cl, Br, I, OR1, CO2R1, CN, SR1or R1(where R1represents hydrogen or C1-4-alkyl);

X and Z independently represents a C1-6-alkyl, C3-12-cycloalkyl or hydrogen; or X and Z taken together form a bridging C0-3group; however, preferably, if X and Z are hydrogen;

U, V and W independently represent C1-6-alkyl, F, Cl, Br, hydrogen or C1-6-alkyl, substituted by one or more atoms of F, Cl, Br or I, and preferably, if U and V are fluorine, and W is hydrogen;

R represents hydrogen, C1-12-alkyl, C3-12-cycloalkyl; C1-6-alkoxy, C1-6-alkyl, substituted by one or more substituents selected from F, Cl, Br, I or OH;

q is 0-4, inclusive.

In the formula I preferably, if U and V are fluorine, and W is hydrogen; or U is fluorine, and V and W is hydrogen. Y is preferably selected from the group comprising: H, methyl, ethyl, isopropyl, tert-butyl, benzyl, phenyl, pyridyl, acetyl, deepthroater, hydroxyacetic, Benz, -benzoylacetonitrile, 2-methoxyethoxymethyl, 2,2,2-triperoxonane, cyanomethyl, 2-cyanoethyl, carbomethoxyamino, 2-carbomethoxyamino, 2-foretakstyper, benzyloxycarbonyl, tert-butoxycarbonyl, methylsulphonyl, phenylsulphonyl or paratoluenesulfonyl; and more preferably, if Y is methoxycarbonyl or cyanomethyl. Preferably also, if R is stands, H, methoxy or CHCl2and n=1. In addition, it is preferable that the compounds of formula I represented the optically pure enantiomers having the S-configuration at C5 oxazolidinone rings.

Preferred compounds of the present invention are the following:

(a) Methyl ester 4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-forefeel)-1-piperazinecarboxamide acid;

(b) Ethyl ester 4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2 - forefeel)-1-piperazinecarboxamide acid;

(c) Methyl ester 4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)phenyl)-1-piperazinecarboxamide acid;

(d) N-((2-oxo-3-(4-(4-(phenylcarbamoyl)-1-piperazinil)phenyl)-5-oxazolidinyl)methyl) ndimethylacetamide;

(e) N-((3-(4-(3-the fluorescent-4-(4-(2-cyanoethyl)-1-piperazinil))-phenyl)-2-oxo-5-oxazolidinyl) Teal)-ndimethylacetamide;

(g) N-((3-(4-(3-the fluorescent-4-((phenylcarbamoyl)-1-piperazinil))-phenyl)2-oxo-5-oxazolidinyl)methyl)-ndimethylacetamide;

(h) 2-methoxyethoxy ester 4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-forefeel]-1-piperazinecarboxamide acid;

(i) 4-[4-[5(acetylamino)methyl] -2-oxo-3-oxazolidinyl]-2-forefeel]-1-piperazineethanol;

(j) (+/-)-N-[[3-[4-[4-] 4-(1,4-Dioxaphetyl)-1-piperazinil]-3-forefeel]-2-oxo-5-oxazolidinyl]methyl)-ndimethylacetamide;

(k) (S)-N-[[3-[3-fluorescent-4-[4-(2-methoxyethyl)-1-piperazinil]-phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(l) (S)-N-[[3-[3,5-Diptera-4-[4-(2-methoxyethyl)-1-piperazinil] phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide.

More preferred are compounds:

(a) 4-[4-[5-(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-forefeel]-1-piperazinylcarbonyl acid methyl ester;

(i) 4-[4-[5-(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-forefeel]-1-piperazineethanol.

In another embodiment, the present invention relates to a method of treating microbial infections in warm-blooded animals by the introduction of a warm-blooded animal in need of such treatment, an effective amount of the compounds of formula I, described above. Preferably, if the specified connection is lo 50 mg/kg of body weight per day.

The invention relates to desiniecation structural formula I above. These compounds have antimicrobial activity and are effective against a number of pathogens of humans and animals, including multidrug-resistant staphylococci and streptococci, as well as anaerobic organisms such as bacteroids and Clostridium, and acid-fast organisms such as Micobacterium tuberculosis and Micobacterium avium.

Used in this description, the definition of "C1-6or C1-12-alkyl" means methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. and also from isomeric form.

"Cycloalkyl" means C3-12-cyclopropyl-cyclobutyl-cyclopentyl, -cyclohexyl, etc., and their isomeric forms.

"Alkoxy" includes such groups as methoxy, ethyloxy, bucalossi, etc. in which 1-6 carbon atoms linked by an oxygen atom, and their isomeric forms. In addition, in some cases, groups defined in the present description as "alkoxycarbonyl", in the nomenclature of chemical compounds are identified complex alcelaphinae (such as methoxycarbonyl and methyl ester).

"Aryl" means phenyl, pyridyloxy or naftalina part, optional , or R1(where R1is hydrogen or C1-4by alkyl).

The term "pharmaceutically acceptable salt" means a salt that can be used to administer compounds of the present invention and which are hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesilate, maleate, malate, succinate, tartrate, citrate, 2-hydroxyethylsulphonic, fumarate, etc., These salts may be present in the form of hydrates.

The ring A can have 6-8 atoms, and the larger rings may contain two or three carbon atoms between the nitrogen atoms, for example:

< / BR>
In the case of larger ring sizes this ring may have an internal bridge and form a bicyclic system, as shown below:

< / BR>
If the ring size is 6 atoms, the ring may be optionally substituted at positions X and Z are alkyl groups, cycloalkyl groups, fluorescent groups or bridging alkyl groups, as shown below:

< / BR>
In addition to the above examples below is an example of alternative bicyclic system:

< / BR>
Ring B may be unsubstituted or substituted by one or neskonlith models of substitution independently represent either hydrogen atoms, or halogen atoms.

The group Y at the nitrogen atom of ring A can be introduced by standard methods (described below) using commercially available reagents. Preferably, if Y is chosen from the group comprising H, methyl, ethyl, isopropyl, t-butyl, benzyl, phenyl, pyridyl, acetyl, deepthroater, hydroxyacetic, benzoyl, methoxycarbonyl, etoxycarbonyl, 2-chloroperoxybenzoic, 2-hydroxyethoxymethyl, 2-benzoyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-triperoxonane, cyanomethyl, 2-cyanoethyl, carbomethoxyamino, 2-carbomethoxyamino, 2-foretakstyper, benzyloxycarbonyl, tertbutoxycarbonyl, methylsulphonyl, phenylsulphonyl or paratoluenesulfonyl; and more preferably, if Y is methoxycarbonyl or cyanomethyl.

R-Deputy is preferably the stands, but it may also represent H, methoxy or CHCl2.

The most preferred compound can be obtained in the form of optically pure enantiomers, with (S)-configuration at C5 oxazolidinone rings.

Optically pure material can be obtained by one of the methods of asymmetric synthesis or an alternative method of separation R is h can be obtained from the intermediate amine 12 (as described in example 1 and shown in figure 1) using an appropriate optically active acid, such as dibenzoyltartaric or 10-campusology acid, followed by treatment with a base.

Optically pure material can be obtained in another way (for example as described in schemes). By treating the commercially available 3-ferienresort commercially available (R)-glycidylether in terms Herweh and Kauffmann (Tetrahedron Letters, 1871, 809) may be obtained the corresponding optically pure oxazolidinone with the desired (S)-configuration at the 5-position oxazolidinone rings. After removal butyrate group by treatment with potassium carbonate in methanol or sodium methoxide in methanol to obtain the corresponding alcohol, which can then be derivatization standard methods, for example by metilirovaniya with subsequent replacement with the use of sodium azide, the result of azidopyridine. After recovery azide by hydrogenation and subsequent acylation of the obtained amine by treatment with acetic anhydride and pyridine get the target optically active acetylaminofluorene. With regard to the specified acetylaminofluorene, in this case it is necessary the formation of piperazinone part. Nitration veronikalove the ring at the ortho-position ring atom of fluorine. In the recovery of the nitro group by hydrogenation receive a corresponding aniline derivative and after processing the hydrochloride of bis-(2-chloroethyl)amine in the presence of potassium carbonate in boiling diglyme are optically active pieperazinove derived N-[3-[4-[3-the fluorescent-4-(1-piperazinil)]phenyl-2-oxo-5-oxazolidinyl]methyl]-ndimethylacetamide (22), which can then be used to obtain some compounds, examples of which are disclosed in the present description.

These compounds can be used to treat microbial infections in humans and other warm-blooded animals by parenteral and oral administration of these compounds to humans or animals. Of the compounds of formula I are most active and therefore most active and most preferred are the methyl ester 4-[4-[5-(acetylamino)methyl-2-oxo-3-oxazolidinyl] -2-forefeel] -1-piperazinecarboxamide acid (23) and 4-[4-[5-(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-forefeel]-1 - piperazineethanol. In the above compounds of General formula I, ring A is piperazinone part.

The pharmaceutical compositions of the present invention can be obtained by mixing compounds AO is farmacevtichesky acceptable adjuvants and fillers using commonly used standard techniques. examples of solid compositions include powders, tablets, dispersible granules, capsules, pills and suppositories. Solid media represents at least one substance, which can also serve as a diluent, flavoring agent, solvent, lubricating agent, a suspending agent, a binder, dezintegriruetsja agent and encapsulating agent. examples of inert solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulose materials, low melting wax, cocoa butter, etc., Examples of liquid compositions include solutions, suspensions, and emulsions. These compositions can be, for example, obtained as solutions of the compounds of the present invention in water or in a solvent system such as water-glycol and water-glycol, optionally containing commonly used coloring agents, flavoring agents, stabilizers and thickeners.

The pharmaceutical compositions preferably made using standard techniques in the form of a unit dosage forms containing effective or appropriate quantities of the active ingredient the means of the present invention of the formula I, in the pharmaceutical composition or its standardized form may vary within a wide range depending on the particular application of this compound, its effectiveness and the desired concentration. Basically, the amount of active ingredient is from 0.5 to 90% by weight of the composition.

In therapeutic use for the treatment of or against bacterial infections in warm-blooded animals, the compounds of the present invention or pharmaceutical compositions can be administered orally and/or parenterally in a dose providing and maintaining appropriate concentrations (i.e., the number or levels of the active compounds in the blood of warm-blooded animal being treated, which are effective against bacterial infections. Basically, these antibacterial effective dose of active ingredient is from about 0.1 to about 100, and more preferably from about 3.0 to 50 mg per 1 kg of body weight per day. It should be noted that these doses may vary depending on the needs of the patient, the severity of the bacterial infection and specifically used for the connection. It should also be noted that for more rapid achievement of the s limit of the above range; either this initially injected dose may be less than the optimal value, but the daily dose may be gradually increased during the course of treatment depending on the specific situation. If necessary, the daily dose can be divided into several doses, for example, for the introduction of 2-4 times a day.

Compounds of the present invention of formula I can be introduced parenterally, i.e., by injection, for example by intravenous injection, or any other means of parenteral administration. Pharmaceutical compositions for parenteral administration contain mostly pharmaceutically acceptable amount of the compounds of formula I in the form of soluble salts (kislotoupornoj salt or basic salt) dissolved in a pharmaceutically acceptable liquid carrier such as water for injection, and buffer to obtain appropriately buffered isotonic with, for example, a pH of about 3.5-6. Suitable sautereau agents are, for example, trinatriumfosfaat, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine and some other famous tabularasa agents. Usually the compounds of formula I dissolved in an appropriate n is apatone from about 1 mg/ml to about 400 mg/ml. The liquid pharmaceutical composition is administered in an amount such that the result to get the desired antibacterial effective dose. Compounds of the present invention of the formula I is administered predominantly oral in the form of a solid or liquid dosage forms.

Antimicrobial activity of the compounds of the present invention were tested in vivo using a murine model. The mice-females (six mice for 18-20 g each) were injected intraperitoneal injection of bacteria that before using them were thawed extract the "brain" of the heart, containing 4% brewer's yeast (Staphylococcus aureus) or extract the "brain" of the heart (streptococci). After 1 h and 5 h after injection of bacteria (i.e., after infection) were treatment with antibiotics in six different doses or by oral intubation or by subcutaneous injection. Daily for six days recorded the number of surviving animals. Then, based on the relative number of dead animals and using probit analysis to calculate the value of the ED50. As a control and for comparison with the compounds of the present invention used a well-known antimicrobial agents. R IS:

Example 1. 9-(4-(5-(Acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-forefeel)-1 - piperazinecarboxamide acid methyl ester (23);

Example 3. 4-(4-(5-Acetylamino)methyl)-2-oxo-3-oxazolidinyl)-1-piperazinecarboxamide acid methyl ester;

Example 5. N-((3-(4-(3-the fluorescent-4-(4-(2-cyanoethyl)-1-piperazinil))phenyl-2-oxo-5 - oxazolidinyl)methyl)-ndimethylacetamide;

Example 6. 4-(4-(5((Acetylamino)methyl-2-oxo-3-oxazolidinyl)-2-forefeel)-1-piperazinecarboxamide acid 2-hydroxyethyloxy esters;

Example 7. N-((3-(4-(3-the fluorescent-4-((phenylcarbamoyl)-1-piperazinil))phenyl)-2-oxo-5-oxazolidinyl)methyl)-ndimethylacetamide;

Example 10. (+/-)-N-[[3-[4-[4-(1,4-dioxaphetyl)-1-piperazinil]-3-forefeel]-2-oxo-5-oxazolidinyl]methyl)-ndimethylacetamide;

Example 36. (S)-N-[[3-[3-fluorescent-4-[4-(2-methoxyethyl)-1-piperazinil]phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide;

Example 37. (S)-N-[[3-[3,5-Diptera-4-[4-(2-methoxyethyl)-1-piperazinil] phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide.

General method for the synthesis of methyl ether complex 4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-forefeel)-1 - piperazinecarboxamide acid, methyl ester (23) and ethyl ether complex 4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-forefeel)-1-piperazinecarboxamide acid (24) op who have digital signs, specific chemical names). In accordance with these schemes, commercially available differentpoints (2) is treated with excess piperazine, resulting in a product substitution 3. After the reaction protection with the formation of tert-butoxycarbonyl (BOC) derivative 4 carry out the reaction for reduction of the nitro group using reagents containing format ammonium and Pd/C, resulting in a gain of aniline derivative 5. After the reaction protection of the obtained compound 5 get benzyloxycarbonyl (CBZ) derivative 6, which is then subjected to allilirovanii with the formation of compound 7. In the result of ominirovaniya compound 7 according to the method of Kelly and Van Rheenen (Tetrahedron Letters, 1973 (1976) receive diol 8, which upon treatment with potassium carbonate in boiling acetonitrile cyclist with the formation of oxazolidinone 9. After metilirovaniya oxazolidinone 9 in classic conditions are mesilate 10, which is then subjected to mild substitution reactions with the use of sodium azide, resulting in a gain azide 11. This azide 11 is subjected to reaction recovery by hydrogenation in the presence of Pd/C and get Amin 12, which is then subjected to acylation in-situ use the mediate connection, namely 1,1-dimethylethylene ester 4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-forefeel)-1-piperazinecarboxamide acid.

After the reaction unprotect using triperoxonane acid get key intermediate compound N-((3-(4-(3-the fluorescent-4-(1-piperazinil))phenyl)-2-oxo-5-oxazolidinyl)methyl) -ndimethylacetamide (22), which is then used for obtaining analogs. After processing the connection 22 or methylchloroform or etelcharge.com, preferably under conditions of Schotten-Baumann (NaHCO3/acetone-water), get methyl ester 4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-forefeel)-1-piperazinecarboxamide acid 23 and ethyl ester 4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-forefeel)-1-piperazinecarboxamide acid (24), respectively.

Although the above-described method disclosed in example 1 can be used for all target compounds, however, there is another way (albeit less effective), which is to obtain the intermediate compounds to obtain the target compounds such as N-((2-oxo-3-(4-(4-((phenylcarbamoyl)-1-piperazinil)phenyl)-5-oxazolidinyl)methyl)ndimethylacetamide (20) and methyl ester of 4-(4-(5((based on piperazine and p-pteronotropis way similar to the method described for obtaining the diol 8 (see scheme 1), is treated with one equivalent of methylchloride or tailhold, resulting in a gain of mono-derivateservlet connection 14 with unchanged starting material and batterybattery material. After chromatographic selection nelfinavir 14a or tosilata 14b and processing of any of these materials sodium azide get sidesplit 15. After processing this aspidosperma 15 base (for implementation cyclization) received oxazolidinone 16, which can then be turned into an acetamide derivative 17 in accordance with the method of recovery-acylation (held in a single tank), described in example 1. As shown in the diagram, after convolutional unprotect the connection 17 receive N-((2-oxo-3-(4-(1-piperazinil)-phenyl)-5-oxazolidinyl)-methyl)-ndimethylacetamide (18), which is then subjected to acylation with getting two non-fluorinated analogues, namely, methyl ester 4-(4-(5-((acetylamino)methyl)-2-oxo-4-oxazolidinyl)phenyl-1-piperazinecarboxamide acid (19) and N-((2-oxo-3-(4-(phenylcarbamoyl)-1-piperazinil)phenyl)-5-oxazolidinyl)methyl)- ndimethylacetamide (20).

Obtaining analogues of methyl ether complex 4-(4-(5-((ACE the RA 4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-fluorescent-phenyl)-1 - piperazinecarboxamide acid (24) can be easily implemented by simply replacing piperazine with other cyclic amines, and join 2 other nitrobenzoate derivative; or by treatment with N-((3-(4-(3-the fluorescent-4-(1-piperazinil))phenyl)-2-oxo-5-oxazolidinyl)methyl)-ndimethylacetamide (22) (or their equivalents) other allerease or alkylating agents.

Example 1. 4-(4-(5-(Acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-forefeel)-1 - piperazinecarboxamide acid methyl ester (23).

(a) Obtaining 1-(2-fluorescent-4-nitrophenyl)piperazine (3):

A solution of 12.0 g (75,42 mm) of 3,4-diferentiate (2) in 150 ml of acetonitrile was treated 16,24 g (RUR 188.6 mm) piperazine, and then was heated under reflux for 3 hours the resulting solution was cooled to room temperature and concentrated in vacuum. The residue was diluted with 200 ml of water and was extracted with ethyl acetate (3x250 ml). Then the combined organic layers were extracted with water (200 ml) and a saturated solution of sodium chloride (200 ml) and then dried with sodium sulfate. The resulting solution was concentrated in vacuum, which formed the orange oily substance, which was chromatographically on 450 g of silica gel (230-400 mesh mesh), elwira first dichloromethane until then, have not yet been polyuretane the least polar fraction. Then continued elution with 2% (vol. /about.) m what about the pieperazinove derivative (3), so pl. 68,5-71oC.

(b) Obtaining 1-(tert-butoxycarbonyl)-4-(2-fluorescent-4-nitrophenyl)piperazine (4):

A solution of 12.0 g (53,29 mm) nitro-derivatives (3) in 110 ml of tetrahydrofuran drop was treated with a solution 14,53 g (66,61 mm) di-tributylphosphate in 110 ml of tetrahydrofuran. After addition the solution was stirred at room temperature for 24 h then the solution was concentrated in vacuo, and the residue was chromatographically on 450 g of silica gel (230-400 mesh mesh), elwira 20% (vol./about.) the ethyl acetate in hexane, 30% (vol./about.) the ethyl acetate in hexane and then 50% (vol./about.) the ethyl acetate in hexane. The result has been 16.6 g (96%) of the BOC-derivative (4) in the form of a yellow solid, so pl. 151-153,5oC.

(c) Obtaining 1-(tert-butoxycarbonyl)-4-(2-fluorescent-4-AMINOPHENYL) piperazine (5):

A solution of 1.73 g (5,32 mm) nitro compounds (4) in 30 ml of methanol and 20 ml of tetrahydrofuran and 10 ml of acetate was treated with 1.68 g (26,59 mm) format ammonium and 200 mg of 10% palladium charcoal. Immediately after processing was observed greenhouse gas emissions, which is approximately 30 minutes stopped. After that, the mixture was stirred overnight and then filtered through celite, and the precipitate on the filter was washed with methanol. The filtrate concentration of sodium (30 ml). After drying with sodium sulfate and concentration under vacuum was obtained 1.6 g (approx. 100%) of the amine (5) in the form of a brown solid, which was purified for use in the subsequent stage.

(d) Obtaining 1-(tert-butoxycarbonyl)-4-(2-fluorescent-4-benzyloxycarbonylamino)piperazine (6):

A solution of 1.57 g (5,32 mm) amine 5 and 806 mg (from 0.84 ml, 6.65 mm) of dimethylaniline in 25 ml of tetrahydrofuran at -20oC drop was treated with benzylchloride (1.0 g, 0,84 ml, 5,85 mm). After this solution was stirred at -20oC for 30 min, and then heated to room temperature. The resulting mixture was diluted with 125 ml ethyl acetate and was extracted with water (I ml) and a saturated solution of sodium chloride (50 ml). After drying with sodium sulfate and concentration under vacuum formed inhomogeneous material. This material was adsorbing layer silica gel and was chromatographically 115 g of silica gel (230-400 mesh mesh), elwira 18% (about./about.) the ethyl acetate in hexane, then 25% (about. /about. ) ethyl acetate in hexane and finally 30% (vol./about.) the ethyl acetate in hexane. The result has been to 1.15 g (50%) of CBZ-derivative (6) in the form of a white solid substance, so pl. 150-153oC.

(e) Obtaining 1-(tert-butoxycarbonyl)-4-(2-fluorescent-4-benzyloxycarbonylamino is 77 mg (129 mg of a 60% solution in oil, 3,21 mm) of sodium hydride, and then stirred at room temperature for 20 min then the solution was treated with 356 mg (0.26 per ml, 2.95 mm) allylbromide, and then stirred at room temperature for 18 h the resulting solution was carefully treated with 75 ml of water and was extracted with diethyl ether (CH ml). The combined organic layers were extracted with saturated solution of sodium chloride (100 ml) and dried with sodium sulfate. After concentration in vacuo received inhomogeneous material, which was dissolved in dichloromethane and dried with sodium sulfate. The residue was concentrated in vacuo and obtained oily substance amber color, which was chromatographically on 60 g of silica gel (230-400 mesh mesh), elwira 25% (vol./about.) the ethyl acetate in hexane. The result obtained 1.12 g (90%) of the allyl derivative (7) in the form of an oily substance.

(f) Obtaining 1-(tert-butoxycarbonyl)-4-[2-fluorescent-4-benzyloxycarbonyl(2,3-dihydroxypropyl-1-yl)AMINOPHENYL]piperazine (8):

A solution of 2.18 g (with 4.64 mm) allyl compounds 7 and 3.26 g (27,86 mm) N-oxide N-methylmorpholine in 21 ml of acetone and 6.4 ml of water was treated with 5 ml of 2.5% (by weight) solution of osmium tetroxide in tert-butyl alcohol. The resulting solution was stirred at kotara NaHSO3, then was stirred at 0oC for 15 min and warmed up to room temperature for 2 hours the mixture was diluted with 50 ml water and 50 ml saturated sodium chloride solution, and then extracted with ethyl acetate (CH ml). The combined organic layers were dried with sodium sulfate and concentrated in vacuo to obtain a brown oily substance. This substance was chromatographically on 150 g of silica gel (230-400 mesh mesh), elwira 10% (vol./about.) methanol in chloroform. The result was obtained 2.0 g (86%) of the diol (8) in the form of whitish hygroscopic rigid foam.

(g) Obtaining 3-[3-fluorescent-4-(4-tert-butoxycarbonylmethyl-1-yl)phenyl] -5-hydroxymethyl-2-oxazolidinone (9):

A solution of 2.0 g (4,01 mm) diol 8 in 20 ml of acetonitrile was treated with potassium carbonate (1.1 g, 8,02 mm) and then heated under reflux for 3 hours then the solution was cooled and concentrated in vacuum. The residue was dissolved in 100 ml ethyl acetate and the resulting solution was extracted with water (I ml) and then saturated sodium chloride solution (50 ml). After drying with sodium sulfate and concentration under vacuum formed an oily substance, which was chromatographically on 80 g of silica gel (230-400 mesh mesh), elwira 20% (about what, the.sq. 144-146,5oC.

(h) Obtaining 3-[3-fluorescent-4-(4-tert-butoxycarbonylmethyl-1-yl)phenyl] -5-methanesulfonylaminoethyl-2-oxazolidinone (10):

In a solution of 375 mg (0,95 mm) oxazolidinone 9 and 144 mg (0,20 ml of 1.42 mm) of triethylamine in 3.8 ml of dichloromethane at 0oC one drop was added 130 mg (0,09 ml, 1.14 mm) methanesulfonamide, and then was stirred at 0oC for one hour. The resulting solution was diluted with 30 ml of dichloromethane, and then was extracted with water (I ml) and saturated sodium bicarbonate (25 ml). The resulting residue was dried with sodium sulfate and concentrated in vacuo, resulting in a received 440 mg (98%) nelfinavir 10 in the form of a white solid, which was pure enough to use this connection in the next stage.

(i) Obtaining 3-[3-fluorescent-4-(4-tert-butoxycarbonylmethyl-1-yl)phenyl] -5-azidomethyl-2-oxazolidinone (11):

A solution of 440 mg (0,93 mm) nelfinavir 10 in 22 ml of acetone was treated with a solution of sodium azide (604 mg, 9,29 mm) 6.4 ml of water. The resulting mixture was heated under reflux for 18 hours Then the mixture was cooled, the solution was added 600 mg of sodium azide in 6 ml of water, and then heated under reflux for another 18 hours, the mixture is again cooled, calladine the mixture was diluted with 60 ml of water and was extracted with ethyl acetate (h mm). The combined organic layers were extracted with 100 ml of saturated solution of sodium chloride, then dried with sodium sulfate. After concentration in vacuo received 358 mg (92%) of azide 11 in the form of a white solid (so pl. 130,5-132,5oC) which was sufficiently pure for use in subsequent stages.

(j) Obtaining 3-[3-fluorescent-4-(4-tert-butoxycarbonylmethyl-1-yl)phenyl] -5-aminomethyl-2-oxazolidinone (12) and 3-[3-fluorescent-4-tert-butoxycarbonylmethyl-1-yl)phenyl]-5 - acetylamino-methyl-2-oxazolidinone (21).

A solution of 1.42 g (3,38 mm) azide 11 in 200 ml of ethyl acetate was treated with 400 mg of 10% palladium carbon, and then hydrogenosomal at atmospheric pressure for 48 hours Received an ethyl acetate solution (12) was treated with of 1.34 g (1,37 ml and 16.9 mm) of pyridine and 870 mg (0,80 ml, 8.5 mm) of acetic anhydride, and then stirred at room temperature for 48 hours then the solution was processed to 1.37 ml of pyridine and 0.8 ml of acetic anhydride, and then was stirred at room temperature for another 48 hours the solution was filtered through celite, and the precipitate on the filter was washed with ethyl acetate. The filtrate was washed with water (4x50 ml), 1.0 M solution of copper sulfate (50 ml) and again water (50 ml). After osscore and was stirred for one hour with a saturated solution of sodium bicarbonate.

The resulting mixture was extracted with dichloromethane and the combined organic layers were dried with sodium sulfate and concentrated in vacuum, which formed an oily substance amber color. This substance was chromatographically 74 g of silica gel (230-400 mesh mesh), elwira 2% (vol./about. )methanol in dichloromethane and then 5% (vol./about.) methanol in dichloromethane. The result obtained 1.19 g (81%) of 3-(3-fluorescent-4-tert-butoxycarbonylmethyl-1-yl)phenyl)-5-acetamidomethyl-2-oxazolidinone (21) in the form of whitish rigid foam (so pl. 162-164oC).

(k) Obtaining N-((3-(4-(3-the fluorescent-4-(1-piperazine) phenyl)-2-oxo-5-oxazolidinone)methyl)ndimethylacetamide (22).

A solution of 1.19 g (2,73 mm) of the BOC-derivative [3-(3-fluorescent-4-tert-butoxycarbonylmethyl-1-yl)phenyl)-5-acetamidomethyl-2-oxazolidinone (21)] in 40 ml dichloromethane at 0oC was treated with 15 ml triperoxonane acid. This solution was stirred 30 min at 0oC, and then heated to room temperature, after which the reaction was fully completed. The resulting solution was concentrated in vacuo, and the residue was diluted with ethyl acetate and a saturated solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, after which it was clear that the pain is of astora NaOH. After extraction with ethyl acetate, drying with sodium sulfate and concentration in vacuo received 179 mg of the oily substance amber color. This substance was subjected to circular chromatography on a 2 mm-plates, elwira 10% (vol./about.) methanol in chloroform, and then 15% (vol./about.) methanol in chloroform. As a result received 125 mg (79%) N-((3-(4-(3-the fluorescent-4-(1-piperazinil))phenyl)-2-oxo-5-oxazolidinyl)methyl)- ndimethylacetamide (22) in the form of whitish hard foam.

(I) Receiving 4-(4-(5-((Acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2 - forefeel)-1-piperazinecarboxamide acid methyl ether complex (23).

A solution of 120 mg (0.36 mm) N-((3-(4-(3-the fluorescent-4-(1-piperazinil))phenyl)-2 - oxo-5-oxazolidinyl)methyl)-ndimethylacetamide and 60 mg (0.71 mm) solid sodium hydrogen carbonate in 1.5 ml of acetone and 0.7 ml of water at 0oC was treated with 37 mg (30 μl, of 0.39 mm) of methylchloroform. After this solution was stirred for 1 h at 0oC, and then diluted with 20 ml water. The resulting mixture was extracted with ethyl acetate (30 ml) and the organic layer was extracted with water (2x10 ml) and a saturated solution of sodium bicarbonate (10 ml). Then the solution was dried with sodium sulfate and concentrated in vacuum to obtain 95 mg of the crude product. This neocide is Tanya, and then 50% (vol./about.) acetone in dichloromethane. As a result received 81 mg (57%) of ester methyl 4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-forefeel)-1-piperazinecarboxamide acid in the form of a white solid substance, so pl. 177-179oC.

Example 2. Ethyl ester 4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-forefeel)-1-piperazinecarboxamide acid (24).

Were used the same techniques described in example 1 (stage a-k). A solution of 100 mg (0.30 mm) N-(33-(4-(3-the fluorescent-4-(1-piperazinil))phenyl)-2-oxo-5-oxazolidinyl)-methyl)ndimethylacetamide (23) (product of stage (k) described above) and 50 mg (0,59 mm) of solid sodium bicarbonate in 2 ml acetone and 1 ml of water at 0oC was treated with 35 mg (31 μl, 0.33 mm) of ethylchloride. The resulting solution was stirred at 0oC for 2 h, and then warmed up to room temperature for 18 hours the solution was diluted with 30 ml of water and was extracted with ethyl acetate (40 ml). The organic layer was washed with 30 ml water and 30 ml of saturated solution of sodium bicarbonate. After drying with sodium sulfate and concentration in vacuo received a white solid. This material was subjected to radial chromatography on a 22 mm-plates, elwira 2% (vol./about.) the methanol in Inyl)-2-forefeel)-1-piperazinecarboxamide acid (24) as a white solid, so pl. 224-226oC.

Example 3. Methyl ester 4-(4-(5-((acetylamino)methyl)-2-oxo-3 - oxazolidinyl)phenyl)-1-piperazinecarboxamide acid.

The target compound was obtained in accordance with the procedure described in example 1, except that instead of starting material (3,4-diferentiate (2)) used 4-pernitrate.

Example 4. N-((2-Oxo-3-4-(4-phenylcarbamoyl)-1-piperazine)-phenyl)-5-oxazolidinone)methyl)-ndimethylacetamide.

The target compound was obtained in accordance with the procedure described in example 2, except that the source material (3,4-differentpoints (2)) was replaced with 4-pteronotropis.

Example 5. N-((3-(4-(3-the fluorescent-4-(4-(2-cyanoethyl)-1-piperazinil))phenyl)-2 - oxo-5-oxazolidinone)methyl)-ndimethylacetamide.

A solution of 75 mg (0.22 mm) N-((3-(4-(3-the fluorescent-4-(1-piperazinil))phenyl-2-oxo-5-oxazolidinyl)methyl)-ndimethylacetamide (22) (example 1, part k) in 5 ml of methanol was treated with 13 mg (17 μl, 0.25 mm) of Acrylonitrile, and then was heated under reflux for 3 hours then the solution was cooled and concentrated in vacuum. The resulting residue was subjected to radial chromatography on a 4 mm plate, elwira 5% (vol./about.)methanol in chloroform. The result has been 84 mg (97%de white solid product, so pl. 125-130oC.

Example 6. 2-Hydroxyethyloxy ester 4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2-forefeel)-1-piperazinecarboxamide acid.

A solution of 208 mg (0.25 mm) N-(93-(4-(3-the fluorescent-4-(1-piperazinil))phenyl)-2-oxo-5-oxazolidinyl)methyl)-ndimethylacetamide (22) (product of example 1, part k) in 3 ml acetone and 2 ml of water was treated with sodium bicarbonate (21 mg, 0.25 mm), and then was cooled to 0oC. the resulting mixture was treated with 54 ml of solution (0.25 mm) 2-benzyloxyethanol in 2 ml of acetone. Then the solution was left to warm to room temperature for 22 h, and then diluted with 30 ml ethyl acetate and was extracted with water (I ml) and saturated sodium bicarbonate solution (20 ml). This solution was dried with sodium sulfate and concentrated in vacuum to obtain a white solid. This material was subjected to radial chromatography on a 4 mm plates (eluent: 20% (about. /about. ) acetone in dichloromethane). As a result of these procedures was received 113 mg (approx. 100%) of chloroformate, 4-(4-(5-((acetylamino)methyl)2-oxo-3-oxazolidinyl)-2-forefeel)-1 - piperazinecarboxamide acid 2-hydroxyethylamide of ester in the form of a white solid substance, so pl. 121-123oC. Solution of the material obtained in 5 ml of methanol formation is ATM. The resulting mixture was filtered through celite, and the precipitate on the filter was washed with methanol. The filtrate was concentrated in vacuo and obtained white solid. This substance was subjected to radial chromatography on a 2 mm-plates, elwira 5% (vol./about.)methanol in chloroform, and then with 10% (vol./about.) methanol in chloroform. The result obtained 76 mg (82%) of hydroxyethylphosphonate, 2-hydroxytyrosol of ester 4-(4-(5-((acetylamino)methyl)-2-oxo-3-oxazolidinyl)-2 - forefeel)-1-piperazinecarboxamide acid in the form of a white solid product, so pl. 203-206oC.

Example 7. N-((3-(4-(3-the fluorescent-4-((phenylcarbamoyl)-1-piperazinil))phenyl)-2-oxo-5 - oxazolidinyl)methyl)-ndimethylacetamide.

In accordance with the procedure described in example 1, a target compound was obtained from 100 mg (0,297 mm) N-((3-(4-(3-the fluorescent-4-(1-piperazinil))phenyl)-2-oxo-5-oxazolidinyl)- methyl)-ndimethylacetamide (22) (product of example 1, part k) except that methylchloroform (source material) was substituted for benzoyl chloride. The result of this procedure received 73 mg (56%) N-((3-(4-(3-the fluorescent-4-(phenylcarbamoyl)-1-piperazinil))phenyl)-2-oxo-5-oxazolidinyl)methyl)-ndimethylacetamide in the form of a fine white powder, so pl. 184-187oC.

Example 8. 2-Methoxyethoxy ester 4-[4-75 mg (0.22 mm) pieperazinove derivative 22 in 4 ml acetone and 2 ml of water was treated with sodium bicarbonate (2 mg, 0.25 mm), and then was cooled to 0oC and the solution was added 35 mg (0.25 mm) 2-ethoxyethylacetate in 0.5 ml of tetrahydrofuran. The resulting mixture was heated to room temperature for 22 hours then the mixture was diluted with 30 ml of ethyl acetate, and then was extracted with water (3h20 ml) and saturated sodium bicarbonate solution (20 ml). The combined aqueous layers were extracted with ethyl acetate (2x20 ml) and the combined organic layers were dried with sodium sulfate and concentrated in vacuum to obtain a white solid. The resulting material was subjected to radial chromatography on a 4 mm plate, elwira first 20% (vol./about.) acetone in dichloromethane, and then 30% (vol./about.) acetone in dichloromethane. The result has been 92 mg (96%) of the desired compound as a white solid.

Example 9. 4-[4-[5(Acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2 - forefeel]-1-piperazineethanol.

A solution of 75 mg (0.22 mm) pieperazinove derivative 22 in 4 ml acetone and 2 ml of water was treated with 21 mg (0.25 mm) of sodium bicarbonate, and then was cooled to 0oC. the resulting mixture was treated with 226 mg (190 μl, 3.0 mm) of freshly distilled chloroacetonitrile, after which the mixture was left to warm up on and saturated sodium bicarbonate solution (20 ml). The combined aqueous layers were extracted with ethyl acetate (3h20 ml) and the combined organic layers were dried with sodium sulfate and concentrated in vacuum to obtain a white solid. This substance was subjected to circular chromatography on a 4 mm plates (eluent: 5% (vol./about.) methanol in chloroform). As a result of these procedures was received 80 mg (96%) of the desired nitrile as a shiny white solid.

Example 10. (+/-)-N-[[3-[4-[4-(1,4-dioxaphetyl)-1-piperazinil]-2-oxo-5-oxazolidinyl]methyl)ndimethylacetamide (Y=MeCO(CH2)2-CO-, F, racemic.).

The compound of example 1 (stage k) (0.104 g g) were treated 0,041 g levulinate acid, 0.083 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 0.005 g of N, N-dimethylaminopyridine in 2 ml of pyridine. The resulting mixture was stirred 2 days at 20oC. After aqueous extraction carried out using methylene chloride, got 0,139 g of residue. This material was purified using liquid chromatography medium pressure (GHSD) on silica gel (eluent: 5% (about. /about.) methanol in ethyl acetate), resulting in a received amount of 0.118 g of white solid product, so pl. 148-150oC.

Example 11. N-[[3-[4-[4-(1,4-dioxaphetyl)-1-piperazinil]-3,5-differerential]-2-oxo-5 - oxazolidinyl]methyl)-acetophenone in example 10, but using triperoxonane salt piperazine U-99472 (obtained as described below), received 0,291 g of salt. This salt was subjected to liquid chromatography, medium pressure, and then subjected to preparative thin-layer chromatography (1000 μm, eluent: 20% acetone/methylene chloride (about./vol.), resulting received 0,103 g foamy white solid substance, so pl. 52-56oC.

Example 12. (+/-)-N-[[3-[4-[4-[(1-oxo-6-oxa-7-phenyl)heptyl]-1-piperazinil]-3-forefeel]-2 - oxo-5-oxazolidinyl]-methyl)-ndimethylacetamide (Y= PhCH2O(CH2)4CO-).

Used General technique described in example 10, except that levulin acid was substituted for 5-benzyloxycarbonyl acid (0,074 g), resulting in a received 0,101 g connection. This compound was subjected to liquid chromatography, medium pressure (eluent: 10% methanol in ethyl acetate) and received 0,130 g of target compound, TLC: Rf= 0,24 (eluent: 10% methanol in ethyl acetate.vol.).

Example 13. (+/-)-N-[[3-[4-[4-(1-oxo-5-hydroxyphenyl)-1 - piperazinil] -3-peroperty]-2-oxo-5-oxazolidinyl]methyl)- ndimethylacetamide (Y=HO(CH2)4CO-).

The compound of example 12 (66 mg) was dissolved in 5 ml of methanol, the reaction vessel was purged and nepanaudotos from a container (3 times). The resulting mixture was stirred in an atmosphere of hydrogen for 3 h, and then filtered through diatomaceous earth, washed with methanol, and the filtrate evaporated. The resulting residue triturated with chloroform, and precipitated white solid precipitate was collected and received by the target connection, so pl. 171-172oC. TLC: Rf= 0,07 (10% methanol in ethyl acetate.vol.).

Example 14. N-[[3-[3,5-Diptera-4-[4-[5-R, S-methyl-[(1,3-di-oxa-2-oxo)cyclopentyl] ] ] -1-piperazinil]phenyl)-2-oxo-5-oxazolidinyl] methyl]acetamide", she -(5S) (Y=cyclic carbonate: optically active oxazolidinone, but with the racemate under cyclic carbonate, diF)

BOC-piperazine, diF, optically active compound (0,094 g) was treated with 1.0 ml triperoxonane acid in 1.5 ml of methylene chloride at 0oC for 50 min, and then heated to 20oC. the Resulting volatiles were removed in vacuum and received a red oily substance (triptorelin piperazine U-99472). This substance was added 0.036 g of chlorotrimethylsilane and 0,069 g of potassium carbonate in acetonitrile, after which the mixture was heated under reflux for 1 day. Then the mixture was filtered and evaporated in vacuum to obtain a yellow oily substance. Obtained oscategui preparative TLC (eluent: 7% methanol in methylene chloride), as a result, we got to 0.022 g of a white solid substance, so pl. 106-111oC.

Example 15. N-[[3-[3,5-Diptera-4-[4-(1-oxo-2-methoxyethyl)-1-piperazinil] phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide, (S) -(Y=MeOCH2CO-optically active, diF).

To a solution of triptoreline salt piperazine (0,192 g) in 3 ml of methylene chloride and 1.0 ml of triethylamine in a nitrogen atmosphere and at 0oC was added 0,071 g methoxyacetanilide. The resulting mixture was stirred at 0oC, and then subjected to aqueous extraction carried out using methylene chloride. The organic layer was dried with magnesium sulfate and concentrated to a volume of 5-10 ml, then cooled, and the resulting solid residue was collected and recrystallized from ethyl acetate. The result has been 44 mg of a white solid product, so pl. 239-241oC.

Example 16. (+/-)-N-[[3-[4-[4-(N-carbobenzoxy)-2-amino-1-oxo-ethyl)-1-piperazinil] ] -3-forefeel] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide (Y=Ph CH2O2CNHCH2CO-racemic., F).

To the compound of example 1 k (0,115 g) was added of 0.085 g of N-carbobenzoxy in 4 ml of tetrahydrofuran and 2 ml of water, and then pH was brought to 4 by addition of 3 N. hydrochloric acid and 0,203 g of 1-ethyl-3-(3-dimethylaminopropyl)Kislitsina and 0,225 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and pJ brought up to values of 3-4 and 5 by addition of 2n sodium hydroxide. The resulting mixture was stirred over night. After that, the mixture was subjected to aqueous extraction carried out using ethyl acetate, the organic layers were concentrated and the residue was purified by concentration of methylene chloride and methanol. In the trituration with methanol received 0.042 mg of a white solid substance, so pl. 189-191oC.

Example 17. (S)-N-[[3-[4-[4-(cyanomethyl)-1-piperazinil]-3-forefeel]-2-oxo-5-oxazolidinyl]methyl-ndimethylacetamide (U-97665).

In subsequent stages is disclosed obtaining mono-F-substituted product of the present invention.

(a) 1,1-Dimethylethylene ester (S)-4-[4-[5-(hydroxymethyl)-2-oxo-3-oxazolidinyl]-2-forefeel]-1-piperazinecarboxamide acid (2):

in a solution of 7.5 g (17.5 mm) CBZ-derivative 1 in 240 ml of tetrahydrofuran at -78oC drop of approximately 3 min was added 12.0 ml (1.6 M, 19,25 mm) n-utility in hexane. Then this solution was stirred at -78oC for 30 min; after approximately 5 min was added 2,78 g (2,73 ml, 19,25 mm) pure R-(-)-glycidylether (drop by drop), and the solution was heated to 0oC. Then the solution was heated to room temperature in the course is sodium chloride. The organic layer was dried with sodium sulfate and concentrated to obtain a resinous residue. This residue was recrystallized from hot ethyl acetate with the addition of a certain amount of hexane, which was obtained 6.4 g (93%) of the desired product, so pl. 130,5-133oC.

(b) 1,1-Dimethylethylene ester (S)-4-[4-[5-(methanesulfonylaminoethyl)-2-oxo-3-oxazolidinyl] -2-forefeel] -1-piperazinecarboxamide acid (3):

the solution is 2.88 g (7,28 mm) alcohol (2) in 32 ml of dichloromethane at 0oC was treated with 1.29 g (1.77 ml, 12.7 mm) of triethylamine, and then was added 1.04 g (0,70 ml, 9,10 mm) methanesulfonanilide. The resulting solution was stirred for 15 min at 0oC, then diluted with dichloromethane and extracted with water. This solution was dried with sodium sulfate and concentrated in vacuum to obtain 3.4 g (98%) nelfinavir 3 as a pale pink solid (mass spectroscopy high resolution: for C20H28FN3O7S calculated: 4731632 found: 4731631), sufficiently pure for use in subsequent stages.

(c) 1,1-Dimethylethylene ester (S)-4-[4-[5-(azidomethyl)-2-oxo-3-oxazolidinyl]-2-forefeel]-1-piperazinecarboxamide acid (4):

a solution of 16.8 g (35.5 mm) nelfinavir poluchenii the solution was diluted with ethyl acetate and was extracted with water. The organic layer was dried with sodium sulfate and concentrated in vacuo, resulting in a received 14.9 g (100%) of the azide 4 as a pale yellow solid (so pl. 101-104oC), sufficiently pure for use in subsequent stages.

(d) 1,1-Dimethylethylene ester (S)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-forefeel]-1-piperazinecarboxamide acid (5):

the solution 14,92 g (35.5 mm) azide 4 in 200 ml of ethyl acetate was treated with 2 g of 10% palladium on carbon, and then hydrogenosomal for 24 h under a pressure of 1 ATM. The reaction flask was purged with nitrogen, and then was added 14.0 g (14.4 ml, 177,5 mm) of pyridine and 9.1 g (8,4 ml, and 88.8 mm) of acetic anhydride. The resulting mixture was stirred at room temperature for 72 h, then filtered through celite. The filtrate was extracted with water, 1 N. a copper sulfate solution, was dried, concentrated in vacuo and received a brownish solid. This substance was purified by chromatography on silica gel; received 12.7 g (82%) of product 5 in the form of a powdery white solid, so pl. 153-158oC.

(e) (S)-N-[[3-[4-[3-the fluorescent-4-(1-piperazinil)phenyl] -2-oxo-5-oxazolidinyl] methyl]ndimethylacetamide:

35 ml triperoxonane acid at 0oC obra is actor was concentrated in vacuum and the obtained residue, which was dissolved in water and mixed with 125 ml of ion-exchange resin AGI-18 (OH-form) for 2.5 hours and Then the resin was removed by filtration, washed with water and the combined filtrates were dried by freezing, which was obtained 2.7 g (69%) of the desired compound as white solid flakes, so pl. 73-76oC.

(f) (S)-N-[[3-[4-[4-(cyanomethyl)-1-piperazinil] -3-forefeel]-2-oxo-5-oxazolidinyl]methyl]-ndimethylacetamide:

the solution to 2.42 g (7.2 mm) describes the connection stage (e) in 242 ml of acetone and 74 ml of water was cooled to 0oC and was treated with 1.20 g (14.4 mm) of sodium bicarbonate, after which was added to 26.2 g (22,0 ml, 0.35 M) chloroacetonitrile. The resulting solution was heated to room temperature within 36 hours the Mixture was diluted with ethyl acetate and was extracted with water and then a saturated solution of sodium chloride. After drying with sodium sulfate and concentration in vacuo received whitish solid, which was purified by chromatography on silica gel (eluent: solvent system methanol/chloroform). The result was obtained 2.2 g (82%) of target compound as a white solid chapeaurouge substances, so pl. 166-167oC.

Example 18. (S)-N-[[3-[4-[4-(cyanomethyl)-1-piperazinil]-3,5-defloriani] -2-oxo-5 - oxazolo monitora-derivative of example 17 (e) was replaced by difterophorina derivative ((S)-N-[[3-[3,5-Diptera-4-(1-piperazinil)phenyl]-2-oxo-5,5-oxazolidinyl] methyl] -ndimethylacetamide)), received target compound in the form of a white powder with so pl. 150-154oC.

Example 19. (+)-N-[[3-[4-[4-(2-cyanoethyl)-1-piperazinil]-3-forefeel]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide.

A solution of 75 mg (0.22 mm) of racemic mixture of example 17 (stage e) in 5 ml of methanol was treated with 13 mg (17 μl, 0.25 mm) of Acrylonitrile, and then was heated under reflux for 3 hours the Solution was concentrated in vacuum. The resulting residue was subjected to circular chromatography (eluent: 5% (about. /about. ) methanol in chloroform). The result has been 84 mg (97%) of target compound in the form of a white solid substance, so pl. 125-130oC.

Example 20. (+)-N-[[3-[4-[4-(2-cyano-2-propyl)-1-piperidinyl]-3-forefeel]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide.

A solution of 75 mg (0.22 mm) of racemic mixture of example 17 (e) in 1 ml dry acetonitrile was sequentially treated with 5 mg (33 μl, 0.45 mm) of dry acetone and 44 mg (59 μl, 0.45 mm) trimethylsilylacetamide. The resulting solution was heated under reflux for 18 h, and then diluted with ethyl acetate and was extracted with water. After drying with sodium sulfate and concentration in vacuo received a brownish solid. This substance was subjected to circular chromatography, elwira 5% the society, so pl. 139-143oC.

Example 21. (S)-N-[[3-[4-[4-(4-cyanoethylidene-4-yl)-1-piperazinil] -3-forefeel]-2-oxo-5-oxazolidinyl]methyl-ndimethylacetamide.

A solution of 50 mg (0.15 mm) of the product of example 17(e) in 2 ml dry acetonitrile was treated sequentially 3 mg (0.02 mm) of anhydrous zinc chloride, 30 mg (28 μl, 0.30 mm) tetrahydropyran-4-it's a and 29 mg (40 μl, 0.30 mm) trimethylsilylacetamide. The resulting solution was heated under reflux for 30 h, diluted with ethyl acetate and was extracted with water. After drying with sodium sulfate and concentration under vacuum was obtained a light yellow solid. This material was subjected to circular chromatography, elwira methanol/dichloromethane. As a result received 24 mg (36%) of target compound in the form of a white solid substance, so pl. 134-137oC.

Example 22. (+)-N-[[3-[3-fluorescent-4-(4-formyl-1-piperazinil)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-ndimethylacetamide.

A solution of 0.250 g (0,267 mm) of racemic product of example 17 (e) in 4 ml of THF and 2 ml of water was treated with 11 mg (9 μl, 0,243 mm) formic acid and the pH was brought to 4.5 by adding 0.1 G. of aqueous hydrochloric acid. After that, the mixture was added 153 mg (0.80 mm) of the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide in 1 ml of water, stirring prin.hydrochloric acid solution. After approximately 1-hour stirring was added carbodiimide (100 mg, 0,54 mm) and formic acid (30 mg, 0.80 mm), after which the mixture was stirred at room temperature for 16 hours the mixture was diluted with water and extracted with ethyl acetate. The organic layer was extracted with saturated sodium bicarbonate solution and saturated sodium chloride solution, then dried with sodium sulfate and concentrated in vacuum. The resulting white solid was subjected to chromatography on silica gel (eluent: methanol/methylene chloride) and received 0,094 g (97%) of target compound in the form of a white solid product, so pl. 190-193,5oC.

Example 23. Methyl ester (S)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidine)]-2-forefeel]-1-piperazinecarboxamide acid.

A solution of the product of example 17 (stage e) in 22 ml of acetone and 11 ml of water was treated with 150 mg (1,80 mm) of sodium bicarbonate and cooled to 0oC, and then added 0,170 g (of 0.14 ml, 1,80 mm) of methylchloroform. After incubation for 2 h the mixture was diluted with ethyl acetate and was extracted with water and saturated sodium chloride solution. After drying with sodium sulfate and concentration in vacuo received a white solid, which Acimall (77%) of target compound in the form of a white solid, so pl. 179,5-182oC.

Example 24. Methyl ester (S)-4-[4-[5-[(acetylamino)-methyl]-2-oxo-3-oxazolidine)]-2,6-defloriani]-1-piperazinecarboxamide acid.

In accordance with the procedure described in example 23, except that the product of example 17(e) was replaced by deferability, received the target compound as a white powder, so pl. 175-178oC.

Example 25. (+)-N-[[3-[4-[3-the fluorescent-4-[(phenylcarbamoyl)-1-piperazinil]]phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide.

In accordance with the procedure described in example 23 (using the racemic mixture of example 17(e), except that methylchloroform substituted for benzoyl chloride, obtained target compound as a white powder, so pl. 184-187oC.

Example 26. 2-Methoxyethoxy ester(+)-4-[4-[5-[(acetylamino) methyl]-2-oxo-3-oxazolidine)]-2-forefeel]-1-piperazinecarboxamide acid.

A solution of 75 mg (0.22 mm) monitoremerging derivative of example 25 in 4 ml acetone and 2 ml of water was treated with 21 mg (0.25 mm) of sodium bicarbonate, and then was cooled to 0oC. the resulting solution was treated with 35 mg (0.25 mm) solution of 2-methoxyethylamine in 0.5 ml of tetrahydrofuran. After this, the solution was heated to room of temperance sodium, and then a saturated solution of sodium chloride. The organic layer was dried with sodium sulfate and concentrated in vacuum to obtain a white solid residue. This residue was subjected to circular chromatography, elwira 30% (vol./about.)acetone/dichloromethane). The result has been 92 mg (96%) of target compound in the form of a white solid substance, so pl. 166-167oC.

Example 27. 2-Methoxyethoxy ester (S)-4-[4-[5-[(acetylamino)methyl] -2-oxo-3-oxazolidine)] -2,6-defloriani]-1-piperazinecarboxamide acid.

In accordance with the procedure described in example 26, except that the product of example 17 (e) was replaced by deferability 7, received the target compound in the form of a white solid substance, so pl. 154,5-156oC.

Example 28. 2-(Phenylmethoxy)ethyl ester()-4-[4-5-[(acetylamino)methyl]-2-oxo-3-oxazolidin-2-forefeel]-1-piperazinecarboxamide acid.

A solution of 208 mg (0.25 mm) of the product of example 25 in 3 ml acetone and 2 ml of water was treated with sodium bicarbonate (21 mg, 0.25 mm), and then was cooled to 0oC. thereafter, the mixture was again treated with 54 mg (0.25 mm) solution of 2-(phenylmethoxy) ethylchloride in 2 ml of acetone. This solution was left to warm to room temperature for 22 h, after drying with sodium sulfate and concentration in vacuo received a white solid, which were subjected to circular chromatography (eluent: 20% (about. /about. ) acetone in dichloromethane). Thus received 113 mg (100%) of target compound in the form of a white solid with so pl. 121-123oC.

Example 29. 2-(phenylmethoxy)ethyl ester (S)-4-[4-[5-[(acetylamino)methyl] -2-oxo-3-oxazoline-2,6-defloriani]-1-piperazinecarboxamide acid.

In accordance with the procedure described in example 28, except that the compound of example 17 (e) was replaced by deferability 7, received the target compound in the form of a white solid substance, so pl. 108-110oC.

Example 30. 2-Hydroxyethyloxy ester()-4-[4-[5-[(acetylamino)methyl] -2-oxo-3-oxazoline-2,6-defloriani]-1-piperazinecarboxamide acid.

A solution of 113 mg of the compound of example 28 in 5 ml of methanol was treated with 35 mg of 10% palladium carbon, and then hydrogenosomal at atmospheric pressure for one hour. The resulting mixture was filtered through celite and the filter cake washed with methanol. The filtrate was concentrated in vacuo and obtained white solid. This substance was purified by chromatography using a circular, elwira a solvent system of methanol and chloroform. The result obtained 76 mg (82%) teleoperate-2-furanyl)carbonyl]-1-piperazinil]phenyl]-2-oxo-5-oxazolidinyl]- methyl]ndimethylacetamide.

A solution of 100 mg (0.28 mm) giftwrapping derivative ((S)-N-[[3-[3,5-Diptera-4-(1-piperazinil)phenyl] -2-oxo-5-5-oxazolidinyl] methyl]-ndimethylacetamide) and 144 mg (1.25 mm) (R)-2-tetrahydropyranol acid in 4 ml of tetrahydrofuran and 2 ml of water was brought to pH=4.5 by adding 2 n NaOH solution. This solution was treated with a solution of 324 mg (1,69 mm) of the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide in 2 ml of water. Then this solution was maintained at pH=4,6 by adding 2 n NaOH solution, stirring at room temperature for 1.5 hours the resulting solution was diluted with water and extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate and concentrated in vacuo, resulting in a received brownish solid, which was subjected to circular chromatography (eluent: solvent system of methanol/dichloromethane). As a result received 106 mg (83%), the target amide as a white solid, so pl. 198-200oC.

Example 32. (S)-N-[[3-[3,5-Diptera-4-[4-[2-(1-piperidinyl)-ethyl]-1-piperazinil]phenyl]-2-oxo-5-oxazolidinyl]methyl]-ndimethylacetamide.

In subsequent stages disclosed receipt difterophorina compounds of the present invention.

(a) 2,6-Diptera-4-nitrobenzene(terpyridine (29,15 ml, 360,38 mm). The resulting suspension was cooled to 0oC in an ice bath and one drop of processed anhydride triperoxonane acid (31.8 ml, 189,2 mm) for 45 min the Reaction mixture was left for stirring at 0oC for 2 h, and then kept overnight in a refrigerator at 5oC. Completion of the reaction was controlled by TLC (15% EtOAc/hexane, short-wave UV). Then the reaction mixture was concentrated under reduced pressure, and then was treated with water (50 ml) and ethyl acetate (50 ml). This mixture was transferred into a separating funnel with 100 ml ethyl acetate and washed with 1N. solution of hydrochloric acid up until the washing became acidic (g ml). The aqueous phase was subjected to reverse extraction with ethyl acetate (CH ml). United an ethyl acetate extracts were again combined and washed with 1 N. hydrochloric acid (400 ml), then once washed with brine (400 ml). The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to obtain 54,092 g red-Golden oily substance. Although this substance was pure, as evidenced by NMR analysis, it was combined with the crude products of other reactions and chromatographically on column with Etat received target compound (total yield 95%) as a pale yellow oily substance, VRMS (M+for C7H2F5NO5S: calculated: 3069574; found: 3069590.

(b) 1-(tert-Butoxycarbonyl)-4-(2,6-Diptera-4-nitrophenyl)-piperazine.

A solution of 2,6-Diptera-4-nitrobenzene(trifloromethyl)sulfonate (55 g, 179 mm) in dry DMF (275 ml) was treated with 1-(tert-butoxycarbonyl)piperazine (45,71 g, 250 mm). The resulting clear yellow solution became orange after adding N,N-diisopropylethylamine (47 ml, 269 mm). The reaction mixture was heated under reflux for 15 h under nitrogen atmosphere. The completion of the reaction was controlled by TLC (30% EtOAc/hexane, short-wave UV). The reaction mixture was concentrated to dryness and combined with the crude product from another reaction for cleaning. This crude material was dissolved in hot methylene chloride (420 ml; some solids, not related to this product, it was not dissolved, and then was chromatographically on 3 separate columns (2 columns: 750 g of silica gel; elution 1 l each of 1-5% EtOAc/CH2Cl2one column: 250 g of silica gel; packaging with methylene chloride; the loading of 60 ml compounds; elution with 2.5 and 5% EtOAc/CH2Cl2), resulting in a received target compound (yield 87%) as an orange solid the ptx2">

(c) 1-(tert-butoxycarbonyl)-4-[2,6-Diptera-4-(benzyloxy-carbonyl)AMINOPHENYL]piperazine.

1-(tert-Butoxycarbonyl)-4-(2,6-Diptera-4-nitrophenyl)- piperazine (44,7 g, 130 mm) was dissolved in 20% THF/MeOH (600 ml) in a 2-liter flask. Then portions to the mixture was added format ammonium (41 g, 651 mm), after which was added 10% palladium on carbon (1.12 g, 2.5 wt.%), cooling on an ice bath. When you are finished adding bath was removed. The contents of the flask was gently heated, resulting in a yellow color disappeared. The completion of the reaction was controlled by TLC (30% EtOAc/hexane, short-wave UV) for 1.5 hours then the reaction mixture was filtered through celite and the filter cake was washed with 500 ml MeOH. The filtrate was concentrated under reduced pressure and obtained solid substance was treated with 1 l of EtOAc and 500 ml of water. The layers were separated, and the organic layer was washed with water (500 ml) and brine (500 ml). The aqueous portion was subjected to reverse extraction with additional EtOAc (g ml). The combined organic extracts were dried with anhydrous sodium sulfate, filtered and concentrated to obtain yellow solid (40,8 g), which was immediately dissolved in dry DMF (500 ml) and cooled to -20oC (in the drops was added benzylchloride (21,5 ml, 143 mm). The ice bath was left to melt over night. The completion of the reaction was controlled by TLC (30% EtOAc/hexa, short-wave UV). The mixture was concentrated to obtain a yellow oily substance, which was dissolved in 1 l of EtOAc and washed with 500 ml of saline solution. The water portion was subjected to back extraction with additional EtOAc (2x 300 ml). The combined organic extracts were dried with anhydrous sodium sulfate, filtered and concentrated to obtain a yellow solid. This crude material was recrystallized from hot EtOAc/hexane and obtained 39,11 g (67%) of target compound as a pale yellow crystalline solid, so pl. 171-172oC.

(d) [3-[3,5-Diptera-4-[4-(tert-butoxycarbonyl)-1-piperazinil] phenyl]-2-oxo-5-oxazolidinyl]methanol.

1-(tert-Butoxycarbonyl)-4-[2,6-Diptera-4-(benzyloxycarbonyl)AMINOPHENYL]piperazine (14,05 g, 31 mm) was dissolved in anhydrous THF (158 ml), and then was cooled to -78oC (in a bath of dry ice/acetone). After that the reaction mixture drop by drop in the course of 25 min was added n-utility (to 21.6 ml, 35 mm). This reaction mixture was left for 30 min stirring at -78oC, then drop by drop in for 7 min donadelli, and slowly heated the mixture to room temperature over night. The completion of the reaction was controlled by TLC (5% MeOH/CHCl3long wave UV). The resulting reaction mixture was diluted with 500 ml of methylene chloride, and then washed with water (HH ml) and brine (300 ml). The aqueous portion was subjected to back extraction with additional CH2Cl2(3x400 ml). The combined organic extracts were dried with sodium sulfate, filtered and concentrated, which formed a creamy yellow solid. This crude substance was purified by recrystallization from hot EtOAc/hexane, and received 11,063 g (85%) of target compound in the form of a white solid substance, so pl. 164-166oC.

(e) [[3-[3,5-Diptera-4-[4-(tert-butoxycarbonyl)-1-piperazinil]phenyl]-2-oxo-5 - oxazolidinyl]methyl]-p-toluensulfonate.

[[3-3,5-Diptera-4-[4-(tert-butoxycarbonyl)-1-piperazinil] phenyl] -2-oxo-5-oxazolidinyl]methanol (24.2 g, 59 mm) was dissolved in pyridine (110 ml), and then was cooled to 0oC in an ice bath. After this was added just recrystallized p-toluensulfonate (13,4 g, 70 mm), and the reaction mixture was left for 2.5 h stirring at 0oC in the atmosphere and the time, the reaction mixture became a pale pink suspension. TLC revealed the presence of a certain amount of alcohol. After that, the mixture was treated with another of 1.12 g of p-toluensulfonate (5,85 mm), catalytic amount of 4-(dimethylamino)pyridine and 20 ml of anhydrous methylene chloride in order to facilitate the mixing. After keeping the mixture for 4 h at 0oC the reaction was completed, as evidenced by TLC (5% MeOH/CH2Cl3long wave UV). Then to the mixture was added 750 ml of ice water and the precipitated product was isolated by vacuum filtration, rinsing 1 l of water and 500 ml of ether. After drying the product in vacuo received 29,921 g (yield 90%) of target compound in the form of a white solid substance, so pl. 150,5-151,5oC.

(f) [[3-[3,5-Diptera-4-[4-(tert-butoxycarbonyl)-1-piperazinil] -2-oxo-5 - oxazolidinyl]methyl]methanesulfonate.

[3-[3,5-Diptera-4-[4-(tert-butoxycarbonyl)-1-piperazinil] phenyl] -2-oxo-5-oxazolidinyl methanol (3,831 g, 9,27 mm) was dissolved in methylene chloride (40 ml), cooled to 0oC, and then treated with triethylamine (1,74 g, 2.4 ml, 17,22 mm) under nitrogen atmosphere. Then within one minute was slowly added methanesulfonamide (1.48 g, 1 ml, 12.9 mm). After half an hour, TLC analysis (2) - Rev. ohms (200 ml), washed with water (I ml) and brine (50 ml), then dried with sodium sulfate, filtered and concentrated in vacuo, resulting in a received target compound in the form of a whitish solid product, VRMS (M+for C20H27F2N3O7S: calculated: 4911538 found:4911543.

(g) [[3-[3,5-Diptera-4-[4-(tert-butoxycarbonyl)-1-piperazinil]phenyl]-2-oxo-5-oxazolidinyl]methyl]azide.

[3-[3,5-Diptera-4-[4-(tert-butoxycarbonyl)-1-piperazinil] phenyl] -2-oxo-5-oxazolidinyl] methyl] -p-toluensulfonate (29,661 g, 52 mm) was dissolved in dry DMF (125 ml) and then treated solid NaN3(10,19 g, 156 mm) at room temperature. Then the reaction mixture was heated to 60oC for 3 h and left to cool to room temperature overnight under nitrogen atmosphere. The completion of the reaction was controlled by TLC (30% EtOAc/hexane; two run; short-wave UV). This reaction mixture was concentrated in vacuum and received a creamy discolored solid. This crude product was dissolved in 600 ml of EtOAc, and then washed with water (2x500 stretch-forming press ml) and brine (500 ml). Water fraction was subjected to reverse the extraction of additional EtOAc (h resulting received 22,41 g (91%) of target compound as a pale yellow solid, so pl. 115-117oC.

Using mostly identical conditions, the corresponding mesilate turned in the same azide.

(h) N-[[3-[3,5-Diptera-4-[4-(tert-butoxycarbonyl)-1-piperazinil]phenyl] -2-oxo-5-oxazolidinyl methyl ndimethylacetamide.

[[3-[3,5-Diptera-4-[4-(tert-butoxycarbonyl)-1-piperazinil]phenyl]- 2-oxo-5-oxazolidinyl] methyl]azide (22,4 g, 51 mm) was dissolved in 1 l of ethyl acetate, and then three times was degirolami nitrogen. After this was added 10% palladium charcoal (4,48 g, 20% by weight), and the solution again three times was degirolami nitrogen, then the nitrogen was replaced with hydrogen (balloon). After 3 h the completion of the reaction was controlled by TLC (20% MeOH/CHCl3long wave UV). Then was added pyridine (compared to 8.26 ml, 102 mm), after which the mixture was treated with acetic anhydride (for 9.64 ml, 102 mm). The resulting reaction mixture was left over night at room temperature for mixing. The completion of the reaction was monitored using thin layer chromatography (20% MeOH/CHCl3, short-wave UV radiation). Then the reaction mixture was filtered through celite, and the filter residue was washed with 500 ml of ethyl acetate. The filtrate was concentrated to a final volume of approximately 600 ml, and then washed amount of ethyl acetate (2x500 stretch-forming press ml). The combined organic extracts were dried with anhydrous sodium sulfate, filtered and concentrated to obtain a yellow solid. This crude product is recrystallized from hot CHCl3and hexane, resulting in received 19,167 g (83%) of target compound in the form of a white solid product, so pl. 177-179oC.

(i) N-[[3-[3,5-Diptera-4-(1-piperazinil)phenyl] -2-oxo-5-oxazolidinyl] methyl] ndimethylacetamide.

N-[[3-[3,5-Diptera-4-[4-(tert-butoxycarbonyl)-1-piperazinil] phenyl]-2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide (1,00 g, 2,20 mm) was dissolved in methylene chloride (6 ml) and cooled to 0oC in an ice bath. After adding 20 ml triperoxonane acid cooling bath was removed and the reaction mixture was left to warm to room temperature for 1 h then the reaction mixture was concentrated in vacuo and the resulting residue was dissolved in water (15 ml). The resulting solution was added to ion-exchange resin AG-I-X8 (Bio Pad) (12 ml; OH-form; washed with water until neutralization). After addition of 5 ml water the mixture was stirred for 10 minutes Then the mixture was filtered and the resin washed with additional water (3x5 ml). This aqueous filtrate was lioresalbuy and received 0,559 g (72%) of the target issue for lighting the 1-piperidinyl)ethyl] -1-piperazinil] phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide.

A mixture of (S)-N-[[3-[3,5-Diptera-4-(1-piperazinil)phenyl] - 2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide (0,200 g of 0.565 mm), monohydrochloride 1-(2-chloroethyl)piperidine (0.125 g, 0,678 mm) and potassium carbonate (0,478 g, 3,39 mm) in acetonitrile (10 ml) was heated under reflux for one and a half hours. The resulting reaction mixture was cooled to room temperature and concentrated in vacuum. The resulting residue triturated with dichloromethane, the solid was filtered, and the filtrate was concentrated in vacuo, resulting in a received whitish solid (0,248 g). This crude material was chromatographically on silica gel (5 g), elwira 5% methanol/chloroform, and then 10% methanol/chloroform. After concentration of appropriate fractions were obtained 0,137 g (52%) of target compound in the form of a whitish solid, so pl. 198-200oC.

Example 33. (S)-N-[[3-[3-fluorescent-4-[4-[2-(1-piperidinyl)ethyl]-1-piperidinyl)ethyl]-1 - piperazinil]phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide

A mixture of (S)-N-[[3-[3-fluorescent-4-(1-piperazinil)phenyl]-2-oxo-5-oxazolidinyl] methyl] ndimethylacetamide (0,200 g, 0,595 mm), monohydrochloride 1-(2-chloroethyl)piperidine (0,131 g, 0,714 mm) and potassium carbonate (0,493 g, 3,57 mm) in acetonitrile (12 ml) was heated from the reverse was holocentridae in vacuum. The solids were filtered off and the filtrate was concentrated in vacuo to obtain the crude product (0,308 g). This crude material was chromatographically on 5 g of silica gel, elwira 5% methanol/chloroform, and then 10% methanol/chloroform. After concentration of appropriate fractions were obtained 0,192 g (72%) of target compound in the form of a whitish solid, so pl. 169-170oC.

Example 34. (S)-N-[[3-[3-fluorescent-4-[4-[2-(4-morpholinyl)ethyl]-1-piperazinil] phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide.

A mixture of (S)-N-[[3-[3-fluorescent-4-(1-piperazinil)phenyl]-2-oxo-5-oxazolidinyl] methyl] ndimethylacetamide (0,200 g, 0,595 mm), hydrochloride 4-(2-chloroethyl)of the research (of 0.133 g, 0,714 mm) and potassium carbonate (0,493 g, 3,57 mm) in acetonitrile (12 ml) was heated under reflux for one hour. The resulting reaction mixture was cooled to room temperature and concentrated in vacuum. The residue is triturated with dichloromethane, the solid was filtered, and the filtrate was concentrated in vacuum to obtain resin amber (0,201 g). This crude material was chromatographically on silica gel (5 g), elwira 5% methanol/chloroform, and then 10% methanol/chloroform. After concentration of the appropriate coat the Sample 35. (S)-N-[[3-[4-[2-(diethylamino)ethyl]-1-piperazinil]-3-forefeel]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide.

A mixture of (S)-N-[[3-[3-fluorescent-4-(1-piperazinil)phenyl]-2-oxo-5-oxazolidinyl] methyl] ndimethylacetamide (0,200 g, 0,595 mm), hydrochloride 2-diethylaminoethylamine (0,123 g, 0,714 mm) and potassium carbonate (0,493 g, 3,57 mm) in acetonitrile (12 ml) was heated under reflux for one hour. The resulting reaction mixture was cooled to room temperature and concentrated in vacuum. The resulting residue triturated with dichloromethane, the solid was filtered, and the filtrate was concentrated in vacuum to obtain 0,241 g whitish resinous solids. This crude material was chromatographically on silica gel (5 g), elwira 5% methanol/chloroform, and then 10% methanol/chloroform. After concentration of appropriate fractions were received strength of 0.159 g (61%) of target compound in the form of a whitish solid, so pl. 131-133oC.

Example 36. (S)-N-[[3-[3-fluorescent-4-[4-(2-methoxyethyl)-1-piperazinil]phenyl] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide.

A mixture of (S)-N-[[3-[3-fluorescent-4-(1-piperazinil)phenyl]-2-oxo-5-oxazolidinyl] methyl] ndimethylacetamide (0,450 g of 1.34 mm), 2-chloroethylnitrosourea ether (1,220 ml, 13,40 mm) and potassium carbonate (1,110 land only g 8,04 gave to room temperature and concentrated in vacuum. The resulting residue triturated with dichloromethane, the solid was filtered, and the filtrate was concentrated in vacuum to obtain a yellow foamy solid (0,326 g). This crude material was chromatographically on silica gel (25 g), elwira 1% methanol/chloroform, 3% methanol/chloroform and then with 5% methanol/chloroform. After concentration of appropriate fractions were obtained 0,296 g (56%) of target compound in the form of a whitish solid, so pl. 144,5-146oC.

Example 37. (S)-N-[[3-[3,5-Diptera-4-[4-(2-methoxyethyl)-1-piperazinil] phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide.

A solution of (S)-N-[[3-[3,5-Diptera-4-[4-(tert-butoxycarbonyl)-1-piperazinil] phenyl] -2-oxo-5-oxazolidinyl] methyl] ndimethylacetamide (0,200 g, 0,441 mm) in dichloromethane (1 ml) was treated triperoxonane acid (4 ml) at room temperature for one hour. The reaction mixture was concentrated in vacuo and the resulting residue was combined with 2-chloroethylamino ether (403 μl, to 4.41 mm), potassium carbonate (at 0.730 g, 5,28 mm) and acetonitrile (9 ml) and the resulting mixture was heated under reflux for 15 hours, the Reaction mixture was cooled to room temperature and concentrated in vacuum. The residue is triturated with d the th product. This crude material was chromatographically on silica gel (10 g), elwira 1% methanol/chloroform, 3% methanol/chloroform and then with 5% methanol/chloroform. After concentration of appropriate fractions were obtained 0,097 g (53%) of target compound in the form of a whitish solid, so pl. 162-164oC.

Example 38. (S)-N-[[3-[3-fluorescent-4-[4-(3-hydroxypropyl)-1-piperazinil]phenyl]-2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide.

A mixture of (S)-N-[[3-[3-fluorescent-4-(1-piperazinil)phenyl] -2-oxo-5 - oxazolidinyl] methyl] ndimethylacetamide (0,200 g, 0,595 mm) 3-chloro-1-propanol (299 μl, 3,57 mm) and potassium carbonate (0,493 g, 3,57 mm) in acetonitrile (12 ml) was heated under reflux for 7 hours, the Reaction mixture was cooled to room temperature and concentrated in vacuum. The crude material was dissolved in 10% methanol/chloroform and adsorbing on a layer of silica gel (2 g). The resulting residue was chromatographically on 10 g of silica gel, elwira 1% methanol/chloroform, 3% methanol/chloroform, and then 6% methanol/chloroform. After concentration of appropriate fractions were obtained 0,096 g (41%) of target compound in the form of a white solid substance, so pl. 154-155,5oC.

Example 39. (S)-N-[[3-[3,5-Diptera-the Oro-4-[4-(tert-butoxycarbonyl)-1-piperazinil] phenyl] -2-oxo-5-oxazolidinyl] methyl] ndimethylacetamide (0.400 g, 0,881 mm) in dichloromethane (3 ml) at room temperature and within hours was treated with 7 ml triperoxonane acid. The resulting reaction mixture was concentrated in vacuo, and the resulting syrup amber color was combined with 2-chloroethanol (354 μl, 5,27 mm), potassium carbonate (at 0.730 g, 5,27 mm) and acetonitrile (20 ml). The resulting mixture was heated under reflux for 24 hours then the mixture was cooled to room temperature and concentrated in vacuum. The resulting crude product was chromatographically on silica gel (10 g), elwira 1% methanol/chloroform, 3% methanol/chloroform, and then 6% methanol/chloroform. After concentration of appropriate fractions were obtained 0,067 g (yield 19%) of target compound in the form of a whitish solid, so pl. 172 and 174oC.

Example 40. (S)-N-[[3-[3-fluorescent-4-[4-[3-(4-morpholinyl)-1-oxopropyl]-1-piperazinil]phenyl]-2-oxo-5-oxazolidinyl]-methyl] ndimethylacetamide.

3-(4-Morpholinyl)propionic acid (0,600 g, 2,11 mm), obtained by condensation of the research with acrylate (3 equivalent) in boiling ethanol, and then by distillation, saponification (1 N. aqueous sodium hydroxide solution; boiling tetrahydrofuran), neutralization (1 N. HCl) and lyophilization, abberational)phenyl] -2-oxo-5-oxazolidinyl]-methyl]ndimethylacetamide (0,354 g, 1,05 mm) and tetrahydrofuran/dichloromethane (1:1) (50 ml) at room temperature. After 3 days the reaction mixture was filtered to remove the precipitated 1,3-dicyclohexylamine, and the filtrate was concentrated in vacuum. The crude product was chromatographically on silica gel (20 g), elwira gradient 1-6% methanol/chloroform, resulting in received 0,446 g (95%) of target compound in the form of a white solid substance, so pl. 209-210oC.

1. Derived oxazolidinone formula I

< / BR>
or its pharmaceutically acceptable salt, where n 1;

ring And represents pieperazinove ring;

Y-C1-6-alkyl;

-C(O)-C1-6-alkyl; -C(O)-O-C1-6-alkyl; benzoyl, 2-benzyloxycarbonyl; 1,4-dioxaphetyl; -N(C1-4-alkyl)2piperidyl, morpholinyl, a group of the formula

< / BR>
< / BR>
X and Z independently1-6is alkyl or hydrogen,

moreover, in each case specified WITH1-6the alkyl may be substituted by one or more substituents selected from F, Cl, Br, CN or or1where R1hydrogen or C1-4-alkyl;

U, V and W are independently fluorine or hydrogen;

R ness is 1, where U and V fluorine, and W is hydrogen.

4. Connection on p. 1, where U fluorine, and V and W are hydrogen.

5. Connection on p. 1, where Y is chosen from the group comprising methyl, ethyl, isopropyl, tert-butyl, acetyl, divercity, hydroxyacetic, benzoyl, methoxycarbonyl, etoxycarbonyl, 2-chlorocarbons, 2-hydroxyethoxymethyl, 2-benzyloxycarbonyl, 2-methoxyethoxymethyl, 2,2,2-cryptgetuserkey, cyanomethyl, 2-cyanoethyl, 2-forecasterror, tert-butoxycarbonyl.

6. Connection on p. 4, where Y methoxycarbonyl or cyanomethyl.

7. Connection on p. 1, where R is methyl.

8. Connection on p. 1, in which the optically pure enantiomer has the S-configuration at C5-oxazolidinone rings.

9. Connection on p. 1, where n 1.

10. Connection on p. 1, which are:

(and) 4-(4-(5-((acetylamino)methyl) -2-oxo-3-oxazolidinyl)-2-forfinal)-1-piperazinecarboxamide acid methyl ester;

(b) 4-(4-(5-((acetylamino)methyl)- 2-oxo-3-oxazolidinyl)-2-forfinal)-1-piperazinecarboxamide acid ethyl ester;

() 4-(4-(5-((acetylamino)methyl)- 2-oxo-3-oxazolidinyl)phenyl)-1-piperazinecarboxamide acid methyl ester;

(d) N-((2-oxo-3-(4-(phenylcarbamoyl) -CSR-5-oxazolidinyl)methyl)ndimethylacetamide;

(f) N-((3-(4-(3-fluoro-4-(4-(2 - hydroxyethyl)carbonyl-1 - piperazinil))phenyl)-2-oxo-5-oxazolidinyl)methyl)ndimethylacetamide;

(g) N-((3-(4-(3-fluoro-4-((phenylcarbamoyl)-1-piperazinil))phenyl)-2 - oxo-5-oxazolidinyl)methyl)ndimethylacetamide;

(h) 4-[4-[5-[(acetylamino)methyl] -2-oxo-3-oxazolidinyl] -2-forfinal] -1-piperazinecarboxamide acid 2-methoxyethylamine esters;

(i) 4-[4-[5-(acetylamino)methyl]-2 - oxo-3-oxazolidinyl]-2-forfinal]-1-piperazineethanol;

(j) ()-N-[[3-[4-[4-(1,4-dioxaphetyl)-1-piperazinil]-3-forfinal] -2-oxo-5-oxazolidinyl]methyl]ndimethylacetamide;

(k) (S)-N-[[3-[3-fluoro-4-[4-(2-methoxyethyl)-1-piperazinil] phenyl] -2-oxo-5 - oxazolidinyl]methyl]ndimethylacetamide or

(l) (S)-N-[[3-[3,5-debtor-4-[4-(2-methoxyethyl)-1-piperazinil] phenyl]-2 - oxo-5-oxazolidinyl]methyl]ndimethylacetamide.

11. The compound according to any one of paragraphs.1 to 10 as an active start when getting medicines for the treatment of microbial infections.

12. A method of treating microbial infections in warm-blooded animals which consists in the fact that the specified warm-blooded animal in need of such treatment, injected from 0.1 to 100 mg/kg of body weight per day of the compounds of formula I, as defined in paragraph 1.

13. The method according to p. 12, in which the indicated compound is administered in a quantity amounting

 

Same patents:

The invention relates to a derivative of pyrazine, which has antagonistic activity relative to the glutamate receptor, represented by the formula:

< / BR>
in which Z represents C or N, provided that two Z are nitrogen atoms; R1is:

< / BR>
in whichisor, R6represents H or alkyl, and R7and R8are each H, alkyl, nitro or phenyl, or alternatively, R7and R8taken together, represent butadiene or 1,4-butylene; R2and R3are each H, F, cyano, acyl, nitro, alkyl, morpholino or one of the above definitions for R1; R4and R5are each H, hydroxyl, alkyl, cycloalkyl, heterocycle, phenyl, or Y-substituted alkyl; Y represents a hydroxyl, acyloxy, F - substituted methyl, cycloalkyl, tetrahydrofuranyl, carboxyl, alkoxycarbonyl or

The invention relates to the field of chemistry of biologically active substances, which may have application in medicine

The invention relates to new, therapeutically valuable derivative tetrazole, method of their production and their use

The invention relates to a new alkylenediamine derivative, a method for obtaining and drug treatment for dysuria containing the specified new alkylenediamine derivative or its pharmaceutically acceptable salt as an active ingredient

The invention relates to new oxazolidone derivative having the formula:

to their pharmaceutically acceptable additive salts, and stereochemical isomeric forms, where a1AND2AND3AND4is a bivalent radical having the formula

-CH CH-CH CH- (a-1),

-N CH-CH CH- (a-2)

-CH N-CH CH- (a-3)

-CH CH-N CH- (a-4),

-CH CH-CH N- (a-5),

-N CH-N CH- (a-6) or

-CH N-CH N- (a-7), where one or two hydrogen atoms in said radicals (a-1) to(a-7) can be independently substituted by a halogen atom, a C1-C6-alkyl, C1-C6-alkyloxy, hydroxy, or trifluoromethyl; R represents hydrogen or C1-C4-alkyl; R1represents hydrogen, C1-C6-alkyl or hydroxy WITH1-C6-alkyl;

m is 1 or 2;

represents a C1-C4-alcander; B is an R2CH2, O, SO or SO2where R2is hydrogen or C1-4-alkyl;

n is 0, 1 or 2;

L represents hydrogen; C1-2-alkyl; C3-6-cycloalkyl; C3-C6alkenyl, optionally substituted by aryl; C1-C6-alkylsulphonyl; C1-C6-алкилоксикBR>
-Alк-Y-R4(o-2);

-Alк-Z1-C X-2-R5(o-3); or

-CH2-CHOH-CH2-O-R6(o-4); where R3represents cyano, aryl or Het; R4represents hydrogen, aryl, Het, or1-C6-alkyl, optionally substituted aryl or Het; R5represents hydrogen, aryl, Het or1-C6-alkyl, optionally substituted aryl or Het; R6represents aryl or naphthalenyl; Y represents O, S, NR7where R7is hydrogen, C1-C6-alkyl or C1-C6-alkylcarboxylic;

Z1and Z2each independently represents O, S, NR8or a simple link, where R8is hydrogen or C1-C6-alkyl; X represents O, S or NR9where R9is hydrogen, C1-C6-alkyl or cyano; Alк each independently is a C1-C6-Alcantara; each Het represents: (i) optionally substituted heterocyclic ring with 5 or 6 members containing 1, 2, 3 or 4 heteroatoms selected from oxygen, sulfur and nitrogen, provided that there is not more than 2 oxygen atoms and/or sulfur; (ii) optionally substituted heterocyclic ring with 5 or 6 members which of substituted five - or six-membered ring through 2 carbon atoms or 1 nitrogen atom; and that in the rest of the condensed ring contains only carbon atoms; (iii) optionally substituted heterocyclic ring with 5 or 6 members, which contains 1 or 2 heteroatoms selected from oxygen atoms, sulfur and nitrogen, and optionally substituted five - or six-membered ring through 2 carbon atoms or 1 carbon atoms and 1 nitrogen atom; and which in the rest of the condensed ring contains 1 or 2 heteroatoms selected from oxygen atoms, sulfur and nitrogen; and, if Het is a monocyclic ring system, it is not necessary to have up to 4 substituents; and if Het is a bicyclic ring system, it may not necessarily be up to 6 substituents, which are selected from halogen, amino, mono - and di(C1-C6-alkyl)amino, aryl WITH1-C6-amino, nitro, cyano, aminocarbonyl,1-C6-alkyl, C1-C6alkyloxy,1-C6-alkylthio,1-C6-allyloxycarbonyl,1-6-alkyloxy-FROM1-6-alkyl, C1-6-allyloxycarbonyl1-6-alkyl, hydroxy, mercapto, hydroxy1-C6-alkyl, C1-C6-alkylcarboxylic aryl, Rilc1-C6-alkylamino is whether 3 substituents, each of which is independently selected from halogen, hydroxy, nitro, cyano, trifloromethyl,1-C6-alkyl, C1-C6-alkyloxy,1-C6-alkylthio, mercapto, amino, mono - and di-(C1-C6-alkyl)amino, carboxyl,1-6-allyloxycarbonyl, and C1-C6-alkylcarboxylic

The invention relates to new derivatives of 3(2H)-pyridazinone and to their pharmaceutically acceptable salts, possessing inhibitory activity against the aggregation of platelets, cardiotonic activity, vasodilating activity, anti-SRS-A activity, to processes for their preparation and to pharmaceutical compositions containing them as active ingredient

The invention relates to a compact, crystalline 3-cyan - 2-morpholino-5-(pyrid-4-yl)-pyridine with high apparent (bulk) density and method thereof

The invention relates to heterocyclic compounds having excellent pharmacological properties, and to intermediate compounds used for the synthesis of these compounds

The invention relates to a neuroprotective (anti-ischemic and excited by blocking amino acid receptor) analogues 5-(1-hydroxy-2-piperidinophenyl)-2-(1H, 3H)-indole-defined formula (I), (II) and (III) below; their pharmaceutically acceptable salts; method of using these compounds in the treatment of stroke, traumatic brain injury or degenerative diseases of the CNS (Central nervous system), such as disease Alzheimer, senile dementia Alzheimers.com type, Huntington's disease and Parkinson's disease; and some of their intermediates

The invention relates to a new derivative of uracil with herbicide action

Derivative oxazole // 2032677
The invention relates to heterocyclic carbon compounds that have medicinal and biosdecode properties and to their preparation and use

The invention relates to new biologically active chemical compounds, in particular to cyclic amino compounds of the formula I

BANwhere In - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner (lower) accelgroup, phenylketone (lower) alkyl group, phenylcarbamoyl (lower) alkyl group or phenyl (lower) alkyl group, each of which may be substituted by a halogen atom or a lower alkoxygroup; p is 1 or 2; And -- is a bond, or two-, or trivalent aliphatic C1-6hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino or hydroxy-group;means either simple or double bond, provided that when a represents a bond, thenmeans of a simple bond; R2and R3independent means ATO condition, both R2and R3are not hydrogen atoms, or R2and R3together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine, pieperazinove or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl (lower) alkyl group, a lower alkylcarboxylic group or diphenyl (lower) alkyl group or a physiologically acceptable salt additive acid

The invention relates to a new alkylenediamine derivative, a method for obtaining and drug treatment for dysuria containing the specified new alkylenediamine derivative or its pharmaceutically acceptable salt as an active ingredient

The invention relates to a new use some diphenylmethyl-piperazinecarboxamide, in particular amperozide, 4 [4,4-bis(forfinal)butyl] N-ethyl-1-piperazinecarboxamide and their salts in the treatment of substance abuse

The invention relates to pharmaceutical industry concerns (l)-(-)-2(aminocarbonyl)-N-(4-amino-2,6-dichlorophenyl) -4-[5,6-bis(4-forfinal)pentyl]-1-piperazineethanol, its pharmaceutically acceptable acid additive salt or hydrate and method of its production
Up!