Derivatives of thiazolidinone or oxazolidinone and method of production thereof

 

(57) Abstract:

Usage: in heterocyclic chemistry, in particular in methods for obtaining derivatives of thiazolidinone or oxazolidinone with vasodilatory activity. The inventive product is the compounds of formula I, where W is sulfur or oxygen, and X is the group NR1or W is a group NR1and X is sulfur or oxygen; R1is hydrogen or C1-C6-alkyl; R2and R3- equal or different is hydrogen, C1-C6-alkyl, phenyl (possibly substituted by a nitro-group, chlorine or C1-C6-alkoxy), thienyl, furyl, pyridyl, naphthyl or benzyl; R4- C1-C4-alkyl or hydrogen; And - C2-C6-standards-or ISO-alkylen. Reagent 1: compound of formula II or its reactive compound. Reagent 2: compound of formula III where Z is hydrogen or a nitro-group, and when Z is hydrogen, the nitration of compounds of formula IV have the compound of formula I. the structure of the compounds of formulas I - IV listed in the description. 2 S. and 9 C. p. F.-ly.

The invention relates to a series of new derivatives of thiazolidinone and oxazolidinone containing nitroacetanilide group, and to methods of producing these compounds may find use of these compounds as vasodilators, e.g. the iroko common and are an increasing cause of death and disability worldwide, therefore expended great efforts in the search for drugs that can treat or prevent such diseases.

Nitroglycerin belongs to often and for many years used drugs for the treatment of cardiovascular diseases such as angina. However, this connection has some drawbacks when it is used as medicine. For example, the connection is easily deactivated in the liver (first pass effect) and the duration of its effect is very small. Moreover, the drug sometimes causes unwanted reactions, such as headache, dizziness, and tachycardia because of lowering them in a patient's blood pressure. Thus, for many years, there is a need in the opening protivorevmaticakih drugs with duration, but does not create the problem of the effect of the first pass.

Closest to the invention are compounds (U.S. patent N 4200640), including N-(2-nitroxyethyl)-3-pyridinecarboxamide, which, as indicated, has activity as coronary vasodilator.

Proposed connection similar to the connection of the prototype that have nitroacetanilide group, but they are those who completely and because they have minor unwanted side effects, it can be expected that the compounds will find use for the treatment and prevention of cardiovascular disorders or cardiovascular disease, such as angina.

The purpose of the invention is the creation of some new derivatives of thiazolidinone and oxazolidinones with nitroacetanilide group.

The purpose of the invention lies in the creation of these compounds with vasodilatory activity.

The present compounds include the compounds of formula

O

(I) where W represents a sulfur atom or oxygen and X represents a group of formula-N(R1)-, or W represents a group of formula-N(R1) and X represents a sulfur atom or oxygen,

R1represents a hydrogen atom, alkyl with 1-6 carbon atoms,

R2and R3the same or different and each represents a hydrogen atom,

alkyl with 1-6 carbon atoms,

phenyl, optionally substituted by a nitro-group, a chlorine atom or WITH1-C6alkoxy group, thienyl, furyl, pyridyl, naphthyl or benzyl,

R4represents a hydrogen atom or alkyl with 1-6 carbon atoms,

A represents alkylene with 2-6 carbon atoms in a straight or branched carbon capili cardiovascular insufficiency in the form of a composition with a pharmaceutically acceptable carrier or diluent.

Method for the treatment or prevention of cardiovascular disorders or cardiovascular disease is the introduction of at least one coronary vasodilator a mammal such as a human, suffering from or susceptible to cardiovascular disorders or cardiovascular disease, and coronary vasodilator selected from the group comprising the compounds of formula (I).

The proposed compounds are derivatives of either of thiazolidinone or oxazolidinone, and nitroxyethyl-carnemolla group may be in either the 4-Ohm position (W represents an oxygen atom or sulfur and X represents a group of formula-N(R1)- or in the 5th position (W represents a group of formula-N(R1)- and X is oxygen atom or sulfur), and such compounds can be represented respectively by the formulas:

O

(Ia)

O

(Ib) where A, R1, R2, R3and R4take the above meanings and X1represents an oxygen atom or sulfur.

In the proposed compounds, alkyl with 1-6 carbon atoms may be a group of normal or isotrate with 1-6 carbon atoms. Examples of such groups include methyl, ethyl, propyl, isopropyl who, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexyl and isohexyl, recommended alkali with 1-4 carbon atoms. More preferably, if R1, R2, R3, R4the same or different and each represents alkyl with 1 or 2 carbon atoms, most preferably methyl.

If a represents alkylene, it can be a group of normal or ISO-structure with 2-6 carbon atoms. Examples of such groups include ethylene, propylene, trimethylene, tetramethylene, pentamethylene and hexamethylene, of which more preferred alkylene with 2-4 carbon atoms, and most preferred ethylene. Such alkylene can be unsubstituted or can be substituted by at least one and preferably only one carboxypropyl.

The proposed compounds contain in their molecule several asymmetric carbon atoms at least in the heterocycle, which can form optical isomers. Although they are all represented by a single molecular formula, however, the invention includes in a separate, isolated isomers and mixtures, FL optically active compounds can be obtained directly separate the isomers, on the other hand, upon receipt of a mixture of isomers of the individual isomers can be obtained by using conventional separation techniques.

The proposed compound can be obtained in a variety of ways, widely used for producing compounds of this type. For example, in General they can be obtained by reaction of compounds of formula

O

(II) in which W, X, R2and R3take the above values, or its active derivative with the compound of the formula

HA-OZ (III) in which R4and And agree to the above meanings and Z represents a hydrogen atom or a nitro-group, with the formation of the compounds of formula

O

(IV) in which W, X, R2, R3, R4A and Z agree to the above values, and, if Z represents hydrogen, by nitration of compounds of formula (IV) with the formation of the compounds of formula (I).

In more detail the receipt of the proposed compounds is illustrated by the following schemes of reactions a and b:

The reaction scheme A:

O + HA

O (I)

The reaction scheme:

O + H

O O

In the above formulas, W, X, R2, R3, R4and And agree to the above values.

On stage A1 shows the scheme of the reaction of the compound of formula is (IVa). Reactive derivative may be represented, for example by halogenerator acid, mixed acid anhydride or activated ester, acid, or the reaction can be carried out with the use of free acid in the presence of a condensing means.

When using galodamadruga the compounds of formula (II) (a way of using galodamadruga acid) compound of formula (II) are initially introduced into a reaction with palodiruyut agent (e.g. thionyl chloride or with phosphorus pentachloride) with the formation of galodamadruga acid, which is then injected into the reaction with the compound of the formula (IIIa). The reaction can be carried out in the presence or absence of a base.

Special restrictions regarding the nature of the employed are no grounds under the condition that the substrate does not adversely affect the reactants. Examples of bases for use may include organic amines such as triethylamine, N-methylmorpholine, pyridine or 4-dimethylaminopyridine, bicarbonates of alkali metals such as sodium bicarbonate or sodium bicarbonate and carbonates of alkali metals such as sodium carbonate or carbonate. Of the enumerated grounds re is Italia. Special restrictions on the nature of the employed solvent there is no subject that does not adversely affect the course of the reaction or on the reagents and capable at least to some extent, to dissolve the reagents. Examples of acceptable solvents include hydrocarbons, which can be aliphatic, cycloaliphatic or aromatic, such as hexane, cyclohexane, benzene, toluene or xylene, halogenated hydrocarbons, preferably halogenated aliphatic hydrocarbons, such as methylene chloride, 1,2-dichloroethane or carbon tetrachloride, ethers, such as diethyl ether, tetrahydrofuran or dioxane, ketones, such as acetone, amides, especially amides of fatty acids, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or triamide hexamethylphosphoric acid and sulfoxidov, such as dimethylsulfoxide. Of the following solvents are recommended hydrocarbons, halogenated hydrocarbons, ethers, and amides.

The above reaction can proceed in a wide temperature range. It is convenient to conduct the reaction in the temperature range from -20 to 150aboutAs for the reaction of compounds of formula (IV) with palodiruyut means the compounds of the formula (II) with palodiruyut means is carried out at a temperature of -10 to 50aboutC, and the reaction of the compound of formula (IIIa) with halogenerator acid at a temperature of 0-100aboutC. the Time required for completion of the reaction, also vary widely depending on many factors, such as the reaction temperature, the nature of the reagents and solvent. However, if the reaction is carried out in accordance with the terms above to complete each reaction is usually sufficient period of 15 min to 24 h, more preferably from 30 min to 16 h

The method using mixed acid anhydride may be carried out by reaction of the compound of formula (II) with alkylaminocarbonyl (in which the alkyl has 1-4 carbon atoms), dialkylanilines (in which each alkyl has 1-4 carbon atoms) or diarylheptanoids (in which each aryl takes the values specified above in connection with the definition of R2and R3) with the formation of the mixed anhydride of the acid, which is then injected into the reaction with the compound of the formula (IIIa).

Getting mixed acid anhydride may be carried out by reaction of the compound of formula (II) with alkylaminocarbonyl, such as ethylchloride or isobutylparaben, dialkylanilines, such as dimethylsulfate Yazid or disatisfaction. The reaction recommend in an inert solvent and preferably in the presence of a base.

Special restrictions concerning the nature used in this reaction grounds of inert solvents, and they are similar to those as described above can be used in method with the use of galodamadruga acid.

The reaction may proceed in a wide temperature range. In General, it is convenient to conduct the reaction in the range of -20 to 50aboutC, more preferably at 0-30aboutC. the Time required for completion of the reaction may also vary widely, depending on many factors, mainly on the reaction temperature, the nature of the reagents and solvent. However, with the reaction in the recommended conditions for completion of the reaction enough period of from 15 minutes to 25 hours, more preferably from 30 min to 16 h

The reaction of the compound of formula (IIIa) with the obtained mixed acid anhydride recommended in an inert solvent and it can be carried out in the presence or absence of a base. Any restrictions concerning the nature of the grounds of inert solvents that can be used in deem of galodamadruga acid.

The reaction may proceed in a wide temperature range. It is convenient to conduct the reaction in the range of from -20 to 100aboutS, more preferably from -10 to 50aboutC. the Time required for completion of the reaction may also vary widely, depending on many factors, mainly on the reaction temperature and the reagents and solvent. However, when conducting the reaction in usercontainer conditions for completion of the reaction is usually sufficient period of 15 min to 24 h, more preferably from 30 min to 16 h

In this way when used as a reagent dialkylanilines or directorrelated the reaction of the compound of formula (II) may preferably be carried out in the presence in the reaction system, the compounds of formula (II) and the base.

The method with the use of activated complex ester can be carried out by reaction of the compound of formula (II) in the presence of a condensing means (for example, dicyclohexylcarbodiimide or carbonyldiimidazole) with active etherification means (for example, N-hydroxy, such as N-hydroxy - succinimide or N-hydroxybenzotriazole) with the formation of the activated ester derivative ª activated ester derivative response is recommended in an inert solvent, the solvent which can be used in the reaction, similar to the solvents used in the method using galodamadruga acid.

These reactions may be carried out in a wide temperature range. In General, it is convenient to conduct the reaction produce an activated ester derivative at a temperature of from -20 to 50aboutS, more preferably from -10 to 30aboutC, and the reaction of the activated ester derivative with the compound of the formula (IIIa) recommended in the temperature range from -20 to 50aboutS, more preferably from -10 to 30aboutC. the Time required for completion of the reaction may also vary widely, depending on many factors, mainly on the reaction temperature and the nature of the applied reagent and solvent. However, when conducting the reaction in the above recommended reaction conditions for completion of the reaction can be quite a period of 15 min to 24 h, more preferably from 30 min to 16 h

How carry out condensation reaction of compounds of formula (II) with the compound of the formula (IIIa) directly in the presence of a condensing means, such as dicyclohexylcarbodiimide, carbonyldiimidazole similar conditions, used, as described above, in the method of the activated complex ether.

If the compound of the formula (II) contains an amino group or monoalkylamines, and the compound of formula (IIIa) contains carboxyl, in this case it is recommended to use compounds in which these groups are protected. Regarding the nature of the protective group, there are no special restrictions may be applied to any of these groups commonly used in organic chemistry synthesis. Examples of acceptable amino - or monoalkylamines protective groups include tert-butoxycarbonyl and kalaidzidis, for example chloroacetyl, bromo, acetyl or iodine-acetyl. Examples carboxyamide groups include tert-butyl and alkoxybenzyl in which alkoxides has 1-4 carbon atoms, such as p-methoxybenzyl.

After the above-mentioned reaction of the protective group can be removed by conventional, well known in the field of organic synthesis tools, the specific method of removing the protective group is selected depending on its nature.

For example, if the protective group is tert-butoxycarbonyl, tert-bootrom or alkoxybenzyl, the protective group can be removed by reaction of the protected compound in an inert races is glendorado, such as methylene chloride or 1,2 dichloroethane, aromatic hydrocarbons such as benzene, toluene or xylene) with acid (for example, mineral acid, such as hydrochloric acid, sulfuric acid or nitric acid, or organic acid, such as acetic acid, triperoxonane acid, methanesulfonate acid or benzosulfimide) at a temperature of 0-50aboutWith (more preferably at about room temperature for from 30 minutes to 5 hours (more preferably 1-2 hours). If the protective group represented by calidarium, it can be removed by reaction of the protected compound in an inert solvent (for example, amide, such as dimethylformamide or dimethylacetamide, or a sulfoxide such as dimethylsulfoxide) with thiourea at 0-50aboutWith (more preferably at about room temperature) for 30 min to 5 h (more preferably 1-2 hours).

Upon completion of the reaction obtained in each reaction, the target compound can be isolated from the reaction mixture by conventional methods. For example, in appropriate cases, the target compound can be isolated by separation of the resulting crystals by filtration, or the connection can be isolated by diluting latitat, then the extract is dried and finally the solvent is removed, for example, by distillation under reduced pressure. If necessary, the product may be subjected to further purification by conventional means, such as recrystallization or the various chromatography techniques, such as column chromatography or preparative thin-layer chromatography.

The compounds of formula (II) used as starting products method, are well known or can be easily synthesized by known methods (for example, described in Aust. J. Chem.21, 1891 (1968), J. Chem. Soc. 4614(1958), J. Pharm. Soc. Japan 73, 949 (1953), Chem.Berichte, 91, 160 (1958) and J. Chem. Soc. Japan, 82, 1075 (1961).

The reaction scheme is given In an alternative method of preparing compounds of formula (I).

At stage B1 of the reaction scheme, the compound of formula (IVa) is obtained by reaction of compounds of formula (II) or its reactive derivative with hydroxy of the formula (IIIb). The reaction can be conducted by using, for example, galodamadruga acid, mixed acid anhydride, activated complex ester or method of condensation. All of these methods described above in connection with the discussion stage A1 of reaction scheme A.

At stage B2, the compound of formula (1) poluchaetsya solvent, or in the presence of an inert solvent.

Special restrictions concerning the nature nitrouse means, no. Examples of such tools include fuming nitric acid, nitrotoluidines-Tetra-perborate, nitrate chloride tiomila and tetrafluoroborate nitronium. One of them recommended fuming nitric acid, nitrotoluidines-tetrafluoroborate and nitrate chloride tiomila.

Typically and preferably the reaction is carried out in a solvent. Special restrictions concerning the nature of the solvent, there is no subject that does not adversely affect the course of the reaction or participating in the reaction reagents and capable at least to some extent, to dissolve the reagents. Examples of acceptable solvents include hydrocarbons, which may be aliphatic, cycloaliphatic or aromatic, such as hexane, cyclohexane, benzene, toluene or xylene, halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride, 1,2-dichloroethane or carbon tetrachloride, ethers, such as diethyl ether, tetrahydrofuran or dioxane, ketones, such as acetone, NITRILES, such as acetonitrile, amides, especially fatty amides kislota and sulfoxidov, such as dimethyl sulfoxide. One of them recommended hydrocarbons, halogenated hydrocarbons, ethers, amides and sulfoxidov.

The reaction proceeds in a wide temperature range. In General, it is convenient to conduct the reaction at a temperature of from -20 to 50aboutC, more preferably at about room temperature. The time required for completion of the reaction may also vary widely, depending on many factors, mainly on the reaction temperature and the nature of the reagents and solvent. However, when conducting the reaction in the above recommended conditions for completion of the reaction is usually sufficient period of from 30 minutes to 24 hours, more preferably from 1-10 PM

Upon completion of the reaction, the target compound can be isolated from the reaction mixture by conventional means. For example, in appropriate cases, the target compound can be isolated by filtration of the formed crystals, or it may be isolated by adding water, extracting the mixture of water-insoluble solvent, such as ethyl acetate, drying of the extract, and finally distillation of the solvent under reduced pressure. If desired, the resulting product may be subjected dalnevosochny chromatography or preparative thin-layer chromatography.

As will be shown below, the proposed connection can be used for the treatment and prevention of angina. For this purpose, they can be introduced in pure form or in mixture with conventional, well-known pharmaceutically acceptable carriers, diluents, excipients or adjuvants. The compounds may be introduced by any acceptable means, such as orally or parenterally. If desired, the compounds may be entered into any composition that is acceptable for the intended route of administration. For example, they may be in the form of powders, granules, tablets or capsules for oral administration or injection for parenteral administration. The dosage may vary depending on the severity and nature of the violation, as well as symptoms, age and weight of the patient and the selected route of administration. However, in the case of oral administration recommends that the usual single dose of 1-1000 mg, in particular 5 are 300 mg, and in the case of intravenous injection single dose of 0.1 to 100 mg, in particular 0.5 to 50 mg of the Compounds can be administered once or several times a day, for example 1-3 times a day.

Receipt of the proposed compounds are further illustrated by the following, not limiting the invention, examples, and obtaining certain icchokusen biological activity of the individual proposed connections.

P R I m e R 1. (4R)-N-(2-nitroxyethyl)-2 - oxothiazolidine-4-carboxamide (compound N 1-1). To a suspension of 4 g of (4R)-2-oxothiazolidine-4-carboxylic acid and 4.6 g of nitrate N-(2-nitroxyethyl)amine in 80 ml of dry tetrahydrofuran under cooling with ice add 11,4 ml of triethylamine and 5.3 ml diethylthiophosphate and the resulting mixture stirred for 2 h at room temperature. At the end of this period the solvent is distilled off under reduced pressure, and the residue is mixed with ethyl acetate.

The resulting mixture was then washed with saturated aqueous sodium chloride, then dried over anhydrous magnesium sulfate. The solvent is then removed under reduced pressure, and the obtained residue brown oil is purified column chromatography on silica gel using ethyl acetate as eluent. By recrystallization of the obtained brown crystals obtain 1.68 g of the title compound as colorless needles, melting point 130-131aboutC (with decomposition). Spectrum of nuclear magnetic resonance (CDCl3) + hexadeuterated dimethyl sulfoxide) million-1: 3,54 of 3.73 (4H, multiplet) or 4.31 (1H, triplet, I 7 Hz), 4,58 (2H, triplet, I 5 Hz), 7,81 (1H, singlet), 8,02 (1H, broad singlet).

P R I m m e R 2. (4R, 5R)-N-(2-Nein-4-carboxylic acid and 406 mg of nitrate N-(2-nitroxyethyl)-amine in 40 ml of dry tetrahydrofuran under cooling with ice add to 1.33 ml of triethylamine and 0.36 ml diethylthiophosphate and the resulting mixture was stirred for 1 h and 25 min at room temperature. At the end of this period the solvent is removed by distillation under reduced pressure, and the residue is mixed with ethyl acetate. The resulting mixture was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the obtained residue, a yellow oil is purified column chromatography on silica gel using as eluent a mixture of methylene chloride-methanol (20: 1 by volume) and obtain 324 mg of the title compound as a pale yellow oil. Spectrum of nuclear magnetic resonance (CDCl3) million-1: to 1.61 (3H, doublet, I 6 Hz) 3,55-of 3.77 (2H, multiplet) of 4.04 (2H, broad singlet) 4,59 (2H, triplet, I 5 Hz) to 7.61 (1H, singlet) 7,73 (1H, triplet, I 6 Hz).

P R I m e R 3. N-(2-nitroxyethyl)-2-oxo-5-phenylthiazole-4-carboxamide (compound N 1-7). To a solution of 105 mg of 2-oxo-5-phenylthiazole-4-carboxylic acid and of 79.5 mg of nitrate N-(2-nitroxyethyl)amine in 10 ml of dry tetrahydrofuran under ice cooling type of 0.07 ml of triethylamine and 90 mg of the hydrochloride of 1-(N,N-diethylaminopropyl)-3-ethylcarbodiimide and the resulting mixture is stirred for about a day at room temperature. At the end of this period the solvent is distilled off under reduced pressure is Argonaut, and the residual yellow oil is rinsed with diethyl ether. Precipitated precipitated crystals are filtered off and purified column chromatography on silica gel using as eluent a mixture of methylene chloride-methanol (40:1 by volume) and obtain 34 mg of the title compound as pale yellow crystals with a melting point 139-140aboutC. Spectrum of nuclear magnetic resonance (CDCl3+ hexadeuterated dimethyl sulfoxide) million-1: 3,62-3,8 (2H, multiplet) to 4.28 (1H, doublet, I 4 Hz) 4,58 (2H, triplet, I 5 Hz) of 5.24 (2H, broad singlet) 7,32-7,52 (5H, multiplet) to 7.64 (1H, broad singlet).

P R I m e R 4. N-(2-nitroxyethyl)-5,5-dimethyl-2-oxothiazolidine-4-carboxamide (compound N 1-17). To a suspension of 360 mg of 5,5-dimethyl-2-oxothiazolidine-4-carbon - howl acid and 417 mg of nitrate N-(2-nitroxyethyl)amine in 50 ml of dry tetrahydrofuran under cooling with ice add to 1.38 ml of triethylamine and 0.37 ml diethylthiophosphate and the resulting mixture was stirred for 4 h at room temperature, after which the solvent is distilled off under reduced pressure. The residue is mixed with ethyl acetate and the resulting mixture washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled at ponies who eat as elution solvent a mixture of methylene chloride-methanol (50:1) and obtain 180 mg of the title compound as colourless crystals with a melting point 98-100aboutC. Spectrum of nuclear magnetic resonance (CDCl3) :is 1.51 (3H, singlet) of 1.74 (3H, singlet) 3,63-and 3.72 (2H, multiplet), 4,13 (1H, singlet) 4,59 (2H, triplet, I 5 Hz) of 6.52 (1H, singlet) to 6.95 (1H, broad singlet).

P R I m e R 5. N-(2-nitroxyethyl)-5-(furan-2-yl)-2-oxothiazolidine-4 - carboxamide (compound 1-10). To a suspension of 500 mg of 5-(furan-2-yl)-2-oxothiazolidine-4-carboxylic acid and 476 mg of nitrate N-(2-nitroxyethyl)-amine in 50 ml of dry tetrahydrofuran under cooling with ice add 1,58 ml of triethylamine and 0.47 ml diethylthiophosphate, the resulting mixture was stirred for 3.5 h at room temperature, after which the solvent is distilled off under reduced pressure. Saducees crystals washed with diisopropyl ether and filtered. By recrystallization of the resulting crystals from methylene chloride receive 400 mg of the title compound as colourless crystals with a melting point of 117-118aboutC.

Spectrum of nuclear magnetic resonance (CDCl3+ hexadeuterated dimethyl sulfoxide) million-1: 3,53-3,74 (2H, multiplet) to 4.41 (1H, singlet) of 4.57 (2H, triplet, I 5 Hz), lower than the 5.37 (1H, doublet, I 3 Hz) 6,34-6,38 (2H, multiplet), and 7.4 (1H, singlet) and 7.8 (1H, singlet) 7,87 (1H, broad singlet).

P R I m e R 6. N-methyl-N-(2-nitroxy-ethyl)-2-oxothiazolidine the CSO N,N-dimethylformamide while cooling with ice added to 0.95 ml of triethylamine, 1 g 2-oxothiazolidine-4-carboxylic acid and 1.3 g hydrochloride 1-(N,N-dimethylaminopropyl)-3 - ethylcarbodiimide, the resulting mixture was stirred for 45 min at room temperature, after which the solvent is distilled off under reduced pressure. The residue is mixed with ethyl acetate, the mixture was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure. The residual yellow oil is purified column chromatography on silica gel using as eluent a mixture of methylene chloride-ethyl acetate (4:1 by volume). The resulting colorless oil, to cause crystallization rinsed with a small amount of tetrahydrofuran. The precipitated crystals are filtered and recrystallization from acetone receive 50 mg of the title compound as colourless crystals with a melting point 110-112aboutC. Spectrum of nuclear magnetic resonance (hexadeuterated dimethyl sulfoxide) million-1: of 2.64 (3H, singlet) 3,23-of 3.27 (2H, multiplet) to 3.6 (1H, doublet of doublets, j=4 and 12 Hz), of 3.77 (1H, doublet of doublets, I 8 and 12 Hz), 4,33-4,37 (2H, multiplet) to 4.7 (1H, doublet of doublets I 4 and 8 Hz) of 8.47 (1H, singlet).

P R I m e R 7. N-(2-nitroxyethyl)-3-methyl-thiazolidin-4-carboxylic acid in 35 ml of dry tetrahydrofuran under cooling with ice and stirring of 1.33 ml of triethylamine and 0.36 ml diethylthiophosphate, the resulting mixture was stirred for 3.5 h at room temperature, after which the solvent is distilled off under reduced pressure. The residue is mixed with ethyl acetate and the resulting mixture washed with saturated aqueous sodium chloride. Then dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. By recrystallization of the crystalline residue from ethanol obtain 247 mg of the title compound as colourless crystals with a melting point 105-106aboutC. Spectrum of nuclear magnetic resonance (CDCl3) million-1: to 2.94 (3H, singlet) 3,32 (doublet of doublets, I 4 and 12 Hz) 3,63-of 3.78 (3H, multiplet), to 4.23 (1H, doublet of doublets I 4 and 9 Hz) 4,56-of 4.67 (2H, multiplet) 7,13 (1H, broad singlet).

P R I m e R 8. N-(2-nitroxyethyl)-5-(1-naphthyl)-2-oxothiazolidine-4-carboxamide (compound N 1-25). To a suspension of 370 mg of nitrate N-(2-nitroxyethyl)amine and 500 mg of 5-(1-naphthyl)-2-oxothiazolidine-4-carbon-howl acid in 50 ml of dry tetrahydrofuran under cooling with ice and stirring of 1.23 ml of triethylamine and 0.36 ml dicalciumphosphate and the resulting mixture was stirred for 4 h at room temperature. At the end of this period the solvent is distilled off under reduced pressure, and the residue is mixed with ethyl acetate. the magnesium. The solvent is distilled off under reduced pressure and recrystallization of the crystalline residue from ethanol obtain 367 mg of the title compound as colourless crystals with a melting point of 151-153aboutC. Spectrum of nuclear magnetic resonance (CDCl3+ + hexadeuterated dimethyl sulfoxide) million-1:3,4-3,6 (2H, multiplet), 4,51 (1H, doublet I 3 Hz) 4,55 (2H, triplet, I 5 Hz) of 5.83 (1H, doublet, I 3 Hz) 7,53-to 7.64 (3H, multiplet) 7,76 (1H, doublet, I 7 Hz) to $ 7.91-8,03 (2H, multiplet 7,76 (1H, doublet, I 7 Hz) to $ 7.91-8,03 (2H, multiplet) charged 8.52 (1H, triplet I 6 Hz) 8,61 (1H, singlet).

P R I m e R 9. N-(2-nitroxyethyl)-2-oxo-5-(2-thienyl)-oxazolidin-4 - carboxamide (compound N 1-8). Playback - management techniques of example 1, but using 350 mg of nitrate N-(2-nitroxy - ethyl)amine and 400 mg of 2-oxo-5-(2-thienyl)thiazolidin-4-carboxylic acid obtained 260 mg of the title compound as colourless crystals with a melting point 120-122aboutC (after recrystallization from ethanol). Spectrum of nuclear magnetic resonance (CDCl3+ hexadeuterated dimethyl sulfoxide) million-1:3,5-of 3.78 (2H, multiplet) 4,28 of 4.3 (1H, multiplet) of 4.57 (2H, triplet, I 5 Hz) to 5.56 (1H, doublet, I 3 Hz) to 6.95 (1H, doublet of doublets, I 3 and 5 Hz) 7,13 (1H, doublet I 3 Hz) 7,26 (1H, doublet I 5 Hz) 7,74 (1H, singlet) to 7.77 (1H, decision N 1-16). The play - based methods of example 1 but using nitrate N-(2-nitroxyethyl)amine (300 mg) and 2-oxo-5-(3-predil)thiazolidin-4-carboxylic acid (330 mg) obtained 140 mg of the title compound as colourless crystals with a melting point 139-140aboutC (after recrystallization from ethanol). Spectrum of nuclear magnetic resonance (CDCl3+ hexadeuterated dimethyl sulfoxide) million-1: a 3.5 to 3.75 (2H, multiplet) is 4.21 (1H, doublet, I 3 Hz) of 4.57 (2H, doublet of doublets, I 5 and 12 Hz) 5,31 (1H, doublet, I 3 Hz), 7,31 (1H, doublet of doublets I 5 and 8 Hz) 7,78-a 7.92 (2H, multiplet) to 8.57 (1H, doublet, I 5 Hz) 8,72 (1H, singlet).

P R I m e R 11. N-(2-nitroxyethyl)-5-(3-nitrophenyl)-2-oxothiazolidine-4 - carboxamide (compound N 1-12). Playback - management techniques of example 1, but using 380 mg of nitrate N-(2-nitroxy - ethyl)amine and 500 mg of 5-(3-nitrophenyl)-2-oxothiazolidine-4-carboxylic acid obtained 450 mg of the title compound as a pale yellow powder. Spectrum of nuclear magnetic resonance (CDCl3) million-1: 3,65-of 3.85 (2H, multiplet) of 4.35 (1H, doublet, I 3 Hz) with 4.64 (2H, triplet, I 3 Hz) to 5.3 (1H, doublet, I 3 Hz) 7,02 (1H, singlet) 7,27 (1H, broad singlet) 7,62 (1H, triplet, I 8 Hz) to 7.84 (1H, doublet, I 8 Hz) by 8.22 (1H, doublet, I 8 Hz) scored 8.38 (1H, singlet).

P R I m e R 12. N-(2-nitroxyethyl)-5-(4-m is the Finance 401 mg of nitrate N-(2-nitroxy - ethyl)amine and 500 mg of 5-(4-methoxyphenyl)-2-oxothiazolidine-4-carboxylic acid obtained 408 mg of the title compound as colourless crystals with a melting point 142-143aboutC (after recrystallization from methylene chloride). Spectrum of nuclear magnetic resonance (CDCl3+ hexadeuterated dimethyl sulfoxide) million-1: 3,5-and 3.72 (2H, multiplet) 3,81 (3H, singlet) 4,2 (1H, doublet, I3 Hz), 4,56 (2H, triplet, I 5 Hz) to 5.21 (1H, doublet, I 3 Hz) 6,87 (2H, doublet, I 9 Hz) of 7.4 (1H, doublet, I 9 Hz) to 7.67 (1H, singlet) 7,76 (1H, broad singlet).

P R I m e p 13. N-(2-nitroxyethyl)-5-(4-chlorophenyl)-2-oxothiazolidine-4-carboxy - MFA (compound N 1-13). Playback - management techniques of example 1, but using 394 mg of nitrate N-(2-nitroxy - ethyl)amine and 500 mg of 5-(4-chlorophenyl)-2-oxothiazolidine-4-carboxylic acid obtained 350 mg of the title compound as colorless needles with a melting point 125-127aboutC (after recrystallization from methylene chloride). Spectrum of nuclear magnetic resonance (CDCl3+ hexadeuterated dimethyl sulfoxide) million-1: 3,5-3,8 (2H, multiplet) 4,18 (1H, singlet) of 4.57 (2H, triplet, I 5 Hz), 5,24 (1H, doublet, I 3 Hz) 7,33 (2H, doublet, I 9 Hz), the 7.43 (1H, doublet, I 9 Hz) to $ 7.91 (1H, singlet) 7,94 (1H, broad singlet).

P R I m e R 14. N-(3-nitroxymethyl)-2-oxothiazolidine-4 - carboxamide (compound 1-68 N). Playback method of example 1, but using a 1.25 g of nitrate N-(3-nitroxymethyl)amine and 1 g of 2-oxothiazolidine 83-85aboutC. Spectrum of nuclear magnetic resonance (CDCl3) million-1: a 2.01 (2H, multiplet) 3,35 of 3.56 (2H, multiplet) 3,63 (1H, doublet of doublets, I 4 and 11 Hz) 3,81 (1H, doublet of doublets, I 4 and 11 Hz) 4,34 and 4.4 (1H, multiplet) of 4.54 (2H, triplet, I 6 Hz), 6,97 (1H, singlet)? 7.04 baby mortality (1H, broad singlet).

P R I m e R 15. N-(2-nitroxyethyl)-5-benzyl-2-oxothiazolidine-4-carboxamide (compound N 1-28). Playback method of example 1, but using 210 mg of nitrate N-(2-nitroxyethyl)amine, and 250 mg of 5-benzyl-2-oxothiazolidine-4-carboxylic acid obtained 220 mg of the title compound as a yellow columnar crystals with a melting point 123-124aboutC (after recrystallization from ethanol). Spectrum of nuclear magnetic resonance (CDCl3+ hexadeuterated dimethyl sulfoxide) million-1: to 3.09 (1H, doublet of doublets, I 9 and 14 Hz) of 3.23 (1H, doublet of doublets I 7 and 14 Hz) 3,45 of 3.75 (2H, multiplet) is 4.03 (1H, singlet), a 4.3 and 4.4 (1H, multiplet) 4,55 (2H, triplet I 5 Hz) 7,2-7,38 (5H, multiplet) 7,53 (1H, singlet) to 7.68 (1H, broad singlet).

P R I m e R 16. (4R)-N-(2-nitroxyethyl)-2-oxothiazolidine-4 - carboxamide (compound N 1-1).

16(a) of (4R)-N-(2-hydroxyethyl)-2-oxothiazolidine-4-carboxamide. To a suspension of 1 g of (4R)-2-oxothiazolidine-4-carboxylic acid in 20 ml of benzene add 0.9 ml oxacillin the years of the specified period, the solvent is distilled off under reduced pressure. The solution of the residual pale yellow oil in 10 ml of methylene chloride under ice cooling are added dropwise to a solution of 1.25 g of 2-ethanolamine in 25 ml of methylene chloride and the mixture is stirred under ice cooling for 1.5 hours, the Solvent is then distilled off under reduced pressure and the resulting residue purified kolacny chromatography on silica gel using as eluent a mixture of methylene chloride-methanol (9:1 by volume). By recrystallization of the obtained colorless crystals from ethyl acetate to obtain 0.65 g of the title compound as colourless plates with a melting point 116-118aboutC. Spectrum of nuclear magnetic resonance (CDCl3+hexadeuterated dimethyl sulfoxide) million-1: the 3.2 and 3.4 (1H, multiplet) 3.5 to 3.8 (5H, multiplet) to 4.33 (1H, multiplet), was 7.36 (1H, broad singlet) EUR 7.57 (1H, singlet). 16 (C) (4R)-N-(2-nitroxyethyl)-2-oxothiazolidine-4 - carboxamide.

To 30 ml of acetonitrile at a temperature between -10 and 0aboutWith the type of 0.44 g of tetrafluoroborate nitronium and a solution of 0.41 g of 2,4,6-collidine in 20 ml of acetonitrile and the resulting mixture was stirred at the same temperature for 30 minutes after the specified period added to the mixture of 0.5 g of (4R)-N-(2-hydroxyethyl)-2-oxothiazolidine-4 - carboxamide, and then stirred for 4 h Ave the La. The residue is mixed with ethyl acetate and the insoluble part is filtered off. The filtrate is concentrated by evaporation under reduced pressure, and the resulting residue is purified column chromatography on silica gel using ethyl acetate as eluent. By recrystallization of the obtained pale-yellow crystals from ethyl acetate to obtain 86 mg of the title compound as colorless crystals.

The melting temperature range and nuclear magnetic resonance resulting product is identical to the melting temperature and spectrum of the compound obtained by the method of example 1.

P R I m e R 17. (4R)-N-(1-nitroxymethyl)-ethyl-2-oxothiazolidine-4 - carboxamide (compound 1-30 N). Playback method of example 1, but using 1.5 g of (4R)-2-oxothiazolidine-4 - carboxylic acid and 2.3 g of nitrate N-(nitroxymethyl)ethylamine obtained 0.35 g of the title compound as colourless crystals with a melting point of 112-114aboutC (after recrystallization from ethanol). Spectrum of nuclear magnetic resonance (CDCl3+hexadeuterated dimethyl sulfoxide) million-1: of 1.27 (3H, doublet, I 7 Hz) 3,68 (2H, doublet, I 7 Hz) 4,25-4,6 (4H, multiplet) 7,49 (1H, doublet, I 7 Hz) 7,72 (1H, singlet).

P R I m e R 18. (4R)-N-(2-nitroxy the 2 g of (4R)-2-oxothiazolidine-4-carboxylic acid and 3 g of nitrate N-(2-nitroxymethyl)-amine received 24 mg of the title compound as pale yellow crystals with a melting point 70-72aboutC (after recrystallization from ethanol). Spectrum of nuclear magnetic resonance (CDCl3) million-1: to 1.38 (3H, doublet, I 6 Hz) 3,35-3,9 (4H,multiplet) 4,35-4,5 (1H, multiplet) 5,2-5,4 (1H, multiplet) of 6.99 (1H, singlet) 7,16 (1H, broad singlet).

P R I m e R 19. (4R)-N-(2-nitroxyethyl)-2-oxothiazolidine-4 - carboxamide (compound N 1-34). To a suspension of 1 g of (4S)-2-oxota - solidin-4-carboxylic acid and 1.55 g of nitrate N-(2-nitroxyethyl)amine in 20 ml of dry tetrahydrofuran under cooling with ice add 3.2 ml of triethylamine and 1.5 ml diethylthiophosphate and the resulting mixture stirred for 2 h at room temperature. At the end of this period the solvent is distilled off under reduced pressure, the residue diluted with ethyl acetate, the mixture was washed with saturated aqueous sodium chloride, then dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the resulting brown oil is purified column chromatography on silica gel using as eluent ethyl acetate and obtaining the title compound as yellowish-brown crystals by recrystallization from ethyl acetate obtain 0.25 g of the title compound as colourless needles with a temperature of plvl) million-1: 3,4-to 3.58 (2H, multiplet) of 4.1 and 4.3 (2H, multiplet) of 4.45 (1H, triplet, I 8 Hz) 4,56 (2H, triplet, I 5 Hz) of 7.96 (1H, singlet), 8,42 (1H, triplet, I 5 Hz).

P R I m e R 20. (4S, 5R)-N-(2-nitroxy-ethyl)-5-methyl-2-oxoacridine-4-Carbo-camid (compound N 1-35). Playback method of example 19, but using 180 mg of (4S, 5R)-5-methyl - 2-oxoacridine-4-carboxylic acid and 230 mg of nitrate N-(2-nitroxyethyl)amine followed by recrystallization of the resulting product from methylene chloride obtained 41 mg of the title compound as colorless needles with a melting point of 81.5-82,5aboutC. Spectrum of nuclear magnetic resonance (CDCl3+hexadeuterated dimethyl sulfoxide) million-1: of 1.55 (3H, doublet, I 6 Hz) 3,53-3,71 (2N-multiplet) 3,789 (1H, doublet I 7 Hz), 4,58 (2H, triplet, I 5 Hz) 4,65-of 4.75 (1H, multiplet) 7,17 (1H, broad singlet) and 7.8 (1H, broad singlet).

P R I m e R 21. (4S, 5R)-N-(2-nitroxy-ethyl)-2-oxo-5-phenyloxazolidine-4 - Carbo - camid (compound 1-40 N). Playback method of example 19, but using 130 mg of (4S, 5R)-2-oxo-5-vinyloxy - solidin-4-carboxylic acid, 127 mg of nitrate N-(2-nitroxyethyl)amine obtained 72 mg of the title compound as colourless plates with a melting point 122-124aboutC. Spectrum of nuclear magnetic resona,6 (2H, triplet, I 5 Hz) to 5.66 (1H, doublet, I 5 Hz) 7,33-7,53 (6N, multiplet) to 7.99 (1H, broad singlet).

P R I m e R 22. N-(2-nitroxyethyl)-2-oxo-5-(2-thienyl)oxazolidine-4 - carboxamide (compound N 1-41). Playback method of example 19, but using 500 mg of 2-oxo-5-(2-thienyl)-oxazolidin-4 - carboxylic acid and 480 mg of nitrate N-(2-nitroxyethyl)amine obtained 190 mg of the title compound as pale yellow plates with a melting point 101-103aboutC. Spectrum of nuclear magnetic resonance (CDCl3+ hexadecacarbonyl dimethyl - sulfoxide) million-1: 3,54-to 3.73 (2H, multiplet) 4,32 (1H, doublet, I 5 Hz), 4,58 (2H, triplet, I 5 Hz) 5,88 (1H, doublet, I 5 Hz) 7,02 (1H, triplet, I 3 Hz) 7,19 (1H, doublet, I 3 Hz) to 7.35 (1H, doublet, I 6 Hz) 7,58 (1H, broad singlet) and 7.8 (1H, broad singlet).

P R I m e R 23. N-(2-nitroxyethyl)-2-oxothiazolidine-5-carboxamide (compound N 2-1). To a suspension of 0.3 g of 2-oxothiazolidine-5-carboxylic acid (receipt see preparative example 3) and 0.41 g of nitrate N-(2-nitroxyethyl)amine in 10 ml of dry tetrahydrofuran under cooling with ice add to 0.85 ml of triethylamine and of 0.53 ml diphenylphosphinite and the resulting mixture was stirred for 2.5 h at room temperature. At the end of this period the solvent is distilled off under reduced pressure, and the military resulting crude crystal was washed with diisopropyl ether, filtered and after washing obtain 0.4 g of the title compound as a colourless powder with a melting point 114-115aboutC. Spectrum of nuclear magnetic resonance (CDCl3+hexadeuterated dimethyl sulfoxide) million-1: 3.5mm-to 3.67 (2H, multiplet) 3,68 to 3.8 (1H, multiplet) 3,9-was 4.02 (1H, multiplet), 4,34 (1H, doublet of doublets, I 4 and 8 Hz) of 4.57 (2H, triplet, I 5 Hz) of 6.96 (1H, broad singlet) to 7.9 (1H, broad singlet).

P R I m e R 24. (5S)-N-(2-nitroxyethyl)-2-oxoacridine-5-carboxamid (with-unity N 2-34). To a suspension of 110 mg of (5S)-2-oxoacridine-5 - carboxylic acid (obtained by the method similar to the method of preparative example 3) and 170 mg of nitrate N-(2-nitroacetanilide in 10 ml of dry tetrahydrofuran under cooling with ice and stirring, add 0.35 ml of triethylamine and 0.22 ml diphenylphosphinite and the resulting mixture was stirred for 6 h at room temperature. At the end of this period the solvent is distilled off under reduced pressure, and the residue is purified column chromatography on silica gel using ethyl acetate as eluent. The resulting pale yellow oil was washed with ethyl acetate, the precipitate is filtered and after washing get to 79.8 mg of the title l3+hexadeuterated dimethyl sulfoxide) million-1: 3,55-of 3.78 (3H, multiplet) 3,88 (1H, triplet, I 9 Hz), 4,58 (2H, triplet, I 5 Hz) 4,94 (1H, doublet of doublets, I 5 and 9 Hz) 6,72 (1H, singlet) 7,62 (1H, broad singlet).

P R I m e R 25. (4R)-N-(4-nitroxymethyl)-2-oxothiazolidine-4-carboxamide (compound N 1-67).

25 (a) (4R)-N-(4-hydroxybutyl)-2-oxothiazolidine-4-carboxamide.

Playback method of example 16(a), but using 1.2 g of (4R)-2-oxothiazolidine-4-carboxylic acid and of 2.23 g of N-(4-hydroxybutyl)amine obtained 0,735 g of the title compound as colourless crystals with a melting point 81-83aboutC. Spectrum of nuclear magnetic resonance (CDCl3+hexadeuterated dimethyl sulfoxide) million-1: 1,51-of 1.75 (4H, multiplet) of 3.25 to 3.4 (3H, multiplet) 3,55 of 3.75 (4H, multiplet) 4,27 (1H, tri-plet, I 7 Hz) 7,44 (1H, broad singlet) 7,76 (1H, singlet).

25 (C) (4R)-N-(4-nitroxymethyl)-2-oxothiazolidine-4 - carboxamide.

Playback method of example 16(b), but using 195 mg of Tetra-perborate nitronium, 157 mg of 2,4,6-collidine and 218 mg of (4R)-N-(4-hydroxybutyl)-2-oxothiazolidine-4-carboxamide (obtained by the method of the above stage (a)) obtained 55 mg of the title compound as colourless needles with temperature PL is 2N, multiplet) 3,61 (1H, doublet of doublets, I 5 and 11 Hz) 3,79 (1H, doublet of doublets, I 9 and 11 Hz) to 4.38 (1H, doublet of doublets, I 5 and 9 Hz), 4,49 (2H, triplet, I 6 Hz) to 7.15 (1H, triplet, I 6 Hz) to 7.35 (1H, singlet).

P R I m e R 26. (4S)-N-(2-nitroxyethyl)-2-oxothiazolidine-4-carboxamide (compound N 1-1). Playback method of example 1, but using 1 g of (4S)-2-oxothiazolidine-4-carboxylic acid and 1.15 g of nitrate N-(2-nitroxyethyl)amine obtained 0.5 g of the title compound as pale yellow needles with a melting point of 129-130aboutC (with decomposition). Spectrum of nuclear magnetic resonance (hexadeuterated dimethyl sulfoxide ) million-1: 3,3-3,37 (1H, multiplet) 3,47 (2H, doublet of doublets I 5 and 11 Hz) 3,63-3,71 (1H, multiplet) 4,25 of 4.3 (1H, multiplet) 4,56 (2H, triplet, I 5 Hz) 8,28 (1H, singlet) at 8.36 (1H, triplet, I 5 Hz).

P R I m e R 27. (4R)-N-(2-nitroxyethyl)-2-oxoacridine-4-carboxamide (compound N 1-34). According to the method of example 1, but using a 0.23 g of (4R)-2-oxoacridine-4-carboxylic acid and 0.36 g of nitrate N-(2-nitroxyethyl)amine obtained 0.16 g of the title compound as colorless needles with a melting point 110-112aboutC.

Spectrum of nuclear magnetic resonance (CDCl3and hexadecylamine dimethyl sulfoxide) million-1: 3,47-and 3.72 (2H, multiplet) 4, rootsier)-2-oxoacridine-5-carboxamide (compound N 2-34). Playback method of example 1, but using 0.32 g of (5R)-2-oxoacridine-5-carboxylic acid, 0.5 g of nitrate N-(2-nitroxyethyl)amine and 0.63 ml diphenylphosphinite obtained 0.11 g of the title compound as pale yellow plates with a melting point 103-105aboutC. Spectrum of nuclear magnetic resonance (CDCl3and hexadeuterated dimethyl sulfoxide) million-1: 3,57-of 3.77 (3H, multiplet) x 3.9 (1H, triplet, I 9 Hz) of 4.6 (2H, triplet, I 5 Hz) 4,96 (1H, doublet of doublets, I 5 and 9 Hz), only 6.64 (1H, singlet), 7,58 (1H, broad singlet).

P R I m e R 29. (4R, 5S)-N-(2-nitroxy-ethyl)-4-methyl-2-oxoacridine-5-Carbo-camid (compound N 2-38). Playback method of example 1, but using 167 mg of (4R, 5S)-2-oxo-4-methyloxan - lidin-5-carboxylic acid, 234 mg of nitrate N-(2-nitroxy)amine and 0.3 ml diphenylphosphinite received 40 mg of the title compound as a colourless oil. Spectrum of nuclear magnetic resonance (CDCl3and hexadeuterated dimethyl sulfoxide) million-1: the 1.44 (3H, doublet, I6 Hz) 3,57-3,72) (2H, multiplet) 3,94-Android 4.04 (1H, multiplet) 4,43 (1H, doublet, I 6 Hz), 4,58 (2H, triplet I 5 Hz) 6,86 (1H, singlet) to 7.59 (1H, broad singlet).

P R I m e R 30. (4S, 5R)-N-(2-nitroxy-ethyl)-4-methyl-2-oxoacridine-4-5-CT - basamid (compound N 2-38). In the, 72 mg of nitrate N-(2-nitroxyethyl)amine and 0.47 ml diphenylphosphinite obtained as a colourless oil, 83 mg of the title compound. Spectrum of nuclear magnetic resonance (CDCl3) million-1: of 1.46 (3H, doublet, j=7 Hz) 3,57 of 3.75 (2H, multiplet) 4-4,1 (1H, multiplet) of 4.49 (1H, doublet, j=6 Hz) to 4.52-of 4.66 (2H, multiplet) 6,23 (1H, singlet) 7,44 (1H, tri-plet, I 6 Hz).

P R I m e R 31. N-(2-nitroxyethyl)-4-phenyl-2-oxoacridine-5-carboxamide (compound N 2-40). Playback method of example 1, but using 112 mg of 2-oxo-4-phenyloxazolidine-5-carboxylic acid, 110 g of nitrate N-(2-nitroxyethyl)amine (0.24 ml definites - triazide received 12 mg of the title compound as colourless crystals with a melting point 122-124aboutC. Spectrum of nuclear magnetic resonance (CDCl3and hexadeuterated dimethyl sulfoxide) million-1: 3,62 is 3.76 (2H, multiplet) 4,55 with 4.65 (2H, multiplet) to 4.7 (1H, doublet, I 5 Hz) of 5.05 (1H, doublet, I 5 Hz) of 6.45 (1H, singlet) 7,3-7,43 (6N, multiplet).

P R I m e R 1 (preparative). Methyl ester of 3-(N-benzyldimethylamine)-2-hydroxypropionic acid. To a suspension of 2 g DL-azaserine in 20 ml of methanol, add 5 ml of 4 n solution of hydrogen chloride in dioxane and the resulting mixture left at room temperature for 2 days eshivot with benzene and the solvent is distilled off by azeotropic distillation to dryness. The residue is dissolved in 13 ml of pyridine and 2.8 ml of triethylamine and the resulting solution under stirring and cooling with ice add 1.6 ml of carbon disulfide. The resulting mixture was stirred for 4 h at room temperature, then add 1.6 ml of benzylchloride and the reaction mixture is left for about a day while cooling with ice. At the end of this period the mixture is transferred into ice-cold water and extracted with diethyl ether. The first extract is washed with 1 N. aqueous hydrochloric acid, then with an aqueous solution of sodium bicarbonate, then dried over anhydrous magnesium sulfate. After distillation of the solvents under reduced pressure the residue is purified column chromatography on silica gel using as eluent a mixture of ethyl acetate-hexane (1:2 by volume) and receipt of 2.68 g of the title compound as a pale yellow oil. Spectrum of nuclear magnetic resonance (CDCl3) million-1: 2,9-3,3 (1H, broad singlet) is 3.82 (3H, singlet) 3,95-of 4.05 (1H, multiplet) 4,13-4,32 (1H, multiplet) of 4.45 (1H, broad singlet) a 4.53 (2H, singlet) 7,2-7,43 (6N, multiplet).

P R I m m e R 2 (preparative). Hydrochloride 3-amino-2-(sensitiivity)propionic acid. To 2,68 g of methyl ester of 3-(N-benzyldimethylamine)-2-hydroxypropionate nnuu the mixture is stirred for 30 min at the same temperature. At the end of the specified period by distillation under reduced pressure released from an excess of chloride tiomila. The resulting yellow oil is mixed with 40 ml of 3 N. aqueous hydrochloric acid and the mixture is boiled for 2 hours, After cooling the mixture, the solvent is distilled off under reduced pressure. The residue is washed with acetone, precipitated pale yellow crystals are filtered off and get 1.42 g of the title compound with a melting point 182-185aboutC (with decomposition). Spectrum of nuclear magnetic resonance (CDCl3+ hexadeuterated dimethyl sulfoxide) million-1: 3,1-3,6 (2H, multiplet) to 4.38 (2H, singlet) a 4.53 (1H, triplet, I 7 Hz), 7,28-7,42 (5H, multiplet).

P R I m e R 3 (preparative). 2-oxothiazolidine-5-carboxylic acid. To a suspension of 1.2 g of the hydrochloride of 3-amino-2- (sensitiivity)propionic acid in 35 ml of ethanol is added 12 ml of 1N. an aqueous solution of sodium hydroxide, the resulting mixture was stirred for 30 min at room temperature, and then cooling with ice add 1 N. aqueous hydrochloric acid. The solvent is then distilled off under reduced pressure, the obtained residue is dissolved in diethyl ether and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure unity in the form of colorless columnar crystals with a melting point 148-150aboutC. Spectrum of nuclear magnetic resonance (CDCl3+ hexadeuterated dimethyl sulfoxide) million-1: 3,68 to 3.8 (1H, multiplet) of 3.94 (1H, doublet of doublets, I 5 and 10 Hz) 4,43 (1H, doublet of doublets, I 5 and 8 Hz) 6,34 (1H, broad singlet).

Biological activity.

Found that the proposed compounds have a powerful ability to expand collateral vessels and is not subject to first pass effect, as shown by the following experiments on shot the dog, i.e., it is shown that the connection is very useful for the treatment and prevention of angina.

Experience 1. Test method extends the action on collateral vessels.

Dogs hound breed weighing 9-13 kg anaesthetize intravenous injection of 30 mg/kg pentobarbital, then measure systemic blood pressure in the left femoral artery. To measure peripheral blood pressure below the clamping of the carotid artery in the side of the vessel thyroid artery insert a polyethylene cannula (This Venous Catheter, 2G). The left carotid artery compress using arterial clamp for 1 min and measure your blood pressure immediately before the compression of P and the maximum decrease in peripheral blood dcert 5, 15, 30, 45 and 60 min after injection of the test sample left carotid artery pinch, each time for 1 min and re-measure your blood pressure immediately before the clamp R', and the maximum decrease in peripheral blood pressure P'. Expanding effect on the collateral vessels of each test sample (collateral index-CI) calculated by the following equation:

KI-100 ( P'/P') x 100 ( p/P).

Were tested compounds of examples 1, 19 and 23 and all showed excellent widening effect on the collateral vessels. For examples 1, 19 and 23 KI (60%) is equal to 20, 17 and 12, respectively. KI(60) the average value of KI for 60 min at a dose of 0.1 mg/kg

Experience 2. Extends the effect on collateral vessels after injection via the portal vein.

The animals in the study and their preparation are the same as in experiment 1. For introduction of the test sample through the portal vein abdominal part cut along the middle line, with exposure of one of the lateral vessels mesenteric vein. In the vein of in the direction of blood flow insert a polyethylene cannula. To identify the effect of the first pass the test sample is first injected, and then for 60 min to determine its expanding action to the widening effect on the collateral vessels.

Tested compounds of examples 1, 19 and 23 and they all showed in this test fine widening effect on the collateral vessels.

When tested for toxicity on 5 rats was not observed not a single fatal case for oral use dose of 300 mg/kg

Derivatives of thiazolidinone or oxazolidinone formula I

< / BR>
where W is sulfur or oxygen and X is a group of formula-N(R1)-,

or W is a group of formula-N(R1)- and X is sulfur or oxygen;

R1is hydrogen or C1- C6-alkyl;

R2and R3- same or different, are each hydrogen, C1- C6- alkyl, phenyl, optionally substituted by a nitro-group, a chlorine atom or a C1- C6-alkoxygroup, thienyl, furyl or pyridyl, naphthyl or benzyl;

R4is hydrogen or C1- C6-alkyl;

A - alkylene with 2 to 6 carbon atoms in straight or branched carbon chain.

2. Connection on p. 1, characterized in that it corresponds to the formula Ia

< / BR>
where A, A1, R2, R3and R4have a specified value;

X1is oxygen or sulfur.

3. Connection on p. 2, wherein X1the oxygen.

4. Connection on p. 2, great

where A, R1, R2, R3and R4have the specified values;

X1oxygen and sulfur.

6. Connection on p. 5, wherein X1the oxygen.

7. Connection on p. 5, wherein X1- sulphur.

8. Connection on p. 1, characterized in that it W is oxygen or sulfur and X is a group of formula-NH-, or X is sulfur and W is a group of formula-NH-, R2is hydrogen, benzyl, phenyl, which is unsubstituted or substituted by at least one Deputy, selected from metoxygroup, R3is hydrogen, R4- hydrogen and - C2- C4-alkylen.

9. Connection on p. 1, characterized in that it W is oxygen or sulfur and X is a group of formula - NH -, R2is hydrogen, benzyl, phenyl, which is unsubstituted or substituted by at least one methoxy group, R3is hydrogen, R4- hydrogen and ethylene.

10. Connection on p. 1, characterized in that it is chosen from N-(2-nitroxyethyl)-2-exotic solidin-4-carboxamide, N-(2-nitroxyethyl)-5-(4-methoxyphenyl)-2-oxothiazolidine-4 - carboxamide, N-(2 - nitroxyethyl)-5-benzyl-2-oxothiazolidine-4-carboxamide, N- (2-nitroxyethyl)-2-oxoacridine-4-carboxamide, N-(2 - nitroxyethyl)-5-(4-methoxyphenyl)-2-oxoacridine-4-carboxamide, N-(2 - nitroacetate)-4-(4-methoxyphenyl)-2 - oxothiazolidine-5-carboxamide.

11. The method of obtaining derivatives of thiazolidinone or oxazolidinone General formula I

< / BR>
where W is sulfur or oxygen and X is a group of formula-N(R1) or W is a group of formula-N(R1)- and X is sulfur or oxygen;

R1is hydrogen or C1- C6-alkyl;

R2and R3- same or different, are each hydrogen, C1- C6-alkyl, phenyl, optionally substituted by a nitro-group, a chlorine atom or a C1- C6-alkoxygroup, thienyl, furyl or pyridyl, naphthyl or benzyl;

R4is hydrogen or C1- C6-alkyl;

A - alkylene with 2 to 6 carbon atoms in straight or branched carbon chain,

characterized in that carry out the reaction of compounds of General formula II

< / BR>
where W, X, R2and R3have the specified values

or its reactive derivative with the compound of General formula III

< / BR>
where R4and a have the above meanings;

Z is hydrogen or a nitro-group,

with the formation of compounds of General formula IV

/IV/

where W, X, R2, R3, R4And Z have the above values,

and, if Z is hydrogen, carry out the nitration of compounds of formula IV with the formation of compounds of formula I.

Priority >- C6-alkyl, R2and R3- same or different, are each hydrogen, C1- C6-alkyl, phenyl, optionally substituted by a nitro-group, a chlorine atom, a C1- C6-alkoxygroup, thienyl, furyl or pyridyl, naphthyl or benzyl, R4is hydrogen or C1- C6-alkyl, And - alkylene with 2 to 6 carbon atoms in straight or branched carbon chain;

08.05.91 - the compounds of formula I, where W is oxygen, X is a group-N(R1)-, R1is hydrogen or C1- C6-alkyl, R2and R3- same or different, each is hydrogen, C1- C6-alkyl, phenyl, optionally substituted by a nitro-group, a chlorine atom, a C1- C6-alkoxygroup, thienyl, furyl, pyridyl, naphthyl or benzyl, R4is hydrogen or C1- C6-alkyl, And - alkylene with 2 to 6 carbon atoms in straight or branched carbon chain;

13.12.91 - the compounds of formula I where W is a group-N(R1)-, X is oxygen or sulfur, R1is hydrogen or C1- C6-alkyl, R2and R3- same or different, are each hydrogen, C1- C6-alkyl, phenyl, optionally substituted by a nitro-group, a chlorine atom or a C1- C6-alkoxygroup, thienyl, furyl or pyridyl, naphthyl or benzyl, R4chain.

 

Same patents:

The invention relates to new compounds 1,2,5,6-tetrahydropyridine number of General formula

(I) where Z is oxygen or sulfur;

R is hydrogen or C1-3-alkyl; when Z stands for oxygen, R1is a halogen, amino group, acetylamino or-O-R2where R2is4-6-alkyl or C6-quinil; Z, meaning sulfur, R1is halogen, C1-8-alkyl, C6-alkenyl straight chain, cyclopropylmethyl, benzyloxypropionic, morpholino-, 4-methylpiperidino - or 4-hexylamino or a group-O-R2where R2linear or branched C3-6alkenyl,3-6-quinil, cyclopropylmethyl, -R3-O-R4or-R3-O-R4-O-R5where each of R3, R4and R5means1-4-alkyl, or R1represents a group S-R2where R2linear C2-8-alkyl, or their pharmaceutically acceptable salts

The invention relates to a method for producing 6-fluoro-1,2-benzisothiazole formula

(I) where R is a hydrogen atom, a lower alkyl or a group of the formula

orwhere R1means-Cho or - CN, namely, that on-halogenoalkane derivative of the formula:

where R has the above meanings, is subjected to the interaction with R3SH, where R3- benzyl, environment aprotic organic solvent, with the formation of the compounds of formula

(III)where R and R3have the specified values, which are subjected to interaction with a halogenation agent to obtain the corresponding sulfanilamide formula

(IV)Subjected to interaction obtained sulfanilamide with ammonia in the compounds of the formula

(I)

Polucheniya pharmaceutically active compounds, which can be used, for example, as antipsychotic agents and as inhibitors of reuptake of serotonin

The invention relates to new pyridazinyl, derivatives which have the General formula:

(1) where one or two carbon atoms of methylene groups in the residue-NX - can be substituted by alkyl WITH1-C4, alkoxygroup1-C4or two carbon atom of the methylene groups of the above-mentioned residue can be connected by bridge with alkane(C2-C4)delovym radical; X represents CH or a nitrogen atom; each of m and n, independently of one another, denotes 1, 2, 3, and the sum m+n is 3, 4 or 5; R1denotes a hydrogen atom, alkyl WITH1-C4the halogen atom; each of R2and R3independently denotes a hydrogen atom or alkyl WITH1-C4; Аlк denotes alkane(C1-C4)diyl, each of R4and R5independently denotes hydrogen atom or halogen atom, or WITH1-C4-alkyl, and Неt denotes the group of one of formulae

where R6denotes a hydrogen atom, alkyl (C1-C6), oxyalkyl(C1-C6), cycloalkyl(C3-C6), phenyl or amino; each of R7independently denotes a hydrogen atom, alkyl (C1-C6), cycloalkyl(C3-C6), phenyl or trifluoromethyl, and their salts or a stereochemical isomeric form

The invention relates to the production of new proizvodnyh of thiazolidine that are used in pharmaceutical compositions

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

The invention relates to a new di-tert-butylaniline derivative used for the treatment of inflammatory processes, as well as caused by ischemia cell damage

The invention relates to new azetidinone derived isothiazol-pyridone: 2,3,4,9-tetrahydroindazole[5,4-b]China - in-3,4-dione, 2,3,4,9-tetrahydrothieno [5,4-b] [1,8]-naphthiridine-3,4-dione, 1,2,8,9-tetrahydro-7H-isothiazol-[4',5',5,6]pyrido [1,2,3-de]benzoxazine-7,8-dione and its salts

The invention relates to benzothiazole derivative that is highly effective as a medicinal product, namely, benzothiazole derivative, useful as a preventive and therapeutic agent for diseases in which the function of suppressing the production of leukotrienes and thromboxanes are effective
The invention relates to medicine and used to replenish the Arsenal of normalizing the immune status of the organism

The invention relates to medicine and can be used to enhance antibacterial activity and expansion of the spectrum of antibacterial action

The invention relates to medicine, in particular to the surgery and the result they have proved
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