Novel oxazolidinone derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to oxazolidinone derivatives of formula (I) or pharmaceutically acceptable salts thereof, synthesis method thereof and pharmaceutical compositions containing said derivatives which are used as an antibiotic. Oxazolidinone derivatives, where R1 and R1' independently denote hydrogen or fluorine; R2 denotes -OR7, fluorine, monophosphate or metal phosphate; and R7 denotes hydrogen, C1-3alkyl or an acylated amino acid group, where the amino acid is alanine, glycine, proline, proline, isoleucine, leucine, phenylalanine, β-alanine or valine; R3 denotes hydrogen, a C1-4alkyl group which is unsubstituted or substituted cyano, , -(CH2)m-OR7 (m equals 0, 1, 2, 3, 4) or a ketone group. Oxazolidinone derivatives of formula (I) have antibacterial activity against different human and animal pathogens.

EFFECT: oxazolidinone derivatives, having inhibiting activity towards a wide range of bacteria and having low toxicity.

27 cl, 4 tbl, 73 ex

 

The technical field

This invention relates to new derivatives of oxazolidinone, methods for their preparation and pharmaceutical compositions containing them for use as antibiotics.

The level of technology

Used as input oral antibacterial agents oxazolidinone connections are not products of fermentation, and is obtained by synthesis, various known derivatives of these substances. For example, derivatives of 3-phenyl-2-oxazolidinone containing one or two Deputy, stated in U.S. patents 4948801, 4461773, 4340606, 4476136, 4250318 and 4128654. Derivatives of 3-[(monosubstituted) phenyl]-2-oxazolidinone formula 2 described in EP 0 312 000, J. Med. Chem. 32, 1673 (1989), J. Med. Chem. 33, 2569 (1990), Tetrahedron, 45, 123 (1989), etc.

<Formula 2>

Pharmacia and decision Upjohn developed derivative oxazolidinone formulas 3 and 4 (WO 93/23384, WO 95/14684 and WO 95/07271). Being approved by the Food and Drug Administration (FDA) in the United States derived oxazolidinone formula 3, called "Zyvox", went on sale. However, it was found that these conventional synthetic oxazolidinone connections have the disadvantage antibacterial activity against a narrow spectrum of bacteria, they are toxic to people and have a low therapeutic activity in vivo. Zyvox can be applied is limited by injection, because the solubility of Zvox in the water is not suitable for use in injection, this solubility is approximately 3 mg/ml

<Formula 3>

<Formula 4>

In WO 93/09103 described derivatives of phenyloxazolidine, substituted heterocycles such as thiazole, indole, oxazole and China, as well as pyridine, in position 4 of the phenyl ring. However, it is known that these derivative oxazolidinone lack of medical activity, as well as heterocycles substituted by simple substituents, such as alkyl or amino group.

In WO 01/94342 was described the synthesis of derivatives of phenyloxazolidine containing a pyridine group, or derivatives of phenyl in position 4 of the phenyl ring. The compounds possess inhibitory activity against a broad spectrum of bacteria and surpass Zyvox as antibiotics. However, these compounds cannot be entered in the form of injections, as their solubility less than 30 mcg/ml

Accordingly, intensive and thorough research derivatives oxazolidinone conducted by the inventors and intended to overcome the problems encountered in the prior art led to the creation of derivatives oxazolidinone, and their prodrugs, and prodrugs are obtained by the reaction of amino acids or phosphate derivative of oxazolidinone containing a hydroxyl group. In addition, salt deposition is level oxazolidinone easily synthesized using amino acids with obtaining an organic acid or inorganic acid and application of the hydroxyl group of the phosphate, and the element selected from sodium and calcium. Derivative oxazolidinone have excellent antibiotic properties, and their solubility is greatly increased.

Brief description of the invention

The purpose of this invention to provide new derivatives of oxazolidinone.

Another objective of the invention is to provide a method for obtaining the above derivatives.

Another objective of the invention consists in obtaining pharmaceutical compositions containing these derivatives, for use as an antibiotic.

Detailed description of the invention

This invention provides new derivatives of oxazolidinone formula 1, below.

<F1>

In formula 1, X represents carbon or nitrogen;

R1and R1', respectively, denote hydrogen or fluorine;

R2refers to-NR5R6, -OR7, triazole, fluorine, alkylphosphate, monophosphate or metal phosphate salt;

R5and R6identical or different, denote hydrogen, substituted C1-4alkyl group or acetyl; and

R7denotes hydrogen, substituted C1-3alkyl group or an acylated amino group. When R7indicates an acylated amino group, the amino acid is alanine, glycine, Proline, isoleucine, leucine, f is kilalanin, β-alanine or valine;

Het represents a heterocyclic ring or a heteroaromatic ring and relates to pyrrole, furan, piperazine, piperidine, imidazole, 1,2,4-triazole, tetrazole, pyrazole, pyrrolidine, oxazole, isoxazol, oxadiazole, pyridine, pyrimidine, thiazole or pyrazine;

R3and R4identical or different, denote hydrogen, substituted C1-4alkyl group which is unsubstituted or substituted by cyano, -(CH2)m-OR7(m is equal to 0, 1, 2, 3, 4) or catography.

Derivative oxazolidinone corresponding to formula 1, can be applied in the form of a pharmaceutically acceptable salt, which is a salt of accession to the acid, obtained using a pharmaceutically acceptable free acid. The free acid may be inorganic or organic. Inorganic free acid may be a hydrochloric acid, bromobutyl acid, sulfuric acid, phosphoric acid, etc. free Organic acid may be citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonate, glycolic acid, succinic acid, 4-toluensulfonate, triperoxonane acid, glucuronate acid, monowai acid, glutamic acid, etc.

Preferred compounds according to this invention include the following compounds, listed in Table 1:

1) (S)-3-(4-(2-(2-oxo-4-glycidoxypropyl-1-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate triperoxonane acid,

2) (S)-3-(4-(2-(4-glycerokinase-1,2,3-triazole-1-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate triperoxonane acid,

3) (S)-3-(4-(2-(5-glyceroltrinitrate-3-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate triperoxonane acid,

4) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-([1,2,4]-triazole-1-yl)methyloxazolidine-2-it,

5) (S)-3-(4-(2-(2-oxo-3-glycidoxypropyl-1-yl)pyridin-5-yl)-3-fluoro-phenyl)-2-oxo-5-oxazolidinecarboxylate triperoxonane acid,

6) (S)-3-(4-(2-(5-glycerokinase-[1,2,4]oxadiazol-3-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate triperoxonane acid,

7) (S)-3-(4-(2-(5-glycerokinase-4,5-dihydroisoxazole-3-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate triperoxonane acid,

8) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-([1,2,3]-triazole-2-yl)-methyloxazolidine-2-it,

9) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-([1,2,3]-triazole-1-yl)-methyloxazolidine-2-it,

10) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-guide-Oxymetazoline--he,

11) (S)-3-(4-(4-(4,5-dimethyloxazole-2-yl)phenyl)-3-forfinal)-2-oxo-5-oxa-soldnermentalitat,

12) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-glycyl-oxitetraciclina-2-he-triperoxonane acid,

13) (R)-3-(4-(2-2-methyl-[1,3,4] oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-([1,2,3]triazole-1-yl)-methyloxazolidine-2-it,

14) (R)-3-(4-(2-[1,2,4]triazole-1-yl)pyridin-5-yl)-3-forfinal)-5-([1,2,3]-triazole-1-yl)-methyloxazolidine-2-it,

15) (S)-3-(4-(2-(4,5-dimethyloxazole-2-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate,

16) (R)-3-(4-(2-2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-hydroxymethylimidazole-2-it,

17) (R)-3-(4-(2-[1,2,4]triazole-1-yl-pyridine-5-yl)-3-forfinal)-5-hydroxy-methyloxazolidine-2-it,

18) (R)-3-(4-(2-2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-fluoro-methyloxazolidine-2-it,

19) (S)-3-(4-(2-(imidazol-1-yl)pyridin-5-yl)-3-forfinal)-5-aminomethyl-oxazolidin-2-she hydrochloride

20) (R)-3-(4-(2-2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-Wallace)methyloxazolidine-2-he-triperoxonane acid,

21) (R)-3-(4-(4-(4,5-dimethyloxazole-2-yl)phenyl)-3-forfinal)-5-hydroxy-methyloxazolidine-2-it,

22) (R)-3-(4-(2-[1,2,3]triazole-1-yl)pyridin-5-yl)-3-forfinal)-5-glycyl-oxitetraciclina-2-he-triperoxonane acid,

23) (R)-3-(4-(4-(4,5-dimethyloxazole-2-yl)phenyl)-3-forfinal)-5-glycyl-oxitetraciclina-2-he-triperoxonane acid,

24) (R)-3-(4-(-[1,2,3]triazole-1-yl)pyridin-5-yl)-3-forfinal)-5-hydroxy-methyloxazolidine-2-it,

25) (S)-3-(4-(2-[1,2,3]triazole-2-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate,

26) (S)-3-(4-(4-(4(S)-hydroxymethyl-4,5-dihydrooxazolo-2-yl)phenyl)-3-fluoro-phenyl)-2-oxo-5-oxazolidinecarboxylate,

27) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluoro-phenyl)-5-glycinexylidide-2-he-triperoxonane acid,

28) (S)-3-(4-(4-(4-hydroxymethylimidazole-2-yl)phenyl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate,

29) (R)-3-(4-(2-[1,2,3]triazole-2-yl)pyridin-5-yl)-3-forfinal)-5-hydroxy-methyloxazolidine-2-it,

30) (S)-3-(4-(4-(4-glycinexylidide-2-yl)phenyl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate triperoxonane acid,

31) (S)-3-(4-(4-(4-seanmeister-2-yl)phenyl)-3-forfinal)-2-oxo-5-oxa-soldnermentalitat,

32) (R)-3-(4-(4-(4-seanmeister-2-yl)phenyl)-3-forfinal)-5-hydroxy-methyloxazolidine-2-it,

33) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-meth-oxitetraciclina-2-it,

34) (R)-3-(4-(4-(4-seanmeister-2-yl)phenyl)-3-forfinal)-5-glycyl-oxitetraciclina-2-he-triperoxonane acid,

35) (R)-3-(4-(2-[1,2,3]triazole-2-yl)pyridin-5-yl)-3-forfinal)-5-glycyl-oxitetraciclina-2-he-triperoxonane acid,

36) (R)-3-(4-(4-(4-hydroxymethylimidazole-2-yl)phenyl)-3-forfinal)-5-([1,2,3]-triazole-1-yl)methyloxazolidine-2-it,

37) (R)-3-(4-(4-(4-glycinexylidide-2-yl)phenyl)-3-forfinal)-5-([1,2,3]triazole-1-yl)methoxazole the DIN-2-he-triperoxonane acid,

38) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl) - for 3,5-differenl)-5-hydroxymethylimidazole-2-it,

39) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl) - for 3,5-debtor-phenyl)-5-hydroxymethylimidazole-2-it,

40) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(N,N-dimethylaminomethyl)oxazolidin-2-it,

41) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(N-methylaminomethyl)oxazolidin-2-it,

42) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-Ala-yloxy)methyloxazolidine-2-he-triperoxonane acid,

43) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-Wallace)methyloxazolidine-2-she hydrochloride

44) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-alanylons)methyloxazolidine-2-she hydrochloride

45) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-glycinexylidide-2-she hydrochloride

46) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-propenyloxy)methyloxazolidine-2-he-triperoxonane acid,

47) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-propenyloxy)methyloxazolidine-2-she hydrochloride

48) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-glycinexylidide-2-she hydrochloride

49) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(β-alanylons)methyloxazolidine-2-he-triperoxonane acid,

50) (R)-3-(4-(2-(2-methyl shall tetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(β-alanylons)methyloxazolidine-2-she hydrochloride

51) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-alanylons)methyloxazolidine-2-he-triperoxonane acid,

52) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-alanylons)methyloxazolidine-2-she hydrochloride

53) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-Wallace)methyloxazolidine-2-he-triperoxonane acid,

54) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-Wallace)methyloxazolidine-2-she hydrochloride

55) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-propenyloxy)methyloxazolidine-2-he-triperoxonane acid,

56) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-propenyloxy)methyloxazolidine-2-she hydrochloride

57) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(β-alanylons)methyloxazolidine-2-he-triperoxonane acid,

58) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(β-alanylons)methyloxazolidine-2-she hydrochloride

59) (R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinyl]matildastreet,

60) (R)-[3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinyl]matildastreet,

61) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-hydroxymethylimidazole-2-it,

62) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl-3-forfinal)-5-or-celexamedication-2-he-triperoxonane acid,

63) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-gli-celexamedication-2-she hydrochloride

64) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-alanylons)methyloxazolidine-2-he-triperoxonane acid,

65) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-alanylons)methyloxazolidine-2-she hydrochloride

66) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-Wallace)methyloxazolidine-2-he-triperoxonane acid,

67) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-Wallace)methyloxazolidine-2-she hydrochloride

68) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(β-alanylons)methyloxazolidine-2-he-triperoxonane acid,

69) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(β-alanylons)methyloxazolidine-2-she hydrochloride

70) (R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinyl]matildastreet,

71) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-([1,2,3]-triazole-1-yl)methyloxazolidine-2-it,

72) mono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinyl]methyl]phosphate and

73) mono-[(R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinyl]methyl]phosphate.

In Table 1 as "OSN which includes acyl and fO" means triperoxonane acid.

Further, the invention provides a method of obtaining derivatives oxazolidinone formula 1, which is shown in Scheme 1 below.

<1>

Scheme 1 Z denotes C-substituted C1-4alkyl group, X, R1, R'1, R2, R3and R4indicated for formula 1, Y denotes a halogen.

The method of obtaining derivatives oxazolidinone according to the invention includes:

substitution of the hydrogen atom of halogen in the phenyl ring derivative (II) of hydroxymethylcytosine obtaining compound (III) (stage 1);

substitution of the halogen atom (Y) stanila derived in (III) to obtain the compound (IV) (stage 2);

interaction derivative (IV) with pyridine or phenyl derivative which is substituted by bromine or iodine, with the formation of a derivative (V) oxazolidinone containing a pyridine ring or a phenyl ring (stage 3), and

interaction derivative (V) with an amino acid containing a protective group, and then with acid to remove the protective group and with the formation of salts of the compounds of formula 1, or interaction derivative (V) with phosphate and then with the salt of the metal with the formation of salts of the compounds of formula 1 (stage 4).

Derivative (II) of hydroxymethylcytosine used in stage 1 can be obtained by conventional methods. For example, such a method m which may include the substitution of the amino group of aniline benzyloxycarbonyloxy group and the interaction of substituted compounds with glycidylether in the form of strong bases with obtaining derivative (II). This basis can be obtained by adding a strong base; preferably a strong base can include n-utility, Deut. utility, trebutaries etc., more preferred is n-utillity. In addition, it is preferable to carry out this method at a temperature of about -78°C. in a medium of liquid nitrogen.

Stage 1 is carried out in order to substitute the hydrogen atom of the phenyl group derivative (II) a halogen atom, preferably an iodine atom. When the hydrogen atom is replaced by an atom of iodine, the reaction preferably takes place by adding monochloride iodine (ICl) or a silver salt triperoxonane acid (CF3COOAg) and iodine at room temperature.

Stage 2 represents the reaction of a derivative (III) with hexamethyldisilane, hexabutylditin or tributyltinhydride adding palladium catalyst to obtain the derivative (IV), iodine atom which is substituted trimethylaniline group or tributylstannyl group. Palladium-based catalyst may include dichlorobistriphenylphosphine palladium (II), tetrakis-triphenylphosphine palladium (0) and so it is Preferable to carry out Stage 2 in 1,4-dioxane as solvent, and in dimethylformamide, tetrahydrofuran, 1-methyl-2-pyrrolidone, etc. at a temperature of about 90-150°C.

At Stage 3 carry out R the action of a derivative (IV) with the compound, containing heterocycle attached to a phenyl or pyridine ring with obtaining derivative (V). Palladium-based catalyst, is added to the Stage 3 can be identical palladium catalyst in Stage 2. It is preferable to carry out a Stage 3 in a medium of dimethylformamide, 1-methyl-2-pyrrolidone, etc. at a temperature of about 100-120°C.

In Stage 4 there is an interaction derivative (V) with the amino acid, the amino group of which is protected tert. butoxycarbonyl, dicyclohexylcarbodiimide and 4-dimethylaminopyridine with derivatization (I)containing an amino group.

The amino acid may include alanine, glycine, Proline, isoleucine, leucine, phenylalanine, β-alanine, valine and the like, the Solvent may be dimethylformamide, 1-methyl-2-pyrrolidone, etc. it is Preferable to conduct the reaction of the derivative (V) with an amino acid under stirring for about 5 hours at a temperature above room temperature.

A mixture of the derivative (V) and amino acid reacts with a strong acid, such as triperoxonane and the like, for removal of the protective group. The solvent is removed from the mixture, the mixture thus crystallized with the formation of salts derived oxazolidinone formula 1. It is preferable to add derivative (V) to the amino acid under stirring for about 2 h at a temperature above room temperature.

You can receive is to be salt of a derivative of formula 1, obtained with the use of amino acids in a manner similar to that described above. (S)-3-(4-trimethyl-stannyl-3-forfinal)-2-oxo-5-oxazolidinedione, which is the original substance known, and the method described in WO 01/94342.

Phosphate salt derivative (I) can be obtained by adding sodium methoxide, sodium hydroxide, etc. to the composition in the environment of a solvent, such as methanol, ethanol and the like, the composition is produced by dissolving the derivative (V) in trimethylphosphate or triethyl phosphate, the addition of phosphorus oxychloride and stirring for about 12 hours at room temperature. Metal phosphate salt can be obtained by the reaction of a derivative (V) with tetrazole and derivatives amidite room temperature, the oxidation of the compounds obtained by derivatization of alkylphosphate, removing alkyl groups strong acid derivatization phosphate and transformation derived phosphate metal salt of phosphate as described above.

In addition, this invention provides a pharmaceutical composition comprising a derivative oxazolidinone formula 1, used as an antibiotic.

Derivative oxazolidinone of the present invention have inhibitory activity against a broad spectrum of bacteria, methicillin-resistant Staphylococcus aureus (MRSA) and re is istennoy to vancomycin Enterococci (VRE), and show excellent antibiotic activity at low concentrations in vivo.

In addition, the derivatives according to this invention can exhibit strong antibacterial activity against various pathogens in humans and animals, including gram-positive bacteria, such as Susceptible, Enterococci and Streptococci, anaerobic organisms such as Bacteroides and Clostridia, and acid-resistant microorganisms, such as Mycobacterium tuberculosis and Mycobacterium avium.

Derivative oxazolidinone containing hydroxyl groups react with the amino or phosphate with getting their prodrugs. These prodrugs are better soluble in water than connections that are not prodrugs: solubility of prodrugs are more equal than 28 mg/ml and the solubility of compounds 10 mg/ml (compound 10). Prodrugs are stable in water and acidic solution and turn into hydroxymethylene compounds under the action of esterase and phosphatase in the blood, which makes it possible to obtain the composition for injection or oral administration.

The composition according to this invention may include at least one active ingredient, acting like a derivative of oxazolidinone.

To obtain pharmaceutical compositions, at least one compound of formula 1 can be mixed with at least one pharmaceutically acceptable carrier.

Pharmaceutically acceptable carrier may include saline, sterile water, ringer's solution, sauverny saline solution, dextrose solution, maltodextrin, glycerin, ethanol and the like, In accordance with user needs, the pharmaceutical composition may contain conventional additives, such as antioxidant, buffer, cleaner, etc. of the Composition are mixed with diluents, disintegrants, surfactants, binders, lubricating agents, aqueous solution, suspension, etc. to obtain compositions for injections, powders, capsules, granules, tablets and other Formulations are prepared in appropriate methods described in Remington''s Pharmaceutical Science (the newest edition), Mack Publishing Company, Easton PA, taking into account disease and ingredients.

The connection according to this invention can be administered orally or parenterally, for example intravenously, subcutaneously, intraperitoneally, locally and so the Dose of a compound may vary depending on the specific compound, method of administration, the condition, the degree of its severity, as well as from various physical factors related to the patient undergoing treatment. Satisfactory results are obtained when the compounds according to the invention is administered to a patient in need this, with a daily dose from about 10 mg to primer is 25 mg per kg of body weight, preferably from about 13 mg to about 20 mg per kg of body weight, and more preferably each of the divided doses several times a day.

Lethal dose (LD50) derivatives oxazolidinone is more than 1 g/kg in the determination of acute toxicity, the compounds are stable.

Useful properties

Derivative oxazolidinone of the present invention have inhibitory activity against a broad spectrum of bacteria and have low toxicity. Prodrugs obtained by the reaction of compounds containing hydroxyl groups, amino acid or phosphate is highly soluble in water.

In addition, the derivatives according to this invention can exhibit strong antibacterial activity against various pathogens in humans and animals, including gram-positive bacteria, such as Susceptible, Enterococci and Streptococci, anaerobic organisms such as Bacteroides and Clostridia, and acid-resistant microorganisms, such as Mycobacterium tuberculosis and Mycobacterium avium.

In accordance with this composition containing the derivative oxazolidinone, used as an antibiotic.

Examples of carrying out the invention

The examples are only to illustrate and not limit the invention, since it is not beyond the scope of this invention it is possible to implement many of its variations is AI.

Preparative example 1: Obtaining N-carbobenzoxy-3-foronline

3-ftoranila, 100 g, was dissolved in 1 l of tetrahydrofuran (THF) and the solution was added 150 g (1.8 M) of sodium bicarbonate (NaHCO3). After cooling to 0°C. to the solution was slowly added 154 ml of N-carbobenzoxy (CbzCl). The temperature was maintained at 0°C and stirred the mixture for 2 hours Then the reaction mixture for extraction was treated with 0.5 l of ethyl acetate. The organic layer after separation was washed with brine, dried over anhydrous magnesium sulfate (MgSO4) and concentrated in vacuum. The residue was twice washed with n-hexane, obtaining the target compound as white crystals (132 g). The output is 85%.

Preparative example 2: Obtaining (R)-3-(3-forfinal)-2-oxo-5-oxazo-latinillegal

132 g of N-carbobenzoxy-3-foronline obtained in preparative example 1 was dissolved in 1.3 l of tetrahydrofuran and cooled the solution to -78°C. To this solution was added to 370 ml of n-utility (n-BuLi, 1.6 M /n-hexane) under nitrogen atmosphere and was stirred for 10 minutes. To the reaction mixture slowly added 84 ml (R)-(-)-glycidylmethacrylate, was stirred at the same temperature for 2 h and left for 24 h at room temperature. After completion of the reaction the solution was added a solution of ammonium chloride (NH4Cl) and for the extraction of added 0.5 l of ethyl acetate at room tempera is ur. Selected organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuum. The residue was dissolved in 100 ml ethyl acetate and washed with hexane to obtain white crystals, which were purified with 80 g of the target compound. The yield was 70%.

1H NMR (DMSO-d6) δ 7.85 (t, 1H), 7.58 (dd, 1H), 7.23 (dd, 1H), 4.69 (m, 1H), 4.20 (t, 1H), 3.80 (dd, 1H), 3.60 (br dd, 2H).

Preparative example 3: Obtaining (R)-3-(4-iodine-3-forfinal)-2-oxo-5-oxazolidinyl

In 300 ml of acetonitrile was dissolved in 30 g of (R)-3-(3-forfinal)-2-oxo-5-oxazo-latinillegal obtained in preparative example 2, and 46 g of the silver salt triperoxonane acid (CF3COOAg) and 43 g of iodide added to the obtained solution. After stirring for 1 day at room temperature to the solution was added water and was extracted with ethyl acetate. Selected organic layer was washed with brine and dehydrational. Then the residue was filtered, concentrated in vacuum and dried to obtain 44 g of the target compound. The yield was 94%.

1H NMR (DMSO-d6) δ 7.77 (t, 1H), 7.56 (dd, 1H), 7.20 (dd, 1H), 5.20 (m, 1H), 4.70 (m, 1H), 4.07 (t, 1H), 3.80 (m, 1H), 3.67 (m, 2H), of 3.56 (m, 3H).

Preparative example 4: Obtaining (R)-3-(4-tributylstannyl-3-fluoro-phenyl)-2-oxo-5-oxazolidinyl

In 660 ml of 1,4-dioxane was dissolved 50 g of (R)-3-(4-iodine-3-forfinal)-2-oxo-5-oxa-solidariedade, poluchennogo preparative example 3. To the solution was added 52 g hexabutylditin ((VI3Sn)2) and 9.3 g dichlorobistriphenylphosphine and was stirred for 2 h the Solution was filtered through celite and concentrated in vacuum. The residue was purified through column chromatography and obtained 45 g of target compound.

1H NMR (DMSO-d6) δ 7.74 (m, 3H), 5.20 (t, 1H), 4.71 (m, 1H), 4.08 (t, 1H), 3.82 (dd, 1H), 3.68 (m, 1H), 3.52 (m, 1H), 1.48 (m, 6H), 1.24 (m, 6H), 1.06 (m, 6H), 0.83 (t, 9H).

Preparative example 5: Getting 2-cyan-5-bromopyridine

100 g of 2,5-dibromopyridine was dissolved in 1 l of dimethylformamide, to the solution was added 32 g of copper cyanide and 17.8 g of sodium cyanide and stirred the solution at 150°C for 7 h After cooling to room temperature the reaction mixture was added water, and extraction was added ethyl acetate. The organic layer was washed with brine, dehydrational, filtered and concentrated in vacuum. Received 54 g of target compound. The yield was 70%.

1H NMR (CDCl3) δ 8.76 (s, 1H), 7.98 (dd, 1H), 7.58 (dd, 1H).

Preparative example 6: Obtain 2-(tetrazol-5-yl)-5-bromopyridine

10 g of 2-cyan-5-bromopyridine obtained in preparative example 5, was dissolved in 100 ml of dimethylformamide. At room temperature to the resulting solution was added 5,33 g of sodium azide and 4.4 g of ammonium chloride and stirred the solution at 110°C for 3 h In the reaction mixture were added water and for which straccia was added ethyl acetate. The organic layer was washed with brine, dehydrational, filtered and concentrated in vacuum. Received of 10.5 g of the target compound. The yield was 85%.

Preparative example 7: Obtain 2-(1-methyltetrazol-5-yl)-5-bromopyridine and 2-(2-methyltetrazol-5-yl)-5-bromopyridine

of 10.5 g of 2-(tetrazol-5-yl)-5-bromopyridine obtained in preparative example 6, was dissolved in 100 ml of dimethylformamide. To the solution was added 6.5 g of sodium hydroxide and at a temperature of 0°C was slowly added 9.3 g of iodomethane. The solution was stirred 6 h at room temperature, added water and ethyl acetate for extraction. Then the organic layer was washed with brine, dehydrational, filtered, concentrated in vacuum and purified through column chromatography, receiving 4 g of 2-(1-methyltetrazol-5-yl)-5-bromopyridine and 5 g of 2-(2-methyltetrazol-5-yl)-5-bromopyridine.

1) 2-(1-methyltetrazol-5-yl)-5-bromopyridin

1H NMR (CDCl3) δ 8.77 (t, 1H), 8.23 (dd, 1H), 8.04 (dd, 1H), 4.46 (s, 3H).

2) 2-(2-methyltetrazol-5-yl)-5-bromopyridine.

1H NMR (CDCl3) δ 8.80 (t, 1H), 8.13 (dd, 1H), 7.98 (dd, 1H), 4.42 (s, 3H).

Preparative example 8: Obtaining 2-(2-methyl-[1.3.4]oxadiazol-5-yl)-5-bromopyridine

In 130 ml of acetic anhydride was dissolved 8.6 g of 2-(tetrazol-5-yl)-5-bromopyridine obtained in preparative example 6. Then to the resulting solution was added 15 ml of pyridine and stirred for 3 hours To the reaction with the art was added was extracted with ethyl acetate and the organic layer. Then the organic layer was washed with water and brine. The organic layer dehydrational, filtered, concentrated in vacuum, obtaining of 7.3 g of the target compound. The yield was 80%.

1H NMR (Dl3) δ 7.99 (t, 1H), 7.40 (dd, 1H), 7.27 (dd, 1H), 1.83 (s, 3H).

Preparative example 9: Getting 2-([1.2.3]triazole-1-yl)-5-bromopyridine and 2-([1.2.3]triazole-2-yl)-5-bromopyridine

20 g of 2,5-dibromopyridine was dissolved in 200 ml of 1-methyl-2-pyrrolidone. To the solution was added 35 g of potassium carbonate and stirred for 10 h at a temperature of 100°C. To the reaction mixture was added ethyl acetate, and the thus obtained organic layer was washed with water and brine. The organic layer was dried, filtered and concentrated under vacuum, received 6 g of 2-([1.2.3]triazole-1-yl)-5-bromopyridine and 4 g of 2-([1.2.3]triazole-2-yl)-5-bromopyridine.

1) 2-([1.2.3]triazole-1-yl)-5-bromopyridin

1H NMR (CDCl3) δ 8.53 (dd, 2H), 8.10 (d, 1H), 8.03 (dd, 1H), 7.82 (s, 1H).

2) 2-([1.2.3]triazole-2-yl)-5-bromopyridine

1H NMR (CDCl3) δ 8.60 (t, 1H), 7.97 (s, 2H), 7.87 (s, 2H).

Example 1: Obtaining (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-hydroxymethylimidazole-2-on (compound 10)

In 150 ml of 1-methyl-2-pyrrolidone was dissolved 37 g (R)-3-(4-tributylstannyl-3-forfinal)-2-oxo-5-oxazolidinone. To the solution was added to 19.7 g of 2-(2-methyltetrazol-5-yl)-5-bromopyridine, 10,44 g of lithium chloride and 2.9 g dichlorobistriphenylphosphine lady (II) at room temperature and then stirred at 120°C for 4 h In the reaction mixture were added water and ethyl acetate. The separated organic layer was washed with water, dehydrational, filtered, concentrated in vacuum and purified through column chromatography to obtain 8 g of the target compound. The yield was 26%.

1H NMR (DMSO-d6) δ 8.90 (s, 1H), 8.18 (m, 2H), 7.70 (m, 2H), 7.49 (dd, 1H), 5.25 (t, 1H), 4.74 (m, 1H), 4.46 (s, 3H), 4.14 (t, 1H), 3.88 (dd, 1H), 3.68 (m, 1H), to 3.58 (m, 1H).

Example 2: Obtaining (R)-3-(4-(2-2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-hydroxymethylimidazole-2-she (compound 16)

This compound (6.6 g, 30%yield) was obtained in a manner analogous to the one described in Example 1, except that as the starting compound instead of 2-(2-methyltetrazol-5-yl)-5-bromopyridine applied 14.3 g of 2-(2-methyl-[1,3,4]-oxadiazol-5-yl)-5-bromopyridine.

1H NMR (DMSO-d6) δ 8.93 (s, 1H), 8.21 (s. 2H), 7.71 (m, 2H), 7.50 (dd, 1H), 5.25 (t, 1H), 4.74 (m, 1H), 4.14 (t, 1H), 3.89 (dd, 1H), 3.68 (m, 1H), 3.59 (m, 1H), 2.64 (s, 3H).

Example 3: Obtaining (R)-3-(4-(2-[1,2,4] triazole-1-yl-pyridine-5-yl)-3-forfinal)-5-hydroxymethylimidazole-2-she (compound 17)

Repeating the procedure described in Example 1, but instead of 2-(2-methyltetrazol-5-yl)-5-bromopyridine used 200 mg of 2-([1,2,4] triazole-1-yl)-5-bromopyridine received target compound (150 mg, yield 48%).

Example 4: Obtaining (R)-3-(4-(4-(4,5-dimethyloxazole-2-yl)phenyl)-3-fluoro-phenyl)-5-hydroxymethylimidazole-2-she (compound 21)

Repeated procedures is, described in Example 1, but instead of 2-(2-methyltetrazol-5-yl)-5-bromopyridine used 1 g of 4-(4,5-dimethyloxazole-2-yl) bromine benzol, got 780 mg of target compound (yield 76%).

1H NMR (DMSO-d6) δ 7.96 (s, 1H), 7.94 (s, 1H), 7.63 (m, 4H), 7.44 (dd, 1H), 5.23 (t, 1H), 4.72 (m, 1H), 4.12 (t, 1H), 3.87 (dd, 1H), 3.68 (m, 1H), 3.56 (m, 1H), 2.32 (s, 3H), 2.10 (s, 3H).

Example 5: Receiving (R)-3-(4-(2-[l,2,3]triazole-1-yl)pyridin-5-yl)-3-forfinal)-5-hydroxymethylimidazole-2-she (compound 24)

Repeating the procedure described in Example 1, but instead of 2-(2-methyltetrazol-5-yl)-5-bromopyridine used 2 g of 2-([1,2,3]triazole-1-yl)-5-bromopyridine, received 1.2 g of the target compound.

1H NMR (DMSO-d6) δ 8.88 (s, 1H), 8.76 (s, 1H), 8.28 (d, 1H), 8.21 (d, 1H), 8.01 (s, 1H), 7.70 (m, 2H), 7.51 (dd, 1H), 5.26 (t, 1H), 4.75 (m, 1H), 4.14 (t, 1H), 3.90 (dd, 1H), 3.68 (m, 1H), 3.58 (m, 1H).

Example 6: Obtaining (R)-3-(4-(2-[l,2,3]triazole-2-yl)pyridin-5-yl)-3-forfinal)-5-hydroxyisoquinoline-2-she (compound 29)

Repeating the procedure described in Example 1, but instead of 2-(2-methyltetrazol-5-yl)-5-bromopyridine used 1 g of 2-([1,2,3]triazole-2-yl)-5-bromopyridine, was obtained 0.7 g of the target compound.

1H NMR (DMSO-d6) δ 8.74 (s, 1H), 8.25 (dd, 1H), 8.23 (s, 1H), 8.11 (d, 1H), 7.69 (m, 3H), 7.49 (dd, 1H), 5.24 (t, 1H), 4.75 (m, 1H), 4.14 (t, 1H), 3.89 (dd, 1H), 3.68 (m, 1H), 3.59 (m, 1H).

Example 7: Obtaining (R)-3-(4-(4-(4-seanmeister-2-yl)phenyl)-3-fluoro-phenyl)-5-hydroxymethylimidazole-2-she (compound 32)

Repeating the procedure described in Example 1, but instead is about 2-(2-methyltetrazol-5-yl)-5-bromopyridine used 1 g of 4-(4-seanmeister-2-yl)bromine benzol, received 520 mg of the target compound.

1H NMR (DMSO-d6) δ 8.04 (s, 1H), 8.00 (s, 1H), 7.65 (m, 5H), 7.47 (dd, 1H), 5.24 (t, 1H), 4.74 (m, 1H), 4.23 (s, 2H), 4.13 (t, 1H), 3.88 (dd, 1H), 3.68 (m, 1H), 3.59 (m, 1H).

Example 8: Obtaining (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl) - for 3,5-differenl)-5-hydroxymethylimidazole-2-she (compound 38)

Repeating the procedure described in Example 1, but instead of (R)-3-(4-tributyl-stannyl-3-forfinal)-2-oxo-5-oxazolidinyl used (R)-3-(4-tributylstannyl-3,4-differenl)-2-oxo-5-oxazolidinyl.

1H NMR (DMSO-d6) δ 8.81 (s, 1H), 8.25 (d, 1H), 8.10 (d, 1H), 7.54 (d, 2H), 5.25 (t, 1H), 4.77 (m, 1H), 4.47 (s, 3H), 4.13 (t, 1H), 3.89 (dd, 1H), 3.68 (m, 1H), 3.57 (m, 1H).

Example 9: Obtaining (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3,4-differenl)-5-hydroxymethylimidazole-2-she (compound 39).

Repeating the procedure described in Example 1, using as starting compounds (R)-3-(4-tributylstannyl-3,4-differenl)-2-oxo-5-oxazolidinone and 2-(2-methyl-[1,3,4]oxadiazol-5-yl)-5-bromopyridin.

1H NMR (DMSO-d6) δ 8.83 (s, 1H), 8.25 (d, 1H), 8.15 (d, 1H), 7.55 (d, 2H), 5.25 (t, 1H), 4.77 (m, 1H), 4.13 (t, 1H), 3.89 (dd, 1H), 3.68 (m, 1H), 3.59 (m, 1H), 2.63 (s, 3H).

Example 10: Obtaining (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-glycinexylidide-2-he-triperoxonane acid (compound 12)

In 25 ml of dimethylformamide was dissolved 4 g of (R)-3-(4-(2-(2-methyltetrazol-5-yl)-pyridine-5-yl)-3-forfinal)-5-hydroxymethylimidazole is n-2-she (compound 10). To the solution was added to 3.34 g of 1,3-dicyclohexylcarbodiimide, a 2.36 g of BOC-glycine and 0.2 g of 4-dimethylaminopyridine at room temperature and was stirred for 10 hours

In the reaction mixture were added water and ethyl acetate. Selected organic layer was washed with brine, dehydrational, filtered, concentrated in vacuum and purified through column chromatography. The obtained residue was dissolved in 70 ml of methylene chloride, was added 30 ml triperoxonane acid and stirred 2 h at room temperature. The residue was washed with ethanol and ethyl ether, concentrated in vacuum, obtaining 4.7 g of the target compound. Yield 76%.

1H NMR (DMSO-d6) δ 8.92 (s, 1H), 8.19 (s, 1H), 8.17 (m, 2H), 7.77 (t, 1H), 7.69 (dd, 1H), 7.49 (dd, 1H), 5.00 (m, 1H), 4.46 (m, 2H), 4.47 (s, 3H), 4.24 (t, 1H), 3.92 (dd, 1H), 3.90 (s, 2H).

Example 11: Obtain (R)-3-(4-(2-2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-Wallace)methyloxazolidine-2-he-triperoxonane acid (compound 20)

This compound was obtained by the method described in Example 10, using BOC-valine instead of BOC-glycine.

1H NMR (DMSO-d6) δ 8.92 (s, 1H), 8.40 (s, 3H), 8.21 (m, 2H), 7.76 (t, 1H), 7.65 (dd, 1H), 7.48 (dd, 1H), 5.05 (m, 1H), 4.63 (dd, 1H), 4.47 (s, 3H), 4.43 (dd, 1H), 4.28 (t, 1H), 4.01 (d, 1H), 3.93 (dd, 1H), 2.14 (m, 1H), 0.98 (d, 3H), 0.95 (d, 3H).

Example 12: Obtaining (R)-3-(4-(2-[1,2,3]triazole-1-yl)pyridin-5-yl)-3-forfinal)-5-glycinexylidide-2-he-triperoxonane acid (compound 22)

This compound p which were given, as described in Example 10, using the compound 24.

1H NMR (DMSO-d6) δ 8.87 (s, 1H), 8.76 (s, 1H), 8.33 (s, 3H), 8.29 (d, 1H), 8.00 (s, 1H), 7.77 (t, 1H), 7.76 (t, 1H), 7.67 (dd, 1H), 7.47 (dd, 1H), 5.02 (m, 1H), 4.49 (m, 2H), 4.23 (t, 1H), 3.93 (m, 3H).

Example 13: Obtaining (R)-3-(4-(4-(4,5-dimethyloxazole-2-yl)phenyl)-3-forfinal)-5-glycinexylidide-2-he-triperoxonane acid (compound 23)

This compound was obtained as described in Example 10, using the connection 21.

1H NMR (DMSO-d6) δ 8.31 (s, 3H), 7.97 (d, 2H), 7.64 (m, 4H), 7.45 (dd, 1H), 5.01 (m, 1H), 4.47 (m, 2H), 4.25 (t, 1H), 3.94 (dd, 1H), 3.90 (s, 2H).

Example 14: Obtaining (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-glycinexylidide-2-he-triperoxonane acid (compound 27)

This compound was obtained as described in Example 10, using the connection 16.

1H NMR (DMSO-d6) δ 8.96 (s, 1H), 8.31 (s, 3H), 8.22 (s, 2H), 7.76 (t, 1H), 7.66 (dd, 1H), 7.50 (dd, 1H), 5.04 (m, 1H), 4.50 (m, 2H), 4.25 (t, 1H), 3.94 (dd, 1H), 3.91 (s, 2H), 2.63 (s, 3H).

Example 15: Obtaining (R)-3-(4-(4-(4-seanmeister-2-yl)phenyl)-3-forfinal)-5-glycinexylidide-2-he-triperoxonane acid (compound 34)

This compound was obtained as described in Example 10, using the connection 32.

1H NMR (DMSO-d6) δ 8.25 (s, 3H), 8.03 (d, 2H), 7.68 (m, 5H), 7.44 (dd, 1H), 5.01 (m, 1H), 4.48 (m, 2H), 4.25 (m, 3H), 3.92 (m, 3H).

Example 16: Obtaining (R)-3-(4-(2-[1,2,3]triazole-2-yl)pyridin-5-yl)-3-forfinal)-5-glycinexylidide-2He-triperoxonane acid (compound 35)

This compound was obtained as described in Example 10, using the connection 29.

1H NMR (DMSO-d6) δ 8.78 (s, 1H), 8.23 (m, 2H), 8.22 (s, 3H), 8.20 (s, 1H), 8.12 (d, 1H), 7.75 (t, 1H), 7.67 (dd, 1H), 7.48 (dd, 1H), 5.01 (m, 1H), 4.49 (m, 2H), 4.24 (t, 1H), 3.92 (dd, 1H), 3.89 (s, 2H).

Example 17: Obtaining (S)-3-(4-(2-(2-oxo-4-glycidoxypropyl-1-yl) pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate triperoxonane acid (compound 1)

The first stage.

In 14 ml of 1-methyl-2-pyrrolidone was dissolved 1.8 g of (S)-3-(4-tributylstannyl-3-forfinal)-2-oxo-5-oxazolidinecarboxylate. To this solution was added to 1.03 g of 2-(2-oxo-4-hydroxyethylpyrrolidine-1-yl)-5-bromopyridine, 0.55 g of lithium chloride and 0.15 g dichlorobistriphenylphosphine (II) at room temperature and then was stirred at 110°C for 2 hours To the reaction mixture was added water and was extracted with ethyl acetate. After washing with brine selected organic layer dehydrational, filtered, concentrated in vacuum and purified through column chromatography to obtain 410 mg of (S)-3-(4-(2-(2-oxo-4-hydroxyethylpyrrolidine-1-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate. The yield was 21%.

2. The second stage

2.3 ml of dimethylformamide was dissolved 50 mg of the compound obtained in the first stage. To the solution was added at room temperature to 35 mg of 1,3-ditic-logicalgroove, 25 mg of BOC-glycine and 1 mg of 4-dimethylaminopyridine and then was stirred for 10 hours To the reaction mixture was added water and was extracted with ethyl acetate. After washing with brine selected organic layer dehydrational, filtered, concentrated in vacuum and purified through column chromatography. The residue was dissolved in 2 ml of methylene chloride was added 1 ml triperoxonane acid and then stirred at room temperature for 2 hours, the Residue was washed with ethanol and ethyl ether, evaporated in vacuum to obtain 140 mg of the target compound.

1H NMR (DMSO-d6) δ 8.60 (s, 1H), 8.40 (d, 1H), 8.28 (s, 3H), 8.25 (m. 1H), 8.08 (dd, 1H), 7.63 (m, 2H), 7.42 (dd, 1H), 4.76 (m, 1H), 4.27 (s, 2H), 4.16 (q, 2H), 3.87 (s, 2H), 3.80 (m, 2H), 3.42 (m, 2H), 2.62 (m, 1H), 2.11 (m, 1H), 1.83 (s, 3H).

Example 18: Obtaining (S)-3-(4-(2-(4-glycerokinase-[1,2,3]-triazole-1-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate triperoxonane acid (compound 2)

The reaction was carried out as described in Example 17, using instead 2-(2-oxo-4-hydroxyethylpyrrolidine-1-yl)-5-bromopyridine 2-(4-hydroxymethyl-[1,2,3]-triazole-1-yl)-5-bromopyridin.

1H NMR (DMSO-d6) δ 8.96 (s, 1H), 8.89 (s, 1H), 8.22 (m, 6H), 7.74 (t, 1H), 7.68 (dd, 1H), 7.48 (dd, 1H), 5.42 (s, 2H), 4.78 (m, 1H), 4.19 (t, 1H), 3.91 (s, 2H), 3.79 (dd. 1H), 3.43 (m, 2H), 1.83 (s, 3H).

Example 19: Obtaining (S)-3-(4-(2-(5-glyceroltrinitrate-3-yl)-pyridine-5-yl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate triperoxonane acid (compound 3)

The reaction was carried out as described in Example 17, using instead 2-2-oxo-4-hydroxyethylpyrrolidine-1-yl)-5-bromopyridine 2-(5-hydroxymethylimidazole)-5-bromopyridin.

1H NMR (DMSO-d6) δ 8.89 (s, 1H), 8.26 (s, 3H), 8.12 (m, 2H), 7.72 (t, 1H), 7.64 (dd, 1H), 7.48 (dd, 1H), 7.21 (s, 1H), 5.49 (s, 2H), 4.77 (m, 1H), 4.17 (t, 1H), 3.98 (s, 2H), 3.79 (m, 1H), 3.43 (m, 2H), 1.83 (s, 3H).

Example 20: Obtaining (S)-3-(4-(2-(2-oxo-3-glycidoxypropyl-1-yl)-pyridine-5-yl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate triperoxonane acid (compound 5)

The reaction was carried out as described in Example 17, using instead 2-(2-oxo-4-hydroxyethylpyrrolidine-1-yl)-5-bromopyridine 2-(2-oxo-3-hydroxypyrrolidine-1-yl)-5-bromopyridin.

1H NMR (DMSO-d6) δ 8.60 (s, 1H), 8.33 (d, 1H), 8.28 (s, 3H), 8.25 (m, 1H), 8.05 (d, 1H), 7.63 (m, 2H), 7.42 (dd, 1H), 5.78 (t, 1H), 4.78 (m, 1H), 4.16 (q, 2H), 3.98 (s, 2H), 3.85 (m, 1H), 3.78 (m, 1H), 3.43 (m, 2H), 2.62 (m, 1H), 2.12 (m, 1H), 1.83 (s, 3H).

Example 21: Obtaining (S)-3-(4-(2-(5-glycerokinase-[1,2,4]oxadiazol-3-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate triperoxonane acid (compound 6)

The reaction was carried out as described in Example 17 using 2-(5-hydroxymethyl-[1,2,4]-oxadiazol-3-yl)-5-bromopyridin instead of 2-(2-oxo-4-hydroxymethyl-pyrrolidin-1-yl)-5-bromopyridine.

1H NMR (DMSO-d6) δ 8.95 (s, 1H), 8.32 (s, 3H), 8.21 (m, 3H), 7.75 (t, 1H), 7.65 (dd, 1H), 7.47 (d, 1H), 5.67 (s, 1H), 4.78 (m, 1H), 4.18 (t, 1H), 4.05 (s, 2H), 3.80 (m, 1H), 3.43 (m, 2H), 1.83 (s, 3H).

Example 22: Obtaining (S)-3-(4-(2-(5-glycerokinase-4,5-dihydroisoxazole-3-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate triperoxonane acid (compound 7)

The reaction was carried out as description is but in Example 17, instead of using 2-(2-oxo-4-hydroxyethylpyrrolidine-1-yl)-5-bromopyridine 2-(5-hydroxymethyl-4,5-di-hydrosocial-1-yl)-5-bromopyridin.

1H NMR (DMSO-d6) δ 8.81 (s, 1H), 8.27 (t, 1H), 8.24 (s, 3H), 8.05 (m, 2H), 7.69 (m, 2H), 7.44 (d, 1H), 5.04 (m, 1H), 4.76 (m, 1H), 4.41 (dd, 1H), 4.32 (m, 1H), 4.17 (t, 1H), 3.86 (s, 2H), 3.77 (m, 1H), 3.60 (m, 1H), 3.44 (m, 2H), 1.83 (s, 3H).

Example 23: Obtaining (S)-3-(4-(4-(4-glycinexylidide-2-yl) phenyl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate triperoxonane acid (compound 30)

The reaction was carried out as described in Example 17, using instead 2-(2-oxo-4-hydroxyethylpyrrolidine-1-yl)-5-bromopyridine 4-(4-hydroxymethylimidazole-2-yl)bramasol.

1H NMR (DMSO-d6) δ 8.25 (s, 3H), 8.00 (d, 2H), 7.85 (s, 1H), 7.69 (m, 4H), 7.44 (dd, 1H), 5.63 (s, 2H), 4.76 (m, 1H), 4.16 (t, 1H), 3.93 (s, 2H), 3.79 (dd, 1H), 3.43 (m, 2H), 1.83 (s, 3H).

Example 24: Obtaining (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-([1,2,4]-triazole-1-yl)methyloxazolidine-2-she (compound 4)

1. The first stage

In 14 ml of methylene chloride was dissolved 1 g of (R)-3-(4-(2-(2-methyltetrazol-5-yl)-pyridine-5-yl)-3-forfinal)-5-hydroxymethylimidazole-2-she (compound 10). To the solution was added at room temperature and 0.46 g of methanesulfonamide and 0.75 ml of triethylamine and stirred at the same temperature for 30 minutes. The reaction mixture was washed with water and brine, and then extraction was performed. The organic layer dehydrational, filtered and concentrated in in the cosmology vacuum receiving 1 g (R)-3-(4-(2-(2-methyltetrazol-5-yl)-pyridine-5-yl)-3-forfinal)-5-methanesulfonylaminoethyl-2-it. The yield was 82%.

2. The second stage

The compound obtained in the first stage, was dissolved in 15 ml of dimethylformamide. To the solution was added 300 mg of 1,2,4-triazole and 100 mg of sodium hydride (60%) and stirred at room temperature for 2 days. The reaction mixture for extraction was treated with ethyl acetate and then the organic layer was washed with water and brine. The organic layer dehydrational, was filtered and concentrated in vacuum. The residue was purified through column chromatography and received 400 mg of the target compound. The output was equal to 43%.

1H NMR (DMSO-d6) δ 8.91 (s, 1H), 8.57 (s, 1H), 8.19 (m, 2H), 7.74 (t, 1H), 7.58 (dd, 1H), 7.42 (dd, 1H), 5.13 (m, 1H), 4.64 (m, 2H), 4.46 (s, 3H), 4.28 (t, 1H), 3.99 (dd, 1H).

Example 25: Obtaining (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-([1,2,3]-triazole-2-yl)methyloxazolidine-2-she (compound 8) and (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-([1,2,3]-triazole-1-yl) methyloxazolidine-2-she (compound 9)

The synthesis was performed as described in Example 24, but instead of 1,2,4-triazole was added 1,2,3-triazole, obtained compound 8 and compound 9 were separated on a chromatographic column.

(compound 8): (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluoro-phenyl)-5-([1,2,3]-triazole-2-yl)methyloxazolidine-2-he:

1H NMR (DMSO-d 6) δ 8.90 (s, 1H), 8.19 (m, 2H), 7.82 (s, 2H), 7.71 (t, 1H), 7.59 (dd, 1H), 7.41 (dd, 1H), 5.22 (m, 1H), 4.86 (m, 2H), 4.46 (s, 3H), 4.30 (t, 1H), 3.98 (dd, 1H).

(compound 9): (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-([1,2,3]-triazole-1-yl)methyloxazolidine-2-he

1H NMR (DMSO-d6) δ 8.90 (s, 1H), 8.18 (m, 3H), 7.75 (s, 1H), 7.72 (t, 1H), 7.59 (dd, 1H), 7.42 (dd, 1H), 5.22 (m, 1H), 4.86 (m, 2H), 4.46 (s, 3H), 4.30 (t, 1H), 3.98 (dd, 1H).

Example 26: Obtaining (R)-3-(4-(2-2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-([1,2,3]triazole-1-yl)-methyloxazolidine-2-she (compound 13)

The synthesis was performed as described in Example 24, but was added 1,2,3-triazole and used the connection 16 as the source.

1H NMR (DMSO-d6) δ 8.92 (s, 1H), 8.20 (s, 2H), 8.17 (s, 1H), 7.75 (s, 1H), 7.73 (t, 1H), 7.61 (dd, 1H), 7.43 (dd, 1H), 5.18 (m, 1H), 4.85 (m, 2H), 4.29 (t, 1H), 3.96 (dd, 1H), 2.62 (s, 3H).

Example 27: Obtaining (R)-3-(4-(2-[1,2,4]triazole-1-yl)pyridin-5-yl)-3-forfinal)-5-([1,2,3]triazole-1-yl)methyloxazolidine-2-she (compound 14)

The synthesis was performed as described in Example 24, but was added 1,2,3-triazole and used the connection 17 as the source.

1H NMR (DMSO-d6) δ 9.40 (s, 1H), 8.70 (s, 1H), 8.32 (s, 2H), 8.25 (d, 1H), 8.17 (s, 1H), 7.96 (d, 1H), 7.75 (s, 1H), 7.71 (t, 1H), 7.60 (dd, 1H), 7.42 (dd, 1H), 5.18 (m, 1H), 4.86 (m, 2H), 4.29 (t, 1H), 3.96 (dd, 1H).

Example 28: Obtaining (R)-3-(4-(2-2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-formationsolder-2-she (compound 18)

In 5 ml of methylene chloride was dissolved 100 mg of compound 10. To the solution was added 43 mg of diethylaminosulfur (DAS) and 0,078 ml of triethylamine and stirred 24 hours

After concentration of the reaction mixture was purified through column chromatography to obtain 75 mg of the target compound. The yield was 75%.

1H NMR (DMSO-d6) δ 8.91 (s, 1H), 8.19 (m, 2H), 7.74 (t, 1H), 7.66 (dd, 1H), 7.49 (dd, 1H), 5.06 (m, 1H), 4.89 (m, 2H), 4.46 (s, 3H), 4.23 (t, 1H), 3.95 (dd, 1H).

Example 29: Obtaining (S)-3-(4-(2-(imidazol-1-yl)pyridin-5-yl)-3-fluoro-phenyl)-5-aminotetrazolium-2-hydrochloride (compound 19)

3.4 ml of ethanol and 30.6 ml of pyridine was dissolved 2.5 g of (S)-3-(4-(2-imidazol-1-yl)-pyridine-5-yl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate. To the solution was added at 2.36 g of hydroxylamine at room temperature and was stirred at a temperature of 100°C for 10 h, the Reaction mixture was treated with ethyl acetate and separate the organic layer was washed with water and brine. The organic layer dehydrational, was filtered and concentrated in vacuum. The residue was purified through column chromatography and then dissolved in tetrahydrofuran saturated hydrochloric acid and was stirred for 10 minutes the resulting product was recrystallized and received 1 g of the target compound.

Example 30: Obtaining (S)-3-(4-(4-(4,5-dimethyloxazole-2-yl)phenyl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate (compound 11)

The synthesis was performed as described in Example 1, but was added 4-(4,5-dimethyl - oxazol-2-yl)bramasol and used as the source connection (S)-3-(4-three is athelstane-3-forfinal)-2-oxo-5-oxazolidinedione.

1H NMR (DMSO-d6) δ 8.24 (m, 1H), 7.96 (m, 2H), 7.62 (m, 4H), 7.45 (dd, 1H), 4.78 (m, 1H), 4.16 (t, 1H), 3.79 (dd, 1H), 3.41 (m, 2H), 2.32 (s, 3H), 2.10 (s, 2H), 1.83 (s, 3H).

Example 31: Obtaining (S)-3-(4-(2-(4,5-dimethyloxazole-2-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate (compound 15)

Repeated the procedure described in Example 1, but was added 4-(4,5-dimethyl - oxazol-2-yl)-5-bromopyridin and used as the source connection (S)-3-(4-tributylstannyl-3-forfinal)-2-oxo-5-oxazolidinedione.

1H NMR (DMSO-d6) δ 8.81 (s, 1H), 8.24 (t, 1H), 8.07 (m, 2H), 7.77 (t, 1H), 7.62 (dd, 1H), 4.78 (m, 1H), 4.18 (t, 1H), 3.79 (dd, 1H), 3.42 (m, 2H), 2.35 (s, 3H), 2.12 (s, 3H), 1.84 (s, 3H).

Example 32: Obtaining (S)-3-(4-(2-[1,2,3]triazole-2-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate (compound 25)

Repeated the procedure described in Example 1, but was added 2-([1,2,3]triazole-2-yl)-5-bromopyridin and used as the source connection (S)-3-(4-tributylstannyl-3-forfinal)-2-oxo-5-oxazolidinedione.

1H NMR (DMSO-d6) δ 8.74 (s, 1H), 8.24 (m, 2H), 8.19 (s, 2H), 8.11 (d, 1H), 7.72 (t, 1H), 7.64 (dd, 1H), 7.45 (dd, 1H), 4.79 (m, 1H), 4.18 (t, 1H), 3.79 (dd, 1H), 3.43 (m, 2H), 1.84 (s, 3H).

Example 33: Obtaining (S)-3-(4-(4-(4(S)-hydroxymethyl-4,5-dihydrooxazolo-2-yl)phenyl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate (compound 26)

Repeated the procedure described in Example 1, but was added 4-(4(S)-hydroxy-methyl-4,5-dihydrooxazolo-2-yl)bramasol and used is as a source connection (S)-3-(4-tributylstannyl-3-forfinal)-2-oxo-5-oxazolidinedione.

1H NMR (DMSO-d6) δ 8.23 (t, 1H), 7.91 (d, 2H), 7.62 (m, 4H), 7.42 (dd, 1H), 4.82 (t, 1H), 4.78 (m, 1H), 4.41 (t, 1H), 4.28 (m, 2H), 4.16 (t, 1H), 3.79 (dd, 1H), 3.61 (m, 1H), 3.48 (m, 1H), 3.43 (m,2H), 1.84 (s, 3H).

Example 34: Obtaining (S)-3-(4-(4-(4-seanmeister-2-yl)phenyl)-3-fluoro-phenyl)-2-oxo-5-oxazolidinecarboxylate (compound 31)

The synthesis was performed as described in Example 1, but was added 4-(4-seanmeister-2-yl)bramasol and used as the source connection (S)-3-(4-three-MailScanner-3-forfinal)-2-oxo-5-oxazolidinedione.

1H NMR (DMSO-d6) δ 8.25 (t, 1H), 8.00 (d, 2H), 7.67 (m, 4H), 7.44 (dd, 1H), 4.79 (m, 1H), 4.23 (s, 2H), 4.14 (t, 1H), 3.79 (dd, 1H), 3.43 (m, 2H), 1.83 (s, 3H).

Example 35: Obtaining (R)-3-(4-(4-(4-hydroxymethylimidazole-2-yl)phenyl)-3-forfinal-5-([1,2,3]triazole-1-yl)methyloxazolidine-2-she (compound 36)

The synthesis was performed as described in Example 1, but was added 4-(4-hydroxymethyl - thiazol-2-yl)bramasol and used as a starting compound (R)-3-(4-tributylstannyl-3-forfinal)-5-[1,2,3]triazole-1-yl)-oxazolidin-2-it.

1H NMR (DMSO-d6) δ 8.16 (s, 1H), 8.00 (d, 2H), 7.75 (s, 1H), 7.64 (dd, 2H), 7.62 (t, 1H), 7.52 (dd, 1H), 7.48 (s, 1H), 7.36 (dd, 1H), 5.40 (t, 1H), 5.18 (m, 1H), 4.85 (d, 2H), 4.62 (d, 2H), 4.28 (t, 1H), 3.95 (dd, 1H).

Example 36: Obtaining (R)-3-(4-(4-(4-glycinexylidide-2-yl)phenyl)-3-forfinal)-5-([1,2,3]triazole-1-yl)methyloxazolidine-2-he-triperoxonane acid (compound 37)

Repeating the method described in Example 10, but as the parent compound COI is litovali (R)-3-(4-(4-(4-hydroxymethylimidazole-2-yl)phenyl)-3-forfinal)-5-[1,2,3] triazole-1-eletrostatic-2-it.

1H NMR (DMSO-d6) δ 8.29 (s, 3H), 8.17 (s, 1H), 8.00 (d, 2H), 7.85 (s, 1H), 7.75 (s, 1H), 7.69 (dd, 2H), 7.67 (t, 1H), 7.55 (dd, 1H), 7.43 (dd, 1H), 5.36 (s, 2H), 5.19 (m, 1H), 4.86 (d, 2H), 4.28 (t, 1H).

Example 37: Obtaining (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-ethoxyethylacetate-2-she (compound 33)

In 10 ml of methanol was dissolved 400 mg of (R)-3-(4-(2-(2-methyltetrazol-5-yl)-pyridine-5-yl)-3-forfinal)-5-methanesulfonylaminoethyl-2-it is obtained in the first stage of Example 24. To the solution at room temperature was added 90 mg of sodium methoxide and stirred at this temperature for 1 day. The solution was treated with ethyl acetate, the obtained organic layer was washed with water and brine. The organic layer dehydrational, was filtered, concentrated in vacuum and purified through column chromatography to obtain 200 mg of the compound indicated in the title of the example. The yield was 58%.

1H NMR (DMSO-d6) δ 8.90 (s, 1H), 8.29 (d, 1H), 8.04 (d, 1H), 7.61 (dd, 1H), 7.58 (t, 1H), 7.38 (dd, 1H), 4.80 (m, 1H), 4.45 (s, 3H), 4.08 (t, 1H), 3.96 (dd, 1H), 3.67 (m, 2H), 3.43 (s, 3H).

Example 38: Obtaining (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(N,N-dimethylaminomethyl)oxazolidin-2-she (compound 40)

In 5 ml of dimethylformamide was dissolved 100 mg (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-methanesulfonylaminoethyl-2-it is obtained in the first stage of Example 24. To the solution at room tempera is ur was added 30 mg of hydroxychloride dimethylamine at room temperature. The solution was stirred for 30 hours at 60°C. Then the solution was treated with ethyl acetate, the obtained organic layer was washed with water and brine. The residue obtained by de-hydration, filtering and concentrating the organic layer was purified through column chromatography to obtain 70 mg of the target compound. The yield was 76%.

1H NMR (DMSO-d6) δ 8.91 (s, 1H), 8.19 (m, 2H), 7.76 (t, 1H), 7.65 (dd, 1H), 7.49 (dd, 1H), 4.98 (m, 1H), 4.63 (s, 3H), 4.27 (m, 3H), 3.94 (dd, 1H), 2.79 (s, 3H), 2.74 (s, 3H).

Example 39: Obtaining (S)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-N-methyliminodiacetic-2-she (compound 41)

In 7 ml of dimethylformamide was dissolved 200 mg (R)-3-(4-(2-(2-methyltetrazol-5-yl) pyridin-5-yl)-3-forfinal)-5-methanesulfonylaminoethyl-2-it is obtained in the first stage of Example 24. To the solution at room temperature was added 100 mg of methylamine hydrochloride and 240 mg of potassium carbonate. The solution was stirred for 30 hours at a temperature of 80°C. Then the solution was treated with ethyl acetate, the obtained organic layer was washed with water and brine. The residue obtained by de-hydration, filtering and concentrating the organic layer was purified through column chromatography to obtain 80 mg of the target compound. The yield was 45%.

1H NMR (DMSO-d6) δ 8.91 (s, 1H), 8.18 (m, 2H), 7.73 (t, 1H), 7.66 (dd, 1H), 7.47 (dd, 1H), 7.17 (m, 1H), 4.94 (m, 1H), 4.46 (s, 3H), 4.25 (m, 3H), 3.85 (dd, 1H), 2.49 (d, 3H).

Example 40: Obtaining (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-alanylons)methyloxazolidine-2-he-triperoxonane acid (compound 42)

Repeated the synthesis described in Example 10, using BOC-alanine instead of BOC-glycine.

1H NMR (DMSO-d6) δ 8.91 (s, 1H), 8.42 (s, 3H), 8.20 (m, 2H), 7.75 (t, 1H), 7.67 (dd, 1H), 7.48 (dd, 1H), 5.05 (m, 1H), 4.61 (dd, 1H), 4.46 (s, 3H), 4.41 (dd, 1H), 4.26 (t, 1H), 4.18 (m, 1H), 3.96 (dd, lH), 1.36 (d, 3H).

Example 41: Obtaining (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-Wallace) methyloxazolidine-2-hydrochloride (compound 43)

500 mg of compound 20 obtained in Example 11, was dissolved in water. the pH of the solution was brought to 5 by adding an aqueous solution of sodium bicarbonate. The aqueous solution was treated with ethyl acetate and the resulting organic layer was slowly added ether saturated with hydrochloric acid. The obtained solid product was filtered and concentrated in vacuum, receiving 200 mg of the target compound. The output was equal to 46%.

1H NMR (DMSO-d6) δ 8.92 (s, 1H), 8.54 (bs, 3H), 8.20 (m, 2H), 7.76 (t, 1H), 7.65 (dd, 1H), 7.49 (dd, 1H), 5.04 (m, 1H), 4.58 (dd, 1H), 4.46 (s, 3H), 4.41 (dd, 1H), 4.26 (t, 1H), 3.95 (dd, 1H), 2.17 (m, 1H), 0.97 (d, 3H), 094 (d, 3H).

Example 42: Obtaining (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-alanylons)methyloxazolidine-2-hydrochloride (compound 44)

Repeated Example 41, but using connection 42.

1H NMR (DMS-d 6) δ 8.92 (s, 1H), 8.52 (bs, 3H), 8.20 (m, 2H), 7.75 (t, 1H), 7.66 (dd, 1H), 7.49 (dd, 1H), 5.05 (m, 1H), 4.60 (dd, 1H), 4.46 (s, 3H), 4.41 (dd, 1H), 4.26 (t, 1H), 4.18 (m, 1H), 4.00 (dd, 1H), 1.37 (d, 3H).

Example 43: Obtaining (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-glycinexylidide-2-hydrochloride (compound 45)

Repeated Example 41, but using compound 12.

1H NMR (DMSO-d6) δ 8.91 (s, 1H), 8.48 (bs, 3H), 8.18 (m, 2H), 7.75 (t, 1H), 7.65 (dd, 1H), 7.49 (dd, 1H), 5.03 (m, 1H), 4.48 (m, 2H), 4.46 (s, 3H), 4.24 (t, 1H), 3.99 (dd, 1H), 3.86 (m, 2H).

Example 44: Obtaining (S)-3-(4-(4-(4-hydroxymethylimidazole-2-yl)phenyl)-3-forfinal)-2-oxo-5-oxazolidinecarboxylate (compound 28)

Repeating Example 1, but using compound (S)-3-(4-tributylstannyl-3-forfinal)-2-oxo-5-oxazolidinecarboxylate and 4-(4-hydroxymethylimidazole-2-yl)bromine benzol as the original substances.

1H NMR (DMSO-d6) δ 8.24 (t, 1H), 7.98 (d, 2H), 7.65 (m, 2H), 7.59 (m, 2H), 7.43 (s, 1H), 7.41 (dd, 1H). 5.40 (t, 1H), 4.79 (m, 1H), 4.63 (d, 2H), 4.16 (t, 1H), 3.79 (dd, 1H), 3.43 (m, 2H), 1.84 (s, 3H).

Example 45: Obtaining (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-propenyloxy)methyloxazolidine-2-he-triperoxonane acid (compound 46)

Repeated Example 10, but instead of BOC-glycine was used BOC-L-Proline.

1H NMR (DMSO-d6) δ 9.25 (bs, 2H), 8.91 (s, 1H), 8.20 (m, 2H), 7.76 (t, 1H), 7.65 (dd, 1H), 7.48 (dd, 1H), 5.05 (m, 1H), 4.57 (dd, 1H), 4.45 (s, 3H), 4.41 (dd, 1H), 4.26 (t, 1H), 3.96 (dd, 1H), 3.23 (m, 2H), 2.21 (m, 1H), 1.92 (m, 3H).

Example 46: Obtaining (R)-3-(4-(2-(2-methyltetrazol-5-is)pyridine-5-yl)-3-forfinal)-5-(L-propenyloxy)methyloxazolidine-2-hydrochloride (compound 47)

Repeated Example 41, but using connection 46.

1H NMR (DMSO-d6) δ 9.11 (bs, 2H), 8.91 (s, 1H), 8.20 (m, 2H), 7.76 (t, 1H), 7.65 (dd, 1H), 7.49 (dd, 1H), 5.05 (m, 1H), 4.55 (dd, 1H), 4.46 (s, 3H), 4.41 (dd, 1H), 4.25 (t, 1H), 4.01 (dd, 1H), 3.36 (m, 2H), 2.07 (m, 1H), 1.89 (m, 3H).

Example 47: Obtaining (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-glycinexylidide-2-hydrochloride (compound 48)

Repeated Example 41, but using compound 27.

1H NMR (DMSO-d6) δ 8.92 (s, 1H), 8.48 (s, 3H), 8.21 (s, 2H), 7.76 (t, 1H), 7.66 (dd, 1H), 7.48 (dd, 1H), 5.04 (m, 1H), 4.47 (m, 2H), 4.23 (t, 1H), 3.94 (m, 1H). 3.84 (d, 2H), 2.62 (s, 3H).

Example 48: Obtaining (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(β-alanylons)methyloxazolidine-2-he-triperoxonane acid (compound 49)

Repeated Example 10, but instead of BOC-glycine was used BOC-β-alanine.

1H NMR (DMSO-d6) δ 8.91 (s, 1H), 8.20 (m, 2H), 7.75 (t, 1H), 7.73 (bs, 3H), 7.68 (dd. 1H), 7.48 (dd, 1H), 5.02 (m, 1H), 4.46 (s, 3H), 4.36 (m, 2H), 4.26 (t, 1H), 3.93 (dd, 1H), 3.02 (m, 2H), 2.70 (t, 2H).

Example 49: Obtaining (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(β-alanylons)methyloxazolidine-2-hydrochloride (compound 50)

Repeated Example 41, but using compound 49.

1H NMR (DMSO-d6) δ 8.91 (s, 1H), 8.22 (m, 2H), 8.11 (bs, 3H), 7.76 (t, 1H), 7.65 (dd, 1H), 7.48 (dd, 1H), 5.02 (m, 1H), 4.46 (s, 3H), 4.36 (m, 2H), 4.23 (t, 1H), 3.95 (m, 1H), 3.00 (m, 2H), 2.74 (t, 2H).

Example 50: Obtaining (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-alanylons)methyl who oxazolidin-2-he-triperoxonane acid (compound 51)

Repeated Example 10, but using compound 16 and BOC-L-alanine.

1H NMR (DMSO-d6) δ 8.93 (s, 1H), 8.39 (bs, 3H), 8.21 (s, 2H), 7.76 (t, 1H), 7.68 (dd, 1H), 7.49 (dd, 1H), 5.04 (m, 1H), 4.61 (dd, 1H), 4.40 (dd, 1H), 4.28 (t, 1H), 4.18 (dd, 1H), 3.95 (dd, lH), 2.62 (s, 3H), 1.36 (d, 3H).

Example 51: Obtaining (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-alanylons)methyloxazolidine-2-hydrochloride (compound 52)

Repeated Example 41, but using compound 51.

1H NMR (DMSO-d6) δ 8.93 (s, 1H), 8.61 (bs, 3H), 8.21 (s, 2H), 7.76 (t, 1H), 7.65 (dd, 1H), 7.49 (dd, 1H), 5.05 (m, 1H), 4.58 (dd, 1H), 4.39 (dd, 1H), 4.25 (t, 1H), 4.12 (m, 1H), 4.00 (dd, 1H), 2.62 (s, 3H), 1.36 (d, 3H).

Example 52: Obtaining (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-Wallace)methyloxazolidine-2-he-triperoxonane acid (compound 53)

Repeated Example 10, but using compound 16 and BOC-L-alanine.

1H NMR (DMSO-d6) δ 8.93 (s, 1H), 8.40 (bs, 3H), 8.21 (s, 2H), 7.75 (t, 1H), 7.68 (dd, 1H), 7.48 (dd, 1H), 5.04 (m, 1H), 4.62 (dd, 1H), 4.40 (dd, 1H), 4.26 (t, 1H), 3.99 (dd, 1H), 3.92 (dd, 1H), 2.62 (s, 3H), 2.12 (m, 1H), 0.97 (d, 3H), 0.94 (d, 3H).

Example 53: Obtaining (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-Wallace)methyloxazolidine-2-hydrochloride (compound 54)

Repeated Example 41, but using compound 53.

1H NMR (DMSO-d6) δ 8.93 (s, 1H), 8.60 (bs, 3H), 8.21 (s, 2H), 7.75 (t, 1H), 7.67 (dd, 1H), 7.49 (dd, 1H), 5.04 (m, 1H), 4.58 (dd, 1H), 4.42 (dd, 1H), 4.26 (t, 1H), 3.92 (m, 1H), 2.62 (s, 3H), 2.12 (m, 1H), 0.97 (d, 3H), 0.94 (d, 3H).

Example 54: Received the e (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-propenyloxy)methyloxazolidine-2-he-triperoxonane acid (compound 55)

Repeated Example 10, but using compound 16 and BOC-L-Proline.

1H NMR (DMSO-d6) δ 9.20 (bs, 2H), 8.93 (s, 1H), 8.21 (s, 2H), 7.77 (t, 1H), 7.66 (dd, 1H), 7.50 (dd, 1H), 5.04 (m, 1H), 4.59 (dd, 1H), 4.43 (m, 2H), 4.26 (t, 1H), 3.96 (dd, 1H), 3.21 (m, 2H), 2.62 (s, 3H), 2.12 (m, 1H), 1.95 (m. 1H), 1.89 (m, 2H).

Example 55: Obtaining (R)-3-(4-(2-(2-methyl-[1,3,4] oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-propenyloxy) methyloxazolidine-2-hydrochloride (compound 56)

Repeated Example 41, but using connection 55.

1H NMR (DMSO-d6) δ 9.18 (bs, 2H), 8.93 (s, 1H), 8.21 (s. 2H), 7.76 (t, 1H), 7.65 (dd, 1H), 7.49 (dd, 1H), 5.05 (m, 1H), 4.57 (dd, 1H), 4.43 (m, 2H), 4.26 (t, 1H), 4.00 (dd, 1H), 3.21 (m, 2H), 2.62 (s, 3H), 2.21 (m, 1H), 1.95 (m, 1H), 1.89 (m, 2H).

Example 56: Obtaining (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(β-alanylons)methyloxazolidine-2-he-triperoxonane acid (compound 57)

Repeated Example 10, but using compound 16 and BOC-β-alanine.

1H NMR (DMSO-d6) δ 8.92 (s, 1H), 8.21 (s, 2H), 7.88 (bs, 3H), 7.76 (t, 1H), 7.68 (dd, 1H), 7.49 (dd, 1H), 5.02 (m, 1H), 4.36 (m, 2H), 4.25 (t, 1H), 3.94 (dd, 1H), 3.03 (m, 2H), 2.70 (t, 2H), 2.62 (s, 3H).

Example 57: Obtaining (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(β-alanylons)methyloxazolidine-2-hydrochloride (compound 58)

Repeated Example 41, but using compound 57.

1H NMR (DMSO-d6) δ 8.92 (s, 1H), 8.21 (s, 2H), 8.08 (bs, 3H), 7.76 (t, 1H), 7.68 (dd, 1H), 7.49 (dd, 1H), 5.02 (m, 1H), 4.36 (m, 2H), 4.25 (t, 1H), 3.96 (dd, 1H), 3.00 (m, 2H), 2.71 (t, 2H), 2.62 (s. 3H).

Example 58: Obtaining mono-[()-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinyl]methyl]phosphate (compound 72) and (R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinyl]methylenediphosphonate (compound 59)

1. The first stage.

In 10 ml solvent (tetrahydrofuran:methylene chloride, 1:1) was dissolved 1 g of compound 10. To the solution was added 0.6 g of tetrazole and 2.3 g diatribution-propylphosphonate and stirred at room temperature for 15 hours, the Reaction mixture was cooled to -78°C, was added 0.7 g of metallocarboranes acid and was stirred for 2 hours After cooling to -78°C was added 0.7 g of metallocarboranes acid. After stirring the reaction mixture for 2 h, the temperature of the reaction mixture was increased to room temperature. Then to the reaction mixture were added ethyl acetate. The obtained organic layer was washed with sodium bisulfate, sodium bicarbonate and brine and dehydrational, filtered and concentrated in vacuo, and then purified through column chromatography to obtain diatribution ether (R)-[3-(4-(2-(2-methyltetrazol-5-yl)-3-forfinal)-2-oxo-5-oxazolidinyl]methylphosphonous acid (0.71 g, 71%).

1H NMR (DMSO-d6) δ 8.90 (s, 1H), 8.18 (m, 2H), 7.74 (t, 1H), 7.68 (dd, 1H), 7.49 (dd, 1H), 4.98 (m, 1H), 4.46 (s, 3H), 4.23 (t, 1H), 4.18 (m, 1H), 4.09 (m, 1H), 3.89 (dd, 1H), 1.39 (s, 9H), 1.38 (s, 9H).

The resulting crystalline product was dissolved in a mixture of methanol and chloroform. Then at room temperature to the solution was added 3.4 ml of sodium methoxide (0.3 M solution in methanol) and stirred for 10 hours, the Reaction mixture was concentrated. Estato who had led and was filtered to obtain 300 mg of compound 59.

1H NMR (DMSO-d6) δ 8.27 (s, 1H), 7.56 (dd, 2H), 7.06 (m, 2H), 6.90 (m, 1H), 4.79 (m, 1H), 4.63 (s, 3H), 3.90 (m, 4H).

2. The second stage

In 30 ml of methylene chloride was dissolved 0.7 g of the compound obtained in the first stage. To the solution was added 15 ml triperoxonane acid and then stirred at room temperature for 1 h the Reaction mixture was concentrated in vacuum. The obtained residue was led in ethanol and ethyl ether, and received 400 mg of mono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)-pyridine-5-yl)-3-forfinal)-2-oxo-5-oxazolidinyl]methyl]phosphate (compound 72).

1H NMR (DMSO-d6) δ 8.92 (s, 1H), 8.20 (m, 2H), 7.74 (t, 1H), 7.66 (dd, 1H), 7.50 (dd, 1H), 4.95 (m, 1H), 4.46 (s, 3H), 4.21 (t, 1H), 4.05 (m, 2H), 3.91 (dd, 1H).

Example 59: Obtaining (R)-(3-(4-(2-(2-yl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinyl]methylenediphosphonate (compound 60)

Repeated example 58, but using compound 16.

1H NMR (DMSO-d6) δ 8.33 (s, 1H), 7.65 (dd, 2H), 7.17 (m, 2H), 6.90 (m, 1H), 4.79 (m, 1H), 4.63 (s, 3H), 3.94 (t, 1H), 3.78 (m, 3H).

Example 60: Obtaining (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-hydroxymethylimidazole-2-she (compound 61)

Repeating example 1, using 2-(1-methyltetrazol-5-yl)-5-bromopyridin.

1H NMR (DMSO-d6) δ 8.98 (s, 1H), 8.30 (m, 2H), 7.75 (m, 2H), 7.53 (dd, 1H), 5.25 (t, 1H), 4.76 (m, 1H), 4.44 (s, 3H), 4.14 (t, 1H), 3.89 (dd, 1H), 3.69 (m, 1H), 3.58 (m, 1H).

Example 61: Obtaining (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-torfin the l)-5-glycinexylidide-2-he-triperoxonane acid (compound 62)

Repeated example 10, using 2-(1-methyltetrazol-5-yl)-5-bromopyridin.

1H NMR (DMSO-d6) δ 8.95 (s, 1H), 8.20 (s, 3H), 8.19 (m, 2H), 7.80 (t, 1H), 7.69 (dd, 1H), 7.49 (dd, 1H), 5.00 (m, 1H), 4.46 (m, 2H), 4.45 (s, 3H), 4.24 (t, 1H), 3.92 (dd, 1H), 3.90 (s, 2H).

Example 62: Obtaining (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-glycinexylidide-2-hydrochloride (compound 63)

Repeated example 43 using 2-(1-methyltetrazol-5-yl)-5-bromopyridin.

1H NMR (DMSO-d6) δ 8.95 (s, 1H), 8.50 (bs, 3H), 8.21 (m, 2H), 7.80 (t, 1H), 7.65 (dd, 1H), 7.49 (dd, 1H), 5.03 (m, 1H), 4.48 (m, 2H), 4.43 (s, 3H), 4.24 (t, 1H), 3.99 (dd, 1H), 3.86 (m, 2H).

Example 63: Obtaining (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-alanylons)methyloxazolidine-2-he-triperoxonane acid (compound 64)

Repeated example 40, using 2-(1-methyltetrazol-5-yl)-5-bromopyridin.

1H NMR (DMSO-d6) δ 8.95 (s, 1H), 8.43 (s, 3H), 8.25 (m, 2H), 7.77 (t, 1H), 7.68 (dd, 1H), 7.48 (dd, 1H), 5.05 (m, 1H), 4.63 (dd, 1H), 4.44 (s, 3H), 4.42 (dd, 1H), 4.24 (t, 1H), 4.24 (m, 1H), 3.98 (dd, 1H), 1.36 (d, 3H).

Example 64: Obtaining (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-alanylons)methyloxazolidine-2-hydrochloride (compound 65)

Repeated example 42, using 2-(1-methyltetrazol-5-yl)-5-bromopyridin.

1H NMR (DMSO-d6) δ 8.95 (s, 1H), 8.53 (bs, 3H), 8.24 (m, 2H), 7.77 (t, 1H), 7.67 (dd, 1H), 7.49 (dd, 1H), 5.05 (m, 1H), 4.60 (dd, 1H), 4.43 (s, 3H), 4.42 (dd, 1H), 4.26 (t, 1H), 4.20 (m, 1H), 4.00 (dd, 1H), 1.37 (d, 3H).

Example 65: Obtaining (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-terphenyl)-5-(L-Wallace)methyloxazolidine-2-he-triperoxonane acid (compound 66)

Repeating Example 11, using 2-(1-methyltetrazol-5-yl)-5-bromopyridin.

1H NMR (DMSO-d6) δ 8.95 (s, 1H), 8.42 (s, 3H), 8.25 (m, 2H), 7.79 (t, 1H), 7.70 (dd, 1H), 7.48 (dd, 1H), 5.05 (m, 1H), 4.64 (dd, 1H), 4.44 (s, MN), 4.43 (dd, 1H), 4.30 (t, 1H), 4.01 (d, 1H), 3.93 (dd, 1H), 2.14 (m, 1H), 0.98 (d, 3H), 0.95 (d, 3H).

Example 66: Obtaining (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-Wallace)methyloxazolidine-2-hydrochloride (compound 67)

Repeated Example 41, using 2-(1-methyltetrazol-5-yl)-5-bromopyridin.

1H NMR (DMSO-d6) δ 8.94 (s, 1H), 8.57 (bs, 3H), 8.22 (m, 2H), 7.79 (t, 1H), 7.67 (dd, 1H), 7.49 (dd, 1H), 5.04 (m, 1H), 4.59 (dd, 1H), 4.43 (s, 3H), 4.41 (dd, 1H), 4.27 (t, 1H), 3.99 (m, 2H), 2.17 (m. 1H), 0.97 (d, 3H), 0.94 (d, 3H).

Example 67: Obtaining (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(β-alanylons)methyloxazolidine-2-he-triperoxonane acid (compound 68)

Repeated Example 48, using 2-(1-methyltetrazol-5-yl)-5-bromopyridin.

1H NMR (DMSO-d6) δ 8.94 (s, 1H), 8.24 (m, 2H), 7.77 (t, 1H), 7.33 (bs, 3H), 7.70 (dd, 1H), 7.49 (dd, 1H), 5.02 (m, 1H), 4.44 (s. MN), 4.36 (m, 2H), 4.27 (t, 1H), 3.93 (dd, 1H), 3.05 (m, 2H), 2.70 (t, 2H).

Example 68: Obtaining (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(β-alanylons)methyloxazolidine-2-hydrochloride (compound 69)

Repeated Example 49, using 2-(1-methyltetrazol-5-yl)-5-bromopyridin.

1H NMR (DMSO-d6) δ 8.96 (s, 1H), 8.25 (m, 2H), 8.13 (bs, 3H), 7.79 (t, 1H), 7.66 (dd, 1H), 7.48 (dd, 1H), 5.02 (m, 1H), 4.43 (s, MN), 4.36 (m, 2H), 4.25 (t, 1H), 3.97 (m, 1H), 3.01 (m, 2H), 2.74 (t, 2H).

Example 69: Recip is of mono-[(R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinyl]methyl]phosphate (compound 73) and (R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinyl]methylenediphosphonate (connection 70)

1. The first stage

Using the connection 61, get diatribution ether (R)-[3-(4-(2-(l-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinyl]-methyl] phosphoric acid by a method similar to that described in Example 58.

1H NMR (DMSO-d6) δ 8.94 (s, 1H), 8.20 (m, 2H), 7.78 (t, 1H), 7.68 (dd, 1H), 7.49 (dd, 1H), 4.98 (m, 1H), 4.44 (s, 3H), 4.21 (t, 1H), 4.18 (m, 1H), 4.10 (m, 1H), 3.89 (dd, 1H), 1.39 (s, 9H), 1.38 (s, 9H).

2. The second stage

In the manner similar to that described in Example 58, using the compound obtained in the first stage, receive 400 mg of mono-[(R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinyl]methyl]-phosphate (compound 73).

1H NMR (DMSO-d6) δ 8.95 (s, 1H), 8.23 (m, 2H), 7.76 (t, 1H), 7.66 (dd, 1H), 7.500 (dd, 1H), 4.95 (m, 1H), 4.44 (s, 3H), 4.21 (t, 1H), 4.05 (m, 2H), 3.91 (dd, 1H).

Compound 70 was obtained in a manner analogous to the one described in Example 58.

1H NMR (DMSO-d6) δ 8.29 (s, 1H), 7.60 (dd, 2H), 7.10 (m, 2H), 6.90 (m, 1H), 4.79 (m, 1H), 4.60 (s, 3H), 3.90 (m, 4H).

Example 70: Obtaining (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-([1,2,3]-triazole-1-yl)methyloxazolidine-2-she (compound 71)

Using the connection 61, the specified connection get a way similar to that described in Example 24.

1H NMR (DMSO-d6) δ 8.95 (s, 1H), 8.21 (m, 3H), 7.77 (s, 1H), 7.75 (t, 1H), 7.59 (dd, 1H), 7.42 (dd, 1H), 5.22 (m, 1H), 4.86 (m, 2H), 4.44 (s, 3H), 4.31 (t, 1H), 3.98 (dd, 1H).

Experimental Example 1: Determination of in vitro antibacterial activity

Antibacterial activity of derivatives oxazolidinone was determined as the minimum inhibitory concentration (MIC50µg/ml) when using methicillin-resistant Staphylococcus aureus (MRSA) and resistant to vancomycin Enterococci (VRE) and a known method dilution agar (Chemotherapy, 76 (1981)). As a control sample was used Zyvox, Pharmacia and decision Upjohn, Inc, corresponding to the formula 3. The results are shown in Table 2.

Table 2
ConnectionMinimum inhibitory concentration (MIC50ΜG/ML)ConnectionMinimum inhibitory concentration (MIC50µg/ml)
MRSAVREMRSAVRE
Zyvox22370,50,5
110,25380,5 1
20,50,1253911
30,250,254048
4224148
50,50,25420,50,25
6NANA430,50,25
70,50,5440,50,25
81616450,50,25
90,25 0,125460,50,25
100,50,25470,50,25
110,50,25480,51
120,50,25490,50,25
130,250,25500,50,25
140,250,25510,51
1511520,51
160,51530,5 1
1711540,51
1812550,51
193232560,51
200,50,25570,51
2111580,51
2211590,50,25
2322600,51
240,5610,50,25
250,250,125620,50,25
260,50,5630,50,25
270,51640,50,25
280,50,5650.50,25
290,51660,50,25
300,50,5670,50,25
310,50,568 0,50,25
320,51690,50,25
3322700,50,25
3411710,50,125
3511723232
360,50,5733232
NA=not determined
MRSA: methicillin-resistant Staphylococcus aureus
VRE: resistant to vancomycin Enterococci.

As shown in Table 2, the derivatives according to this invention possess antibacterial activity against Staphylococcus aureus (MRSA) and Enterococci (VRE), despite the lower concentration of roizvodnykh compared to Zyvox. Therefore, the compounds according to the invention can be used as antibiotics.

Experimental Example 2: Determination of solubility

The experiment for the determination of solubility was carried out as follows. Derivatives according to the invention was added to 200 μl of distilled water and stirred the solution for 2 minutes. Visually watched the turbidity of the solution.

If the connection was not completely dissolved, the solution was added 50 μl of distilled water and again watched the turbidity of the solution for finding the moment when the solution becomes transparent.

When you first add 2 mg of the compounds in distilled water, the solution became transparent, then add another 2 mg of the compounds and determined the status of the solution. Compounds were added into the water five times and determined the solubility. The results were averaged after three repeated measurements. Average values of solubility are shown in Table 3.

Table 3
ConnectionSolubilityConnectionSolubility
Zyvox3 mg/ml51>50 mg/ml
1010 mg/ml52>50 mg/ml
1228 mg/ml53of 30.3 mg/ml
1620 mg/ml542,9 mg/ml
204,7 mg/ml557.2 mg/ml
27>50 mg/ml56>50 mg/ml
42>50 mg/ml57>50 mg/ml
434,2 mg/ml585,5 mg/ml
44>50 mg/ml59>50 mg/ml
4512 mg/ml60>50 mg/ml
46<1,63 mg/ml62 28 mg/ml
472 mg/ml64>50 mg/ml
48>50 mg/ml664,7 mg/ml
492.6 mg/ml682.6 mg/ml
5020,4 m70>50 mg/ml

As can be seen from Table 3, the solubility of compound 42 (>50 mg/ml), which is a prodrug, more than Zyvox (3 mg/ml) and compound 10 (10 µg/ml). Accordingly, when receiving oral compositions based on derivatives according to the invention the absorption derivative can be increased. If the derivative is administered in the form of injections, you can get different compositions on the basis of these derivatives.

Experimental Example 3: Determination of acute toxicity derivatives when administered orally to mice

To determine the acute toxicity of the compounds according to the invention was carried out the following experiment.

A mixture of 1% hydroxypropylmethylcellulose and 200 mg of the compounds selected from the group consisting of compounds 10, 12, 16, 17, 20, 22, 24 and 27, were injected 5 ICR mice (males aged 5 weeks, weight 20 g±2 g). C is to determine the minimum lethal dose (MLD, mg/kg) was determined mortality within 2 weeks, weight, symptoms, etc.

As control compounds were used Zyvox, Pharmacia and decision Upjohn, Inc. The results are shown in Table 4.

Table 4
ConnectionThe minimum lethal dose (MLD, mg/kg)
Zyvox>1000
10>1000
12>1000
16>1000
17>1000
20>1000
22>1000
24>1000
27>1000

Monitoring survival, weight change, blood tests and symptoms of toxicity, etc. showed that the compounds according to the invention is non-toxic.

Compounds according to the invention have excellent antibacterial activity and is not toxic according to Table 4.

Examples of formulations: Obtaining pharmaceutical compositions.

Derived oxazolidinone2 g
Lactose1 g

These substances were mixed and placed in a closed container.

2. Getting it in tablet form

Derived oxazolidinone500 mg
Corn starch100 mg
Lactose100 mg
Magnesium stearate2 mg

These substances were mixed and were given a pill by known methods.

3. Receiving in the form of capsules

Derived oxazolidinone500 mg
Corn starch100 mg
Lactose100 mg
Magnesium stearate2 mg

These substances were mixed and known methods was filled with a mixture of a gelatin capsule.

4. Cooking with the composition for injection

Derived oxazolidinone500 mg
Nitrate bufferto pH 3
Dextroseto achieve isotonicity

Derived oxazolidinone, nitrate salt of sodium, citric acid and dextrose was placed into the vial of 20 ml, sterilized and covered aluminum tube for leaks. Mixture for injection was dissolved when used in distilled water and added distilled water to the desired volume.

1. Derived oxazolidinone formula I or its pharmaceutically acceptable salt

R1and R1'independently represent hydrogen or fluorine;
R2means-OR7, fluorine, monophosphate or metal phosphate salt; and
R7denotes hydrogen, C1-3alkyl or acylated amino group, where the amino acid is alanine, glycine, Proline, isoleucine, leucine, phenylalanine, β-alanine or valine;
R3denotes hydrogen, C1-4alkyl group which is unsubstituted or substituted by cyano, -(CH2)m-OR7(m is equal to 0, 1, 2, 3, 4) or catography.

2. Derived oxazolidinone according to claim 1, where Rsub> 1denotes hydrogen and R1'denotes fluorine.

3. Derived oxazolidinone according to claim 1 or 2, where R2means-HE.

4. Derived oxazolidinone according to claim 1, where R2means-OR7and R7denotes hydrogen.

5. Derived oxazolidinone according to claim 1 or 2, where R2selected from the group consisting of monophosphate and a metal salt of phosphate.

6. Derivative oxazolidinone according to claim 1, where R3denotes methyl.

7. Derived oxazolidinone according to claim 1, characterized in that the pharmaceutically acceptable salt is selected from the group consisting of the salts of hydrochloric acid, banowati acid, sulfuric acid, phosphoric acid, citric acid, banowati acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonate, Gelikonov acid, succinic acid, 4-toluenesulfonic acid, triperoxonane acid, glucuronate acid, monowai acid, glutamic acid and aspartic acid.

8. Derived oxazolidinone according to claim 7, characterized in that the pharmaceutically acceptable salt is selected from salts of hydrochloric acid and triperoxonane acid.

9. Derived oxazolidinone according to claim 1, selected from the group including:
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-Fortini is)-5-hydroxymethylimidazole-2-it,
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-glycyl-oxitetraciclina-2-he-triperoxonane acid,
(R)-3-(4-(2-2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-formationsolder-2-it,
(R)-3-(4-(2-2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-Wallace)methyloxazolidine-2-he-triperoxonane acid,
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-ethoxyethylacetate-2-it,
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-alanylons)methyloxazolidine-2-he-triperoxonane acid,
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-Wallace)methyloxazolidine-2-she hydrochloride
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-alanylons)methyloxazolidine-2-she hydrochloride
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-glycinexylidide-2-she hydrochloride
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-propenyloxy)methyloxazolidine-2-he-triperoxonane acid,
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-propenyloxy)methyloxazolidine-2-she hydrochloride
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(β-alanylons)methyloxazolidine-2-he-triperoxonane acid,
(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(β-alanylons)methyloxazolidine-2-she hydrochloride
(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-FPO is phenyl)-2-oxo-5-oxazolidinyl]matildastreet,
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-hydroxymethylimidazole-2-it,
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-glycinexylidide-2-he-triperoxonane acid,
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-glycinexylidide-2-she hydrochloride
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-alanylons)methyloxazolidine-2-he-triperoxonane acid,
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-alanylons)methyloxazolidine-2-she hydrochloride
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-Wallace)methyloxazolidine-2-he-triperoxonane acid,
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(L-Wallace)methyloxazolidine-2-she hydrochloride
(R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-5-(β-alanylons)methyloxazolidine-2-he-triperoxonane acid,
(R)-3-(4-(2-(1-methyltetrazol-5-yl)piridin-5-yl)-3-forfinal)-5-(β-alanylons)methyloxazolidine-2-she hydrochloride
(R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinyl]matildastreet,
mono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinyl]methyl]phosphate,
mono-[(R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-forfinal)-2-oxo-5-oxazolidinyl]methyl]phosphate.

10. Derived oxazolidinone according to claim 1 of the formula:

where R2denotes hydroxyl, monophosphate or metal phosphate salt.

11. Derived oxazolidinone according to claim 1 of the formula:

where R2denotes hydroxyl, monophosphate or metal phosphate salt.

12. Derived oxazolidinone according to claim 1 of the formula:

where R2denotes hydroxyl, monophosphate or metal phosphate salt.

13. Derived oxazolidinone according to claim 1 of the formula:

where R2denotes hydroxyl, monophosphate or metal phosphate salt.

14. Derived oxazolidinone on any of PP-13, which has the R stereochemical configuration.

15. Derived oxazolidinone according to claim 1 of the formula:

16. Derived oxazolidinone according to claim 1 of the formula:

17. Derived oxazolidinone according to claim 1 of the formula:

18. Pharmaceutical composition for treating bacterial infections comprising as an active ingredient the compound according to any one of claims 1 to 17 and a pharmaceutically acceptable carrier.

19. A method of treating bacterial infection in a subject comprising administration to the subject the compound according to any one of claims 1 to 17 or the composition of p.

20. The method according to claim 19, in which the infection is caused by gram-positive bacteria is.

21. The method according to claim 20, in which gram-positive bacteria selected from the group including Staphylococcus, Enterococcus, Streptococcus, Bacteroides, Clostridium and Mycobacterium.

22. The method according to item 21, where gram-positive bacteria selected from the group including Staphylococcus, Enterococcus and Streptococcus.

23. The use of compounds according to any one of claims 1 to 17 or the composition of p for the treatment of bacterial infection in the subject.

24. The application of item 23, where the infection is caused by gram-positive bacteria.

25. The application of paragraph 24, where gram-positive bacteria selected from the group including Staphylococcus, Enterococcus, Streptococcus, Bacteroides, Clostridium and Mycobacterium.

26. Use A.25, where gram-positive bacteria selected from the group including Staphylococcus, Enterococcus and Streptococcus.

27. The method of obtaining derivatives oxazolidinone Formula I:

or its pharmaceutically acceptable salt, where
R1and R'1independently represent hydrogen or fluorine;
R2means-OR7, fluorine, monophosphate or metal phosphate salt; and
R7denotes hydrogen, C1-3alkyl or acylated amino group, where the amino acid is alanine, glycine, Proline, isoleucine, leucine, phenylalanine, β-alanine or valine;
R3denotes hydrogen, C1-4alkyl group which is unsubstituted or substituted by cyano, -(CH2)m-OR7(m p the veins 0, 1, 2, 3, 4) or geography;
includes the following stages:
the interaction of the compounds of formula III, where Y is a halogen:

with stanila with obtaining the compounds of formula IV where Z denotes1-4alkyl:

the interaction of the compounds of formula IV with the compound of the formula VI:

obtaining the compounds of formula V:

and, if necessary, the interaction of the compounds of formula V with an amino acid containing a protective group, and then with acid, or the interaction of the compounds of formula V with phosphate and then with the salt of the metal.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrrolidine derivatives of general formula (1) or its pharmaceutically acceptable salts where R101 and R102 values are described by the patent claim. The compounds inhibit serotonin and/or norepinephrine and/or dopamine reabsorption thereby allowing to be used for treating depression and anxiety disorder. A method for preparing thereof is described.

EFFECT: preparation of new pyrrolidine derivatives.

10 cl, 162 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula I and to their pharmaceutically acceptable salts. In formula I p is integer, equal to 0-1; L2 is selected from group including -XOX-, -XSX- and -XSXO-; where X is independently selected from group, including bond and C1-C4alkylene; R13 is selected from group, including halogen, C1-C6alkyl, C1-C6alkoxygroup, -C(O) C1-C6alkyl; R14 is selected from group, including -XOXC(O)OR17 and -C1-C4alkylene-C(O)OR17; where X represents bond or C1-C4alkylene; and R17 is selected from group, including hydrogen and C1-C6alkyl; R15 and R16 are independently selected from group, including -R18 and -YR18; where Y represents C2-C6alkenylene, and R18 is selected from group, including C6-C10aryl, benzo[1,3]dioxolyl, pyridinyl, pyrimidinyl, quinolyl, phenoxatiinyl, benzofuranyl, dibenzofuranyl, benzoxasolyl, 2,3-dihydrobenzofuranyl, 2-oxo-2,3-dihydrobenzooxasolyl, indolyl, 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazinyl, 2,3-dihydrobenzo[1,4]dioxinyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, where any C6-C10aryl, pyridinyl, benzoxasolyl, indolyl in R18 is optionally substituted by 1-2 radicals, independently selected from group, including halogen, nitrogroup, cyanogroup, C1-C6alkyl, C1-C6alkoxygroup, C1-C6alkylthiogroup, hydroxy-C1-C6alkyl, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxygroup, piperidinyl, morpholinyl, pyrrolidinyl, phenyl, XS(O)0-2R17, -XNR17R17, -XNR17S(O)2R17, -XNR17C(O)R17, -XC(O)NR17R17, -XC(O)NR17R19, -XC(O)R17, -XC(O)R19 and -XOXR19, where X represents bond; R17 is selected from group, including hydrogen, C1-C6alkyl, halogen-substituted C1-C6alkyl, and R19 is selected from group, including C3-C12cycloalkyl, phenyl, piperidinyl, morpholinyl.

EFFECT: ensuring application of invention compounds for production of medication, modulating activity of activated receptors of peroxisome proliferators δ (ARPPδ), to pharmaceutical composition, possessing properties of ARPPδ activity modulator, including therapeutically efficient quantity of invention compound and to application of pharmaceutical composition for medication manufacturing.

8 cl, 1 tbl, 301 ex

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula I

, where R1 is selected from a group comprising hydrogen, lower alkyl, lower hydroxyl, lower alkoxyalkyl, lower halogenalkyl, lower cyanoalkyl; unsubstituted or substituted phenyl; lower phenylalkyl, where the phenyl ring can be unsubstituted or substituted; and heteroaryl, selected from pyridyl and pyrimidinyl; R2 denotes hydrogen or halogen; G denotes a group selected from

, where m equals, 0, 1; R3 is selected from lower alkyl, cycloalkyl and lower cycloalkylalkyl; n equals 0, 1; R4 denotes lower alkyl, as well as pharmaceutical compositions.

EFFECT: said compounds are used to treat or prevent diseases associated with histaminase receptor modulation.

19 cl, 1 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula 1, its pharmaceutically acceptable salts and stereoisomers: $ (1), where: R1 means H, amidino, C1-C4-alkyl amidino, C1-C4alkanoylamidino, C1-C10-alkyl, C3-C7-cycloalkyl, C6-C10-aryl, 6-members heterocycle with O atom, 5-members heterocycle with two N atoms, 6-members heteroaryl with one or two N atoms, 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, C1-C6-alkylcarbonyl, C3-C7-cycloalkylcarbonyl, C1-C4-alkoxycarbonyl, C6-C10-aryl-C1-C4-alkoxycarbonyl, -SO2-C1-C4-alkyl, -C(O)-N(R6)(R7) or -C(S)-N(R6)(R7); and, R6, R7 means H, C1-C6-alkyl, C3-C7-cycloalkyl; alkyl, cycloalkyl, heterocycle, aryl or heteroaryl are unsubstituted or substituted; R2 means C6-C10-aryl which is unsubstituted or mono- or disubstituted; R3 means H, CN, C1-C6-alkyl, C3-C7-cycloalkyl, C2-C6-alkenyl, monocyclic 5-members heterocycle with N and O, monocyclic 5-members heteroaryl with two heteroatoms, one of which is N, and the other is O or S, C(O)-R8 or -C(S)-R8; and R8 means OH, C1-C4-alkyl, C1-C4-alkyloxy or N(R9)(R10); R9, R10 mean N, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C4-alkyloxy, phenyl or 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, 6-members heteroaryl with N; R9, R10 together with N whereto attached can form a single 4-6-members ring which can include in addition O or S; and alkyl, cycloalkyl, heterocycle, phenyl or heteroaryl are unsubstituted or substituted. R4 means C3-C8-cycloalkyl, C6-C10-aryl, 5-members heteroaryl with two heteroatoms, one of which is N, and the other is S, 6-members heteroaryl with N, 6-members heterocycle with O, and C6-C10-aryl or heteroaryl are unsubstituted or mono- or polysubstituted. R5 means N, C1-C6-alkyl, -C(O)-R11, C1-C6-alkylsulphonyl, C6-C10-arylsulphonyl, -(CH2)p-C6-C10-aryl, -(CH2)p-heteroaryl or -(CH2)p-C3-C8-cycloalkyl where heteroaryl means 5-members heteroaryl with O or with N or with S which can contain in addition N. p is equal to 1 or 2; R11 means C1-C10-alkyl, C1-C6-alkenyl, C3-C8-cycloalkyl, C3-C8-cycloalkenyl, NH2, C1-C4alkylamino, (C1-C4-alkyl)(C1-C4-alkyl)amino, C6-C10-aryl, 5-members heteroaryl with N or with O or with 8 which can contain in addition N, 6-members heterocycle with N and O, 5- or 6-members heterocycle with O, and alkyl is unsubstituted or substituted with one substitute. Aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycle are unsubstituted or mono- or disubstituted.

EFFECT: compounds are melanocortin receptor agonists so presented to be used in a pharmaceutical composition for treatment and prevention of obesity, diabetes, inflammation, erectile dysfunction.

19 cl, 18 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel derivatives of cis-2,4,5-triarylimidazoline of general formula I and pharmaceutically acceptable salts thereof, where X1 is selected from a group comprising lower alkoxy; X2 and X3 are independently selected from a group comprising hydrogen, halogen, cyano, lower alkyl, lower alkoxy, piperidinyl, -NX4X5, -SO2NX4X5, -C(O)NX4X5, -C(O)X6, -SOX6, -SO2X6, -NC(O)-lower alkoxy, -C≡C-X7, provided that both X2 and X3 do not denote hydrogen, lower alkyl or lower alkoxy, provided that when X2 or X3 denote hydrogen, the other does not denote lower alkyl, lower alkoxy or halogen, provided that when X2 denotes -HX4X5, X3 does not denote hydrogen, X2 and X3 together can form a ring selected from 5-7-member unsaturated rings which can contain three heteroatoms selected from S, N and O, X4 and X5 are independently selected from a group comprising hydrogen, lower alkyl, lower alkoxy, lower alkyl, substituted by a lower alkoxy, -SO2-lower alkyl, -C(O)piperazinyl-3-one; X6 is selected from a group comprising lower alkyl, morpholine, piperidine, pyrrolidine; X7 is selected from a group comprising hydrogen, lower alkyl, trifluoromethyl; Y1 and Y2 are independently selected from a group comprising halogen; R is selected from a group comprising lower alkoxy, piperidinyl substituted with a five-member heterocyclic ring which contains one nitrogen heteroatom, piperidinyl substituted with a hydroxy, -CH2OH or -C(O)NH2, piperazinyl substituted with one or two R1 [1,4]diazepanyl, substituted R1, R1 can denote one or two substitutes selected from a group comprising oxo, lower alkyl substituted with one R2, -C(O)R3, -SO2-lower alkyl, -SO2-five-memer heterocyclyl, which is selected from isoxazolyl, dimethylisoxazolyl, pyrrolidinyl, pyrrolyl, thiophenyl, imidazolyl, thiazolyl, thiazolidinyl, imidazolidinyl; R2 is selected from a group comprising -SO2-lower alkyl, hydroxy, lower alkoxy, -NH-SO2-lower alkyl, -cyano, -C(O)R4; R3 is selected from a group comprising a five-member heterocyclyl which is selected from isoxazolyl, dimethylisoxazolyl, pyrrolidinyl, pyrrolyl, thiophenyl, imidazolyl, thiazolyl, thiazolidinyl, imidazolidinyl, lower alkyl, lower alkenyl, lower alkyl substituted with a six-member heterocyclyl selected from piperidinyl, piperazinyl, 3-oxopiperazinyl, morpholinyl, C3-cycloalkyl; R4 is selected from a group comprising hydroxy, morpholine, piperidine, 4-acetylpiperazinyl, -NR5R6; R5 and R6 are independently selected from a group comprising hydrogen, lower alkyl, lower alkyl substituted with lower alkoxy or cyano, lower alkoxy and C3-cycloalkyl. The invention also relates to a pharmaceutical composition based on the formula I compound, use of the formula I compound in preparing a medicinal agent and a method for synthesis of the formula I compound.

EFFECT: novel derivatives of cis-2,4,5-triarylimidazoline of general formula I are obtained, which can be used to treat diseases, based on reaction of the MDM2 protein with p53-like protein, particularly as anticancer agent.

54 cl, 412 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), where R1 denotes a 5- or 6-member ring of formulae

(II) or (III), respectively: R2 denotes H, C1-C7-alkyl, C3-C6-cycloalkyl or -(CH2)m,-Ra; R3 denotes aryl or heteroaryl, which can be substituted with CN, Cl, F, Br, CF3, CHF2, C3-C6-cycloalkyl or denotes heteroaryl which can be possibly substituted with C1-C7-alkyl; R4 denotes H, -OH, Cl, F, Br, CN, -CHF2, CF3, C1-C7-alkyl, C3-C6-cycloalkyl or -(CH2)m-Re; R5 denotes C1-C7-alkyl, -(CH2)n-O-Rf, or -(CH2)n-Re; Ra denotes -OH; Re denotes -OH; Rf denotes C1-C7-alkyl; m equals 1-4; n equals 2-6; and pharmaceutically acceptable salts thereof. The invention also relates to a medicinal agent containing said derivatives, use thereof in preparing medicinal agents suitable for treating diseases of the central nervous system.

EFFECT: novel compounds suitable for treating diseases of the central nervous system are obtained and described.

29 cl, 111 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel antibacterial compounds of formula (I). Compounds of formula (I) Q-NH-CO-R3, where Q stands for group of the following structure , R1 represents hydrogen, halogen, hydroxy, amino, mercapto, alkyl, heteroalkyl, alkeloxy, heteroalkyloxy, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, cycloalkyloxy, alkylcycloalkyloxy, heterocycloalkyloxy or heteroalkylcycloalkyloxy, X1, X2, X3, X4, X5 and X6 each independently on each other represent nitrogen atom or group of formula CR2, R2 represents hydrogen, halogen or hydroxy, amino, alkyl, alkenyl, alkinyl or heteroalkyl group, R3 is selected from the following groups R5 represents group of formula -B-Y, where B represents alkylene, alkenylene, alkinylene, -NH- or heteroalkylene, and Y represents aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl or heteroalkylcycloalkyl, or their pharmaceutically acceptable salt, solvate, hydrate or pharmaceutically acceptable composition, as well as to pharmaceutical composition, which possesses antibacterial activity, based on said compounds and to their application for preparation of medication, intended for treatment of bacterial infections.

EFFECT: obtained and described are compounds, which can be useful in medicine.

9 cl, 147 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new compounds of formula (1) or its pharmaceutically acceptable salts, with properties of antagonist CXCR2 of human neutrophils receptor. In formula (1) R1 represents a group selected from C1-8alkyl; where this group is possibly substituted with 1 substituent, independently selected from phenyl or 5-6-unit heteroaryl, containing 1-2 heteroatoms selected from N, S; where phenyl and heteroaryl are possibly substituted by 1, 2 or 3 substitutors, independently selected from halogeno, cyano, -OR4, -COOR7, -SO2R10, C1-6alkyl; X represents -CH2-, oxygen, sulfur; R2 represents C3-7carbocyclil, possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4; or R2 represents 5-unit ring, containing 2 heteroatoms, selected from O, -NR8, and where this ring is possibly substituted with 1 substituent, independently selected from C1-3alkyl; or R2 represents group, selected from C1-8alkyla, where this group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-C1-6alkylcarbamoyl, N,N-di(C1-6alkyl)carbamoyl, carboxy, -NR8COR9 and -CONR5R6; R3 represents group -NR5R6, or R3 represents phenyl, possibly condensed with 6-unit heterocyclil, containing nitrogen, naphthyl, 4-8-unit monocyclic heterocyclil, containing 1-3 heteroatoms, selected from N, O, S, possibly condensed with benzole ring or 3-unit nitrogen-containing ring, where heteroring may be non-saturated, partially or fully saturated, and one or more than one circular atom of carbon may form carbonyl group, and where each phenyl or heterocyclil group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, phenyl, 5-6-unit heteroaryl, containing 1-2 atoms of nitrogen, -OR4, -NR5R6, -CONR5R6, -COR7, -COR20, -COOR7, -NR8COR9, -SO2R10, -SO2NR5R6 or C1-6alkyl [possibly additionally substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR20, -COOR20, -NR18R19, -CONR18R19, phenyl or 5-6-unit of monocyclic heteroaryl, containing 1-2 heteroatoms O, N, S, or 10-unit bicyclic heteroaryl, containing 1 heteroatom O, where heteroring may be partially or fully saturated, and where each phenyl or heteroaryl is group possibly substituted with 1 or 2 substituents, independently selected from halogeno, cyano, nitro, -OR20, -NR5R6, -COOR7, -NR8COR9, 6-unit heterocyclil, containing two heteroatoms, selected from O and N, 5-unit heteroaryl, containing 3 heteroatoms N, C1-6alkyl (possibly additionally substituted with 1 substituent, independently selected from halogeno, cyano, nitro, -OR20, -COOR20; or R3 represents group, selected from C3-7carbocyclil, C1-8alkyl, where this group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6; R4 represents hydrogen; R5 and R6 independently represent hydrogen or group, selected from C1-6alkyl and monocyclic 6-unit saturated heterocyclil containing 1 heteroatom N; where C1-6alkyl is possibly substituted with 1 substituent, independently selected from -NR15R16; or R5 and R6 together with atom of nitrogen, to which they are linked, form 4-7-unit saturated heterocyclic circukar system, possibly containing additional heteroatom, selected from oxygen, -SO(n)- (where n equals 0, 1 or 2) and atoms of nitrogen; R10 represents hydrogen or group, selected from C1-6alkyl; and each of R7, R8, R9, R15, R16, R17 independently represents hydrogen, C1-6alkyl; R18, R19 and R20 represent hydrogen or group, selected from C1-6alkyl, where this group is possibly substituted with 1 substituent, independently selected from -NR8R9, -CONR8R9.

EFFECT: production of new compounds, which may find application in production of medicinal agent for use in treatment of diseases and disorders mediated with chemokines, such as asthma, allergic rhinitis, chronic obstructive pulmonary disease, inflammatory intestine disease, irritable colon syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis or psoriasis, and also for treatment of cancer.

12 cl, 155 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula (I): or to any of its stereoisomers, or to any mixture of their stereoisomers, or to their pharmaceutically acceptable salts where Ra, Rb and Rc independently represent hydrogen, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, arylalkyl, formyl or alkylcarbonyl; Rd represents a heteroaryl group; where said heteroaryl group means a 5-6-member aromatic heterocyclic group which contains one or two heteroatoms in the ring structure, specified from nitrogen (N) or sulphur (S) and where the heteroaryl group is optionally substituted with one or more substitutes independently specified from the group including: halogeno, hydrazino and alkoxy. Also the invention refers to a pharmaceutical composition, the application of a chemical compound under any of cl. 1-6, as well as to a method of GABAa-receptor complex modulation in the central nervous system.

EFFECT: preparation of the new biologically active compounds exhibiting gamma-amino-butyric acid (GABAa) receptor complex modulating activity in the central nervous system.

11 cl, 10 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I): , optical isomers of said compounds, as well as salts thereof having peroxisome proliferator-activated receptor subtype y (PPARy) modulating property. Values of R1, R2, X, Ar1 and Ar2 are given in the formula of invention.

EFFECT: preparation of compositions based on said compounds, as well as use of said compounds in cosmetic and pharmaceutical industry.

11 cl, 30 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or its pharmaceutically acceptable salt or its solvate, where ring A is a monocyclic heterocyclic group optionally substituted with 1-2 substitutes selected from the following group A, where the monocyclic heterocyclic group is selected from 1-pyrrolidinyl group, 2-oxopyrrolidin-1-yl group, piperidine group, 2-oxopiperidin-1-yl group, 1-piperazinyl group, morpholine group, 3-oxomorpholin-4-yl group, thiomorpholine group, 1,1-dioxoisothiazolin-2-yl group, 2-pyridyl group, 2-thiazolyl group and 1,2,4-oxadiazol-3-yl group; group A consists of a halogen atom, C1-4alkyl group, -(CH2)n-ORa1 and -CORa2, where Ra1 and Ra2 are identical or different and each of them is a hydrogen atom or a C1-4alkyl group and n equals 0; R1 is a C1-6alkyl group optionally substituted with 1 substitute selected from the following group B; group B consists of -ORb1, where Rb1 is a C1-4alkyl group; R2 is a hydrogen atom, C1-4alkyl group or -OR11, where R11 is an atom, C1-4alkyl group; R3 and R4 are identical or different and each is a halogen atom; R5 is a halogen atom; m equals 0 or 1; and R6 is a hydrogen atom. The invention also relates to a pharmaceutical composition, anti-HIV agent, HIV integrase inhibitor, anti-HIV compositions which contain an active ingredient in form of a formula I compound; to use of formula I compounds to prepare an anti-HIV agent and HIV integrase inhibitor; to a method of preventing or treating infectious diseases caused by HIV and to a method of inhibiting HIV integrase in mammals, involving administration of formula I compounds.

EFFECT: useful biological properties.

27 cl, 9 tbl, 67 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I , where: R1, R2, R3 and R4 independently from each other mean hydrogen, F, CI, Br, I; R5 designates hydrogen, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, or cycloalkyl with 3, 4, 5 or 6 C atoms; R6 designates hydrogen; R7 and R8 independently from each other mean hydrogen, W means CrH2r or CsH2S-2; and one or more CH2-groups in C2H2r and CsH2s-2 can be substituted with NR17, oxygen or S; R17 means hydrogen, alkyl with 1, 2, 3 or 4 C atoms; r means 1, 2, 3, 4, 5 or 6; s means 2, 3 or 4; X designates-with C(O)- or -S(O)2-; Z means -C(O)- or a bond; and also to their pharmaceutically acceptable salts and trifluoroacetates. The invention also concerns application of the compounds of formula I, and also to a pharmaceutical composition.

EFFECT: preparation of new biologically active compounds exhibiting NHE3 inhibiting activity.

16 cl, 64 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, and more specifically to novel ethyl 5-R1-7-R2-1'-benzyl-3,3-dimethyl-1,2' -dioxo-5'-phenyl- 1',2,2',3,4,10-hexahydro-1H-spiro[acridine-9,3'-pyrrol]-4'-carboxylates of formula , where R1=H, Me; R2=H, OMe; R3=H, Me, OMe, Br, and to a method for synthesis of the said compounds.

EFFECT: obtaining novel compounds which can be used as primary products for synthesis of novel heterocyclic systems and in pharmacology as compounds with analgesic activity.

5 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 1-thio-D-glucitol compounds of formula I or to pharmaceutically acceptable salts thereof or hydrates of the compound or salts: , [where R1, R2, R3 and R4 are identical or different, and each is a hydrogen atom, C1-C6-alkyl group), A is -(CH2)n-, -CONH(CH2)n-, -O- or -(CH2)nCH=CH- (where n is an integer from 0 to 3, Ar1 is an arylene group, heteroarylene group, which is an unsaturated 5-9-member mono- or bicyclic group, containing 1-2 heteroatoms, selected from S and N, Ar2 is an aryl group or heteroaryl group which is an unsaturated 5-9-member mono- or bicyclic group containing 1-2 heteroatoms selected from O, S and N, and R5, R6, R7, R8, R9 and R10 are identical or different, and each is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) C1-8-alkyl group, optionally substituted with hydroxyl group(s), (v) -(CH2)m-Q {where m is an integer from 0 to 4, and Q is -CO2H, -ORc1, -CO2Ra3, -SRe1, -NHRa6 or -NRa7Ra7 (where each of Ra3, Ra6 and Ra7 is a C1-6-alkyl group, Rc1 is a C1-6-alkyl group, and Rc1 is a C1-6-alkyl group)}, (vi) -O-(CH2)m'-Q' {where m' is an integer from 1 to 4, and Q' is a hydroxyl group,-CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12 (where each of Ra8, Ra10 and Ra12 is a C1-6-alkyl group)}, (vii) -ORf {where Rf is C3-7-cycloalkyl group or tetrahydropyranyl group)}, (viii) morpholine group, (ix) phenyl group, (x) pyridyl group]. The invention also relates to 1-thio-D-glucitol compounds of formulae IA, II, III, IV, to a pharmaceutical agent, to methods of obtaining 1-thio-D-glucitol compounds, as well as to compounds of formulae XIII, XIV.

EFFECT: obtaining novel biologically active compounds which are inhibitors of sodium-dependent co-transporter-2-glucose.

25 cl, 140 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: in formula (1), R1 is di-C1-6alkoxyphenyl group; A is one of the following groups (i)-(vi); (i) -CO-B-, where B is C1-6alkylene group; (ii) -CO-Ba-, where Ba is C2-6alkenylene group; (iii) -CH(OH)-B-; (iv) -COCH((C)OOR3)-Bb-, where R3 is C1-6alkyl group and Bb is C1-6alkylene group. Values of the other radicals are specified in the patent claim. Invention also concerns the pharmaceutical composition exhibiting properties of a phosphodiesterase PDE4 inhibitor containing the compound under the invention; the phosphodiesterase 4 inhibitor containing as an active component the compound of the invention; preventive or therapeutic preparation for atopic dermatitis containing as an active component the compound of the invention.

EFFECT: higher effectiveness of application of the compound.

8 cl, 24 tbl, 262 ex

FIELD: pharmacology.

SUBSTANCE: invention deals with formula I compounds and their sals pharmaceutically relevant in the capacity of phosphatidylinositol 3-kinase inhibitors, their preparation method as well as their application for production of a pharmaceutical preparation, a pharmaceutical compounds based thereon and a therapy method envisaging their application. In a formula compound R1 is represented by aminocarbonyl, non-obligatorily displaced with nitrile, or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with hydroxi, carboxi, C1-C8-alcoxicarbonyl, nitrile, phenyl, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkyl aminocarbonyl alkylcarbonyl that is non-obligatorily displaced with halogen, hydroxi, C1-C8-alkylanimo, di(C1-C8-alkyl)amino, carboxi, C1-C8-alcoxicarbonyl, nitrile, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, non-obligatorily displaced with C1-C8-cycloalkyl or R1 is represented by C1-C8-alkylcarbonyl or C1-C8-alkylaminocarbonyl, each of them non-obligatorily displaced with C1-C8-alcoxi, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, displaced with phenyl, additionally displaced with hydroxi or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-4 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with C1-C8-alkyl on condition that the 6-membered heterocyclic ring is no 1-piperidyl or R1 is represented by C1-C8-alkylaminocarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring is non-obligatorily displaced with C1-C8-alkyl or R1 is represented by -(C=O)-(NH)a-Het, where a stands to denote 0 or 1 and Het stands to denote a 4-, 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with hydroxi, C1-C8-alkyl, C1-C8-alcoxi or a 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 0 or 1 and T stands to denote C3-C8-cycloalkyl that is non-obligatorily displaced with hydroxi or C1-C8-alkyl displaced with hydroxi or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 1 and T stands to denote phenyl that is non-obligatorily displaced with C1-C8-alkyl or C1-C8-alkyl displaced with hydroxi, R2 is represented by C1-C3-alkyl; one of R3 and R4 is represented by R6 while the other is represented by R7; R5 is represented by hydrogen or a halogen; R6 is represented by hydrogen, hydroxi, amino, -SOR8, -SO2R8, -SO2NH2, -SO2NR9R10, -COR8, -CONHR8, -NHSO2R8, nitrile, carboxi, -OR8 or C1-C8-halogenalkyl; R7 is represented by hydrogen, R11, -OR11, halogen, -SO2R8, ciano or C1-C8-halogenalkyl or, when R4 is represented by R7, R7 may equally be represented by -NR12R13; R8 and R11 are independently represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, nitrile, amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino; any R9 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, C1-C8-alcoxi, nitrile, amino, C1-C8-akrylamino, di(C1-C8-alkyl)amino or 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring where the ring is non-obligatorily displaced with C1-C8-alkyl, and R10 is represented by hydrogen or C1-C8-alkyl or R9 and R10 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl; any R12 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino and R13 is represented by halogen or C1-C8-alkyl or R12 and R13 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl.

EFFECT: proposed compounds are to be utilised for treatment of diseases mediated by phosphatidilinozitol 3-kinase such as allergy, psoriasis, diabetes, atherosclerosis, diabetes, cancer.

19 cl, 3 tbl, 181 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns novel compounds of formula (1a), formula (1b), formula (1c) and formula (1d), as well as pharmaceutical composition based on them and their application in medicine obtainment. R1-R4, G, W, X, X1, U, V, a, b are defined in the invention claim.

EFFECT: compound with antagonistic effect on vasopressin V1A receptor.

73 cl, 133 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrrolidine derivatives of general formula (1) or its pharmaceutically acceptable salts where R101 and R102 values are described by the patent claim. The compounds inhibit serotonin and/or norepinephrine and/or dopamine reabsorption thereby allowing to be used for treating depression and anxiety disorder. A method for preparing thereof is described.

EFFECT: preparation of new pyrrolidine derivatives.

10 cl, 162 tbl, 7 ex

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