Hypoglycemic drug, containing polyhydroxybutyrates, new polyhydroxybutyrate and methods for their production

 

(57) Abstract:

Describes hypoglycemic drug containing as an active beginning at least one polyhydroxybutyrate formula I, in which either (a) each of R9and R10means the radical-CH2HE either a) R3means methylene, R4means the radical-SNON - and one of the radicals R1, R2, R5, R6means methylene, -CHF -, or-CH(OR8)- and each other-SNON-; b) each of R2and R5means SNON-, R3means methylene, and R1R4and R6are the same and each means-CH(OR8)-; each of R1and R6means SNON-, R3means methylene, and R2, R4and R5are the same and each means-CH(OR8)-; each of R1, R4, R5and R6means the radical-SNON - and-R2-R3means the radical-CH=CH-; or (B) each of R1, R2R4, R5and R6means the radical-SNON-, R3is methylene, R9means the radical-CH2HE, R10means-CH2F, R8means alkyl with 1-6 carbon atoms in linear or branched chain, one of its stereoisomers or operatino formula I and the use of polyhydroxybutyrate formula And the effective beginning of the medicinal product, suitable for the treatment or prevention of diabetes and complications of diabetes. 10 S. and 2 C.p. f-crystals.

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The present invention relates to medicines containing the active beginning at least one compound of formula (I)

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or one of its stereoisomers or one of its salts, to new compounds of the formula (I), their stereoisomers and their salts and method of production thereof. In the formula (I):

either (a) each of R9and R10means the radical-CH2HE or

a) R5means methylene, R4means the radical-SNON - and one of the radicals R1, R3, R5and R6means carbonyl, methylene, -CHF-, -CH(other7)- or-CH(OR8)-, and each of the other means the radical-SNON-;

b) each of R2and R5means the radical-SNON-, R3means methylene, and R1, R4and R5are the same and each means a carbonyl, methylene, -CHF-, -CH(other7)- or-CH(OR8)-;

C) each of R1and R6means the radical-SNON-, R3means methylene, and R2, R4and R5are the same and each means a carbonyl, methylene, -CHF-, -CH(other7)- or-CH(OR8)-;

g) each of R1, R4, R5and R2, R4, R5and R6means the radical-SNON-, R3means methylene, R9means the radical-CH2F or-CH2HE, R10means the radical-CH2F or-CH2HE, and R9and R10both do not mean the radical-CH2IT;

R7means a hydrogen atom or alkyl, -CO-ALK, -CO-AG or-CO-Het;

R8means alkyl, ALK-COOH or-ALK-HE;

Ala means alkyl;

Ar denotes phenyl or phenyl substituted by one or more substituents selected from the group consisting of halogen atom, alkyl, alkoxy, alkoxycarbonyl, amino, monoalkylamines or dialkylamino;

Het denotes a saturated or unsaturated mono-, di - or trigeneration containing 1-9 carbon atoms and one or more heteroatoms selected from the group consisting of oxygen atoms, sulfur and nitrogen.

In the above and below the definitions of alkyl and CNS radicals and alkyl and CNS parts contain 1-6 carbon atoms in linear or branched chain, and halogen atoms are chlorine atoms, fluorine, iodine and bromine.

The compounds of formula (I), which includes several asymmetric carbon atoms have stereoisomers -R3means the radical-CH=CH-, can be in CIS - or TRANS-form; these forms are also part of the invention.

Preferably Het means a heterocycle selected from cycles: 2-, 3 - or 4-pyridyl, imidazolyl, thiazolyl and oxazolyl.

In other words, the compounds of formula (I) meet the following formula:

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in which R is carbonyl, methylene, -F-, -CH(other7)- or-CH(OR8)-, R7, R8, R9and R10have the above meanings; their stereoisomeric forms and CIS - and TRANS-forms of the compounds including chain-CH=CH-.

Preferred drugs are those which contain as an active beginning at least one compound of formula (I) selected from the following compounds:

1-[5-(3R,4-dihydroxy-2-oxobutyl)pyrazin-2-yl]butane-1R,23,3 R,4-tetraol;

1-[5-(3S,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

1-[5-(2S-fluoro-3R, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R, 2S,3R,4-tetraol;

1-[5-(2R-fluoro-3R, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R,2S,3R, 4-tetraol;

1-[5-(2S-amino-3S, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R,2S,3R,4-tetraol;

1-[5-(2R-amino-3S, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R,2S,3R,but-3S, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R,2S, 3R,4-tetraol;

1-[5-(2S-(N-ethyl)amino-3S,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R, 4-tetraol;

1-[5-(2R-(N-ethyl)amino-3S,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R, 4-tetraol;

1-[5-(2S-(N-n-butyl)amino-3S,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S, 3R,4-tetraol;

1-[5-(2R-(N-n-butyl)amino-3S,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S, 3R,4-tetraol;

1-[5-(2S-(N-benzyl)amino-3S, 4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S, 3R,4-tetraol;

1-[5-(2R-(N-benzyl)amino-3S, 4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S, 3R,4-tetraol;

1-[5-(2S-(N-acetyl)amino-3S, 4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S, 3R,4-tetraol;

1-[5-(2R-(N-acetyl)amino-3S, 4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S, 3R,4-tetraol;

1-[5-(2S-(N-butanoyl)amino-3S, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R, 2S,3R,4-tetraol;

1-[5-(2R-(N-butanoyl)amino-3S, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R, 2S,3R,4-tetraol;

1-[5-(2S-(N-benzoyl)amino-3S,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S, 3R,4-tetraol;

1-[5-(2R-(N-benzoyl)amino-3S,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S, 3R,4-tetraol;

1-[5-(2S-methoxy-3R,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

1-[5-(2R-methoxy-3R,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

1-[5-(2S-ethoxy-3R, 4-dihydroxybutyl)pyrazin-2-yl]butane-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

1-[5-(2R-n-butoxy-3R, 4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

1-[5-(2S-(2-hydroxyethyl)oxy 3R, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R,2S,3R,4-tetraol;

1-[5-(2R-(2-hydroxyethyl)oxy 3R, 4-dihydroxybutyl)pyrazin-2-yl]butane-1R, 2S,3R,4-tetraol;

1-[5-(2S-(3-hydroxy-n-propyl)oxy-3R,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

1-[5-(2R-(3-hydroxy-n-propyl)oxy-3R,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

1-[5-(2S-(carboxymethyl)oxy 3R,4-dihydroxybutyl)pyrazin-2-yl]butane-1R, 2S,3R,4-tetraol;

1-[5-(2R-(carboxymethyl)oxy 3R,4-dihydroxybutyl)pyrazin-2-yl]butane-1R, 2S,3R,4-tetraol;

1-[5-(2S-(3-carboxy-n-propyl)oxy-3R,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

1-[5-(2R-(3-carboxy-n-propyl)oxy-3R,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

1-[5-(2S,4-dihydroxy-3-oxobutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

1-[5-(2S,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

1- [5-(3R-fluoro-2S, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R, 2S, 3R,4-tetraol;

1-[5-(3S-fluoro-2S, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R, 2S,3R,4-tetraol;

1-[5-(3R-amino-2R, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R,2S,3R,4-tetraol;

1-[5-(3S-amino-2R, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R,2S,3R,4-tetraol;

1-[5-(3R-(N-methyl)amino-2R, 4-Dian-1R,2S, 3R,4-tetraol;

1-[5-(3R-(N-ethyl)amino-2R,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R, 4-tetraol;

1-[5-(3S-(N-ethyl)amino-2R,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R, 4-tetraol;

1-[5-(3R-(N-n-butyl)amino-2R,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S, 3R,4-tetraol;

1-[5-(3S-(N-n-butyl)amino-2R,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S, 3R,4-tetraol;

1-[5-(3R-(N-benzyl)amino-2R, 4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S, 3R,4-tetraol;

1-[5-(3S-(N-benzyl)amino-2R, 4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S, 3R,4-tetraol;

1-[5-(3R-(N-acetyl)amino-2R, 4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S, 3R,4-tetraol;

1-[5-(3S-(N-acetyl)amino-2R, 4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S, 3R,4-tetraol;

1-[5-(3R-(N-butanoyl)amino-2R, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R, 2S,3R,4-tetraol;

1-[5-(3S-(N-butanoyl)amino-2R, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R, 2S,3R,4-tetraol;

1-[5-(3R-(N-benzoyl)amino-2R,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S, 3R,4-tetraol;

1-[5-(3S-(N-benzoyl)amino-2R,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S, 3R,4-tetraol;

1-[5-(3R-methoxy-2S, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R, 2S,3R,4-tetraol;

1-[5-(3S-methoxy-2S, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R, 2S,3R,4-tetraol;

1-[5-(3R-ethoxy-2S, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R, 2S, 3R,4-tetraol;

1-[5-(3S-ethoxy-2S and an-1R,2S,3R,4-tetraol;

1-[5-(3S-n-butoxy-2S, 4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

1-[5-(3R-(2-hydroxyethyl)oxy-2S, 4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

1-[5-(3S-(2-hydroxyethyl)oxy-2S, 4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

1-[5-(3R-(3-hydroxy-n-propyl)oxy-2S,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

1-[5-(3S-(3-hydroxy-n-propyl)oxy-2S,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

1-[5-(3R-(carboxymethyl)oxy-2S,4-dihydroxybutyl)pyrazin-2-yl]butane-1R, 2S,3R,4-tetraol;

1-[5-(3S-(carboxymethyl)oxy-2S,4-dihydroxybutyl)pyrazin-2-yl]butane-1R, 2S,3R,4-tetraol;

1-[5-(3R-(3-carboxy-n-propyl)oxy-2S,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

1-[5-(3S-(3-carboxy-n-propyl)oxy-2S,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

4-[5-(2S, 3R,4-trihydroxybutane)pyrazin-2-yl]-1,3 S,4R-trihydroxybutane-2-he;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]butane-1R,2R,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-3R-verboten-1R,2S,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-3S-verboten-1R,2S,4-triol;

1-[5-(2S, 3R,4-trihydroxybutane)pyrazin-2-yl]-3R-aminobutane-1R,2R,4-triol;

1-[5-(2S, 3R,4-trihydroxybutane)pyrazin-2-yl]-3S-aminobutane-1R,2R,4-triol;

1-[5-(2S, 3R,4-trihydroxybutane)Pirat-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl]-3R-(N-ethyl)aminobutane-1R, 2R,4-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl]-3S-(N-ethyl)aminobutane-1R, 2R,4-triol;

1-[5-(2S, 3R,4-trihydroxybutane)pyrazin-2-yl]-3R-(N-n-butyl)aminobutane-1R,2R,4-triol;

1-[5-(2S, 3R,4-trihydroxybutane)pyrazin-2-yl]-3S-(N-n-butyl)aminobutane-1R,2R,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-3R-(N-benzyl)aminobutane-1R, 2R,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-3S-(N-benzyl)aminobutane-1R, 2R,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-3R-(N-acetyl)aminobutane-1R, 2R,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-3S-(N-acetyl)aminobutane-1R, 2R,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-3R-(N-butanoyl)aminobutane-1R,2R,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-3S-(N-butanoyl)aminobutane-1R,2R,4-triol;

1-[5-(2S, 3R,4-trihydroxybutane)pyrazin-2-yl]-3R-(N-benzoyl)aminobutane-1R,2R,4-triol;

1-[5-(2S, 3R,4-trihydroxybutane)pyrazin-2-yl]-3S-(N-benzoyl)aminobutane-1R,2R,4-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl]-3R-methoxybutan-1R,2S,4-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl]-3S-methoxybutan-1R,2S,4-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl] -3R-ethoxilated-1R,2S,4-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl] -3S-toxicokinetic)pyrazin-2-yl] -3S-n-butoxymethyl-1R,2S, 4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-3R-(2-hydroxyethyl)oxybutin-1R,2S,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-3S-(2-hydroxyethyl)oxybutin-lR,2S,4-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl] -3R-(3-hydroxy-n-propyl)oxybutin-1R,2S,4-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl] -3S-(3-hydroxy-n-propyl)oxybutin-1R,2S,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-3R-(carboxymethyl)oxybutin-1R,2S,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-3S-(carboxymethyl)oxybutin-1R,2S,4-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl] -3R-(3-carboxy-n-propyl)oxybutin-1R,2S,4-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl] -3S-(3-carboxy-n-propyl)oxybutin-1R,2S,4-triol;

1-[5-(2S, 3R,4-trihydroxybutane)pyrazin-2-yl]-1R,3R,4-trihydroxybutane-2-he;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]butane-1R,3R,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-2R-verboten-1R,3R,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-2S-forutan-1R,3R,4-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl] -2R-aminobutane-1S, 3S,4-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl] -2S-aminobutane-1S, 3S,4-triol;

1-[5-(2S, 3R,4-trihydroxybutane)pyrazin-2-yl]-2R-(N-methyl)aminobutane-1S, 3S,4-triol;

1-[5-(2S, 3R,4-trihydroxybutane the n-1S, 3S,4-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl]-2S-(N-ethyl)aminobutane-1S, 3S,4-triol;

1-[5-(2S, 3R,4-trihydroxybutane)pyrazin-2-yl]-2R-(N-n-butyl)aminobutane-1S,3S,4-triol;

1-[5-(2S, 3R,4-trihydroxybutane)pyrazin-2-yl]-2S-(N-n-butyl)aminobutane-1S,3S,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-2R-(N-benzyl)aminobutane-1S, 3S,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-2S-(N-benzyl)aminobutane-1S, 3S,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-2R-(N-acetyl)aminobutane-1S, 3S,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-2S-(N-acetyl)aminobutane-1S, 3S,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-2R-(N-butanoyl)aminobutane-1S,3S,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-2S-(N-butanoyl)aminobutane-1S,3S,4-triol;

1-[5-(2S, 3R,4-trihydroxybutane)pyrazin-2-yl]-2R-(N-benzoyl)aminobutane-1S,3S,4-triol;

1-[5-(2S, 3R,4-trihydroxybutane)pyrazin-2-yl]-2S-(N-benzoyl)aminobutane-1S,3S,4-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl]-2R-methoxybutan-1R,3R,4-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl]-2S-methoxybutan-1R,3R,4-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl] -2R-ethoxilated-1R,3R,4-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl] -2S-ethoxilated-1R,3R,4-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl] -2R-H2S,3R,4-trihydroxybutane)pyrazin-2-yl]-2R-(2-hydroxyethyl)oxybutin-1R,3R,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-2S-(2-hydroxyethyl)oxybutin-1R,3R,4-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl] -2R-(3-hydroxy-n-propyl)oxybutin-1R,3R,4-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl] -2S-(3-hydroxy-n-propyl)oxybutin-1R,3R,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-2R-(carboxymethyl)oxybutin-1R,3R,4-triol;

1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]-2S-(carboxymethyl)oxybutin-1R,3R,4-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl] -2R-(3-carboxy-n-propyl)oxybutin-1R,3R,4-triol;

1-[5-(2S, 3R, 4-trihydroxybutane)pyrazin-2-yl] -2S-(3-carboxy-n-propyl)oxybutin-1R,3R,4-triol;

1-[5-(2S, 4-dihydroxy-3-oxobutyl)pyrazin-2-yl] -2S,4-dihydroxybutyl-1,3-dione;

4-[5-(2S,4-dihydroxybutyl)pyrazin-2-yl]butane-1,3, S-diol;

4-[5-(3R-fluoro-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2R, 4R-diformate-1,3, S-diol;

4-[5-(3S-fluoro-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2S, 4S-diformate-1,3, S-diol;

1-[5-(3R-amino-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2R,4R-diaminobutane-1,3, S-diol;

1-[5-(3S-amino-2S, 4-dihydroxybutyl) pyrazin-2-yl]-2S,4S-diaminobutane-1,3, S-diol;

1-[5-(3R-(N-methyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl]-2R,4R-di(N-methyl)aminobutane-1,3, S-diol;

1-[5-(3S-N-methyl)amino-2S,4-dihydroxybutyl)pyrazin-2-yl]-2S,4S-di(N-methyl)aminobutane-1,3 S)amino-2S,4-dihydroxybutyl)pyrazin-2-yl]-2S,4S-di(N-ethyl)aminobutane-1,3, S-diol;

1-[5-(3R-(N-n-butyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2R, 4R-di(N-n-butyl)aminobutane-1,3, S-diol;

1-[5-(3S-(N-n-butyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2S, 4S-di(N-n-butyl)aminobutane-1,3, S-diol;

1-[5-(3R-(N-benzyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-Il-2R, 4R-di(N-benzyl)aminobutane-1,3, S-diol;

1-[5-(3S-(N-benzyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2S, 4S-di(N-benzyl)aminobutane-1,3, S-diol;

1-[5-(3R-(N-acetyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2R, 4R-di(N-acetyl)aminobutane-1,3, S-diol;

1-[5-(3S-(N-acetyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2S, 4S-di(N-acetyl)aminobutane-1,3, S-diol;

1-[5-(3R-(N-butanoyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2R, 4R-di(N-butanol)aminobutane-1,3, S-diol;

1-[5-(3S-(N-butanoyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2S, 4S-di(N-butanol)aminobutane-1,3, S-diol;

1-[5-(3R-(N-benzoyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2R, 4R-di(N-benzoyl)aminobutane-1,3, S-diol;

1-[5-(3S-(N-benzoyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2S, 4S-di(N-benzoyl)aminobutane-1,3, S-diol;

1-[5-(3R-methoxy-2S, 4-dihydroxybutyl) pyrazin-2-yl] -2R,4R-diethoxybutane-1,3, S-diol;

1-[5-(3S-methoxy-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2S,4S-diethoxybutane-1,3, S-diol;

1-[5-(3R-ethoxy-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2R, 4R-diethoxybutane-1,3, S-diol;

1-[5-(3S-atxn-2-yl]-2R,4R-di-n-butoxide - 1,3, S-diol;

1-[5-(3S-n-butoxy-2S, 4-dihydroxybutyl)pyrazin-2-yl]-2S,4S-di-n-butoxide-1,3, S-diol;

1-[5-(3R-(2-hydroxyethyl)oxy-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2R, 4R-di(2-hydroxyethyl)oxybutin-1,3, S-diol;

1-[5-(3S-(2-hydroxyethyl)oxy-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2S, 4S-di(2-hydroxyethyl)oxybutin-1,3, S-diol;

1-[5-(3R-(3-hydroxy-n-propyl)oxy-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2R,4R-di(3-hydroxy-n-propyl)oxybutin-1,3, S-diol;

1-[5-(3S-(3-hydroxy-n-propyl)oxy-2S, 4-dihydroxybutyl)pyrazin - 2-yl] -2S,4S-di(3-hydroxy-n-propyl)oxybutin-1,3, S-diol;

1-[5-(3R-(carboxymethyl)oxy-2S, 4-dihydroxybutyl)pyrazin-2-yl]-2R,4R-di(carboxymethyl)oxybutin-1,3, S-diol;

1-[5-(3S-(carboxymethyl)oxy-2S, 4-dihydroxybutyl)pyrazin-2-yl]-2S,4S-di(carboxymethyl)oxybutin-1,3, S-diol;

1-[5-(3R-(3-carboxy-n-propyl)oxy-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2R,4R-di(3-carboxy-n-propyl)oxybutin-1,3, S-diol;

1-[5-(3S-(3-carboxy-n-propyl)oxy-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2S,4S-di(3-carboxy-n-propyl)oxybutin-1,3, S-diol;

1-[5-(3R, 4-dihydroxy-2-oxobutyl)pyrazin-2-yl] -3R,4-dihydroxybutyl-1,2-dione;

4-[5-(2S,4-dihydroxybutyl)pyrazin-2-yl]butane-1,3, S-diol;

4-[5-(3R-fluoro-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2R, 4R-diformate-1,3, S-diol;

4-[5-(3S-fluoro-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2S-amino-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2S,4S-diaminobutane-1,3, S-diol;

4-[5-(3R-(N-methyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl]-2R,4R-di(N-methyl)-aminobutane-1,3, S-diol;

4-[5-(3S-(N-methyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl]-2S,4S-di(N-methyl)aminobutane-1,3, S-diol;

4-[5-(3R-(N-ethyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2R,4R-di(N-ethyl)aminobutane-1,3, S-diol;

4-[5-(3S-(N-ethyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2S,4S-di(N-ethyl)aminobutane-1,3, S-diol;

4-[5-(3R-(N-n-butyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2R, 4R-di(N-n-butyl)aminobutane-1,3, S-diol;

4-[5-(3S-(N-n-butyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2S, 4S-di(N-n-butyl)aminobutane-1,3, S-diol;

4-[5-(3R-(N-benzyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl] 2R, 4R-di(N-benzyl)aminobutane-1,3, S-diol;

4-[5-(3S-(N-benzyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl] - 2S, 4S-di(N-benzyl)aminobutane-1,3, S-diol;

4-[5-(3R-(N-acetyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2R, 4R-di(N-acetyl)aminobutane-1,3, S-diol;

4-[5-(3S-(N-acetyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2S, 4S-di(N-acetyl)aminobutane-1,3, S-diol;

4-[5-(3R-(N-butanoyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2R, 4R-di(n-butanol)aminobutane-1,3, S-diol;

4-[5-(3S-(N-butanoyl)amino-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2S, 4S-di(N-butanol)aminobutane-1,3, S-diol;

4-[5-(3R-(N-benzoyl)amino-2S, the Thiel)pyrazin-2-yl] -2S, 4S di(N-benzoyl)aminobutane-1,3, S-diol;

4-[5-(3R-methoxy-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2R,4R-diethoxybutane-1,3, S-diol;

4-[5-(3S-methoxy-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2S,4S-diethoxybutane-1,3, S-diol;

4-[5-(3R-ethoxy-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2R, 4R-diethoxybutane-1,3, S-diol;

4-[5-(3S-ethoxy-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2S, 4S-diethoxybutane-1,3, S-diol;

4-[5-(3R-n-butoxy-2S, 4-dihydroxybutyl)pyrazin-2-yl]-2R,4R-di-n-butoxide-1,3, S-diol;

4-[5-(3S-n-butoxy-2S, 4-dihydroxybutyl)pyrazin-2-yl]-2S,4S-di-n-butoxide-1,3, S-diol;

4-[5-(3R-(2-hydroxyethyl)oxy-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2R, 4R-di(2-hydroxyethyl)oxybutin-1,3, S-diol;

4-[5-(3S-(2-hydroxyethyl)oxy-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2S, 4S-di(2-hydroxyethyl)oxybutin-1,3, S-diol;

4-[5-(3R-(3-hydroxy-n-propyl)oxy-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2R,4R-di(3-hydroxy-n-propyl)oxybutin-1,3, S-diol;

4-[5-(3S-(3-hydroxy-n-propyl)oxy-2S, 4-dihydroxybutyl)pyrazin-2-yl] -2S,4S-di(3-hydroxy-n-propyl)oxybutin-1,3, S-diol;

4-[5-(3R-(carboxymethyl)oxy-2S, 4-dihydroxybutyl)pyrazin-2-yl]-2R,4R-di(carboxymethyl)oxybutin-1,3, S-diol;

4-[5-(3S-(carboxymethyl)oxy-2S, 4-dihydroxybutyl)pyrazin-2-yl]-2S,4S-di(carboxymethyl)oxybutin-1,3, S-diol;

4-[5-(3R-(3-carboxy-n-propyl)oxy-2S, 4-dihydro shall troxerutin)pyrazin-2-yl] -2S,4S-di(3-carboxy-n-propyl)oxybutin-1,3, S-diol;

1-[5-(3S,4-dihydroxy-1E-butenyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

4-fluoro-1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]butane-1R,2S,3S-triol;

1-[5-(4-fluoro-2S, 3S-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol,

and their salts with pharmaceutically acceptable inorganic or organic acid.

Especially preferred are medicinal products that contain as active beginning at least one compound of formula (I) in which:

either (a) each of R9and R10means the radical-CH2HE or

a) R3means methylene, R4means the radical-SNON - and one of the radicals R1, R2, R5and R6means the radical-F - or-CH(OR8)-, and each of the other means the radical-SNON-;

b) each of R2and R5means the radical-SNON-, R3means methylene, and R1, R4and R6are the same and each means a radical-CH(OR8)-;

C) each of R1and R6means the radical-SNON-, R3means methylene, and R2, R4and R5are the same and each means a radical-CH(OR8)-;

g) each of R1, R4, R5and R6means the radical-SNON - and-R2-R the radical-SNON-, R3means methylene, R9means the radical-CH2HE, R10means the radical-CH2F;

R8means alkyl;

their stereoisomers, CIS - and TRANS-forms of the compounds, in which R2-R3- means chain-CH=CH-, and their salts with pharmaceutically acceptable inorganic or organic acid.

Even more preferred drugs are those which contain as an active beginning at least one compound of formula (I) selected from the following compounds:

1-[5-(3S,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

1-[5-(3S,4-dihydroxy-1E-butenyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

1-[5-(2S-methoxy-3R, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R, 2S,3R,4-tetraol;

1-[5-(2R-fluoro-3R, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R, 2S,3R,4-tetraol;

1-[5-(2S,4-dihydroxy-3R-methoxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

4-[5-(3R, 4-dihydroxy-2S-methoxybutyl)pyrazin-2-yl] -3R,4R-diethoxybutane-1,2-diol;

4-fluoro-1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]butane-1R,2S,3R-triol,

and their salts with inorganic or organic pharmaceutically acceptable acid.

The compound of formula (A)

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it is known (Carbohydr. Res. , 77, 205 [1979] ), but it is not the x salts are novel and as such form part of the invention.

Preferred compounds of formula (I) are the compounds listed in the list of preferred drugs with the exception of the compounds of formula (A).

The compounds of formula (I), in which each of R9and R10means the radical-CH2HE or R3means methylene, R4means the radical-SNON - and one of the radicals R1, R2, R5and R6means carbonyl, and each of the other means the radical-SNON-or each of R1and R6means the radical-SNON-, R3means methylene, and R2, R4and R5are the same and each means a carbonyl, or each of R2and R5means the radical-SNON-, R3means methylene, and R1, R4and R6are the same and each means a carbonyl, can be obtained by oxidation of a derivative selected from compounds of formulas

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
in which Ra means trialkylsilyl, alkyldiphenylamine or dialkylanilines, Rb denotes a phenyl, unsubstituted or substituted by at least one alkoxyl, and Rc denotes alkyl or phenyl, or stereoisomer such a derivative with subsequent removal of the hydroxyl protective for relname radicals are trimethylsilyl, tert-butyldiphenylsilyl and dimethylphenylsilane.

The oxidation reaction is carried out by any known method, oxidation of the alcohol functions, and especially the methods described by D. SWERN, etc., Synthesis, 165 (1981) and T. T. TIDWELL, Synthesis, 857 (1990). It is preferable that the oxidation is carried out in dimethyl sulfoxide in the presence of oxalicacid and triethylamine at a temperature in the range from -78 to 0oC.

Remove protective for hydroxyl function groups carried out by any known method of removing the protective groups, and especially the methods described by T. W. GREENE, Protective Groups in Organic Synthesis, J. Wiley-Interscience Publication (1991), or S. V. LEY and others, Tetrahedron, 46, 4995 (1990). Preferably use triperoxonane acid at a temperature in the range from 0 to 100oWith or Tetra(n-butyl)unmonitored in tetrahydrofuran at a temperature of approximately 25oC.

The derivatives of formula (II) and (III) can be obtained by exposure to 2,2-dimethoxypropane 2-(1,2,3,4-tetrahydroquinolin)-5-(2,3,4-trihydroxybutane)pyrazin or one of its stereoisomers and separation of the derivatives of formula (II) and (III).

This reaction is usually carried out in the reaction conditions described in T. W. GREENE, Protective Groups in Organic Synthesis, J. Wiley-Interscience Publication (1991). Preferably operate in the Pris is the temperature value in the range from 0 to 100oC.

The derivatives of formula (IV) and (V) can be obtained by exposure to 2,2-dimethoxypropane 2-(1,2,3,4-tetrahydroquinolin)-5-(2,3,4-trihydroxybutane)pyrazin, hydroxyl group on the end of the chain is pre-blocked with trialkylsilyl or alkyldiphenylamine, or dialkylpolsulfide, or a stereoisomer such a derivative, then the separation of the derivatives of formula (IV) and (V).

This reaction is usually carried out in the reaction conditions described in T. W. GREENE, Protective Groups in Organic Synthesis, J. Wiley-Interscience Publication (1991). Preferably operate in the presence of acid, such as p-toluensulfonate, in an inert solvent, such as dimethylformamide, at a temperature in the range from 0 to 100oC.

Protection of the end hydroxyl groups is usually carried out in the reaction conditions described in T. W. GREENE, Protective Groups in Organic Synthesis, J. Wiley-Interscience Publication (1991). Preferably work in pyridine, at a temperature in the range from 0 to 30oC.

The derivatives of formula (VI) and (VII) can be obtained by exposure to benzaldehyde, phenyl group which is unsubstituted or substituted at least by alkoxyl, or benzaldehydes, phenyl group which nezam oxobutyl)-5-(2,3,4-trihydroxybutane)pyrazin or one of its stereoisomers.

This reaction is usually carried out under reaction conditions described by R. S. COLEMAN and others , J. Org. Chem., 57, 3732 (1992). Preferably operate in the presence of acid, such as D-camphorsulfacid, in an inert solvent, such as dimethylformamide, at a temperature in the range from 0 to 100oC.

The derivatives of formula (VIII) and (IX) respectively, can be obtained by exposure to 1, 3-dichloro-1,1,3,3 - tetraallylsilane or 1,3-dichloro-1,1,3,3-tetraphenylsilane, on the one hand, or dialkylacrylamide, or dialkylanilines(triftoratsetata), or diphenylsilanediol, or diphenylsilane(triftoratsetata), on the other hand, 2-(1,2,3,4-tetrahydroquinolin)-5-(2,3,4-trihydroxybutane)pyrazin or one of its stereoisomers, usually in the reaction conditions described in T. W. GREENE, Protective Groups in Organic Synthesis, J. Wiley-Interscience Publication (1991). Preferably work in pyridine in the presence of, respectively, 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane or diisopropylsalicylic(triftoratsetata) at a temperature in the range from 0 to 30oC.

2-(1,2,3,4-Tetrahydroquinolin)-5-(2, 3, 4-trihydroxybutane)pyrazin and its stereoisomers can be obtained either from one or two aminoacids OHC-CH(NH2) -(SNON)3- predpochtitelno working at a temperature in the range from 15 to 100oWith it; or one or two of ketosis NON2-CO-(SNON)3-CH2HE, or one of its stereoisomers by exposure to ammonium formate and operating preferably at a temperature in the range from 15 to 100oWith, and preferably in the aquatic environment.

Aminoacidos OHC-CH(NH2) - (SNON)3-CH2IT and its stereoisomers are selling products or can be obtained by application or adaptation of the methods described, for example, in:

(a) Methods Carbohydr. Chem., 7, 29 (1976), which consist in the transformation of the aldehyde function corresponding to the aldose in nitroethylene group with nitromethane in the main environment (as, for example, sodium ethylate), then the processing of the received product successively with a saturated solution of ammonium hydroxide at a temperature of 20-30oWith barium hydroxide in aqueous solution at a temperature of 20-30oAnd finally diluted (10-15%) sulfuric acid at a temperature of 20-30oC;

(b) The Amino Sugar", ed. R. W. JeanIoz, Academic Press, New York, 1969, S. 1, or "The Carbohydrates", ed. W. Pigman and D. Horton, Academic Press, New-York, volume IB, 1980, S. 664, which consist in the transformation of the aldehyde function corresponding to the aldose in aminogroup of the primary aromatic amine (e.g., aniline), sati hydrogen in the presence of palladium in a solvent, such as a simple ether (e.g. tetrahydrofuran) or an aliphatic alcohol (e.g. ethanol or methanol) at a temperature of 20-50oC.

Ketosis of NON2-CO-(SNON)3-CH2IT and its stereoisomers are selling products or can be obtained by application or adaptation of the methods described, for example, in:

(a) Adv. Carbohydr. Chem., 13, 63 (1958), which consist in introducing into the interaction corresponding to the aldose or with a base such as calcium hydroxide, sodium hydroxide, pyridine, quinoline, or with acid, such as sulfuric acid, in aqueous solution or without solvent at a temperature of 20-50oC;

(b) Tetrahedron Asymmetry, 7 (8), 2185 (1996); J. Am. Chem. Soc., 118 (33), 7653 (1996); J. Org. Chem., 60 (13), 4294 (1995); Tetrahedron Lett., 33 (36), 5157 (1992); J. Am. Chem. Soc., 113 (17), 6678 (1991); Angew. Chem. , 100 (5), 737 (1988); J. Org. Chem., 57, 5S99 (1992), which consist, for example, condensation or hydroxybenzaldehyde, 1,3-dihydroxyacetone, 1,3-dihydroxyacetonephosphate or hydroxypyridinone acid with 2-hydroxyacetaldehyde, substituted in position 2, if necessary, optically pure, in the presence of, if necessary, an enzyme, such as transketolase. This reaction is usually carried out in aqueous solution at a temperature of 20-50oWith, in case lorida zinc. Derivatives, including 2-hydroxyacetaldehyde group are selling products or can be obtained from aldos by using or adapting the methods described by R. Collins, R. Ferrier, Monosaccharides, their Chemistry and their Roles in Natural Products, ed. J. Wiley (1995); M. Bois, Carbohydrate Building Bloks, ed. J. Wiley (1996).

Corresponding to the aldose and their stereoisomers are selling products or can be obtained:

a) from the sale of aldos:

by the epimerization reactions when using or adapting methods described in the Adv. Carbohydr. Chem., 13, 63 (1958), especially in the primary environment, using water diluted (0,03-0,05%) solution of sodium hydroxide at a temperature of 20-40oC;

by reactions of chain elongation when using or adapting methods described in "The Carbohydrates", ed. W. Pigman and D. Horton, Academic Press, New-York, volume 1A, 133 (1972), and especially through education cyanhydrin source an aldose (for example, by exposure to sodium cyanide in aqueous solution at a temperature of 10-30oWith and in the presence of sodium hydroxide at a pH of about 9), and then hydrolysis of the thus obtained ceanography to the corresponding acid by using or adapting methods described in "Organic Synthesis", volume I, S. 436, and volume III, the ur 20oC to the boiling temperature of the reaction medium), then by restoring the carboxyl function to the corresponding aldehyde using or adapting methods described in J. Am. Chem. Soc., 71, 122 (1949), especially with alkali metal borohydride (e.g. sodium borohydride), in aqueous solution at a temperature of 20oC to the boiling temperature of the reaction medium;

by reactions shortening chains when using or

adaptation of the methods described in "The Carbohydrates", ed. W. Pigman and D. Horton, Academic Press, New-York, volume IB, 1980, S. 929, or Chem. Ber., 83, 559 (1950), and especially by conversion of the aldehyde functions of an aldose to the corresponding hydroxylamine using or adapting methods described in "Organic Synthesis", vol II, S. 314 (e.g., using hydroxylaminopurine in aqueous solution and in the presence of a base such as sodium carbonate, at a temperature of 20-50oC), then the effects of 3,4-dinitrofluorobenzene in the presence of carbon dioxide and a base, such as sodium bicarbonate, in aqueous solution and aliphatic alcohol (e.g. isopropanol) at a temperature of 50-80oC;

b) from the corresponding allyl alcohols by using or adapting methods described in Science, 220, 949 (1983), ilata titanium(IV) with optically pure dialkylamino (for example, diethyltartrate), with subsequent impacts thiophenolate sodium p-chlormadinone acid in acetic anhydride and diisopropylaminoethyl.

The compounds of formula (I), in which each of R9and R10means the radical-CH2HE or R3means methylene, R4means the radical-SNON - and one of the radicals R1, R2, R5and R6means methylene, and each of the other means the radical-SNON-or each of R1and R6means the radical-SNON-, R3means methylene, and R2, R4and R6are the same and each means methylene, or each of R2and R5means the radical-SNON and each of R1, R3, R4and R6means methylene, can be obtained by the condensation reaction of alkylchlorosilanes or finishontasklaunch with a derivative of formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) in which Ra means trialkylsilyl, alkyldiphenylamine or dialkylanilines, Rb denotes a phenyl, unsubstituted or substituted with at least alkoxyl, and Rc denotes alkyl or phenyl, or a stereoisomer such a derivative, then recovery of the obtained product and remove protective for hydroxylean, described by D. H. R. BARTON, J. Chem. Soc. Perkin I, 1574 (1975), and N. PAULSEN and others, Liebigs Ann. Chem., 735 (1992). If the condensation reaction is preferably run in an inert solvent such as a chlorinated solvent (e.g. dichloromethane), a simple ether (e.g. diethyl ether, tetrahydrofuran, dioxane) in the presence of an acid acceptor such as an organic base like pyridine or 4-dimethylaminopyridine, at a temperature of about 20oWith, and in the case of reduction reaction is preferably work with tributyltinhydride, azobis(2-methylpropionitrile), in an inert solvent such as an aromatic solvent (e.g. benzene, toluene) at a temperature of 80-110oC. Removal of protective groups is carried out, as described above.

The compounds of formula (I), in which (A) each of R9and R10means the radical-CH2HE or R3means methylene, R4means the radical-SNON - and one of the radicals R1, R2, R5and R6means the radical-F-, and each of the other means the radical-SNON-or each of R1and R6means the radical-SNON-, R3means methylene, and R2, R4and R5are the same and each means a radical-CHF-, or each of Rakovali and each means a radical-CHF -, or (B) each of R1, R2, R4, R5and R6means the radical-SNON-, R3means methylene, R9means the radical-CH2F or SEN, R10means the radical-CH2F or-CH2HE, and R9and R10both do not mean the radical-CH2IT can be obtained by fluorination of a derivative of formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) in which Ra means trialkylsilyl, alkyldiphenylamine or dialkylanilines, Rb denotes a phenyl, unsubstituted or substituted by at least one alkoxyl and Rc denotes alkyl or phenyl, or stereoisomer such a derivative, with the subsequent removal of the protective for the hydroxyl function groups. Compounds in which each of R1, R2, R4, R5and R6means the radical-SNON-, R3means methylene, R9means the radical-CH2F or-CH2HE, R10means the radical-CH2F or-CH2IT, but R9and R10both do not mean the radical-CH2HE will receive in the form of a mixture with the compounds obtained from the intermediate product of formula (IV).

This fluorination is usually carried out under the operating conditions described by W. J. MIDDLETON, J. Org. Chem., 40, 574 (1975). Preferably fluoridation of ourstories, such as a chlorinated solvent (e.g. dichloromethane) or an ether (e.g. tetrahydrofuran) at a temperature of from -78 to 20oC. Removal of protective groups is carried out, as described above.

The compounds of formula (I), in which each of R9and R10means the radical-CH2HE or R3means methylene, R4means the radical-SNON - and one of the radicals R1, R2, R5and R6means a radical-CH(other7)-, and each of the other means the radical-SNON-or each of R1and R6means the radical-SNON-, R3means methylene, and R2, R4and R5are the same and each means a radical-CH(other7)-, or each of R2and R5means the radical-SNON-, R3means methylene, and R1, R4and R6are the same and each means a radical-CH(other7)-, can be obtained by recovering the derivative chosen from compounds of formulas

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
in which Ra means trialkylsilyl, alkyldiphenylamine or dialkylanilines, Rb denotes a phenyl, unsubstituted or substituted by at least one alkoxyl, Rc denotes alkyl or phenyl, and Rd means Isidori formula R7where R7has the same meanings as in the formula (I), with the exception of hydrogen, and Gal means a halogen atom, and subsequent removal of the protective for the hydroxyl function groups.

Recovery is usually in the reaction conditions described by R. C. LAROCK, Comprehensive Organic Transformations, VCH Publication (1989). Preferably operate using hydrogen in the presence of a catalyst, such as palladium, in an inert solvent such as an aliphatic alcohol with 1 to 4 carbon atoms (e.g. methanol) at a temperature of about 20oWith or hydride of an alkali metal (alkali metal borohydride, such as sodium borohydride, lithium aluminum hydride, in an inert solvent, such as a simple ether (e.g. tetrahydrofuran, diethyl ether) at a temperature in the range from -78 to 100oC.

Reaction with a derivative R7usually carried out under reaction conditions described by R. C. LAROCK, Comprehensive Organic Transformations, VCH Publication (1989). Preferably operate in the presence of organic bases, as Amin (trialkylamine, such as triethylamine, pyridine), or ORGANOMETALLIC bases, as dialkylamide alkali metal (e.g. sodium, lithium), or alkali metal hydride (e.g. sodium hydride) or the ia), in an inert solvent, such as a simple ether (e.g. diethyl ether, tetrahydrofuran, dioxane), aliphatic alcohol with 1 to 4 carbon atoms (e.g. methanol, ethanol), a chlorinated solvent (for example dichloromethane, dimethylformamide or dimethylsulfoxide, at a temperature of from 0oC to the boiling temperature of the reaction medium.

The removal of the protective groups is carried out, as described above.

The derivatives of formula (IIA), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), (IXa) in which Ra means trialkylsilyl, alkyldiphenylamine or dialkylanilines, Rb denotes a phenyl, unsubstituted or substituted by at least one alkoxyl, Rc denotes alkyl or phenyl, and Rd means sidegroup, or their stereoisomers can be obtained by exposure to azide of an alkali metal (preferably sodium) on a derivative of formula (IIA), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa) or (IXa) in which Ra means trialkylsilyl, alkyldiphenylamine or dialkylanilines, Rb denotes a phenyl, unsubstituted or substituted by at least one alkoxyl, Rc denotes alkyl or phenyl, and Rd means the radical-OSO2-Re, where Re denotes methyl, trifluoromethyl or 4-were, or stereoisomer such a derivative.

This reaction usually wire retele, such as dimethylformamide, at a temperature of 0-100oC.

The derivatives of formula (IIA), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), (IXa) in which Ra means trialkylsilyl, alkyldiphenylamine or dialkylanilines, Rb denotes a phenyl, unsubstituted or substituted by at least one alkoxyl, Rc denotes alkyl or phenyl, and Rd means the radical-OSO2-Re, and their stereoisomers can be obtained by exposure derived CISO2-Re or (ReSO2)2Oh, where Re is the above values, the derivative of formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) in which Ra means trialkylsilyl, alkyldiphenylamine or dialkylanilines, Rb denotes a phenyl, unsubstituted or substituted by at least one alkoxyl, and Rc denotes alkyl or phenyl, or a stereoisomer such a derivative.

This reaction is usually carried out under the operating conditions described A. C. RICHARDSON, Methods Carbohydr. Chem. , 6, 218 (1972), and N. PAULSEN, Liebigs Ann. Chem. , 735 (1992). Preferably run in an inert solvent such as a chlorinated solvent (e.g. dichloromethane) in the presence of organic bases such as pyridine, at a temperature in the range -20 to 20oC.

The compounds of formula (I), in which each of R9and R10about the Alov R1, R2, R5and R6means a radical-CH(OR8)-, and each of the other means the radical-SNON-or each of R1and R6means the radical-SNON-, R3means methylene, and R2, R4and R5are the same and each means a radical-CH(OR8)-, or each of R1and R5means the radical-SNON-, R3means methylene, and R1, R4and R6are the same and each means a radical-CH(OR8)- can be obtained by reacting a derivative of formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or a stereoisomer such a derivative with a derivative R8where R8has the same meanings as in the formula (I).

This reaction is usually carried out under reaction conditions described by R. C. LAROCK, Comprehensive Organic Transformations, VCH Publication (1989). Preferably operate in the presence of organic bases, as Amin (trialkylamine, such as triethylamine, pyridine), or ORGANOMETALLIC bases, as dialkylamide alkali metal (for example, diisopropylamide lithium), or alkali metal hydride (e.g. sodium hydride) or an inorganic base (alkali metal hydroxide (e.g. sodium hydroxide or potassium hydroxide) in an inert races, the ethanol, ethanol), a chlorinated solvent (for example dichloromethane, dimethylformamide or dimethylsulfoxide, at a temperature of from 0oC to the boiling temperature of the reaction medium.

The removal of the protective groups is carried out, as described above.

The compounds of formula (I), in which each of R1, R4, R5and R6means the radical-SNON-, R9and R10mean-CH2OH, and-R2-R3means the radical-CH=CH-, can be obtained by dehydration of a derivative of formula (IIA) where Rd denotes the radical-IT or-OSO2-Re, where Re denotes methyl, trifluoromethyl or 4-methyl-phenyl, or stereoisomer such a derivative, then remove protective for hydroxyl function groups.

This reaction is usually carried out under reaction conditions described by R. C. LAROCK, Comprehensive Organic Transformations, VCH Publication (1989). Preferably work with organic bases, such as amine (trialkylamine, such as triethylamine or 1,8-diazabicylo-lo[5,4,0]undec-7-ene), ORGANOMETALLIC base (alcoholate of an alkali metal such as sodium ethylate or dialkylamide alkali or alkaline earth metal (such as, for example, diisopropylamide lithium) or inorganic bases, that is to aliphatic alcohol with 1 to 4 carbon atoms (for example, methanol, ethanol), a simple ether (e.g. diethyl ether, tetrahydrofuran), a chlorinated solvent (e.g. dichloromethane or dimethylformamide, at a temperature in the range of 0oC to the boiling temperature of the reaction medium. This reaction can also be carried out under reaction conditions described by O. MITSUNOBU, Synthesis, p1 (1981). Preferably working in an organic environment, in an inert solvent, such as a simple ether (e.g. diethyl ether, tetrahydrofuran) in the presence of trialkylphosphine (e.g. triphenylphosphine) and dialkyldithiocarbamate (as, for example, diethylazodicarboxylate), at a temperature of from 0oC to the boiling temperature of the reaction medium.

Different stereoisomers of the compounds of formula (I) is obtained from the corresponding stereoisomers various intermediate compounds of formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX). The expert knows that for the above-described methods according to the invention it may be necessary to introduce protective groups for amino, hydroxyl and carboxyl functions in order to avoid secondary reactions. These groups are such that you can remove it without affecting the rest of the molecule. As examples for protective amine is of remedilean. As examples of protection for the hydroxyl group functionality can be called trialkylsilyl (for example, triethylsilyl), benzyl. As protection for the carboxyl function group can be called esters (for example, a complex methoxymethyl ether complex tetrahydropyranyloxy ether complex benzyl ether), oksazolov and 2-alkyl-1,3-oxazoline. Other protective groups used in these ways, also describes W. GREENE and others, Protection Groups in Organic Synthesis, second edition, 1991, John Wiley and Sons, and P. J. KOCIENSKI, Protecting Groups, ed. Thieme Verlag (1994).

The reaction mixture obtained in various above-described method, is treated using classical physical methods, such as evaporation, extraction, distillation, chromatography, crystallization) or chemical methods (e.g., the formation of salts).

The compounds of formula (I), if necessary, can also be converted into salts connection with an inorganic or organic acid by exposure to this acid in an organic solvent, such as alcohol, ketone, simple ether or a chlorinated solvent.

The compounds of formula (I) comprising an acid residue, if necessary, can be converted into salts of masoli can be obtained by exposing metal base (for example, the Foundation of the alkali or alkaline earth metal, ammonia, amine or amine salt on a compound of formula (I) in the solvent. The formed salt emit the usual way.

These salts also form part of the invention.

As examples of pharmaceutically acceptable salts can be called the salt of the merger with inorganic or organic acids (such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, ideational, theophyllinate, salicylate, methylene-bis-xinafoate, hydrochloride, sulfate, nitrate and phosphate), the salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals (calcium, magnesium), ammonium salt, salts of nitrogenous bases (as ethanolamine, trimethylamine, methylamine, benzylamine, N-benzyl-phenethylamine, choline, arginine, leucine, lysine, N-methylglucamine).

The following examples illustrate the invention.

Example 1

To 349 mg of 2-[2,2-dimethyl[1,3]dioxolane-4S-ileti]-5-[2,2,2',2'-tetramethyl-[4R, 4'R] bi[[1,3] dioxolane]-5S-yl]pyrazine add 50 cm3water 80% solution triperoxonane acid. The reaction mixture is stirred at a temperature of approximately 25oC for 4 hours. After concentrer3toluene and again concentrated under the same conditions. The oil obtained is treated with 2 cm3absolute ethanol and placed in a bath with ice for 2 hours. The precipitate is filtered off through a sintered glass filter, wring out, then dried in a desiccator under reduced pressure (2.7 kPa) at a temperature of 25oC. Get a solid beige color, which is recrystallized from a mixture of water with absolute ethanol in a volume ratio of 1:8. The crystals are filtered using sintered glass filter, washed with 0.2 cm3absolute ethanol, drained, then dried under reduced pressure (2.7 kPa) at a temperature of 40oC. Thus emit 158 mg 1-[5-(3S,4-dihydroxybutyl)pyrazin-2-yl] butane-1R,2S,3R,4-tetraol in the form of crystalline powder ivory, melting at 171oC.

1H-NMR spectrum (400 MHz, hexacyanometallate) in M. D. (millionths): 1,63 and a 1.88 (2m, 1H each: - CH25); 2,79 and 2.86 (2m, 1H each: CH25); 3,20-3,70 (m, 7H: CH 2 - CH 2 - CH 5-CH22 and CH2O 5); of 4.38 and 4.51 (respectively, ush.t and t, J=6 Hz, 1H each: 2 and HE 5); 4,43 (d, J=7.5 Hz, 1H:OH); 4,5 S (d, J=5 Hz, 1H:OH); the 4.65 (d, J=5 Hz, 1H:OH); 4,95 (ush.) - Rev. 6; water).

2-[2,2-Dimethyl[1,3] dioxolane-4S-ileti]-5-[2,2,2',2'-tetramethyl[4R,4'R] bi[[1,3]dioxolane]-5S-yl]pyrazin receive the following procedure:

To a solution 0,72 g 1S-2,2-dimethyl[1,3]dioxolane-4R-yl)-2-[5-(2,2,2',2'-tetramethyl[4R, 4'R] bi[[1,3] dioxolane]-5S-yl)pyrazin-2-yl]ethylenethiourea 56 cm3toluene in an argon atmosphere add a solution of 1.1 cm3tributyltinhydride and 13 mg of 2,2'-azobis(2-methylpropionitrile) 14 cm3of toluene. The reaction mixture is heated at a temperature of 80oC for 45 minutes, then refluxed at a temperature of about 110oWith over 70 hours. After filtration through a paper filter the mixture is concentrated under reduced pressure (2.7 kPa) at a temperature of 40oC. the Residual oil chromatographic on a column of silica (0,020-0,045 mm), elwira a mixture of ethyl acetate with cyclohexane in a volume ratio of 1:4 at a pressure of about 1,5105PA. Containing the target product fractions are combined and concentrated under reduced pressure (2.7 kPa) at a temperature of 40oC. Thus obtain 0.36 g of 2-[2,2-dimethyl[1,3]dioxolane-4S-ileti]-5-[2,2,2', 2'-tetramethyl[4R,4'R]b [1,3]DIOXOLANYL]-5S-yl]pyrazine in the form of a yellow oil; Rf= 0,5 (thin layer chromatography on plucked, produces C1,3] dioxolane-4R-yl)-2-[5-(2,2,2', 2'-tetramethyl[4R,4'R] bi[[1,3]dioxolane]-5S-yl)pyrazin-2-yl]ethylenethiourea receive according to the following method:

To a solution 0,72 g 1S-2,2-dimethyl[1,3]dioxolane-4R-yl)-2-[5-(2,2,2',2'-tetramethyl[4R, 4'R] bi[[1,3]dioxolane]-5S-yl)pyrazin-2-yl]ethanol 50 cm3dichloromethane added sequentially 2 cm3pyridine, 0,021 g of 4-dimethylaminopyridine and 0.35 cm3finishontasklaunch. The reaction mixture is stirred at a temperature of approximately 25oC for 1 day, then it is diluted with a mixture of 20 cm3water with 20 cm3dichloromethane. After decanting, the organic phase is washed with three times 20 cm3water, dried over magnesium sulfate, and then concentrated under reduced pressure (2.7 kPa) at a temperature of approximately 45oC. the Residual oil chromatographic on a column of silica (0,020-0,045 mm), elwira mixture of etilatsetata with cyclohexane in a volume ratio of 1: 4 at a pressure of about 1,5105PA. Containing the target product fractions are combined and concentrated under reduced pressure (2.7 kPa) at a temperature of 40oC. Thus obtain 0.74 g of 1S-2,2-dimethyl[1,3]dioxolane-4R-yl)-2-[5-(2,2,2', 2'-tetramethyl[4R, 4'R] bi[[1,3] dioxolane]-5S-yl)pyrazin-2-yl] ethylenethiourea-one as a yellow maslootdelenija 1:4).

1S-2,2-Dimethyl[1,3] dioxolane-4R-yl)-2-[5-(2,2,2', 2'-tetramethyl[4R,4'R] bi[[1,3] dioxolane] -5S-yl)pyrazin-2-yl]ethanol is produced by the following method:

To a solution of 10 g desoximetasone 250 cm3of dimethylformamide with stirring 81 cm32,2-dimethoxypropane, then 0.3 g of p-toluenesulfonic acid. The reaction mixture is stirred at a temperature of approximately 25oC for 20 hours, then add 10 cm32,2-dimethoxypropane and stirring is continued for three hours. The mixture is then heated at a temperature of 50oC for 21 hours. After concentration under reduced pressure (2.7 kPa) at a temperature of 60oThe residual oil is dissolved in 300 cm3dichloromethane and washed twice in 100 cm3a 5% aqueous solution of sodium bicarbonate, then twice with 200 cm3water. The organic phase is dried over magnesium sulfate, and then concentrated under reduced pressure (2.7 kPa) at a temperature of 40oC. the oil Obtained chromatographic on a column of silica (0,020-0,045 mm), elwira a mixture of ethyl acetate with cyclohexane in a volume ratio of 1: 1 under a pressure of about 1,5105PA. Containing the target product fractions are combined and concentrated at reduced,2', 2'-tetramethyl[4R, 4'R] bi[[1,3] dioxolane] -5S-yl)pyrazin-2-yl] ethanol in the form of a solid white color, as well as 2.4 g of the same product with an impurity. This latter is recrystallized from a mixture of water with absolute ethanol in a volume ratio of 5:1. Thus emit 0.6 g 1S-2,2-dimethyl[1,3]dioxolane-4R-yl)-2-[5-(2,2,2',2'-tetramethyl[4R, 4'R] bi[[1,3] dioxolane] -5S-yl)pyrazin-2-yl]ethanol as white crystals, melting at 74oC.

1H-NMR spectrum (400 MHz, hexacyanometallate) in M. D.: 1,04-1,20-of 1.28 and 1.33 and 1.44 (5C respectively 3N-3N-3N-3N and 6N:6 CH3); and 2.79 (DD, J=13 and 9 Hz, 1H:1H from CH25); a 3.06 (DD, J=13 and 2.5 Hz, 1H:the other h of CH25); 3,79 (array, 1H:CH 5); 3,80-3,90 (m, 2H:1H from CH22 and 1H from CH25); 3,91 (m, 1H:CH at 4,00 (t, J=7 Hz, 1H:the other h of CH25); 4,06 (t, J=7.5 Hz, 1H:the other h of CH22); to 4.28 (m, 1H:CH 2); to 4.33 (t, J= 7 Hz, 1H:CH 2); 4,99 (d, J=7.5 Hz, 1H:CH 2); 5,07 (ush. d, J=5 Hz, 1H:HE's 55); 8,54 (s, 1H:=CH 6); 8,66 (s, 1H:=CH 3).

20D=+6, 7o1, 1 (C=0,5; dichloromethane); Rf=0.36 and (thin layer chromatography on silica gel; elution with a mixture of ethyl acetate with cyclohexane in a volume ratio 1:1).

From this column also provide 1.4 g of 2,2-dimethyl-4S-[5-(2,2,2',2'-tetramethyl[4R,4'R]b[1,3]DIOXOLANYL] radiocollared) in M. D.: 0,95-1,18 of 1.28 and 1.44 (4C respectively 3N-6N-3N and 6N:6 CH3); and 2.83 (DD, J=13 and 9 Hz, 1H: 1H from CH25); 3,29 (DD, J=13 and 2.5 Hz, 1H:the other h of CH25); 3,30 is 3.40 (m, 1H:CH 5); of 3.53 (t, J=11 Hz, 1H:1H from CH25); 3,74 (DD, J=11 and 5.5 Hz, 1H: the other h of CH25); a-3.84 (DD, J=9 and 4 Hz, 1H:1H from CH22); 3.95 to to 4.15 (m, 2H: the other h of CH22 and CH 5); 4,20 is 4.35 (m, 2H: CH 2 and CH 2); to 4.98 (d, J=7 Hz, 1H:CH 2); 5,20 (d, J=6 Hz, 1H:HE 5); 8,53 (s, 1H:=CH 6); 8,66 (s, 1H:=CH 3).

20D=-23, 801,1 (C=0,5; dichloromethane); Rf=0.28 in (thin layer chromatography on silica gel; elution with a mixture of ethyl acetate with cyclohexane in a volume ratio 1:1).

Desoximetasone can be obtained according to the method described by K. Sumoto, etc., Chem. Pharm. Bull, 39, 792 (1991).

Example 2

To 0,72 g 2-(2,2,2',2'-tetramethyl[4R,4'R]b[1,3]DIOXOLANYL]-5S-Il)-5-(2-[2,2-dimethyl[1,3] dioxolane-4S-yl] -S-ethynyl)pyrazine add 100 cm3water 80% solution triperoxonane acid. The reaction mixture is stirred at a temperature of approximately 25oC for 2.5 hours. After concentration under reduced pressure (2.7 kPa) at a temperature of 50oWith remaining pasta chestnut color is treated with a mixture of 10 cm3ethanol and 1 cm3water and recrystallized. The precipitate is filtered off on a sintered glass filter, washed the round about 60oC. Thus allocate 200 mg 1-[5-(3S,4-dihydroxy-1E-butenyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol in the form of crystals of impure white, melting at 192oC.

1H-NMR spectrum (400 MHz, hexacyanometallate) in M. D.: 3,20-to 3.50 (m, 3H:1H from CH2About 2 and CH25); 3,55-3,70 (m, 3H:the other h of N2O 2-CH 2 and CH 2); to 4.23 (m, 1H:CH 5); 4,39 (t, J=6 Hz, 1H: 2); to 4.46 (d, J=7 Hz, 1H:OH); of 4.66 (d, J=4 Hz, 1H:OH); at 4.75 (t, J=6 Hz, 1H:HE 5); 4,96 (ush. d, J=6,5 Hz, 1H:CH 2); 5,12 (d, J=5 Hz, 1H:HE 5); of 5.34 (d, J=6,5 Hz, 1H:2); 6,74 (ush. d, J=16 Hz, 1H:=CH 5); 6,91 (DD, J= 16 and 4.5 Hz, 1H:=CH 5); 8,58 (s, 1H:=CH 6); 8,66 (s, 1H:=CH 3).

20D= -29,7o1,0 (C=0,5; water).

2-(2,2,2', 2'-Tetramethyl[4R, 4'R] b[1,3]DIOXOLANYL]-5S-Il)-5-(2-[2,2-dimethyl[1,3] dioxolane-4S-yl] -S-ethynyl)pyrazin receive according to the following method:

To a solution of 0.5 g of 1S-(2,2-dimethyl[1,3]dioxolane-4R-yl)-2-[5-(2,2,2',2'-tetramethyl[4R, 4'R] b[1,3] DIOXOLANYL]-5S-yl)pyrazin-2-yl]ethanol 9.6 cm of tetrahydrofuran successively added 132 mg succinimide and 340 mg of triphenylphosphine. Then added dropwise to 0.62 cm340%-aqueous solution of diethylazodicarboxylate in toluene and the reaction mixture is stirred at a temperature of approximately 25oC for 4 hours, after which add 396 mg is remesiana within 48 hours, the reaction mixture was concentrated under reduced pressure (2.7 kPa) at a temperature of approximately 45oC. the Obtained residue chromatographic on a column of silica (0,020-0,045 mm), elwira a mixture of ethyl acetate with cyclohexane in a volume ratio of 1: 4, then 1: 2,3, under a pressure of about 1,5105PA. Containing the target product fractions are combined and concentrated under reduced pressure (2.7 kPa) at a temperature of 45oC. Thus obtain 340 mg of 2-(2,2,2', 2'-tetramethyl[4R, 4'R]b[1,3]DIOXOLANYL]-5S-Il)-5-(2-[2,2-dimethyl[1,3]dioxolane-4S-yl] -S-ethynyl)pyrazine in the form of a viscous whitish oil. Rf=0,7 (thin layer chromatography on silica gel; elution with ethyl acetate).

Example 3

To 0.45 g of 2- (2,2,2',2'-tetramethyl-[4R,4'R]b[1,3]DIOXOLANYL]-5S-yl)-5-(2S-[2,2-dimethyl[1,3] dioxolane-4R-yl]-2-methoxyethyl)pyrazine add 62 cm3water 80% solution triperoxonane acid. The reaction mixture is stirred at a temperature of approximately 25oC for two hours. After concentration under reduced Dulaney (2.7 kPa) at a temperature of 65oWith residual lacquer brown color treated three times with diethyl ether, then concentrated under reduced pressure (2.7 kPa) at a temperature of 45oC. the Residual paste is treated with 4 cm3ethanol and recrystallized. The precipitate ottelini (2.7 kPa) at a temperature of 40oC. Thus emit 100 mg 1-[5-(2S-methoxy-3R, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R, 2S, 3R,4-tetraol in the form of a crystalline white powder, melting at 144oC.

1H-NMR-spectrum (400 MHz, hexacyanometallate) in M. D.: 2,92 and to 3.02 (2 DD, respectively J=14 and 8 Hz and J=14 and 4 Hz, 1H each:CH25); 3,14 (s, 3H:co35); 3,30-3,50 and 3,50-3,60 (2 m respectively 2N and 6N:CH 2-CH 2-CH2About 2-CH 5-CH 5 and CH2About 5); 4,39 and 4,53 (2 t, J=5.5 Hz, 1H each: 2 and HE 5); of 4.45 (d, J=7.5 Hz, 1H:OH); 4,65 (ush. d, J= 5 Hz, 1H: OH); 4,70 (d, J=5 Hz, 1H:OH); 4,95 (d, J=6,5 Hz, 1H:CH 2); 5,31 (d, J=6,5 Hz, 1H: 2); 8,43 (ush. s, 1H:=CH 6); 8,65 (ush. s, 1H:= CH 3).

2-(2,2,2', 2'-Tetramethyl[4R, 4'R]b[1,3]DIOXOLANYL]-5S-yl)-5-(2S-[2,2-dimethyl[1,3] dioxolane-4R-yl] -2-methoxyethyl)pyrazin receive according to the following method:

To a solution of 1.0 g of 1S-(2,2-dimethyl[1,3]dioxolane-4R-yl)-2-[5-(2,2,2',2'-tetramethyl[4R, 4'R] bi[[1,3] dioxolane]-5S-yl)pyrazin-2-yl]ethanol in 5 cm3of dimethylformamide add suspension 104 mg of sodium hydride (60% in oil) in 5 cm3of dimethylformamide. The reaction mixture is stirred at a temperature of approximately 25oC for 30 minutes, then add 0.15 cm3under the conditions. After stirring for 48 hours the reaction mixture clicks lucrate 25 cm3the ethyl acetate and the organic extracts are combined, dried over magnesium sulfate, and then concentrated under reduced pressure (2.7 kPa) at a temperature of approximately 45oC. the Obtained residue chromatographic on a column of silica (0,020-0,045 mm), elwira a mixture of ethyl acetate with cyclohexane in a volume ratio of 1:2,3. Containing the target product fractions are combined and concentrated under reduced pressure (2.7 kPa) at a temperature of about 50oC. are Thus obtained 0.45 g of 2-(2,2,2',2'-tetramethyl[4R,4'R]b[1,3] DIOXOLANYL] -5S-yl)-5-(2S-[2,2-dimethyl[1,3] dioxolane-4R-yl]-2-methoxyethyl)pyrazine in a solid beige color.

Rf= 0.6 for thin-layer chromatography on silica gel; elution with a mixture of ethyl acetate with cyclohexane in a volume ratio 1:1).

Example 4

To of 0.58 g of 2-(2,2,2',2'-tetramethyl[4R,4'R]b[1,3]DIOXOLANYL]-5S-yl)-5-(2R-[2,2-dimethyl[1,3] dioxolane-4R-yl]-2-foradil)pyrazine add 100 cm3water 80% solution triperoxonane acid. The reaction mixture is stirred at a temperature of approximately 25oC for 16 hours. After concentration under reduced pressure (2.7 kPa) at a temperature of 50oWith residual oil chromatographic on a column of silica (0,020-0,045 mm), the f-products of fractions are combined and concentrated under reduced pressure (2.7 kPa) at a temperature of 50oC. are Thus obtained 1-[5-(2R-fluoro-3R, 4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol in the form of solid sand color, which is treated with a mixture of 1.2 cm3ethanol and 0.2 cm3water and recrystallized. The precipitate is filtered off on a sintered glass filter, washed with diethyl ether, drained, then dried under reduced pressure (2.7 kPa) at a temperature of 60oC. Thus allocate 62 mg 1-[5-(2R-fluoro-3R, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R, 2S,3R,4-tetraol in the form of white crystals, melting at 172oC.

1H-NMR spectrum (400 MHz, hexacyanometallate, at a temperature of 30o(C) in M. D.: 3,00 is 3.40 (m, 2H:CH25); 3,40-3,70 (m, 7H:CH 2-CH 2-CH2About 2-CH 5 and CH2O 5); of 4.38 and 4.73 (extended 2 t, J=5 Hz, 1H each: 2 and HE 5); to 4.46 (d, J=7 Hz, 1H:OH); of 4.66 (d, J=5 Hz, 1H: OH); 4,96 (ush. d, J=5.5 Hz, 1H:CH 2); 5,02 (split d, JHF=44 Hz, 1H: CH 5); to 5.35 (d, J=5.5 Hz, 1H:2); of 8.47 (ush. s, 1H:=CH 6); 8,69 (ush. s, 1H:=CH 3).

2-(2,2,2', 2'-Tetramethyl[4R, 4'R]b[1,3]DIOXOLANYL]-5S-yl)-5-(2R-[2,2-dimethyl[1,3] dioxolane-4R-yl]-2-foradil)pyrazin receive according to the following method:

To a solution of 2.0 g of 1S-(2,2-dimethyl[1,3]dioxolane-4R-yl)-2-[5-(2,2,2',2'-tetramethyl[4R, 4'R] bi[[1,3]dioxol is in the atmosphere of nitrogen, added dropwise 1.25 cm3dimethylaminoacetonitrile. The reaction mixture is left to warm to a temperature of about -10oC. After incubation for 4 hours at this temperature (-10oC) the reaction mixture is treated with 60 cm3methanol, and then stirred for 30 minutes and concentrated under reduced pressure (2.7 kPa) at a temperature of approximately 40oC. the Residual oil chestnut color chromatographic on a column of silica (0,020-0,045 mm), elwira a mixture of ethyl acetate with cyclohexane in a volume ratio of 1:3. Containing the target product fractions are combined and concentrated under reduced pressure (2.7 kPa) at a temperature of approximately 40oC. Thus get to 0.67 g of a mixture of 2- (2,2,2',2'-tetramethyl[4R,4'R]b[1,3] DIOXOLANYL] -5S-yl)-5-(2R-[2,2-dimethyl[1,3] dioxolane-4R-yl] -2-foradil)pyrazine and 2-(2,2,2',2'-tetramethyl[4R,4'R]b[1,3]DIOXOLANYL]-5S-yl)-5-{ 2S-[2,2-dimethyl[1,3] dioxolane-4R-yl]-2-(4-torbooks)ethyl}pyrazine in the approximate ratio of 1:1 as a colorless oil.

Rf= 0.3 for both products (thin layer chromatography on silica gel; elution with a mixture of ethyl acetate with cyclohexane in a volume ratio 1:1).

Example 5

To 0.36 g of 2-(2,2,2',2'-tetramethyl-[4R,4'R]aqueous solution triperoxonane acid. The reaction mixture is stirred at a temperature of approximately 25oC for 18 hours. After concentration under reduced pressure (2.7 kPa) at a temperature of about 60oWith the residual orange oil is treated with 4 cm3ethanol and recrystallized. The precipitate is filtered off on a sintered glass filter, washed with ethanol, drained, then dried under reduced pressure (2.7 kPa) at a temperature of approximately 40oC. Thus allocate 88 mg 1-[5-(2S,4-dihydroxy-3R-methoxybutyl)pyrazin-2-yl] butane-1R, 2S, 3R, 4-tetraol in the form of crystalline powder beige color, melting at 96oC.

1H-NMR spectrum (400 MHz, hexacyanometallate with a few drops of tetradecanoate acid) in M. D.: 2,79 and 2,97 (2 DD, respectively J=14 and 9 Hz and J=14 and 3 Hz, 1H each:CH25); 3,10 (m, 1H: CH 5); to 3.38 (s, 3H:co35); 3,40-3,70 (m, 4H:CH 2-CH 2 and CH2O 2); 3,50 and to 3.64 (respectively DD, J=5 and 12 Hz, and m, 1H each:CH2About 5); 3,93 (m, 1H:CH 5); 4,95 (ush. s, 1H:CH 2); to 8.40 (s, 1H:=CH 6); 8,64 (s, 1H:=CH 3).

2-(2,2,2', 2'-Tetramethyl[4R, 4'R] b[1,3] DIOXOLANYL]-5S-yl)-5-([5-methoxy-2,2-dimethyl[1,3] dioxane-4S-yl] methyl)pyrazin receive according to the following method:

the olo 0oC and under nitrogen atmosphere, add a solution of 1.24 g of 2,2-dimethyl-4S-[5-(2,2,2',2'-tetramethyl[4R, 4'R]b[1,3]DIOXOLANYL]-5S-yl)pyrazin-2-ylmethyl][1,3]dioxane-5-ol in 15 cm3of dimethylformamide. The reaction mixture is stirred at a temperature of about 0oC for 30 minutes, then add 0,19 cm3under the conditions. The reaction mixture is left to warm to a temperature of about 25oC. After stirring for 16 hours the reaction mixture is treated with 25 cm3water and 25 cm3ethyl acetate, then decanted. The aqueous phase is extracted with twice 25 cm3the ethyl acetate and the organic extracts are combined, dried over magnesium sulfate, and then concentrated under reduced pressure (2.7 kPa) at a temperature of 50oC. the Obtained residue chromatographic on a column of silica (0,020-0,045 mm), elwira a mixture of ethyl acetate with cyclohexane in a volume ratio of 1: 2,3. Containing the target product fractions are combined and concentrated under reduced pressure (2.7 kPa) at a temperature of 50oC. Thus obtain 0.36 g of 2-(2,2,2',2'-Tetramethyl[4R,4'R]b[1,3]DIOXOLANYL] -5S-yl)-5-([5-methoxy-2,2-dimethyl[1,3] dioxane-4S-yl] methyl)pyrazine in the form of a colorless oil.

Rf= 0,5 (thin-layer chromatography for the
I. To 573 mg of 2-(1R,2S)-2[(2R)-1,4-dioxaspiro[4,5]Dec-2-yl]-1,2-dimethoxymethyl-5-(2S)-2-[(2R)-1,4-dioxaspiro[4,5] -Dec-2-yl] -2-methoxyethylamine add 12.5 cm3water 80% solution triperoxonane acid. The reaction mixture is stirred at a temperature of approximately 25oC for 5.5 hours. After concentration under reduced pressure (2.7 kPa) at a temperature of 45oThe residual oil is treated with 10 cm3toluene and again concentrated under the same conditions. The oil obtained chromatographic on a column of silica (0,040-0,063 mm), elwira a mixture of dichloromethane with methanol in a volume ratio of 95: 5, then a mixture of ethanol with n-butanol and aqueous ammonia solution in a volume ratio of 8:2:1, at a pressure of 1,6105PA. Containing the target product fractions are combined and concentrated under reduced pressure (2.7 kPa) at a temperature of 50oC. the Thus obtained oil is treated with ethanol, the solvent is evaporated, then the residue proscout several times in dichloromethane, then treated with toluene. The solvent is evaporated and the precipitate is filtered off, getting a solid yellowish color, which again proscout in dichloromethane. Thus obtain 135 mg of 4-[5-(3R, 4-dihydroxy-2S-methoxy what I at a temperature of 84oC.

1H-NMR spectrum (400 MHz, hexacyanometallate) in M. D.: 2,82-is 3.08 and 3.33 (3 s, 3H each: co3); 2,93 and 3.05 (2 DD, respectively J=14 and 9 Hz and J=14 and 4 Hz, 1H each: - CH25); 3,30-3,50 (m:3H corresponding to the CH2About 5 and CH 2); 3,50-3,70 (m, 5H:CH 2-CH2O 2-CH 5 and CH 5); to 4.46 (t, J=5.5 Hz, 1H:2); 4,55 (t, J=5.5 Hz, 1H:HE 5); to 4.62 (d, J= 2.5 Hz, 1H:CH 2); to 4.81 (m, 2H:2 and HE 5); charged 8.52 (s, 1H:=CH 6); 8,56 (s, 1H:=CH 3).

2-(1R, 2S)-2[(2R)-1,4-Dioxaspiro[4,5] Dec-2-yl] -1,2-dimethoxymethyl-5-(2S)-2-[(2R)-1,4-dioxaspiro[4,5] Dec-2-yl] -2-methoxyethylamine can be obtained in the following way:

To a suspension of 150 mg of sodium hydride in 5 cm3of dimethylformamide in an argon atmosphere and at a temperature of 0oTo add a solution of 0.5 g of 2-(1R,2S)-2-[(2R)-1,4-dioxaspiro[4,5] Dec-2-yl] -1,2-dihydroxyethyl-5-(2S)-2-[(2R)-1,4-dioxaspiro[4,5] Dec-2-yl] -2-hydroxyethylpiperazine 7 cm3of dimethylformamide. Suspension yellowish stand thus with stirring for 0.5 hours, then slowly add to 0.21 cm3under the conditions. Then the temperature was raised to 15oC and added dropwise to 25 cm3water. The reaction mixture is extracted with three 25 cm3the ethyl acetate. The organic phase is dried over magnesium sulfate, filtered, ZAT[(2R)-1,4-dioxaspiro[4,5]Dec-2-yl]-1,2-dimethoxymethyl-5-(2S)-2-[(2R)-1,4-dioxaspiro[4,5] Dec-2-yl] -2-methoxyethylamine in the form of a yellow oil, used the same in the next stage.

2-(1R, 2S)-2[(2R)-1,4-Dioxaspiro[4,5] Dec-2-yl] -1,2-dihydroxyethyl-5-(2S)-2-[(2R)-1,4-dioxaspiro[4,5] Dec-2-yl]-2-hydroxyethylpiperazine can be obtained in the following way:

To 500 mg of 2-[(1R,2S,3R)-(1,2,3,4-tetrahydroquinolin)]-5-[(2'S,3'R)-(2', 3', 4'-trihydroxysilyl)]pyrazine in suspension in 12 cm3of dimethylformamide at a temperature of about 20oGradually add 2.54 cm3cyclohexanone and 31 mg of the monohydrate of p-toluenesulfonic acid. The resulting solution, after stirring for 15 minutes at a temperature of about 20oWith, again stirred for 2.5 hours at a temperature of about 20oC. Then add magnesium sulfate and the reaction medium is stirred for an additional 16 hours at a temperature of about 20oC. then the medium is heated at a temperature of about 60oWith in a few minutes and it becomes a white, milky color. The reaction medium is left to stand to raise the temperature to about 20oWith and diluted with a mixture of 10 cm3distilled water and 10 cm3ethyl acetate. The organic phase, after decantation, washed twice in 10 cm3with distilled water. The aqueous phase are combined and extrage, filtered through a sintered glass filter, and then concentrated to dryness under reduced pressure (to 0.27 kPa) at a temperature of about 30oC. Thus obtain 910 mg meringue is pale yellow color, which is treated with 10 cm3diethyl ether. After stirring for 10 minutes at a temperature of about 20oWith the insoluble part is filtered off on a sintered glass filter, washed with 5 cm3diethyl ether, receiving flocculent white product, which is dried at a temperature of approximately 40oWith under reduced pressure (to 0.27 kPa). Thus obtain 417 mg of 2-(1R,2S)-2[(2R)-1,4-dioxaspiro[4,5] Dec-2-yl] -1,2-dihydroxyethyl-5-(2S)-2-[(2R)-1,4-dioxaspiro[4,5]-Dec-2-yl]-2-hydroxyethylpiperazine in a solid white color.

1H-NMR spectrum (400 MHz, hexacyanometallate) in M. D.: 1,25-1,65 (array, 2HE:10 CH2two cyclohexyl); was 2.76 (DD, J=14 and 9 Hz, 1H:1H from CH25); 3.04 from (DD, J=14 and 3.5 Hz, 1H:the other h of CH25); 3,61 (dt, J= 7 and 1.5 Hz, 1H:CH 2); of 3.77 (m, 1H:CH 5); of 3.80-3.95 to and 3.95-4,10 (2 m, respectively, 3H and 2H:CH 5-CH2O 2 and CH2O 5); 4,18 (m, 1H:CH 2); 4,80 (m, 2H:CH 2 and HE 2); 5,02 (d, J=7 Hz, 1H:HE 5); 5,54 (d, J=6, 5 Hz, 1H:2); 8,43 (s, 1H:=CH 6); 8,65 (s, 1H:=CH 3).

II. 4-[5-(3R,4-Di is based on 1-{ 5-[2(S)-hydroxy-2-(2,2,4,4-tetraisopropyl[1,3,5,2,4] trioxadecyl-6(R)-yl)ethyl] pyrazin-2-yl}-2-(2,2,4,4-tetraisopropyl[1,3,5,2,4]trioxadecyl-6(R)-yl)ethane-1(R),2(S)-diol.

1-{ 5-[2(S)-Hydroxy-2-(2,2,4,4-tetraisopropyl[1,3,5,2,4] trioxadecyl-6(R)-yl)ethyl] pyrazin-2-yl}-2-(2,2,4,4-tetraisopropyl[1,3,5,2,4]trioxadecyl-6(R)-yl)ethane-1(R),2(S)-diol can be obtained in the following way:

To a solution of 1 g desoximetasone 27 cm3pyridine under stirring and in a nitrogen atmosphere add 2.3 cm31,3-dichloro-1,1,3,3-tetraisopropyldisiloxane. The reaction mixture is stirred at a temperature of approximately 25oWith over 41 hours. After concentration under reduced pressure (2.7 kPa) at a temperature of about 60oThe residual oil is treated three times at 30 cm3pentane, and then concentrated under the same conditions. The obtained solid residue is dissolved in 50 cm3dichloromethane and washed successively twice 30 cm31 N. aqueous solution of hydrochloric acid, twice 30 cm3water, then twice for 30 cm3aqueous saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate, and then concentrated under reduced pressure (2.7 kPa) at a temperature of 40oC. the oil Obtained chromatographic on a column of silica (0,020-0,045 mm), elwira mix

ethyl acetate with cyclohexane with a gradient in a volume ratio a reduced pressure (2.7 kPa) at a temperature of 40oC. Thereby obtaining 1.5 g of 1-{5-[2(S)-hydroxy-2-(2,2,4,4-tetraisopropyl[1,3,5,2,4]trioxadecyl-6(R)yl)ethyl]pyrazin-2-yl}-2-(2,2,4,4-tetraisopropyl[1,3,5,2,4] trioxadecyl-6(R)yl)ethane-1(R), 2(S)-diol in the form of a meringue white, melting at 87oC.

1H-NMR spectrum (250 MHz, hexacyanometallate) in M. D.: 0,80-1,30 (m, N: 8 CH(CH3)2); 2,78 (DD, J=14 and 9 Hz, 1H:1H from CH, 5); 3,17 (DD, J= 14 and 3.5 Hz, 1H:the other h of CH25); 3,53 (ush. t, J=9 Hz, 1H:CH 2); 3,60-3,70 (m, 4H:CH 5-CH 5-1N from CH2O 2 and 1H from CH2O 5); 4,05-4,30 (m, 3H): CH 2-the other h of CH2About 2 and the other n of CH2O 5); 4,82 (d, J=8 Hz, 1H:2); 4,90-of 5.05 (m, 2H:CH 2 and HE 5); 5,46 (d, J=6 Hz, 1H:2); 8,43 (s, 1H:=CH 6); 8,66 (s,1H: =CH 3).

20D=-11,1o0, 5 (C=0,5; dichloromethane).

III. 4-[5-(3R, 4-Dihydroxy-2S-methoxybutyl)pyrazin-2-yl] -3R,4R-diethoxybutane-1,2-diol can be obtained in a similar way, but on the basis of 1-[5-(3,4-O-benzyliden-2S, 3R, 4-trihydroxybutane)pyrazin-2-yl] butane-3,4-O-benzyliden-1R,2S,3R,4-tetraol.

1-[5-(3,4-O-Benzyliden-2S, 3R, 4-trihydroxybutane)pyrazin - 2-yl]butane-3,4-O-benzyliden-1R,2S,3R,4-tetraol can be obtained in the following way:

To a solution of 2.0 g desoximetasone 24 cm3of dimethylformamide at temperature is up to a temperature of 50oWith getting colourless solution, then add 5 cm3benzaldehydes. The yellow solution is maintained at a temperature of 50oC and under stirring for 20 hours, then allowed to cool to room temperature and add 60 cm3water. The mixture is extracted with ethyl acetate (2 times) and washed with 20 cm3a saturated solution of sodium bicarbonate, then dried over magnesium sulfate and filtered. The organic phase concentrated under reduced pressure (2.7 kPa) at a temperature of 40oFrom getting oily orange residue, which chromatographic on a column of silica (0,040-0,063 mm), elwira a mixture of dichloromethane with methanol in a volume ratio of 95: 5. Containing the target product fractions are combined and concentrated under reduced pressure (2.7 kPa) at a temperature of 40oWith receiving 1.2 g of pure 1-[5-(3,4-O-benzyliden-2S, 3R, 4-trihydroxybutane)pyrazin-2-yl]butane-3,4-O-benzyliden-1R,2S,3R,4-Tetra-ol as a mixture of diastereoisomers in the ratio of 4: 6 in the form of a pale yellow oil. This last gives a solid white product, which melts at a temperature of 70oAfter powdering in diethyl ether.

1H-NMR-spectrum (400 Laporte 40/60: 2,34 (ush. DD, J=14 and 10 Hz, 1H:1H from CH25); 3,09 (ush. d, J=14 Hz, 1H: the other h of CH25); 3,70-4,50 (multiplets, 8H:CH 2-CH 2-CH2About 2-CH 5-CH 5 and CH2About 5); a 4.83 (ush. s, 1H;CH 2); 5,00 (ush. d, J=5 Hz, 1H: 2); to 5.21 (ush. d, J=3 Hz, 1H:HE 5); 5,69 (m, 1H:2); 5,77-5,79 and 5,90 (3, 2N in General: 2 BASIS); 8,46 and 8,49 (2 s, 1H on the whole:=CH 6); to 8.70 (s, 1H:=CH 3).

Other fractions result from the chromatography was carried out gives 1-[5-(2,4-About-benzyliden-2S, 3R,4-trihydroxybutane)pyrazin-2-yl]butane-2,4-O-benzylidene-1R, 2S,3R,4-tetraol.

Example 7

Following the procedures of the previous examples, but on the basis of (2,2-aminobutiramida[1,3,2]doxyciline-5R-ol-4S-yl)-{5-[(2,2-aminobutiramida[1,3,2]doxyciline-5R-ol-4S-yl)methyl] pyrazin-2-yl}methane-1R-ol, receive 4-[5-(3R-methoxy-2S,4-dihydroxybutyl)pyrazin-2-yl]-2R,4R-diethoxybutane-1,3, S-diol.

(2,2-Aminobutiramida[1,3,2] doxyciline-5K-ol-4S-yl)-{ 5-[(2,2-aminobutiramida[1,3,2] doxyciline-5R-ol-4S-yl)methyl] pyrazin-2-yl} methane-1R-ol may be obtained in the following way:

To a solution of 1 g desoximetasone 27 cm3pyridine under stirring and in a nitrogen atmosphere add 2.1 cm3diiso-propylsilane(triftoratsetata). The reaction mixture is stirred at a temperature of approximately 25oWith over 71 hours. After concentration under demoted the m then again concentrated under the same conditions. The obtained residual oil is dissolved in 50 cm3dichloromethane and washed successively twice 30 cm31 N. aqueous solution of hydrochloric acid, twice 30 cm3water, then twice for 30 cm3aqueous saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate, and then concentrated under reduced pressure (2.7 kPa) at a temperature of 40oC. the resulting meringue chromatographic on a column of silica (0,020-0,045 mm), elwira a mixture of ethyl acetate with cyclohexane in a volume ratio of 1:1 under a pressure of about 1,5105PA. Containing the target product fractions are combined and concentrated under reduced pressure (2.7 kPa) at a temperature of 40oC. Thus allocate 60 mg (2,2-aminobutiramida[1,3,2]doxyciline-5R-ol-4S-yl)-{5-[(2,2-aminobutiramida[1,3,2] doxyciline-5R-ol-4S-yl)methyl]pyrazin-2-yl}methane-1R-ol in the form of a meringue white, melting at 54oC.

1H-NMR-spectrum (400 MHz, hexacyanometallate) in M. D.: 0,65-1,15 (m, 28N: 4 CH(CH3)2); 2,80 (DD, J=14 and 9 Hz, 1H:1H from CH25); or 3.28 (m, another n of CH25); 3,40 (m, 1H:CH 5); 3,68 (m, 2H:1H from CH2About 2 and 1H from CH2O 5); 3,83 sh. d, J=6,5 Hz, 1H:CH 2); 5,22 (d, J=6,5 Hz, 1H:2); of 5.34 (d, J= 6 Hz, 1H:HE 5); of 5.39 (d, J=6,5 Hz, 1H:2); to 8.41 (s, 1H:=CH 6); to 8.70 (s, 1H:=CH 3).

20D=-38,3o0,8 (C=0,5; dichloromethane).

Example 8

To 54 mg of 2-fluoro-1S-[5R-(5-{[5-(hydroxymethyl)-2,2-dimethyl[1,3]dioxolane-4S-yl] methyl}pyrazin-2-yl)-2,2-dimethyl[1,3]dioxolane-4R-yl]ethanol add 8 cm3water 80% solution triperoxonane acid. The reaction mixture was stirred for 1.5 hours at a temperature of approximately 25oC. After concentration under reduced pressure (2.7 kPa) at a temperature of 45oThe residue is treated with toluene, and then concentrate in the same operation is repeated once). The residual brown oil is dissolved in 5 cm3methanol, filtered through a paper filter, then concentrate in the same conditions. The residual yellow oil is treated with 0.4 cm3ethanol and recrystallized. The precipitate is filtered off on a sintered glass filter, washed with 0.1 cm3ethanol, drained, then dried under reduced pressure (2.7 kPa) at a temperature of 25oC. Thus allocate 31 mg of 4-fluoro-1-[5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl] butane-1R, 2S,3R-triol as crystallites stateregulated) in M. D.: was 2.76 and is 3.08 (2 DD, respectively J=14 and 9 Hz and J=14 and 2 Hz, 1H each: CH25); 3,30 is-3.45 (m, 2H: 1H from CH2About 5 and CH 5); 3,50-3,70 (m, 1H:the other h of N2About 5); 3,64 (ush. d, J=9 Hz, 1H:CH 2); of 3.80 (m, 1H:CH 5); 3,70-3,90 (m, 1H:CH 2); 4,35-4,70 (m, JNF=48 Hz, 2H:CH2F 2); equal to 4.97 (ush. s, 1H:CH 2); 8,44 (ush. s, 1H:=CH 6); 8,67 (ush.s,1H:=CH 3).

2-Fluoro-1S-[5R-(5-{ [5-(hydroxymethyl)-2,2-dimethyl[1,3] dioxolane-4S-yl] methyl}pyrazin-2-yl)-2,2-dimethyl[1,3]dioxolane-4R-yl]ethanol is produced by the following method:

To a solution of 210 mg of 2-fluoro-1S-[5R-(5-{[5-(tert-butyldiphenylchlorosilane)-2,2-dimethyl[1,3] dioxolane-4S-yl]methyl}pyrazin-2-yl)-2,2-dimethyl[1,3] dioxolane-4R-yl]ethanol in 20 cm3of tetrahydrofuran in an argon atmosphere is added dropwise 0,84 cm31.0 M solution of Tetra(n-butyl)unmonitored in tetrahydrofuran. The reaction mixture is stirred at a temperature of approximately 25oC for 1.5 hours. After concentration under reduced pressure (2.7 kPa) at a temperature of approximately 40oWith residual oil amber color chromatog-referat on a column of silica (0,040-0,063 mm), elwira a mixture of ethyl acetate with cyclohexane in a volume ratio of 9:1, at a pressure of about 1,5105PA. Containing the target product fractions are combined and concentrated under reduced pressure (2.7 kPa) at a temperature of 40oC. the methyl[1,3] dioxolane-4R-yl] ethanol in the form of a yellow oil.

Rf= 0,2 (thin layer chromatography on silica gel; elution with a mixture of ethyl acetate with cyclohexane in a volume ratio 9:1).

2-Fluoro-1S-[5R-(5-{ [5-(tert-butyldiphenylchlorosilane)-2,2-dimethyl[1,3]dioxolane-4S-yl]methyl}pyrazin-2-yl)-2,2-dimethyl[1,3]dioxolane-4R-yl] ethanol is produced by the following method:

To a solution of 1.0 g of 2-(tert-butyldiphenylsilyl)-1R-(5-{5-[5-(tert-butyldiphenylchlorosilane)-2,2-dimethyl[1,3] dioxolane-4S-ylmethyl] pyrazin-2-yl} -2,2-dimethyl[1,3]dioxolane-4S-yl)ethanol 6 cm3of tetrahydrofuran, cooled to a temperature of -45oWith, and in an argon atmosphere is added dropwise 0,32 cm3diethylaminosalicylaldehyde. The reaction mixture is stirred at a temperature of -45oC for two hours, then treated dropwise with 0.2 cm3of methanol. After that, the mixture is left to warm to a temperature of 25oWith, then concentrate under reduced pressure (2.7 kPa) at a temperature of 40oC. the Residual brown oil is dissolved in 50 cm3dichloromethane and extracted with three 5 cm3water. The organic phase is dried over magnesium sulfate, and then concentrated under reduced pressure (2.7 kPa) at a temperature of 40oC. the Residual is the one with cyclohexane in a volume ratio of 1: 9, at a pressure of about 1,5105PA. Containing the target product fractions are combined and concentrated under reduced pressure (2.7 kPa) at a temperature of 40oC. are Thus obtained 0.17 g of 2-fluoro-1S-[5R-(5-{[5-(tert-butyldiphenylchlorosilane)-2,2-dimethyl[1,3] dioxolane-4S-yl]methyl}pyrazin-2-yl)-2,2-dimethyl[1,3]dioxolane-4R-yl]ethanol as a yellow viscous oil.

Rf= 0,3 (thin layer chromatography on silica gel; elution with a mixture of ethyl acetate with cyclohexane in a volume ratio of 1 : 2,3.

2-(tert-Butyldiphenylsilyl)-1R-(5-{ 5-[5-(tert-butyldiphenylchlorosilane)-2,2-dimethyl[1,3] dioxolane-4S-ylmethyl] pyrazin-2-yl}-2,2-dimethyl[1,3]dioxolane-4S-yl)ethanol according to the following method:

To a solution of 1 g of 1-[5-(4-tert-butyldiphenylsilyl)-2S,3R-dihydroxybutyl)pyrazin-2-yl]-4-[tert-butyldiphenylsilyl]butane-1R,2S,3R-Tirol 50 cm3of dimethylformamide was added with stirring 5 cm32,2-dimethoxypropane, and then 0.01 g of p-toluenesulfonic acid. The reaction mixture is stirred at a temperature of 60oC for 42 hours. After concentration under reduced pressure (2.7 kPa) at a temperature of 60oThe residual oil is dissolved in 60 cm3dichloromethane and washed twice for 20 Su dried over magnesium sulfate, then concentrate under reduced pressure (2.7 kPa) at a temperature of 40oC. the oil Obtained chromatographic on a column of silica (0,020-0,045 mm), elwira a mixture of ethyl acetate with cyclohexane in a volume ratio of 1:9 at a pressure of about 1,5105PA. Containing the target product fractions are combined and concentrated under reduced pressure (2.7 kPa) at a temperature of 40oC. are Thus obtained 0.3 g of 2-(tert-butyldiphenylsilyl)-1R-(5-{ 5-[5-(tert-butyldiphenylchlorosilane)-2,2-dimethyl[1,3]dioxolane-4S-ylmethyl]pyrazin-2-yl}-2,2-dimethyl[1,3]dioxolane-4S-yl)ethanol in the form of a viscous yellow oil.

1H-NMR-spectrum (400 MHz, hexacyanometallate) in M. D.: of 0.90 and 1.01 (2C, N each: 2 C(CH3)2); 1,22-1,35-1.44MB and 1,46 (4 s, 3H each: 4 CH3); is 3.08 (DD, J=14 and 9 Hz, 1H:1H from CH25); a 3.15 (DD, J=14 and 3.5 Hz, 1H:the other h of CH25); of 3.60 (AB limited., 2H:CH2O 2); 3,71 (DD, J=11 and 5 Hz, 1H:1H from CH2O 5); 3,80-3,95 (m, 2H:the other h of CH25 and CH 2); 4,32 (K, J= 5 Hz, 1H:CH 5); 4,48 (DD, J=7 and 5 Hz, 1H:CH 2); 4,70 (m, 1H: CH 5); 5,14 (d, J=7 Hz, 1H:CH 2); 5,19 (d, J=5 Hz, 1H:2); 7,35-7,80 (m, 20N: N aromatic four fanilow); 8,53 (s, 1H:=CH 6); 8,68 (s, 1H:=CH 3).

20D= -32,6o0,8 (C=0,5; dichloromethane);

Rf= 0,30 (thin-layer="ptx2">

From this column also emit 0.2 g 4R-(tert-butyldiphenylchlorosilane)-6R-{5-[5-(tert-butyldiphenylchlorosilane)-2,2-dimethyl[1,3]dioxolane-4S-ylmethyl] pyrazin-2-yl} -2,2-dimethyl[1,3]dioxane-5-ol as a yellow oil.

1H-NMR-spectrum (400 MHz, hexacyanometallate) in M. D.: a 1.01 and 1.05 (2, N each:2 C(CH3)2); 1,24-of 1.36 and 1.50 (3 s, respectively 3N-6N and 3N:4 CH3); 3,03 (DD, J=14 and 9 Hz, 1H:1H from CH25); of 3.12 (DD, J=14 and 3, 5 Hz, 1H: the other h of CH25); 3,70 (DD, J=11 and 5.5 Hz, 1H:1H from CH2O 5); 3.75 to 3,95 (m, 4H:CH 2-CH2O 2 and the other n of CH2About 5); a 4.03 (m, 1H:CH 2); 4,32 (m, 1H:CH 5); 4,70 (m, 1H:CH 5); 4,95-of 5.05 (m, 2H:CH 2 and HE 2); 7,35-of 7.55 and 7.60-7,80 (2m respectively N and 8H:aromatic four fanilow); 8,46 (s, 1H:=CH 6); 8,53 (s, 1H:=CH 3).

20D=-47,5o1,5 (=0,5; dichloromethane); Rf=0,24 (thin layer chromatography on silica gel; elution with a mixture of ethyl acetate with cyclohexane in a volume ratio 1:4).

1-[5-(4-tert-Butyldiphenylsilyl)-2S, 3R-dihydroxybutyl)pyrazin-2-yl] -4-[tert-butyldiphenylsilyl] butane-1R,2S,3R-triol receive according to the following method:

To a solution of 2 g desoximetasone 55 cm3pyridine was added with stirring 4.3 cm3tert-buildif the keys of 0.5 cm3tert-butyldiphenylchlorosilane and continue stirring for 8 days. After concentration under reduced pressure (2.7 kPa) at a temperature of 60oThe residual oil is dissolved in 100 cm3dichloromethane and washed with three times 30 cm3water. The organic phase is dried over magnesium sulfate, and then concentrated under reduced pressure (2.7 kPa) at a temperature of 40oC. the oil Obtained chromatographic on a column of silica (0,020-0,045 mm), elwira mixture of methanol with dichloromethane in a volume ratio of 1:49, under a pressure of about 1,5105PA. Containing the target product fractions are combined and concentrated under reduced pressure (2.7 kPa) at a temperature of 40oC. are Thus obtained 4 g of 1-[5-(4-tert-butyldiphenylsilyl)-2(S),3(R)-dihydroxybutyl)pyrazin-2-yl] -4-[tert-butyldiphenylsilyl] butane-1(R), 2(S), 3(R)-triol in the form of a meringue yellow.

Rf= 0,13 (thin layer chromatography on silica gel; elution with a mixture of methanol with dichloromethane in a volume ratio 1:19).

The compounds of formula (I) have valuable pharmacological properties. They are substances that lower the concentration of glucose in the blood.

Hypoglycemic activity of the CE normal glucose content in the blood according to the following Protocol.

Mice Swiss albinos weighing from 22 to 26 g stand on an empty stomach for two hours. At the end of this period determine the glucose content in the blood and immediately after introducing an oral dose of glucose (2 g/kg). After thirty minutes we determine the content of glucose in the blood. Mice that give response by hyperglycemia above 170 mg/DL, is selected and used to determine the hypoglycemic activity of the compounds according to the invention.

Thus selected mice are placed into groups that include at least 10 animals. Individual groups have the solution 3-50 mg/kg of the tested product in excipient, such as water or a mixture of methylcellulose and/or twin and water, or excipient once a day by catheterism stomach. Treatment lasts 4 days. On the fourth day after the last treatment, the animals receive a dose of glucose (2 g/kg) and after 20-40 minutes to determine the content of glucose in the blood. The percentage of inhibition of the hyperglycemic response to a glucose calculated relative to the response detected in the group treated with excipient.

In this test, the compounds according to the invention show a percentage inhibition of blood glucose, higher SUB>50
is the value above 2000 mg/kg oral in the case of the mouse.

In human therapy, these products are suitable for the prevention and treatment of diabetes and particularly type II diabetes (non-insulin-dependent diabetes), diabetes "fat" diabetes "fifty years", metalurgicheskogo diabetes, senile diabetes or labile diabetes. They can be used in addition to insulin therapy in insulin-dependent diabetes, where they allow you to gradually reduce the dose of insulin, unstable diabetes, insulinorezistentne diabetes, in addition to sulfa hypoglycemic means, when they do not cause a sufficient reduction of glucose in the blood. These products can also be used in the complications of diabetes, such as hyperlipemia, lipid metabolism, dyslipemia, obesity. They are also suitable for the prevention and treatment atherosclerotic lesions and their complications (as colonopathy, myocardial infarction, cardiomyopathy, the development of these three complications to left ventricular failure, various arteriopathy, arteritis of the lower limbs with lameness and development to ulcers and gangrene, cerebral vascular insufficiency and its complications, impotence vascular produced the thrombosis of capillaries, microaneurysms, arterio-venous shunt, varicose veins, punctured and macular hemorrhages, exudates, macular edema, symptoms proliferating retinopathy: newly formed vessels in the damaged tissue during regeneration, scars proliferative retinitis, vitreous hemorrhage, retinal detachment), diabetic cataract, diabetic neuropathy in all its various forms (peripheral polyneuropathy and their symptoms, such as paresthesia, hyperesthesia and pain, mononeuropathy, radiculopathy, Autonomous neuropathy, diabetic disease), symptoms of diabetic feet (ulcers of the lower limbs and feet), diabetic nephropathy in two forms: diffuse and nodular - atheromatosis (increased levels of high density lipoprotein [HDL] conducive to the removal of cholesterol from atheromatous plaques; lowering of low-density lipoprotein [LDL], the decrease in the ratio of LDL/HDL, inhibition of LDL oxidation, decrease in platelet adhesion), hyperlipemia and dyslipemia (hypercholesterolemia, hypertriglyceridemia, normalizing the proportion of fatty acids, normalization of uricemia, normalization of apoproteins a and b), cataracts, hypertension, and finding or a combination thereof, as such or in the form of a composition in which the compound according to the invention is connected with any other pharmaceutically acceptable product, which can be inert or physiologically active. Medicinal product according to the invention can be applied orally, parenterale, rectally or locally.

As solid compositions for administration orally can be used in tablets, pills, powders (gelatin capsules, starch wafers or pellets. In these compositions, the active principle according to the invention are mixed in a stream of argon, with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica. These compositions can also contain substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a means for coating the protective sheath (pills) or lacquer.

As liquid compositions for administration orally can be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. These compositions can vklyuchayushchii.

Sterile compositions for injection parenterale can preferably be an aqueous or nonaqueous solutions, suspensions or emulsions. As a solvent or excipient you can use water, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, complex organic esters for injection as, for example, etiloleat, or other suitable organic solvents. These compositions can also contain additives, in particular wetting, isotonic components, emulsifiers, dispersing agents and stabilizers. Sterilization can be done in several ways, for example by asamisimasa filtering, including the composition of the sterilizing agent, by irradiation or by heating. They can also prepare in the form of sterile solid compositions, which at the time of use can be dissolved in sterile water or any other sterile environment for injection.

Compositions for administration rectally are candles or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

Song for locallog is lost mouth and appliques on the gums, nasal drops or aerosols.

Doses depend on the desired effect, the duration of treatment and the route of administration; they are usually 150-600 mg per day orally for an adult with single doses of 50 mg to 200 mg of active substance.

In General, the physician determines the appropriate dosage depending on the age, weight and all other factors inherent treatable entity.

The following examples illustrate compositions according to the invention.

An example of a

The usual way to prepare gelatin capsules with doses of 50 mg of active product having the following composition:

Active product 50 mg

Cellulose - 18 mg

Lactose - 55 mg

Colloidal silicon dioxide 1 mg

Sodium salt of carboxymethyl amylum 10 mg

Talc 10 mg

Magnesium stearate 1 mg

Example B

The usual way to prepare tablets with a dose of 50 mg of active product having the following composition:

Active product 50 mg

Lactose - 104 mg

Cellulose 40 mg

Polyvidone 10 mg

Sodium salt of carboxymethyl amylum - 22 mg

Talc 10 mg

Magnesium stearate 2 mg

Colloidal silicon dioxide 2 mg

The mixture hydroxamate - 245 mg

The example IN

Prepare a solution for injection containing 50 mg of active product and having the following composition:

Active product 50 mg

Benzoic acid 80 mg

Benzyl alcohol - 0.06 ml

Sodium benzoate - 80 mg

95% ethanol, 0.4 ml

Sodium hydroxide - 24 mg

Propylene glycol - 1,6 ml

Water to a total volume of 4 ml

The invention also relates to the use of compounds of General formula (I) to obtain pharmaceutical compositions suitable for the treatment or prevention of diabetes and complications of diabetes.

1. Hypoglycemic drug containing as an active beginning at least one polyhydroxybutyrate formula I

< / BR>
in which either (a) each of R9and R10means the radical-CH2IT; and either (a) R3means methylene, R4means the radical-SNON - and one of the radicals R1, R2, R5, R6means methylene, -F - or-CH(OR8)- and each other-SNON-; b) each of R2and R5means SNON-, R3means methylene, and R1, R4and R6are the same and each means-CH(OR8)-; each of R1and R6means SNON-, R3means UB>, R4, R5and R6means the radical-SNON - and-R2-R3means the radical-CH-CH=;

or (B) each of R1, R2, R4, R5and R6means the radical-SNON-, R3methylene, R9means the radical-CH2HE, R10means-CH2F, R8means alkyl with 1-6 carbon atoms in linear or branched chain,

one of its stereoisomers or one of its salts.

2. Hypoglycemic drug under item 1, containing as an active beginning at least one of the following connections:

1-[5-(3S,4-dihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

1-[5-(3S,4-dihydroxy-1E-butenyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

1-[5-(2S-methoxy-3R, 4-dihydroxybutyl)pyrazin-2-yl] butane-lR, 2S,3R,4-tetraol;

1-[5-(2R-fluoro-3R, 4-dihydroxybutyl)pyrazin-2-yl] butane-1R, 2S,3R,4-tetraol;

1-[5-(2S,4-dihydroxy-3R-methoxybutyl)pyrazin-2-yl]butane-1R,2S,3R,4-tetraol;

4-[5-(3R, 4-dihydroxy-2S-methoxybutyl)pyrazin-2-yl] -3R,4R-diethoxybutane-1,2-diol;

4-fluoro-1-(5-(2S,3R,4-trihydroxybutane)pyrazin-2-yl]butane-1R,2S,3R-triol;

and their salts with pharmaceutically acceptable inorganic or organic acid.

3. Polyhydroxybutyrate formula I

et methylene, R4means the radical-SNON - and one of the radicals R1, R2, R5, R6means methylene, -F - or-CH(OR8)- and each other-SNON-; b) each of R2and R5means SNON-, R3means methylene, and R1, R4and R6are the same and each means-CH(OR8)-; each of R1and R6means SNON-, R3means methylene, and R2, R4and R5are the same and each means-CH(OR8)-;

or (B) each of R1, R2, R4, R5and R6means the radical-SNON-, R3is methylene, R9means the radical-CH2HE, R10means-CH2F, R8means alkyl with 1-6 carbon atoms in linear or branched chain,

one of its stereoisomers or one of its salts.

4. The compounds of formula I on p. 3 for the preparation of drugs suitable for the treatment or prevention of diabetes and complications of diabetes.

5. The method of producing polyhydroxybutyrate formula I,

where each of R9and R10means the radical-CH2HE and R3means methylene, R4means the radical-SNON - and one of the radicals R1, R2, R5, R6oznacza formula II

< / BR>
in the presence of an organic base, then restore the product by using tributyltinhydride, azobis(2-methylpropionitrile) and remove protective for hydroxyl functions group by treating the compounds obtained triperoxonane acid, the desired product is isolated and, if necessary, turn it into salt.

6. The method of producing polyhydroxybutyrate formula I, where each of R9and R10means the radical-CH2HE and R3means methylene, R4means the radical-SNON - and one of the radicals R1, R2, R5, R6means-CHF-and each other - SNON, characterized in that foryouth dialkylaminomethyl derivative of the formula II

< / BR>
then remove protective for hydroxyl group features by processing triperoxonane acid.

7. The method of producing polyhydroxybutyrate formula I, where each of R1, R2, R4, R5and R6means SNON-, R3means methylene, R9means of CH2HE, R10means-CH2F, wherein foryouth dialkylaminomethyl derivative of formula IV

< / BR>
where Rameans alkylbiphenyls the th.

8. The method of producing polyhydroxybutyrate formula I, where each of R9and R10means the radical-CH2HE and R3means methylene, R4means the radical-SNON - and one of the radicals R1, R2, R5, R6means a radical-CH(OR8)-, and each of the other means the radical-SNON-, wherein the derivative of formula II or III

< / BR>
< / BR>
enter into interaction with the derived aR8where R8means alkyl with 1-6 carbon atoms in linear or branched chain, Gal means a halogen atom, in the presence of alkali metal hydride, then remove protective for hydroxyl group features by processing triperoxonane acid.

9. The method of producing polyhydroxybutyrate formula I, where each of R9and R10means the radical-CH2Each of R1and R6means SNON-, R3means methylene, and R2, R4and R5are the same and each means a radical-CH(OR8)-, wherein the derivative of formula VIII

< / BR>
enter into interaction with the derived R8where R8means alkyl with 1-6 carbon atoms in linear or branched chain, Gal means the atom Gal is m processing triperoxonane acid.

10. The method of producing polyhydroxybutyrate formula I, where each of R9and R10means the radical-CH2Each of R2and R5means SNON-, R3means methylene, and R1, R4, R6are the same and each means-CH(OR8)-, wherein the derivative of formula IX

< / BR>
where Rcmeans alkyl with 1-6 carbon atoms in linear or branched chain,

enter into interaction with the derived R8where R8means alkyl with 1-6 carbon atoms in linear or branched chain, Gal means a halogen atom, in the presence of alkali metal hydride, then remove sisanie for hydroxyl group features by processing triperoxonane acid.

11. The method of producing polyhydroxybutyrate formula I, where each of R9and R10means the radical-CH2Each of R1, R4, R5and R6means SNON and R2-R3means-CH=CH-, wherein dehydration derivative of the formula IIA

< / BR>
where Rdmeans-HE,

in the presence of triphenylphosphine and dialkyldithiocarbamate, then remove protective for hydroxyl functions group by treatment of the Sabbath.

12. The use of polyhydroxybutyrate formulas AND

< / BR>
as the beginning of the current drugs suitable for the treatment or prevention of diabetes and complications of diabetes.

 

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