Triazole compounds, pharmaceutical composition comprising thereof, using triazole compounds and method for treatment of fungal infection

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes new derivatives of triazole of the general formula (I): wherein X represents group of the general formula (II): wherein R' means halogen atom; R4 means (C1-C6)-alkyl; L means group of the formula: -La-Lb wherein La means a simple bond, oxygen atom, phenyl group that can be optionally substituted with halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group or (C1-C6)-alkyl substituted with a single group -O-P(=O)(OH)2, naphthyl group, 5-membered heteroaryl group comprising as a heteroatom oxygen (O) or sulfur (S) atom, or (C3-C7)-cycloalkyl group that is substituted with carboxyl group; and Lb means (C1-C5)-alkylene group that can be optionally substituted with (C1-C6)-alkyl, carboxyl group or di-[(C1-C6)-alkyl]-amino-(C1-C6)-alkyl group; R means hydrogen atom, (C1-C6)-alkanoyl that can be optionally substituted with group: -Q-NR2'R3' wherein Q means a simple bond or carbonyl group, and R2' and R3' in common with nitrogen atom with that they are bound form piperazinyl ring substituted with (C1-C6)-alkyl and/or carboxyl group, or group: -O-P(=O)(OH)2; or their pharmacologically acceptable salts, pharmaceutical composition based on thereof, and a method for treatment of fungal infections.

EFFECT: valuable medicinal properties of compounds and composition, improved method for treatment of infections.

24 cl, 14 tbl, 1 dwg, 45 ex

 

The scope of the invention

The present invention relates to triazole compounds and their pharmacologically acceptable salts, with excellent pharmacokinetic properties and antifungal activity, in the quality of medicines (in particular, for injection), and medicines (in particular, antifungal, containing as active ingredient the above compounds or their salts.

Background of the invention

To date there have been reports about the different types of triazole compounds as tools for the treatment of fungal infections. For example, triazole compounds containing tertiary hydroxy-group, described in Japanese patent application No. Hei 8-333350, Japanese patent application No. Hei 11-80135, Japanese patent application No. Hei 10-279567 and Japanese patent application No. 2001-342187. In Japanese patent application No. Sho 62-14766 described 2-(2,4-differenl)-1,3-bis(1H-1,2,4-triazole-1-yl)-2-propanol (fluconazole). In Japanese patent application No. Hei 8-53426 described 3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)-2-butanol (ravuconazole). In WO 99/45008 described 2-(2,5-differenl)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazole-1-yl)-2-butanol (RO 0094815). In Japan patent No. 2625584 described 2-(2,4-differenl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazole-1-yl)-2-butanol (voriconazole). In Japanese patent application No. Hei 9-183769 described 1-[(1R,2R)-2(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (TAK-456). In Japanese patent application No. Hei 11-240871 described 2-(2,4-differenl)-1-(ethylsulfonyl)-1,1-debtor-3-(1H-1,2,4-triazole-1-yl)-2-propanol (SS750). In WO 98/31675 described (2R,3R)-2-(2,4-differenl)-3-[4-[4-[3-oxo-2-(4-cryptomaterial)-2H-1,2,4-triazole-4-yl]phenyl]-1-piperazinil]-1-(1H-1,2,4-triazole-1-yl)-2-butanol (Syn-2869). In WO97/05130 described for 7-chloro-3-[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]hinzelin-4(3H)-he (UR-9825). Similar triazole compounds are also described in Japan Patent No. 3050982, WO 95/25107, WO 00/27852, WO 01/66551 and WO 01/79196.

In addition, ester compounds, the chain of which is interrupted methylendioxy group, in order to improve water solubility means for the treatment of fungal infections, described in WO 00/30655, WO 99/61017 and WO 01/52852.

Introduction means for the treatment of fungal infections depends on the type of fungus that is the target, and type of infection. The introduction, for example, can be administered orally and by injection. Because these routes of administration have their advantages and disadvantages, both ways are necessary for the introduction of the preferred drug for treatment of fungal infection. Although the above funds on the basis of triazole for the treatment of fungal infections have excellent antifungal activity, they also have the disadvantage associated with the difficulty of their administration by injection, because they have low solubility in water.

In order to improve the of low water solubility, can be considered a transformation of the hydroxy-group in the ester group. However, because the hydroxy-group, which is common to all such therapeutics is a tertiary hydroxy-group, there is a disadvantage in that the specified ester group cannot easily be broken down in vivo immediately after the introduction because of its low reactivity, and therefore is not efficient extraction of active substances. Ester compound, the chain of which is interrupted methylendioxy group, form formaldehyde in the cleavage of ester.

The problem to be solved by the present invention is to obtain compounds of the triazole, esterified on tertiary hydroxy-group, which have high solubility in water, are capable of rapid metabolism in vivo and are safe compounds, since the splitting of the form formaldehyde. The triazole compounds containing ester group at the tertiary hydroxy-group related to the present invention, up to this time were not known.

Description of the invention

The authors of the present invention has identified the ester group at the tertiary hydroxy-group, which relates to the present invention, carried out the synthesis and found that triazole compounds, relative to the bill to the present invention, are useful as medicines (in particular, as antifungal agents), especially for injection), since these compounds can be easily obtained at low cost, they have excellent chemical stability and high solubility in water, undergo rapid cleavage of the ester group in vivo at high percent conversion, demonstrating excellent antifungal activity, do not form in the decomposition of formaldehyde, have a selectivity in relation to the authorities and show favorable pharmacokinetic properties and a high degree of security, and it is, therefore, led to the creation of the present invention.

The present invention relates to the connection of a triazole of the General formula (I) or its pharmacologically acceptable salt:

[where X represents a group of General formula (II)

(where Ar represents a C6-C10aryl group, which optionally can be substituted by 1-3 identical or different groups selected from the group consisting of a halogen atom and a halogen-substituted C1-C6alkyl group, and R1is a group of organic residue) (provided that the compound of the formula X-OH has antifungal activity),

p> L represents a group of General formula-La-Lb-

[where Larepresents a simple bond, an oxygen atom, a C6-C10aryl group, which optionally can be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies α, heterocyclic group which optionally may be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies αor C3-C7cycloalkyl group, which optionally can be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies αand

Lbrepresents a C1-C5alkylenes group, which optionally can be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies α]

R represents a hydrogen atom, a C1-C6alkanoyloxy group, which optionally can be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies βgroup

formula-C(O)-NR2R3(where R2and R3are the same or different and independently represent a hydrogen atom or a C1-C6alkyl group, or R2 and R3together with the nitrogen atom to which they are bound, form a 4-7-membered heterocyclic group containing the atom(s) or nitrogen or a group-P(=O)(OH)2]

<Group Vice α>

C1-C6alkyl group, a C1-C6alkoxygroup, halogen atom, cyano, hydroxy-group, amino group, C1-C6alkylamino, di (C1-C6alkylamino, amino, C1-C6alkyl group, a C1-C6alkylamino-C1-C6alkyl group, di (C1-C6alkylamino-C1-C6alkyl group, carboxypropyl, -O-P(=O)(OH)2group, and C1-C6alkyl group substituted by a group-O-P(=O)(OH)2.

<Group Vice β>

the hydroxy-group, group-Q-NR2′R3′[where Q represents a simple bond or a carbonyl group, and R2′and R3′are the same or different and independently represent a hydrogen atom or a C1-C6alkyl group, or R2′and R3′together with the nitrogen atom to which they are bound, form a 4-7-membered heterocyclic group containing the atom(s) nitrogen (this heterocyclic group containing the atom(s) of nitrogen, optionally may be substituted by 1 or 2 identical or different C1-C6alkyl group], carboxypropyl, the group-O-P(=O)(OH)2and the group-SO3H.

Of the above compounds mentioned General formula (I) and their pharmacologically acceptable salts, preferred compounds are:

(1) connection of a triazole or its pharmacologically acceptable salt, where Larepresents a C6-C10aryl group, which optionally can be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies α, heterocyclic group which optionally may be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies αor C3-C7cycloalkyl group, which optionally can be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies α,

(2) the connection of a triazole or its pharmacologically acceptable salt, where the carbon atom in the group-La-associated with a group of the formula X-O-C(=O)-, and the carbon atom in the group-La-associated with a group of the formula-Lb-O-R are adjacent to each other,

(3) the connection of a triazole or its pharmacologically acceptable salt, where Lbrepresents a methylene group or a methylene group which is substituted by 1 or 2 identical or different groups selected from the group consists of a group of deputies α,

(4) the connection of a triazole or its pharmacologically acceptable salt, where L represents a group -(o-phenylene)-CH2- or a group -(o-phenylene)-CH2-that is substituted with one group selected from the group consisting of a group of deputies α,

(5) the connection of a triazole or its pharmacologically acceptable salt, where L represents a group -(o-phenylene)-CH2-that is substituted with one group selected from the group consisting of a group of deputies α,

(6) the connection of a triazole or its pharmacologically acceptable salt, where R represents a hydrogen atom,

(7) connection of a triazole or its pharmacologically acceptable salt, where R represents a C1-C6alkanoyloxy group, which optionally can be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies β,

(8) the connection of a triazole or its pharmacologically acceptable salt, where R represents a group-P(=O)(OH)2,

(9) the connection of a triazole or its pharmacologically acceptable salt, where a Group of deputies α represents a Group of deputies α1, which consists of a methyl group, metoxygroup, halogen atom, ceanography and group-CH2-O-P(=O)(OH)2,

(10) the connection of a triazole or its pharmaco is logicheskie acceptable salt, where a Group of deputies β represents a Group of deputies β1, which consists of an amino group, a C1-C6alkylamino and di (C1-C6alkylamino,

(11) the connection of a triazole or its pharmacologically acceptable salt, where a Group of deputies β represents a di (C1-C6alkylamino,

(12) the connection of a triazole or its pharmacologically acceptable salt, where a Group of deputies β represents N,N-dimethylamino group,

(13) the connection of a triazole or its pharmacologically acceptable salt, where a Group of deputies β represents carboxypropyl,

(14) the connection of a triazole or its pharmacologically acceptable salt, where a Group of deputies β represents a 4-7-membered heterocyclic group containing the atom(s) nitrogen (this heterocyclic group containing the atom(s) of nitrogen, optionally may be substituted by 1 or 2 identical or different C1-C6alkyl groups),

(15) the connection of a triazole or its pharmacologically acceptable salt, where a Group of deputies β represents a 4-7-membered heterocyclic group containing the atom(s) nitrogen (this heterocyclic group containing the atom(s) nitrogen substituted by 1 or 2 identical or different C1-C6alkyl groups),

16) the connection of a triazole or its pharmacologically acceptable salt, where a Group of deputies β is a 4-methyl-1-piperazinilnom group,

(17) the connection of a triazole or its pharmacologically acceptable salt, where a Group of deputies β represents a group of formula-C(O)-W [where W is a 4-7-membered heterocyclic group containing the atom(s) nitrogen (this heterocyclic group containing the atom(s) of nitrogen, optionally may be substituted by 1 or 2 identical or different C1-C6alkyl groups)],

(18) the connection of a triazole or its pharmacologically acceptable salt, where a Group of deputies β represents a group of formula-C(O)-W1[where W1is a 4-7-membered heterocyclic group containing the atom(s) nitrogen (this heterocyclic group containing the atom(s) nitrogen substituted by 1 or 2 identical or different C1-C6alkyl groups)],

(19) the connection of a triazole or its pharmacologically acceptable salt, where a Group of deputies β represents (4-methyl-1-piperazinil)carbonyl group,

(20) the connection of a triazole or its pharmacologically acceptable salt, where X represents a group of General formula (III),

[where Ar1represents a phenyl group, which optionally can be substituted by 1-3 identical or different is diversified groups, selected from the group consisting of a halogen atom and triptorelin group,

Ar2represents a phenyl group, which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of a group of deputies γ, monocyclic heteroaryl group, which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of a group of deputies γ, naftalina group, which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of a group of deputies γor condensed bicyclic heteroaryl group, which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of a group of deputies γ,

E represents a methylene group or a group of the formula

-S(O)n1- (where n1 is an integer from 0 to 2),

A1represents a C4-C7cycloalkyl group or heterocyclyl group,

R4and R5independently represent a hydrogen atom or a C1-C6alkyl group,

G represents a group of formula (Ga)

(where R6, R7, R8and R9independent representation is given in an atom of hydrogen or C 1-C6alkyl group, which optionally may be substituted by 1-5 identical or different halogen atoms,

p represents an integer of 0 or 1,

q is an integer from 0 to 3, and

r and s independently represent an integer from 0 to 2),

or G represents a group of formula (Gb)

(where φ is fenelonov group, which optionally may be substituted by 1 or 2 identical or different groups selected from the group consisting of a fluorine atom and chlorine atom, or Neftyanoy group, which optionally may be substituted by 1 or 2 identical or different groups selected from the group consisting of a fluorine atom and chlorine atom,

RΨrepresents a hydrogen atom or a C1-C6alkyl group, and

T represents a simple bond or a linear or branched C1-C8alkylenes group)],

(21) the connection of a triazole or its pharmacologically acceptable salt according to (20), where Ar2represents a phenyl group, which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of a group of deputies γor monocyclic heteroaryl group, which optionally may be substituted by 1-5 one is the same or different groups, selected from the group consisting from the Group of substituents γ,

E represents a group of formula-S(O)n1- (where n1 is an integer from 0 to 2),

R4represents a C1-C4alkyl group,

R5represents a hydrogen atom or a C1-C4alkyl group,

G represents a group of formula (Ga′)

(where R6′, R7′, R8′and R9′independently represent a hydrogen atom or a C1-C6alkyl group, which optionally may be substituted by 1-5 identical or different halogen atoms,

p′ represents an integer of 0 or 1, and

q′, r′ and s′ independently represent an integer from 0 to 2),

(22) the connection of a triazole or its pharmacologically acceptable salt, where X represents a group of General formula (IV)

(23) the connection of a triazole or its pharmacologically acceptable salt according to (20), where

E represents a methylene group,

A1represents a group selected from the group consisting of

G represents a group of formula (Ga′′)

(where q′′ represents an integer num is 0 to 3, and r′′ and s′′ independently represent an integer from 0 to 2, provided that q′′, r′′ and s′′ total $ 3 or less)

(24) the connection of a triazole or its pharmacologically acceptable salt, where X represents a group of General formula (V),

(25) the connection of a triazole or its pharmacologically acceptable salt according to (20), where

Ar2represents naftalina group, which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of a group of deputies γor condensed bicyclic heteroaryl group, which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of a group of deputies γ,

E represents a group of formula-S(O)n1- (where n1 is an integer from 0 to 2),

R4represents a C1-C6alkyl group,

R5represents a hydrogen atom,

G represents a group of formula (Ga′)

(where R6′, R7′, R8′and R9′independently represent a hydrogen atom or a C1-C6alkyl group, which optionally may be substituted by 1-5 of Odin is new or different halogen atoms,

p′ represents an integer of 0 or 1, and

q′, r′ and s′ independently represent an integer from 0 to 2),

(26) the connection of a triazole or its pharmacologically acceptable salt according to (20), where

Ar2represents a phenyl group, which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of a group of deputies γor naftalina group, which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of a group of deputies γ,

E represents a methylene group or a sulfur atom,

R5represents a hydrogen atom, and

G represents a group of formula (Gb)

(where φ is fenelonov group, which optionally may be substituted by 1 or 2 identical or different groups selected from the group consisting of a fluorine atom and chlorine atom, or Neftyanoy group, which optionally may be substituted by 1 or 2 identical or different groups selected from the group consisting of a fluorine atom and chlorine atom,

RΨrepresents a hydrogen atom or a C1-C6alkyl group, and

T represents a simple bond or a linear or branched C1 -C8alkylenes group)

(27) the connection of a triazole or its pharmacologically acceptable salt, where X represents a group of formula (VI)

(28) the connection of a triazole or its pharmacologically acceptable salt, where X represents a group of formula (VII)

(29) the connection of a triazole or its pharmacologically acceptable salt, where X represents a group of formula (VIII),

(30) the connection of a triazole or its pharmacologically acceptable salt, where X represents a group of formula (IX),

(31) the connection of a triazole or its pharmacologically acceptable salt, where X represents a group of formula (X),

(32) the connection of a triazole or its pharmacologically acceptable salt, where X represents a group of formula (XI),

(33) the connection of a triazole or its pharmacologically acceptable salt, where X represents a group of formula (XII),

(34) the connection of a triazole or its pharmacologically acceptable salt, where X represents a group of the formula (XIII).

<Group Vice γ>

halogen atom, a hydroxy-group, mercaptopropyl is, the nitro-group, amino group, cyano, carboxypropyl, C1-C6alkyl group, which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of a group of deputies ς, C1-C6alkoxy group which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of a group of deputies ς, C1-C6alcoolica group, which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of a group of deputies ς, C2-C6alkanoyloxy group, which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of a group of deputies ς, C2-C7alkoxycarbonyl group, C2-C5alkanolamine group, a group of the formula-C(O)-NR2aR3a(where R2aand R3aindependently represent a hydrogen atom or a C1-C6alkyl group, or R2aand R3atogether with the nitrogen atom to which they are bound, form a 4-7-membered heterocyclic group containing the atom(s) of nitrogen), a group of the formula-S(O)μ1-Rξ1(where μ1 represents an integer from 0 to 2 and Rξ1represents a C1-C6alkiline the group, which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of a group of deputies η)a group of formula-S(O)μ2-O-Rξ2(where μ2 represents an integer from 0 to 2 and Rξ2represents a C1-C6alkyl group, which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of a group of deputies η)a group of formula-O-S(O)μ3-Rξ3(where μ3 represents an integer from 0 to 2 and Rξ3represents a C1-C6alkyl group, which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of a group of deputies η), imidazolidine group, which optionally may be substituted by 1 or 2 identical or different groups selected from the group consisting of a group of deputies δ, pyrazolidine group, which optionally may be substituted by 1 or 2 identical or different groups selected from the group consisting of a group of deputies δ, thiazolidine group, which optionally may be substituted by 1 or 2 identical or different groups selected from the group consisting of a group of deputies δ, tetrataenia group to which I optionally may be substituted by 1 or 2 identical or different groups, selected from the group consisting from the Group of substituents δ, C2-C6Alchemilla group, C2-C6Alchemilla group, C3-C6cycloalkyl group, and C1-C6an alkyl group which is substituted C3-C6cycloalkyl group.

<Group Vice δ>

C1-C4alkyl group, a C1-C4alkyl group which is substituted by 1-5 identical or different halogen atoms, and a halogen atom.

<Group Vice ς>

halogen atom, a hydroxy-group, cyano, and C1-C6alkoxygroup.

<Group Vice η>

halogen atom and a hydroxy-group.

Alternatively, the present invention partially relates to triazole compounds represented by the General formula (I') below, and their pharmaceutically acceptable salts:

X′ represents a group of General formula (II′),

[where

Ar0represents a C6-C10aryl group, which optionally may be substituted with group(s)selected from the group comprising a halogen atom and a halogen-substituted C1-C6alkyl group, and

R1′is a group of organic residue]

provided that the compound of the formula X'-OH today is antifungal activity

L′ represents a C3-C4alkylenes group, which optionally can be substituted by 1-3 groups selected from the group consisting of a group of deputies α0, described below, -O-(C2-C3alkylene) group, which optionally can be substituted by 1-3 groups selected from the group consisting of a group of deputies α0, described below, -(related substituted C6-C10aryl)-CH2the group, which optionally can be substituted by 1-3 groups selected from the group consisting of a group of deputies α0, described below, or adjacent substituted C3-C7cycloalkyl)-CH2the group, which optionally can be substituted by 1-3 groups selected from the group consisting of a group of deputies α0, described below, and

R′ represents a hydrogen atom, a C1-C6alkanoyloxy group, C1-C6alkanoyloxy group, which is substituted by 1-3 groups selected from the group consisting of a group of deputies β0, or a group-P(=O)(OH)2.

Group Vice α0 represents a group selected from the group comprising C1-C6alkyl group, a C1-C6alkoxygroup, a halogen atom, a cyano, a hydroxy-group, group-NR20R30(where R20and R30independently represent a hydrogen atom or Csub> 1-C6alkyl group), a group of the formula -(C1-C6alkyl)NR20R30(where R20and R30have some higher values), carboxypropyl, a group of formula-OP(O)(OH)2and a group of the formula -(C1-C6alkyl)OP(O)(OH)2.

Group Vice β0 represents a group selected from the group comprising a hydroxy-group, amino group, carboxypropyl, a group of formula-OP(O)(OH)2and a group of the formula-SO3H.

"Aryl group" is an aromatic hydrocarbon ring group, and C6-C10aryl group, for example, can be a phenyl, 1-naftalina or 2-naftalina group, and preferably represents a phenyl group.

"Halogen atom", for example, may be a fluorine atom, chlorine atom, bromine atom or iodine atom, and preferably represents a fluorine atom or a chlorine atom.

"Alkyl group" represents a linear or branched saturated hydrocarbon group, and C1-C4alkyl group, for example, may represent a group of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and C1-C6alkyl group, for example, can represent, in addition to the above-mentioned alkyl groups, a group of pentyl, sec-pentyl, isopentyl, 2-methylbut is l, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl (isohexyl), 3-methylpentyl, 2-methylpentyl, 1-methylpentyl (sec-hexyl), 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl, and preferably represents a C1-C4alkyl group, more preferably a C1-C2alkyl group, most preferably a methyl group.

"Alkoxygroup" represents a linear or branched alkoxygroup, and C1-C4alkoxygroup, for example, can be a methoxy group, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy, and C1-C6alkoxygroup, for example, can represent, in addition to the above alkoxygroup, group pentox, isopentane, 2-methylbutoxy, neopentane, 1 ethylpropoxy, hexyloxy, 4-methylphenoxy, 3 methylpentane, 2-methylpentane, 3,3-Dimethylbutane, 2,2-Dimethylbutane, 1,1-Dimethylbutane, 1,2-Dimethylbutane, 1,3-Dimethylbutane, 2,3-Dimethylbutane or 2-ethylbutane, and preferably represents a C1-C4alkoxygroup, more preferably C1-C2alkoxygroup, most preferably a methoxy group.

"Halogen-substituted alkyl group" represents a monovalent group in which the atom(s) in Dorada mentioned alkyl groups substituted(s) 1-5 atom(s) halogen, and C1-C6halogen-substituted alkyl group, for example, can represent a trifluoromethyl group, trichloromethyl, deformity, dichloromethyl, dibromomethyl, vermeil, 2,2,2-triptorelin, 2,2,2-trichloroethyl, 2-bromacil, 2-chloroethyl, 2-foretel, 2-Iodate, pentafluoroethyl, 3-chloropropyl, 4-terbutyl, 6-iohexol or a 2,2-dibromoethyl, and preferably represents a C1-C4halogen-substituted alkyl group, more preferably a C1-C2halogen-substituted alkyl group, most preferably, triptorelin group.

"Allenova group" is a divalent group derived from a linear saturated hydrocarbon, in which both terminal hydrogen atom is removed, and, for example, can be a methylene group (-(CH2)-), ethylene (-(CH2)2-), trimethylene (-(CH2)3-or tetramethylene (-(CH2)4-), and where Larepresents a simple bond, Allenova group preferably represents trimethylene group; where Larepresents an oxygen atom, Allenova group preferably is an ethylene group; where Larepresents a C6-C10aryl group, which optionally can be substituted by 1-3 identical or different groups selected from the group consisting of the C Group Vice α , heterocyclic group which optionally may be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies αor C3-C7cycloalkyl group, which optionally can be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies α, Allenova group preferably represents a methylene group; and L'the group-O-(C2-C3alkylene), for example, may represent a group-O-(CH2)2- or a group-O-(CH2)3-, and preferably represents a group-O-(CH2)2-.

"Alcoolica group" is a monovalent group in which a hydrogen atom or an alkyl group, as defined above, linked to the carbonyl group, and C1-C6alcoolica group, for example, may represent a group of formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl or isovaleryl, and preferably represents a C1-C4alkanoyloxy group.

"Alkanoyloxy group" represents a group in which an oxygen atom substituted alkanoyloxy group, as defined above, and C2-C6alkanoyloxy group, for example, may represent a group of atomic charges, propionyloxy, butere is hydroxy, isobutyryloxy, pentanoate, pivaloyloxy, valeriansee or isovalerianic, and preferably represents a C1-C4alkanoyloxy group.

"Alkanolamine group" represents a group in which the amino group substituted alkanoyloxy group, as defined above, and C2-C6alkanolamine group, for example, may be an acetylamino group, propionamido, bucillamine, isobutylamino, pentanediamine, paulolino, Valeriano or isovaleramide, and preferably represents a C1-C4alkanolamine group.

"Alkoxycarbonyl group" represents a group in which a carbonyl group substituted by alkoxygroup defined above, and C2-C6alkoxycarbonyl group, for example, can represent a group methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, second-butoxycarbonyl or tert-butoxycarbonyl, phenoxycarbonyl, isoinokosterone, 2-methylbutadiene, neopentecostal or 1-ethylpropoxy, and C2-C7alkoxycarbonyl group, for example, can represent, in addition to the above alkoxycarbonyl groups, group hexyloxybenzoyl, 4-methylpentadiene, 3-methylpentadiene, 2-methylpentan carbonyl, 3,3-dimethylbutyryl, 2,2-dimethylbutyryl, 1,1-dimethylethoxysilane, 1,2-dimethylbutadiene, 1,3-dimethylbutadiene, 2,3-dimethylbutadiene or 2-ethylbutanol, and preferably represents a C2-C5alkoxycarbonyl group, more preferably a C2-C3alkoxycarbonyl group, most preferably ethoxycarbonyl group.

"C1-C6alkylamino" represents a group in which the amino group is substituted by one C1-C6alkyl group, as defined above, and, for example, can represent a group methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamine, isopentylamine, 2-methylbutylamine, neopentylene, 1 ethylpropylamine, n-hexylamino, isohexane, 4-methylpentylamino, 3 methylpentylamino, 2-methylpentylamino, 1 methylpentylamino, 3,3-dimethylbutylamino, 2,2-dimethylbutylamino, 1,1-dimethylbutylamino, 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3-or dimethylbutylamino 2 ethylbutylamine, and preferably represents methylaminopropyl.

"Di (C1-C6alkylamino" represents a group in which the amino group is substituted by two C1-C6the alkyl groups defined above, and, for example, may predstavljati a linear or branched dialkylamino with the number of 2-12 carbon atoms, such as dimethylamino, diethylamino, ethylmethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamine, di(sec-butyl)amino, di(tert-butyl)amino, diphenhydamine, diisobutylamine, dineopentyl, di(1-ethylpropyl)amino, digoxigenin or deisohexanizer group, and preferably dimethylamino or diethylaminopropyl, more preferably, diethylaminopropyl.

"-NR20R30group (R20and R30independently represent a hydrogen atom or a C1-C6alkyl group" is an amino group, "C1-C6alkylamino" or "di (C1-C6alkylamino", and preferably represents amino, dimethylamino or diethylaminopropyl, more preferably diethylaminopropyl.

"Amino-C1-C6alkyl group" represents a group in which C1-C6an alkyl group, as defined above, substituted with one amino group, and, for example, can represent a group aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminohexyl or 2-amino-ethyl, and preferably represents an aminomethyl group.

"C1-C6alkylamino-C1-C6alkyl group" represents a group in which the amino group of amino-C1-C6alkyl group as defined above, substituted with one C1-C alkyl group, as defined above, and, for example, can represent a group methylaminomethyl, ethylaminomethyl, propylaminoethyl, isopropylaminomethyl, butylaminoethyl, pentylamine or hexylamine, and preferably represents methylaminomethyl group.

"Di (C1-C6alkylamino-C1-C6alkyl group" represents a group in which the amino group of amino-C1-C6alkyl group as defined above, substituted with two C1-C6the alkyl groups defined above, and, for example, can represent a group dimethylaminomethyl, diethylaminomethyl, diisopropylaminomethyl, dimethylaminoethyl, diethylaminoethyl, dimethylaminopropyl, diethylaminopropyl, diethylaminomethyl, diethylaminoethyl or diethylaminoethyl, and preferably represents diethylaminomethyl group.

"-(C1-C6alkyl)NR20R30" the group is a group in which C1-C6an alkyl group, as defined above, substituted by one group of the formula-NR20R30defined above, and represents the amino-C1-C6alkyl group", "C1-C6alkylamino-C1-C6alkyl group or di (C1-C6alkylamino-C1-C6alkyl group, and preferably represents g is the SCP-CH 2-NR20R30more preferably diethylaminomethyl group.

"Cycloalkyl group" is a cyclic saturated aliphatic hydrocarbon group, and C3-C7cycloalkyl group, for example, can represent a group cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and preferably represents a C3-C6cycloalkyl group.

"Heterocyclic group containing the atom(s) of nitrogen represents a 4-7-membered heterocyclic group containing 1-3 atoms(a) nitrogen and, for example, may represent a group pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazole, 1,2,3-oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, azetidine, tylenol, pyrrolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidine, thiazolidine, isothiazolinones, piperidinyl, piperazin, morpholinyl, thiomorpholine, pyrazolines, pyrrolidyl, imidazolyl, azepine, azepane or diazepino, and preferably represents a saturated 4-7 membered heterocyclic group, more preferably, piperazinilnom group.

"Monocyclic heteroaryl group" is a 5 - or 6-membered monocyclic aromatic heterocyclic group, sotiriadou to 4 heteroatom(s), selected from the group consisting of atom(s), oxygen atom(s) and nitrogen atom(s) of sulfur, and, for example, may represent a 5-membered monocyclic heteroaryl group such as furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazole, 1,2,3-oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or 6-membered monocyclic heteroaryl group such as pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl; and preferably represents a 5-membered monocyclic heteroaryl group, more preferably follow, thienyl or pyridyloxy group.

"Heterocyclyl group" is a 4-6-membered non-aromatic heterocyclic group containing 1-3 heteroatom(s)selected from the group consisting of atom(s), oxygen atom(s) and nitrogen atom(s) of sulfur, and, for example, may be a 4-membered heterocyclic group, such as group oxetanyl, titanyl or azetidine; 5-membered heterocyclic group, such as group tetrahydrofuryl, tylenol, pyrrolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidine, thiazolidine or isothiazolinones; or 6-membered heterocyclic group such as group dioxane, oxetanyl, dithienyl, tetrahydropyranyl, tiani, piperidinyl, piperazin, morpholinyl or thiomorpholine; and prepact the sory is a 6-membered heterocyclyl group, more preferably, dioxinlike, occationally or dianilino group.

"Condensed bicyclic heteroaryl group" is a condensed bicyclic aromatic heterocyclic group containing 1-3 heteroatom(s)selected from the group consisting of atom(s), oxygen atom(s) and nitrogen atom(s) of sulfur, and, for example, can be a 9-membered polycyclic heteroaryl group, such as isobenzofuranyl, benzofuranyl, isobenzofuranyl, benzothiophene, indolizinyl, isoindolyl, indolyl, benzoxazolyl or benzothiazolyl; or 10-membered polycyclic heteroaryl group, such as chromanol, ethenolysis, chinoline or hintline; and preferably is hyalinella, benzothiophene or indolenine group.

"Heterocyclic group" includes a heterocyclic group containing the atom(s) of nitrogen", "monocyclic heteroaryl group", "heterocyclyl group" and "condensed bicyclic heteroaryl group, as defined above, and preferably represents a monocyclic heteroaryl group" or "heterocyclyl group", more preferably "monocyclic heteroaryl group".

In the General formula (I′), group(related substituted C6-C10aryl)-CH2- and the group -(Smin the substituted C 3-C7cycloalkyl)-CH2- in the definition of L′ shall have the same meaning as in the definition of ″the carbon atom in the group-La-it is linked to the group X-O-C(=O)-, and the carbon atom in the group-La-associated with the group-Lb-O-R are adjacent to each other″.

That is, the adjacent carbon atoms in the aryl group or cycloalkyl group are substituted. The structure is shown below.

With the proviso that when aryl fragment -(related substituted C6-C10aryl)-CH2the group represents a naphthalene, substituted position on the naphthalene ring may be positions 1 and 8.

When R represents negitively group, namely, when R represents a C1-C6alkanoyloxy group, Group Vice α preferably chosen from the Group of substituents α2, consisting of a hydroxy-group, an amino group, a C1-C6alkylamino, di (C1-C6alkylamino, amino-C1-C6alkyl group, a C1-C6alkylamino-C1-C6alkyl groups, di (C1-C6alkylamino-C1-C6alkyl group, carboxypropyl, group-O-P(=O)(OH)2and C1-C6alkyl group substituted by a group-O-P(=O)(OH)2.

When R1represents a group of the organic residue, there are no specific limitations regarding the nature of the "group of organic residue", provided that the group contains carbon atoms, and the compound of the formula X-OH, which includes R1shows antifungal activity.

"Antifungal activity of the compound indicates that the compound is intended for use in the treatment of fungal infection (mycosis), such as deep mycosis, deep cruris, Epigenomics and the like, and has particular connection this effect can easily be determined by a specialist in accordance with the methods described below.

Such methods include the determination of MIC(minimum inhibitory concentration) of compounds against common fungi such as Canida, Aspergillus, Cryptococcus neoformans or Trichophyton, in accordance with the method (M27-A, M38-P), standard NCCLS (National Committee for Clinical Laboratory Standards) or with the method described in Journal of Clinical Microbiology, 38, 341-344 (2000), and if the MIC is equal to or below the standard (preferably 64 µg/ml), a compound is considered active against the fungus.

"Pharmacologically acceptable salt" of the compound of the present invention is a commonly used in pharmaceutical compounds salt of an acid group, such as carboxypropyl, a group-P(=O)(OH)2or group-SO3H, or a basic group such as triazole group, amino group or piperidyl is owned by the group.

Salts formed with an acidic group of the General formula (I), for example, can be an alkali metal salts (e.g. sodium salt, potassium salts and lithium salts), salts of alkaline earth metals (e.g. calcium salts and magnesium salts); metal salts (for example, aluminum salts, iron salts, zinc salts, salts of copper, Nickel salts and cobalt salts), inorganic salts (e.g. ammonium salts); and salts of organic amine (for example, tert-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, salt phenylglycylamino esters, ethylendiamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procainamide salt, diethanolamine salt, N-benzyl-N-phenethylamine salt, pieperazinove salt, Tetramethylammonium salt and salt of Tris(hydroxymethyl)aminomethane).

Salts formed with the main group of General formula (I), for example, can be a salt halogenation acids (for example, hydrohloride, hydrochloride, hydrobromide and hydroiodide); inorganic salts (e.g., nitrates, perchlorates, sulfates and phosphates); lower alkanesulfonyl (for example, methanesulfonate, triftoratsetata and econsultancy); arylsulfonate (for example, be solarvent and p-toluensulfonate); salts of amino acids (for example, salt of ornithine and glutamate) and salts of carboxylic acids (for example, fumarate, succinate, citrates, tartratami, oxalates and maleate).

Compounds of the present invention can sometimes absorb water or to form hydrate under the influence of atmospheric conditions or by recrystallization, and such hydrates are also covered by the connection of a triazole or its pharmacologically acceptable salt according to the present invention.

In addition, some solvents can be absorbed by the compounds of the present invention with the formation of a solvate, which also form part of the compounds of the triazole or its pharmacologically acceptable salt according to the present invention.

Compounds of the present invention include various isomers. For example, the compound of General formula (II) contain asymmetric carbon atoms, and on the basis of such carbon atoms in the compounds of the present invention are stereoisomers.

Alternatively, the group R1compounds of General formula (II) may have asymmetric carbon and the carbon-carbon double bond(connection), compounds of the present invention include various stereoisomers.

Therefore, the present invention includes both the individual isomers and mixtures of these isomers in any proportion.

Such counterpart shall isomers can be obtained using a stereoregular parent compounds, or by synthesis of the compounds of the present invention in accordance with the methods of asymmetric synthesis or asymmetric induction, or traditional methods of optical separation or partitioning methods.

Ester portion of the triazole compounds of the present invention includes, for example, the groups described in the Tables of examples 1, 1A, 2, 2A, 2B, 2C and 3, the scope of the present invention is not limited to these groups.

Next, mark [″] is the same chemical structure as specified above.

Abbreviations in the tables represent the following structural formulas.

1-20td align="center" namest="c1" nameend="c3"> ″ COCH2CH2CH2-(4-Me-1-Piz) 2B-93td align="center"> COCH2CH2N(CH3)2
AbbreviationThe structural formula
1-Azt
1-Pyrd
1-Pip
1-Azp
Mor
Thz
4-Me-1-Piz
Table of examples 1
Example No.LR
1-1CH2CH2CH2H
1-2CH2CH2CH2CHO
1-3CH2CH2CH2CONH2
1-4CH2CH2CH2C(=O)COOH
1-5CH2CH2CH2COCH3
1-6CH2CH2CH2COCH2NH2
1-7CH2CH2CH2COCH2COOH
1-8CH2CH2CH2COCH2CH2OH
1-9CH2CH2CH2COCH2CH2NH2
1-10CH2CH2CH2COCH2CH2COOH
1-11CH2CH2CH2COCH(CH3)NH2
1-12CH2CH2CH2COCH(CH3)COOH
1-13CH2CH2CH2COCH2CH2CH2OH
1-14CH2CH2CH2COCH2CH2CH2NH2
1-15CH2CH2CH2COCH2CH2CH2COOH
1-16CH2CH2CH2COC(CH3)2COOH
1-17CH2CH2CH2COC(CH3)2CH2OH
1-18CH2CH2CH2COC(CH3)2CH2NH2
1-19CH2CH2CH2COC(CH3)2CH2COOH
CH2CH2CH2COCH(NH2)COOH
1-21CH2CH2CH2COCH(NH2)CH2COOH
1-22CH2CH2CH2COCH2CH(NH2)COOH
1-23CH2CH2CH2COCH(NH2)CH2CH2COOH
1-24CH2CH2CH2COCH2CH2CH(NH2)COOH
1-25CH2CH2CH2P(=O)(OH)2
1-26CF2CH2CH2H
1-27CF2CH2CH2COCH2COOH
1-28CF2CH2CH2COCH2CH2COOH
1-29CF2CH2CH2COCH2CH2CH2COOH
1-30CF2CH2CH21-31C(CH3)2CH2CH2H
1-32C(CH3)2CH2CH2COCH2COOH
1-33C(CH3)2CH2CH2COCH2CH2COOH
1-34C(CH3)2CH2CH2COCH2CH2CH2COOH
1-35C(CH3)2CH2CH2P(=O)(OH)2
1-36CH2C(CH3)2CH2H
1-37CH2C(CH3)2CH2COCH2COOH
1-38CH2C(CH3)2CH2COCH2CH2COOH
1-39CH2C(CH3)2CH2COCH2CH2CH2COOH
1-40CH2C(CH3)2CH2P(=O)(OH)2
1-41CH2CH2CH(COOH)H
1-42CH2CH2CH(COOH)COCH3
1-43CH2CH2CH(COOH)COCH2NH2
1-44CH2CH2CH(COOH)COCH2COOH
1-45CH2CH2CH(COOH)COCH2CH2COOH
1-46CH2CH2CH(COOH)COCH2CH2CH2COOH
1-47CH2CH2CH(COOH)P(=O)(OH)2
1-48CH2CH2CH2CH2H
1-49CH2CH2CH2CH2COCH2COOH
1-50CH2CH2CH2CH2COCH2CH2COOH
1-51CH2CH2CH2CH2COCH2CH2CH2COOH
1-52CH2CH2CH2CH2P(=O)(OH)2
1-53CF2CH2CH2CH2H
1-54CF2CH2CH2CH2COCH2COOH
1-55CF2CH2CH2CH2COCH2CH2COOH
1-56CF2CH2CH2CH2COCH2CH2CH2COOH
1-57CF2CH2CH2CH2P(=O)(OH)2
1-58C(CH3)2CH2CH2CH2H
1-59C(CH3)2CH2CH2CH2COCH2COOH
1-60C(CH3)2CH2CH2CH2COCH2CH2COOH
1-61C(CH3)2CH2CH2CH2P(=O)(OH)2
1-62 CH2C(CH3)2CH2CH2H
1-63CH2C(CH3)2CH2CH2COCH2COOH
1-64CH2C(CH3)2CH2CH2COCH2CH2COOH
1-65CH2C(CH3)2CH2CH2P(=O)(OH)2
1-66CH2CH2C(CH3)2CH2H
1-67CH2CH2C(CH3)2CH2COCH2COOH
1-68CH2CH2C(CH3)2CH2COCH2CH2COOH
1-69CH2CH2C(CH3)2CH2P(=O)(OH)2
1-70OCH2CH2H
1-71OCH2CH2CHO
1-72OCH2CH2CONH2
1-73OCH2CH2C(=O)COOH
1-74OCH2CH2COCH2OH
1-75OCH2CH2COCH2NH2
1-76OCH2CH2COCH2COOH
1-77OCH2CH2COCH2CH2OH
1-78OCH2CH2COCH2CH2NH2
1-79OCH2CH2COCH2CH2COOH
1-80OCH2CH2COCH(CH3)NH2
1-81OCH2CH2COCH(CH3)COOH
1-82OCH2CH2COCH2CH2CH2OH
1-83OCH2CH2COCH2CH2CH2NH2
1-84 OCH2CH2COCH2CH2CH2COOH
1-85OCH2CH2COC(CH3)2COOH
1-86OCH2CH2COC(CH3)2CH2OH
1-87OCH2CH2COC(CH3)2CH2NH2
1-88OCH2CH2COC(CH3)2CH2COOH
1-89OCH2CH2COCH(NH2)COOH
1-90OCH2CH2COCH(NH2)CH2COOH
1-91OCH2CH2COCH2CH(NH2)COOH
1-92OCH2CH2COCH(NH2)CH2CH2COOH
1-93OCH2CH2COCH2CH2CH(NH2)COOH
1-94OCH2CH2P(=O)(OH)2
1-5 OCH2CH2CH2H
1-96OCH2CH2CH2COCH2COOH
1-97OCH2CH2CH2COCH2CH2COOH
1-98OCH2CH2CH2COCH2CH2CH2COOH
1-99OCH2CH2CH2P(=O)(OH)2
1-100OCH2C(CH3)2CH2H
1-101OCH2C(CH3)2CH2COCH2COOH
1-102OCH2C(CH3)2CH2COCH2CH2COOH
1-103OCH2C(CH3)2CH2P(=O)(OH)2
1-104CH2CH2CH(CH2N(C2H5)2)H
1-105CH2CH2CH(CH2N(C2H5) 2)COCH3
1-106CH2CH2CH(CH2N(C2H5)2)P(=O)(OH)2
Table of examples 1A
Example No.LR
1A-1CH2H
1A-2CH2COCH2CH2COOH
1A-3CH2P(=O)(OH)2
1A-4CH2CH2H
1A-5CH2CH2P(=O)(OH)2
1A-6CH2CH2CH2COCH2NHCH3
1A-7CH2CH2CH2COCH2N(CH3)2
1A-8CH2CH2CH2COCH2-(1-Pyrd)
1A-9 CH2CH2CH2COCH2-(4-Me-1-Piz)
1A-10CH2CH2CH2COCH2CH2N(CH3)2
1A-11CH2CH2CH2COCH2CH2-(1-Pyrd)
1A-12CH2CH2CH2COCH2CH2-(4-Me-1-Piz)
1A-13CH2CH2CH2COCH2CH2CO-(4-Me-1-Piz)
1A-14CH2CH2CH2COCH2CH2CH2N(CH3)2
1A-15CH2CH2CH2COCH2CH2CH2-(1-Pyrd)
1A-16CH2CH2CH2COCH2CH2CH2-(4-Me-1-Piz)
1A-17OCH2CH2COCH2NHCH3
1A-18OCH2CH2COCH2N(CH3)2
1A-19 OCH2CH2COCH2-(1-Pyrd)
1A-20OCH2CH2COCH2-(4-Me-1-Piz)
1A-21OCH2CH2COCH2CH2CO-(4-Me-1-Piz)
1A-22CF2CH2CH2COCH2NHCH3
1A-23CF2CH2CH2COCH2N(CH3)2
1A-24CF2CH2CH2COCH2-(1-Pyrd)
1A-25CF2CH2CH2COCH2-(4-Me-1-Piz)
1A-26CF2CH2CH2COCH2CH2CO-(4-Me-1-Piz)
1A-27C(CH3)2CH2CH2COCH2NHCH3
1A-28C(CH3)2CH2CH2COCH2N(CH3)2
1A-29C(CH3)2CH2CH2COCH2 -(1-Pyrd)
1A-30C(CH3)2CH2CH2COCH2-(4-Me-1-Piz)
1A-31C(CH3)2CH2CH2COCH2CH2CO-(4-Me-1-Piz)
1A-32CH2C(CH3)2CH2COCH2NHCH3
1A-33CH2C(CH3)2CH2COCH2N(CH3)2
1A-34CH2C(CH3)2CH2COCH2-(1-Pyrd)
1A-35CH2C(CH3)2CH2COCH2-(4-Me-1-Piz)
1A-36CH2C(CH3)2CH2COCH2CH2CO-(4-Me-1-Piz)
Table of examples 2
Example No.LR
2-1H
2-2CHO
2-3CONH2
2-4C(=O)COOH
2-5COCH2OH
2-6COCH2NH2
2-7COCH2COOH
2-8COCH2CH2OH
2-9COCH2CH2NH2
2-10COCH2CH2COOH
2-11COCH(CH3)NH2
2-12COCH(CH3)COOH
2-13COCH2CH2CH2OH
2-14COCH2CH2CH2NH2
2-15COCH2CH2CH2COOH
2-16COC(CH3)2COOH
2-17COC(CH3)2CH2 OH
2-18COC(CH3)2CH2NH2
2-19COC(CH3)2CH2COOH
2-20COCH(NH2)COOH
2-21COCH(NH2)CH2COOH
2-22COCH2CH(NH2)COOH
2-23COCH(NH2)CH2CH2COOH
2-24COCH2CH2CH(NH2)COOH
2-25P(=O)(OH)2
2-26H
2-27P(=O)(OH)2
2-28H
2-29P(=O)(OH)2
2-30H
2-31P(=O)(OH)2
2-32 H
2-33P(=O)(OH)2
2-34H
2-35P(=O)(OH)2
2-36H
2-37COCH2COOH
2-38COCH2CH2COOH
2-39COCH2CH2CH2COOH
2-40P(=O)(OH)2
2-41H
2-42COCH2COOH
2-43COCH2CH2COOH
2-44COCH2CH2CH2COOH
2-45P(=O)(OH)2
2-46H
2-47COCH2COOH
2-48COCH2CH2COOH
2-49COCH2CH2CH2COOH
2-50P(=O)(OH)2
2-51H
2-52P(=O)(OH)2
2-53H
2-54P(=O)(OH)2
2-55H
2-56P(=O)(OH)2
2-57H
2-58COCH2COOH
2-59COCH2CH2COOH
2-60COCH2CH2CH2COOH
2-61P(=O)(OH)2
2-62 H
2-63COCH2COOH
2-64COCH2CH2COOH
2-65COCH2CH2CH2COOH
2-66P(=O)(OH)2
2-67H
2-68COCH3
2-69COCH2COOH
2-70P(=O)(OH)2
2-71H
2-72COCH3
2-73COCH2COOH
2-74P(=O)(OH)2
2-75H
2-76COCH3
2-77COCH2/sub> COOH
2-78P(=O)(OH)2
2-79H
2-80COCH3
2-81COCH2COOH
2-82P(=O)(OH)2
2-83H
2-84COCH3
2-85COCH2COOH
2-86H
2-87COCH3
2-88COCH2COOH
2-89H
2-90COCH3
2-91COCH2COOH
2-92H
2-93COCH3
2-94COCH2COOH
2-95H
2-96P(=O)(OH)2
2-97H
2-98P(=O)(OH)2
2-99H
2-100P(=O)(OH)2
2-101H
2-102P(=O)(OH)2
2-103H
2-104P(=O)(OH)2
2-105H
2-106P(=O)(OH)2
2-107H
2-108P(=O)(OH)2
Table of examples 2A
Example No.LR
2A-1COCH2NHCH3
2A-2COCH2N(CH3)2
2A-3COCH2-(1-Azt)
2A-4COCH2-(1-Pyrd)
2A-5COCH2-(1-Pip)
2A-6COCH2-(1-Azp)
2A-7COCH2Mor
2A-8COCH2Thz
2A-9COCH2-(4-Me-1-Piz)
2A-10COCH2CONH2
2A-11COCH2CONHCH3
2A-12COCH2CON(CH3)2
2A-13COCH2CO-(1-Azt)
2A-14COCH2CO-(1-Pyrd)
2A-15COCH2CO-(1-Pip)
2A-16COCH2CO-(1-Azp)
2A-17COCH2COMor
2A-18COCH2COThz
2A-19COCH2CO-(4-Me-1-Piz)
2A-20COCH2CH2NHCH3
2A-21COCH2CH2N(CH3)2
2A-22COCH2CH2-(1-Azt)
2A-23COCH2CH2-(1-Pyrd)
2A-24COCH2CH2-(1-Pip)
2A-25COCH2CH2-(1-Azp)
2A-26COCH2CH2Mor
2A-27COCH2CH2Thz
2A-28COCH2CH2-(4-Me-1-Piz)
2A-29COCH2CH2CONH2
2A-30COCH2CH2CONHCH3
2A-31COCH2CH2CON(CH3)2
2A-32COCH2CH2CO-(1-Azt)
2A-33COCH2CH2CO-(1-Pyrd)
2A-34COCH2CH2CO-(1-Pip)
2A-35COCH2CH2CO-(1-Azp)
2A-36COCH2CH2COMor
2A-37COCH2CH2COThz
2A-38COCH2CH2CO-(4-Me-1-Piz)
2A-39COCH2CH2CH2NHCH3
2A-40COCH2CH2CH2N(CH3)2
2A-41COCH2CH2CH2-(-Azt)
2A-42COCH2CH2CH2-(1-Pyrd)
2A-43COCH2CH2CH2-(1-Pip)
2A-44COCH2CH2CH2-(1-Azp)
2A-45COCH2CH2CH2Mor
2A-46COCH2CH2CH2Thz
2A-47COCH2CH2CH2-(4-Me-1-Piz)
2A-48COCH2CH2CH2CONH2
2A-49COCH2CH2CH2CONHCH3
2A-50COCH2CH2CH2CON(CH3)2
2A-51COCH2CH2CH2CO-(1-Azt)
2A-52COCH2CH2CH2CO-(1-Pyrd)
2A-53COCH2CH2CH2CO-(1-Pip)
2A-54COCH2C 2CH2CO-(1-Azp)
2A-55COCH2CH2CH2COMor
2A-56COCH2CH2CH2COThz
2A-57COCH2CH2CH2CO-(4-Me-1-Piz)
2A-58COCH(CH3)NHCH3
2A-59COCH(CH3)NH(CH3)2
2A-60COC(CH3)2NHCH3
2A-61COC(CH3)2N(CH3)2
2A-62COCH[N(CH3)2]CON(CH3)2
2A-63COCH[N(CH3)2]CO-(1-Azt)
2A-64COCH[N(CH3)2]CO-(1-Pyrd)
2A-65COCH[N(CH3)2]CO-(1-Pip)
2A-66COCH[N(CH3)2]CO-(1-Azp)
2A-67COCH[N(CH3)2]COMor
2A-68COCH[N(CH3)2]COThz
2A-69COCH[N(CH3)2]CO-(4-Me-1-Piz)
2A-70COCH[N(CH3)2]CH2CON(CH3)2
2A-71COCH[N(CH3)2]CH2CO-(1-Azt)
2A-72COCH[N(CH3)2]CH2CO-(1-Pyrd)
2A-73COCH[N(CH3)2]CH2CO-(1-Pip)
2A-74COCH[N(CH3)2]CH2CO-(1-Azp)
2A-75COCH[N(CH3)2]CH2COMor
2A-76COCH[N(CH3)2]CH2COThz
2A-77COCH[N(CH3)2]CH2CO-(4-Me-1-Piz)
2A-78COCH2CH[N(CH3)2]CON(CH3)2
2A-79COCH2CH[N(CH3)2]CO-(1-Azt)
2A-80COCH 2CH[N(CH3)2]CO-(1-Pyrd)
2A-81COCH2CH[N(CH3)2]CO-(1-Pip)
2A-82COCH2CH[N(CH3)2]CO-(1-Azp)
2A-83COCH2CH[N(CH3)2]COMor
2A-84COCH2CH[N(CH3)2]COThz
2A-85COCH2CH[N(CH3)2]CO-(4-Me-1-Piz)
2A-86COCH[N(CH3)2]CH2CH2CON(CH3)2
2A-87COCH[N(CH3)2]CH2CH2CO-(1-Azt)
2A-88COCH[N(CH3)2]CH2CH2CO-(1-Pyrd)
2A-89COCH[N(CH3)2]CH2CH2CO-(1-Pip)
2A-90COCH[N(CH3)2]CH2CH2CO-(1-Azp)
2A-91COCH[N(CH3)2]CH2CH2COMor
2A-92COCH[(CH 3)2]CH2CH2COThz
2A-93COCH[N(CH3)2]CH2CH2CO-(4-Me-1-Piz)
2A-94COCH2CH2CH[N(CH3)2]CON(CH3)2
2A-95COCH2CH2CH[N(CH3)2]CO-(1-Azt)
2A-96COCH2CH2CH[N(CH3)2]CO-(1-Pyrd)
2A-97COCH2CH2CH[N(CH3)2]CO-(1-Pip)
2A-98COCH2CH2CH[N(CH3)2]CO-(1-Azp)
2A-99COCH2CH2CH[N(CH3)2]COMor
2A-100COCH2CH2CH[N(CH3)2]COThz
2A-101COCH2CH2CH[N(CH3)2]CO-(4-Me-1-Piz)
2A-102CONH2
2A-103C(=O)COOH
2A-104 COCH2OH
2A-105COCH2NH2
2A-106COCH2COOH
2A-107COCH2CH2NH2
2A-108COCH2CH2COOH
2A-109COCH2CH2CH2OH
2A-110COCH2CH2CH2NH2
2A-111COCH2CH2CH2COOH
2A-112COCH2NHCH3
2A-113COCH2N(CH3)2
2A-114COCH2-(1-Azt)
2A-115COCH2-(1-Pyrd)
2A-116COCH2-(1-Pip)
2A-117COCH2-(1-Azp)
2A-118COCH2Mor
2A-119COCH2Thz
2A-120COCH2-(4-Me-1-Piz)
2A-121COCH2CONH2
2A-122COCH2CONHCH3
2A-123COCH2CON(CH3)2
2A-124COCH2CO-(1-Azt)
2A-125COCH2CO-(1-Pyrd)
2A-126COCH2CO-(1-Pip)
2A-127COCH2CO-(1-Azp)
2A-128COCH2COMor
2A-129COCH2COThz
2A-130COCH2CO-(4-Me-1-Piz)
2A-131COCH2CH2NHCH3
2A-132COCH2CH2N(CH3)2
2A-133COCH2CH2-(1-Azt)
2A-134COCH2CH2-(1-Pyrd)
2A-135COCH2CH2-(1-Pip)
2A-136COCH2CH2-(1-Azp)
2A-137COCH2CH2Mor
2A-138COCH2CH2Thz
2A-139COCH2CH2-(4-Me-1-Piz)
2A-140COCH2CH2CONH2
2A-141COCH2CH2CONHCH3
2A-142COCH2CH2CON(CH3)2
2A-143COCH2CH2CO-(1-Azt)
2A-144COCH2CH2CO-(1-Pyrd)
2A-145COCH2CH2CO-(1-Pip)
2A-146COCH2CH2CO-(1-Azp)
2A-147COCH2CH2COMor
2A-148COCH2CH2COThz
2A-149COCH2CH2CO-(4-Me-1-Piz)
2A-150COCH2CH2CH2NHCH3
2A-151COCH2CH2CH2N(CH3)2
2A-152COCH2CH2CH2-(1-Azt)
2A-153COCH2CH2CH2-(1-Pyrd)
2A-154COCH2CH2CH2-(1-Pip)
2A-155COCH2CH2CH2-(1-Azp)
2A-156COCH2CH2CH2Mor
2A-157COCH2CH2CH2Thz
2A-158COCH2CH2CH2-(4-Me-1-Piz)
2A-159COCH2CH2CH2CONH2
2A-160COCH2CH2CH2CONHCH3
2A-161COCH2CH2CH2CON(CH3)2
2A-162COCH2CH2CH2CO-(1-Azt)
2A-163COCH2CH2CH2CO-(1-Pyrd)
2A-164COCH2CH2CH2CO-(1-Pip)
2A-165COCH2CH2CH2CO-(1-Azp)
2A-166COCH2CH2CH2COMor
2A-167COCH2CH2CH2COThz
2A-168COCH2CH2CH2CO-(4-Me-1-Piz)
2A-169COCH(CH3)NHCH3
2A-170COCH(CH3)NH(CH3)2
2A-171COC(CH3)2NHCH3
2A-172COC(CH3)2N(CH3)2
2A-173COCH[N(CH3)2]CON(CH3)2
2A 174COCH[N(CH3)2]CO-(1-Azt)
2A-175COCH[N(CH3)2]CO-(1-Pyrd)
2A-176COCH[N(CH3)2]CO-(1-Pip)
2A-177COCH[N(CH3)2]CO-(1-Azp)
2A-178COCH[N(CH3)2]COMor
2A-179COCH[N(CH3)2]COThz
2A-180COCH[N(CH3)2]CO-(4-Me-1-Piz)
2A-181COCH[N(CH3)2]CH2CON(CH3)2
2A-182COCH[N(CH3)2]CH2CO-(1-Azt)
2A-183COCH[N(CH3)2]CH2CO-(1-Pyrd)
2A-184COCH[N(CH3)2]CH2CO-(1-Pip)
2A-185COCH[N(CH3)2]CH2CO-(1-Azp)
2A-186COCH[N(CH3)2]CH2COMor
2A-187COCH[N(CH3)2]CH2COThz
2A-188COCH[N(CH3)2]CH2CO-(4-Me-1-Piz)
2A-189COCH2CH[N(CH3)2]CON(CH3)2
2A-190COCH2CH[N(CH3)2]CO-(1-Azt)
2A-191COCH2CH[N(CH3)2]CO-(1-Pyrd)
2A-192COCH2CH[N(CH3)2]CO-(1-Pip)
2A-193COCH2CH[N(CH3)2]CO-(1-Azp)
2A-194COCH2CH[N(CH3)2]COMor
2A-195COCH2CH[N(CH3)2]COThz
2A-196COCH2CH[N(CH3)2]CO-(4-Me-1-Piz)
2A-197COCH[N(CH3)2]CH2CH2CON(CH3)2
2A-198COCH[N(CH3)2]CH2CH2CO-(1-Azt)
2A-199 COCH[N(CH3)2]CH2CH2CO-(1-Pyrd)
2A-200COCH[N(CH3)2]CH2CH2CO-(1-Pip)
2A-201COCH[N(CH3)2]CH2CH2CO-(1-Azp)
2A-202COCH[N(CH3)2]CH2CH2COMor
2A-203COCH[N(CH3)2]CH2CH2COThz
2A-204COCH[N(CH3)2]CH2CH2CO-(4-Me-1-Piz)
2A-205COCH2CH2CH[N(CH3)2]CON(CH3)2
2A-206COCH2CH2CH[N(CH3)2]CO-(1-Azt)
2A-207COCH2CH2CH[N(CH3)2]CO-(1-Pyrd)
2A-208COCH2CH2CH[N(CH3)2]CO-(1-Pip)
2A-209COCH2CH2CH[N(CH3)2]CO-(1-Azp)
2A-210COCH2CH2CH[N(CH3)2]COMor
2A-211COCH2CH2CH[N(CH3)2]COThz
2A-212COCH2CH2CH[N(CH3)2]CO-(4-Me-1-Piz)
Table of examples 2B
Example No.LR
2B-1C(=O)COOH
2B-2COCH2NH2
2B-3COCH2CH2NH2
2B-4COCH2CH2CH2NH2
2B-5COCH2CH2COOH
2B-6COCH2NHCH3
2B-7COCH2N(CH3)2
2B-8COCH2-(1-Pyrd)
2B-9COCH2-(4-Me-1-Piz)
2B-10COCH2 CH2NHCH3
2B-11COCH2CH2N(CH3)2
2B-12COCH2CH2-(1-Pyrd)
2B-13COCH2CH2-(4-Me-1-Piz)
2B-14COCH2CH2CO-(4-Me-1-Piz)
2B-15COCH2CH2CH2N(CH3)2
2B-16COCH2CH2CH2-(1-Pyrd)
2B-17COCH2CH2CH2-(4-Me-1-Piz)
2B-18C(=O)COOH
2B-19COCH2NH2
2B-20COCH2CH2NH2
2B-21COCH2CH2CH2NH2
2B-22COCH2CH2COOH
2B-23COCH2NHCH3
COCH2N(CH3)2
2B-25COCH2-(1-Pyrd)
2B-26COCH2-(4-Me-1-Piz)
2B-27COCH2CH2NHCH3
2B-28COCH2CH2N(CH3)2
2B-29COCH2CH2-(1-Pyrd)
2B-30COCH2CH2-(4-Me-1-Piz)
2B-31COCH2CH2CO-(4-Me-1-Piz)
2B-32COCH2CH2CH2N(CH3)2
2B-33COCH2CH2CH2-(1-Pyrd)
2B-34COCH2CH2CH2-(4-Me-1-Piz)
2B-35C(=O)COOH
2B-36COCH2NH2
2B-37COCH2C 2NH2
2B-38COCH2CH2CH2NH2
2B-39COCH2OH
2B-40COCH2NHCH3
2B-41COCH2N(CH3)2
2B-42COCH2-(1-Pyrd)
2B-43COCH2-(4-Me-1-Piz)
2B-44COCH2CH2NHCH3
2B-45COCH2CH2N(CH3)2
2B-46COCH2CH2-(1-Pyrd)
2B-47COCH2CH2-(4-Me-1-Piz)
2B-48COCH2CH2CO-(4-Me-1-Piz)
2B-49COCH2CH2CH2N(CH3)2
2B-50COCH2CH2CH2-(1-Pyrd)
2B-51
2B-52C(=O)COOH
2B-53COCH2NH2
2B-54COCH2CH2NH2
2B-55COCH2CH2CH2NH2
2B-56COCH2OH
2B-57COCH2NHCH3
2B-58COCH2N(CH3)2
2B-59COCH2-(1-Pyrd)
2B-60COCH2-(4-Me-1-Piz)
2B-61COCH2CH2NHCH3
2B-62COCH2CH2N(CH3)2
2B-63COCH2CH2-(1-Pyrd)
2B-64COCH2CH2-(4-Me-1-Piz)
2B-65 COCH2CH2CO-(4-Me-1-Piz)
2B-66COCH2CH2CH2N(CH3)2
2B-67COCH2CH2CH2-(1-Pyrd)
2B-68COCH2CH2CH2-(4-Me-1-Piz)
2B-69C(=O)COOH
2B-70COCH2NH2
2B-71COCH2CH2NH2
2B-72COCH2CH2CH2NH2
2B-73COCH2OH
2B-74COCH2NHCH3
2B-75COCH2N(CH3)2
2B-76COCH2-(1-Pyrd)
2B-77COCH2-(4-Me-1-Piz)
2B-78COCH2CH2NHCH3
2B-79COCH2CH2N(CH3)2
2B-80COCH2CH2-(1-Pyrd)
2B-81COCH2CH2-(4-Me-1-Piz)
2B-82COCH2CH2CO-(4-Me-1-Piz)
2B-83COCH2CH2CH2N(CH3)2
2B-84COCH2CH2CH2-(1-Pyrd)
2B-85COCH2CH2CH2-(4-Me-1-Piz)
2B-86COCH2OH
2B-87C(=O)COOH
2B-88COCH2NH2
2B-89COCH2CH2NH2
2B-90COCH2CH2CH2NH2
2B-91COCH2CH2CH2COOH
2B-92CONH2
COCH2NHCH3
2B-94COCH2N(CH3)2
2B-95COCH2-(1-Pyrd)
2B-96COCH2-(4-Me-1-Piz)
2B-97COCH2CH2NHCH3
2B-98COCH2CH2N(CH3)2
2B-99COCH2CH2-(1-Pyrd)
2B-100COCH2CH2-(4-Me-1-Piz)
2B-101COCH2CH2CO-(4-Me-1-Piz)
2B-102COCH2CH2CH2N(CH3)2
2B-103COCH2CH2CH2-(1-Pyrd)
2B-104COCH2CH2CH2-(4-Me-1-Piz)
2B-105C(=O)COOH
2B-106OCH 2NH2
2B-107COCH2CH2NH2
2B-108COCH2CH2CH2NH2
2B-109COCH2OH
2B-110COCH2NHCH3
2B-111COCH2N(CH3)2
2B-112COCH2-(1-Pyrd)
2B-113COCH2-(4-Me-1-Piz)
2B-114COCH2CH2NHCH3
2B-115COCH2CH2N(CH3)2
2B-116COCH2CH2-(1-Pyrd)
2B-117COCH2CH2-(4-Me-1-Piz)
2B-118COCH2CH2CO-(4-Me-1-Piz)
2B-119COCH2CH2CH2N(CH3)2
2B-120COCH2CH2CH2-(1-Pyrd)
2B-121COCH2CH2CH2-(4-Me-1-Piz)
2B-122H
2B-123C(=O)COOH
2B-124COCH2NH2
2B-125COCH2CH2NH2
2B-126COCH2CH2CH2NH2
2B-127COCH2CH2CH2COOH
2B-128P(=O)(OH)2
2B-129COCH2NHCH3
2B-130COCH2N(CH3)2
2B-131COCH2-(1-Pyrd)
2B-132COCH2-(4-Me-1-Piz)
2B-133COCH2CH2NHCH3
2B-1342B-135COCH2CH2-(1-Pyrd)
2B-136COCH2CH2-(4-Me-1-Piz)
2B-137COCH2CH2CO-(4-Me-1-Piz)
2B-138COCH2CH2CH2N(CH3)2
2B-139COCH2CH2CH2-(1-Pyrd)
2B-140COCH2CH2CH2-(4-Me-1-Piz)
2B-141C(=O)COOH
2B-142COCH2NH2
2B-143COCH2CH2NH2
2B-144COCH2CH2CH2NH2
2B-145COCH2CH2CH2COOH
2B-146COCH2NHCH3
2B-147COCH2N(CH3) 2
2B-148COCH2-(1-Pyrd)
2B-149COCH2-(4-Me-1-Piz)
2B-150COCH2CH2NHCH3
2B-151COCH2CH2N(CH3)2
2B-152COCH2CH2-(1-Pyrd)
2B-153COCH2CH2-(4-Me-1-Piz)
2B-154COCH2CH2CO-(4-Me-1-Piz)
2B-155COCH2CH2CH2N(CH3)2
2B-156COCH2CH2CH2-(1-Pyrd)
2B-157COCH2CH2CH2-(4-Me-1-Piz)
2B-158C(=O)COOH
2B-159COCH2NH2
2B-160COCH2CH2NH2
2B-161COCH2CH2CH2NH2
2B-162COCH2CH2CH2COOH
2B-163COCH2NHCH3
2B-164COCH2N(CH3)2
2B-165COCH2-(1-Pyrd)
2B-166COCH2-(4-Me-1-Piz)
2B-167COCH2CH2NHCH3
2B-168COCH2CH2N(CH3)2
2B-169COCH2CH2-(1-Pyrd)
2B-170COCH2CH2-(4-Me-1-Piz)
2B-171COCH2CH2CO-(4-Me-1-Piz)
2B 172COCH2CH2CH2N(CH3)2
2B-173COCH2CH2CH2-(1-Pyrd)
2B 174COCH2CH2CH2-4-Me-1-Piz)
Table of examples 2C
Example No.LR
2C-1H
2C-2COCH2NH2
2C-3P(=O)(OH)2
2C-4COCH2NHCH3
2C-5COCH2N(CH3)2
2C-6COCH2-(1-Pyrd)
2C-7COCH2-(4-Me-1-Piz)
2C-8COCH2CH2NHCH3
2C-9COCH2CH2N(CH3)2
2C-10COCH2CH2-(1-Pyrd)
2C-11COCH2CH2-(4-Me-1-Piz)
2C-12COCH2CH2CO-(4-Me-1-Piz)
2C-13COCH2CH2CH2N(CH3)2
2C-14COCH2CH2CH2-(1-Pyrd)
2C-15COCH2CH2COOH
2C-16H
2C-17COCH2NH2
2C-18P(=O)(OH)2
2C-19COCH2NHCH3
2C-20COCH2N(CH3)2
2C-21COCH2-(1-Pyrd)
2C-22COCH2-(4-Me-1-Piz)
2C-23COCH2CH2NHCH3
2C-24COCH2CH2N(CH3)2
2C-25COCH2CH2-(1-Pyrd)
2C-26COCH2CH2-(4-Me-1-Piz)
2C-27COCH2CH2CO-(4-Me-1-Piz)
2C-28COCH2CH2CH2N(CH3)2
2C-29COCH2CH2CH2-(1-Pyrd)
2C-30COCH2CH2COOH
2C-31H
2C-32COCH2NH2
2C-33P(=O)(OH)2
2C-34COCH2NHCH3
2C-35COCH2N(CH3)2
2C-36COCH2-(1-Pyrd)
2C-37COCH2-(4-Me-1-Piz)
2C-38COCH2CH2NHCH3
2C-39COCH2CH2N(CH3)2
2C-40COCH2CH2-(1-Pyrd)
2C-41COCH2CH2-(4-Me-1-Piz)
2C-42COCH2CH2CO-(4-Me-1-Piz)
2C-43COCH2CH2CH2N(CH3)2
2C-44COCH2CH2CH2-(1-Pyrd)
2C-45COCH2CH2COOH
2C-46H
2C-47COCH2NH2
2C-48P(=O)(OH)2
2C-49COCH2NHCH3
2C-50COCH2N(CH3)2
2C-51COCH2-(1-Pyrd)
2C-52COCH2-(4-Me-1-Piz)
2C-53COCH2CH2NHCH3
2C-54COCH2CH2N(CH3)2
2C-55COCH2CH2-(1-Pyrd)
2C-56COCH2CH2-(4-Me-1-Piz)
2C-57COCH2CH2CO-(4-Me-1-Piz)
2C-58COCH2CH2CH2N(CH3)2
2C-59COCH2CH2CH2-(1-Pyrd)
2C-60COCH2CH2COOH
2C-61H
2C-62COCH2NH2
2C-63P(=O)(OH)2
2C-64COCH2NHCH3
2C-65COCH2N(CH3)2
2C-66COCH2-(1-Pyrd)
2C-67COCH2-(4-Me-1-Piz)
2C-68COCH2CH2NHCH3
2C-69
2C-70COCH2CH2-(1-Pyrd)
2C-71COCH2CH2-(4-Me-1-Piz)
2C-72COCH2CH2CO-(4-Me-1-Piz)
2C-73COCH2CH2CH2N(CH3)2
2C-74COCH2CH2CH2-(1-Pyrd)
2C-75COCH2CH2COOH
2C-76H
2C-77COCH2NH2
2C-78P(=O)(OH)2
2C-79COCH2NHCH3
2C-80COCH2N(CH3)2
2C-81COCH2-(1-Pyrd)
2C-82COCH2-(4-Me-1-Piz)
2C-83 2CH2NHCH3
2C-84COCH2CH2N(CH3)2
2C-85COCH2CH2-(1-Pyrd)
2C-86COCH2CH2-(4-Me-1-Piz)
2C-87COCH2CH2CO-(4-Me-1-Piz)
2C-88COCH2CH2CH2N(CH3)2
2C-89COCH2CH2CH2-(1-Pyrd)
2C-90COCH2CH2COOH
2C-91H
2C-92COCH2NH2
2C-93P(=O)(OH)2
2C-94COCH2NHCH3
2C-95COCH2N(CH3)2
2C-96COCH2-(1-Pyrd)
2C-97 COCH2-(4-Me-1-Piz)
2C-98COCH2CH2NHCH3
2C-99COCH2CH2N(CH3)2
2C-100COCH2CH2-(1-Pyrd)
2C-101COCH2CH2-(4-Me-1-Piz)
2C-102COCH2CH2CO-(4-Me-1-Piz)
2C-103COCH2CH2CH2N(CH3)2
2C-104COCH2CH2CH2-(1-Pyrd)
2C-105COCH2CH2COOH
2C-106H
2C-107COCH2NH2
2C-108P(=O)(OH)2
2C-109COCH2NHCH3
2C-110COCH2N(CH3)2
2C-111COCH2-(1-Pyrd)
2C-112COCH2-(4-Me-1-Piz)
2C-113COCH2CH2NHCH3
2C-114COCH2CH2N(CH3)2
2C-115COCH2CH2-(1-Pyrd)
2C-116COCH2CH2-(4-Me-1-Piz)
2C-117COCH2CH2CO-(4-Me-1-Piz)
2C-118COCH2CH2CH2N(CH3)2
2C-119COCH2CH2CH2-(1-Pyrd)
2C-120COCH2CH2COOH
2C-121H
2C-122COCH2NH2
2C-123P(=O)(OH)2
2C-124COCH2NHCH3
2C-125COCH2N(CH3)2
2C-126COCH2-(1-Pyrd)
2C-127COCH2-(4-Me-1-Piz)
2C-128COCH2CH2NHCH3
2C-129COCH2CH2N(CH3)2
2C-130COCH2CH2-(1-Pyrd)
2C-131COCH2CH2-(4-Me-1-Piz)
2C-132COCH2CH2CO-(4-Me-1-Piz)
2C-133COCH2CH2CH2N(CH3)2
2C-134COCH2CH2CH2-(1-Pyrd)
2C-135COCH2CH2COOH
2C-136H
2C-137COCH2NH2
2C-138P(=O)(OH)2
2C-139COCH2NHCH3
2C-140COCH2N(CH3)2
2C-141COCH2-(1-Pyrd)
2C-142COCH2-(4-Me-1-Piz)
2C-143COCH2CH2NHCH3
2C-144COCH2CH2N(CH3)2
2C-145COCH2CH2-(1-Pyrd)
2C-146COCH2CH2-(4-Me-1-Piz)
2C-147COCH2CH2CO-(4-Me-1-Piz)
2C-148COCH2CH2CH2N(CH3)2
2C-149COCH2CH2CH2-(1-Pyrd)
2C-150COCH2CH2COOH
Table of examples 3
Example No.LR
3-1 H
3-2P(=O)(OH)2
3-3H
3-4COCH3
3-5COCH2COOH
3-6P(=O)(OH)2
3-7H
3-8COCH3
3-9COCH2COOH
3-10P(=O)(OH)2
3-11H
3-12COCH3
3-13COCH2COOH
3-14H
3-15COCH3
3-16COCH2COOH
3-17H
3-18P(=O)(OH)2
3-19H
3-20P(=O)(OH)2
3-21H
3-22P(=O)(OH)2

In the tables above, the preferred groups are groups of examples No.: 1-1, 1-6, 1-7, 1-9, 1-10, 1-11, 1-12, 1-14, 1-15, 1-20, 1-21, 1-22, 1-23, 1-24, 1-25, 1-30, 1-35, 1-40, 1-42, 1-43, 1-44, 1-45, 1-46, 1-47, 1-52, 1-57, 1-61, 1-65, 1-69, 1-70, 1-75, 1-76, 1-78, 1-79, 1-80, 1-81, 1-83, 1-84, 1-89, 1-90, 1-91, 1-92, 1-93, 1-94, 1-99, 1-103, 2-1, 2-6, 2-7, 2-9, 2-10, 2-11, 2-12, 2-14, 2-15, 2-20, 2-21, 2-22, 2-23, 2-24, 2-25, 2-29, 2-31, 2-33, 2-35, 2-40, 2-45, 2-50, 2-61, 2-66, 2-72, 2-73, 2-74, 2-76, 2-77, 2-78, 2-80, 2-81, 2-82, 2-87, 2-88, 2-90, 2-91, 2-93, 2-94, 2-98, 2-100, 3-2, 3-4, 3-5, 3-6, 3-8, 3-9, 3-10, 3-12, 3-13, 3-15, 3-16, 3-18, 3-20, 3-22, 1A-1, 1A-2, 1A-3, 1A-6, 1A-7, 1A-9 1A-10 1A-12 1A-13 1A-14 1A-17, 1A-18, 1A-20 1A-21 1A-22, 1A-23, 1A-25, 1A-26, 1A-27, 1A-28, 1A-30, 1A-31 1A-32, 1A-33, 1A-35, 1A-36, 2A-1, 2A-2, 2A-3, 2A-4, 2A-5, 2A-6, 2A-7, 2A-8, 2A-9, 2A-20, 2A-21, 2A-22, 2A-23, 2A-24, 2A-25, 2A-26, 2A-27, 2A-28, 2A-38, 2A-39, 2A-40, 2A-57, 2A-105, 2A-106, 2A-107, 2A-108, 2A-109, 2A-110, 2A-111, 2A-112, 2A-113, 2A-114, 2A-115, 2A-116, 2A-117, 2A-118, 2A-119, 2A-120, 2A-131, 2A-132, 2A-133, 2A-134, 2A-135, 2A-136, 2A-137, 2A-138, 2A-139, 2A-149, 2A-150, 2A-151, 2A-168, 2B-6, 2B-7, 2B-9, 2B-10, 2B-11, 2B-14, 2B-3, 2B-24, 2B-26, 2B-27, 2B-28, 2B-31, 2B-40, 2B-41, 2B-43, 2B-44, 2B-45, 2B-48, 2B-57, 2B-58, 2B-60, 2B-61, 2B-62, 2B-65, 2B-74, 2B-75, 2B-77, 2B-78, 2B-79, 2B-82, 2B-92, 2B-93, 2B-94, 2B-96, 2B-97, 2B-98, 2B-101, 2B-128, 2B-146, 2B-147, 2B-148, 2B-149, 2B-150, 2B-151, 2B-154, 2B-163, 2B-164, 2B-166, 2B-171, 2C-3, 2C-7, 2C-12, 2C-18, 2C-22, 2C-27, 2C-33, 2C-37, 2C-42, 2C-48, 2C-52, 2C-57, 2C-78, 2C-82, 2C-87, 2C-97, 2C-102, 2C-112, 2C-117, 2C-127, 2C-132, 2C-142 and 2C-147.

More preferred groups are groups of examples No.: 1-7, 1-10, 1-15, 1-25, 1-30, 1-35, 1-40, 1-42, 1-47, 1-76, 1-79, 1-84, 1-94, 2-7, 2-10, 2-15, 2-25, 2-29, 2-31, 2-33, 2-35, 2-40, 2-45, 2-50, 2-61, 2-66, 2-87, 2-90, 2-100, 3-4, 3-6, 3-10, 3-12, 1A-9 1A-13, 2A-1, 2A-2, 2A-9, 2A-20, 2A-21, 2A-22, 2A-28, 2A-38, 2A-39, 2A-40, 2A-57, 2A-105, 2A-107, 2A-108, 2A-110, 2A-111, 2A-112, 2A-113, 2A-120, 2A-131, 2A-132, 2A-139, 2A-149, 2A-150, 2A-151, 2A-168, 2B-7, 2B-9, 2B-14, 2B-24, 2B-26, 2B 31, 2B-41, 2B-43, 2B-58, 2B-60, 2B-65, 2B-75, 2B-77, 2B-82, 2B-92, 2B-94, 2B-96, 2B-101, 2B-128, 2B-147, 2B-149, 2B-154, 2B-164, 2B-166 and 2B-171.

And even more preferred groups are groups of examples No.: 2-25, 2-29, 2A-9, 2A-28, 2A-38, 2A-120, 2A-139 and 2A-149.

The connection of the triazole according to the present invention includes, for example, compounds described in the Tables of examples 4, 4A, 5, 5A, 5B, 5C and 6, but the scope of the present invention is not limited to these compounds.

Table of examples 4
Example No.LR
4-1CH2CH2CH2H
4-2CH2CH2CH2 COCH3
4-3CH2CH2CH2COCH2NH2
4-4CH2CH2CH2COCH2COOH
4-5CH2CH2CH2COCH2CH2NH2
4-6CH2CH2CH2COCH2CH2COOH
4-7CH2CH2CH2COCH(CH3)NH2
4-8CH2CH2CH2COCH(CH3)COOH
4-9CH2CH2CH2COCH2CH2CH2NH2
4-10CH2CH2CH2COCH2CH2CH2COOH
4-11CH2CH2CH2COCH(NH2)COOH
4-12CH2CH2CH2COCH(NH2)CH2COOH
4-13CH2CH2CH2COCH2CH(NH2)COOH
4-14CH2CH2CH2COCH(NH2)CH2CH2COOH
4-15CH2CH2CH2COCH2CH2CH(NH2)COOH
4-16CH2CH2CH2P(=O)(OH)2
4-17CF2CH2CH2P(=O)(OH)2
4-18C(CH3)2CH2CH2P(=O)(OH)2
4-19CH2C(CH3)2CH2P(=O)(OH)2
4-20CH2CH2CH(COOH)COCH3
4-21CH2CH2CH(COOH)COCH2NH2
4-22CH2CH2CH(COOH)COCH2COOH
4-23CH2CH2CH(COOH)COCH2CH2COOH
4-24CH2CH2CH(COOH)COCH2CH2CH2COOH
4-25CH2CH2CH(COOH)P(=O)(OH)2
4-26CH2CH2CH2CH2P(=O)(OH)2
4-27CF2CH2CH2CH2P(=O)(OH)2
4-28C(CH3)2CH2CH2CH2P(=O)(OH)2
4-29CH2C(CH3)2CH2CH2 2
4-30CH2CH2C(CH3)2CH2P(=O)(OH)2
4-31OCH2CH2H
4-32OCH2CH2COCH2NH2
4-33OCH2CH2COCH2COOH
4-34OCH2CH2COCH2CH2NH2
4-35OCH2CH2COCH2CH2COOH
4-36OCH2CH2COCH(CH3)NH2
4-37OCH2CH2COCH(CH3)COOH
4-38OCH2CH2COCH2CH2CH2NH2
4-39OCH2CH2COCH2CH2CH2COOH
4-40OCH2CH2COCH(NH2)COOH
4-41OCH2CH2COCH(NH2)CH2COOH
4-42OCH2CH2COCH2CH(NH2)COOH
4-43OCH2CH2COCH(NH2)CH2CH2COOH
4-44 OCH2CH2COCH2CH2CH(NH2)COOH
4-45OCH2CH2P(=O)(OH)2
4-46OCH2CH2CH2P(=O)(OH)2
About 4-47OCH2C(CH3)2CH2P(=O)(OH)2
4-48CH2CH2CH(CH2N(C2H5)2)H
4-49CH2CH2CH(CH2N(C2H5)2)COCH3
4-50CH2CH2CH(CH2N(C2H5)2)P(=O)(OH)2
Table of examples 4A
Example No.LR
4A-1CH2H
4A-2CH2COCH2CH2COOH
4A-3CH2P(=O)(OH)2
4A-4CH2CH2CH2COCH2NHCH3
4A-5CH2CH2CH2COCH2N(CH3)2
4A-6CH2CH2 CH2COCH2-(4-Me-1-Piz)
4A-7CH2CH2CH2COCH2CH2N(CH3)2
4A-8CH2CH2CH2COCH2CH2-(4-Me-1-Piz)
4A-9CH2CH2CH2COCH2CH2CO-(4-Me-1-Piz)
4A-10CH2CH2CH2COCH2CH2CH2N(CH3)2
4A-11OCH2CH2COCH2NHCH3
4A-12OCH2CH2COCH2N(CH3)2
4A-13OCH2CH2COCH2-(4-Me-1-Piz)
4A-14OCH2CH2COCH2CH2CO-(4-Me-1-Piz)
Table of examples 5
Example No.LR
5-1H
5-2COCH2NH2
5-3COCH2COOH
5-4COCH2C 2NH2
5-5COCH2CH2COOH
5-6COCH(CH3)NH2
5-7COCH(CH3)COOH
5-8COCH2CH2CH2NH2
5-9COCH2CH2CH2COOH
5-10COCH(NH2)COOH
5-11COCH(NH2)CH2COOH
5-12COCH2CH(NH2)COOH
5-13COCH(NH2)CH2CH2COOH
5-14COCH2CH2CH(NH2)COOH
5-15P(=O)(OH)2
5-16P(=O)(OH)2
5-17P(=O)(OH)2
5-18P(=O)(OH)2
5-19P(=O)(OH)2
5-20 P(=O)(OH)2
5-21P(=O)(OH)2
5-22P(=O)(OH)2
5-23P(=O)(OH)2
5-24P(=O)(OH)2
5-25COCH3
5-26COCH2COOH
5-27P(=O)(OH)2
5-28COCH3
5-29COCH2COOH
5-30P(=O)(OH)2
5-31COCH3
5-32COCH2COOH
5-33P(=O)(OH)2
5-34COCH3
5-35COCH2COOH
5-36 COCH3
5-37COCH2COOH
5-38COCH3
5-39COCH2COOH
5-40P(=O)(OH)2
5-41P(=O)(OH)2
5-42P(=O)(OH)2
5-43P(=O)(OH)2
5-44P(=O)(OH)2
5-45P(=O)(OH)2

td align="center"> 5A-39td align="center" namest="c0" nameend="c1"> 5C-29
Table of examples 5A
Example No.LR
5A-1COCH2NHCH3
5A-2COCH2N(CH3)2
5A-3COCH2-(1-Azt)
5A-4COCH2-(1-Pyrd)
5A-5COCH2-(1-Pip)
5A-6COCH2-(1-Azp)
5A-7COCH2Mor
5A-8COCH2Thz
5A-9COCH2-(4-Me-1-Piz)
5A-10COCH2CO-(4-Me-1-Piz)
5A-11COCH2CH2NHCH3
5A-12COCH2CH2N(CH3)2
5A-13COCH2CH2-(1-Azt)
5A-14COCH2CH2-(1-Pyrd)
5A-15COCH2CH2-(1-Pi)
5A-16COCH2CH2-(1-Azp)
5A-17COCH2CH2Mor
5A-18COCH2CH2Thz
5A-19COCH2CH2-(4-Me-1-Piz)
5A-20COCH2CH2CO-(4-Me-1-Piz)
5A-21COCH2CH2CH2NHCH3
5A-22COCH2CH2CH2N(CH3)2
5A-23COCH2CH2CH2-(1-Azt)
5A-24COCH2CH2CH2-(1-Pyrd)
5A-25COCH2CH2CH2-(1-Pip)
5A-26COCH2CH2CH2-(1-Azp)
5A-275A-28COCH2CH2CH2Thz
5A-29COCH2CH2CH2-(4-Me-1-Piz)
5A-30COCH2CH2CH2CO-(4-Me-1-Piz)
5A-31COCH(CH3)NHCH3
5A-32COCH(CH3)NH(CH3)2
5A-33COC(CH3)2NHCH3
5A-34COC(CH3)2N(CH3)2
5A-35COCH[N(CH3)2]CON(CH3)2
5A-36COCH[N(CH3)2]CO-(1-Azt)
5A-37COCH[N(CH3)2]CO-(1-Pyrd)
5A-38COCH[N(CH3)2]CO-(1-Pip)
COCH[N(CH3)2]CO-(1-Azp)
5A-40COCH[N(CH3)2]COMor
5A-41COCH[N(CH3)2]COThz
5A-42COCH[N(CH3)2]CO-(4-Me-1-Piz)
5A-43COCH[N(CH3)2]CH2CON(CH3)2
5A-44COCH[N(CH3)2]CH2CO-(1-Azt)
5A-45COCH[N(CH3)2]CH2CO-(1-Pyrd)
5A-46COCH[N(CH3)2]CH2CO-(1-Pip)
5A-47COCH[N(CH3)2]CH2CO-(1-Azp)
5A-48COCH[N(CH3)2]CH2COMor
5A-49COCH[N(CH3)2]CH2COThz
5A-50 COCH[N(CH3)2]CH2CO-(4-Me-1-Piz)
5A-51COCH2CH[N(CH3)2]CON(CH3)2
5A-52COCH2CH[N(CH3)2]CO-(1-Azt)
5A-53COCH2CH[N(CH3)2]CO-(1-Pyrd)
5A-54COCH2CH[N(CH3)2]CO-(1-Pip)
5A-55COCH2CH[N(CH3)2]CO-(1-Azp)
5A-56COCH2CH[N(CH3)2]COMor
5A-57COCH2CH[N(CH3)2]COThz
5A-58COCH2CH[N(CH3)2]CO-(4-Me-1-Piz)
5A-59COCH[N(CH3)2]CH2CH2CON(CH3)2
5A-60COCH[N(CH3)2]CH2CH2CO-(1-Azt)
5A-61COCH[N(CH3)2]CH2CH2CO-(1-Pyrd)
5A-62COCH[N(CH3)2]CH2CH2CO-(1-Pip)
5A-63COCH[N(CH3)2]CH2CH2CO-(1-Azp)
5A-64COCH[N(CH3)2]CH2CH2COMor
5A-65COCH[N(CH3)2]CH2CH2COThz
5A-66COCH[N(CH3)2]CH2CH2CO-(4-Me-1-Piz)
5A-67COCH2CH2CH[N(CH3)2]CON(CH3)2
5A-68COCH2CH2CH[N(CH3)2]CO-(1-Azt)
5A-69COCH2CH2CH[N(CH3)2]CO-(1-Pyrd)
5A-70COCH2CH2CH[N(CH3)2]CO-(1-Pip)
5A-71COCH 2CH2CH[N(CH3)2]CO-(1-Azp)
5A-72COCH2CH2CH[N(CH3)2]COMor
5A-73COCH2CH2CH[N(CH3)2]COThz
5A-74COCH2CH2CH[N(CH3)2]CO-(4-Me-1-Piz)
5A-75H
5A-76CONH2
5A-77C(=O)COOH
5A-78COCH2OH
5A-79COCH2NH2
5A-80COCH2COOH
5A-81COCH2CH2NH2
5A-82COCH2CH2COOH
5A-83COCH2CH2CH 2OH
5A-84COCH2CH2CH2NH2
5A-85COCH2CH2CH2COOH
5A-86COCH2NHCH3
5A-87COCH2N(CH3)2
5A-88COCH2-(1-Azt)
5A-89COCH2-(1-Pyrd)
5A-90COCH2-(1-Pip)
5A-91COCH2-(1-Azp)
5A-92COCH2Mor
5A-93COCH2Thz
5A-94COCH2-(4-Me-1-Piz)
5A-95COCH2CO-(4-Me-1-Piz)
5A-96COCH2 CH2NHCH3
5A-97COCH2CH2N(CH3)2
5A-98COCH2CH2-(1-Azt)
5A-99COCH2CH2-(1-Pyrd)
5A-100COCH2CH2-(1-Pip)
5A-101COCH2CH2-(1-Azp)
5A-102COCH2CH2Mor
5A-103COCH2CH2Thz
5A-104COCH2CH2-(4-Me-1-Piz)
5A-105COCH2CH2CO-(4-Me-1-Piz)
5A-106COCH2CH2CH2NHCH3
5A-107COCH2CH2CH2N(CH3)2
5A-108 COCH2CH2CH2-(1-Azt)
5A-109COCH2CH2CH2-(1-Pyrd)
5A-110COCH2CH2CH2-(1-Pip)
5A-111COCH2CH2CH2-(1-Azp)
5A-112COCH2CH2CH2Mor
5A-113COCH2CH2CH2Thz
5A-114COCH2CH2CH2-(4-Me-1-Piz)
5A-115COCH2CH2CH2CO-(4-Me-1-Piz)
5A-116COCH(CH3)NHCH3
5A-117COCH(CH3)NH(CH3)2
5A-118COC(CH3)2NHCH3
5A-119COC(CH3)2N(CH3)2
5A-120COCH[N(CH3)2]CON(CH3)2
5A-121COCH[N(CH3)2]CO-(1-Azt)
5A-122COCH[N(CH3)2]CO-(1-Pyrd)
5A-123COCH[N(CH3)2]CO-(1-Pip)
5A-124COCH[N(CH3)2]CO-(1-Azp)
5A-125COCH[N(CH3)2]COMor
5A-126COCH[N(CH3)2]COThz
5A-127COCH[N(CH3)2]CO-(4-Me-1-Piz)
5A-128COCH[N(CH3)2]CH2CON(CH3)2
5A-129COCH[N(CH3)2]CH2CO-(1-Azt)
5A-130COCH[N(CH3)2]CH2CO-(1-Pyrd)
5A-131#8243; COCH[N(CH3)2]CH2CO-(1-Pip)
5A-132COCH[N(CH3)2]CH2CO-(1-Azp)
5A-133COCH[N(CH3)2]CH2COMor
5A-134COCH[N(CH3)2]CH2COThz
5A-135COCH[N(CH3)2]CH2CO-(4-Me-1-Piz)
5A-136COCH2CH[N(CH3)2]CON(CH3)2
5A-137COCH2CH[N(CH3)2]CO-(1-Azt)
5A-138COCH2CH[N(CH3)2]CO-(1-Pyrd)
5A-139COCH2CH[N(CH3)2]CO-(1-Pip)
5A-140COCH2CH[N(CH3)2]CO-(1-Azp)
5A-141COCH2CH[N(CH3)2]COMor
5A-142̷ COCH2CH[N(CH3)2]COThz
5A-143COCH2CH[N(CH3)2]CO-(4-Me-1-Piz)
5A-144COCH[N(CH3)2]CH2CH2CON(CH3)2
5A-145COCH[N(CH3)2]CH2CH2CO-(1-Azt)
5A-146COCH[N(CH3)2]CH2CH2CO-(1-Pyrd)
5A-147COCH[N(CH3)2]CH2CH2CO-(1-Pip)
5A-148COCH[N(CH3)2]CH2CH2CO-(1-Azp)
5A-149COCH[N(CH3)2]CH2CH2COMor
5A-150COCH[N(CH3)2]CH2CH2COThz
5A-151COCH[N(CH3)2]CH2CH2CO-(4-Me-1-Piz)
5A-152COCH2CH2 CH[N(CH3)2]CON(CH3)2
5A-153COCH2CH2CH[N(CH3)2]CO-(1-Azt)
5A-154COCH2CH2CH[N(CH3)2]CO-(1-Pyrd)
5A-155COCH2CH2CH[N(CH3)2]CO-(1-Pip)
5A-156COCH2CH2CH[N(CH3)2]CO-(1-Azp)
5A-157COCH2CH2CH[N(CH3)2]COMor
5A-158COCH2CH2CH[N(CH3)2]COThz
5A-159COCH2CH2CH[N(CH3)2]CO-(4-Me-1-Piz)
Table of examples 5B
Example No.LR
5B-1C(=O)COOH
5B-2 COCH2NH2
5B-3COCH2CH2NH2
5B-4COCH2CH2CH2NH2
5B-5COCH2CH2COOH
5B-6COCH2NHCH3
5B-7COCH2N(CH3)2
5B-8COCH2-(1-Pyrd)
5B-9COCH2-(4-Me-1-Piz)
5B-10COCH2CH2NHCH3
5B-11COCH2CH2N(CH3)2
5B-12COCH2CH2-(1-Pyrd)
5B-13COCH2CH2-(4-Me-1-Piz)
5B-14COCH2CH2CO-(4-Me-1-Piz)
5B-15COCH2CH2CH2N(CH3)2
5B-16COCH2CH2CH2-(1-Pyrd)
5B-17COCH2CH2CH2-(4-Me-1-Piz)
5B-18C(=O)COOH
5B-19COCH2NH2
5B-20COCH2CH2NH2
5B-21COCH2CH2CH2NH2
5B-22COCH2CH2COOH
5B-23COCH2NHCH3
5B-24COCH2N(CH3)2
5B-25COCH2-(1-Pyrd)
5B-26COCH2-(4-Me-1-Piz)
5B-27COCH2CH2NHCH3
5B-28COCH2CH2N(CH3)2
5B-29COCH2CH2-(1-Pyrd)
5B-30COCH2CH2-(4-Me-1-Piz)
5B-31COCH2CH2CO-(4-Me-1-Piz)
5B-32COCH2CH2CH2N(CH3)2
5B-33COCH2CH2CH2-(1-Pyrd)
5B-34COCH2CH2CH2-(4-Me-1-Piz)
5B-35C(=O)COOH
5B-36COCH2NH2
5B-37COCH2CH2NH2
5B-38 COCH2CH2CH2NH2
5B-39COCH2CH2COOH
5B-40COCH2NHCH3
5B-41COCH2N(CH3)2
5B-42COCH2-(1-Pyrd)
5B-43COCH2-(4-Me-1-Piz)
5B-44COCH2CH2NHCH3
5B-45COCH2CH2N(CH3)2
5B-46COCH2CH2-(1-Pyrd)
5B-47COCH2CH2-(4-Me-1-Piz)
5B-48COCH2CH2CO-(4-Me-1-Piz)
5B-49COCH2CH2CH2N(CH3)2
5B-50 2CH2CH2-(1-Pyrd)
5B-51COCH2CH2CH2-(4-Me-1-Piz)
5B-52C(=O)COOH
5B-53COCH2NH2
5B-54COCH2CH2NH2
5B-55COCH2CH2CH2NH2
5B-56COCH2CH2COOH
5B-57COCH2NHCH3
5B-58COCH2N(CH3)2
5B-59COCH2-(1-Pyrd)
5B-60COCH2-(4-Me-1-Piz)
5B-61COCH2CH2NHCH3
5B-62COCH2CH2N(CH 3)2
5B-63COCH2CH2-(1-Pyrd)
5B-64COCH2CH2-(4-Me-1-Piz)
5B-65COCH2CH2CO-(4-Me-1-Piz)
5B-66COCH2CH2CH2N(CH3)2
5B-67COCH2CH2CH2-(1-Pyrd)
5B-68COCH2CH2CH2-(4-Me-1-Piz)
5B-69C(=O)COOH
5B-70COCH2NH2
5B-71COCH2CH2NH2
5B-72COCH2CH2CH2NH2
5B-73COCH2CH2COOH
5B-74 COCH2NHCH3
5B-75COCH2N(CH3)2
5B-76COCH2-(1-Pyrd)
5B-77COCH2-(4-Me-1-Piz)
5B-78COCH2CH2NHCH3
5B-79COCH2CH2N(CH3)2
5B-80COCH2CH2-(1-Pyrd)
5B-81COCH2CH2-(4-Me-1-Piz)
5B-82COCH2CH2CO-(4-Me-1-Piz)
5B-83COCH2CH2CH2N(CH3)2
5B-84COCH2CH2CH2-(1-Pyrd)
5B-85COCH2CH2CH2-(4-Me-1-Piz)
5B-86 H
5B-87C(=O)COOH
5B-88COCH2NH2
5B-89COCH2CH2NH2
5B-90COCH2CH2CH2NH2
5B-91COCH2CH2COOH
5B-92P(=O)(OH)2
5B-93COCH2NHCH3
5B-94COCH2N(CH3)2
5B-95COCH2-(1-Pyrd)
5B-96COCH2-(4-Me-1-Piz)
5B-97COCH2CH2NHCH3
5B-98COCH2CH2N(CH3)2
5B-99 COCH2CH2-(1-Pyrd)
5B-100COCH2CH2-(4-Me-1-Piz)
5B-101COCH2CH2CO-(4-Me-1-Piz)
5B-102COCH2CH2CH2N(CH3)2
5B-103COCH2CH2CH2-(1-Pyrd)
5B-104COCH2CH2CH2-(4-Me-1-Piz)
5B-105C(=O)COOH
5B-106COCH2NH2
5B-107COCH2CH2NH2
5B-108COCH2CH2CH2NH2
5B-109COCH2CH2COOH
5B-110COCH2NHCH3
5B-111COCH2N(CH3)2
5B-112COCH2-(1-Pyrd)
5B-113COCH2-(4-Me-1-Piz)
5B-114COCH2CH2NHCH3
5B-115COCH2CH2N(CH3)2
5B-116COCH2CH2-(1-Pyrd)
5B-117COCH2CH2-(4-Me-1-Piz)
5B-118COCH2CH2CO-(4-Me-1-Piz)
5B-119COCH2CH2CH2N(CH3)2
5B-120COCH2CH2CH2-(1-Pyrd)
5B-121COCH2CH2CH2-(4-Me-1-Piz)
5B-122 H
5B-123C(=O)COOH
5B-124COCH2NH2
5B-125COCH2CH2NH2
5B-126COCH2CH2CH2NH2
5B-127COCH2CH2COOH
5B-128P(=O)(OH)2
5B-129COCH2NHCH3
5B-130COCH2N(CH3)2
5B-131COCH2-(1-Pyrd)
5B-132COCH2-(4-Me-1-Piz)
5B-133COCH2CH2NHCH3
5B-134COCH2CH2N(CH3)2
5B-135COCH2CH2-(1-Pyrd)
5B-136COCH2CH2-(4-Me-1-Piz)
5B-137COCH2CH2CO-(4-Me-1-Piz)
5B-138COCH2CH2CH2N(CH3)2
5B-139COCH2CH2CH2-(1-Pyrd)
5B-140COCH2CH2CH2-(4-Me-1-Piz)
5B-141C(=O)COOH
5B-142COCH2NH2
5B-143COCH2CH2NH2
5B-144COCH2CH2CH2NH2
5B-145COCH2CH2COOH
5B-146COCH2NHCH3
5B-147 COCH2N(CH3)2
5B-148COCH2-(1-Pyrd)
5B-149COCH2-(4-Me-1-Piz)
5B-150COCH2CH2NHCH3
5B-151COCH2CH2N(CH3)2
5B-152COCH2CH2-(1-Pyrd)
5B-153COCH2CH2-(4-Me-1-Piz)
5B-154COCH2CH2CO-(4-Me-1-Piz)
5B-155COCH2CH2CH2N(CH3)2
5B-156COCH2CH2CH2-(1-Pyrd)
5B-157COCH2CH2CH2-(4-Me-1-Piz)
5B-158C(=OCOOH
5B-159COCH2NH2
5B-160COCH2CH2NH2
5B-161COCH2CH2CH2NH2
5B-162COCH2CH2COOH
5B-163COCH2NHCH3
5B-164COCH2N(CH3)2
5B-165COCH2-(1-Pyrd)
5B-166COCH2-(4-Me-1-Piz)
5B-167COCH2CH2NHCH3
5B-168COCH2CH2N(CH3)2
5B-169COCH2CH2-(1-Pyrd)
5B-170COCH2CH2-(4-Me-1-Piz)
5B171 COCH2CH2CO-(4-Me-1-Piz)
5B-172COCH2CH2CH2N(CH3)2
5B-173COCH2CH2CH2-(1-Pyrd)
5B is 174COCH2CH2CH2-(4-Me-1-Piz)
Table of examples 5C
Example No.LR
5C-1H
5C-2COCH2NH2
5C-3P(=O)(OH)2
5C-4COCH2NHCH3
5C-5COCH2N(CH3)2
5C-6COCH2-(1-Pyrd)
5C-7COCH2-(4-Me-1-Piz)
5C-8COCH2CH2NHCH3
5C-9COCH2CH2N(CH3)2
5C-10COCH2CH2-(1-Pyrd)
5C-11COCH2CH2-(4-Me-1-Piz)
5C-12COCH2CH2CO-(4-Me-1-Piz)
5C-13COCH2CH2CH2N(CH3)2
5C-14COCH2CH2CH2-(1-Pyrd)
5C-15COCH2CH2COOH
5C-16H
5C-17COCH2NH2
5C-18P(=O)(OH)2
5C-19COCH2NHCH3
5C-20COCH2N(CH3)2
5C-21COCH2-(1-Pyrd)
5C-22COCH2-(4-Me-1-Piz)
5C-23COCH2CH2NHCH3
5C-24COCH2CH2N(CH3)2
5C-25COCH2CH2-(1-Pyrd)
5C-26COCH2CH2-(4-Me-1-Piz)
5C-27COCH2CH2CO-(4-Me-1-Piz)
5C-28COCH2CH2CH2N(CH3)2
COCH2CH2CH2-(1-Pyrd)
5C-30COCH2CH2COOH
5C-31H
5C-32COCH2NH2
5C-33P(=O)(OH)2
5C-34COCH2NHCH3
5C-35COCH2N(CH3)2
5C-36COCH2-(1-Pyrd)
5C-37COCH2-(4-Me-1-Piz)
5C-38COCH2CH2NHCH3
5C-39COCH2CH2N(CH3)2
5C-40COCH2CH2-(1-Pyrd)
5C-41COCH2CH2-(4-Me-1-Piz)
5C-42COCH2CH2CO-(4-Me-1-Piz)
5C-43COCH2CH2CH2N(CH3)2
5C-44COCH2CH2CH2-(1-Pyrd)
5C-45COCH2CH2COOH
5C-46H
5C-47COCH2NH2
5C-48P(=O)(OH)2
5C-49COCH2NHCH3
5C-50COCH2N(CH3)2
5C-51COCH2-(1-Pyrd)
5C-52COCH2-(4-Me-1-Piz)
5C-53COCH2CH2NHCH3
5C-54COCH2CH2N(CH3)2
5C-55COCH2CH2-(1-Pyrd)
5C-56COCH2CH2-(4-Me-1-Piz)
5C-57COCH2CH2CO-(4-Me-1-Piz)
5C-58COCH2CH2CH2N(CH3)2
5C-59COCH2CH2CH2-(1-Pyrd)
5C-60COCH2CH2COOH
5C-61 H
5C-62COCH2NH2
5C-63P(=O)(OH)2
5C-64COCH2NHCH3
5C-65COCH2N(CH3)2
5C-66COCH2-(1-Pyrd)
5C-67COCH2-(4-Me-1-Piz)
5C-68COCH2CH2NHCH3
5C-69COCH2CH2N(CH3)2
5C-70COCH2CH2-(1-Pyrd)
5C-71COCH2CH2-(4-Me-1-Piz)
5C-72 COCH2CH2CO-(4-Me-1-Piz)
5C-73COCH2CH2CH2N(CH3)2
5C-74COCH2CH2CH2-(1-Pyrd)
5C-75COCH2CH2COOH
5C-76H
5C-77COCH2NH2
5C-78P(=O)(OH)2
5C-79COCH2NHCH3
5C-80COCH2N(CH3)2
5C-81COCH2-(1-Pyrd)
5C-82COCH2-(4-Me-1-Piz)
5C-83 COCH2CH2NHCH3
5C-84COCH2CH2N(CH3)2
5C-85COCH2CH2-(1-Pyrd)
5C-86COCH2CH2-(4-Me-1-Piz)
5C-87COCH2CH2CO-(4-Me-1-Piz)
5C-88COCH2CH2CH2N(CH3)2
5C-89COCH2CH2CH2-(1-Pyrd)
5C-90COCH2CH2COOH
5C-91H
5C-92COCH2NH2
5C-93P(=O)(OH)2
5C-94COCH2NHCH3
5C-95COCH2N(CH3)2
5C-96COCH2-(1-Pyrd)
5C-97COCH2-(4-Me-1-Piz)
5C-98COCH2CH2NHCH3
5C-99COCH2CH2N(CH3)2
5C-100COCH2CH2-(1-Pyrd)
5C-101COCH2CH2-(4-Me-1-Piz)
5C-102COCH2CH2CO-(4-Me-1-Piz)
5C-103COCH2CH2CH2N(CH3)2
5C-104COCH2CH2CH2-(1-Pyrd)
5C-105COCH2CH2COOH
5C-106H
5C-107COCH2NH2
5C-108P(=O)(OH)2
5C-109COCH2NHCH3
5C-110COCH2N(CH3)2
5C-111COCH2-(1-Pyrd)
5C-112COCH2-(4-Me-1-Piz)
5C-113COCH2CH2NHCH3
5C-114COCH2CH2N(CH3)2
5C-115COCH2CH2-(1-Pyrd)
5-116 COCH2CH2-(4-Me-1-Piz)
5C-117COCH2CH2CO-(4-Me-1-Piz)
5C-118COCH2CH2CH2N(CH3)2
5C-119COCH2CH2CH2-(1-Pyrd)
5C-120COCH2CH2COOH
5C-121H
5C-122COCH2NH2
5C-123P(=O)(OH)2
5C-124COCH2NHCH3
5C-125COCH2N(CH3)2
5C-126COCH2-(1-Pyrd)
5C-127COCH2-(4-Me-1-Piz)
5C-128COCH2CH2NHCH3
5C-129COCH2CH2N(CH3)2
5C-130COCH2CH2-(1-Pyrd)
5C-131COCH2CH2-(4-Me-1-Piz)
5C-132COCH2CH2CO-(4-Me-1-Piz)
5C-133COCH2CH2CH2N(CH3)2
5C-134COCH2CH2CH2-(1-Pyrd)
5C-135COCH2CH2COOH
5C-136H
5C-137 COCH2NH2
5C-138P(=O)(OH)2
5C-139COCH2NHCH3
5C-140COCH2N(CH3)2
5C-141COCH2-(1-Pyrd)
5C-142COCH2-(4-Me-1-Piz)
5C-143COCH2CH2NHCH3
5C-144COCH2CH2N(CH3)2
5C-145COCH2CH2-(1-Pyrd)
5C-146COCH2CH2-(4-Me-1-Piz)
5C-147COCH2CH2CO-(4-Me-1-Piz)
5C-148 COCH2CH2CH2N(CH3)2
5C-149COCH2CH2CH2-(1-Pyrd)
5C-150COCH2CH2COOH
Table of examples 6
Example No.LR
6-1P(=O)(OH)2
6-2COCH3
6-3COCH2COOH
6-4P(=O)(OH)2
6-5COCH3
6-6COCH2COOH
6-7P(=O)(OH)2
6-8 COCH3
6-9COCH2COOH
6-10COCH3
6-11COCH2COOH
6-12P(=O)(OH)2
6-13P(=O)(OH)2
6-14P(=O)(OH)2

In the tables above, the preferred compounds are the compounds of examples No.: 4-3, 4-4, 4-5, 4-9, 4-15, 4-16, 4-17, 4-18, 4-19, 4-24, 4-32, 4-33, 4-34, 4-38, 4-44, 4-45, 5-2, 5-3, 5-5, 5-8, 5-9, 5-15, 5-16, 5-17, 5-18, 5-19, 5-20, 5-21, 5-22, 5-23, 5-24, 5-34, 5-36, 5-41, 5-45, 6-2, 6-4, 6-7, 6-8, 4A-6 4A-9, 5A-1, 5A-2, 5A-9, 5A-11, 5A-12, 5A-19, 5A-20, 5A-21, 5A-22, 5A-29, 5A-30, 5A-79, 5A-82, 5A-84, 5A-85, 5A-86, 5A-87, 5A-94, 5A-96, 5A-97, 5A-104, 5A-105, 5A-106, 5A-107, 5A-114, 5A-115, 5B-9, 5B-15, 5B-26, 5B-31, 5B-43, 5B-48, 5B-60, 5B-65, 5B-77, 5B-82, 5B-92, 5B-96, 5B-101, 5B-113, 5B-118, 5B-128, 5B-132, 5B-137, 5B-149, 5B-154, 5B-166, 5B-171, 5C-3, 5C-7, 5C-12, 5C-18, 5C-22, 5C-27, 5C-33, 5C-37, 5C-42, 5C-48, 5C-52, 5C-57, 5C-63, 5C-67, 5C-72, 5C-78, 5C-82, 5C-87, 5C-93, 5C-97, 5C-102, 5C-108, 5C-112, 5C-117, 5C-123, 5C-127, 5C-132, 5C-138, 5C-142 and 5C-147.

Even more preferred compounds are : is:

Example No. 4-16: 4-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-4-oxobutyl dihydrophosphate.

Example No. 4-19: 4-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-2,2-dimethyl-4-oxobutyl dihydrophosphate.

Example No. 5-15: 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]benzyl dihydrophosphate.

Example No. 5-16: 4-cyano-2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]benzyl dihydrophosphate.

Example No. 5-20: 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-4-terbisil dihydrophosphate.

Example No. 5-21: 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-5-terbisil dihydrophosphate.

Example No. 5-22: 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-6-terbisil dihydrophosphate.

Example No. 5-23: 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-boutade the Nile]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-6-methylbenzyl dihydrophosphate.

Example No. 5-24: 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-6-methoxybenzyl dihydrophosphate.

Example No. 5-41: [8-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-1-naphthyl]methyl dihydrophosphate.

Example No. 5-45: 2-chloro-6-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]benzyl dihydrophosphate.

Example No. 4A-6: (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 4-[2-(4-methyl-1-piperazinil)acetoxy]butyrate.

Example No. 4A-9: (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 4-[[4-(4-methyl-1-piperazinil)-4-oxobutyryl]oxy]butyrate.

Example No. 5A-1: (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[2-(N-methylamino)acetoxy]methyl]benzoate.

Example No. 5A-2: (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[2-(N,N-dimethylamino)acetoxy]methyl]benzoate.

Example No. 5A-9: (1R,2R)-2-[[TRANS-2-[(1E,3E)4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[2-(4-methyl-1-piperazinil)acetoxy]methyl]benzoate.

Example No. 5A-11: (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[3-(N-methylamino)propanol]oxymethyl]benzoate.

Example No. 5A-12: (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[3-(N,N-dimethylamino)propionyl]oxymethyl]benzoate.

Example No. 5A-19: (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[3-(4-methyl-1-piperazinil)propionyl]oxymethyl]benzoate.

Example No. 5A-20: (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[4-(4-methyl-1-piperazinil)-4-oxobutyryl]oxymethyl]benzoate.

Example No. 5A-21: (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[4-(N-methylamino)butyryl]oxymethyl]benzoate.

Example No. 5A-22: (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[4-(N,N-dimethylamino)butyryl]oxymethyl]benzoate.

Example No. 5A-86: (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-[[2-(N-methylamino)acetoxy]methyl]benzo is at.

Example No. 5A-87: (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-[[2-(N,N-dimethylamino)acetoxy]methyl]benzoate.

Example No. 5A-94: (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-[[2-(4-methyl-1-piperazinil)acetoxy]methyl]benzoate.

Example No. 5A-96: (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-[[3-(N-methylamino)propanol]oxymethyl]benzoate.

Example No. 5A-97: (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-[[3-(N,N-dimethylamino)propanol]oxymethyl]benzoate.

Example No. 5A-104: (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-[[3-(4-methyl-1-piperazinil)propanol]oxymethyl]benzoate.

Example No. 5A-105: (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-[[4-(4-methyl-1-piperazinil)-4-oxobutyryl]oxymethyl]benzoate.

Example No. 5A-106: (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]prop is l 5-cyano-2-[[4-(N-methylamino)butyryl]oxymethyl]benzoate and

Example No. 5A-107: (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-[[4-(N,N-dimethylamino)butyryl]oxymethyl]benzoate.

Compounds of General formula (I) according to the present invention can be obtained in accordance with the methods described below.

[Method A]

Method A is a method of obtaining the compounds (Ia) [compounds (Ia) are compounds of General formula (I) according to the present invention, where Larepresents a simple bond, C6-C10aryl group, which optionally can be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies α, heterocyclic group which optionally may be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies αor C3-C7cycloalkyl group, which optionally can be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies αand R represents a C1-C6alkanoyloxy group, which optionally can be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies β, a group of the formula-C(O)-NR2R3 (R 2and R3independently represent a hydrogen atom or a C1-C6alkyl group, or R2and R3together with the nitrogen atom to which they are bound, form a 4-7-membered heterocyclic group containing the atom(s) of nitrogen) or-P(=O)(OH)2group], and the reaction scheme is shown below.

In above reaction scheme, X is as defined above, L1such as defined above for L (assuming Lanot an atom of oxygen), R#such as defined above for R (provided that R is not a hydrogen atom), and Pg1is carboxyl-protective group.

In this case, the protective group Pg1is a protective group of the ester type, conventionally used in organic synthesis for the protection of carboxylic acids (examples of such groups are described in T.W.Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)).

There are no specific limitations regarding the nature of such a protective group, provided that when the group R#enter on alcohol hydroxy-group of the compound (2) phase A-2, a protective group is not removed, but when execute the removal of the protective group stage A-3, the removal of the protective group can be performed without any damage to the connection (3). Examples of protective groups include: long is correctly substituted C 1-C10alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, 1-ethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, heptyl, octyl, nonyl, decyl, methoxymethyl, methylthiomethyl, 2-(trimethylsilyl)ethoxymethyl, carbamoylmethyl, N-phthalimidomethyl, trichlorethyl, chloroethyl, chlorbutol, chloropentyl, 2-(trimethylsilyl)ethyl, methylthioethyl, 2-(diphenylphosphino)ethyl, 2-(p-nitrobenzylidene)ethyl or 2-(p-toluensulfonyl)ethyl; optionally substituted C3-C10alkenylphenol group, such as allyl, cinnamyl or 3-butene-1-yl; optionally substituted C3-C10cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, cyclooctyl, cyclonona or cyclodecyl; optionally substituted C4-C10cycloalkylcarbonyl group, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclononylmethyl, cyclobutylmethyl, (cyclopropyl)ethyl, (cyclobutyl)ethyl, (cyclopentyl)ethyl (cyclohexyl)ethyl, (cycloheptyl)ethyl or (cyclooctyl)ethyl; optionally substituted C6-C10aryl group such as phenyl, tolyl or naphthyl; optionally substituted heterocyclic group such as tetrahydropyranyl, tetrahydrofuranyl or pyridyl; optionally substituted C7-C19aracelio group, such as benzyl, phenethyl, 3-phenylpropyl, 1-methyl-1-phenylethyl, benzhydryl, trityl, fluorenyl, fluorenylmethyl, 9-antimetal, trimethylbenzyl, bromobenzyl, nitrobenzyl, methoxybenzyl or dimethoxybenzyl; C1-C4alkyl group which is substituted heterocyclic(their) group(s), such as (1,3-dition-2-yl)methyl, pyridylmethyl or 2-(2′-pyridyl)ethyl; (C7-C11aralkyl)oxymethylene group, such as benzoyloxymethyl, penetrometer or naphthalocyanines; (substituted)arylcarbamoyl group, such as pencil; optionally substituted 1-(acyloxy)methyl group, such as acetoxymethyl, 1-(acetoxy)ethyl or pivaloyloxymethyl; or a silyl group which is substituted C1-C6alkyl group(s) or phenyl group(s), such as trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, isopropylimidazole, phenyldimethylsilane, tert-butyldiphenylsilyl or di(tert-butyl)methylsilyl.

Of these groups, preferred are methyl, ethyl, propyl, isopropyl, tert-butyl, methoxymethyl, methylthiomethyl, 2-(trimethylsilyl)ethoxymethyl, trichlorethyl, chloroethyl, 2-(trimethylsilyl)ethyl, allyl, cyclohexyl, phenyl, benzyl, benzhydryl, trityl, fluorenyl, Fluor is ylmethyl, bromobenzyl, nitrobenzyl, methoxybenzyl, benzoyloxymethyl, pivaloyloxymethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, isopropylimidazole, phenyldimethylsilane, tert-butyldiphenylsilyl or di(tert-butyl)methylsilyl, the preferred groups are methyl, ethyl, tert-butyl, methoxymethyl, methylthiomethyl, 2-(trimethylsilyl)ethoxymethyl, trichlorethyl, chloroethyl, allyl, phenyl, benzyl, benzhydryl, trityl, nitrobenzyl, methoxybenzyl, benzoyloxymethyl, pivaloyloxymethyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, isopropylideneglycerol or tert-butyldiphenylsilyl, even more preferred groups are 2-(trimethylsilyl)ethoxymethyl, benzyl, 4-methoxybenzyl, benzhydryl or pivaloyloxymethyl group, and most preferred group is a 4-methoxybenzyl.

The method involves first obtaining carboxyl-secure connection (2) protection of carboxypropyl hydroxycarboxylic acid (1) Phase A-1), then, obtaining the compounds (3) the introduction of the group R#in the compound (2) Phase A-2), then getting carboxylic acid (4) removing the protection connection (3) Phase A-3) and, finally, obtaining the compound (Ia) esterification of carboxylic acids (4) alcohol (5) (Stage A-4). Alternatively, the compound (4) can be obtained by the direct introduction of the group R #the alcohol group of compound hydroxycarboxylic acid (1) without protection carboxypropyl.

Each stage is described in detail below.

(Stage A-1)

Stage A-1 is a step for compounds (2) protection of carboxypropyl hydroxycarboxylic acid (1), if necessary.

Hydroxycarboxylic acid (1), which is used as starting substance, is commercially available, or, if this compound is not commercially available, can be obtained by Method F described below, or using methods known from the prior art.

This stage can be performed using a reaction injection protection carboxypropyl, and such reactions are well known in the chemistry of organic synthesis (examples of such groups are described in T.W.Greene et al., Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc. (1991)).

For example, the reaction may be carried out by the method of obtaining 1 or the method of obtaining 2, which are described below.

(Method of obtaining 1)

Secure connection (2) is produced by interaction of the compound (1) with an alkylating agent in a solvent under alkaline conditions.

The alkylating agent is a compound of the formula Pg1-Z1(where Pg1such as defined above, and Z1represents a halogen atom or a leaving group) and, for example, can be a halide, for example, chlorite is, bromide or iodide; or a sulfonate, for example, methanesulfonate, triftorbyenzola or toluensulfonate; and preferably is a halide.

Solvent used, for example, may be a hydrocarbon, such as hexane, cyclohexane, benzene, toluene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like; a ketone, such as acetone, 2-butanone and the like; sulfoxide such as dimethylsulfoxide and the like; amide such as N,N-dimethylformamide and the like; a nitrile such as acetonitrile and the like; or an ether, such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; and is preferably an amide (in particular, N,N-dimethylformamide).

Used the base is not specifically limited, provided that it is a base, generally used in chemistry, organic synthesis, and, for example, may be a hydroxide of an alkali metal, e.g. sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; a carbonate of an alkali metal, e.g. sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate and the like; organic amine, e.g. triethylamine, diisopropylethylamine, dicyclohexylamine, pyridine, lutidine, 4-(N,N-dimethylamino)pyridine, diazabicyclo, Diisobutylene and the like; or an alkoxide of an alkaline metal, for example, methoxy is sodium and the like; and is preferably a hydroxide of an alkali metal (in particular sodium hydroxide or carbonate of an alkali metal (in particular sodium carbonate).

The reaction temperature is usually from 80°C to 100°C.

The time required for the reaction is different, but mostly, it depends on the type of the protective group and is usually from 5 minutes to 3 hours, preferably from 15 min to 1 hour).

(Method of obtaining 2)

Secure connection (2) can also be obtained by the interaction of the compounds (1) with diazoketones in the solvent.

Vatsayana, for example, can be a diazomethane, trimethylsilyldiazomethane or diphenyldiazomethane and preferably represents diphenyldiazomethane.

Solvent used, for example, may be a halogenated hydrocarbon such as dichloromethane, dichloroethane and the like; a ketone, such as acetone, 2-butanone and the like; ester such as ethyl acetate and the like; an alcohol, such as methanol, ethanol and the like; or an ether, such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; and preferably is a simple ether (particularly tetrahydrofuran).

The reaction temperature is usually from 0°C to the boiling point of the used solvent, preferably from 0°C to room temperature).

Time, required for the reaction is different, but mostly, it depends on the type of diazocompounds, and is usually from 0.5 hour to 24 hours (preferably from 0.5 hour to 6 hours).

After completion of the reaction, the compound (2) can be isolated from the reaction mixture by conventional means. For example, it can be obtained by neutralization of the reaction mixture, the addition is not miscible with water and organic solvent to the reaction mixture or to the residue obtained after removal of the solvent from the reaction mixture, washing the mixture with water and then distillation of the solvent.

If necessary, the obtained compound (2) can be further purified by conventional means, such as recrystallization, re-precipitation, chromatography or the like

(Stage A-2)

Stage A-2 is a step for compounds (3) the introduction of the group R#on alcohol hydroxy-group of the compounds (2), and the reaction may be carried out using methods well-known to specialists in this field of technology.

For example, when the group R#enter C1-C6alkanoyloxy group (specified C1-C6alcoolica group optionally may be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies β), the reaction may be carried out by the interaction between the receiving of the compound (2) with reactive alkanoyl derivative in a solvent and, usually, in the presence of a base, or when the group R#enter a group of the formula-C(O)-NR2R3(where R2and R3such as defined above), the reaction may be carried out by the interaction of the compound (2) with reactive carbamoyl derivative in a solvent and usually in the presence of a base, or when the group R#enter the group-P(=O)(OH)2the reaction may be carried out by interaction of the compound (2) with the reactive phosphoryl derivative in a solvent and usually in the presence of a base.

In this case, reactive alkanoyl derivative is a compound of the formula Z2-R##(where R##represents a C1-C6alkanoyloxy group (specified C1-C6alcoolica group optionally may be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies β) in the definition of R#and Z2represents a leaving group. Specified leaving group, for example, may be a halogen atom such as chlorine atom or bromine atom; a cyano; alloctype, such as a group of the formula R##-O - or pivaloyloxy; or sulfonyloxy, such as methanesulfonate, toluensulfonate or tripterocalyx is); and reactive alkanols derived can be obtained from the carboxylic acids of the formula H-O-R##ways well known in the prior art. For example, when Z2represents a chlorine atom, a reactive alkanoyl derivative can be obtained by the interaction of the carboxylic acid of the formula H-O-R##with oxalylamino.

Reactive carbamoyl derivative is a compound of the formula Z2′-C(O)-NR2R3(where R2and R3such as defined above, and Z2′represents a leaving group such as halogen atom) or isocyanate compound of the formula O=C=N-R2(where R2the same as defined above); and reactive carbamoyl derivative can be obtained using an amine such as a compound of the formula HNR2R3or of the formula H2NR2using means well known in the prior art. For example, carbamoylated Cl-C(O)-NR2R3can be obtained by the interaction of the amine of the formula HNR2R3with phosgene in an aprotic solvent and isocyanate compound of the formula O=C=N-R2can be obtained by the interaction of the amine of the formula H2NR2with phosgene in an aprotic solvent.

Reactive phosphoryl derivative represents the connection is a group of formula Z 3-P(=O)(OPg2)(OPg3) (where Pg2and Pg3represent a protective group, and, for example, can be a C1-C6alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like; C2-C6alkenylphenol group, such as allyl, 2-methylallyl, 2-butenyl, 2-propenyl, prenyl etc.; C6-C10aryl group, which optionally can be substituted by 1-3 substituent(s)selected(s) from the group comprising C1-C6alkyl group, a C1-C6alkoxygroup and halogen atoms, for example, phenyl, methoxyphenyl, tolyl, naphthyl and the like; C7-C11aracelio group (the aryl fragment optionally may be substituted by 1-3 substituent(s)selected(s) from the group comprising C1-C6alkyl group, a C1-C6alkoxygroup and halogen atoms), for example, benzyl, methoxybenzyl, naphthylmethyl and the like; or Pg2and Pg3taken together form a C2-C6alkylenes group, such as ethylene, trimethylene, tetramethylene and the like; and Z3represents a leaving group, for example, may be a halogen atom, e.g. a chlorine atom or a bromine atom; a cyano; alloctype, such as pivaloyloxy group; or sulfonyloxy, such as methanesulfonate, toluensulfonate or triternata is sulfonyloxy), and reactive phosphoryl derivative can be obtained by using alcohol of the formula H-O-Pg2or H-O-Pg3(when Pg2and Pg3taken together form a C2-C6alkylenes group, the connection is diatomic alcohol of the formula H-O-(C2-C6alkylene)-O-H) by methods well known to specialists in this field of technology.

The number of reactive balkanologie derivative, reactive karamolegos derived and reactive phosphoryl derivative used for the reaction, usually about 1-3 molar equivalents relative to the amount of compound (2).

Solvent used, for example, may be a hydrocarbon, such as hexane, cyclohexane, benzene, toluene and the like; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane and the like; a simple ether, such as diethyl ether, tetrahydrofuran and the like; and heteroaromatic compound containing an atom(s) of nitrogen such as pyridine, picoline, lutidine and the like; ester such as ethyl acetate and the like; a ketone, such as acetone, 2-butanone and the like; or an amide such as N,N-dimethylformamide etc.

Used basis, for example, can be an amine, such as triethylamine, diisopropylethylamine, dicyclohexylamine and the like; or heteroaromatic the ical connection, containing the atom(s) of nitrogen such as pyridine, picoline, lutidine, 4-(N,N-dimethylamino)pyridine, etc.

The amount of base is typically 1-5 molar equivalents relative to the amount of compound (2), however, when the solvent used basic compound such as pyridine, picoline, lutidine and the like, there is no need to add the base.

The reaction temperature is usually from -10°C to the boiling point of the used solvent, preferably from 0°C to room temperature.

The time required for the reaction is different, but mostly, it depends on the reaction temperature and is usually from 0.5 hour to 24 hours, preferably from 1 hour to 5 hours.

Alternatively, when the R#group enter the group-P(=O)(OH)2the esterification can also be carried out using reactive pospisilova derived instead of reactive phosphoryl derivative, and then oxidizing the obtained ester compound of trivalent phosphorus may be carried out by methods well known in the prior art.

Reactive phosphaniline derivative is a compound of the formula Z3-P(OPg2)(OPg3) (where Pg2and Pg3are protective groups, as defined above, and Z3p is ecstasy a leaving group, as defined above), and reactive phosphaniline derivative can be obtained by using alcohol of the formula H-O-Pg2or H-O-Pg3(when Pg2and Pg3taken together form a C2-C6alkylenes group, the compound is a diatomic alcohol of the formula H-O-(C2-C6Allenova group)-O-H) by methods well known to specialists in this field of technology.

The oxidizing agent used in the oxidation of ester compounds of trivalent phosphorus to the compound (3)is not specifically limited, provided that it is an oxidizer commonly used in organic chemistry synthesis, and, for example, can be a halogen, such as iodine; oxygen molecule; a peroxide such as hydropeaking hydroperoxide, tert-butylhydroperoxide and hydrogen peroxide; peroxynitrate, such as peracetic acid, cryptocercus acid and m-chloroperoxybenzoic acid; salt of halogenated acids, such as salt of hypochlorous acid, a salt of chloric acid, salt charnawati acid and perchloro acid; and is preferably a peroxide (in particular, tert-butylhydroperoxide).

After completion of the esterification reaction, the compound (3) can be isolated from the reaction mixture by conventional means. For example, it is possible to get added on the m is not miscible with water and organic solvent to the reaction mixture or to the residue, obtained after removal of the solvent from the reaction mixture, washing the mixture with water and then distillation of the solvent.

If necessary, the obtained compound (3) can be further purified by conventional means, such as recrystallization, re-precipitation, chromatography or the like

(Stage A-3)

Stage A-3 is a step for compounds (4) removing the protective group of the compound (3), and the reaction may be carried out using methods well known in the art (examples of this are described in T.W.Greene et al., Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc. (1991)).

For example, when Pg1in the compound (3) is methoxybenzyloxy or dimethoxybenzyl group, the compound (4) can be obtained by treating compound (3) acid in the presence or in the absence of solvent.

Solvent used, for example, may be a hydrocarbon, such as hexane, cyclohexane, benzene and toluene; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; or an ether, such as anisole; and preferably is a hydrocarbon (particularly toluene).

Acid, for example, may be a mineral acid such as hydrochloric acid and sulfuric acid; carboxylic acid such as triperoxonane acid; what do sulfonic acid, such as triftoratsetata; and preferably represents a carboxylic acid (in particular, triperoxonane acid).

There are no specific restrictions regarding the used amount of acid, and this number varies depending on the type of acid used and the type of solvent. For example, when the acid is used triperoxonane acid, the amount of acid is usually from 5 molar equivalents relative to the amount of compound (3) to the number that is used as the solvent, preferably from one-tenth to one-half of the number that is used as a solvent.

The reaction temperature processing acid varies and mainly depends on the used solvent, and is usually from 0°C to room temperature.

The time required for the reaction is different, but mostly, it depends on the type you want to remove the protective group and the type and quantity of acid used, and when the protective group is methoxybenzyloxy group and the acid is triperoxonane acid and the acid number is 1/4 of the used amount of the solvent, the time is usually from 0.1 hour to 24 hours (preferably from 0.1 hour up to 2 hours).

After completion of the reaction, the compound (4) may be the Adelino from the reaction mixture by conventional means. For example, it can be obtained by the addition is not miscible with water and organic solvent to the reaction mixture or to the residue obtained after removal of the solvent from the reaction mixture, washing the mixture with water and then distillation of the solvent.

If necessary, the obtained compound (4) can be further purified by conventional means, such as recrystallization, re-precipitation, chromatography or the like

Alternatively, the compound (4) can be obtained by introduction of the group R#directly on the alcohol hydroxy-group of compounds (1) without holding stages A-1 through A-3. In this case, preferably, the compound (1) can be processed using reaction conditions similar to the conditions of Stage A-2.

The compound (4) can also be obtained in accordance with Method G Method H, which are described below.

(Stage A-4)

Stage A-4 is a step for compounds (Ia) of the present invention by esterification of the compound (4) alcohol (5). The compound (4) is converted into its reactive derivative, then this derivative is subjected to interaction with alcohol (5) in a solvent in the presence of a base method, well known in the art.

In this case, the reactive derivative of compound (4) is a compound of the formula Z4-C(=O)-L1 -O-R#and its get method, well known in the art, using the compounds (4)

formula HO-C(=O)-L1-O-R#. R#and L1such as defined above, and Z4represents a halogen atom or a leaving group.

The amount of the reactive derivative is usually 1-3 molar equivalents relative to the amount of the alcohol (5).

The combination of alcohol (5) is either a known compound or can be easily obtained using methods similar to the methods of production of known compounds.

Use the following methods.

For example, compounds where X represents General formula (III)can be synthesized in accordance with methods described in Japanese patent application No. Hei 8-333350, Japanese patent application No. Hei 10-279567, Japanese patent application No. Hei 11-80135 and Japanese patent application No. 2001-342187.

In particular, compounds where X represents General formula (III), Ar2represents a phenyl group, which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of a group of deputies γor monocyclic heteroaryl group, which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of Group C is mustiala γ E represents a group of formula-S(O)n1- (where n1 is an integer from 0 to 2), R4represents a C1-C4alkyl group, R5represents a hydrogen atom or a C1-C4alkyl group, and G represents a group of formula (Ga′), can be synthesized in accordance with methods described in Japanese patent application No. Hei 8-333350.

Compounds where X represents General formula (III), E represents a methylene group, A1represents a group selected from the group

and G represents a group of formula (Ga′′), can be synthesized in accordance with methods described in Japanese patent application No. Hei 11-80135.

Compounds where X represents General formula (III), Ar2represents naftalina group, which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of a group of deputies γor condensed bicyclic heteroaryl group, which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of a group of deputies γE represents a group of formula-S(O)n1- (where n1 is an integer from 0 to 2), R4is Soboh the C 1-C6alkyl group, R5represents a hydrogen atom, and G represents a group of formula (Ga′), can be synthesized in accordance with methods described in Japanese patent application No. Hei 10-279567.

Compounds where X represents General formula (III), Ar2represents a phenyl group, which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of a group of deputies γor naftalina group, which optionally may be substituted by 1-5 identical or different groups selected from the group consisting of a group of deputies γE represents a methylene group or a sulfur atom, R5represents a hydrogen atom, and G represents a group of formula (Gb), can be synthesized in accordance with methods described in Japanese patent application No. 2001-342187.

Compounds where X represents General formula (VI)can be synthesized in accordance with methods described in Japanese patent application No. Sho 62-14766.

Compounds where X represents General formula (VII)can be synthesized in accordance with methods described in Japanese patent application No. Hei 8-53426.

Compounds where X represents General formula (VIII)can be synthesized in accordance with methods described is no WO 99/45008.

Compounds where X represents General formula (IX)can be synthesized in accordance with methods described in Japan patent No. 2625584.

Compounds where X represents General formula (X)can be synthesized in accordance with methods described in Japanese patent application No. Hei 9-183769.

Compounds where X represents General formula (XI)can be synthesized in accordance with methods described in Japanese patent application No. Hei 11-240871.

Compounds where X represents General formula (XII)can be synthesized according to methods described in WO 98/31675.

Compounds where X represents General formula (XIII)can be synthesized according to methods described in WO 97/05130.

Compounds can also be synthesized in accordance with methods described in Japan patent No. 3050982, WO 95/25107, WO 00/27852, WO 01/66551 and WO 01/79196.

The basis used for the esterification, is not specifically limited, provided that it can remove alcohol active proton of the alcohol (5), and for example may be an organic amine, such as triethylamine and the like; aromatic compound containing an atom(s) of nitrogen such as pyridine and the like; alkali metal hydride such as lithium hydride, sodium hydride, potassium hydride and the like; organolithium compound, such as utility, finality and the like; which preferably is a metal hydride (in particular, sodium hydride).

The amount used of the base is usually from 0.9 to 3.5 molar equivalents relative to the amount of compound (5), and preferably from 1 to 2 molar equivalents relative to the amount of compound (5).

There are no particular restrictions on the nature of the solvent, provided that it has no adverse influence on the reaction and that it can, at least partially dissolving the source materials. Examples of suitable solvents that can be used include: simple ether, such as tetrahydrofuran, dioxane and dimethoxyethane; hydrocarbons such as hexane, cyclohexane, benzene and toluene; sulfoxide such as dimethylsulfoxide; an amide such as N,N-dimethylformamide and hexamethylphosphoramide; the connection of urea such as 1,3-dimethyl-2-imidazolidinone; preferably, a simple ether (particularly tetrahydrofuran) and amide (particularly N,N-dimethylformamide).

The temperature of the condensation reaction varies mainly on the used reagents and is usually from -78°C to room temperature, preferably from 0°C to room temperature.

The time required for the reaction varies mainly on the reaction temperature and solvent used, and is usually from 30 minutes to 24 hours, prefer the Ino from 30 minutes to 5 hours.

After completion of the reaction, the compound (Ia) can be isolated from the reaction mixture by conventional means. For example, it can be obtained by the addition is not miscible with water and organic solvent to the reaction mixture or to the residue obtained after removal of the solvent from the reaction mixture, washing the mixture with water and then distillation of the solvent.

If necessary, the obtained compound (Ia) may be further purified by conventional means, such as recrystallization, re-precipitation, chromatography or the like

In addition, Pg2and Pg3that are protective groups for the phosphoryl group can be removed at an appropriate time after the completion of stage A-2 through A-4. The reaction of removing the protective groups from the compound will vary depending on the type protective groups, and can be carried out by methods well known in the prior art. For example, when Pg2and Pg3represent an allyl group, the reaction may be carried out using nucleophilic (a reducing agent and a metal catalyst in an inert solvent.

Used inert solvent, for example, can represent water; alcohol such as methanol, ethanol and the like; hydrocarbons such as hexane and toluene; halogenated hydrocarbons, such to the to dichloromethane; nitrile, such as acetonitrile; an amide such as N,N-dimethylformamide; or a simple ether, such as tetrahydrofuran; and preferably is a simple ether (particularly tetrahydrofuran), halogenated hydrocarbon (particularly dichloromethane) or water. Alternatively, the amine used as the nucleophilic agent, can also be used as a solvent.

Nucleophilic (RS) agent, for example, can be an amine, such as pyrrolidine and morpholine salt of formic acid, such as formate, sodium; salt of carboxylic acid such as 2-ethylhexanoate and potassium; 1,3-dicarbonyl compound such as acetylacetone and dimedone; or tin hydride, such as anti-hydride; and preferably is pyrrolidin or anti-hydride.

The number of nucleophilic (reducing) agent is usually from 1 to 1000 molar equivalents relative to the amount of the original substance. Preferably, when the nucleophilic (reducing) agent use amine, such as pyrrolidine etc., the number of nucleophilic (a reducing agent ranges from 1-5 molar equivalents per one protective group of the original substance (when the starting material is difficult dellroy ether phosphate is islote, the number of nucleophilic (a reducing agent ranges from 2 to 10 molar equivalents), and when the nucleophilic (reducing) agent, use the tin hydride, such as anti-hydride and the like, the number of nucleophilic (reducing) agent is 1-3 molar equivalents per one protective group of the original substance (when the starting material is difficult dellroy ester of phosphoric acid, the amount of the nucleophilic (reducing) agent is from 2 to 6 molar equivalents).

Metal catalyst, for example, may be a palladium complex such as tetrakis(triphenylphosphine)palladium(O) and dichlorobis-(triphenylphosphine)palladium(II), etc.

The amount used of the catalyst is usually from 0.0001 to 1 molar equivalents relative to the amount of original substance, preferably from 0.001 to 0.05 molar equivalents relative to the amount of the original substance.

To the reaction mixture can be added phosphine compounds such as triphenylphosphine and the like, the Maximum number of phosphine compounds is usually 5 molar equivalents relative to the amount of metal catalyst.

The reaction temperature is usually from -20°C to 60°C (preferably about the 0° C to room temperature).

The time required for the reaction varies mainly depending on the reaction temperature and the type of agent removal protection, and is usually from 1 minute to 6 hours, preferably from 10 min to 2 hours).

[Method B]

Method B is a method of producing compound (Ib) [compounds (Ib) are compounds of General formula (I) according to the present invention, where Larepresents a simple bond, C6-C10aryl group, which optionally can be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies α, heterocyclic group which optionally may be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies αor C3-C7cycloalkyl group, which optionally can be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies αand R represents a hydrogen atom], and the reaction scheme is shown below.

In above reaction scheme, X, L1and Pg1such as defined above, and Pg4represents a hydroxy - protective group.

In this case, the protective group Pg4is a group, and usually is used in organic synthesis for the protection of alcohols (examples of such groups are described in T.W.Greene et al., Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc. (1991)).

There are no specific limitations regarding the nature of such a protective group, provided that when on Stage B-2 carry out the removal of the protective group Pg1compounds (6), the protective group Pg4not removed, and when on Stage B-3 carry out the etherification of carboxypropyl connection (7), the protective group Pg4do not delete, but when the protective group Pg4compound (8) is removed at Stage B-4, removal of the protective group can be carried out without any adverse effect on the connection (8). Protective group, for example, may be a C1-C6alkanoyloxy group, which optionally may be substituted by 1 to 3 atom(s) halogen, such as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, peracetyl, divercity, TRIFLUOROACETYL, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl and the like; (C6-C10aryl)carbonyl group, which optionally may be substituted by 1 to 3 group(s)independently selected from C1-C6alkyl groups, C1-C6alkoxy groups and halogen atoms, such as benzoyl, chlorobenzoyl, methoxybenzoyl, dimethoxybenzoyl, methylbenzoyl, naphtol and the like; silyl group which is substituted by 3 groups independently selected from C1-C6alkyl groups and fenil what's groups, such as trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl etc.; C2-C7alkoxycarbonyl group or a C3-C7altneratively group, which optionally may be substituted by 1 to 3 atom(s) halogen, such as methoxycarbonyl, etoxycarbonyl, trichlorocyanuric, propoxycarbonyl, allyloxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, phenoxycarbonyl, hexyloxybenzoyl etc.; or (C7-C11aralkyl)oxycarbonyl group, which optionally may be substituted by 1 to 3 group(s)independently selected from C1-C6alkoxy groups and halogen atoms, such as benzyloxycarbonyl, methoxybenzeneboronic, dimethoxybenzoquinone, chlorobenzenesulfonyl, naphthylethylenediamine and the like; and preferably represents a C3-C7altneratively group (in particular, allyloxycarbonyl group or silyl group which is substituted by 3 groups independently selected from C1-C6alkyl groups and phenyl groups (in particular, tert-butyldiphenylsilyl group).

This method involves first obtaining the compound (6) by protection of the hydroxy-group of the compounds (2), which is an intermediate compound for the synthesis in A Way, the group Pg4(Stadiu-1), then, obtaining the compound (7) by selective removal of compounds (6) carboxyl-protective group Pg1(Phase B-2), then, obtaining the compound (8) esterification of carboxylic acids (7) alcohol (5) (Stage B-3), and, finally, obtaining the compound (Ib) removing the protection of the alcohol group Pg4(Stage B-4).

Each stage is described in detail below.

(Stage B-1)

Stage B-1 is a step for compounds (6) protection of the alcohol hydroxy-group of the compounds (2), which is an intermediate compound for the synthesis in Method A.

This stage can be made by the reaction of introducing protective groups for alcohol, and such reactions are well known in the chemistry of organic synthesis (examples of this are described in T.W.Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)).

For example, a secure connection (6) is produced by interaction of the compound (2) with a protective agent in a solvent under alkaline conditions.

The protective agent is a compound of the formula Z5-Pg4(where Pg4such as defined above, and Z5represents a halogen atom or a leaving group), and, for example, can be a halide, such as chloride, bromide, iodide and the like; or a sulfonate such as methanesulfonate, triftorbyenzola, toluensulfonate and the like; and preferably is a halide.

Solvent used, for example, may be a hydrocarbon, such as hexane, cyclohexane, benzene, toluene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like; a ketone, such as acetone, 2-butanone and the like; sulfoxide such as dimethylsulfoxide and the like; amide such as N,N-dimethylformamide and the like; a nitrile such as acetonitrile and the like; or an ether, such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; and is preferably an amide (in particular, N,N-dimethylformamide), a simple ether (particularly tetrahydrofuran) or a halogenated hydrocarbon (particularly dichloromethane).

Used the base is not specifically limited provided that it is a base, generally used in chemistry, organic synthesis, and its examples include carbonates of alkali metals such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate and the like; organic bases such as triethylamine, diisopropylethylamine, dicyclohexylamine, pyridine, lutidine, 4-(N,N-dimethylamino)pyridine, diazabicyclo, Diisobutylene, imidazole and the like; and alkoxides of alkali metals such as sodium methoxide and the like; preferred organic bases (in particular, 4-(N,N-dimethylamino)pyridine and imidazole).

The reaction temperature is usually faced is t 0° C to the boiling point of the solvent, preferably from 0°C to room temperature). The time required for the implementation of the reaction varies mainly depending on the type of protective group, and is usually from 0.5 hour to 24 hours (preferably from 0.5 hour to 6 hours).

After completion of the reaction, the compound (6) can be isolated from the reaction mixture by conventional means. For example, it can be obtained by neutralization of the reaction mixture, the addition is not miscible with water and organic solvent to the reaction mixture or to the residue obtained after removal of the solvent from the reaction mixture, washing the mixture with water and then distillation of the solvent.

If necessary, the obtained compound (6) can be further purified by conventional means, such as recrystallization, re-precipitation, chromatography or the like

(Phase B-2)

Stage B-2 is a step for connection carboxylic acid (7) removing the protective group Pg1the compounds (6), and this stage can be made by reactions similar to those described for Stage A-3.

Alternatively, the compound (7) can be obtained directly by protection of the hydroxy-group of compounds (1) protecting group Pg4without Stage A-1, parts B-1 and Stage B-2. In this case, preferably, the compound (1) can be processing what about the reaction, similar to that described for Stage B-1.

Compound (7) can also be obtained in accordance with Method G Method H as described below.

(Stage B-3)

Stage B-3 represents the stage of obtaining the compound (8) esterification of compounds of carboxylic acid (7) alcohol (5), and this reaction can be carried out by the method similar to that described in Stage A-4.

(Stage B-4)

Stage B-4 is a step for the compound (Ib) by removing the hydroxy-protective group Pg4compounds (8).

This stage can be accomplished by reaction of the removal of protection of alcohol in accordance with the reactions that are well known in the chemistry of organic synthesis (examples of this are described in T.W.Greene et al., Protective Groups in Organic Synthesis, 2nd Edition, John Wiley & Sons, Inc. (1999)).

For example, when the protective group Pg4represents allyloxycarbonyl group, the reaction may be carried out using nucleophilic (a reducing agent and a metal catalyst in an inert solvent.

Inert solvent, for example, can represent water; alcohol such as methanol, ethanol and the like; hydrocarbons such as hexane and toluene; halogenated hydrocarbons such as dichloromethane; NITRILES, such as acetonitrile; an amide such as N,N-dimethylformamide; or a simple ether, such as tetrahydrofuran; and preferably represents p Estoy ether (in particular, tetrahydrofuran) or a halogenated hydrocarbon (particularly dichloromethane).

Nucleophilic (RS) agent, for example, can be an amine, such as pyrrolidine and morpholine salt of formic acid, such as formate, sodium; salt of carboxylic acid such as 2-ethylhexanoate and potassium; 1,3-dicarbonyl compound such as acetylacetone and dimedone; or tin hydride, such as anti-hydride; and preferably is pyrrolidin or anti-hydride.

The number of nucleophilic (reducing) agent is usually from 1 to 1000 molar equivalents relative to the amount of compound (8), preferably 1-3 molar equivalents relative to the amount of compound (8).

Metal catalyst, for example, may be a palladium complex such as tetrakis(triphenylphosphine)palladium(O) and dichlorobis(triphenylphosphine)palladium(II), etc. the Amount of metal catalyst is usually from 0.0001 to 1 molar equivalents relative to the amount of compound (8), preferably from 0.001 to 0.05 molar equivalents relative to the amount of compound (8).

To the reaction mixture can be added phosphine compounds such as triphenylphosphine and the like, the Maximum number of phosphine with whom unity is usually 5 molar equivalents relative to the amount of metal catalyst.

The reaction temperature removal allyloxycarbonyl group is usually from -20°C to 60°C (preferably from 0°C to room temperature). The time required for the implementation of the reaction varies mainly depending on the reaction temperature and the type of agent removal protection, and is usually from 1 minute to 6 hours, preferably from 10 min to 2 hours).

Alternatively, for example, when the protective group Pg4represents a silyl group which is substituted by 3 groups independently selected from C1-C6alkyl groups and phenyl groups, for example, tert-butyldiphenylsilyl group, the reaction of removing the protective group can be carried out by the interaction of the compound (8) with a fluoride salt in a solvent.

Solvent used, for example, can represent water; hydrocarbons such as hexane, cyclohexane, benzene, toluene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like; an alcohol, such as methanol, ethanol, tert-butyl alcohol and the like; a ketone, such as acetone, 2-butanone and the like; ester such as ethyl acetate and the like; sulfoxide such as dimethylsulfoxide and the like; amide such as N,N-dimethylformamide and the like; a nitrile such as acetonitrile and the like; or a simple ether, such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; and predpochtitel is but represents a hydrocarbon halogenated hydrocarbon or an ether, more preferably a simple ether (particularly tetrahydrofuran).

Fluoride salt, for example, may be a fluoride of an alkali metal such as potassium fluoride and the like; or organic fluoride ammonium, such as tetrabutylammonium etc.

The reaction may be carried out by bringing the environment of the reaction mixture to neutral by adding acid, such as acetic acid, etc.

The reaction temperature of desirelove is usually from 0°C to room temperature.

The time required to implement the response desirelove, is usually from 1 hour to 4 hours.

After completion of the reaction, the removal of the protective group Pg4the desired compound (Ib) can be isolated from the reaction mixture by conventional means. For example, it can be obtained by the addition is not miscible with water and organic solvent to the reaction mixture or to the residue obtained after removal of the solvent from the reaction mixture, washing the mixture with water and then distillation of the solvent.

If necessary, the obtained compound (6) can be further purified by conventional means, such as recrystallization, re-precipitation, chromatography or the like

[Method C]

Method C is a method of obtaining the compounds (Ic) [compound (Ic) to depict ablaut a compound of General formula (I) according to the present invention, where Larepresents an oxygen atom, R represents a C1-C6alkanoyloxy group, which optionally can be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies β, a group of the formula-C(O)-NR2R3(where R2and R3independently represent a hydrogen atom or a C1-C6alkyl group, or R2and R3together with the nitrogen atom to which they are bound, form a 4-7-membered heterocyclic group containing the atom(s) of nitrogen), or a group-P(=O)(OH)2], and the reaction scheme is shown below.

In above reaction scheme, X and R#such as defined above, L2has the same meaning as defined for L (assuming Larepresents an oxygen atom), and Z6and Z7independently represent a halogen atom or a leaving group. Examples of leaving groups include halogen atom such as chlorine atom or bromine; C1-C6alkoxygroup, which optionally may be substituted atom(s) halogen, such as trichloromethane group; C6-C10alloctype, such as fenoxaprop; and a 5-7 membered heteroaryl group containing 1-4 nitrogen atom, such as imidazolyl, triazolyl or tetrazolyl.

This way p is educative first obtaining reactive carbonate compound (10) by the interaction of the alcohol (5) with compound (9) (Stage C-1), then, obtaining the compound (Ic) by esterification of the compound (10) alcohol (11) (Stage C-2).

Compound (9) is a compound mainly known in the chemistry of organic synthesis as "fogedby equivalent, such as phosgene, trichlorochloroform, bis(trichloromethyl)carbonate, 1,1′-carbonyldiimidazole, phenylchloropyruvate, and can be used commercially available compounds, of which 1,1′-carbonyldiimidazole is preferred.

The alcohol (11) can be obtained in accordance with Method I.

(Stage C-1)

Stage C-1 is a step for reactive carbonate compound (10) by the interaction of the alcohol (5) with compound (9) in an inert solvent and usually in the presence of a base.

There are no specific limitations regarding the nature of the used inert solvent, provided that it has no adverse effect on the reaction and that it can, at least partially dissolving the source materials.

Solvent used, for example, may be a halogenated hydrocarbon such as dichloromethane; simple ether, such as tetrahydrofuran, dioxane and dimethoxyethane; hydrocarbons such as hexane, cyclohexane, benzene and toluene; sulfoxide such as dimethylsulfoxide; or an amide such as N,N-dimethylformamide and exam is teliospore; and is preferably a halogenated hydrocarbon (particularly dichloromethane), a simple ether (particularly tetrahydrofuran) or an amide (particularly N,N-dimethylformamide).

Used the base is not specifically limited, provided that it can remove alcohol active proton of the alcohol (5), and, for example, can be an organic amine, such as triethylamine and the like; aromatic compound containing an atom(s) of nitrogen such as pyridine and the like; alkali metal hydride such as lithium hydride, sodium hydride, potassium hydride and the like; organolithium compound, such as utility, finality and the like; or an alkoxide of an alkali metal, such as tert-piperonyl potassium; and preferably is a metal hydride (in particular, sodium hydride or alkoxide of the alkali metal (in particular, tert-piperonyl potassium).

The amount used of the base is usually from 0.01 to 5 molar equivalents relative to the amount of compound (5), preferably 0.01 to 3 molar equivalents relative to the amount of compound (5).

The temperature of the reaction varies mainly depending on the type of connection (9), and is usually from -78°C to 50°C, preferably from 0°C to 40°C.

The time required for the implementation of the reaction varies mainly depending on the type of connection (9), and typically ranges from 30 min to 24 hours, preferably from 1 hour to 5 hours.

After the completion of Stage C-1, reactive carbonate compound (10) can be used in the next Stage C-2 without selection. Namely, Stage C-2 can be accomplished by the addition of alcohol (11) to the reaction mixture.

If necessary, the thus obtained reactive carbonate compound (10) can be isolated by conventional means, for example, by solvent extraction, recrystallization, re-precipitation, chromatography or the like

(Stage C-2)

Stage C-2 represents the stage of obtaining the compound (Ic) esterification reactive carbonate compounds (10) of the compound (11) in an inert solvent and usually in the presence of a base.

Used in this reaction, the solvent and base are solvent and a base of the same type that was used on Stage C-1. The amount used of the base is the same what was used on Stage C-1.

The reaction temperature in Stage C-2 varies, mainly depending on the type of connection (11), and is usually from -78°C to the boiling point of the used solvent, preferably from 0°C to 40°C.

The time required to perform the reaction at a Stage C-2, differs mainly in zavisimost and on the reaction temperature and the type of connection (11), and typically ranges from 10 min to 24 hours, preferably 10 minutes to 1 hour.

Alternatively, this method can be implemented by changing the order of the reaction of the alcohol (5) and reaction of the alcohol (11) with compound (9).

Namely, this method can be carried out by the interaction of the alcohol (11) with compound (9) in an inert solvent and usually in the presence of base, followed by the addition of alcohol (5).

After completion of the reaction, the compound (Ic) can be isolated from the reaction mixture by conventional means. For example, it can be obtained by the addition is not miscible with water and organic solvent to the reaction mixture or to the residue obtained after removal of the solvent from the reaction mixture, washing the mixture with water and then distillation of the solvent.

If necessary, the obtained compound (Ic) can be further purified by conventional means, such as recrystallization, re-precipitation, chromatography or the like

[Method D]

Method D is a method of obtaining the compounds (Id) [compounds (Id) are compounds of General formula (I) according to the present invention, where Larepresents an oxygen atom, and R represents a hydrogen atom], and the reaction scheme is shown below.

In above reaction scheme, X, Z7, Pg4 and L2such as defined above.

This method involves first obtaining the compound (13) esterification of the intermediate compound (10) Method C alcohol (12) (Stage D-1), then, obtaining the compound (Id) by removing the hydroxy-protective group Pg4the compound (13) (Stage D-2).

(Stage D-1)

Stage D-1 is a step for compound (13) by esterification of the compound (10) alcohol (12). This stage can be done analogously to the reaction described for Stage C-2. The compound (12) can also be obtained in accordance with Method I, described below.

Alternatively, the compound (13) can be obtained by changing the order of the reaction of the alcohol (5) and reaction of the alcohol (12) with compound (9) by the method similar to that described in Method C.

Namely, this method can be carried out by the interaction of the alcohol (12) with compound (9) in an inert solvent and usually in the presence of base, followed by the addition of alcohol (5).

(Stage D-2)

Stage D-2 carry out reactions remove the protection of the alcohol group, and such reactions are well known in the chemistry of organic synthesis (examples described in T.W.Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)).

The reaction can be performed in a manner analogous to that described for the reaction in Stage B-4 above.

[Method E]

Method E, not only is no other way to obtain the compounds (If) [compounds (If) are compounds of General formula (I) according to the present invention, where R represents a C1-C6alkanoyloxy group, which optionally can be substituted by 1-3 identical or different groups selected from the group consisting of a group of deputies β, a group of the formula-C(=O)-NR2R3(where R2and R3independently represent a hydrogen atom or a C1-C6alkyl group, or R2and R3taken together with the nitrogen atom to which they are bound, form a 4-7-membered heterocyclic group containing the atom(s) of nitrogen) or the group-P(=O)(OH)2], and the reaction scheme is shown below.

In above reaction scheme, X, L, and R#have the meanings given above.

The original connection (Ie) is a compound of General formula (I) according to the present invention, where R represents a hydrogen atom, namely, the compound (Ib) or compound (Id), and can be obtained in accordance with Method B or Method D as described above.

This method can be carried out by esterification, carbamoylethyl or phosphorylation of the compound (Ie) using techniques well known to specialists in this field of technology.

For example, this method can be carried out similarly to that described for the reaction in Stage A-2, the interaction of the compound (Ie) with reactive alkanols derived reactive carbamoyl derived or reactive phosphoryl derivative in a solvent and usually in the presence of a base.

After completion of the reaction, the compound (If) can be isolated from the reaction mixture by conventional means. For example, it can be obtained by the addition is not miscible with water and organic solvent to the reaction mixture or to the residue obtained after removal of the solvent from the reaction mixture, washing the mixture with water and then distillation of the solvent.

If necessary, the obtained compound (If) can be further purified by conventional means, such as recrystallization, re-precipitation, chromatography or the like

[Method F]

Method F is a method of obtaining a hydroxycarboxylic acid (1) or its salts, which are used as starting substances in Method A, and the reaction scheme is shown below.

In above reaction scheme, L1such as defined above.

The lactone (14), which is the starting material, commercially available, or can be obtained using techniques well known in the art, or by known methods.

For example, the specified connection (14) can be obtained by subjecting the corresponding cyclic ketone reaction Bayer-Villiger (see Matsumoto et al., Heterocycles, 24, 2443-2447 (1986)), the corresponding cyclic simple ester reaction of oxylene (see H.Firouzabadi et al., Synthesis, 4, 285-288 (1986)), the corresponding cyclic anhydride reaction in which Stanovlenie (see D.M.Bailey et al., J.Org.Chem., 35, 3574-3576 (1970)), and similar methods.

This method can be carried out using techniques well known to specialists in this field of technology. For example, hydroxycarboxylic acid (1) or its salt can be obtained by the interaction of the lactone (14) with a base in a solvent.

The salt of compound (1) is a salt of the metal, where the specified metal is used in the base, and examples include alkali metal salts such as sodium salt and potassium salt.

There are no particular restrictions on the nature of the solvent, provided that it has no adverse influence on the reaction and that it can, at least partially dissolving the source materials. Solvent used, for example, can represent water; alcohol such as methanol and ethanol; a simple ether, such as tetrahydrofuran, dioxane and dimethoxyethane; hydrocarbons such as hexane, cyclohexane, benzene and toluene; sulfoxide such as dimethylsulfoxide; a ketone, such as acetone and 2-butanone; or a mixture thereof; and preferably is a mixture of water and alcohol (particularly methanol) or a mixture of water and simple ether (particularly tetrahydrofuran).

Used the base is not specifically limited provided that it exhibits the basic properties adding to the reaction mixture,and, for example, there may be a hydroxide of an alkali metal such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali earth metal hydroxide such as calcium hydroxide and barium hydroxide; a carbonate of an alkali metal such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal alkoxide such as sodium methoxide and tert-piperonyl potassium; tiolet metal, such as meantioned sodium; or alkali metal cyanide such as sodium cyanide and potassium cyanide; and is preferably a hydroxide of an alkali metal (in particular sodium hydroxide). The amount used of the base is 1-5 molar equivalents relative to the amount of original substance, preferably from 1 to 1.5 molar equivalents relative to the amount of the original substance.

The reaction temperature varies depending on the type and amount used of the base and is usually from -10°C to 70°C (preferably from 0°C to 50°C).

The time required for implementation of the response varies depending on the type and amount used of the base and the reaction temperature and is usually from 0.3 hours to 24 hours (preferably from 0.5 hour to 3 hours).

After completion of the reaction, the compound (1) or its salt can be separated from the reaction mixture of the usual ways is AMI. For example, the salt of the compound (1) can be obtained by adding to the reaction mixture is not miscible with water, an organic solvent, separation of the aqueous layer and then distillation of the solvent. On the other hand, the compound (1) can be obtained by neutralizing the reaction mixture, the addition is not miscible with water, an organic solvent, separation of the aqueous layer and then distillation of the solvent.

If necessary, the obtained compound (1) or its salt can be further purified by conventional means, such as recrystallization, re-precipitation, chromatography or the like

[Method G]

This method represents an alternative way to obtain the intermediate compound (4) of Method A, and the reaction scheme is shown below.

In above reaction scheme, L1and R#such as defined above, and Pg5represents a hydroxy-protective group.

The protective group Pg5is a group traditionally used in organic synthesis for the protection of alcohols (examples of such groups are described in T.W.Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)). There are no specific limitations regarding the nature of such a protective group, provided that when a specified protective group is removed from compound (17) on Stage (G-3, remove the safety group can be carried out without any adverse effect on other parts of the compound (17). Examples of the protective group include a 5-7-membered heterocyclic group containing one oxygen atom, such as tetrahydropyranyl, oxolane and the like; (C1-C6alkoxy)methyl group, such as methoxymethyl and the like; (C6-C10aryl)methyl group, which optionally can be substituted with 1-3 groups independently selected from C1-C6alkyl groups, C1-C6alkoxygroup and halogen atoms, such as benzyl, methoxybenzyl, dimethoxybenzyl, chlorbenzyl, methylbenzyl etc.; C1-C6alkanoyloxy group, which optionally can be substituted by 1-3 halogen atoms, such as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, peracetyl, divercity, TRIFLUOROACETYL, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl and the like; (C6-C10aryl)carbonyl group, which optionally can be substituted with 1-3 groups independently selected from C1-C6alkyl groups, C1-C6alkoxygroup and halogen atoms, such as benzoyl, chlorobenzoyl, methoxybenzoyl, dimethoxybenzoyl, methylbenzoyl, naphtol and the like; silyl group which is substituted by 3 groups independently selected from C1-C6alkyl groups and phenyl groups, such as trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyl is fenercell etc.; C2-C7alkoxycarbonyl group or a C3-C7altneratively group, which optionally can be substituted by 1-3 halogen atoms, such as methoxycarbonyl, etoxycarbonyl, trichlorocyanuric, propoxycarbonyl, allyloxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, phenoxycarbonyl, hexyloxybenzoyl and the like; and (C7-C11aralkyl)oxycarbonyl group, which optionally can be substituted with 1-3 groups independently selected from C1-C6alkoxygroup and halogen atoms, such as benzyloxycarbonyl, methoxybenzeneboronic, dimethoxybenzoquinone, chlorobenzenesulfonyl, naphthylethylenediamine and the like; of these, preferred are a silyl group which is substituted by 3 groups independently selected from C1-C6alkyl groups and phenyl groups (in particular, tert-butyldimethylsilyl group).

This method involves first obtaining a mono-protected compound (16) protection one hydroxy-group diatomic alcohol (15) (Stage G-1), then, obtaining ester, urethane or phosphoryl compounds (17) esterification, carbamoylethyl or phosphorylation of the compound (16) (under G-2), and, finally, obtaining the compound (18) by removing the protective group of the compound (17) (under G-3).

Viola is native, the compound (18) can be obtained by the reaction of esterification or carbamylcholine directly from compound (15), without protection. Then the desired compound (4) can be obtained by oxidation of compound (18).

Each stage is described in detail below.

(Stage G-1)

Stage G-1 is a step for connection (16) protection one hydroxy-group diatomic alcohol (15).

Diatomic alcohol (15), which is the starting material, commercially available or, if necessary, can be obtained using techniques well known to specialists.

This stage can be done using the reactions of the introduction of protective groups for alcohol, and such reactions are well known in the chemistry of organic synthesis (examples of such reactions are described in T.W.Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)).

For example, hydroxy-protected compound (16) can be obtained by the interaction of the compound (15) with a protective agent in a solvent under alkaline conditions.

The protective agent is a compound of the formula Pg5-Z8(where Pg5such as defined above, and Z8represents a halogen atom or a leaving group) and, for example, can be a halide, such as chloride, bromide, iodide and the like; or a sulfonate such as methanesulfonate, triftorbyenzola, toluensulfonyl and the like; and preferably is a halide.

Solvent used, for example, may be a hydrocarbon, such as hexane, cyclohexane, benzene, toluene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like; a ketone, such as acetone, 2-butanone and the like; sulfoxide such as dimethylsulfoxide and the like; amide such as N,N-dimethylformamide and the like; a nitrile such as acetonitrile and the like; or an ether, such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; and preferably is a simple ether, halogenated hydrocarbon or amide.

Used the base is not specifically limited, provided that it is a base, generally used in chemistry, organic synthesis, and, for example, may be a carbonate of an alkali metal such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate and the like; organic amine, such as triethylamine, diisopropylethylamine, dicyclohexylamine, pyridine, lutidine, 4-(N,N-dimethylamino)pyridine, diazabicyclo, Diisobutylene, imidazole and the like; or an alkali metal alkoxide such as sodium methoxide and the like; and is preferably an organic amine.

The reaction temperature is usually from 0°C to the boiling temperature used dissolve the I (preferably from 0° C to room temperature). The time required for the implementation of the reaction varies mainly depending on the type of protective group, and is usually from 0.5 hour to 24 hours (preferably from 0.5 hour to 6 hours).

After completion of the reaction, the compound (16) can be isolated from the reaction mixture by conventional means. For example, it can be obtained by neutralization of the reaction mixture, the addition is not miscible with water and organic solvent to the reaction mixture or to the residue obtained after removal of the solvent from the reaction mixture, washing the mixture with water and then distillation of the solvent.

If necessary, the obtained compound (16) can be further purified by conventional means, such as recrystallization, re-precipitation, chromatography or the like

Alternatively, at this stage, in addition to the desired compound (16), we can obtain a by-product, in which both hydroxy-group are protected. In this case, if it is desirable that the compound (16) can be separated from the specified by-product using techniques such as recrystallization, re-precipitation or chromatography.

(Stage G-2)

Stage G-2 is a step for compound (17)with the hydroxy-group of the mono-protected compound (16) is subjected to the esterification reaction, it is ramilisonina or phosphorylation.

This stage can be performed in a manner similar to that described for Stage A-2.

(Stage G-3)

Stage G-3 is a step for alcohol (18) removing the protective group of the compound (17).

This stage is carried out using a reaction of removing the protective groups of the alcohol, which are reactions that are well known in the chemistry of organic synthesis (examples of such reactions are described in T.W.Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)).

For example, when the protective group Pg5represents a silyl group which is substituted by 3 groups independently selected from C1-C6alkyl groups and phenyl groups, such as tert-butyldimethylsilyl group, the reaction can be performed by treating compound (17) of the fluoride salt in the solvent.

Solvent used, for example, can represent water; hydrocarbons such as hexane, cyclohexane, benzene, toluene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like; an alcohol, such as methanol, ethanol, tert-butyl alcohol and the like; a ketone, such as acetone, 2-butanone and the like; ester such as ethyl acetate and the like; sulfoxide such as dimethylsulfoxide and the like; amide such as N,N-dimethylformamide and the like; a nitrile such as acetonitrile and the like; or a simple ether, such as diethyl ether, tetrahedr is furan, 1,4-dioxane, 1,2-dimethoxyethane and the like; and preferably is a hydrocarbon, halogenated hydrocarbon or an ether, more preferably a simple ether.

Fluoride salt, for example, may be a fluoride of an alkali metal, e.g. potassium fluoride and the like; or organic fluoride ammonium, for example, tetrabutylammonium etc.

The reaction may be carried out by bringing the environment of the reaction mixture to neutral by adding acid, such as acetic acid.

The reaction temperature is usually from 0°C to room temperature. The time required to perform the reaction is usually from 1 hour to 4 hours.

After completion of the reaction, the compound (18) can be isolated from the reaction mixture by conventional means. For example, it can be obtained by neutralization of the reaction mixture, the addition is not miscible with water and organic solvent to the reaction mixture or to the residue obtained after removal of the solvent from the reaction mixture, washing the mixture with water and then distillation of the solvent.

If necessary, the obtained compound (18) can be further purified by conventional means, such as recrystallization, re-precipitation, chromatography or the like

Alternatively, the compound (18) can be obtained by introduction of the group R#neposredno is but one hydroxy-group of the compound (15) without carrying out the stages of G-1 through G-3. In this case, the connection (15), preferably, treated under reaction conditions analogous to Stage G-2.

(Stage G-4)

Stage G-4 is a step for the intermediate (4) method A by oxidation of the alcohol (18).

This stage is carried out by treating compound (18) with an oxidant in an inert solvent.

There are no particular restrictions on the nature of the solvent, provided that he may at least partially dissolve the original connection and has no adverse effects on the reaction. Solvent used, for example, can represent water; hydrocarbons such as hexane, cyclohexane, benzene, toluene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like; an alcohol such as tert-butyl alcohol and the like; a ketone, such as acetone, 2-butanone and the like; ester such as ethyl acetate and the like; sulfoxide such as dimethylsulfoxide and the like; amide such as N,N-dimethylformamide and the like; a nitrile such as acetonitrile and the like; or an ether, such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; and preferably is a water, hydrocarbon, halogenated hydrocarbon, ketone, amide or ester, more preferably a halogenated hydrocarbon (particularly dichloromethane), to the tone (in particular, acetone) or an amide (particularly N,N-dimethylformamide).

The oxidizing agent used in the oxidation reaction, is not specifically limited, provided that it is an oxidizer commonly used in the chemistry of organic synthesis for the oxidation of alcohol to carboxylic acid and, for example, may be a salt, oxide or complex of chromium, such as chromium trioxide, potassium dichromate, chlorproma pyridinium, Jones reagent, Collins reagent, and the like; salt, oxide or complex of ruthenium, for example, ruthenium tetroxide, perruthenate of tetrapropylammonium and the like; salt, oxide or complex of lead, for example, leads to compounds, which lead etc.; salt, oxide or the complex of manganese, for example, potassium permanganate, manganese dioxide and the like; salt, oxide or complex of silver, such as silver oxide and silver carbonate; salt, oxide or complex of tungsten, for example, tungstic acid and the like; salt, oxide or complex of molybdenum, for example, molybdenum acid; a free radical, for example, radical 2,2,6,6-tetramethylpiperidine and the like; halogen, for example chlorine, bromine, iodine and the like; halogenated acid or its salt, such as sodium hypochlorite, sodium chlorite, sodium perchlorate and the like; or an N-halogenated, for example, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide and the like; and preferably is a salt, oxide or complex of a chromium salt, oxide or complex rutin is I; salt, oxide or complex of manganese; salt or complex of silver; or halogenated acid or its salt; and more preferably is a salt, oxide or complex of chromium.

The amount of oxidizing agent is usually from 2 to 10 molar equivalents relative to the amount of alcohol (18), preferably from 2 to 3 molar equivalents relative to the amount of compound (18).

The temperature of the reaction varies mainly depending on the oxidant and source materials, and is usually from -78°C to the boiling point of the used solvent, preferably from -20°C to room temperature.

The time required for the implementation of the reaction varies mainly depending on the oxidant, the starting materials and the reaction temperature and is usually from 0.1 hour to 24 hours, preferably 0.5 hour to 2 hours.

After completion of the reaction, the compound (4) can be isolated from the reaction mixture by conventional means. For example, it can be obtained by the addition is not miscible with water and organic solvent to the reaction mixture or to the residue obtained after removal of the solvent from the reaction mixture, washing the mixture with water and then distillation of the solvent.

If necessary, the obtained compound (4) can be advanced about Ishino conventional methods, such as recrystallization, re-precipitation, chromatography or the like

In the same way can be obtained intermediate compound (7) Method B.

The compound (19) obtained by protection of the mono-protected compound (16) protective group Pg4in a manner analogous to that described for Stage G-2 (under G′-1), then the compound (20) obtained by removing the protective group Pg5(under G′-2), and, finally, the compound (7) obtained by oxidation of compound (20).

Alternatively, compound (20) can be obtained by secure connection (15) protective group Pg4directly, without holding Stage G-1, Stage G′-1 and Stage G′-2. In this case, compound (20) can be obtained, preferably, by treating compound (15) in conditions similar to the conditions of the reaction Stage G′-1.

[Method H]

This method represents an alternative way to obtain the intermediate compound (4) of Method A, and the reaction scheme is shown below.

In above reaction scheme, L1and R#such as defined above.

This method involves first obtaining the compound (22) by etherification or carbamylcholine hydroxy-group of the aldehyde (21) (Stage H-1), then obtain the compound (4) oxidation of the compound (22).

Ka is Daya stage is described in detail below.

Stage H-1 represents the stage of obtaining the compound (22) by etherification or carbamylcholine hydroxy-group of the aldehyde (21).

The aldehyde (21), which is the starting material, commercially available or can be obtained by methods well known to specialists in this field of technology. For example, the corresponding lactone is subjected to reductive cleavage (examples of this are described in D.Johnston et al., Tetrahedron Lett., 40, 4913-4916, (1999)).

This stage is carried out in a manner analogous to that described for Stage A-2.

Stage H-2 is a step for the intermediate (4) Method A by oxidation of the aldehyde (22).

This stage is carried out by oxidation of the aldehyde using reactions well known in the chemistry of organic synthesis. For example, this stage can be performed in a manner analogous to that described for Stage (G-4.

The same method can be obtained intermediate compound (7) synthesis Method B.

The compound (23) obtained by protection of the hydroxy-group of the compound (21) with a protective group Pg4in a manner analogous to that described for Stage B-1 (under H′-1), then the compound (7) obtained by oxidation of the aldehyde group of the compound (23) (under H′-2).

[Method I]

Method I is a method of obtaining compound (11), awsume the Osia intermediate in Method C, and the reaction scheme is shown below.

In above reaction scheme, R#L2and Pg5such as defined above.

This method involves first obtaining mono-substituted compounds (25) protection one hydroxy-group diatomic alcohol (24) (Stage I-1), then the connection (26) the introduction of the group R#in the compound (25) (Stage I-2), and finally obtain the desired compound (11) by removing the protective group of the compound (26) (Stage I-3). This method can be carried out similarly as described in Method G (Stage G-1 through G-3).

Alternatively, the desired compound (11) can be obtained by introduction of the group R#directly in the connection (24), without his protection.

In the same way can be obtained compound (12), which is an intermediate in Method D.

Compound (27) obtained by protection of the hydroxy-group of the compound (25) protective group Pg4(Phase I′-1), then get a connection (12) removing the protective group Pg5from the compound (27) (Phase I′-2). These reactions are carried out in a manner analogous to that described for Stage G′-1 on Stage G′-2.

When the compounds (Ia), (Ib), (Ic), (Id) or (If) of the present invention, obtained by Method A, Method B, Method C, Method D or E, clucalc protective group of the group L or group R, the final desired compounds can be obtained by the removal of these protective groups using methods well known in the prior art. Namely, the compound comprising a hydroxy-group, a group of the formula-NH-, carboxypropyl, a group-P(=O)(OH)2or group-SO3H, can be obtained using the original connection in which these groups are protected, and disposal at the end of these protective groups.

The removal of the protective groups is carried out using reactions well known in the chemistry of organic synthesis (examples of such reactions are described in T.W.Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)) and similar reactions. For example, in the case where the group L or group R includes carboxypropyl or a group-P(=O)(OH)2as the protective group can be used allyl group, and indicated the protective group is removed in a manner analogous to the method of removing Pg2and Pg3described in Method A, and method of removal Pg4described in Method B.

The triazole compounds and their pharmacologically acceptable salts of the present invention have a high solubility in water, so when administered as a drug (in particular, for injection), they are able to cleavage in vivo and, as a result, they exhibit excellent antifungal activity against, for example, g is bcov Candida, Aspergillus, Cryptococcus, Mucor, Histoplasma, Blastomyces, Coccidioides, Paracoccidioides, Trichophyton, Epidermophyton, Microsporum, Malassezia, Pseudallescheria, Sporothrix, Rhinosporidium, Fonsecaea, Wangiella, Phialophora, Exophiala, Cladosporium, Alternaria, Aureobasidium, Chaetomium, Curvularia, Cereals, Mycocentrospora, Phoma, Hendersonula, Scytalidium, Corynespora, Leptosphaeria, Madurella, Neotestudina, Sedosporium, Pyrenochaeta, Geotrichum, Trichosporon, Chrysosporium, Coprinus, Schizophyllum, Pneumocystis, Conidiobolus, Basidiobolus, Paecilomyces, Penicilliun, Acremonium, Fusarium, Scopulariopsis, Saccharomyces, Cephalosporium, Loboa, Rhizopus, Rhizomucor and Absidia.

The amount used varies depending on the patient's symptoms (warm-blooded animal, especially of a person), age, route of administration (intravenous, intramuscular administration, subcutaneous administration and the like), etc. and, in the case of intravenous administration, preferably infusion of 0.1 mg (preferably 0.5 mg) as a lower limit and 600 mg (preferably 500 mg) as an upper limit, per the introduction, for an adult patient, and from one to six times per day, depending on the symptoms.

The drawing is a graph showing the result of test Example 1. The x-axis represents the incubation time, and the ordinate axis represents the percentage of the stability of the compounds of example 5 or the percentage of the connection A.

[Best mode for carrying out the invention]

The following examples, reference examples, examples, test examples and compositions are intended to further illustrate the present from which retene and should not be construed as limiting the scope of the present invention.

[Example]

[Example 1]

4-(Acetoxymethyl)-3-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]benzyl phosphate sodium (mono-sodium salt of example number 5-34)

(1) 2-Bromo-1,4-benzylimidazole

To a solution of sodium borohydride (6,61 g, 174,8 mmol) in ethanol (150 ml) under stirring at 0°C for 20 min was added powdered calcium chloride (14,55 g, RB 131.1 mmol), and then thereto was added a solution of dimethyl 2-bromoterephthalic (described in J. Med. Chem., 13, 1235 (1970); 11,94 g, 43,7 mmol) in ethanol (20 ml). After stirring the mixture at the same temperature for 30 min thereto was further added sodium borohydride (5,3 g, 140 mmol) and calcium chloride (1 g, 9.0 mmol). The resulting mixture was stirred for 40 min and was added 2 N. aqueous solution of hydrochloric acid (250 ml). The product was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride. The extract was concentrated under reduced pressure and obtained a solid residue. The residue was washed with a small amount of ethyl acetate to obtain specified in the header of the compound (7.98 g, yield 84%) as a colourless solid (TPL 104°C).

NMR-spectrum (400 MHz, DMSO-d6) δ ppm: 4,48 (2H, d, J=5 Hz), 4,49 (2H, d, J=6 Hz), 5,27 (1H, t, J=6 G is), lower than the 5.37 (1H, t, J=5 Hz), 7,31 (1H, d, J=7 Hz), 7,46 is 7.50 (2H, m).

IR-spectrum ν max KBr cm-1: 3332, 3244, 1435, 1404, 1201, 1058, 1018, 825.

Mass spectrum m/z (EI): 216, 218 (M+).

(2) 2-Bromo-1,4-bis[(tetrahydropyran-2-yl)oxymethyl]benzene

3,4-Dihydro(2H)Piran (7,22 g, 84,9 mmol) was added dropwise to a solution of 2-bromo-1,4-benzylimidazole (7,76 g, 35.8 mmol)obtained in Example 1-(1), monohydrate p-toluenesulfonic acid (340,2 mg of 1.80 mmol) in dichloromethane (180 ml) under stirring at 0°C. the Mixture was stirred for 1 hour and then thereto was added an additional amount of 3,4-dihydro(2H)Piran (0.8 g, 9.3 mmol). After stirring the mixture for 40 min was added saturated aqueous sodium hydrogen carbonate solution (100 ml), then the resulting mixture was stirred for 5 min and the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and the solvent is kept at reduced pressure. The obtained residue was subjected to chromatography on a column of silica gel (250 g) (eluent: ethyl acetate:hexane=1:10) to obtain specified in the connection header (12,07 g, yield 88%) as oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,52-1,91 (12H, m), 3,52-3,59 (2H, m), 3,85-3,93 (2H, m), 4,47 (1H, d, J=12 Hz), of 4.57 (1H, d, J=13 Hz), 4,69 (1H, t, J=4 Hz), 4,74 (1H, d, J=12 Hz), of 4.77 (1H, t, J=4 Hz), to 4.81 (1H, d, J=13 Hz), 7,30 (1H, DD, J=8, 1 Hz)of 7.48 (1H, d, J=8 Hz), EUR 7.57 (1H, d, J=1 Hz).

IR-spectrum ν max CHCl3cm-1: 2947, 108, 1562, 1388, 1345, 1075, 1032, 973, 906.

Mass spectrum m/z (FAB): 385, 387 (M++1).

(3) 2,5-Bis[(tetrahydropyran-2-yl)oxymethyl]benzoic acid

n-Utility (1,57 M solution in hexane; 8,33 ml of 13.1 mmol) was added dropwise to a solution of 2-bromo-1,4-bis[(tetrahydropyran-2-yl)oxymethyl]benzene (3.55 g, which 9.22 mmol)obtained in example 1-(2), in tetrahydrofuran (30 ml) under stirring at -78°C. After stirring the mixture at this temperature for 20 min in it for 40 min was injected gaseous carbon dioxide. The resulting mixture was stirred at the same temperature for 1 hour and then the reaction was stopped by adding a saturated aqueous solution of ammonium chloride. The mixture was heated to 0°C and then the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and the solvent drove under reduced pressure to obtain a residue. The residue was subjected to chromatography on a column of silica gel (100 g) (eluent: ethyl acetate:hexane=1:3) to obtain the specified title compound (1.63 g, yield 50%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,55-of 1.92 (12H, m), 3,56-of 3.60 (2H, m), 3,88-of 3.95 (2H, m), 4,55 (1H, d, J=12 Hz), to 4.73 (1H, t, J=4 Hz), to 4.81 (1H, t, J=4 Hz), 4,82 (1H, d, J=12 Hz), 4,96 (1H, d, J=15 Hz), further 5.15 (1H, d, J=15 Hz), to 7.59 (1H, DD, J=8, 1 Hz), of 7.70 (1H, d, J=8 Hz), of 8.06 (1H, d, J=1 Hz).

IR-spectrum ν max CHCl3cm-1: 2947, 1730, 1693, 1261, 1031, 908.

<> Mass spectrum m/z (FAB): 351 (M++1).

(4) 6-(Hydroxymethyl)-1(3H)-isobenzofuranone

To a solution of 2,5-bis[(tetrahydropyran-2-yl)oxymethyl]benzoic acid (1,62 g, with 4.64 mmol)obtained in example 1-(3), in methanol (30 ml) was added monohydrate p-toluenesulfonic acid (103,0 mg, 0.54 mmol) and the mixture was stirred at room temperature for 2 hours. The resulting solution was concentrated under reduced pressure to obtain a solid residue. The residue was subjected to chromatography on a column of silica gel (50 g) (eluent: ethyl acetate:hexane=1:1˜1:0) to obtain specified in the connection header (587,5 mg, yield 77%) as a colourless solid (TPL 107-108°C).

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,91 (1H, t, J=5 Hz), a 4.83 (2H, d, J=5 Hz), 5,33 (2H, s), 7,49 (1H, d, J=8 Hz), 7,72 (1H, d, J=8 Hz), to 7.93 (1H, s).

IR-spectrum ν max KBr cm-1: 3461, 1735, 1048, 996, 771.

Mass spectrum m/z (EI): 164 (M+).

(5) Methyl 2,5-bis(acetoxymethyl)benzoate

Sodium acetate (10.4 g, to 126.8 mmol) was added to a solution of methyl 2,5-bis(methyl bromide)benzoate (described in J. Am. Chem. Soc., 121, 1192 (1999); 12,65 g, at 39.3 mmol) in dimethyl sulfoxide (80 ml) and the mixture was stirred at room temperature for 1 hour. After adding a saturated aqueous solution of ammonium chloride (150 ml) the product was extracted with ethyl acetate. The organic layer was washed with water, then saturated aq is m solution of sodium chloride and the solvent is kept at reduced pressure. The obtained oily residue was subjected to chromatography on a column of silica gel (200 g) (eluent: ethyl acetate:hexane=1:5˜1:2) to obtain specified in the connection header (7,72 g, yield 70%) as oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2,12 (3H, s), and 2.14 (3H, s)to 3.92 (3H, s)to 5.13 (2H, s), the 5.51 (2H, s), 7,49 (1H, d, J=8 Hz), 7,53 (1H, DD, J=8, 1 Hz), 7,98 (1H, d, J=1 Hz).

IR-spectrum ν max CHCl3cm-1: 1737, 1255, 1037.

Mass spectrum m/z (FAB): 281 (M++1).

(6) 6-(Hydroxymethyl)-1(3H)-isobenzofuranone

To a solution of methyl 2,5-bis(acetoxymethyl)benzoate (7,72 g, 27.5 mmol)obtained in example 1-(5), in methanol (100 ml) was added potassium carbonate (380,7 mg, 2.7 mmol) and after stirring the mixture at room temperature for 2 hours, thereto was added 2 N. aqueous solution of hydrochloric acid (10 ml). The solvent is kept under reduced pressure and the resulting solid residue was recrystallized from methanol to obtain specified in the title compound (2.20 g) as a colourless solid. Then the mother liquor was concentrated under reduced pressure to obtain a solid residue. The residue was subjected to chromatography on a column of silica gel (100 g) (eluent: ethyl acetate:hexane=2:1˜3:1) to obtain specified in the connection header (1,05 g) as colorless solids (total number; 3.25 g, yield 76%). The data of the spectra of this link is consistent with the data, described in Example 1-(4).

(7) 6-[(tert-Butyldimethylsilyl)oxymethyl]-1(3H)-isobenzofuranone

tert-BUTYLCARBAMATE (647,3 mg, 4.30 mmol) and imidazole (292,3 mg, 4.30 mmol) was added to 6-(hydroxymethyl)-1(3H)-isobenzofuranone (587,5 mg, 3.58 mmol)obtained in Example 1-(4) or Example 1-(6)in N,N-dimethylformamide (10 ml). After stirring the mixture at room temperature for 1 hour, thereto was added water (20 ml) and then the product was extracted with a mixed solvent (ethyl acetate and hexane). The organic layer was washed with water, then saturated aqueous sodium chloride and the solvent drove under reduced pressure to obtain an oily residue. The residue was subjected to chromatography on a column of silica gel (25 g) (eluent: ethyl acetate:hexane=1:10˜1:1) to obtain specified in the connection header (940,1 mg, yield 94%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 0,12 (6H, s)of 0.95 (9H, s), a 4.83 (2H, s), 5,31 (2H, s), 7,45 (1H, d, J=8 Hz), to 7.67 (1H, d, J=8 Hz), 7,88 (1H, s).

IR-spectrum ν max CHCl3cm-1: 2956, 2931, 2958, 1766, 1156, 840.

Mass spectrum m/z (FAB): 279 (M++1).

(8) 4-Methoxybenzyl 2-(acetoxymethyl)-5-[(tert-butyldimethylsilyl)oxymethyl]benzoate

An aqueous solution (1.2 ml) of potassium hydroxide (188,0 mg, 3.35 mmol) was added to a solution of 6-[(tert-butyldimethylsilyl)oxymethyl]-1(3H)-isobenzofuranone (932,9 mg, 3.35 mmol)obtained in example 1(7), in tetrahydrofuran (3 ml). After stirring the reaction mixture at room temperature for 4 hours the solution was concentrated under reduced pressure and the residue was dried using a vacuum pump to obtain an amorphous solid. The solid was dissolved in N,N-dimethylformamide (10 ml), was added 4-methoxybenzylamine (577,3 mg of 3.69 mmol) and the mixture is then stirred at 80°C for 1 hour. After cooling the mixture to it was added a saturated aqueous solution of ammonium chloride and the product was extracted with ethyl acetate. The organic layer was washed with water, then saturated aqueous sodium chloride and the solvent drove under reduced pressure to obtain an oily residue. The residue was dissolved in dichloromethane (10 ml), and then at 0°C was added 4-(N,N-dimethylamino)pyridine (450,3 mg of 3.69 mmol) and acetylchloride (289,4 mg of 3.69 mmol). The mixture was stirred at this temperature for 30 min and was added saturated aqueous sodium hydrogen carbonate solution to stop reaction. The product was extracted with ethyl acetate and the extract was concentrated to obtain an oily residue. The residue was subjected to chromatography on a column of silica gel (50 g) (eluent: ethyl acetate:hexane=1:10 ˜ 1: 5) to obtain specified in the connection header (905,6 mg, yield 59%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) #x003B4; ppm: of 0.08 (6H, s)to 0.92 (9H, s), of 2.08 (3H, s), 3,82 (3H, s), 4,74 (2H, s), 5,28 (2H, s)5,49 (2H, s)6,91 (2H, d, J=8 Hz), 7,38 (2H, d, J=8 Hz), the 7.43 (1H, d, J=7 Hz), of 7.48 (1H, DD, J=7, 1 Hz), 7,94 (1H, d, J=1 Hz).

IR-spectrum ν max CHCl3cm-1: 2957, 2931, 2858, 1721, 1257, 909, 839.

Mass spectrum m/z (FAB): 457 (M+-1).

(9) 4-Methoxybenzyl 2-(acetoxymethyl)-5-(hydroxymethyl)benzoate

The tetrabutylammonium fluoride (1 n solution in tetrahydrofuran; to 9.9 ml, 9.9 mmol) and acetic acid (592,9 mg, 9,87 mmol) was added to a solution of 4-methoxybenzyl 2-(acetoxymethyl)-5-[(tert-butyldimethylsilyl)oxymethyl]benzoate (905 mg, 1.97 mmol)obtained in example 1-(8), in tetrahydrofuran (5 ml). The mixture was stirred at 50°C for 1 hour and the solvent is then drove away under reduced pressure. The oily residue was subjected to chromatography on a column of silica gel (25 g) (eluent: ethyl acetate:hexane=1:1) to obtain specified in the connection header (500,1 mg, yield 74%) as a colorless amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2,09 (3H, s), 3,82 (3H, s), 4.72 in (2H, s), from 5.29 (2H, s), of 5.50 (2H, s)6,91 (2H, d, J=9 Hz), 7,39 (2H, d, J=9 Hz), 7,47 (1H, d, J=8 Hz), 7,53 (1H, DD, J=8, 1 Hz)of 7.97 (1H, d, J=1 Hz).

IR-spectrum ν max KBr cm-1: 1737, 1714, 1519, 1253, 1039.

Mass spectrum m/z (FAB): 345 (M++1).

(10) 4-Methoxybenzyl 2-(acetoxymethyl)-5-[[bis(allyloxy)phosphoryl]oxymethyl]benzoate

A solution of 4-methoxybenzyl 2-(acetoxymethyl)-5-(hydroxymethyl)benzoate (480,4 mg, 1,40 IMO the b) obtained in example 1-(9), in dichloromethane (10 ml) was cooled to 0°C, then under stirring was added tetrazole (195,4 mg, and 2.79 mmol) and bis(allyloxy)(diisopropylamino)phosphine (Tetrahedron Lett., 30, 4219 (1989); 444,9 mg, 1.82 mmol), followed by stirring the mixture at this temperature for 15 minutes After the reaction mixture was heated to room temperature and was stirred for 1 hour, thereto was added methanol (12 drops). The mixture was stirred for 5 min and then was cooled to 0°C was added tert-butyl hydroperoxide (80% solution of di-tert-butylperoxide; Merck; 0,54 g, 4.8 mmol), then the mixture was heated to room temperature and was stirred for 15 minutes To the mixture was added saturated aqueous sodium hydrogen carbonate solution and aqueous sodium thiosulfate solution, and the mixture was stirred for 10 min and was distributed between ethyl acetate and water. The obtained organic layers were combined and the solvent drove under reduced pressure to obtain an oily residue. The residue was subjected to chromatography on a column of silica gel (25 g) (eluent: ethyl acetate:hexane=1:2˜1:1) to obtain specified in the connection header (598,3 mg, yield 85%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2,10 (3H, s), 3,82 (3H, s), 4,50-a 4.53 (4H, m)5,08 (2H, d, J=8 Hz), 5,23 (2H, DD, J=11, 1 Hz), from 5.29 (2H, s), 5,33 (2H, DD, J=17, 1 Hz), the 5.51 (2H, s), 5,90 (2H, DDT, J=17, 11, 5 Hz), 6,91 (2H, d, J=8 Hz, 7,39 (2H, d, J=8 Hz), 7,49 (1H, d, J=8 Hz), 7,55 (1H, DD, J=8, 2 Hz), 7,98 (1H, d, J=2 Hz)

IR-spectrum ν max CHCl3cm-1: 1721, 1516, 1256, 1031, 989

Mass spectrum m/z (FAB): 505 (M++1).

(11) 2-(Acetoxymethyl)-5-[[bis(allyloxy)phosphoryl]-oxymethyl]benzoic acid

A mixture of 4-methoxybenzyl 2-(acetoxymethyl)-5-[[bis-(allyloxy)phosphoryl]oxymethyl]benzoate (590,3 mg, at 1.17 mmol)obtained in example 1-(10), and anisole (600 mg, 5,55 mmol) was cooled to 0°C and then under stirring was added triperoxonane acid (2 ml). The mixture was heated to room temperature and left for 20 minutes the Mixture was diluted with toluene, concentrated under reduced pressure to remove volatile components (repeated three times) and to the mixture was added aqueous sodium hydrogen carbonate solution, then the aqueous layer was washed with ethyl acetate. To the aqueous layer was carefully added 2 N. aqueous solution of hydrochloric acid (10 ml) and the released carboxylic acid was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and the solvent drove under reduced pressure to obtain specified in the connection header (477,5 mg, quantitative yield) as a colorless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2,17 (3H, s), of 4.57 (4H, m), 5,15 (2H, d, J=8 Hz), 5,27 (2H, d, J=10 Hz), are 5.36 (2H, DD, J=17, 1 Hz), to 5.57 (2H, s), of 5.92 (2H, DDT, J=17, 10, 7 Hz), 7,55 (1H, d, J=8 Hz), to 7.61 (1H, DD, J=8, 2 Hz), 8,13 (1H, user. C)./p>

IR-spectrum ν max CHCl3cm-1: 1738, 1700, 1256, 1167, 1028, 989.

Mass spectrum m/z (FAB): 385 (M++1).

(12) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-(acetoxymethyl)-5-[[bis(allyloxy)phosphoryl]oxymethyl]benzoate

2-(Acetoxymethyl)-5-[[bis(allyloxy)phosphoryl]oxymethyl]benzoic acid (475,5 mg of 1.24 mmol)obtained in example 1-(11), was dissolved in tetrahydrofuran (5 ml) and the solution was cooled to 0°C, then under stirring was added oxalicacid (189,2 mg, 1,49 mmol) and N,N-dimethylformamide (15 ml). The mixture was heated to room temperature and then was stirred for 40 minutes, the Solvent is kept at reduced pressure to obtain crude 2-(acetoxymethyl)-5-[[bis(allyloxy)phosphoryl]oxymethyl]benzoyl chloride.

To a mixture of 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (544,6 mg, 1.00 mmol), described below in reference example 1, and tetrahydrofuran (5 ml) was added sodium hydride (55% dispersion in mineral oil; 56,9 mg of 1.31 mmol) and the mixture was treated with ultrasound for 30 min using a commercially available ultrasonic cleaner. The mixture was removed from the ultrasonic cleaner and cooled to 0°C under stirring to the mixture was added the whole amount of the crude 2-(acetoxymethyl)-5-[[bis(allyloxy)phosphoryl]oxymethyl]benzoyl chloride, obtained above. The resulting mixture was stirred at room temperature for 40 minutes After cooling, the reaction mixture was distributed between ethyl acetate and an aqueous solution of ammonium chloride, the organic layer was washed with a saturated aqueous solution of sodium chloride and the solvent is kept at reduced pressure. The oily residue was subjected to chromatography on a column of silica gel (30 g) (eluent: ethyl acetate:hexane=2:1) to obtain specified in the connection header (368,3 mg, yield 41%) as a pale yellow amorphous solid.

NMR-spectrum (400 MHz, CDCl3) δ ppm: of 1.46 (3H, DD, J=7, 2 Hz), of 2.15 (3H, s), 3.04 from (1H, TT, J=11, 5 Hz), 3,53 (1H, t, J=11 Hz), of 3.54 (1H, t, J=11 Hz), was 4.02 (1H, q, J=7 Hz), 4,11-4,20 (2H, m), 4,49-of 4.57 (4H, m), free 5.01 (1H, d, J=4 Hz), 5,11 (2H, d, J=8 Hz), 5,23 (2H, DD, J=10, 5 Hz), 5,33 (2H, DDD, J=17, 6, 1 Hz), 5,43 (1H, d, J=14 Hz), 5,47-of 5.55 (3H, m), of 5.83-5,96 (3H, m), 6,56 (1H, DD, J=15, 11 Hz), was 6.73 (1H, d, J=16 Hz), 6.89 in-6,97 (3H, m), 7,33 (1H, DD, J=10, 1 Hz), 7,40 (1H, DD, J=8, 1 Hz), 7,42-7,46 (1H, m), 7,56-of 7.60 (2H, m), a 7.62 (1H, DD, J=8, 1 Hz), the 7.85 (1H, d, J=1 Hz), 7,89 (1H, s), of 7.96 (1H, s).

IR-spectrum ν max Liquid film, cm-1: 2232, 1731, 1504, 1276, 1258, 1026, 733.

Mass spectrum m/z (FAB): 909 (M++1).

(13) 4-(Acetoxymethyl)-3-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]benzyl phosphate sodium (specified in the header of the target connection)

To a solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyan is-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-(acetoxymethyl)-5-[[bis(allyloxy)phosphoryl]oxymethyl]benzoate (368,3 mg, 0.41 mmol)obtained in example 1-(12), in dichloromethane (5 ml) was added bis(triphenylphosphine)dichloropalladium (14,7 mg, 0.02 mmol) and anti-hydride (240,1 mg, 0.83 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and to the residue was added hexane (30 ml) and saturated aqueous sodium hydrogen carbonate solution (30 ml), then the resulting mixture was stirred at room temperature for 30 minutes To the mixture was added methanol, and then water-methanol layer was separated and the solvent drove under reduced pressure to obtain a residue. To the residue was added methanol (30 ml) for washing the solids, then the combined washing liquid was concentrated to obtain an oily residue. The residue was subjected to column chromatography with reversed phase using Cosmosil 75 C18-PREP (Nacalai Tesque, Inc.; 20 g) (eluent: water:methanol=4:6˜3:7). The fractions obtained were concentrated and the residue was liofilizovane obtaining specified in the header of the target compounds (for 85.6 mg, yield 25%) as a colourless solid.

NMR-spectrum (400 MHz, CD3OD) δ ppm: the 1.44 (3H, DD, J=7, 2 Hz), 2,12 (3H, s), 2,97 (1H, TT, J=11, 5 Hz), of 3.54 (1H, t, J=11 Hz), 3,55 (1H, t, J=11 Hz), Android 4.04 (1H, q, J=7 Hz), 4,08-4,16 (2H, m), 4,96 (2H, d, J=5 Hz), to 5.03 (1H, d, J=5 Hz), of 5.39 (1H, d, J=14 Hz), of 5.48 (1H, d, J=14 Hz), of 5.55 (1H, d, J=15 Hz), 5,61 (1H, DD, J=15, 2 Hz), by 5.87 (1H, DD, J=15, 5 Hz), to 6.57 (1H, DD, J=1, 11 Hz), 6,78 (1H, d, J=16 Hz), 7,02-to 7.09 (2H, m), 7,10 (1H, DD, J=16, 11 Hz), 7,49-7,66 (4H, m), 7,79 (1H, t, J=8 Hz), 7,86 (1H, DD, J=8, 1 Hz), 7,92 (1H, s), 7,94 (1H, d, J=1 Hz), of 8.28 (1H, s).

IR-spectrum ν max KBr cm-1: 3433, 2231, 1733, 1503, 1384, 1141, 1120, 975, 543.

Mass spectrum m/z (FAB): 851 (M++1).

[Example 2]

Sodium 2-acetoxy-5-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-5-oxopentanoate (sodium salt of example number 4-20)

(1) Allyl 5-[(4-methoxybenzyl)oxy]-2,5-dioxopentanoate

2-Oxoglutaric acid (2,92 g, 20.0 mmol), dicyclohexylamine (3,63 g, 20.0 mmol) and allibiotic (2,01 ml of 22.0 mmol) was dissolved in N,N-dimethylformamide (30 ml) and the mixture was heated to 60°C and was stirred for 30 minutes To the mixture was added dicyclohexylamine (3,63 g, 20.0 mg) and 4-methoxybenzylamine (3.13 g, 20.0 mmol) and the resulting mixture was stirred at this temperature for 30 minutes After cooling, the mixture was distributed between water and ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride and the solvent drove under reduced pressure to obtain an oily residue. The residue was subjected to chromatography on a column of silica gel (85 g) (eluent: ethyl acetate:hexane=1:5 ˜ 9:25) to obtain specified in the header is connected to the I (1.48 g, yield 24%) as a pale yellow oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2,70 (2H, t, J=7 Hz), 3,17 (2H, t, J=7 Hz), 3,81 (3H, s), and 4.75 (2H, DD, J=6, 1 Hz), is 5.06 (2H, s), 5,33 (1H, DD, J=10, 1 Hz), 5,41 (1H, DD, J=17, 1 Hz), 5,95 (1H, DDT, J=17, 10, 6 Hz), 6.89 in (2H, d, J=9 Hz), 7,28 (2H, d, J=9 Hz).

IR-spectrum ν max CHCl3cm-1: 1732, 1516, 1252, 1173, 1080, 1036.

Mass spectrum m/z (EI): 306 (M+).

(2) Allyl 2-hydroxy-5-[(4-methoxybenzyl)oxy]-5-oxopentanoate

Zinc chloride (a 1.0 M solution in diethyl ether; and 8.8 ml of 8.8 mmol) was added to tetrahydrofuran (5 ml) and to the mixture under stirring at 0°C was added sodium borohydride (605,3 mg, 16.0 mmol). The mixture was treated with ultrasound for 10 minutes using a commercially available ultrasonic cleaner. The mixture was removed from the ultrasonic cleaner and cooled to -5°C was added a solution of allyl 5-[(4-methoxybenzyl)oxy]-2,5-dioxopentanoate (1.84 g, 6.0 mmol)obtained in example 2-(1)in tetrahydrofuran (5 ml) over a period of time of 10 minutes the resulting mixture was stirred for 30 min and then thereto was added a saturated aqueous solution of ammonium chloride to stop the reaction, followed by extraction of the product with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and the solvent drove under reduced pressure to obtain an oily residue. The residue was subjected to chromatography on columns is e with silica gel (65 g) (eluent: ethyl acetate:hexane=3:10˜ 2:5) to obtain the specified title compound (1.26 g, yield 68%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,91-2,05 (1H, m), 2,16-of 2.24 (1H, m), 2,43-to 3.58 (2H, m), 3,81 (3H, s), 4,23-4,27 (1H, m), of 4.67 (2H, dt, J=6, 1 Hz), is 5.06 (2H, s), 5,28 (1H, dt, J=10, 1 Hz), of 5.34 (1H, DQC, J=18, 1 Hz), 5,91 (1H, DDT, J=18, 10, 6 Hz), 6.89 in (2H, d, J=9 Hz), 7,29 (2H, d, J=9 Hz).

IR-spectrum ν max CHCl3cm-1: 3322, 1743, 1252, 1171.

Mass spectrum m/z (FAB): 309 (M++1).

(3) Allyl 2-acetoxy-5-[(4-methoxybenzyl)oxy]-5-oxopentanoate

Allyl 2-hydroxy-5-[(4-methoxybenzyl)oxy]-5-oxopentanoate (1.26 g, 4.09 to mmol)obtained in example 2-(2), was dissolved in pyridine (15 ml) at 0°C was added acetylchloride (481,2 mg, 6,13 mmol). The mixture was heated to room temperature and was stirred for 30 min, then, after cooling to 0°C, to the mixture was added saturated aqueous solution of sodium bicarbonate, followed by extraction of the product with ethyl acetate. The organic layer was washed with diluted aqueous hydrochloric acid solution and saturated aqueous sodium chloride and the solvent drove under reduced pressure to obtain an oily residue. The residue was subjected to chromatography on a column of silica gel (60 g) (eluent: ethyl acetate:hexane=1:5) to obtain specified in the connection header (1,36 g, yield 95%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2,11 (3H, s),2,12-of 2.30 (2H, m), 2,41-2,52 (2H, m), 3,81 (3H, s), 4,63 (2H, d, J=6 Hz), 5,04 is 5.07 (1H, m), is 5.06 (2H, in), 5.25 (1H, DD, J=10, 1 Hz), 5,33 (1H, DD, J=18, 1 Hz), of 5.89 (1H, DDT, J=18, 10, 6 Hz), 6.89 in (2H, d, J=9 Hz), 7,29 (2H, d, J=9 Hz).

IR-spectrum ν max CHCl3cm-1: 1742, 1614, 1516, 1252, 1170, 1036.

Mass spectrum m/z (FAB): 351 (M++1).

(4) 4-Acetoxy-5-allyloxy-5-oxopentanoic acid

According to the method similar to that described in Example 1-(11)was subjected to the reaction of allyl 2-acetoxy-5-[(4-methoxybenzyl)oxy]-5-oxopentanoate (1,36 g, 3.88 mmol)obtained in example 2-(3), anisole (1.50 g, 13,87 mmol) and triperoxonane acid (3 ml) and the reaction mixture was treated with obtaining specified in the title compound (1.04 g, quantitative yield).

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2,15 (3H, s)to 2.18 (1H, DDD, J=16, 8, 1 Hz), 2,23-of 2.30 (1H, m), 2,45 at 2.59 (2H, m)and 4.65 (2H, dt, J=6, 1 Hz), 5,09 (1H, DD, J=8, 5 Hz), 5,27 (1H, dt, J=17, 1 Hz), to 5.35 (1H, DD, J=10, 1 Hz), 5,91 (1H, DDT, J=17, 10, 6 Hz).

IR-spectrum ν max CHCl3cm-1: 1746, 1714, 1375, 1276, 1248, 1184, 1077.

Mass spectrum m/z (FAB): 231 (M++1).

(5) Allyl 2-acetoxy-5-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-5-oxopentanoate

According to the method similar to that described in Example 1-(12), carried out the reaction of 4-acetoxy-5-allyloxy-5-oxopentanoic acid (345,3 mg, 1.50 mmol)obtained in example 2-(4), and ACS is lillolita (209,4 mg, of 1.65 mmol) and the reaction mixture was treated with obtaining 4-acetoxy-5-allyloxy-5-oxopentanoate in the form of a crude product.

According to the method similar to that described in Example 1-(12), carried out the reaction of 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (542,6 mg, 1.00 mmol)described in reference example 1, sodium hydride (55% dispersion in mineral oil; 96.0 mg, of 2.20 mmol) and the crude 4-acetoxy-5-allyloxy-5-oxopentanoate obtained above in tetrahydrofuran (7 ml) and the reaction mixture was treated with obtaining, after extraction, is specified in the header connection in the form of crude oil. The crude oil was subjected to chromatography on a column of silica gel (50 g) (eluent: ethyl acetate:hexane=1:1) mixture (567,4 mg, corresponds to 283 mg specified in the connection header) specified in the connection header and the source of the substance 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate.

(6) Sodium 2-acetoxy-5-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-5-oxopentanoate (specified in the header of the target connection)

According to the method similar to that described in the ore 1-(13), spent reaction mixture of allyl 2-acetoxy-5-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-5-oxopentanoate and 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (all amounts obtained in example 2-(5)), bis(triphenylphosphine)dichloropalladium (12.9 mg, 0.018 mmol) and anti-hydride (116,4 mg, 0.40 mmol) and the reaction the mixture was treated with obtaining specified in the header of the target compound in the form of crude oil. The crude oil was subjected to column chromatography with reversed phase using Cosmosil 75 C18-PREP (Nacalai Tesque, Inc.; 20 g) (eluent: water:methanol=4:6 ˜ 3:7). The fractions obtained were concentrated and the residue was liofilizovane obtaining specified in the title target compound (86,0 mg, total yield obtained in Example 2-(5), 12%) as a colourless solid.

NMR-spectrum (400 MHz, CD3OD) δ ppm: 1,31 (3H, DD, J=7, 1 Hz), 2,11 (3H, s), 2,04-of 2.27 (2H, m), 2,45-2,62 (2H, m), 3,01 (1H, TT, J=11, 5 Hz), 3,52 (1H, t, J=11 Hz), 3,53 (1H, t, J=11 Hz), 3,82 ((1/2)H, q, J=7 Hz), 3,84 ((1/2)H, q, J=7 Hz), 4,11-is 4.21 (2H, m), 4,86-4,91 (1H, m), 5,04 (1H, d, J=4 Hz), 5,41 (1H, d, J=15 Hz), 5,46 (1H, DD, J=15, 2 Hz), by 5.87 (1H, DD, J=15, 4 Hz), 6,59 (1H, DD, J=15, 11 Hz), 6,79 (1H, d, J=15 Hz), 6,97-7,05 (2H, m), to 7.09 (1H, DD, J=15, 11 Hz), 7,50-of 7.55 (3H, m), 7,78 (1H, t, J=8 Hz), 7,98 ((1/2)H, (C), 7,99 ((1/2)H, (C), 8,31 ((1/2)H, (C), 8,33 ((1/2)H, is).

IR-spectrum ν max KBr cm-1: 3436, 2231, 1734, 1615, 1417, 1385, 1257, 1142, 1051.

Mass spectrum m/z (FAB): 737 (M++1).

[Example 3]

Sodium [(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl]TRANS-2-(acetoxymethyl)-1,1-cyclopropanecarboxylate (sodium salt of example number 6-2)

(1) Allyl 4-methoxybenzyl CIS-2-(acetoxymethyl)-1,1-cyclopropanedicarboxylic

Allyl 2-oxo-3-oxabicyclo[3,1,0]hexane-1-carboxylate (described in J. Org. Chem., 54, 5684 (1989); 644,2 mg, 3.54 mmol) was dissolved in allyl alcohol was added potassium hydroxide (178,6 mg, 3,18 mmol) followed by stirring the mixture at room temperature for 20 minutes, the Solvent is kept under reduced pressure and the residue was dried using a vacuum pump to obtain an amorphous solid. The solid was dissolved in N,N-dimethylformamide (3 ml) and to the mixture was added 4-methoxybenzylamine (664,0 mg, 4,11 mmol) followed by stirring the mixture at 80°C for 20 min After cooling the mixture to it was added a saturated aqueous solution of ammonium chloride and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and the solvent is kept at reduced pressure with the teachings of oily residue. The residue was dissolved in dichloromethane (10 ml) and to it was added 4-(N,N-dimethylamino)pyridine (432,0 mg, 3.54 mmol) and acetylchloride (277,6 mg, 3.54 mmol) at 0°C. the resulting mixture was stirred at this temperature for 1 hour, then added water to stop reaction. The reaction product was extracted with dichloromethane and the extract was concentrated under reduced pressure to obtain an oily residue. The residue was subjected to chromatography on a column of silica gel (35 g) (eluent: ethyl acetate:hexane=1:4 ˜ 1:2) to obtain specified in the connection header (521,9 mg, yield 41%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,48 (1H, DD, J=9, 5 Hz), of 1.57 (1H, DD, J=8, 5 Hz), 1,95 (3H, s), 2,25 of-2.32 (1H, m), 3,81 (3H, s), 3,93 (1H, DD, J=12, 8 Hz), 4,19 (1H, DD, J=12, 6 Hz), 4,55-of 4.66 (2H, m), 5,11 (1H, d, J=12 Hz), further 5.15 (1H, d, J=12 Hz), to 5.21 (1H, d, J=11 Hz), from 5.29 (1H, dt, J=17, 1 Hz), of 5.83 (1H, DDT, J=17, 11, 5 Hz), to 6.88 (2H, d, J=8 Hz), 7,30 (2H, d, J=8 Hz).

IR-spectrum ν max CHCl3cm-1: 1730, 1516, 1321, 1255, 1132, 1035, 909.

Mass spectrum m/z (FAB): 363 (M++1).

(2) Alligero TRANS-2-(acetoxymethyl)-1,1-cyclopropane-in primary forms

According to the method similar to that described in Example 1-(11)was subjected to the reaction of allyl 4-methoxybenzyl CIS-2-(acetoxymethyl)-1,1-cyclopropanecarboxylate (521,9 mg, 1.44 mmol)obtained in example 3-(1), anisole (600 mg, 5,55 mmol) and triperoxonane acid (3 ml) and the reaction mixture is about relatively obtaining specified in the connection header (340,1 mg, yield 97%).

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,99 (1H, DD, J=9, 4 Hz), 2,02 (1H, DD, J=9, 5 Hz), was 2.05 (3H, s), 2.40 a-2,48 (1H, m), 4,17 (1H, DD, J=12 and 9 Hz), 4,58 (1H, DD, J=12, 5 Hz), with 4.64-of 4.75 (2H, m), of 5.34 (1H, d, J=10 Hz), to 5.35 (1H, d, J=17 Hz), 5,88 (1H, DDT, J=17, 10, 5 Hz).

IR-spectrum ν max CHCl3cm-1: 1758, 1679, 1410, 1373, 1153, 1036.

Mass spectrum m/z (FAB): 243 (M++1).

(3) Allyl (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl CIS-2-(acetoxymethyl)-1,1-cyclopropanedicarboxylic

According to the method similar to that described in Example 1-(12), carried out the reaction of alligero TRANS-2-(acetoxymethyl)-1,1-cyclopropanecarboxylate (333,8 mg, 1.38 mmol)obtained in example 3-(2), and oxalicacid (159,5 mg of 1.26 mmol) and the reaction mixture was treated with obtaining CIS-2-(acetoxymethyl)-1-[(allyloxy)carbonyl]cyclopropanecarbonitrile in the form of a crude product.

According to the method similar to that described in Example 1-(12), carried out the reaction of 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (547,0 mg, 1.01 mmol)described in reference example 1, sodium hydride (55% dispersion in mineral oil; 57,2 mg of 1.31 mmol) and the crude CIS-2-(acetoxymethyl)-1-[(allyloxy)carbonyl]cyclopropanecarbonitrile (all amount received is passed above in tetrahydrofuran (5 ml) and the reaction mixture was treated with obtaining after extraction is specified in the header connection in the form of crude oil. The crude oil was subjected to chromatography on a column of silica gel (50 g) (eluent: ethyl acetate:hexane=1:1) mixture (669,3 mg, corresponds 270,5 mg specified in the connection header) specified in the connection header and 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate.

(4) Sodium [(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl]TRANS-2-(acetoxymethyl)-1,1-cyclopropanecarboxylate (specified in the header of the target connection)

According to the method similar to that described in Example 1-(13)was subjected to the reaction mixture of allyl (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl]CIS-2-(acetoxymethyl)-1,1-cyclopropanecarboxylate and 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (all amounts obtained in example 3-(3)), bis(triphenylphosphine)dichloropalladium (12,4 mg, 0.018 mmol) and anti-hydride (112,9 mg, 0,39 mmol) and the reaction mixture was treated with obtaining specified in the connection header in the form of crude oil. The crude oil was subjected to column chromatography with reversed phase used is eat Cosmosil 75 C 18-PREP (Nacalai Tesque, Inc.; 50 g)(eluent: water:methanol=1:1 ˜ 3:7). The fractions obtained were concentrated and the residue was liofilizovane obtaining specified in the title target compound (100,1 mg, yield 38%) as a colourless solid.

NMR-spectrum (400 MHz, CD3OD) δ ppm: 1,06 ((1/2)H, DD, J=6, 4 Hz), of 1.27 to 1.31 ((1/2)H, overlapped), 1,29 ((3/2)H, DD, J=7, 2 Hz), 1,32 ((3/2)H, J=7, 1 Hz), 1,43 ((1/2)H, DD, J=9, 4 Hz), 1,44 ((1/2)H, DD, J=9, 4 Hz), 1,86-1,94 ((1/2)H, m), 1,97-2,04 ((1/2)H, m)2,03 ((3/2)H, C)2,05 ((3/2)H, (C), 2,99 ((1/2)H, TT, J=11, 5 Hz), 3,09 ((1/2)H, TT, J=11, 5 Hz), 3,51 ((1/2)H, t, J=11 Hz), 3,53 ((1/2)H, t, J=11 Hz), 3,54 ((1/2)H, t, J=11 Hz), 3,55 ((1/2)H, t, J=11 Hz), 3,68 ((1/2)H, q, J=7 Hz), to 3.73 ((1/2)H, q, J=7 Hz), 4.04 the-4,30 (4H, m), 5,02 ((1/2)H, d, J=5 Hz), 5,04 ((1/2)H, d, J=5 Hz), 5,35 ((1/2)H, d, J=15 Hz), 5,41 ((1/2)H, d, J=15 Hz), 5,48 ((1/2)H, DD, J=15, 2 Hz), of 5.53 ((1/2)H, d, J=15 Hz), by 5.87 (1H, DD, J=15, 5 Hz), 6,59 (1H, DD, J=15, 11 Hz), 6,76 (1H, d, J=16 Hz), 6.90 to-7,02 (2H, m), to 7.09 (1H, DD, J=16, 11 Hz), 7,49-rate of 7.54 (2H, m), 7,78 (1H, t, J=8 Hz), 7,86 ((1/2)H, (C), to 7.93 ((1/2)H, dt, J=9, 7 Hz), 7,97 ((1/2)H, (C), 8,39 ((1/2)H, dt, J=9, 7 Hz), 8,58 ((1/2)H, (C), 8,68 ((1/2)H, C).

IR-spectrum ν max KBr cm-1: 3430, 2231, 1733, 1612, 1504, 1370, 1243, 1140, 1051, 972.

Mass spectrum m/z (FAB): 749 (M++1).

[Example 4]

Disodium 5-cyano-2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]benzylester (disodium salt of example number 5-17)

(1) Methyl 2,4-bis(acetoxymethyl)benzoate

According to the method similar to that described in the Application of the e 1-(5), spent the reaction of methyl 2,4-bis(methyl bromide)benzoate (described in Chem. Ber., 127, 2081 (1994); 13,3 g, a 41.3 mmol) and sodium acetate (16.4 g, 200 mmol) and the reaction mixture was treated with obtaining after extraction indicated in the title compound as crude product. The crude product was subjected to chromatography on a column of silica gel (200 g) (eluent: ethyl acetate:hexane=3:17 ˜ 3:5) to obtain specified in the connection header (6,35 g, yield 55%) as oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2,14 (3H, s)of 2.16 (3H, s), 3,91 (3H, s), of 5.15 (2H, s)5,52 (2H, s), 7,37 (1H, d, J=8 Hz), 7,46 (1H, s), to 7.99 (1H, d, J=8 Hz).

IR-spectrum ν max CHCl3cm-1: 1737, 1255, 1056.

Mass spectrum m/z (FAB): 281 (M++1).

(2) 5-(Hydroxymethyl)-1(3H)-isobenzofuranone

According to the method similar to that described in Example 1-(6)was subjected to the reaction of methyl 2,4-bis(acetoxymethyl)benzoate (6,35 g, 22.7 mmol)obtained in example 4-(1), and potassium carbonate (373,2 mg, 2.7 mmol) and the reaction mixture was treated with obtaining after extraction indicated in the title compound as crude product. The crude product was subjected to chromatography on a column of silica gel (200 g) (eluent: ethyl acetate:dichloromethane=0:1 ˜ 1:10) to obtain specified in the connection header (2,94 g, yield 79%) as a colourless solid (TPL 126°C).

NMR-spectrum (400 MHz, CDCl3 ) δ ppm: to 4.87 (2H, s), 5,33 (2H, s), 7,51 (1H, d, J=8 Hz), 7,55 (1H, s), 7,92 (1H, d, J=8 Hz).

IR-spectrum ν max KBr cm-1: 3422, 1738, 1138, 1076, 768.

Mass spectrum m/z (EI): 164 (M+).

(3) 1-Oxo-1,3-dihydroisobenzofuran-5-carbaldehyde

5-(Hydroxymethyl)-1(3H)-isobenzofuranone (2,94 g of 17.9 mmol)obtained in example 4-(2), was dissolved in tetrahydrofuran (100 ml) and to the mixture was added activated manganese dioxide (31 g). The mixture was stirred at room temperature for 30 min and added an additional amount of activated manganese dioxide (3 g). The resulting mixture was stirred for additional 30 min and then filtered. The solid was filtered, washed with tetrahydrofuran and the washing liquid was combined with the previous filtrate, then the combined solution was concentrated under reduced pressure to obtain a solid residue. The residue was subjected to chromatography on a column of silica gel (150 g) (eluent: ethyl acetate:dichloromethane=0:1 ˜ 1:10). The eluate was concentrated under reduced pressure to obtain compound in the form of a solid, which was washed with mixed solvent of ethyl acetate-hexane (1:2) to obtain specified in the connection header (for 2.01 g, yield 69%) as a solid (TPL 160°C).

NMR-spectrum (400 MHz, CDCl3) δ ppm: 5,43 (2H, s), 8,03 (1H, s), of 8.06 (1H, d, J=8 Hz), 8,11 (1H, d, J=8 Hz), 10,18 (1H, s).

IR-spectrum ; max KBr cm-1: 1758, 1699, 1355, 1323, 1049, 993.

Mass spectrum m/z (EI): 162 (M+).

(4) 1-Oxo-1,3-dihydroisobenzofuran-5-carbonitrile

1-Oxo-1,3-dihydroisobenzofuran-5-carbaldehyde (2,01 g, 12.4 mmol)obtained in example 4-(3), suspended in tetrahydrofuran (50 ml) and after cooling the suspension to 0°C thereto was added hydroxylamine hydrochloride (1.04 g, 14.9 mmol) in aqueous sodium hydroxide solution (1.0 n; of 14.8 ml of 14.8 mmol). The resulting mixture was stirred at room temperature for 1 hour and then concentrated to 1/3 volume under reduced pressure. To the concentrated solution was added water and the product was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous solution of sodium chloride and the solvent drove under reduced pressure to obtain crude 1-oxo-1,3-dihydroisobenzofuran-5-carbaldehyde in the form of solids. The crude product was dissolved in tetrahydrofuran (50 ml) and the solution was cooled to 0°C, then to it was added triethylamine (3.04 from g, 30 mmol) and anhydrous triperoxonane acid (3.13 g, 14.9 mmol). The resulting mixture was stirred at this temperature for 30 min and then was heated to room temperature, followed by stirring for 30 minutes the Reaction mixture was again cooled to 0°C was added a saturated aqueous solution of hydrocar is onata sodium. The reaction product was extracted with ethyl acetate and the combined organic layers were washed with saturated aqueous solution of sodium chloride. The extract was concentrated under reduced pressure to obtain a solid residue. The residue was subjected to chromatography on a column of silica gel (150 g) (eluent: ethyl acetate:dichloromethane=0:1 ˜ 1:10) to obtain specified in the connection header (of 1.57 g, yield 79%) as a solid (TPL 200-201°C).

NMR-spectrum (400 MHz, CDCl3) δ ppm: of 5.40 (2H, s), to 7.84 (1H, s), a 7.85 (1H, d, J=9 Hz), to 8.12 (1H, d, J=9 Hz).

IR-spectrum ν max KBr cm-1: 1760, 1055, 1003, 681.

Mass spectrum m/z (EI): 159 (M+).

(5) 4-Methoxybenzyl 2-[[bis(allyloxy)phosphoryl]-oxymethyl]-4-cyanobenzoate

1-Oxo-1,3-dihydroisobenzofuran-5-carbonitrile (1.56 g, 9,78 mmol)obtained in Example 4-(4), suspended in tetrahydrofuran (15 ml) was added an aqueous solution of sodium hydroxide (1,008 n; 9,70 ml, 9,78 mmol). The mixture was stirred at room temperature for 15 min and the solvent drove away under reduced pressure. The residue was dried using a vacuum pump to obtain a solid amorphous material. The solid was dissolved in N,N-dimethylformamide (30 ml) was added 4-methoxybenzylamine (1,53 g, 9,78 mmol), then the mixture was stirred at 80°C for 5 minutes After cooling the mixture to 0°C dobavlenny aqueous solution of ammonium chloride and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and the solvent drove under reduced pressure to obtain an oily residue. The residue was dissolved in dichloromethane (50 ml) was added tetrazole (1.40 g, 20 mmol) and bis(allyloxy)(diisopropylamino)phosphine (Tetrahedron Lett., 30, 4219 (1989); 3,43 g, 14 mmol) at 0°C, then the resulting mixture was stirred at this temperature for 5 minutes the Mixture was heated to room temperature and was stirred for 20 min, then to it was added methanol (0.5 ml). The mixture was stirred for 10 min and cooled to 0°C, was added tert-butylhydroperoxide (80% solution of di-tert-butylperoxide; Merck; 2.7 g, 24 mmol) and the reaction mixture was heated to room temperature, followed by stirring for 20 minutes To the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution and aqueous sodium thiosulfate solution, the resulting mixture was stirred for 10 min and was distributed between ethyl acetate and water. The organic layers were combined and the solvent drove under reduced pressure to obtain a residue. The residue was subjected to chromatography on a column of silica gel (120 g) (eluent: ethyl acetate:hexane=2:3) to obtain a mixture of solid and oily substances. The mixture was washed with a mixed solvent of ethyl acetate-hexane and washing liquid conc the Vali with obtaining balance. The residue was subjected to chromatography on a column of silica gel (50 g) (eluent: ethyl acetate:hexane=2:3) to obtain the specified title compound (1.18 g, yield 26%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 3,82 (3H, s), 4,58-to 4.62 (4H, m), from 5.29 (2H, DD, J=10, 1 Hz), from 5.29 (2H, s), of 5.39 (2H, DD, J=17, 1 Hz), of 5.53 (2H, d, J=7 Hz), 5,96 (2H, DDT, J=17, 10, 5 Hz), 6,92 (2H, d, J=9 Hz), 7,37 (2H, d, J=9 Hz), the 7.65 (1H, DD, J=8, 2 Hz), 8,00 (1H, user. C)of 8.09 (1H, d, J=8 Hz).

IR-spectrum ν max CHCl3cm-1: 2237, 1721, 1613, 1516, 1266, 1031, 990.

Mass spectrum m/z (FAB): 458 (M++1).

(6) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-4-cyanobenzoate

A mixture of 4-methoxybenzyl 2-[[bis(allyloxy)phosphoryl]-oxymethyl]-4-cyanobenzoate (949,1 mg, 2,07 mmol)obtained in example 4-(5), and anisole (1.0 g, 9.2 mmol) was cooled to 0°C and added triperoxonane acid (5 ml). The resulting mixture was heated to room temperature and left for 15 min, diluted with toluene and concentrated under reduced pressure to remove volatile components (repeated three times). To the residue was added hexane, and then the supernatant solution was removed to obtain crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-4-cyanobenzoic acid. The crude product was dissolved in dihl methane (20 ml), and at 0°C to the mixture was added oxalicacid (1.27 g, 10 mmol) and N,N-dimethylformamide (15 ml). The mixture was heated to room temperature and was stirred for 30 min and the solvent drove away under reduced pressure. The residue was diluted with toluene and the solution was concentrated under reduced pressure to remove volatile components (repeated three times) to give the crude 2-[[bis(allyloxy)phosphoryl]-oxymethyl]-4-cyanobenzaldehyde.

According to the method similar to that described in Example 1-(12), carried out the reaction of 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (759,6 mg of 1.40 mmol)described in reference example 1, sodium hydride (55% dispersion in mineral oil; 73,3 mg, 1,68 mmol) and crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-4-cyanobenzaldehyde obtained above in tetrahydrofuran (8 ml) and the reaction mixture was treated with obtaining after extraction is specified in the header connection in the form of crude oil. The crude oil was subjected to chromatography on a column of silica gel (60 g) (eluent: ethyl acetate:hexane=2:1 ˜ 5:1) to obtain specified in the connection header (656,9 mg, yield 54%) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: USD 1.43 (3H, DD, J=7, 2 Hz), 3,01 (1H, TT, J=11, 5 Hz), 3,48 (1H, t, J=11 Hz), 52 (1H, t, J=11 Hz), to 4.01 (1H, q, J=7 Hz), 4.09 to (1H, DDD, J=11, 5, 2 Hz), 4,17 (1H, DDD, J=11, 5, 2 Hz), 4,56-to 4.62 (4H, m), 4,99 (1H, d, J=4 Hz), from 5.29 (2H, d, J=11 Hz), 5,38 (2H, DD, J=17, 1 Hz), the 5.45-5,50 (4H, m), of 5.83 (1H, DD, J=15, 4 Hz), 5,95 (2H, DDT, J=17, 11, 5 Hz), 6,56 (1H, DD, J=15, 10 Hz)of 6.75 (1H, d, J=16 Hz), 6,93-of 6.96 (2H, m)6,94 (1H, DD, J=16, 10 Hz), 7,33-7,39 (2H, m), 7,40 (1H, DD, J=8, 1 Hz), 7,58 (1H, t, J=8 Hz), 7,69 (1H, DD, J=8, 1 Hz), 7,82 (1H, d, J=8 Hz), 7,87 (1H, s), to $ 7.91 (1H, s), 8,03 (1H, s).

IR-spectrum ν max CHCl3cm-1: 2235, 1729, 1616, 1504, 1277, 1141, 1028, 991.

Mass spectrum m/z (FAB): 862 (M++1).

(7) Disodium 5-cyano-2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]benzylester (specified in the header of the target connection)

According to the method similar to that described in Example 1-(13), carried out the reaction of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)-phosphoryl]oxymethyl]-4-cyanobenzoate (643,1 mg, 0.75 mmol)obtained in example 4-(6), bis(triphenylphosphine)dichloropalladium (26,2 mg, 0,037 mmol) and anti-hydride (534 mg and 1.83 mmol) and the reaction mixture was treated with obtaining specified in the header of the target compound in the form of crude oil. The crude oil was subjected to column chromatography with reversed phase using Cosmosil 75 C18-PREP (Nacalai Tesque, Inc.; 25 g)(eluent: water:methanol=4:6 ˜ 3:7). Polucen the e fractions were concentrated and the residue was liofilizovane obtaining specified in the title target compound (488,3 mg, yield 79%) as a colourless solid.

NMR-spectrum (400 MHz, CD3OD) δ ppm: 1,40 (3H, DD, J=7, 1 Hz), to 3.02 (1H, TT, J=11, 5 Hz), of 3.45 (1H, t, J=11 Hz), 3,53 (1H, t, J=11 Hz), of 4.00 (1H, q, J=7 Hz), was 4.02 (1H, DDD, J=11, 5, 2 Hz), 4,16 (1H, DDD, J=11, 5, 2 Hz), free 5.01 (1H, d, J=4 Hz), a total of 5.21 (1H, DD, J=17, 5 Hz), are 5.36 (1H, DD, J=17, 6 Hz), of 5.55 (2H, s), 5,86 (1H, DD, J=15, 4 Hz), to 6.57 (1H, DD, J=15, 11 Hz), to 6.80 (1H, d, J=15 Hz), 7,02-was 7.08 (2H, m), 7,10 (1H, DD, J=15, 11 Hz), 7,49-7,58 (3H, m), 7,66 (1H, DD, J=8, 1 Hz), 7,80 (1H, t, J=8 Hz), 7,83 (1H, d, J=8 Hz), of 7.96 (1H, s)of 8.37 (1H, s), and 8.50 (1H, s).

IR-spectrum ν max KBr cm-1: 3422, 2232, 1731, 1615, 1503, 1276, 1257, 1140, 1053, 977.

Mass spectrum m/z (FAB): 826 (M++1).

Specific rotation [α]D25+31,7° (c=0,97, MeOH).

[Example 5]

Disodium 4-cyano-2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]benzyl phosphate (disodium salt of example number 5-16)

(1) 1-Oxo-1,3-dihydroisobenzofuran-6-carbaldehyde

According to the method similar to that described in Example 4-(3)was subjected to the reaction of 6-(hydroxymethyl)-1(3H)-isobenzofuranone (3.25 g, to 20.8 mmol)obtained in example 1-(4) or Example 1-(6), and activated manganese dioxide (33 g) and the reaction mixture was treated with obtaining specified in the connection header in the form of a crude solid. The crude solid was subjected to chromatography the raffia on a column of silica gel (40 g) (eluent: ethyl acetate) to obtain specified in the connection header (2,45 g, yield 76%) as a solid (TPL 134°C).

NMR-spectrum (400 MHz, CDCl3) δ ppm: 5,42 (2H, s), of 7.69 (1H, d, J=8 Hz), of 8.25 (1H, DD, J=8, 1 Hz), 8,42 (1H, s), 10,14 (1H, s).

IR-spectrum ν max KBr cm-1: 1764, 1707, 1154, 1120, 1000, 770.

Mass spectrum m/z (EI): 162 (M+).

(2) 1-Oxo-1,3-dihydroisobenzofuran-6-carbonitrile

According to the method similar to that described in Example 4-(4)was subjected to reaction 1-oxo-1,3-dihydroisobenzofuran-6-carbaldehyde (2,42 g, 14.9 mmol)obtained in example 5-(1), hydroxylamine hydrochloride (1.35 g, and 19.4 mmol) and an aqueous solution of sodium hydroxide (1.0 n; and 19.3 ml, and 19.3 mmol) and the reaction mixture was treated with obtaining 1-oxo-1,3-dihydroisobenzofuran-6-carbaldehyde in the form of a crude solid. According to the method similar to that described in Example 4-(4)was subjected to the reaction of the crude product obtained above and triethylamine (to 3.92 g, 39 mmol) and anhydrous triperoxonane acid (4,08 g, and 19.4 mmol) and the reaction mixture was treated with obtaining after extraction and concentration of the solid residue. The residue was subjected to chromatography on a column of silica gel (50 g) (eluent: ethyl acetate:dichloromethane=0:1 ˜ 1:10) to obtain specified in the connection header (1,67 g, yield 70%) as a solid (TPL 195-196°C).

NMR-spectrum (400 MHz, CDCl3) δ ppm: 5,42 (2H, s), to 7.67 (1H, d, J=8 Hz), of 7.97 (1H, DD, J=8, 1 Hz), 8,24 (1H, user. C).

IR-spectrum ν max KBr cm -1: 2238, 1765, 1464, 1134, 1056, 1006, 771.

Mass spectrum m/z (EI): 159 (M+).

(3) 4-Methoxybenzyl 2-[[bis(allyloxy)phosphoryl]-oxymethyl]-5-cyanobenzoic

According to the method similar to that described in Example 4-(5)was subjected to reaction 1-oxo-1,3-dihydroisobenzofuran-6-carbonitrile (1.66 g, 10.5 mmol)obtained in example 5-(2)with an aqueous solution of sodium hydroxide (1,008 n, 10,38 ml, 10,46 mmol), 4-methoxybenzylamine (1.64 g, 10.5 mmol), tetrazole (1.47 g, to 20.9 mmol), bis(allyloxy)-(diisopropylamino)phosphine (Tetrahedron Lett., 30, 4219 (1989); 3,68 g, 15 mmol) and tert-butylhydroperoxide (80% solution of di-tert-butylperoxide; Merck; 2.7 g, 24 mmol) and the reaction mixture was treated with obtaining after extraction of the residue in the form of a mixture of a solid (starting material) and oil. The residue was washed with mixed solvent of ethyl acetate-hexane and the washing liquid was concentrated to obtain a residue. The residue was subjected to chromatography on a column of silica gel (40 g) (eluent: ethyl acetate:hexane=1:1 ˜ 3:2) to obtain a mixture of solid and oily substances. The mixture is optionally washed with a mixed solvent of ethyl acetate-hexane, and the washing liquid was concentrated to obtain a residue. The residue was subjected to chromatography on a column of silica gel (40 g) (eluent: ethyl acetate:hexane=2:3) to obtain specified in the connection header (737,9 mg, yield 15%) as a colourless oil.

3) δ ppm: a 3.83 (3H, s), 4,57-br4.61 (4H, m), 5,27 (2H, DD, J=11, 1 Hz), from 5.29 (2H, s), lower than the 5.37 (2H, DD, J=17, 1 Hz), to 5.58 (2H, d, J=7 Hz), 5,94 (2H, DDT, J=17, 11, 5 Hz), 6,94 (2H, d, J=9 Hz), 7,38 (2H, d, J=9 Hz), 7,83 (1H, DD, J=8, 1 Hz), 7,87 (1H, d, J=8 Hz), 8,30 (1H, d, J=1 Hz).

IR-spectrum ν max CHCl3cm-1: 2236, 1722, 1516, 1255, 1175, 1031.

Mass spectrum m/z (FAB): 458 (M++1).

(4) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-cyanobenzoic

According to the method similar to that described in Example 4-(6)was subjected to reaction 4-methoxybenzyl 2-[[bis(allyloxy)-phosphoryl]oxymethyl]-5-cyanobenzoate (737 mg, of 1.61 mmol)obtained in example 5-(3), anisole (1.0 g, 9.2 mmol) and triperoxonane acid (5 ml) and the reaction mixture was treated with obtaining 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-cyanobenzoic acid in the form of a crude product. According to the method similar to that described in Example 4-(6)was subjected to the reaction of the crude product obtained above, oxalicacid (1.27 g, 10 mmol) and N,N-dimethylformamide (15 ml) and the reaction mixture was treated with obtaining 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-cyanobenzoate in the form of a crude product.

According to the method similar to that described in Example 1-(12), carried out the reaction of 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-12,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (651,1 mg, 1.20 mmol)described in reference example 1, sodium hydride (55% dispersion in mineral oil; of 62.8 mg, 1.44 mmol) and crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-cyanobenzoate obtained above in tetrahydrofuran (8 ml) and the reaction mixture was treated with obtaining after extraction is specified in the header connection in the form of crude oil. The crude oil was subjected to chromatography on a column of silica gel (60 g) (eluent: ethyl acetate:hexane=2:1 ˜ 3:1) to obtain specified in the connection header (237,5 mg, yield 23%) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,45 (3H, DD, J=7, 2 Hz), to 3.02 (1H, TT, J=12, 5 Hz), of 3.54 (1H, t, J=12 Hz), 3,55 (1H, t, J=12 Hz), of 4.00 (1H, q, J=7 Hz), 4,14-4,19 (2H, m), 4,58-br4.61 (4H, m), free 5.01 (1H, d, J=4 Hz), of 5.26 (2H, DD, J=10, 1 Hz), are 5.36 (2H, d, J=17 Hz), vs. 5.47 (2H, s)5,52 (2H, d, J=7 Hz), by 5.87 (1H, DD, J=15, 4 Hz), 5,94 (2H, DDT, J=17, 10, 6 Hz), to 6.58 (1H, DD, J=15, 11 Hz), was 6.73 (1H, d, J=16 Hz), 6,90-to 7.00 (3H, m), 7,31-7,37 (2H, m), 7,40 (1H, DD, J=8, 1 Hz), EUR 7.57 (1H, t, J=8 Hz), 7,88-a 7.92 (4H, m), 8,18 (1H, s).

IR-spectrum ν max KBr cm-1: 2232, 1731, 1615, 1504, 1276, 1142, 1027.

Mass spectrum m/z (FAB): 862 (M++1).

(5) Disodium 4-cyano-2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]benzylester (specified in the header of the target connection)

According to the method similar to that described in Example 1-(13), carried out the reaction of (1R,2R-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5 cyanobenzoate (of 230.5 mg, 0.27 mmol)obtained in example 5-(4), bis(triphenylphosphine)dichloropalladium (9.4 mg, of 0.013 mmol) and anti-hydride (155,4 mg of 0.53 mmol) and the reaction mixture was treated with obtaining specified in the header of the target compound in the form of oil. The crude oil was subjected to column chromatography with reversed phase using Cosmosil 75 C18-PREP (Nacalai Tesque, Inc.; 25 g)(eluent: water:methanol=4:6 ˜ 3:7). The fractions obtained were concentrated and the residue was liofilizovane obtaining specified in the title target compound (86,0 mg, yield 39%) as a colourless solid.

NMR-spectrum (400 MHz, CD3OD) δ ppm: of 1.41 (3H, DD, J=7, 1 Hz), 3.04 from (1H, TT, J=11, 5 Hz), 3,48 (1H, t, J=11 Hz), of 3.54 (1H, t, J=11 Hz), to 4.01 (1H, q, J=7 Hz), of 4.05 (1H, DDD, J=11, 5, 2 Hz), 4,18 (1H, DDD, J=11, 5, 2 Hz), free 5.01 (1H, d, J=4 Hz), a 5.25 (1H, DD, J=18, 6 Hz), of 5.39 (1H, DD, J=18, 5 Hz), 5,52 (1H, DD, J=15 and 3 Hz), to 5.58 (1H, d, J=15 Hz), 5,90 (1H, DD, J=15, 4 Hz), to 6.58 (1H, DD, J=15, 11 Hz), 6,79 (1H, d, J=16 Hz), 7,02 for 7.12 (3H, m), 7,50-rate of 7.54 (3H, m), 7,78 (1H, t, J=8 Hz), to 7.93 (1H, DD, J=8, 2 Hz), 8,01 (2H, s), 8,31 (1H, d, J=8 Hz), 8,40 (1H, s).

IR-spectrum ν max KBr cm-1: 3423, 2232, 1729, 1615, 1504, 1141, 1054, 976.

Mass spectrum m/z (FAB): 826 (M++1).

Specific rotation [α]D25+31,2° (c=0,73, MeOH).

[Example 6]

Disodium 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-6-forbindelse (Disodium salt of example number -22)

(1) 4-Methoxybenzyl 2-[[bis(allyloxy)phosphoryl]-oxymethyl]-3-perbenzoate

According to the method similar to that described in Example 4-(5), 4-fluoro-1(3H)-isobenzofuranone (described in Tetrahedron, 54, 7485 (1998); 1.52 g, 10 mmol) was subjected to contact with an aqueous solution of sodium hydroxide (1,008 n, 10 ml, 10 mmol), 4-methoxybenzylamine (of 1.57 g, 10 mmol), tetrazole (1.40 g, 20 mmol), bis(allyloxy)(diisopropylamino)phosphine (described in Tetrahedron Lett., 30, 4219 (1989); 3,43 g, 14 mmol) and tert-butylhydroperoxide (80% solution of di-tert-butylperoxide; Merck; 2.7 g, 24 mmol) and the reaction mixture was treated with obtaining after extraction of oily residue. The residue was subjected to chromatography on a column of silica gel (100 g) (eluent: ethyl acetate:hexane=2:3) to obtain an oily mixture. The mixture was further subjected to chromatography on a column of silica gel (50 g) (eluent: ethyl acetate:hexane=1:2) to obtain the specified title compound (1.40 g, yield 31%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 3,82 (3H, s), 4,49-a 4.53 (4H, m), with 5.22 (2H, d, J=10, 1 Hz), 5,31 (2H, s), 5,33 (2H, d, J=17, 1 Hz), 5,52 (2H, DD, J=7, 1 Hz), 5,91 (2H, DDT, J=17, 10, 5 Hz), 6,91 (2H, d, J=8 Hz), of 7.25 (1H, dt, J=1.8 Hz), 7,37-7,42 (1H, m), 7,39 (2H, d, J=8 Hz), 7,72 (1H, d, J=8 Hz).

IR-spectrum ν max CHCl3cm-1: 1724, 1516, 1462, 1272, 1171, 1029.

Mass spectrum m/z (FAB): 451 (M++1).

(2) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-b is tationil]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-perbenzoate

According to the method similar to that described in Example 4-(6), 4-methoxybenzyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-perbenzoate (1.40 g, 3,12 mmol)obtained in Example 6-(1)were subjected to interaction with anisole (1.4 g, 12.9 mmol) and triperoxonane acid (5 ml) and the reaction mixture was treated with obtaining 2-[[bis(allyloxy)phosphoryl]-oxymethyl]-3-fermenting acid in the form of a crude product. According to the method similar to that described in Example 4-(6)was subjected to the reaction, the crude product obtained above, oxalicacid (1.98 g, 15.6 mmol) and N,N-dimethylformamide (15 ml) was subjected to interaction and the reaction mixture was treated with obtaining 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-tormentilla in the form of a crude product.

According to the method similar to that described in Example 1-(12), carried out the reaction of 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (1,09 g, 2.0 mmol)described in reference example 1, sodium hydride (55% dispersion in mineral oil; 104,7 mg, 2.4 mmol) and crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-tormentilla obtained above in tetrahydrofuran (10 ml) and the reaction mixture was treated with obtaining after extraction is specified in the header connection in the form of crude oil. Neocis the TES oil was subjected to chromatography on a column of silica gel (75 g) (eluent: ethyl acetate:hexane=2:1 ˜ 3:1) to obtain specified in the connection header (876,0 mg, 51%yield) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: the 1.44 (3H, DD, J=7, 2 Hz), 3,03 (1H, TT, J=12, 5 Hz), of 3.46 (1H, t, J=12 Hz), 3,51 (1H, t, J=12 Hz), 3,99 (1H, q, J=7 Hz), 4.09 to (1H, DDD, J=12, 5, 2 Hz), 4,18 (1H, DDD, J=12, 5, 2 Hz), of 4.44-4,56 (4H, m), equal to 4.97 (1H, d, J=4 Hz), a total of 5.21 (2H, d, J=10 Hz), 5,31 (2H, d, J=17 Hz), 5,43-5,54 (4H, m), of 5.83 (1H, DD, J=15, 4 Hz), of 5.89 (2H, DDT, J=17, 10, 5 Hz), 6,55 (1H, DD, J=15, 11 Hz)that was 6.73 (1H, d, J=15 Hz), 6.87 in-6,93 (3H, m), 7,29-to 7.35 (2H, m), 7,39-7,49 (4H, m), EUR 7.57 (1H, t, J=8 Hz), to 7.93 (1H, s), of 8.00 (1H, s).

IR-spectrum ν max CHCl3cm-1: 2233, 1732, 1504, 1462, 1276, 1141, 1023, 991.

Mass spectrum m/z (FAB): 855 (M++1).

(3) Disodium 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-6-forbindelse (specified in the header of the target connection)

According to the method similar to that described in Example 1-(13), (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-perbenzoate (860 mg, 1.0 mmol)obtained in example 6-(2)were subjected to interaction with bis(triphenylphosphine)dichloropalladium (35.1 mg, 0.05 mmol) and anti-hydride (786,2 mg, 2,70 mmol) and the reaction mixture was treated with obtaining specified in the header of the target compound in the form of crude oil. Neojidanno the oil was subjected to column chromatography with reversed phase using Cosmosil 75 C 18-PREP (Nacalai Tesque, Inc.; 40 g)(eluent: water:methanol=4:6 ˜ 3:7). The fractions obtained were concentrated and the residue was liofilizovane obtaining specified in the title target compound (614,2 mg, 75%yield) as a colorless solid.

NMR-spectrum (400 MHz, CD3OD) δ ppm: USD 1.43 (3H, DD, J=7, 1 Hz), 2,98 (1H, TT, J=11, 5 Hz), 3,48 (1H, t, J=11 Hz), 3,53 (1H, t, J=11 Hz), a 4.03 (1H, q, J=7 Hz), of 4.05 (1H, DDD, J=11, 5, 2 Hz), 4,14 (1H, DDD, J=11, 5, 2 Hz)to 5.00 (1H, d, J=4 Hz), a 5.25 (1H, DD, J=12, 5 Hz), 5,32 (1H, DDD, J=12, 5, 2 Hz), 5,52 (1H, DD, J=15 and 3 Hz), 5,69 (1H, d, J=15 Hz), of 5.84 (1H, DD, J=15, 4 Hz), 6,56 (1H, DD, J=15, 10 Hz), is 6.78 (1H, d, J=15 Hz), 7,00-7,13 (2H, m), to 7.09 (1H, DD, J=15, 10 Hz), 7,34 (1H, t, J=9 Hz), 7,42 (1H, TD, J=8, 5 Hz), 7,49-rate of 7.54 (2H, m), 7,62-of 7.70 (2H, m), 7,78 (1H, t, J=8 Hz), of 7.96 (1H, s), 8,70(1H, s).

IR-spectrum ν max KBr cm-1: 2230, 1731, 1614, 1504, 1275, 1142, 1048, 975.

Mass spectrum m/z (FAB): 819 (M++1).

Specific rotation [α]D25+5,4° (c=0,91, MeOH).

[Example 7]

Disodium 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-5-terbisil phosphate (disodium salt of example number 5-21)

(1) 4-Methoxybenzyl 2-[[bis(allyloxy)phosphoryl]-oxymethyl]-4-perbenzoate

According to the method similar to that described in Example 4-(5), 5-fluoro-1(3H)-isobenzofuranone (described in Tetrahedron, 44, 4591 (1988); 1.52 g, 10 mmol) was subjected to contact with an aqueous solution of sodium hydroxide (1,008 n;10 ml, 10 mmol), 4-methoxybenzylamine (of 1.57 g, 10 mmol), tetrazole (1.40 g, 20 mmol), bis(allyloxy)(diisopropylamino)phosphine (described in Tetrahedron Lett., 30, 4219 (1989); 3,05 g, 12.4 mmol) and tert-butylhydroperoxide (80% solution of di-tert-butylperoxide; Merck; 2.7 g, 24 mmol) and the reaction mixture was treated with obtaining after extraction of oily residue. The residue was subjected to chromatography on a column of silica gel (75 g) (eluent: ethyl acetate:hexane=2:1 ˜ 3:1) to obtain an oily mixture. The mixture was further subjected to chromatography on a column of silica gel (50 g) (eluent: ethyl acetate:hexane=1:4 ˜ 1:2) to obtain specified in the connection header (2,07 g, yield 46%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 3,82 (3H, s), 4,58-br4.61 (4H, m), of 5.26 (2H, s), of 5.26 (2H, DQC, J=11, 1 Hz), 5,38 (2H, DQC, J=17, 1 Hz), 5,54 (2H, d, J=7 Hz), 5,95 (2H, DDT, J=17, 11, 5 Hz), 6,91 (2H, d, J=9 Hz), 7,02 (1H, TD, J=9,2 Hz), 7,37 (2H, d, J=9 Hz), the 7.43 (1H, DD, J=10, 2 Hz), of 8.06 (1H, DD, J=9, 6 Hz).

IR-spectrum ν max CHCl3cm-1: 1714, 1613, 1590, 1516, 1261, 1120, 1031.

Mass spectrum m/z (FAB): 451 (M++1).

(2) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-4-perbenzoate

According to the method similar to that described in Example 4-(6), 4-methoxybenzyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-4-fluoro who Insaat (1,41 g, of 3.12 mmol)obtained in example 7-(1)were subjected to interaction with anisole (2 g, 18.5 mmol) and triperoxonane acid (5 ml) and the reaction mixture was treated with obtaining 2-[[bis(allyloxy)phosphoryl]-oxymethyl]-4-fermenting acid in the form of a crude product. According to the method similar to that described in Example 4-(6), the crude product obtained above were subjected to interaction with oxalylamino (1.98 g, 15.6 mmol) and N,N-dimethylformamide (15 ml) and the reaction mixture was treated with obtaining 2-[[bis(allyloxy)phosphoryl]oxymethyl]-4-tormentilla in the form of a crude product.

According to the method similar to that described in Example 1-(12), carried out the reaction of 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (1,09 g, 2.0 mmol)described in reference example 1, sodium hydride (55% dispersion in mineral oil; 104,7 mg, 2.4 mmol) and crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-4-tormentilla obtained above in tetrahydrofuran (10 ml) and the reaction mixture was treated with obtaining after extraction is specified in the header connection in the form of crude oil. The crude product was subjected to chromatography on a column of silica gel (60 g) (eluent: ethyl acetate:hexane=2:1 ˜ 3:1) to obtain specified in the connection header (948,1 mg, yield 55%) in the de pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,45 (3H, DD, J=7, 2 Hz), 3,03 (1H, TT, J=11, 5 Hz), 3,50 (1H, t, J=11 Hz), 3,53 (1H, t, J=11 Hz), to 4.01 (1H, q, J=7 Hz), 4,10-4,20 (2H, m), 4,57-5,61 (4H, m), 4,99 (1H, d, J=4 Hz), of 5.26 (2H, dt, J=10, 1 Hz), lower than the 5.37 (2H, dt, J=17, 1 Hz), 5,41-5,52 (4H, m), of 5.84 (1H, DD, J=15, 4 Hz), 5,95 (2H, DDT, J=17, 10, 5 Hz), to 6.57 (1H, DD, J=15, 11 Hz), 6,74 (1H, d, J=15 Hz), 6.89 in-6,94 (2H, m)6,94 (1H, DD, J=15, 11 Hz), 7,06 (1H, TD, J=8, 3 Hz), 7,26-7,41 (3H, m), 7,46 (1H, DD, J=10, 3 Hz), EUR 7.57 (1H, t, J=8 Hz), 7,81 (1H, DD, J=8, 6 Hz), 7,89 (1H, s), 7,89 (1H, s).

IR-spectrum ν max CHCl3cm-1: 2232, 1721, 1614, 1590, 1504, 1275, 1140, 1028.

Mass spectrum m/z (FAB): 855 (M++1).

(3) Disodium 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-5-terbisil phosphate (specified in the header of the target connection)

According to the method similar to that described in Example 1-(13), (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-4-perbenzoate (940 mg, 1.1 mmol)obtained in example 7-(2)were subjected to interaction with bis(triphenylphosphine)dichloropalladium (38,6 mg, by 0.055 mmol) and anti-hydride (640,1 mg of 2.20 mmol) and the reaction mixture was treated with obtaining specified in the connection header in the form of crude oil. The crude oil was subjected to column chromatography with reversed phase using Cosmosil 75 C18 -PREP (Nacalai Tesque, Inc.; 75 g) (eluent: water:methanol=4:6 ˜ 3:7). The fractions obtained were concentrated and the residue was liofilizovane obtaining specified in the title target compound (574,5 mg, yield 64%) as a colourless solid.

NMR-spectrum (400 MHz, CD3OD) δ ppm: of 1.41 (3H, DD, J=7, 1 Hz), 3.04 from (1H, TT, J=11, 4 Hz), 3,48 (1H, t, J=11 Hz), of 3.54 (1H, t, J=11 Hz), of 4.05 (1H, q, J=7 Hz), 4,08 (1H, DDD, J=11, 4, 2 Hz), 4,17 (1H, DDD, J=11, 4, 2 Hz), to 5.03 (1H, d, J=5 Hz), 5,20 (1H, DD, J=17, 5 Hz), of 5.34 (1H, DD, J=17, 5 Hz), of 5.50 (1H, DD, J=15 and 3 Hz), to 5.58 (1H, d, J=15 Hz), by 5.87 (1H, DD, J=15, 5 Hz), to 6.58 (1H, DD, J=15, 11 Hz), 6,80 (1H, d, J=15 Hz), 6,98-7,05 (3H, m), 7,10 (1H, DD, J=15, 11 Hz), of 7.48-rate of 7.54 (3H, m), to 7.77-7,81 (2H, m), 7,87 (1H, DD, J=10, 3 Hz), of 7.96 (1H, s), 8,31 (1H, s).

IR-spectrum ν max KBr cm-1: 2231, 1724, 1613, 1503, 1256, 1140, 1117, 1051, 977.

Mass spectrum m/z (FAB): 819 (M++1).

Specific rotation [α]D25+28,3° (c=0,86, MeOH).

[Example 8]

Disodium 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-4-terbisil phosphate (disodium salt of example number 5-20)

(1) 4-Methoxybenzyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-perbenzoate

According to the method similar to that described in Example 4-(5), 6-fluoro-1(3H)-isobenzofuranone (described in Tetrahedron, 44, 4591 (1988); 1.52 g, 10 mmol) was subjected to contact with an aqueous solution of sodium hydroxide (1,008 n; 10 ml, 10 mmol), 4-methoxybenzyl what lorida (1,57 g, 10 mmol), tetrazole (1.40 g, 20 mmol), bis(allyloxy)(diisopropylamino)phosphine (described in Tetrahedron Lett., 30, 4219 (1989); 3,0 g, 12.2 mmol) and tert-butylhydroperoxide (80% solution of di-tert-butylperoxide); Merck; 2.7 g, 24 mmol) and the reaction mixture was treated with obtaining after extraction of oily residue. The residue was subjected to chromatography on a column of silica gel (90 g) (ethyl acetate:hexane=1:4 ˜ 1:2) to obtain an oily mixture. The mixture was further subjected to chromatography on a column of silica gel (50 g) (eluent: ethyl acetate:hexane=1:4 ˜ 1:2) to obtain the specified title compound (1.22 g, yield 27%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 3,82 (3H, s), 4.53-in-4,58 (4H, m), 5.25-inch (2H, DQC, J=10, 1 Hz), 5,28 (2H, s), to 5.35 (2H, DQC, J=17, 1 Hz), 5,49 (2H, d, J=7 Hz), to 5.93 (2H, DDT, J=17, 10, 5 Hz), 6,92 (2H, d, J=8 Hz), 7,25 (1H, TD, J=8, 3 Hz), 7,38 (2H, d, J=8 Hz), 7,66 (1H, DD, J=8, 5 Hz), 7,69 (1H, DD, J=9, 3 Hz).

IR-spectrum ν max CHCl3cm-1: 1719, 1516, 1272, 1031, 989.

Mass spectrum m/z (FAB): 451 (M++1).

(2) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-perbenzoate

According to the method similar to that described in Example 4-(6), 4-methoxybenzyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-perbenzoate (1.19 g, of 2.64 mmol)obtained in example 8-(1), the evaluation of the RGALI interaction with anisole (1.5 g, a 13.9 mmol) and triperoxonane acid (5 ml) and the reaction mixture was treated with obtaining 2-[[bis(allyloxy)phosphoryl]-oxymethyl]-5-fermenting acid in the form of a crude product. According to the method similar to that described in Example 4-(6), the crude product obtained above were subjected to interaction with oxalylamino (1.68 g, 13,2 mmol) and N,N-dimethylformamide (15 ml) and the reaction mixture was treated with obtaining 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-tormentilla in the form of a crude product.

According to the method similar to that described in Example 1-(12), carried out the reaction of 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (955,7 mg of 1.76 mmol)described in reference example 1, sodium hydride (55% dispersion in mineral oil; 84,5 mg, 1.94 mmol) and crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-tormentilla obtained above in tetrahydrofuran (10 ml) and the reaction mixture was treated with obtaining after extraction is specified in the header connection in the form of crude oil. The crude oil was subjected to chromatography on a column of silica gel (75 g) (eluent: ethyl acetate:hexane=2:1 ˜ 4:1) to obtain specified in the connection header (839,7 mg, yield 56%) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3/sub> ) δ ppm: 1,45 (3H, DD, J=7,2 Hz), 3,03 (1H, TT, J=11, 4 Hz), 3,53 (1H, t, J=11 Hz), 3,53 (1H, t, J=11 Hz), of 4.00 (1H, q, J=7 Hz), 4,15-4,20 (2H, m), 4,54-4,58 (4H, m)5,00 (1H, d, J=4 Hz), 5,24 (2H, DD, J=10, 1 Hz), to 5.35 (2H, DD, J=18, 1 Hz), 5.40 to-5,49 (4H, m), of 5.85 (1H, DD, J=15, 4 Hz), of 5.92 (2H, DDT, J=18, 10, 5 Hz), to 6.58 (1H, DD, J=15, 11 Hz), was 6.73 (1H, d, J=16 Hz), 6.90 to-to 7.00 (3H, m), 7,29-7,38 (3H, m), 7,40 (1H, DD, J=8, 1 Hz), 7,53-of 7.60 (2H, m), of 7.69 (1H, DD, J=9, 6 Hz), of 7.90 (1H, s), to 7.93 (1H,s).

IR-spectrum ν max CHCl3cm-1: 2233, 1728, 1615, 1504, 1276, 1139, 1025.

Mass spectrum m/z (FAB): 855 (M++1).

(3) Disodium 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-4-terbisil phosphate (specified in the header of the target connection)

According to the method similar to that described in Example 1-(13), (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-perbenzoate (to 805.1 mg of 0.94 mmol)obtained in example 8-(2)were subjected to interaction with bis (triphenylphosphine)dichloropalladium (to 19.8 mg, 0,028 mmol) and anti-hydride (903,1 mg, 3.10 mmol) and the reaction mixture was treated with obtaining specified in the header of the target compound in the form of crude oil. The crude oil was subjected to column chromatography with reversed phase using Cosmosil 75 C18-PREP (Nacalai Tesque, Inc.; 40 g)(eluent: water:methanol=4:6 ˜ 3:7). Received the s fractions were concentrated and the residue was liofilizovane obtaining specified in the title target compound (103,1 mg, yield 13%) as a colourless solid.

NMR-spectrum (400 MHz, CD3OD) δ ppm: of 1.41 (3H, DD, J=7, 1 Hz), to 3.02 (1H, TT, J=11, 5 Hz), 3,49 (1H, t, J=11 Hz), of 3.54 (1H, t, J=11 Hz), Android 4.04 (1H, q, J=7 Hz), 4,08 (1H, DDD, J=11, 5, 2 Hz), 4,17 (1H, DDD, J=11, 5, 2 Hz), 5,02 (1H, d, J=5 Hz), 5,18 (1H, DD, J=16, 6 Hz), and 5.30 (1H, DD, J=16, 6 Hz), the 5.51 (1H, DD, J=15 and 3 Hz), 5,59 (1H, d, J=15 Hz), 5,86 (1H, DD, J=15, 5 Hz), to 6.58 (1H, DD, J=15, 11 Hz), 6,79 (1H, d, J=15 Hz), 7.03 is-7,13 (3H, m), 7,33 (1H, TD, J=9, 3 Hz), the 7.43 (1H, DD, J=10, 3 Hz), 7,49-7,58 (3H, m), 7,79 (1H, t, J=8 Hz), to 7.99 (1H, s), 8,10 (1H, DD, J=9, 6 Hz), at 8.36 (1H, s).

IR-spectrum ν max KBr cm-1: 2231, 1727, 1614, 1503, 1275, 1199, 1140, 1052, 975.

Mass spectrum m/z (FAB): 819 (M++1).

Specific rotation [α]D25+22,8° (c=0,94, MeOH).

[Example 9]

Disodium 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-3-terbisil phosphate (disodium salt of example number 5-19)

(1) 4-Methoxybenzyl 2-[[bis(allyloxy)phosphoryl]-oxymethyl]-6-perbenzoate

According to the method similar to that described in Example 4-(5), 7-fluoro-1(3H)-isobenzofuranone (described in Tetrahedron, 54, 7485 (1998); 1,67 g, 11 mmol) was subjected to contact with an aqueous solution of sodium hydroxide (1,008 n; 10.9 ml, 11 mmol), 4-methoxybenzylamine (of 1.57 g, 10 mmol), tetrazole (1.40 g, 20 mmol), bis(allyloxy)(diisopropylamino)phosphine (described in Tetrahedron Lett., 30, 4219 (1989); 3,1 g, 12.6 mmol) and tert-butylhydrazine what xicom (80% solution of di-tert-butylperoxide; Merck; 2.7 g, 24 mmol) and the reaction mixture was treated with obtaining after extraction of oily residue. The oily residue was subjected to chromatography on a column of silica gel (100 g) (eluent: ethyl acetate:hexane=2:3) to obtain a mixture of solid and oily substances. The mixture was washed with a mixed solvent of ethyl acetate-hexane, the washing liquid was concentrated under reduced pressure to obtain a residue. The residue was subjected to chromatography on a column of silica gel (50 g) (eluent: ethyl acetate:hexane=1:4 ˜ 1:2) to obtain the specified title compound (1.08 g, yield 24%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 3,81 (3H, s), 4,49-of 4.54 (4H, m), 5,22 to 5.35 (6H, m), 5,33 (2H, DD, J=17, 1 Hz), 5,90 (2H, DDT, J=17, 11, 5 Hz), 6,91 (2H, d, J=9 Hz), 7,10 (1H, t, J=8 Hz), 7,32 (1H, d, J=8 Hz), 7,39 (2H, d, J=9 Hz), the 7.43 (1H, TD, J=8.6 Hz).

IR-spectrum ν max CHCl3cm-1: 1727, 1614, 1516, 1465, 1268, 1114, 1034.

Mass spectrum m/z (FAB): 451 (M++1).

(2) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-6-perbenzoate

According to the method similar to that described in Example 4-(6), 4-methoxybenzyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-6-perbenzoate (1.07 g, 2,39 mmol)obtained in example 9-(1)were subjected to interaction with anisole (1.8 g, of 16.6 mmol) and t is everysunday acid (5 ml) and the reaction mixture was treated with obtaining 2-[[bis(allyloxy)phosphoryl]-oxymethyl]-6-fermenting acid in the form of a crude product.

According to the method similar to that described in Example 4-(6), the crude product obtained above were subjected to interaction with oxalylamino (1.52 g, and 11.8 mmol) and N,N-dimethylformamide (15 ml) and the reaction mixture was treated with obtaining 2-[[bis(allyloxy)phosphoryl]oxymethyl]-6-tormentilla in the form of a crude product.

According to the method similar to that described in Example 1-(12), carried out the reaction of 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (864,1 mg of 1.59 mmol)described in reference example 1, sodium hydride (55% dispersion in mineral oil; of 83.4 mg, at 1.91 mmol) and crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-6-tormentilla obtained above in tetrahydrofuran (8 ml) and the reaction mixture was treated with obtaining after extraction is specified in the header connection in the form of crude oil. The crude oily product was subjected to chromatography on a column of silica gel (75 g) (eluent: ethyl acetate:hexane=2:1 ˜ 3:1) to obtain specified in the connection header (698,7 mg, 51%yield) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: USD 1.43 (3H, DD, J=7, 1 Hz), 3,05 (1H, TT, J=11, 5 Hz), 3,44 (1H, t, J=11 Hz), 3,51 (1H, t, J=11 Hz), 3,98 (1H, q, J=7 Hz), 4,08 (1H, DDD, J=11, 5, 2 Hz), 4,18 (1H, DDD, J=11, 5, 2 Hz), 4.53-in-4,59 (4H, m), 4,96 (1H, d, J=4 Hz), 5,24 (2H, the t, J=10, 1 Hz), 5,31-of 5.40 (4H, m), 5,44 (1H, d, J=15 Hz)to 5.56 (1H, DD, J=15 and 3 Hz), of 5.83 (1H, DD, J=15, 4 Hz), to 5.93 (2H, DDT, J=16, 10, 6 Hz), 6,55 (1H, DD, J=15, 11 Hz), was 6.73 (1H, d, J=16 Hz), 6,88-6,98 (2H, m), 6,93 (1H, DD, J=16, 11 Hz), 7,11 (1H, TD, J=8, 1 Hz), 7,34 (1H, DD, J=10, 1 Hz), 7,40 (1H, DD, J=8, 1 Hz)of 7.48-to 7.59 (4H, m), 7,88 (1H, s), 7,89 (1H, s).

IR-spectrum ν max CHCl3cm-1: 2233, 1727, 1614, 1504, 1277, 1140, 1034.

Mass spectrum m/z (FAB): 855 (M++1).

(3) Disodium 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-3-terbisil phosphate (specified in the header of the target connection)

According to the method similar to that described in Example 1-(13), carried out the reaction of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-6-perbenzoate (650 mg, from 0.76 mmol)obtained in example 9-(2), bis(triphenylphosphine)dichloropalladium (16.0 mg, is 0.023 mmol) and anti-hydride (786,7 mg, 2,70 mmol) and the reaction mixture was treated with obtaining specified in the header of the target compound in the form of crude oil. The crude compound was subjected to column chromatography with reversed phase using Cosmosil 75 C18-PREP (Nacalai Tesque, Inc.; 40 g)(eluent: water:methanol=4:6 ˜ 3:7). The fractions obtained were concentrated and the residue was liofilizovane obtaining specified in the header of the target is soedineniya (440,5 mg, yield 71%) as a colourless solid.

NMR-spectrum (400 MHz, CD3OD) δ ppm: 1,39 (3H, DD, J=7, 1 Hz), 3,06 (1H, TT, J=11, 5 Hz)at 3.25 (1H, t, J=11 Hz), 3,49 (1H, t, J=11 Hz), of 3.94 (1H, DDD, J=11, 5, 2 Hz), 4,10 (1H, q, J=7 Hz), 4,15 (1H, DDD, J=11, 5, 2 Hz), of 4.95 (1H, d, J=4 Hz), to 5.03 (1H, DD, J=15, 5 Hz), 5,27 (1H, DD, J=15, 5 Hz), 5,52 (1H, DD, J=15 and 3 Hz), 5,62 (1H, d, J=15 Hz), of 5.83 (1H, DD, J=15, 4 Hz), is 6.54 (1H, DD, J=15, 11 Hz), 6,79 (1H, d, J=16 Hz), 6,99-to 7.15 (4H, m), 7,50-7,58 (3H, m), a 7.62 (1H, TD, J=8, 6 Hz), 7,79 (1H, t, J=8 Hz), 7,88 (1H, d, J=8 Hz), 8,00 (1H, s), with 8.33 (1H, s).

IR-spectrum ν max KBr cm-1: 2231, 1724, 1614, 1504, 1278, 1257, 1140, 1113, 1055, 975.

Mass spectrum m/z (FAB): 819 (M++1).

Specific rotation [α]D25+of 56.4° (c=1,02, MeOH).

[Example 10]

Disodium 4-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-4-oxo-3,3-dimethylbutyl phosphate (disodium salt of example number 4-18)

(1) 4-Methoxybenzyl 4-[[bis(allyloxy)phosphoryl]oxy]-2,2-dimethylbutyl

According to the method similar to that described in Example 4-(5), 2,2-dimethyl-5-pentanolide (described in Tetrahedron, 22, 285 (1966); to 1.14 g, 10 mmol) was subjected to contact with an aqueous solution of sodium hydroxide (1,008 n; 10 ml, 10 mmol), 4-methoxybenzylamine (of 1.57 g, 10 mmol), tetrazole (1.40 g, 20 mmol), bis(allyloxy)(diisopropylamino)phosphine (described in Tetrahedron Lett., 30, 4219 (1989); 3,1 g, 12.6 mmol) and tert-b is tigerpixie (80% solution of di-tert-butylperoxide; Merck; 3.6 g, 32 mmol) and the reaction mixture was treated with obtaining after extraction of oily residue. The oily residue was subjected to chromatography on a column of silica gel (60 g) (eluent: ethyl acetate:hexane=1:2) to obtain an oily mixture. The mixture was subjected to chromatography on a column of silica gel (75 g) (eluent: ethyl acetate:hexane=1:3 ˜ 3:1) to obtain the specified title compound (1.86 g) as a colorless oil along with the fractions containing impurities. The fractions containing impurities, optionally subjected to chromatography on a column of silica gel (20 g) (eluent: ethyl acetate:hexane=1:2 ˜ 1:0) to obtain the specified title compound (0.52 g, the total number of 2.38 g, yield 58%).

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,22 (6H, s)of 1.97 (2H, t, J=7 Hz), 3,81 (3H, s)4,08 (2H, q, J=7 Hz), 4,50-a 4.53 (4H, m), of 5.03 (2H, s), of 5.24 (2H, DD, J=11, 1 Hz), to 5.35 (2H, DQC, J=17, 1 Hz), of 5.92 (2H, DDT, J=17, 11, 5 Hz), to 6.88 (2H, d, J=9 Hz), 7,27 (2H, d, J=9 Hz).

IR-spectrum ν max CHCl3cm-1: 1723, 1516, 1255, 1148, 1029, 990.

Mass spectrum m/z (FAB): 413 (M++1).

(2) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 4-[[bis(allyloxy)phosphoryl]oxy]-2,2-dimethylbutyl

According to the method similar to that described in Example 4-(6), 4-methoxybenzyl 4-[[bis(allyloxy)phosphoryl]oxy]-2,2-dimethylbutyl (1.24 g, 3,mmol), obtained in example 10-(1)were subjected to interaction with anisole (1.8 g, of 16.6 mmol) and triperoxonane acid (5 ml) and the reaction mixture was treated with obtaining 4-[[bis(allyloxy)phosphoryl]oxy]-2,2-dimethylbutanoate acid in the form of a crude product. According to the method similar to that described in Example 4-(6), the crude product obtained above were subjected to interaction with oxalylamino (1.98 g, 15.6 mmol) and N,N-dimethylformamide (15 ml) and the reaction mixture was treated with obtaining 4-[bis(allyloxy)phosphoryl]hydroxy-2,2-dimethylbutylamino in the form of a crude product.

According to the method similar to that described in Example 1-(12), carried out the reaction of 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (1,09 g, 2.0 mmol)described in reference example 1, sodium hydride (55% dispersion in mineral oil; 104,7 mg, 2.4 mmol) and 4-[[bis(allyloxy)phosphoryl]oxy]-2,2-dimethylbutyramide in tetrahydrofuran (10 ml) and the reaction mixture was treated with obtaining after extraction is specified in the header connection in the form of crude oil. The crude oily product was subjected to chromatography on a column of silica gel (75 g) (eluent: ethyl acetate:hexane=2:1 ˜ 3:1) to obtain specified in the connection header (238,8 mg, yield 15%) as a pale yellow solid Amorin the th substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,17 (3H, s)to 1.22 (3H, s)to 1.38 (3H, DD, J=7, 2 Hz), a 2.01 (2H, t, J=7 Hz), 3,03 (1H, TT, J=11, 5 Hz), of 3.54 (2H, t, J=11 Hz), Android 4.04 (1H, q, J=7 Hz), 4,12-4,24 (4H, m), 4,51-4,56 (4H, m), 5,02 (1H, d, J=4 Hz), 5,26 (2H, d, J=10 Hz), and 5.30-of 5.40 (4H, m), 5,86 (1H, DD, J=15, 4 Hz), 5,94 (2H, DDT, J=17, 10, 5 Hz), 6,59 (1H, DD, J=15, 10 Hz), 6,74 (1H, d, J=15 Hz), 6,86-6,97 (3H, m), 7,31-7,38 (2H, m), 7,40 (1H, DD, J=8, 2 Hz), EUR 7.57 (1H, t, J=8 Hz), 7,87 (1H, s), of 7.90 (1H, s).

IR-spectrum ν max CHCl3cm-1: 2233, 1734, 1504, 1275, 1139, 1027, 991.

Mass spectrum m/z (FAB): 817 (M++1).

(3) Disodium 4-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-4-oxo-3,3-dimethylbutyl phosphate (specified in the header of the target connection)

According to the method similar to that described in Example 1-(13), (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 4-[[bis(allyloxy)phosphoryl]oxy]-2,2-dimethylbutyl (230,7 mg, 0.28 mmol)obtained in example 10-(2)were subjected to interaction with bis(triphenylphosphine)dichloropalladium (6.0 mg, 0,0085 mmol) and anti-hydride (280,9 mg, 0.97 mmol) and the reaction mixture was treated with obtaining specified in the header of the target compound in the form of crude oil. The crude oil was subjected to column chromatography with reversed phase using Cosmosil 75 C18-PREP (Nacalai Tesque, Inc.; 50 g)(eluent: water:methanol=4:6 ˜ 3:7). The fractions obtained were concentrated and the residue was liofilizovane obtaining specified in the title target compound (84,0 mg, yield 38%) as a colourless solid.

NMR-spectrum (400 MHz, CD3OD) δ ppm: 1,17 (3H, s)to 1.22 (3H, s)to 1.37 (3H, DD, J=7, 2 Hz)of 1.97 (2H, t, J=7 Hz), of 3.00 (1H, TT, J=11, 5 Hz), 3,55 (1H, t, J=11 Hz), of 3.56 (1H, t, J=11 Hz), 3,92-3,98 (2H, m), 4,08 (1H, kV, J=7 Hz), 4,14-4,19 (2H, m), is 5.06 (1H, d, J=4 Hz), 5,44 (2H, s), 5,88 (1H, DD, J=15, 4 Hz), 6,60 (1H, DD, J=15, 11 Hz), to 6.80 (1H, d, J=16 Hz), 7,01-was 7.08 (2H, m), 7,10 (1H, DD, J=16, 11 Hz), 7,49-at 7.55 (3H, m), 7,79 (1H, t, J=8 Hz), 7,98 (1H, s), of 8.25 (1H, s).

Mass spectrum m/z (FAB): 781 (M++1).

IR-spectrum ν max KBr cm-1: 2231, 1731, 1615, 1503, 1276, 1140, 1049, 974.

[Example 11]

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 4-hydroxybutyrate (example 4-1)

(1) 4-Methoxybenzyl 4-(allyloxycarbonyl)butyrate

To a suspension of commercially available 4-hydroxybutyrate sodium (10.3 g, to 81.7 mmol) in N,N-dimethylformamide (80 ml) was added 4-methoxybenzylamine (12.8 g, to 81.7 mmol) and the mixture was heated at 100°C for 1 hour. After cooling, the mixture was diluted with ethyl acetate and the resulting solution was washed three times with water and once with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure is obtaining a colorless oily residue. The residue was dissolved in dichloromethane (150 ml) was added 4-(N,N-dimethylamino)pyridine (11,0 g, 90 mmol) and allylchloroformate (9,85 g of 81.7 mmol) at 0°C, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate, then sequentially washed with water, saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride and aqueous solution of sodium chloride. The extract was dried over anhydrous magnesium sulfate and the solvent drove under reduced pressure to obtain an oily residue. The residue was subjected to chromatography on a column of silica gel (600 g) (eluent: ethyl acetate:hexane=4:1 ˜ 2:1) to obtain specified in the connection header (15,61 g, yield 62%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,95-of 2.05 (2H, m), of 2.45 (2H, t, J=7 Hz), 3,81 (3H, s), 4,18 (2H, t, J=6 Hz), br4.61 (2H, dt, J=6, 2 Hz), is 5.06 (2H, s), 5,27 (1H, dt, J=10, 2 Hz), are 5.36 (1H, dt, J=18, 2 Hz), to 5.93 (1H, DDT, J=18, 10, 6 Hz), 6.89 in (2H, d, J=9 Hz), 7,22 (2H, d, J=9 Hz).

IR-spectrum ν max netcm-1: 1745, 1614, 1516, 1463, 1255.

Mass spectrum m/z (FAB): 308 (M+).

(2) 4-(Allyloxycarbonyl)butyrylcholine

To a mixture of 4-methoxybenzyl 4-(allyloxycarbonyl)butyrate (5,61 g, 18.2 mmol)obtained in example 11-(1), and anisole (6 ml) at room temperature was added triperoxonane acid (30 ml). The mixture was stirred at room Tempe is the atur for 10 min, then was diluted with toluene and the resulting solution was concentrated under reduced pressure. The residue was again dissolved in toluene, the solvent is then evaporated under reduced pressure. The obtained oily residue suspended in aqueous sodium hydrogen carbonate solution and the resulting suspension was washed with hexane. To the aqueous suspension was slowly added 1 N. aqueous solution of hydrochloric acid to bring the pH to about 2 and the released carboxylic acid was extracted three times with ethyl acetate. The combined organic layers were washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The obtained colorless oil (3.50 g) was dissolved in dichloromethane (17 ml) was added N,N-dimethylformamide (0.05 ml) and oxacillin (3 g). The mixture was stirred at room temperature for 1 hour, then added toluene and the resulting solution was concentrated under reduced pressure. The residue was purified by simple distillation under reduced pressure to obtain specified in the connection header (2,90 g, yield 77%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2,08 (2H, m), totaling 3.04 (2H, t, J=7 Hz), 4,20 (2H, t, J=6 Hz), with 4.64 (2H, dt, J=6, 2 Hz), from 5.29 (1H, dt, J=10, 2 Hz), lower than the 5.37 (1H, dt, J=18, 2 Hz), 5,94 (1H, DDT, J=18, 10, 6 Hz).

(3) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 4-(allyloxycarbonyl-hydroxy)butyrate

4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-Differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (570 mg, 1.05 mmol)obtained in Reference example 1 was dissolved in N,N-dimethylformamide (3 ml) and the room temperature was added sodium hydride (30 mg, 1.3 mmol). The mixture was stirred for 1 hour, then to it was added 4-(allyloxycarbonyl)butyrylcholine (250 mg, to 1.21 mmol)obtained in example 11-(2), and the mixture was stirred for 1 hour. The mixture was diluted with ethyl acetate and poured into saturated aqueous solution of ammonium chloride. The organic layer was separated, washed with aqueous sodium hydrogen carbonate solution and then with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The residue was purified by means of the circulation preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm e × 600 mm) and JAIGEL-2H (20 mm e × 600 mm)connected in series for use; solvent: chloroform] to obtain specified in the title compound (562 mg, 75%yield) as a colorless amorphous solid.

NMR-spectrum (400 MHz, CDCl3) δ ppm: to 1.35 (3H, DD, J=7, 2 Hz), 1,90-2,10 (2H, m), 2,40-2,60 (2H, m), 3.04 from (1H, TT, J=11, 5 Hz), 3,52 (2H, t, J=11 Hz), 3,90 (1H, q, J=7 Hz), 4,15-of 4.25 (4H, m)and 4.65 (2H, d, J=6 Hz), 5,00 (1H, d, J=4 is C), 5,28 (1H, user. d, J=18 Hz), to 5.35 (2H, s), lower than the 5.37 (1H, user. d, J=18 Hz), 5,86 (1H, DD, J=15, 4 Hz), 5,95 (1H, DDT, J=18, 10, 6 Hz), 6,59 (1H, DD, J=16, 11 Hz), 6,74 (1H, d, J=16 Hz), 6,85-to 6.95 (3H, m), 7,25 was 7.45 (3H, m), EUR 7.57 (1H, t, J=8 Hz), of 7.90 (1H, s), to $ 7.91 (1H, s).

IR-spectrum ν max KBrcm-1: 2233, 1743, 1616, 1504.

Mass spectrum m/z (FAB): 713 (M++1).

(4) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 4-hydroxybutyrate (specified in the header of the target connection)

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 4-(allyloxycarbonyl)-butyrate (352 mg, 4,94×10-4mol)obtained in example 11-(3), and bis(triphenylphosphine)dichloropalladium (2 mg) was dissolved in dichloromethane (3 ml). To the mixture at room temperature for 5 min was slowly added to the anti-hydride (215 mg, 7,39×10-4mol). After stirring at room temperature for another 15 min to the reaction mixture was added hexane. Released insoluble oily substance was separated by slow removal of the supernatant liquid. The insoluble residue optionally washed twice with hexane. The oily residue was subjected to chromatography on a column of silica gel (15 g) (eluent: ethyl acetate:hexane=3:1 ˜ 1:0) to obtain the specified title compound (289 mg, yield 93%) in VI is e a colorless amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: of 1.34 (3H, DD, J=7, 2 Hz), 1,75-1,90 (2H, m), 1,90 (1H, t, J=6 Hz), 2,50 (2H, t, J=7 Hz), 3,10 (1H, TT, J=11, 5 Hz), 3,52 (1H, t, J=11 Hz), 3,53 (1H, t, J=11 Hz), 3,68 (2H, m), 3.96 points (1H, q, J=7 Hz), 4,15-of 4.25 (2H, m), free 5.01 (1H, d, J=5 Hz), and 5.30-of 5.40 (2H, m), of 5.85 (1H, DD, J=16 and 4 Hz), to 6.58 (1H, DD, J=16, 11 Hz), 6,74 (1H, d, J=16 Hz), 6,85-to 6.95 (3H, m), 7,25 was 7.45 (3H, m), EUR 7.57 (1H, t, J=8 Hz), 7,94 (1H, s), 7,95 (1H, s).

IR-spectrum ν max KBrcm-1: 3403, 2231, 1741, 1616, 1504.

Mass spectrum m/z (FAB): 629 (M++1).

[Example 12]

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 4-acetoxymethyl (example 4-2)

(1) 4-Chloro-4-oxobutanoate

4-Acetoxyphenyl acid (Tetrahedron, 45, 7783 (1989); 2.00 g, 13.7 mmol) was dissolved in dichloromethane (10 ml) was added N,N-dimethylformamide (0.05 ml) and oxacillin (2.5 g). The mixture was stirred at room temperature for 1 hour, and then thereto was added toluene and the resulting solution was concentrated under reduced pressure. The residue was purified by simple distillation under reduced pressure to obtain specified in the connection header (of 1.57 g, yield 70%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2,05 (2H, m)2,07 (3H, s)of 3.00 (2H, t, J=7 Hz), of 4.12 (2H, t, J=6 Hz).

(2) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 4-amoxibiotic (specified in the header of the target connection)

4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-Differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (1.10 g, 2.03 mmol)obtained in Reference example 1 was dissolved in N,N-dimethylformamide (5 ml) and then at room temperature was added sodium hydride (50 mg, 2.1 mmol). The mixture was stirred for 15 min, then to it was added 4-chloro-oxobutanoate (330 mg, 2.0 mmol)obtained in example 12-(1), and the resulting mixture was stirred for another hour. The mixture was diluted with ethyl acetate and poured into saturated aqueous solution of ammonium chloride. The organic layer was separated, then washed with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, then the solvent is kept at reduced pressure. The crude compound was purified circulating preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm e × 600 mm) and JAIGEL-2H (20 mm e × 600 mm)connected in series for use; solvent, chloroform] to obtain specified in the title compound (662 mg, yield 49%) as a colorless amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: to 1.35 (3H, DD, J=7, 2 Hz), 1.85 to 2.05 is (2H, m), of 2.08 (3H, s), 2,35 is 2.55 (2H, m), 3,06 (1H, TT, J=11, 5 Hz), 3,52 (1H, t, J=11 Hz), 3,53 (1H, t, J=11 Hz), 3,93 (1H, q, J=7 Hz), of 4.12 (2H, t, J=7 Hz), 4,15-of 4.25 (2H, m)5,00 (1H, d, J=4 Hz), are 5.36 (2H, s), 5,86 (1H, DD, J=15, 4 Hz), 6,59 (1H, DD, J=15, 10 Hz), was 6.73 (1H, d, J=15 Hz), 6,85-to 6.95 (3H, m), 7,30 was 7.45 (3H, m), EUR 7.57 (1H, t, J=8 Hz), of 7.90 (1H, s), to 7.93 (1H, s).

IR-spectrum ν max KBrcm-1: 2231, 1739, 1616, 1504.

Mass spectrum m/z (FAB): 671 (M++1).

[Example 13]

Disodium 4-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-4-oxobutyl phosphate (disodium salt of example number 4-16)

(1) 4-Methoxybenzyl 4-[[bis(allyloxy)phosphoryl]-oxy]butyrate

To a suspension of commercially available 4-hydroxybutyrate sodium (630 mg, 5.00 mmol) in N,N-dimethylformamide (3.5 ml) was added 4-methoxybenzylamine (783 mg, 5.00 mmol) and the mixture was heated at 100°C for 3 hours. The mixture was cooled, diluted with ethyl acetate, and the diluted mixture is then washed with water (twice) and aqueous solution of sodium chloride (twice). The solution was dried over anhydrous magnesium sulfate and the solvent drove under reduced pressure to obtain a colorless oily residue. The residue was dissolved in dichloromethane (5 ml) and at 0°C was added tetrazole (700 mg, 10 mmol) and bis(allyloxy)(diisopropylamino)phosphine (Tetrahedron Lett., 30, 4219 (1989); 1,5 g, 6.1 mmol), the mixture is then stirred at this temperature for 5 minutes the Mixture was heated to room temperature, then per massively for 30 min and was added methanol (0.1 ml). The mixture was stirred for 5 min and at 0°C was added tert-butyl hydroperoxide (about 5 M solution in nonane, 1.5 ml, about 7.5 mmol) followed by stirring the mixture at room temperature for 30 minutes To the mixture was added saturated aqueous sodium hydrogen carbonate solution and aqueous sodium thiosulfate solution and the mixture was stirred for 10 min and then was distributed between ethyl acetate and water. The organic layer was sequentially washed with a saturated aqueous solution of sodium bicarbonate, saturated aqueous ammonium chloride and aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate and the solvent drove under reduced pressure to obtain an oily residue. The residue was subjected to chromatography on a column of silica gel (30 g) (eluent: ethyl acetate:hexane=2:3 ˜ 1:1) to obtain the specified title compound (1.55 g, yield 81%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: a 2.01 (2H, Quint, J=7 Hz), 2,47 (2H, t, J=7 Hz), 3,81 (3H, s), 4,10 (2H, q, J=7 Hz), 4,50-4,55 (4H, m), is 5.06 (2H, in), 5.25 (2H, user. d, J=10 Hz), are 5.36 (2H, user. d, J=17 Hz), to 5.93 (2H, DDT, J=17, 10, 5 Hz), at 6.84 (2H, d, J=9 Hz), 7,29 (2H, d, J=9 Hz).

IR-spectrum ν max pure cm-1: 1731, 1613, 1516, 1464, 1254.

Mass spectrum m/z (FAB): 385 (M++1).

(2) Diallyl 4-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,,4-triazole-1-yl)methyl]propoxy]-4-oxobutanoate

To a mixture of 4-methoxybenzyl 4-[[bis(allyloxy)phosphoryl]oxy]butyrate (700 mg, 1.82 mmol)obtained in example 13-(1), and anisole (0.7 ml) was added triperoxonane acid (3 ml) at room temperature. The mixture was stirred at room temperature for 15 min, then was diluted with toluene and the solvent is kept at reduced pressure. The residue was again dissolved in toluene and the solvent drove under reduced pressure to obtain crude 4-[[bis(allyloxy)phosphoryl]oxy]butane acid in the form of a pale yellow oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2,03 (2H, Quint, J=7 Hz), of 2.51 (2H, t, J=7 Hz), of 4.16 (2H, q, J=7 Hz), 4,55-4,60 (4H, m), from 5.29 (2H, user. d, J=10 Hz), of 5.39 (2H, user. d, J=17 Hz), 5,94 (2H, DDT, J=17, 10, 5 Hz), of 11.29 (1H, user. C).

The crude 4-[[bis(allyloxy)phosphoryl]-oxy]butane acid was dissolved in dichloromethane (3.5 ml) was added N,N-dimethylformamide (0.05 ml) and oxacillin (350 mg). The mixture was stirred at room temperature for 1 hour, and then thereto was added toluene and the resulting solution was concentrated under reduced pressure to obtain crude 4-[[bis(allyloxy)phosphoryl]oxy]boilerplated.

4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-Differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (936 mg, at 1.73 mmol)obtained in Reference example is 1, was dissolved in tetrahydrofuran (10 ml) was added sodium hydride (55% dispersion in mineral oil; 80 mg and 1.83 mmol) at room temperature. The mixture was stirred for 3 hours. Received suspended mixture was cooled to 0°C and added to it with stirring the above crude 4-[[bis(allyloxy)phosphoryl]oxy]boilerplated. The mixture was stirred at room temperature for 30 minutes After cooling, the mixture was distributed between ethyl acetate and an aqueous solution of ammonium chloride and the organic layer was washed saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The oily residue was subjected to chromatography on a column of silica gel (30 g) (eluent: ethyl acetate:methanol=1:0 ˜ 10:1) to obtain the specified title compound (862 mg, yield 63%) as a pale yellow amorphous solid.

NMR-spectrum (400 MHz, CDCl3) δ ppm: to 1.35 (3H, DD, J=7, 2 Hz), 1,90-2,10 (2H, m), 2,46 (1H, dt, J=17, 7 Hz), 2.57 m (1H, dt, J= 17, 7 Hz), 3.04 from (1H, TT, J=11, 5 Hz), 3,52 (2H, t, J=11 Hz), 3,90(1H, q, J=7 Hz), of 4.12 (2H, kV, J=7 Hz) 4,15-of 4.25 (2H, m), 4,55-4,60 (4H, m)5,00 (1H, d, J=4 Hz), 5,27 (2H, d, J=11 Hz), to 5.35 (2H, s)5,38 (2H, d, J=17 Hz), to 5.85 (1H, DD, J=15, 4 Hz), 5,90-6,00 (2H, m), to 6.58 (1H, DD, J=16, 11 Hz), 6,74 (1H, d, J=15 Hz), 6,85-to 6.95 (3H, m), 7,30 was 7.45 (3H, m), EUR 7.57 (1H, t, J=8 Hz), of 7.90 (1H, s), 7,92 (1H, s).

IR-spectrum ν max KBr cm-1: 2233, 1741, 1615, 1600, 1504.

Mass spectrum m/z (FAB):789 (M ++1).

(3) Disodium 4-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-4-oxobutyl phosphate (specified in the header of the target connection)

Diallyl 4-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-4-oxobutyl phosphate (350 mg, 4,53×10-4mol)obtained in example 13-(2), tetrakis(triphenylphosphine)palladium (5 mg) and triphenylphosphine (5 mg) was dissolved in dichloromethane (3 ml). To the mixture at room temperature was added pyrrolidine (644 mg, 9,06×10-3mol) and the resulting mixture was stirred for 1 hour, then was diluted with toluene and the solvent is kept at reduced pressure. The residue was subjected to column chromatography with reversed phase using Cosmosil 75 C18-PREP (Nacalai Tesque, Inc.; 15 g) (eluent: water:methanol=1:0 ˜ 4:6). The fractions obtained were concentrated and the residue was subjected to treatment with cation exchange resin (Dowex 50W-8X, in the sodium form, obtained using 1 N. aqueous sodium hydroxide solution; 5 ml) (eluent: water). The collected fractions were concentrated under reduced pressure and was liofilizovane obtaining specified in the title target compound (233 mg, yield 64%) as a colorless amorphous solid.

NMR-spectrum (400 MHz, D2O) δ ppm: of 1.13 (3H, d, J=7 Hz), 1,68 (2H, Quint, J=7 Hz), 2,35-of 2.50 (2H, m), 2,87 (1H,m), of 3.43 (1H, t, J=12 Hz), of 3.46 (1H, t, J=12 Hz), 3,55-the 3.65 (3H, m), 3.95 to of 4.05 (2H, m), equal to 4.97 (1H, d, J=4 Hz), 5,13 (1H, d, J=15 Hz), of 5.26 (1H, d, J=15 Hz), the 5.65 (1H, DD, J=15, 5 Hz), 6.42 per (1H, DD, J=15, 10 Hz), only 6.64 (1H, d, J=16 Hz), 6,80-of 6.90 (3H, m), 7,25-to 7.35 (3H, m), 7,51 (1H, t, J=7 Hz), 7,82 (1H, s), 8,13 (1H with).

IR-spectrum ν max KBr cm-1: 3432, 2231, 1740, 1615, 1599, 1503, 1418, 1387, 1276, 1257, 1142.

Mass spectrum m/z (FAB): 753 (M++1).

Elemental analysis for C31H30F3N4O8PSNa2·3H2O:

Calculated: C:46,16; H:4,50; N:6,95; Na:5,70

Found: C:46,41; H:A 4.83; N:? 7.04 Baby Mortality; Na:Lower Than The 5.37.

[Example 14]

4-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-4-oxobutyl succinate sodium (sodium salt of example number 4-6)

(1) Allyl 4-chloro-4-oxybutyrate

To a solution of commercially available anhydride of succinic acid (2.00 g, 20.0 mmol) in dichloromethane (10 ml) was added allyl alcohol (1.75 g, to 30.1 mmol), N,N-diisopropylethylamine (3.88 g, to 30.1 mmol) and 4-(N,N-dimethylamino)pyridine (10 mg) at room temperature. The mixture was stirred for 1 hour, then to it was added 1 N. hydrochloric acid and the resulting solution was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and the solvent is kept under reduced pressure, the obtaining of the crude allergicreactions.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2,65-of 2.75 (4H, m), br4.61 (2H, d, J=6 Hz), 5,24 (1H, DD, J=10, 2 Hz), 5,33 (1H, DD, J=17, 1 Hz), 5,91 (1H, DDT, J=17, 10, 6 Hz), 11,05 (1H, user. C).

The crude allergicreaction was dissolved in dichloromethane (10 ml) was added N,N-dimethylformamide (0.05 ml) and oxacillin (3.8 g). The mixture was stirred at room temperature for 2 hours, and then thereto was added toluene and the solvent is kept at reduced pressure. The residue was purified by simple distillation under reduced pressure to obtain specified in the connection header (2,89 g, yield 82%) as a pale yellow oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2,72 (2H, t, J=7 Hz), 3,23 (2H, t, J=7 Hz), to 4.62 (2H, d, J=5 Hz), 5,26 (1H, DD, J=10, 1 Hz), 5,33 (1H, DD, J=17, 1 Hz), 5,90 (1H, DDT, J=17, 10, 5 Hz).

(2) Allyl 4-[(4-methoxybenzyl)oxy]-4-oxobutanamide

To a suspension of commercially available 4-hydroxybutyrate sodium (756 mg, 6,00 mmol) in N,N-dimethylformamide (10 ml) was added 4-methoxybenzylamine (987 mg, 6,30 mmol) and the mixture was heated at 100°C for 3 hours. The reaction mixture was cooled and added to it at 0°C allyl 4-chloro-4-oxybutyrate (1.06 g, of 6.02 mmol)obtained in example 14-(1), triethylamine (920 μl, 6,60 mmol) and 4-(N,N-dimethylamino)pyridine (10 mg). The mixture was stirred at room temperature for 18 hours and the resulting mixture was diluted with ethyl acetate, and then receive the hydrated solution was sequentially washed with water, saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride and aqueous solution of sodium chloride. The solution was dried over anhydrous magnesium sulfate and the solvent drove under reduced pressure to obtain an oily residue. The residue was subjected to chromatography on a column of silica gel (50 g) (eluent: hexane:ethyl acetate=3:1 ˜ 2:1) to obtain the specified title compound (1.52 g, yield 70%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,47 (2H, Quint, J=7 Hz), 2,42 (2H, t, J=7 Hz), 2,55-2,70 (4H, m), 3,81 (3H, s), of 4.13 (2H, t, J=7 Hz), 4,59 (2H, dt, J=6, 2 Hz), is 5.06 (2H, s), 5,23 (1H, user. d, J=11 Hz), and 5.30 (1H, user. d, J=18, 2 Hz), of 5.89 (1H, DDT, J=18, 11, 6 Hz), 6.89 in (2H, d, J=8 Hz), 7,29 (2H, d, J=8 Hz).

IR-spectrum ν max, clean, cm-1: 1735, 1614, 1516, 1249 1163.

Mass spectrum m/z (EI): 364 (M+).

(3) Allyl 4-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-4-oxobutyl succinate

According to the method similar to that described in Example 13-(2), allyl 4-[(4-methoxybenzyl)oxy]-4-oxobutyl succinate (546 mg, 1.50 mmol)obtained in example 14-(4)was treated with anisole (0,50 ml) and triperoxonane acid (5 ml) to obtain 4-[4-(allyloxy)-4-oxobutyrate]butane acid, and then treated with oxalylamino (290 mg) to give the crude allyl chlor-4-oxobutanoate.

The crude allyl 4-chloro-4-oxobutanoate was treated with 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-phthorbenzotephum (814 mg, 1.50 mmol)described in reference example 1, and sodium hydride (55% dispersion in mineral oil, 70 mg, 1.6 mmol) by the procedure similar to that described in Example 13-(2). The crude specified in the title compound was purified circulating preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; The GPC column JAIGEL-1H (20 mm e × 600 mm) and JAIGEL-2H (20 mm e × 600 mm)connected in series for use; solvent: chloroform] to obtain specified in the title compound (459 mg, yield 40%) as a colorless viscous substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: to 1.35 (3H, DD, J=7, 2 Hz), 1.85 to 2.05 is (2H, m), 2,35 is 2.55 (2H, m), 2,60-of 2.75 (4H, m), 3,05 (1H, TT, J=12, 5 Hz), 3,52 (2H, t, J=11 Hz), to 3.92 (1H, q, J=7 Hz), 4,15-of 4.25 (4H, m), 4,60 (2H, user. d, J=6 Hz), 5,00 (1H, d, J=4 Hz), 5,23 (1H, user. d, J=11 Hz), 5,31 (1H, user. d, J=17 Hz), to 5.35 (2H, s), to 5.85 (1H, DD, J=15, 4 Hz), 5,90 (1H, DDT, J=17, 11, 6 Hz), to 6.58 (1H, DD, J=16, 11 Hz), 6,74 (1H, d, J=16 Hz), 6,85-to 6.95 (3H, m), 7,30 was 7.45 (3H, m), EUR 7.57 (1H, t, J=8 Hz), of 7.90 (1H, s), 7,92 (1H, s).

IR-spectrum ν max CHCl3cm-1: 2233, 1737, 1616, 1598, 1504.

Mass spectrum m/z (FAB): 769 (M++1).

(4) 4-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-4-oxobutyl succinat sodium (specified in the header of the target connection)

According to the method similar to that described in Example 1-(13)was subjected to the reaction of allyl 4-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-4-oxobutanoate (180 mg, 2,35×10-4mmol)obtained in example 14-(3), bis(triphenylphosphine)dichloropalladium (3 mg) and anti-hydride (100 mg, 3,44×10-4mmol) and the reaction mixture was treated with obtaining specified in the header of the target compound in the form of crude oil. The crude oil was subjected to column chromatography with reversed phase using Cosmosil 75 C18-PREP (Nacalai Tesque, Inc.; 20 g) (eluent:water:methanol=4:6 ˜ 3:7). The fractions obtained were concentrated and the residue was liofilizovane obtaining specified in the title target compound (64 mg, yield 36%) as a colourless solid.

NMR-spectrum (400 MHz, CD3OD) δ ppm: 1,31 (3H, DD, J=7, 2 Hz), 1,90-2,00 (2H, m), 2.40 a-to 2.65 (6H, m), 3,03 (1H, TT, J=12, 5 Hz), 3,52 (2H, t, J=11 Hz), 3,85 (1H, q, J=7 Hz), 4,05-of 4.25 (4H, m), 5,04 (1H, d, J=5 Hz), 5,44 (2H, m), of 5.85 (1H, DD, J=15, 5 Hz), 6,59 (1H, DD, J=15, 10 Hz), to 6.80 (1H, d, J=15 Hz), 6,95-7,05 (2H, m), 7,10 (1H, DD, J=15, 10 Hz), 7,45-of 7.55 (3H, m), 7,80 (1H, t, J=8 Hz), 8,00 (1H, s), 8,32 (1H with).

IR-spectrum ν max CHCl3cm-1: 3438, 2231, 1737, 1614, 1595, 1504, 1419.

Mass spectrum m/z (FAB): 751 (M++1).

[Example 15]

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)1-[(1H-1,2,4-triazole-1-yl)methyl]propyl (2-hydroxyethyl) carbonate (example 4-31)

(1) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl imidazol-1-carboxylate

4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-Differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (4,90 g, 9,03 mmol)described in reference example 1, and 1,1'-carbonyldiimidazole (1,53 g, 9,44 mmol) was dissolved in dichloromethane (20 ml). To the mixture was added sodium hydride (55% dispersion in mineral oil, 10 mg, 2,3×10-4mol) and the reaction mixture is boiled under reflux for 3 hours under stirring. After cooling, to the mixture was added to phosphate buffer solution (pH 7,4) and the product was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The residue was subjected to chromatography on a column of silica gel (120 g) (eluent: ethyl acetate:hexane=1:1 ˜ 1:0) to obtain specified in the connection header (4,00 g, yield 70%) as a colorless amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: of 1.46 (3H, DD, J=7, 2 Hz), 3,01 (1H, TT, J=11, 5 Hz), 3,51 (1H, t, J=12 Hz), 3,52 (1H, t, J=12 Hz)to 4.01 (1H, q, J=7 Hz), 4,10-4,20 (2H, m)5,00 (1H, d, J=5 Hz), 5,28 (1H, user. d, J=18 Hz), of 5.48 (2H, s), to 5.85 (1H, d is, J=15, 4 Hz), to 6.58 (1H, DD, J=15, 11 Hz), 6.90 to-to 7.00 (3H, m), 7,13 (1H, user. C), 7,30 was 7.45 (4H, m), EUR 7.57 (1H, t, J=8 Hz), to 7.84 (1H, s), of 7.97 (1H, s), 8,11 (1H, s).

IR-spectrum ν max KBr cm-1: 2230, 1763, 1615, 1504, 1418, 1390.

Mass spectrum m/z (FAB): 637 (M++1).

(2) 2-[(tert-Butyldiphenylsilyl)oxy]ethanol

Commercially available 2-hydroxyethylated (3.12 g, 30.0 mmol), triethylamine (4.6 ml, 33 mmol) and 4-(N,N-dimethylamino)pyridine (100 mg) was dissolved in dichloromethane (20 ml), then at room temperature was added tert-butylchloroformate (8.65 g, to 31.5 mmol) and the mixture was stirred for 20 hours. The resulting solution was diluted with a mixed solvent of hexane-ethyl acetate (1:1) and then the resulting solution was washed with water and an aqueous solution of sodium chloride. The solution was dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The residue was dissolved in methanol (100 ml) and at room temperature was added a 28% solution of sodium methoxide in methanol (3 ml) followed by stirring for 2 hours. The solvent is kept under reduced pressure and the residue was distributed between ethyl acetate and phosphate buffer solution (pH 7), then the organic layer was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent drove under reduced pressure to get crude specified in the connection header (5,18 g, total yield 57%) in the form b is izvetnogo oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm with 1.07 (9H, s), 2,11 (1H, t, J=6 Hz), 3,65-3,70 (2H, m), of 3.77 (2H, t, J=5 Hz), 7,35 is 7.50 (6H, m), 7,65-of 7.70 (4H, m).

(3) 2-[(tert-Butyldiphenylsilyl)oxy]ethyl (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propylboronic

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl imidazol-1-carboxylate (637 mg, 1.00 mmol)obtained in example 15-(1), and the crude 2-[(tert-butyldiphenylsilyl)oxy]ethanol (315 mg, about 1.05 mmol)obtained in example 15-(2), was dissolved in dichloromethane (3 ml) was added tert-piperonyl potassium (5 mg). The mixture was boiled under reflux for 15 min under stirring. After cooling the mixture was poured phosphate buffer solution (pH 7) and the reaction product was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The residue was purified circulating preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm e × 600 mm) and JAIGEL-2H (20 mm e × 600 mm)connected in series for use; solvent: chloroform] to obtain specified in the connection header (631,4 mg, yield 73%) as a colorless amorphous solid substance.

I have the R-spectrum (400 MHz, CDCl3) δ ppm with 1.07 (9H, s)of 1.35 (3H, DD, J=7, 2 Hz), 3.04 from (1H, TT, J=11, 5 Hz), 3,48 (1H, t, J=11 Hz), 3,50 (1H, t, J=11 Hz), 3,80-of 3.95 (3H, m), 4,15-4,20 (2H, m), 4,30 is 4.35 (2H, m), 4,94 (1H, d, J=5 Hz), are 5.36 (1H, DD, J=15 and 3 Hz), 5,41 (1H, d, J=15 Hz), of 5.84 (1H, DD, J=15, 4 Hz), 6,55 (1H, DD, J=15, 11 Hz), of 6.71 (1H, d, J=16 Hz), 6.75 in-to 6.95 (3H, m), 7,30 is 7.50 (9H, m), 7,56 (1H, t, J=8 Hz), the 7.65 to 7.75 (4H, m), of 7.90 (1H, s), 7,95 (1H, s).

IR-spectrum ν max KBrcm-1: 2230, 1750, 1615, 1503.

Mass spectrum m/z (FAB): 869 (M++1).

(4) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl(2-hydroxyethyl)carbonate (specified in the header of the target connection)

To a solution of 2-[(tert-butyldiphenylsilyl)oxy]ethyl(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propylmalonate (470 mg, 5,41×10-4mol)obtained in example 15-(3), in tetrahydrofuran (1.5 ml) was added sequentially acetic acid (33 mg, 5,5×10-4mol) and tetrabutylammonium (1M solution in tetrahydrofuran; 0,55 ml, 5,5×10-4mol). The mixture was stirred at this temperature for 1 hour, then it was poured in ethyl acetate and phosphate buffer solution (pH 7) and the organic layer was separated. The organic layer was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The residue was purified circus is the air preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm e × 600 mm) and JAIGEL-2H (20 mm e × 600 mm)connected in series for use; solvent: chloroform] to obtain specified in the title compound (186 mg, yield 55%) as a colorless amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: of 1.34 (3H, DD, J=7, 3 Hz), 1,90 (1H, user. C)2,95-3,10 (1H, m), 3,49 (1H, t, J=11 Hz), 3,51 (1H, t, J=11 Hz), 3,80-are 3.90 (3H, m), 4,19 (1H, DDD, J=11, 5, 2 Hz), 4,25-and 4.40 (3H, m), 4,94 (1H, d, J=5 Hz), of 5.39 (2H, m), of 5.85 (1H, DD, J=15, 4 Hz), to 6.58 (1H, DD, J=15, 11 Hz), was 6.73 (1H, d, J=16 Hz), 6,85-to 7.00 (3H, m), 7,33 (1H, DD, J=10, 1 Hz), 7,40 (1H, DD, J=8, 1 Hz), was 7.45 (1H, TD, J=9, 6 Hz), EUR 7.57 (1H, t, J=8 Hz), of 7.96 (1H, s), 8,04 (1H, s).

[Example 16]

Disodium 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyloxy]ethyl phosphate (disodium salt of example number 4-45)

(1) 2-[[Bis(allyloxy)phosphoryl]oxy]ethyl (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propylboronic

To a solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl (2-hydroxyethyl) carbonate (180 mg, 2,85×10-4mol)obtained in example 15, in dichloromethane (2 ml) was added tetrazole (40 mg, 5,7 on; 10-4mol) and bis(allyloxy)(diisopropylamino)phosphine (Tetrahedron Lett., 30, 4219 (1989); 105 mg, 4,28×10-4mol) at room temperature, and the reaction mixture was stirred for 30 minutes At the same temperature to the mixture was added allyl alcohol (0.1 ml) and the resulting mixture was stirred for 20 minutes the Mixture was cooled to 0°C was added thereto tert-butylhydroperoxide (about 5M solution in nonane; 1.5 ml, about 7.5 mmol), then the mixture was stirred at room temperature for 30 minutes To the mixture was added saturated aqueous sodium hydrogen carbonate solution and aqueous sodium thiosulfate solution, then the mixture was stirred for 10 min and distributed between ethyl acetate and water. The organic layer was sequentially washed with a saturated aqueous solution of sodium bicarbonate, saturated aqueous ammonium chloride and aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The obtained residue was purified circulating preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm e × 600 mm) and JAIGEL-2H (20 mm e × 600 mm)connected in series for use; solvent: chloroform] to obtain specified in the title compound (124 mg, yield 55%) as a colorless viscous substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: to 1.35 (3H, DD, J=7, 2 Hz), 3,01 (1H, TT, J=12, 5 Hz), 3,48 (1H, t, J=12 Hz), 3,50 (1H, t, J=12 Hz), a-3.84 (1H, q, J=7 Hz), 4,17 (1H, DDD, J=12, 5, 2 Hz), 4,25 is 4.35 (4H, m), 4,40-4,50 (1H, m), 4,55-4,60 (4H, m), equal to 4.97 (1H, d, J=4 Hz), 5,26 (2H, dt, J=12, 1 Hz), 5,35-of 5.40 (4H, m), of 5.84 (1H, DD, J=15, 4 Hz), 5,85-6,00 (2H, m), to 6.57 (1H, DD, J=15, 11 Hz), was 6.73 (1H, d, J=15 Hz), 6,85-to 7.00 (3H, m), 7,33 (1H, DD, J=10, 1 Hz), 7,40 (1H, DD, J=8, 1 Hz), 7,46 (1H, TD, J=9, 6 Hz), EUR 7.57 (1H, t, J=8 Hz), 7,94 (1H, s), 7,98 (1H, s).

IR-spectrum ν max CHCl3cm-1: 2233, 1753, 1616, 1504, 1276, 1140.

Mass spectrum m/z (FAB): 791 (M++1).

(2) Disodium 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyloxy]ethyl phosphate (specified in the header of the target connection)

2-[[Bis(allyloxy)phosphoryl]oxy]ethyl (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propylmalonate (120 mg, 1,52×10-4mol)obtained in example 16-(1) and tetrakis(triphenylphosphine)palladium (2 mg) was dissolved in dichloromethane (1.2 ml). To the mixture was added pyrrolidine (215 mg, 3.04 from mmol) at room temperature and the solution was stirred for 1 hour, and then according to the method similar to that described in Example 13-(3)has been specified in the header of the target connection (87,5 mg, yield 76%) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, D2O) δ ppm: of 1.18 (3H, d, J=7 Hz), of 2.81 (1H, m), 3,43 (1H, user. t, J=12 Hz), of 3.46 (1H, ush the R. t, J=12 Hz)and 3.59 (1H, m), 3,85 (2H, m), 3.95 to to 4.15 (2H, m), 4,22 (2H, m), equal to 4.97 (1H, user. d, J=4 Hz), a total of 5.21 (1H, user. d, J=15 Hz), of 5.34 (1H, user. d, J=15 Hz), the 5.65 (1H, user. DD, J=15, 5 Hz), 6,41 (1H, m), 6,63 (1H, user. d, J=16 Hz), 6,80-to 6.95 (3H, m), 7,25-of 7.60 (4H, m), 7,88 (1H, s), compared to 8.26 (1H, s).

IR-spectrum ν max KBrcm-1: 3418, 2231, 1749, 1615, 1600, 1504, 1418, 1385, 1276, 1257, 1141.

Mass spectrum m/z (FAB): 755 (M++1).

[Example 17]

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-(hydroxymethyl)benzoate (example 5-1)

(1) 4-Methoxybenzyl 2-[(allyloxycarbonyl)oxymethyl]benzoate

Commercially available 1(3H)-isobenzofuranone (740 mg, 5,52 mmol) and potassium hydroxide (310 mg, 5,52 mmol) suspended in a mixed solvent (10 ml) methanol-water (2:1), followed by stirring for 3 hours while heating the suspension at 70°C. After cooling, the solvent is kept at reduced pressure. The residue was dried using a vacuum pump while heating the residue at 40°C. the Obtained solid is suspended in N,N-dimethylformamide (10 ml) was added 4-methoxybenzylamine (865 mg, 5,52 mmol). The mixture was stirred at 100°C for 1 hour. The mixture was cooled, then diluted with ethyl acetate and the resulting mixture was washed with water and then with an aqueous solution of sodium chloride. The solution was dried over anhydrous sulfa what Ohm magnesium and the solvent drove under reduced pressure to obtain a colorless oily residue. The residue was dissolved in dichloromethane (10 ml), then at 0°C was added 4-(N,N-dimethylamino)pyridine (673 mg, 5.51 mmol) and allylchloroformate (644 mg, 5.51 mmol), followed by stirring at room temperature for 1 hour. The mixture was diluted with ethyl acetate and then washed with water and an aqueous solution of sodium chloride. The resulting solution was dried over anhydrous magnesium sulfate and the solvent drove under reduced pressure to obtain an oily residue. The residue was subjected to chromatography on a column of silica gel (60 g) (eluent: hexane:ethyl acetate=5:1) to obtain the specified title compound (905 mg, yield 46%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 3,82 (3H, s), of 4.66 (2H, dt, J=6, 1 Hz), 5,28 (1H, user. d, J=10 Hz), from 5.29 (2H, s)5,38 (1H, user. d, J=18 Hz), 5,61 (2H, s), 5,95 (1H, DDT, J=18, 10, 6 Hz), 6,91 (2H, d, J=9 Hz), 7,35-7,40 (1H, m), 7,39 (2H, d, J=9 Hz), 7,50-of 7.55 (2H, m), 8,02 (1H, d, J=7 Hz).

IR-spectrum ν max, clean, cm-1: 1750, 1716, 1614, 1516, 1248.

Mass spectrum m/z (FAB): 356 (M+).

(2) 2-[(Allyloxycarbonyl)oxymethyl]benzoic acid

A mixture of 4-methoxybenzyl 2-[(allyloxycarbonyl)oxymethyl]benzoate (to 6.80 g of 19.1 mmol)obtained in example 17-(1), and anisole (5 g)was dissolved in triperoxonane acid (10 ml) at room temperature. The mixture was stirred for 15 min, then was diluted with toluene and the solvent is kept under reduced davlantes washed with hexane to obtain the crude specified in the connection header (a 3.87 g, 86%) as a colourless solid.

NMR-spectrum (400 MHz, CDCl3) δ ppm: and 4.68 (2H, dt, J=6, 1 Hz), from 5.29 (1H, user. d, J=10 Hz), of 5.39 (1H, user. d, J=17 Hz), 5,67 (2H, s)5,94 (1H, DDT, J=17, 10, 6 Hz), 7,40-7,50 (1H, m), 7,60-the 7.65 (2H, m), 8,15 (1H, d, J=8 Hz), and 11.5 (1H, user. C).

(3) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[(allyloxycarbonyl)-oxymethyl]benzoate

2-[(Allyloxycarbonyl)oxymethyl]benzoic acid (850 mg, of 3.60 mmol)obtained in example 17-(2), was dissolved in dichloromethane (5 ml) was added N,N-dimethylformamide (0.05 ml) and oxacillin (570 mg). The mixture was stirred at room temperature for 1 hour, then added toluene and the solution was concentrated under reduced pressure to obtain crude 2-[(allyloxycarbonyl)oxymethyl]benzoyl chloride.

The reaction was carried out according to the method similar to that described in Example 13-(2), using 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)-propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (1.63 g, 3.00 mmol), described in the reference example 1, sodium hydride (55% dispersion in mineral oil; 144 mg, 3.3 mmol) and crude 2-[(allyloxycarbonyl)-oxymethyl]benzoyl chloride obtained above. The obtained crude product was subjected to chromatography on a column with what silicagel (50 g) (eluent: ethyl acetate:hexane=1:1˜ 4:1) to obtain the specified title compound (1.68 g, yield 74%) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: of 1.46 (3H, DD, J=7, 2 Hz), 3,05 (1H, TT, J=11, 5 Hz), 3,50 (1H, t, J=11 Hz), 3,52 (1H, t, J=11 Hz), of 4.00 (1H, q, J=7 Hz), 4,10-4,20 (2H, m), 4,60-4,70 (2H, m), to 4.98 (1H, d, J=4 Hz), 5,28 (1H, user. d, J=10 Hz), lower than the 5.37 (1H, user. d, J=18 Hz), the 5.45 to 5.55 (4H, m), of 5.84 (1H, DD, J=15, 4 Hz), 5,94 (1H, DDT, J=18, 10, 6 Hz), to 6.57 (1H, DD, J=15, 11 Hz), was 6.73 (1H, d, J=15 Hz), 6,85-to 6.95 (3H, m), 7,34 (1H, d, J=9 Hz), 7,35-7,45 (3H, m), 7,55-the 7.65 (3H, m), 7,76 (1H, t, J=7 Hz), to $ 7.91 (1H, s), 7,98 (1H, s).

IR-spectrum ν max KBr cm-1: 2231, 1748, 1728, 1615, 1504.

Mass spectrum m/z (FAB): 761 (M++1).

(4) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-(hydroxymethyl)benzoate (specified in the header of the target connection)

The reaction was carried out according to the method similar to that described in Example 11-(4), using (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[(allyloxycarbonyl)oxymethyl]benzoate (1,52 g, 2.00 mmol), bis(triphenylphosphine)dichloropalladium (5 mg) and anti-hydride (620 mg, 2,13 mmol). The obtained crude product was subjected to chromatography on a column of silica gel (50 g) (eluent: ethyl acetate:hexane=1:1˜1:0) to obtain specified in the connection header (1,096 g, yield 81%) as a colourless solid is th amorphous substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: of 1.46 (3H, DD, J=7, 2 Hz), 3,06 (1H, TT, J=12, 5 Hz)and 3.31 (1H, t, J=7 Hz), 3,50 (1H, t, J=11 Hz), 3,53 (1H, t, J=11 Hz), Android 4.04 (1H, q, J=7 Hz), 4,10-of 4.25 (2H, m), to 4.73 (1H, DD, J=13, 7 Hz), 4,80 (1H, DD, J=13, 7 Hz), to 4.98 (1H, d, J=4 Hz), 5,52 (2H, m), of 5.84 (1H, DD, J=16 and 4 Hz), to 6.57 (1H, DD, J=15, 11 Hz), was 6.73 (1H, d, J=15 Hz), 6,85-to 7.00 (3H, m), 7,33 (1H, DD, J=10, 1 Hz), 7,35-7,45 (3H, m), 7,50-of 7.60 (3H, m), 7,79 (1H, DD, J=8, 1 Hz), 7,89 (1H, s), 7,94 (1H, s).

IR-spectrum ν max KBr cm-1: 3402, 2231, 1722, 1616, 1504.

Mass spectrum m/z (FAB): 677 (M++1).

[Example 18]

Disodium 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]benzyl phosphate (disodium salt of example number 5-15)

(1) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]benzoate

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-(hydroxymethyl)benzoate (540 mg, 7,89×10-4mol)obtained in example 17-(4), was dissolved in a mixed solvent (3 ml), dichloromethane-acetonitrile (1:1). To the mixture at 0°C was added tetrazole (112 mg, 1.6 mmol) and bis(allyloxy)(diisopropylamino)phosphine (Tetrahedron Lett., 30, 4219 (1989); 250 mg, 1,0×10-3mol) and the mixture was stirred is at this temperature for 5 minutes The mixture was heated to room temperature, then was stirred for 30 min and was added allyl alcohol (0.1 ml). The mixture was stirred for 5 min, then at 0°C was added tert-butylhydroperoxide (about 5M solution in nonane, 1.5 ml, about 7.5 mmol) and the resulting mixture was stirred at room temperature for 30 minutes To the mixture was added saturated aqueous sodium hydrogen carbonate solution and aqueous sodium thiosulfate solution, then the mixture was stirred for 10 min and was distributed between ethyl acetate and water. The organic layer was sequentially washed with a saturated aqueous solution of sodium bicarbonate, saturated aqueous ammonium chloride and aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and the solvent drove under reduced pressure to obtain an oily residue. The residue was subjected to chromatography on a column of silica gel (15 g) (eluent: ethyl acetate:hexane=2:1˜1:0) and additionally purified circulating preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm e × 600 mm) and JAIGEL-2H (20 mm e × 600 mm)connected in series for use; solvent: chloroform] to obtain specified in the title compound (363 mg, yield 54%) as a colorless amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,45 (3H, DD, J=7, 2 Hz), 3,05 (1H, TT, J=11, 5 Hz), 3,50 (1H, t, J=11 Hz), 3,53 (1H, t, J=11 Hz), to 4.01 (1H, q, J=7 Hz), 4,10-4,20 (2H, m), 4,50-4,60 (4H, m), 4,99 (1H, d, J=4 Hz), 5,24 (2H, user. d, J=10 Hz), of 5.34 (2H, user. d, J=18 Hz), 5.40 to-5,55 (4H, m), 5,71 (1H, DD, J=15, 4 Hz), 5,85-6,00 (2H, m), to 6.57 (1H, DD, J=15, 11 Hz), was 6.73 (1H, d, J=15 Hz), 6,85-to 6.95 (3H, m), 7,34 (1H, DD, J=10, 1 Hz), 7,35-7,45 (3H, m), EUR 7.57 (1H, t, J=8 Hz), a 7.62 (1H, TD, J=7, 1 Hz), 7,72 (1H, d, J=8 Hz), 7,76 (1H, d, J=9 Hz), of 7.90 (1H, s), to $ 7.91 (1H, s).

IR-spectrum ν max KBr cm-1: 2231, 1724, 1615, 1504.

Mass spectrum m/z (FAB): 837 (M++1).

(2) Disodium 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]benzylester (specified in the header of the target connection)

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]benzoate (1.55 g, of 1.85 mmol)obtained in example 18-(1), and tetrakis(triphenylphosphine)palladium (20 mg) was dissolved in dichloromethane (13 ml). To the mixture was added pyrrolidine (2,63 g, 37,0 mmol) followed by stirring for 0.5 hours. Specified in the title compound (1.22 g, yield 76%) was obtained as an amorphous colorless solid according to the procedure similar to that described in Example 13-(3).

NMR-spectrum (400 MHz, D2O) δ ppm: of 1.27 (3H, d, J=7 Hz), 2,95 (1H, m), 3,40 (1H, t, J=11 Hz), of 3.45 (1H, t, J=11 Hz), with 3.79 (1H, q, J=7 Hz), 3,93 (1H, m), of 4.05 (1H, m), the 4.90 (1H, DD, J=16, 7 Hz), of 4.95 (1H, d, J=5 Hz, to 5.03 (1H, DD, J=16, 7 Hz), to 5.35 (1H, d, J=15 Hz), 5,44 (1H, user. d, J=15 Hz), 5,67 (1H, m), 6,34 (1H, m), of 6.68 (1H, user. d, J=15 Hz), 6,85-to 7.00 (3H, m), 7,20-7,30 (1H, m), 7,30 was 7.45 (3H, m), 7,50-the 7.65 (3H, m), 7,76 (1H, d, J=8 Hz), to 7.84 (1H, s)8,23 (1H, s).

IR-spectrum ν max KBr cm-1: 3414, 2231, 1722, 1615, 1503, 1418, 1387, 1275, 1257, 1205, 1139.

Mass spectrum m/z (FAB): 801 (M++1).

Elemental analysis for C35H30F3N4O8PSNa2·4H2O:

Calculated: C: 48,17; H: 4,39; N: 6,24; Na: 5,27

Found: C: 47,94; H: Or 4.31; N: 6,39; Na: 5,07.

[Example 19]

2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]benzyl hydrosylate (example 5-5)

(1) Allyl[2-(methoxybenzyloxy)carbonyl]benzylsuccinic

Commercially available 1(3H)-isobenzofuranone (805 mg, 6,00 mmol) and potassium hydroxide (0.34 g, 5.9 mmol) suspended in a mixed solvent of methanol-water (2:1) and the suspension was stirred at 70°C for 3 hours. After cooling the reaction mixture, the solvent is evaporated under reduced pressure. The residue was dried using a vacuum pump while heating the residue at 40°C. the Obtained solid is suspended in N,N-dimethylformamide (10 ml) was added 4-methoxybenzylamine (987 mg, 6,30 mmol). The mixture was stirred at 100°C for 1 hour. Received the th mixture was cooled, was diluted with ethyl acetate, washed with water and then with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and the solvent drove under reduced pressure to obtain a colorless oily residue. The residue was dissolved in dichloromethane (10 ml) and at 0°C was sequentially added triethylamine (976 μl, 7,00 mmol), 4-(N,N-dimethylamino)pyridine (10 mg) and allyl 4-chloro-4-oxybutyrate (1.06 g, 6,00 mmol)obtained in example 14-(1), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, then sequentially washed with water and an aqueous solution of sodium chloride, the solution was dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The residue was subjected to chromatography on a column of silica gel (60 g) (eluent: hexane:ethyl acetate=4:1˜3:1) to obtain specified in the connection header (1,00 g, yield 40%) as a pale yellow oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2,68 (4H, m), 3,82 (3H, s), 4,59 (2H, user. d, J=6 Hz), 5,23 (1H, user. d, J=10 Hz), 5,28 (2H, s), 5,31 (1H, user. d, J=18 Hz), 5,54 (2H, s), 5,90 (1H, DDT, J=18, 10, 6 Hz), 6,91 (2H, d, J=9 Hz), 7,35-7,40 (1H, m), 7,39 (2H, d, J=9 Hz), 7,45-of 7.55 (2H, m), 8,00 (1H, DD, J=8, 1 Hz).

IR-spectrum ν max, clean, cm-1: 1737, 1614, 1516, 1249.

Mass spectrum m/z (FAB): 413 (M++1).

(2) Allyl 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]benzylsuccinic

Allyl[2-(4-methoxybenzyloxy)carbonyl]benzylsuccinic (620 mg, 1.50 mmol)obtained in example 19-(1), and anisole (600 mg) was dissolved in triperoxonane acid, followed by stirring at room temperature for 30 minutes the Mixture was diluted with toluene and the solvent is kept at reduced pressure. The obtained residue was dissolved in dichloromethane (3 ml) was added N,N-dimethylformamide (0,02 ml) and oxacillin (300 mg). The mixture was stirred at room temperature for 1 hour, then added toluene and the solvent drove under reduced pressure to obtain the crude allyl 2-(chlorocarbonyl)benzylsuccinic.

The reaction was carried out according to the method similar to that described in Example 13-(2), using 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)-propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (814 mg, 1.50 mmol), described in the reference example 1, sodium hydride (55% dispersion in mineral oil; 74 mg, 1.7 mmol), and the crude allyl 2-(chlorocarbonyl)benzylsuccinic obtained above. The obtained crude product was subjected to chromatography on a column of silica gel (35 g) (eluent: ethyl acetate:hexane=1:1˜4:1) to obtain the specified title compound (368 mg, 30%yield) as a pale yellow amorphous solid substance.

NMR-spectrum (40 MHz, CDCl3) δ ppm: of 1.46 (3H, DD, J=7, 2 Hz), 2,60 is 2.80 (4H, m), 3,05 (1H, TT, J=11, 5 Hz), 3,51 (1H, t, J=11 Hz), 3,53 (1H, t, J=11 Hz), was 4.02 (1H, q, J=7 Hz), 4,10-4,20 (2H, m), 4,59 (2H, d, J=6 Hz), 4,99 (1H, d, J=4 Hz), 5,23 (1H, DD, J=10, 1 Hz), 5,31 (1H, DD, J=18, 1 Hz), the 5.45 to 5.55 (4H, m), of 5.85 (1H, DD, J=15, 4 Hz), 5,90 (1H, DDT, J=18, 10, 6 Hz), to 6.57 (1H, DD, J=15, 10 Hz), 6,74 (1H, d, J=15 Hz), 6,85-to 6.95 (3H, m), 7,34 (1H, d, J=9 Hz), 7,35-7,45 (3H, m), 7,55-the 7.65 (3H, m), 7,79 (1H, t, J=7 Hz), of 7.90 (1H, s), 7,95 (1H, s).

IR-spectrum ν max KBr cm-1: 2231, 1734, 1615, 1504.

Mass spectrum m/z (FAB): 817 (M++1).

(3) 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]benzyl hydrosylate (specified in the header of the target connection)

Allyl 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]benzylsuccinic (150 mg, 1,84×10-4mol)obtained in example 19-(2), and bis(triphenylphosphine)dichloropalladium (2 mg) was dissolved in dichloromethane (1.5 ml). To the mixture was added water (0.1 ml) and slowly over 5 min was added to the anti-hydride (80 mg, 2,7×10-4mol) at room temperature. The resulting mixture was stirred at room temperature for 15 min, and then to the mixture was added hexane. Released oily insoluble substance was separated by slow removal of the supernatant liquid. The insoluble residue dopolnitelnaya hexane (twice). The oily residue was subjected to chromatography on a column of silica gel (8 g) (eluent: ethyl acetate), and then purified circulating preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm e × 600 mm) and JAIGEL-2H (20 mm e × 600 mm)connected in series for use; solvent: chloroform] to obtain specified in the connection header (123,9 mg, yield 87%) as a colorless amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,47 (3H, DD, J=7, 2 Hz), 2,65 is 2.75 (4H, m), 3,06 (1H, TT, J=11, 5 Hz), 3,52 (1H, t, J=11 Hz), of 3.54 (1H, t, J=11 Hz), of 4.05 (1H, q, J=7 Hz), 4,10-4,20 (2H, m), 4,99 (1H, d, J=4 Hz), 5,43 (1H, d, J=13 Hz), 5,49 (1H, user. DD, J=15 and 3 Hz)to 5.56 (1H, d, J=15 Hz), 5,59 (1H, d, J=13 Hz), of 5.84 (1H, DD, J=15, 4 Hz), to 6.57 (1H, DD, J=15, 10 Hz), was 6.73 (1H, d, J=15 Hz), 6,85-to 7.00 (3H, m), 7,33 (1H, d, J=10, 1 Hz), 7,35-7,45 (3H, m), 7,55-of 7.60 (3H, m), 7,89 (1H, t, J=7 Hz), of 7.90 (1H, s), of 8.09 (1H, s).

IR-spectrum ν max KBrcm-1: 2232, 1729, 1616, 1504.

Mass spectrum m/z (FAB): 777 (M++1).

[Example 20]

(S)-3-Amino-4-[4-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-4-oxobutanoic]-4-oxybutyrate sodium (sodium salt the example 4-12)

(1) tert-Butyl (S)-3-[(tert-butyl)oxycarbonyl]-4-oxo-4-(2,2,2-trichloroethane)butyrate

Commercially available dicyclohexylammonium Sol βtert-is etilovogo ester of N-(tert-butoxycarbonyl)-L-aspartic acid (1,00 g, a 2.12 mmol) was subjected to column chromatography using ion-exchange resin (Dowex 50W-8X, in the sodium form, obtained using 1 N. aqueous sodium hydroxide solution; 5 ml) (eluent: methanol). The collected fractions were concentrated under reduced pressure and the residue was dissolved in water (50 ml). To the water solution was added 1 N. aqueous solution of hydrochloric acid (22 ml) to bring the pH to approximately 4, and the released carboxylic acid was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The obtained colorless oil was dissolved in dichloromethane (10 ml) and to the mixture at room temperature was added triethylamine (420 μl, 3.0 mmol) and 2,2,2-trichloroacetimidate (466 mg, of 2.20 mmol) followed by stirring for 1 hour. The mixture was concentrated under reduced pressure, and then the obtained residue was dissolved in ethyl acetate and the organic layer was sequentially washed with an aqueous solution of sodium bicarbonate, an aqueous solution of ammonium chloride and an aqueous solution of sodium chloride. The solution was dried over anhydrous magnesium sulfate and the solvent is then drove away under reduced pressure. The residue was subjected to chromatography on a column of silica gel (15 g) (eluent: hexane:ethyl acetate=2:1) to obtain specified in the header is soedineniya (627 mg, yield 73%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: the 1.44 (9H, s)of 1.46 (9H, s), and 2.79 (1H, DD, J=17, 4 Hz), a 3.01 (1H, DD, J=17, 5 Hz), and 4.68 (1H, m), a 4.86 (2H, s)5,54 (1H, user. d, J=9 Hz).

IR-spectrum ν max CHCl3cm-1: 3439, 2982, 2934, 1769, 1717, 1498.

Mass spectrum m/z (FAB): 420 (M++1).

(2) Allyl (S)-3-(allyloxycarbonyl)-4-oxo-4-(2,2,2-trichloroethane)butyrate

tert-Butyl (S)-3-[(tert-butyl)oxycarbonyl]-4-oxo-4-(2,2,2-trichloroethane)butyrate (605 mg, 1.48 mmol)obtained in example 20-(1), was dissolved in triperoxonane acid (2.5 ml), followed by stirring for 1 hour. The mixture was diluted with toluene and the solvent is kept at reduced pressure. The obtained white powdery substance suspended in dichloromethane (5 ml) and at room temperature was added diisopropylethylamine (1.8 ml, 10 mmol) and allylchloroformate (624 mg, 5.18 mmol). The mixture was stirred for 1 hour, then was added a saturated aqueous solution of ammonium chloride and the product was extracted with ethyl acetate. The organic layer was sequentially washed with water and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The residue was subjected to chromatography on a column of silica gel (25 g) (eluent: hexane:ethyl acetate=4:1) to obtain the specified title compound (384 mg, yield 67%) as a colourless mass is A.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2,95 (1H, DD, J=18, 4 Hz), and 3.16 (1H, DD, J=18, 4 Hz), 4,55 with 4.65 (4H, m), to 4.73 (1H, d, J=12 Hz), 4,79 (1H, m), 4,82 (1H, d, J=12 Hz), 5,23 (1H, user. d, J=10 Hz), 5,26 (1H, user. d, J=10 Hz), 5,32 (2H, user. d, J=18 Hz), 5,77 (1H, user. d, J=9 Hz), 5,85-6,00 (2H, m).

IR-spectrum ν max CHCl3cm-1: 3356, 1767, 1732, 1512.

Mass spectrum m/z (FAB): 388 (M++1).

(3) (S)-4-Allyloxy-2-(allyloxycarbonyl)-4-oxobutanoic acid

Allyl (S)-3-(allyloxycarbonyl)-4-oxo-4-(2,2,2-trichloroethane)butyrate (350 mg, 9,02×10-4mol)obtained in example 20-(2), was dissolved in acetic acid (1.8 ml), then added the powdered zinc (350 mg) and the resulting mixture was stirred at room temperature for 1 hour. The insoluble substance was filtered and washed with ethyl acetate. The filtrates were combined and the solvent is kept at reduced pressure. The residue was dissolved in ethyl acetate and the solution was sequentially washed with 0.2 N. aqueous solution of hydrochloric acid and saturated aqueous sodium chloride. The resulting solution was dried over anhydrous magnesium sulfate and the solvent drove under reduced pressure to get crude specified in the title compound (180 mg, yield 78%) as a pale yellow oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: only 2.91 (1H, DD, J=17, 5 Hz), 3,10 (1H, DD, J=17, 4 Hz), 4,55 with 4.65 (4H, m), and 4.68 (1H, m), 5,23 (1H, DD, J=11, 1 Hz), 5,27 (1H, d, J=10 Hz), 5,32 (2H, user. the, J=17 Hz), 5,79 (1H, user. d, J=9 Hz), 5,85-6,00 (2H, m).

(4) Allyl (S)-3-(allyloxycarbonyl)-4-[4-(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-4-oxobutanoic]-4-oxybutyrate

The crude (S)-4-allyloxy-2-(allyloxycarbonyl)-4-oxobutanoic acid (180 mg, 7,0×10-4mol)obtained in example 20-(3), (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 4-hydroxybutyrate (364 mg, 5,79×10-4mol)obtained in example 11, and 4-(N,N-dimethylamino)pyridine (183 mg, 1.50 is×10-3mol) was dissolved in dichloromethane (2 ml) and to the mixture at room temperature was added 2-chloro-1,3-dimethylimidazolium chloride (118 mg, 6,98×10-4mol) followed by stirring for 30 minutes the Mixture was diluted with ethyl acetate, then sequentially washed with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The residue was subjected to chromatography on a column of silica gel (10 g) (eluent: ethyl acetate:hexane=2:1˜1:0) to obtain the specified title compound (386 mg, yield 77%) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3 ) δ ppm: to 1.35 (3H, DD, J=7, 2 Hz), 1,90-2,00 (2H, m), 2,35 is 2.55 (2H, m), 2,90 (1H, DD, J=17, 5 Hz), 3.00 and-3,10 (2H, m), 3,52 (2H, t, J=11 Hz), to 3.92 (1H, q, J=7 Hz), 4,10-of 4.25 (4H, m), 4,55 with 4.65 (4H, m)and 4.65 (1H, m)5,00 (1H, d, J=4 Hz), 5,20 to 5.35 (6H, m), 5,80-5,95 (4H, m), to 6.58 (1H, DD, J=15, 10 Hz), 6,74 (1H, d, J=15 Hz), 6,85-to 7.00 (3H, m), 7,30-to 7.35 (2H, m), 7,40 (1H, DD, J=8, 1 Hz), EUR 7.57 (1H, t, J=8 Hz), of 7.90 (1H, s), 7,92 (1H, s).

IR-spectrum ν max KBr cm-1: 3359, 2231, 1737, 1615, 1503.

Mass spectrum m/z (FAB): 868 (M++1).

(5) Sodium (S)-3-amino-4-[4-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-4-oxobutanoic]-4-oxybutyrate (specified in the header of the target connection)

Allyl (S)-3-(allyloxycarbonyl)-4-[4-(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-4-oxobutanoic]-4-oxybutyrate (200 mg, 2,30×10-4mol)obtained in example 20-(4), and bis(triphenylphosphine)dichloropalladium (5 mg) was dissolved in dichloromethane (1 ml). To the mixture was added pyrrolidine (65 mg, 9,4×10-4mol) and anti-hydride (67 mg, 2,3×10-4mol), and the resulting mixture was stirred at room temperature for 10 minutes the Mixture was diluted with toluene and the solvent is then drove away under reduced pressure. The residue is suspended in a mixed solvent of methanol-water (3:1), and the suspension was subjected to treatment with cation exchange resin (Dowex 50W-8X, intothree the new form, obtained using 1 N. aqueous sodium hydroxide solution; 10 ml) (eluent: water). The collected fractions were concentrated under reduced pressure and the obtained residue was subjected to column chromatography with reversed phase using Cosmosil 75 C18-PREP (Nacalai Tesque, Inc.; 10 g) (eluent: water:methanol=1:1˜3:7). The fractions obtained were concentrated and the residue was liofilizovane obtaining specified in the title target compound (96,3 mg, yield 55%) as a colorless amorphous solid.

NMR-spectrum (400 MHz, DMSO-d6) δ ppm: 1,24 (3H, d, J=7 Hz), equal to 1.82 (2H, Quint, J=7 Hz), 2,12 (1H, DD, J=15, 8 Hz), 2,22 (1H, DD, J=15, 4 Hz), 2,30-of 2.50 (2H, m), 2,98 (1H, TT, J=11, 5 Hz), 3,40-3,50 (3H, m)and 3.59 (1H, q, J=7 Hz), 4,00-4,10 (4H, m), is 5.06 (1H, d, J=5 Hz), 5,24 (1H, d, J=15 Hz), of 5.40 (1H, user. d, J=15 Hz), 5,90 (1H, DD, J=15, 4 Hz), 6,59 (1H, DD, J=15, 10 Hz), 6,83 (1H, d, J=15 Hz), 7,10-7,20 (1H, m), 7,20 (1H, DD, J=15, 11 Hz), 7,25-to 7.35 (1H, m), 7,45-of 7.55 (1H, m), to 7.67 (1H, DD, J=10, 1 Hz), to 7.84 (1H, DD, J=11, 1 Hz), 7,89 (1H, t, J=7 Hz), with 8.05 (1H, s), 8,42 (1H, s).

Mass spectrum m/z (FAB): 766 (M++1).

[Example 21]

Disodium 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-6-methoxybenzoate (disodium salt of example number 5-24)

(1) 3-Methoxy-1,2-benzodithiol

To a solution of 4-methoxy-1-(3H)-isobenzofuranone (described in J. Org. Chem., 52, 129 (1987); 1,64 g, 10.0 mmol) in tetrahydro the uranium (30 ml) was added lithium borohydride (652,2 mg, 30 mmol) under stirring at 0°C and the mixture is boiled under reflux for 2.5 hours under stirring. After cooling the mixture to room temperature, thereto was added 2 N. aqueous solution of hydrochloric acid (20 ml). The product was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride. The filtrate was concentrated under reduced pressure to obtain a solid residue. The residue was subjected to chromatography on a column of silica gel (30 g) (eluent: ethyl acetate:hexane=2:1˜4:1) to obtain the specified title compound (1.31 g, yield 78%) as a colourless solid (TPL 95°C).

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2,6 (2H, usher.), a 3.87 (3H, s), and 4.75 (2H, s), a 4.86 (2H, s)6,91 (1H, d, J=8 Hz), 6,98 (1H, d, J=8 Hz), 7,28 (1H, t, J=8 Hz).

IR-spectrum ν max KBr cm-1: 3275, 1588, 1262, 1043, 1010, 787.

Mass spectrum m/z (EI): 168 (M+).

(2) 2-[(tert-Butyldimethylsilyl)oxymethyl]-6-methoxybenzyloxy alcohol

3-Methoxy-1,2-benzodithiol (1.30 grams, 7,73 mmol)obtained in example 21-(1)was dissolved in tetrahydrofuran (15 ml) and at 0°C was added imidazole (526,2 mg, 7,73 mmol) and tert-BUTYLCARBAMATE (1,165 g, 7,73 mmol) under stirring. The mixture was stirred at room temperature for 2 hours, then added water and the product was extracted with ethyl acetate. The organic layer was washed with saturated in denim solution of sodium chloride and the solvent is kept at reduced pressure. The residue was subjected to chromatography on a column of silica gel (60 g) (eluent: ethyl acetate:hexane=1:4) to obtain specified in the connection header (1,156 g, yield 53%) as oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 0,11 (6H, s)of 0.91 (9H, s), 3,03 (1H, usher.), 3,86 (3H, s), of 4.77 (2H, s), rate 4.79 (2H, s), to 6.88 (1H, d, J=8 Hz), 6,94 (1H, d, J=8 Hz), 7,24 (1H, t, J=8 Hz).

IR-spectrum ν max CHCl3cm-1: 2957, 2931, 1588, 1472, 1463, 1264.

Mass spectrum m/z (FAB): 283 (M++1).

(3) Diallyl 2-[(tert-butyldimethylsilyl)oxymethyl]-6-methoxybenzyloxy

According to the method similar to that described in example 1-(10), carried out the reaction of 2-[(tert-butyldimethylsilyl)-oxymethyl]-6-methoxybenzamido alcohol (1.13 g, 4.00 mmol)obtained in example 21-(2), tetrazole (672,3 mg, 9.6 mmol), bis(allyloxy)(diisopropylamino)phosphine (described in Tetrahedron Lett., 30, 4219 (1989); 1,37 g, 5.6 mmol) and tert-butylhydroperoxide (80% solution of di-tert-butylperoxide; Merck; 0.9 g, 8 mmol) and the reaction mixture was treated with obtaining after extraction of oily residue. The residue was subjected to chromatography on a column of silica gel (60 g) (eluent: ethyl acetate:hexane=1:6˜1:2) to obtain the specified title compound (1.07 g, yield 60%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: to 0.10 (6H, s)of 0.93 (9H, s), of 3.84 (3H, s), 4,49-to 4.52 (4H, m), a 4.86 (2H, s), with 5.22 (2H, DD, J=10, 1 Hz), a 5.25 (2H, d, J=6 Hz), 5,33 (2H, DD, J=17, 1 Hz), 5,91 (2H, DDT, J=17, 10, 5 Hz), 6,83 (1H, d, J=8 Hz), 7,12 (1H, d, J=8 Hz), 33 (1H, t, J=8 Hz).

IR-spectrum ν max CHCl3cm-1: 2956, 2931, 1591, 1472, 1270, 1015.

Mass spectrum m/z (FAB): 443 (M++1).

(4) Diallyl 2-(hydroxymethyl)-6-methoxybenzyloxy

To a solution of diallyl 2-[(tert-butyldimethylsilyl)oxymethyl]-6-methoxybenzyl phosphate (1,03 g of 2.33 mmol)obtained in example 21(3), in tetrahydrofuran (10 ml) was added tetrabutylammonium fluoride (1 n solution in tetrahydrofuran; 2.5 ml, 2.5 mmol) and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, then the product was extracted with ethyl acetate and the solvent evaporated under reduced pressure to obtain an oily residue. The residue was subjected to chromatography on a column of silica gel (50 g) (eluent: ethyl acetate:hexane=3:1 ˜ 1:0) to obtain specified in the connection header (715,0 mg, yield 93%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 3,3 (1H, usher.), 3,86 (3H, s), 4,42-4,50 (4H, m), and 4.75 (2H, s), with 5.22 (2H, d-like, J=10 Hz), 5,32 (2H, d-like, J=17 Hz), of 5.34 (2H, d, J=10 Hz), of 5.89 (2H, DDT, J=17, 10, 6 Hz), to 6.88 (1H, d, J=8 Hz), 7,06 (1H, d, J=8 Hz), 7,35 (1H, t, J=8 Hz).

IR-spectrum ν max CHCl3cm-1: 3385, 1473, 1463, 1271, 1021, 989.

Mass spectrum m/z (FAB): 329 (M++1).

(5) 2-[[Bis(allyloxy)phosphoryl]oxymethyl]-3-methoxy-benzoic acid

Diallyl 2-(hydroxymethyl)-6-methoxybenzoate (715,0 mg, 2,18 mmol)obtained in example 21-(4), was dissolved in N,N-dimethyl mamide (8 ml) and to the mixture was added pyridinium dichromate (2,87 g, 7,63 mmol). After stirring the mixture at room temperature for 12 hours, was added water (60 ml) and the product was extracted with diethyl ether. The organic layer was sequentially washed with water, 2 N. aqueous solution of hydrochloric acid and saturated aqueous sodium chloride, the solvent is then drove away under reduced pressure to obtain an oily residue. The residue was dissolved in acetone (5 ml) and to the mixture was added Jones reagent (a mixture of chromic anhydride (5.34 g, 4 mmol) and concentrated sulfuric acid (4.6 ml), diluted with water to a total volume of 20 ml; 1.5 ml). The reaction mixture was stirred at room temperature for 1.5 hours and then was added 2-propanol (1 ml) to stop the reaction. Solid insoluble substance was filtered and the filtrate was concentrated under reduced pressure to obtain an oily residue. The residue was dried using a vacuum pump, and then was subjected to chromatography on a column of silica gel (25 g) (eluent: ethyl acetate:dichloromethane=1:1) to obtain specified in the connection header (447,0 mg, yield 60%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: to 3.89 (3H, s), 4,47-of 4.57 (4H, m), a total of 5.21 (2H, d-like, J=10 Hz), 5,32 (2H, d-like, J=17 Hz), of 5.53 (2H, d, J=8 Hz), 5,90 (2H, DDT, J=17, 10, 6 Hz), 7,07 (1H, DD, J=8, 1 Hz), 7,41 (1H, t, J=8 Hz), of 7.48 (1H, d, J=8 Hz).

IR-spectrum ν max CHCl3the m -1: 1725, 1587, 1461, 1272, 1021, 989.

Mass spectrum m/z (FAB): 343 (M++1).

(6) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-methoxybenzoate

According to the method similar to that described in Example 1-(12)were subjected to interaction of 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-methoxybenzoic acid (440 mg, 1,29 mmol)obtained in 21(5), and oxacillin (815,8 mg, 6.4 mmol) and the reaction mixture was treated with obtaining 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-methoxybenzonitrile in the form of a crude product.

According to the method similar to that described in Example 1-(12), carried out the reaction of 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (542,6 mg, 1.00 mmol)described in reference example 1, sodium hydride (55% dispersion in mineral oil; to 52.4 mg, 1.20 mmol) and crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-methoxybenzonitrile in tetrahydrofuran (7 ml) and the reaction mixture was treated with obtaining after extraction is specified in the header connection in the form of crude oil. The crude oil was subjected to chromatography on a column of silica gel (30 g) (eluent: ethyl acetate:hexane=2:1˜4:1) to obtain specified in the connection (425,5 mg, yield 49%).

NMR-spectrum (400 MHz, CDCl3) δ ppm: the 1.44 (3H, DD, J=7, 2 Hz), 3.04 from (1H, TT, J=12, 5 Hz), of 3.45 (1H, t, J=12 Hz), 3,51 (1H, t, J=12 Hz), with 3.89 (3H, s), 3,98 (1H, q, J=7 Hz), 4.09 to (1H, DDD, J=12, 5, 2 Hz), 4,18 (1H, DDD, J=12, 5, 2 Hz), 4,43-4,55 (4H, m), 4,96 (1H, d, J=4 Hz), 5,19 (2H, DD, J=10, 1 Hz), 5,31 (2H, DQC, J=17, 1 Hz), 5,43-of 5.55 (4H, m), of 5.83 (1H, DD, J=15, 4 Hz), of 5.84-5,94 (2H, m), 6,56 (1H, DD, J=15, 10 Hz), was 6.73 (1H, d, J=16 Hz), 6,93 (1H, DD, J=16, 10 Hz), 6,86-7,00 (2H, m), 7,12 (1H, d, J=8 Hz), 7,16 (1H, d, J=8 Hz), 7,34 (1H, DD, J=9, 1 Hz), 7,39 (2H, t, J=8 Hz), of 7.48 (1H, TD, J=9, 6 Hz), EUR 7.57 (1H, t, J=8 Hz), to 7.93 (1H, s), of 8.00 (1H, s).

IR-spectrum ν max CHCl3cm-1: 2233, 1731, 1504, 1462, 1277, 1141, 1059, 1018, 991.

Mass spectrum m/z (FAB): 867 (M++1).

(7) Disodium 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-6-methoxybenzoate (specified in the header of the target connection)

According to the method similar to that described in Example 1-(13), (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-methoxybenzoate (400 mg, 0.46 mmol)obtained in example 21-(6)were subjected to interaction with bis(triphenylphosphine)dichloropalladium (16.2 mg, is 0.023 mmol) and anti-hydride (308,9 mg, 1.06 mmol) and the reaction mixture was treated with obtaining specified in the header of the target compound in the form of crude oil. The crude oil was subjected to Colo the internal chromatography with reversed phase using Cosmosil 75 C 18-PREP (Nacalai Tesque, Inc.; 30 g)(eluent: water:methanol=4:6˜3:7). The fractions obtained were concentrated and the residue was liofilizovane obtaining specified in the title target compound (93,5 mg, yield 24%) as a colourless solid.

NMR-spectrum (400 MHz, CD3OD) δ ppm: to 1.42 (3H, DD, J=7, 2 Hz)of 3.00 (1H, TT, J=11, 5 Hz), of 3.46 (1H, t, J=11 Hz), 3,52 (1H, t, J=11 Hz), 3,88 (3H, s), 4,01-of 4.77 (2H, m), is 4.15 (1H, DDD, J=11, 5, 2 Hz), 5,00 (1H, d, J=4 Hz), 5,28 (1H, DD, J=10, 4 Hz), 5,32 (1H, DD, J=10, 4 Hz), to 5.58 (1H, DD, J=15 and 3 Hz), of 5.68 (1H, d, J=15 Hz), of 5.84 (1H, DD, J=15, 4 Hz), 6,56 (1H, DD, J=11, 15 Hz), 6,78 (1H, d, J=15 Hz), 6,99-7,13 (2H, m), was 7.08 (1H, DD, J=15, 11 Hz), 7,21 (1H, d, J=7 Hz), 7,30 (1H, d, J=7 Hz), was 7.36 (1H, t, J=8 Hz), 7,51 (1H, t, J=8 Hz), 7,52 (1H, t, J=8 Hz), 7,62-of 7.70 (1H, m), 7,78 (1H, t, J=8 Hz,), of 7.97 (1H, s), to 8.62 (1H, s).

IR-spectrum ν max KBr cm-1: 2231, 1730, 1615, 1503, 1278, 1142, 1054.

Mass spectrum m/z (FAB): 831 (M++1).

Specific rotation [α]D25+15,4° (c=0,84, MeOH).

[Example 22]

Disodium 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-6-methylbenzyl phosphate (disodium salt of example number 5-23)

(1) 3-Methyl-1,2-benzodithiol

To a solution of methyl 2,6-dimethylbenzoic (described in J. Am. Chem. Soc., 99, 6405 (1977); 23,4 g, 143 mmol) in dichloroethane (200 ml) was added N-bromosuccinimide (25,46 g, 143 mmol) and α,α'-azobisisobutyronitrile (234,8 mg of 1.43 mmol) and the mixture was irradiated see the m light (tungsten lamp, 375 watts) for 1 hour. After cooling the reaction mixture, the precipitated substance was filtered and the solvent drove away under reduced pressure. The obtained oily residue was subjected to chromatography on a column of silica gel (200 g) (eluent: ethyl acetate:hexane=1:10) to obtain an oily mixture containing about 50% of methyl 2-(methyl bromide)-6-methylbenzoate. The mixture was dissolved in dimethyl sulfoxide (150 ml) was added sodium acetate (16.4 g, 0.2 mol). The resulting mixture was stirred at room temperature for 2 hours, then was added a saturated aqueous solution of ammonium chloride and the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and the solvent drove under reduced pressure to obtain an oily residue. The residue was subjected to chromatography on a column of silica gel (200 g) (eluent: ethyl acetate:hexane=1:10˜1:3) to give methyl 2-(acetoxymethyl)-6-methylbenzoate (of 8.09 g, a content of more than 80%) as a colourless oil. The obtained methyl 2-(acetoxymethyl)-6-methylbenzoate used for the next reaction without further purification.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2,07 (3H, s), of 2.38 (3H, s)to 3.92 (3H, s), of 5.15 (2H, s), 6,99 for 7.12 (3H, m).

Methyl 2-(acetoxymethyl)-6-methylbenzoate, obtained above, was dissolved in methanol (80 ml) was added potassium carbonate (251,5 mg, 1.8 mmol). See the camping was stirred at room temperature for 2 hours, then added 2 N. aqueous solution of hydrochloric acid (3 ml) and the solvent drove away under reduced pressure. The obtained solid residue was dissolved in ethyl acetate and the solution washed with saturated aqueous sodium chloride and the solvent is then drove away under reduced pressure. The solid residue was subjected to chromatography on a column of silica gel (100 g) (eluent: ethyl acetate:hexane=1:2) to give 7-methyl-1(3H)-isobenzofuranone (5,18 g, a content of more than 80%). The obtained 7-methyl-1(3H)-isobenzofuranone used in the next reaction without further purification.

NMR-spectrum (400 MHz, CDCl3) δ ppm: a 2.71 (3H, s), 5,23 (2H, s), 7,25-7,30 (2H, m), 7,56 (1H, t, J=8 Hz).

A solution of 7-methyl-1(3H)-isobenzofuranone obtained above in tetrahydrofuran (80 ml) was cooled to 0°C was added lithium borohydride (1.90 g, 87,2 mmol). The mixture was stirred at 60°C for 2 hours, then was cooled to 0°C and added dropwise 2 N. aqueous solution of hydrochloric acid (50 ml). The product was extracted with ethyl acetate and the solvent evaporated under reduced pressure to obtain an oily residue. The residue was subjected to chromatography on a column of silica gel (75 g) (eluent: ethyl acetate:hexane=2:1˜1:0) to obtain specified in the connection header (4,17 g, 19% of the total output in the calculation of methyl 2,6-dimethylbenzoyl) in the form of oil.

NMR-spectrum (400 MHz, CDCl 3) δ ppm: of 2.45 (3H, s), was 4.76 (2H, s), rate 4.79 (2H, s), 7,17-7,22 (3H, m).

IR-spectrum ν max CHCl3cm-1: 3605, 1469, 1380, 1002.

Mass spectrum m/z (EI): 152 (M+).

(2) 2-[(tert-Butyldimethylsilyl)oxymethyl]-6-methylbenzylamine alcohol

A solution of 3-methyl-1,2-benzylimidazole (4,16 g and 27.3 mmol)obtained in example 22-(1)in tetrahydrofuran (50 ml) was cooled to 0°C and to it was added imidazole (1.86 g, 27,3 mmol) and tert-BUTYLCARBAMATE (4.12 g, 27,3 mmol). The mixture was stirred at room temperature for 3 hours, then, after adding water, the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, the solvent is then drove away under reduced pressure and the residue was subjected to chromatography on a column of silica gel (120 g) (eluent: ethyl acetate:hexane=1:4) to obtain specified in the connection header (4,93 g, yield 68%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 0,13 (6H, s)to 0.92 (9H, s)to 2.46 (3H, s), 3.04 from (1H, t, J=6 Hz), 4.72 in (2H, d, J=6 Hz), 4,80 (2H, s), 7,11 (1H, DD, J=6, 2 Hz), 7,15-7,19 (2H, m).

IR-spectrum ν max CHCl3cm-1: 3459, 1732, 1599, 1471, 1257, 1061, 1038, 1005, 840.

Mass spectrum m/z (FAB): 267 (M++1).

(3) Diallyl 2-[(tert-butyldimethylsilyl)oxymethyl]-6-methylbenzyl phosphate

According to the method similar to that described in example 1-(10)were subjected to interaction of 2-[(tert-butyldimethylsilyl)-oxymethyl]-6-methylbenzyl the first alcohol (4,92 g, 18.5 mmol)obtained in example 22-(2), tetrazole (3,23 g, 46.2 mmol), bis(allyloxy)-(diisopropylamino)phosphine (described in Tetrahedron Lett., 30, 4219 (1989); 5,43 g of 22.2 mmol) and tert-butylhydroperoxide (80% solution of di-tert-butylperoxide; Merck; 1.8 g, 16 mmol) and the reaction mixture was treated with obtaining after extraction of oily residue. The residue was subjected to chromatography on a column of silica gel (200 g) (eluent:ethyl acetate:hexane=1:4˜2:3) to obtain specified in the connection header (6,03 g, yield 74%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 0,09 (6H, s)of 0.93 (9H, s), is 2.44 (3H, s), 4,45-4,51 (4H, m), a 4.86 (2H, s), 5,20-a 5.25 (4H, m), 5,32 (2H, DQC, J=17, 1 Hz), of 5.89 (2H, DDT, J=17, 10, 6 Hz), 7,13 (1H, d, J=7 Hz), 7,25 (1H, t, J=7 Hz), 7,32 (1H, d, J=7 Hz).

IR-spectrum ν max CHCl3cm-1: 1598, 1732, 1471, 1464, 1258, 1005.

Mass spectrum m/z (FAB): 427 (M++1).

(4) Diallyl 2-(hydroxymethyl)-6-methylbenzyl phosphate

To a solution of diallyl 2-[(tert-butyldimethylsilyl)oxymethyl]-6-methylbenzyl phosphate (6,02 g, 14.1 mmol)obtained in example 22-(3), in tetrahydrofuran (50 ml), was added tetrabutylammonium fluoride (1 mol/l solution in tetrahydrofuran; and 17.6 ml, 17.6 mmol) and the mixture was stirred at room temperature for 3 hours. To the mixture was added water and the product was extracted with ethyl acetate. The solvent drove under reduced pressure to obtain an oily residue. The residue was subjected to a chromatograph is on a column of silica gel (75 g) (eluent: ethyl acetate:hexane=3:1) to obtain specified in the connection header (3,84 g, yield 87%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2,46 (3H, s)to 3.33 (1H, t, J=6 Hz), 4,36-of 4.49 (4H, m), and 4.75 (2H, d, J=6 Hz), with 5.22 (2H, user. d, J=11 Hz), and 5.30 (2H, DQC, J=17, 1 Hz), 5,32 (2H, d, J=10 Hz), 5,86 (2H, DDT, J=17, 11, 5 Hz), 7,18 (1H, t, J=4 Hz), 7,26-7,28 (2H, m).

IR-spectrum ν max CHCl3cm-1: 3607, 1732, 1598, 1466, 1266, 1006.

Mass spectrum m/z (FAB): 313 (M++1).

(5) 2-[[Bis(allyloxy)phosphoryl]oxymethyl]-3-methylbenzoic acid

A solution of diallyl 2-(hydroxymethyl)-6-methylbenzylphosphonate (1.22 g, 4.02 mmol)obtained in example 22-(4), in acetone (25 ml) was cooled to 0°C was added Jones reagent (a mixture of chromic anhydride (5.34 g) and concentrated sulfuric acid (4.6 ml), diluted with water to a total volume of 20 ml, 6 ml, about 16 mmol). The reaction mixture was stirred at room temperature for 2 hours and then to the mixture was added 2-propanol (1 ml) to stop the reaction. The insoluble substance was filtered and the filtrate was concentrated under reduced pressure to obtain an oily residue. The residue was dried using a vacuum pump and then subjected to chromatography on a column of silica gel (50 g) (eluent: ethyl acetate:dichloromethane=1:1) to obtain specified in the connection header (905,3 mg, 71%yield) as a colorless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2.49 USD (3H, s), 4,43-4,55 (4H, m), with 5.22 (2H, DD, J=10, 1 Hz), 5,32 (2H, DQC, J=17, 1 Hz), of 5.53 (2H, d, J=8 Hz), 5,88 (2H, DDT, J=17, 10, 6 Hz), 7,34 (1H, t, J=7 Hz), 7,38 (1H, DD, J=8, 1 Hz), 7,72 (1H, d, J=8 Hz).

IR-spectrum ν max CHCl3cm-1: 2960, 1725, 1271, 1012.

Mass spectrum m/z (FAB): 327 (M++1).

(6) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-methylbenzoate

A solution of 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-methylbenzoic acid (880 mg, 2,70 mmol)obtained in example 22-(5), in dichloromethane (15 ml) was cooled to 0°C and then added N,N-dimethylformamide (15 ml) and oxacillin (1,71 g, 13.5 mmol). After stirring the mixture at room temperature for 30 min were obtained crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-methylbenzoate using a technique similar to that described in example 1-(12).

According to the method similar to that described in Example 1-(12), carried out the reaction of 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (976,6 mg of 1.80 mmol)described in reference example 1, sodium hydride (55% dispersion in mineral oil; a 94.2 mg, a 1.96 mmol) and 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-methylbenzonitrile obtained above in tetrahydrofuran (10 ml) and the reaction mixture was treated with obtaining after extraction is specified in the header connection in the form of neocidin the oil. The crude oil was subjected to chromatography on a column of silica gel (100 g) (eluent: ethyl acetate:hexane=3:2˜4:1) to obtain specified in the connection header (1,0641 g, yield 69%) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: the 1.44 (3H, DD, J=7, 2 Hz), of 2.51 (3H, s), 3.04 from (1H, TT, J=11, 5 Hz), of 3.45 (1H, t, J=11 Hz), 3,51 (1H, t, J=11 Hz), of 4.00 (1H, q, J=7 Hz), 4.09 to (1H, DDD, J=11, 5, 2 Hz), 4,19 (1H, DDD, J=11, 5, 2 Hz), 4,42-4,55 (4H, m), 4,96 (1H, d, J=5 Hz), 5,19 (2H, user. d, J=10 Hz), and 5.30 (2H, user. d, J=18 Hz), 5,43-5,56 (4H, m), of 5.83 (1H, DD, J=16, 5 Hz), of 5.82-of 5.92 (2H, m), 6,55 (1H, DD, J=16, 11 Hz), was 6.73 (1H, d, J=16 Hz), 6,86-of 6.99 (3H, m), 7,30-to 7.35 (2H, m), 7,39-the 7.43 (3H, m), of 7.48 (1H, TD, J=9, 6 Hz), EUR 7.57 (1H, t, J=8 Hz), 7,94 (1H, s), of 8.00 (1H, s).

IR-spectrum ν max CHCl3cm-1: 2233, 1727, 1616, 1504, 1419, 1387, 1276, 1141, 1211.

Mass spectrum m/z (FAB): 851 (M++1).

(7) Disodium 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-6-methylbenzyl phosphate (specified in the header of the target connection)

According to the method similar to that described in Example 1-(13), carried out the reaction of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-methylbenzoate (592,2 mg, 0.70 mmol)obtained in example 22-(6), bis(triphenylphosphine)dichloropalladium (24,4 mg, 0.035 mmol) and anti-hydride (706 mg, 2,43 mmol who) and the reaction mixture was treated with obtaining specified in the header of the target compound in the form of crude oil. The crude oil was subjected to column chromatography with reversed phase using Cosmosil 75 C18-PREP (Nacalai Tesque, Inc.; 30 g) (eluent: water:methanol=4:6˜3:7). The fractions obtained were concentrated and the residue was liofilizovane obtaining specified in the title target compound (323,2 mg, yield 57%) as a colourless solid.

NMR-spectrum (400 MHz, CD3OD) δ ppm: of 1.41 (3H, DD, J=7, 2 Hz), 2,58 (3H, s), 2,99 (1H, TT, J=11, 5 Hz), of 3.45 (1H, t, J=11 Hz), 3,52 (1H, t, J=11 Hz), a 4.03 (1H, DDD, J=11, 5, 2 Hz), 4,08 (1H, q, J=7 Hz), 4,14 (1H, DDD, J=11, 5, 2 Hz), 4,99 (1H, d, J=5 Hz), 5,15 (1H, DD, J=11, 4 Hz), and 5.30 (1H, DD, J=11, 4 Hz), the 5.51 (1H, DD, J=15, 4 Hz), 5,69 (1H, d, J=15 Hz), of 5.83 (1H, DD, J=16, 5 Hz), 6,55 (1H, DD, J=15, 11 Hz), 6,77 (1H, d, J=15 Hz), 7,01-7,11 (3H, m), 7,27 (1H, t, J=8 Hz), 7,41 (1H, d, J=7 Hz), 7,49-rate of 7.54 (3H, m), of 7.64 (1H, TD, J=9, 6 Hz), to 7.77 (1H, t, J=8 Hz), 7,98 (1H, s), at 8.60 (1H, s).

IR-spectrum ν max KBr cm-1: 2231, 1725, 1615, 1503, 1276, 1141, 1048, 974.

Mass spectrum m/z (FAB): 815 (M++1).

Specific rotation [α]D25+16,3° (c=a 1.01, MeOH).

[Example 23]

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-(N,N-diethylamino)-4-hydroxyvalerate (example 4-48)

(1) 4-Methoxybenzyl 4-(allyloxycarbonyl)-5-(N,N-diethylamino)valerate

5-(N,N-Dimethylaminomethyl)-tetrahydrofuran-2-he (described in Bull. Soc. Chim. Fr., p.401 (1953); 500 mg, to 2.94 mmol) was dissolved in 1 N. water rest the re potassium hydroxide (3 ml) followed by stirring at room temperature for 30 minutes The mixture was dried under reduced pressure and the obtained residue (670 mg) as a colorless oil. Part of the obtained oil (139 mg, 6,11×10-4mol) was dissolved in dimethylformamide (0.8 ml), then were added 4-methoxybenzylamine (100 mg, of 6.49×10-4mol), followed by stirring at 100°C for 30 minutes the Mixture was cooled to 0°C and then added allylchloroformate (80 mg, 6,6×10-4mol) and 4-(N,N-dimethylamino)pyridine (5 mg). The resulting mixture was stirred at room temperature for 2 hours, then was diluted with ethyl acetate and sequentially washed with a saturated aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The obtained residue was subjected to chromatography on a column of silica gel (5 g) (eluent:ethyl acetate:hexane=3:2) to obtain the specified title compound (125 mg, yield 52%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: to 0.98 (6H, t, J=7 Hz), 1,80-1,90 (1H, m), 2.05 is-to 2.15 (1H, m), 2,40-2,60 (8H, m), 3,81 (3H, s), 4,55 with 4.65 (2H, m), 4.75 V-is 4.85 (1H, m), of 5.05 (2H, in), 5.25 (1H, d-like, J=10 Hz), of 5.34 (1H, d-like, J=18 Hz), of 5.92 (1H, DDT, J=18, 10, 6 Hz), to 6.88 (2H, d, J=9 Hz), 7,29 (2H, d, J=9 Hz).

IR-spectrum ν max, clean, cm-1: 1743, 1614, 1516, 1257.

Mass spectrum m/z (FAB): 394 (M++1).

(2) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-b is tationil]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl]4-(allyloxycarbonyl)-5-(N,N-diethylamino)valerate

To a mixture of 4-methoxybenzyl 4-(allyloxycarbonyl)-5-(N,N-diethylamino)valerate (120 mg, 3,05×10-4mol)obtained in example 23-(1), and anisole (0.1 ml) was added triperoxonane acid (1.2 ml) at room temperature. The mixture was stirred at room temperature for 1 hour, then was diluted with toluene and the solvent is kept at reduced pressure. The residue was dissolved in dichloromethane (0.6 ml) and then was added N,N-dimethylformamide (0,02 ml) and oxacillin (100 mg). The mixture was stirred at room temperature for 1 hour, then added toluene and the resulting solution was concentrated under reduced pressure to obtain crude 4-(allyloxycarbonyl)-5-(N,N-diethylamino)veterinaria.

4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-Differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (346 mg, 6,38×10-4mol), described in reference example 1 was dissolved in N,N-dimethylformamide (2 ml) and to the mixture at room temperature was added sodium hydride (55% dispersion in mineral oil, 30 mg, 6,9×10-4mol), followed by stirring for 1 hour. Obtained in the form of a suspension and the mixture was cooled to 0°C and then thereto was added with stirring, the whole amount of the crude 4-(allyloxycarbonyl)-5-(N,N-diethylamino)veterinaria obtained above. A mixture of p is remedial at room temperature for 30 minutes After cooling, the mixture was distributed between ethyl acetate and an aqueous solution of ammonium chloride, then the organic layer was washed saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent drove under reduced pressure to obtain an oily residue. The residue was subjected to chromatography on a column of silica gel (6 g) (eluent: ethyl acetate:methanol=1:0˜9:1) to obtain the specified title compound (101 mg, yield 20%) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 0,98 (3H, t, J=7 Hz), 0,99 (3H, t, J=7 Hz), of 1.35 (3H, user. d, J=7 Hz), 1,75-1,90 (1H, m), 2.00 in of 2.20 (1H, m), 2.40 a-to 2.65 (8H, m), 3,03 (1H, TT, J=11, 5 Hz), 3,45-3,55 (2H, m), 3,85-of 3.95 (1H, m), 4,15-of 4.25 (2H, m), 4,60-4,70 (2H, m), 4,70-is 4.85 (1H, m), 4,99 (1H, d, J=4 Hz), of 5.26 (1H, d-like, J=10 Hz), to 5.35 (2H,s), lower than the 5.37 (1H, d-like, J=18 Hz), to 5.85 (1H, DD, J=15, 4 Hz), 5,94 (1H, DDT, J=18, 10, 6 Hz), to 6.58 (1H, DD, J=16, 11 Hz), 6,74 (1H, d, J=16 Hz), 6,80-6,95 (3H, m), 7,30 was 7.45 (3H, m), EUR 7.57 (1H, t, J=7 Hz), of 7.90 (1/2H, s)7,906 (1/2H, s), to $ 7.91 (1/2H, s), 7,92 (1/2H, s).

IR-spectrum ν max KBr cm-1: 2232, 1744, 1616, 1504.

Mass spectrum m/z (FAB): 798 (M++1).

(3) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-(N,N-diethylamino)-4-hydroxyvalerate (specified in the header of the target connection)

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triaz the l-1-yl)methyl]propyl] 4-(allyloxycarbonyl)-5-(N,N-diethylamino)valerate (95 mg, 1,2×10-4mol)obtained in example 23-(2), and bis(triphenylphosphine)dichloropalladium (1 mg) was dissolved in dichloromethane (1.5 ml). To the mixture was slowly added to the anti-hydride (52 mg, 1,8×10-4mol) at room temperature for 5 minutes and the Mixture was stirred at room temperature for 10 min and was added hexane. Released oily insoluble substance was separated by slow removal of the supernatant solution. The insoluble residue was twice washed with hexane. The obtained oily residue was subjected to chromatography on a column of silica gel (3 g) (eluent: ethyl acetate:methanol=1:0˜7:3) and further purified by means of the circulation preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm e × 600 mm) and JAIGEL-2H (20 mm e × 600 mm)connected in series for use; solvent: chloroform] to obtain specified in the title compound (78 mg, yield 92%) as a colorless amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: of 1.03 (6H, t, J=7 Hz), of 1.35 (3H, user. d, J=7 Hz), 1,50-1,80 (2H, m), 2,25-2,70 (8H, m), 3,06 (1H, TT, J=12, 4 Hz), 3,35-3,50 (1H, m), 3,52 (2H, t, J=12 Hz), 3,55-the 3.65 (1H, m), 3,80-of 3.95 (1H, m), 4,10-4,30 (2H, m), 4,99 (1H, d, J=4 Hz), 5,30-of 5.40 (2H, m), of 5.85 (1H, DD, J=16 and 4 Hz), to 6.58 (1H, DD, J=16, 10 Hz), 6,74 (1H, d, J=16 Hz), 6,80-to 7.00 (3H, m), 7,30 was 7.45 (3H, m), EUR 7.57 (1H, t, J=8 Hz), to $ 7.91-of 7.96 (2H, m).

IR-spectrum ν max KBrcm-1: 3430, 2232, 1742, 1616, 1504.

Mass spectrum m/z (FAB): 714 (M++1).

[Example 24]

4-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-1-(N,N-diethylaminomethyl)-4-oxobutyl phosphate sodium (example 4-50)

(1) 4-Methoxybenzyl 4-[[bis(allyloxy)phosphoryl]oxy]-5-(N,N-diethylamino)valerate

According to the method similar to that described in example 23-(1), 5-(N,N-dimethylaminomethyl)-tetrahydrofuran-2-he (described in Bull. Soc. Chim. Fr., p.401 (1953); 200 mg of 1.17 mmol) was dissolved in 1 N. aqueous solution of potassium hydroxide (1,17 mmol) followed by stirring at room temperature for 30 minutes the Mixture was dried under reduced pressure, and the resulting oily residue was dissolved in dimethylformamide (1 ml) was added 4-methoxybenzylamine (200 mg, 1.28 mmol) followed by stirring at 90°C for 30 minutes the Mixture was cooled to 0°C, then at room temperature was added tetrazole (420 mg, 6.0 mmol) and bis(allyloxy)(diisopropylamino)phosphine (Tetrahedron Lett., 30, 4219 (1989); 368 mg, 1.5 mmol) followed by stirring for 30 minutes To the mixture was added allyl alcohol (0.1 ml). The resulting mixture was stirred for 1 hour, then at 0°C was added tert-butylhydroperoxide (about 5M solution in nonane, 0.4 ml, 2 mmol) and the mixture was stirred at room is based temperature for 30 minutes To the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution and aqueous sodium thiosulfate solution and the mixture was stirred for 10 min and then distributed between the organic layer and water layer. The organic layer was sequentially washed with a saturated aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The residue was subjected to chromatography on a column of silica gel (6 g) (eluent: ethyl acetate:methanol=1:0˜9:1) and further purified by means of the circulation preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm e × 600 mm) and JAIGEL-2H (20 mm e × 600 mm)connected in series for use; solvent: chloroform] to obtain specified in the title compound (286 mg, yield 61%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: to 0.98 (6H, t, J=7 Hz), 1,80-of 1.95 (1H, m), 2,10-of 2.25 (1H, m), 2.40 a is 2.55 (7H, m)to 2.67 (1H, DD, J=13, 6 Hz), 3,81 (3H, s), 4,40-4,60 (5H, m), 5,00-5,10 (2H, m), with 5.22 (2H, d-like, J=10 Hz), 5,34 (2H, d-like, J=18 Hz), of 5.92 (2H, DDT, J=18, 10, 6 Hz), to 6.88 (2H, d, J=9 Hz), 7,29 (2H, d, J=9 Hz).

IR-spectrum ν max CHCl3cm-1: 1730, 1613, 1516, 1254.

Mass spectrum m/z (FAB): 470 (M++1).

(2) Diallyl 4-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)IU is Il]propoxy]-1-(N,N-diethylaminomethyl)-4-oxobutyl phosphate

To a mixture of 4-methoxybenzyl 4-[[bis(allyloxy)phosphoryl]oxy]-5-(N,N-diethylamino)valerate (275 mg, 5,75×10-4mol) and anisole (0.2 ml) at room temperature was added triperoxonane acid (2.7 ml). The mixture was stirred at room temperature for 30 min, diluted with toluene and the solvent is kept at reduced pressure. The residue was dissolved in dichloromethane (2 ml) and then was added N,N-dimethylformamide (0,02 ml) and oxacillin (200 mg). The mixture was stirred at room temperature for 1 hour, then added toluene and the solvent drove under reduced pressure to obtain crude 4-[[bis(allyloxy)phosphoryl]oxy]-5-(N,N-diethylamino)-veterinaria.

4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-Differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (624 mg, 1.15 mmol)obtained in Reference example 1 was dissolved in N,N-dimethylformamide (4 ml), then was added sodium hydride (55% dispersion in mineral oil; 52 mg, 1.2 mmol) and the mixture was stirred for 1 hour. Obtained in the form of a suspension and the mixture was cooled to 0°C and with stirring was added the whole amount of the crude 4-[[bis(allyloxy)phosphoryl]oxy]-5-(N,N-diethylamino)veterinaria obtained above. The resulting mixture was stirred at room temperature for 30 minutes After cooling the reaction mixture is distributed between ethyl acetate and an aqueous solution of ammonium chloride, then the organic layer was washed saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The oily residue was subjected to chromatography on a column of silica gel (12 g) (eluent: ethyl acetate:methanol=1:0˜9:1) and further purified by means of the circulation preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm e × 600 mm) and JAIGEL-2H (20 mm e × 600 mm)connected in series for use; solvent: chloroform] to obtain specified in the title compound (210 mg, yield 21%) as a colorless amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 0,99 (3H, t, J=7 Hz), and 1.00 (3H, t, J=7 Hz), of 1.35 (3H, DD, J=7, 2 Hz), 1,75-of 1.95 (1H, m), 2.05 is-to 2.15 (1H, m), 2.40 a is 2.75 (8H, m), 2.95 and-3,10 (1H, m), 3,45-3,55 (2H, m), 3,85-of 3.95 (1H, m), 4,10-4,30 (2H, m), 4,35-4,50 (1H, m), 4,50 with 4.65 (4H, m), 4,99 (1H, d, J=4 Hz), 5,26 (2H, d-like, J=10 Hz), a 5.25 to 5.45 (4H,m), of 5.85 (1H, DD, J=15, 4 Hz), 5,95 (2H, DDT, J=18, 10, 6 Hz), to 6.58 (1H, DD, J=15, 11 Hz), 6,74 (1H, d, J=16 Hz), 6,80-to 6.95 (3H, m), 7,30 is 7.50 (3H, m), EUR 7.57 (1H, t, J=7 Hz), of 7.90-a 7.92 (2H, m).

IR-spectrum ν max CHCl3cm-1: 2233, 1742, 1616, 1504.

Mass spectrum m/z (FAB): 874 (M++1).

(3) 4-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-1-(N,N-diethylaminomethyl)-4-oxobutyl phosphate sodium (specified in the header of the target connection)

Diallyl 4-(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-1-(N,N-diethylaminomethyl)-4-oxobutanoate (175 mg, 2,00×10-4mol)obtained in example 24-(2), and bis(triphenylphosphine)dichloropalladium (2 mg) was dissolved in dichloromethane (2 ml). To the mixture at room temperature slowly over 15 min was added to the anti-hydride (145 mg, 5,0×10-4mol). After stirring at room temperature for 10 min to the reaction mixture was added hexane. Released insoluble oily substance was separated by slow removal of the supernatant liquid. Nerastvorim residue optionally washed twice with hexane. The oily residue was dissolved in methanol (2 ml), then was added a saturated aqueous solution of sodium bicarbonate (0.5 ml) and the resulting suspension was stirred at room temperature for 15 hours. The obtained homogeneous mixture was concentrated under reduced pressure. The residue was dissolved in methanol and the insoluble substance was removed. The solvent is evaporated under reduced pressure and the residue was subjected to column chromatography with reversed phase using Cosmosil 75 C18-PREP (Nacalai Tesque, Inc.; 10 g) (eluent: water:methanol=1:1˜3:7). The fractions obtained were concentrated and the residue was liofilizovane obtaining specified in the title target compound (an 80.2 mg, yield 46%) as a colourless solid.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 0,95-of 1.20 (9H, m), 1,50-1,70 (2H, m), 2.05 is-is 2.30 (1H, m), 2,35-of 2.50 (1H, m), 2,50-3,45 (9H, m), 3.45 points-of 3.60 (1H, m), 3,80-of 4.05 (2H, m), 4,15-and 4.40 (1H, m), 4.95 points-of 5.50 (4H, m), 6,05-of 6.20 (1H, m), of 6.20 to 6.35 (1H, m), 6,50-of 6.90 (3H, m), 7,05 is 7.50 (4H, m), a 7.85-of 7.95 (1H, m), 8,00-8,15 (1, m).

IR-spectrum ν max KBr cm-1: 3411, 2232, 1741, 1616, 1504.

Mass spectrum m/z (FAB): 816 (M++1).

[Example 25]

Disodium [8-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-1-naphthyl]methyl phosphate (disodium salt of example number 5-41)

(1) Diallyl [8-[(tert-butyldimethylsilyl)oxymethyl]-1-naphthyl]methyl phosphate

According to the method similar to that described in example 1-(10)was subjected to reaction [8-[(tert-butyldimethylsilyl)oxymethyl]-1-naphthyl]methanol (described in Aust. J. Chem., 49, 793 (1996); 4,04 g, a 13.4 mmol), tetrazole (2,34 g, 33.4 mmol), bis(allyloxy)(diisopropylamino)phosphine (described in Tetrahedron Lett., 30, 4219 (1989); 3,93 g, 16.0 mmol) and tert-butylhydroperoxide (80% solution of di-tert-butylperoxide; Merck; 1.8 g, 16 mmol) and the reaction mixture was treated with obtaining after extraction of oily residue. The residue was subjected to chromatography on a column of silica gel (120 g) (eluent: ethyl acetate:hexane=1:5˜1:2) to obtain specified in the connection header (5,02 g, yield 81%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 0,03 (6H, s)of 0.87 (9H, s), 4,37 is 4.45 (4H, m), 5,16 (2H, user. d, J=10 Hz), 5,24 (2H, the kV, J=18, 1 Hz), a 5.25 (2H, s)5,80 (2H, d, J=10 Hz), 5,77 and 5.86 (2H, m), 7,44-of 7.48 (2H, m), to 7.61 (1H, DD, J=7, 1 Hz), 7,69 (1H, DD, J=7, 1 Hz), to 7.84 (1H, DD, J=8, 1 Hz), 7,89 (1H, DD, J=7, 1 Hz).

IR-spectrum ν max CHCl3cm-1: 1732, 1471, 1464, 1259, 1027, 999.

Mass spectrum m/z (FAB): 463 (M++1).

(2) Diallyl [8-(hydroxymethyl)-1-naphthyl]methyl phosphate

To a solution of diallyl [8-[(tert-butyldimethylsilyl)oxymethyl]-1-naphthyl]methyl phosphate (5,01 g to 10.8 mmol)obtained in example 25-(1)in tetrahydrofuran (50 ml) was added tetrabutylammonium fluoride (1 mol/l solution in tetrahydrofuran; and 13.5 ml, 13.5 mmol) and the mixture was stirred at room temperature for 1 hour. Added water and the product was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain an oily residue. The residue was subjected to chromatography on a column of silica gel (75 g) (eluent: ethyl acetate:hexane=3:1˜4:1) to obtain specified in the connection header (2,22 g, yield 59%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: to 4.41-to 4.46 (4H, m), is 5.18 (2H, user. d, J=10 Hz), 5,19 (2H, s), of 5.26 (2H, user. d, J=17 Hz), of 5.82 (2H, d, J=9 Hz), of 5.84 (2H, DDT, J=17, 10, 6 Hz), 7,47 (1H, t, J=7 Hz), 7,49 (1H, t, J=7 Hz), to 7.61 (1H, DD, J=7, 1 Hz), 7,71 (1H, DD, J=7, 1 Hz), 7,88 (1H, d, J=7 Hz), a 7.92 (1H, d, J=7 Hz).

IR-spectrum ν max CHCl3cm-1: 3603, 1732, 1270, 1028, 990.

Mass spectrum m/z (FAB): 349 (M++1).

(3) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-Fortini is)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 8-[[bis(allyloxy)phosphoryl]oxymethyl]-1-aftout

To a solution of diallyl [8-(hydroxymethyl)-1-naphthyl]methylphosphate (1,1492 g, 3,30 mmol) in acetone (20 ml)obtained in example 25-(2)was added Jones reagent (a mixture of chromic anhydride (5.34 g) and concentrated sulfuric acid (4.6 ml), diluted with water to a total volume of 20 ml, 5 ml, about to 13.2 mmol). The reaction mixture was stirred at room temperature for 90 min, then was cooled to 0°C and then to the mixture was added 2-propanol (0.5 ml) to stop the reaction. The insoluble substance was filtered and the solvent drove under reduced pressure to obtain an oily residue. The residue was dried using a vacuum pump and then subjected to chromatography on a column of silica gel (30 g) (eluent: ethyl acetate:dichloromethane=1:10˜3:10) to give crude 8-[[bis(allyloxy)phosphoryl]oxymethyl]-1-naphthoic acid in the form of oil. The product was dissolved in dichloromethane (10 ml) and then added oxalicacid (1 g, 7,88 mmol) and N,N-dimethylformamide (15 ml). After stirring the mixture at room temperature for 30 min according to the method similar to that described in Example 1-(12)was subjected to reaction received untreated 8-[[bis(allyloxy)phosphoryl]oxymethyl]-1-aftercare. According to the method similar to that described in Example 1-(12), carried out the reaction of 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl--(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (542,7 mg, 1.0 mmol)described in reference example 1, sodium hydride (55% dispersion in mineral oil, 43 mg, 1.0 mmol) and the crude 8-[[bis(allyloxy)phosphoryl]oxymethyl]-1-nafolklore obtained above in tetrahydrofuran (5 ml) and the reaction mixture was treated with obtaining after extraction is specified in the header connection in the form of crude oil. The crude oil was subjected to chromatography on a column of silica gel (50 g) (eluent: ethyl acetate:hexane=1:1˜5:1) to obtain specified in the connection header (459,2 mg, yield 52%) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,47 (3H, DD, J=7, 2 Hz), 3,18 (1H, TT, J=11, 5 Hz), of 3.46 (1H, t, J=11 Hz), 3,55 (1H, t, J=11 Hz), 4,20 (1H, DDD, J=11, 5, 2 Hz), 4,22 was 4.42 (6H, m), 4,94 (1H, d, J=4 Hz), 5,13 (2H, user. d, J=11 Hz), 5,20 (2H, user. d, J=18 Hz), of 5.34 (1H, DD, J=14, 10 Hz), 5,43-5,56 (3H, m), 5,70-of 5.82 (3H, m), 6,50 (1H, DD, J=15, 11 Hz), 6,70 (1H, d, J=15 Hz), make 6.90 (1H, DD, J=15, 11 Hz), 6.90 to-6,95 (1H, m), 7,14 (1H, TD, J=8, 3 Hz), 7,33 (1H, DD, J=10, 1 Hz), 7,38-7,44 (3H, m), 7,56 (1H, t, J=8 Hz), 7,58 (1H, t, J=8 Hz), 7,79 (1H, s), 7,83-7,89 (3H, m), 8,01 (1H, s), with 8.05 (1H, DD, J=6, 3 Hz).

IR-spectrum ν max KBr cm-1: 3431, 2230, 1718, 1615, 1503, 1274, 1143, 1039, 1011.

Mass spectrum m/z (FAB): 887 (M++1).

(4) Disodium [8-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-1-naphthyl]methyl phosphate (specified in the header of the target connection)

According to the technique, anal is the same as described in Example 1-(13), (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 8-[[bis(allyloxy)phosphoryl]oxymethyl]-1-aftout (450,3 mg, 0.51 mmol)obtained in example 25-(3)were subjected to interaction with bis(triphenylphosphine)dichloropalladium (17.9 mg, was 0.026 mmol) and anti-hydride (443 mg, of 1.52 mmol) and the reaction mixture was treated with obtaining specified in the header of the target compound in the form of crude oil. The crude product was subjected to column chromatography with reversed phase using Cosmosil 75 C18-PREP (Nacalai Tesque, Inc.; 30 g)(eluent: water:methanol=4:6˜3:7). The fractions obtained were concentrated and the residue was liofilizovane obtaining specified in the title target compound (117,7 mg, yield 27%) as a colourless solid.

NMR-spectrum (400 MHz, CD3OD) δ ppm: to 1.48 (3H, DD, J=7, 2 Hz)and 3.15 (1H, TT, J=11, 5 Hz), 3,49 (1H, t, J=11 Hz), to 3.58 (1H, t, J=11 Hz), 4,17 (1H, DDD, J=11, 5, 2 Hz), 4,24 (1H, DDD, J=11, 5, 2 Hz), 4,34 (1H, q, J=7 Hz), 5,00 (1H, d, J=4 Hz), a total of 5.21 (1H, DD, J=15, 8 Hz), 5,26 (1H, DD, J=15, 8 Hz), 5,59 (1H, DD, J=15 and 3 Hz), 5,69 (1H, d, J=15 Hz), of 5.82 (1H, DD, J=16 and 4 Hz), is 6.54 (1H, DD, J=16, 11 Hz), 6,77 (1H, d, J=16 Hz), 7,02 (1H, DDD, J=13, 9, 3 Hz), 7,07 (1H, DD, J=16, 11 Hz), 7,30 (1H, TD, J=8, 3 Hz), 7,42 (1H, t, J=8 Hz), 7,49-rate of 7.54 (2H, m), 7,58 (1H, t, J=8 Hz), of 7.70 (1H, d, J=7 Hz), to 7.77 (1H, t, J=7 Hz), to 7.84 (1H, d, J=8 Hz), of 7.96 (1H, TD, J=9, 6 Hz), with 8.05 (1H, s), of 8.09 (1H, DD, J=8, 1 Hz), 8,19 (1H, d, J=7 Hz), 8,39 (1H, s).

Mass spectrum m/z (FAB): 851 (M++1).

A portion is the amount of rotation [α ]D25+63,0° (c=0,61, MeOH).

[Example 26]

Disodium 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-4-methylbenzyl phosphate (disodium salt of example number 5B-92)

(1) 6-Amino-1(3H)-isobenzofuranone

Commercially available 6-nitro-1(3H)-isobenzofuranone (9,9 g, 55 mmol) was dissolved in a mixed solvent of tetrahydrofuran (20 ml) - methanol (60 ml), then added the catalyst is 5% palladium on coal (1.5 g) and the mixture was stirred at room temperature for 20 hours in an atmosphere of hydrogen gas. The reaction mixture was filtered and the solid is then washed with ethyl acetate and methanol. The filtrate and washing liquid were combined and the resulting solution was concentrated under reduced pressure. The obtained solid was washed with ethyl acetate to obtain specified in the connection header (6,21 g) as a crystalline solid. The washing liquid was concentrated and the residue was led from a mixed solvent of ethyl acetate-hexane to obtain additional quantities specified in the title compound (0.95 g, total yield 87%).

NMR-spectrum (400 MHz, CD3OD) δ ppm: 5,225 (2H, s)7,060 (1H, d-like, J=2 Hz), 7,071 (1H, dodany, J=9, 2 Hz), 7,288 (1H, d, J=9 Hz).

IR-spectrum ν max KBr cm-1: 3473, 3372, 3278, 1735, 1631, 1504, 1330, 1059, 992.

(2) 6-Bromo-1(3H)-isobenzofuranone

6-Amino-1(3H)-isobenzofuranone (3.0 g, 20 mmol)obtained in example 26-(1), was dissolved in a mixture of 47% aqueous Hydrobromic acid (15 ml) and water (15 ml), then the mixture was cooled to 0°C and slowly added a solution of sodium nitrite (1.45 g, 21 mmol) in water (7 ml). Then to the reaction mixture was added a solution of copper bromide (I) (3.6 g, 25 mmol)dissolved in 47% aqueous solution of Hydrobromic acid (10 ml) and the resulting mixture was stirred at 80°C for 20 min. After cooling, the mixture separated product was collected by filtration and then washed with water. The obtained pale-brown solid was dissolved in ethyl acetate, and then the insoluble substance was removed by filtration and the filtrate is successively washed with 1 N. aqueous solution of hydrochloric acid, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain specified in the title compound (3.57 g, yield 84%) as a crystalline solid.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 5,289 (2H, s)7,391 (1H, d, J=8 Hz), 7,808 (1H, DD, J=8, 2 Hz), 8,068 (1H, d, J=2 Hz).

IR-spectrum ν max KBr cm-1: 1778, 1458, 1359, 1191, 1046, 998, 768.

p> Mass spectrum m/z (EI): 214, 212 (M+), 185, 183, 157, 155.

(3) 6-Methyl-1(3H)-isobenzofuranone

Tris(dibenzylideneacetone)dipalladium(0) (30 mg, 0,033 mmol), tri-o-tolylphosphino (40 mg, 0.13 mmol) and tetramethylurea (600 mg, 3.35 mmol) was dissolved in hexamethylphosphoramide (0.6 ml) was added 6-bromo-1(3H)-isobenzofuranone (144 mg, 0,676 mmol)obtained in example 26-(2), then the mixture was heated at 50°C for 2 hours. After cooling the reaction mixture, the mixture was diluted with ethyl acetate and then washed twice with water and twice with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was subjected to chromatography on a column of silica gel (5 g) (eluent: hexane:ethyl acetate=3:1). The fractions containing the target compound were concentrated and the obtained solid substance was recrystallized with obtaining specified in the connection header (88,3 mg, yield 88%) as a crystalline solid.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2,472 (3H, s)5,284 (2H, s)7,376 (1H, d, J=8 Hz), 7,497 (1H, d, J=8 Hz), 7,721 (1H, s).

(4) 2-[[Bis(allyloxy)phosphoryl]oxymethyl]-5-methylbenzoic acid

According to the method similar to that described in Example 4-(5), 6-methyl-1(3H)-isobenzofuranone (2,22 g, 14,98 mmol)obtained in example 26-(3), successively treated with sodium hydroxide (1 N. aqueous solution; 14 ml, 14 mmol), 4-tags what benzylchloride (2.58 g, 16.5 mmol), tetrazole (2.10 g, 30 mmol), bis(allyloxy)(diisopropylamino)phosphine (5,52 g of 22.5 mmol) and tert-butylhydroperoxide to obtain after purification column chromatography (eluent: ethyl acetate:hexane=1:2˜2:1) 4-methoxybenzyl 2-[[bis(allyloxy)phosphoryl]-oxymethyl]-5-methylbenzoate. Then the product was treated triperoxonane acid by the procedure similar to that described in Example 4-(6)was subjected to reaction with obtaining after washing with hexane specified in the title compound (2.37 g, yield 48%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2,396 (3H, s), 4,69 (4H, DD-like, J=7, 6 Hz), 5,246 (2H, DD-like, J=10, 1.5 Hz), 5,364 (2H, DD-like, J=17 and 1.5 Hz), 5,590 (2H, d, J=6.6 Hz), 5,938 (2H, DDT, J=17, 10, 7 Hz), 7,391 (1H, d, J=8 Hz,), 7,545 (1H, d, J=8 Hz), 7,803 (1H, users).

IR-spectrum ν max CHCl3cm-1: 1695, 1267, 1167, 1030.

Mass spectrum m/z (FAB): 327 (M++1).

(5) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-methylbenzoate

According to the method similar to that described in Example 4-(6), 4-methoxybenzyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-methylbenzoate (690 mg, 1.54 mmol) was treated triperoxonane acid to obtain 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-methylbenzoic acid in the form of a crude product. By the method similar to the description of the Noi in example 4-(6), the above product was treated with oxalylamino and N,N-dimethylformamide to obtain 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-methylbenzonitrile in the form of a crude product. According to the method similar to that described in Example 1-(12), 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (670 mg, of 1.23 mmol)described in reference example 1, was treated with sodium hydride and then subjected to the interaction with the crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-5-methylbenzylamino (whole number)obtained above, to obtain after purification column chromatography specified in the title compound (448 mg, yield 43%) as a pale yellow, like candy substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,452 (3H, DD, J=7, 2 Hz), KZT 2,382 (3H, s)3,092 (1H, TT, J=11, 5 Hz), 3,481 (1H, t, J=11 Hz), 3,537 (1H, t, J=11 Hz), to 4.016 (1H, q, J=7 Hz), 4,132 (1H, DDD, J=11, 5, 2 Hz), 4,221 (1H, DDD, J=11, 5, 2 Hz), 4,47-4,6 (4H, m)4,981 (1H, d, J=4 Hz), 5,208 (2H, DQC-like, J=11, 1 Hz), 5,26-5,46 (5H, m)5,543 (1H, d, J=15 Hz), 5,836 (1H, DD, J=15, 4 Hz), 5,912 (1H, DDT, J=16, 11, 5 Hz), 5,917 (1H, DDT, J=16, 11, 5 Hz), 6,559 (1H, DD, J=15, 11 Hz), 6,728 (1H, d, J=16 Hz), 6,86-6,97 (3H, m)7,335 (1H, DD, J=10, 1.5 Hz), 7,34-7,44 (1H, m)7,402 (2H, d, J=8 Hz), 7,513 (1H, user. C)7,561 (1H, d, J=8 Hz), 7,571 (1H, t, J=10 Hz), 7,925 (1H, s)7,932 (1H, s).

IR-spectrum ν max CHCl3cm-1: 2233, 1764, 1721, 1616, 1504, 1276.

Mass spectrum m/z (FAB): 851 (M++1).

(6) Disodium 2[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-4-methylbenzylphosphonate (specified in the header of the target connection)

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)phosphoryl]-oxymethyl]-5-methylbenzoate (420 mg, 0,494 mmol)obtained in example 26-(5), was treated with tetrakis(triphenylphosphine)-palladium, triphenylphosphine and pyrrolidine in dichloromethane according to the method similar to that described in example 18-(2). The reaction mixture was treated according to the method similar to that described in example 18-(2), and the residue obtained by extraction was subjected to column chromatography with reversed phase using Cosmosil 75 C18-PREP (Nacalai Tesque, Inc.) (eluent: water:methanol=1:0˜7:3). The fractions obtained were concentrated and the residue was subjected to treatment with cation exchange resin (Dowex 50W-8X, sodium form) (eluent: water). The collected fractions were concentrated under reduced pressure and was liofilizovane obtaining specified in the title target compound (298 mg, yield 74%) as a colorless amorphous solid.

NMR-spectrum (400 MHz, D2O) δ ppm: 1,404 (3H, d, J=7 Hz), 2,327 (3H, s), 3,150 (1H, TT, J=11, 5 Hz), 3,446 (1H, t, J=11 Hz), 3,565 (1H, t, J=11 Hz), 4,06 (1H, DDD, J=11, 5, 2 Hz), 4,120 (1H, q, J=7 Hz), 4,22 (1H, DDD, J=11, 5, 2 Hz), 5,015 (1H, d, J=4 Hz), 5,100 (1H, DD, J=16, 5 Hz), 5,302 (1H, DD, J=16, 5 Hz), the 5.45 (1H, DD, J=14, 2 Hz), 5,625 (1H, d, J=14 Hz), 5,850 (1H, DD, J=15, 4 Hz), 6,565 (1H, DD, J=15, 11 Hz), 6,788 (1H, d, J=15 Hz), 7,024 (2H, t-like, J=about 9 Hz), 7,092 (1H, DD, J=15, 11 Hz), 7,35-7,40 (2H, m), 7,45-,6 (3H, m)7,785 (1H, t, J=8 Hz), 7,955 (1H, d, J=8 Hz), 8,028 (1H, s)8,330 (1H, s).

IR-spectrum ν max KBr cm-1: 3422, 2231, 1721, 1615, 1503, 1276, 1141, 1053, 975.

Mass spectrum m/z (FAB): 815 (M++1).

The mass spectrum of the high-resolution m/z (FAB): Calculated for C36H33F3N4O8PSNa2(M++1): 815, 1504, Found: 815, 1506.

[Example 27]

Disodium 2-chloro-6-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]benzyl phosphate (disodium salt of example number 5-45)

(1) 2-[(tert-Butyldimethylsilyl)oxymethyl]-6-chlorbenzoyl alcohol

A solution of 3-chloro-1,2-benzylimidazole (described in J. Chem. Soc., p.5050 (1952); 3,02 g, 17.5 mmol) in tetrahydrofuran (40 ml) was cooled to 0°C and then added imidazole (1.19 g, 17.5 mmol) and tert-BUTYLCARBAMATE (2.64 g, 17.5 mmol). The mixture was stirred at room temperature for 1 hour, and then thereto was added water and the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and the solvent drove under reduced pressure to obtain a residue. The residue was subjected to chromatography on a column of silica gel (100 g) (eluent: ethyl acetate:hexane=1:5) to obtain specified in the connection header (3,69 g, yield 73%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3 ) δ ppm: 0,13 (6H, s)to 0.92 (9H, s), with 2.93 (1H, t, J=7 Hz), a 4.83 (2H, s), a 4.86 (2H, d, J=7 Hz), 7,19-of 7.25 (2H, m), 7,37 (1H, DD, J=8, 2 Hz).

IR-spectrum ν max CHCl3cm-1: 2959, 2931, 1732, 1257, 1049, 839.

Mass spectrum m/z (FAB): 287 (M++1).

(2) Diallyl 2-[(tert-butyldimethylsilyl)oxymethyl]-6-Chlorobenzilate

According to the method similar to that described in example 1-(10), carried out the reaction of 2-[(tert-butyldimethylsilyl)oxymethyl]-6-Chlorobenzilate alcohol (3,66 g, 12.8 mmol)obtained in example 27-(1), tetrazole (2,23 g, 31.9 per mmol), bis(allyloxy)(aminobutiramida-amino)phosphine (described in Tetrahedron Lett., 30, 4219 (1989); 3,91 g, 16.0 mmol) and tert-butylhydroperoxide (about 80% solution of di-tert-butylperoxide; Merck; 1.8 g, about 16 mmol) and the reaction mixture was treated with obtaining after extraction of oily residue. The residue was subjected to chromatography on a column of silica gel (200 g) (eluent: ethyl acetate:hexane=1:5˜2:3) to obtain the specified title compound (4.52 g, yield 79%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 0,11 (6H, s)to 0.94 (9H, s), 4,51-4,55 (4H, m), 4,88 (2H, s), 5,23 (2H, user. d, J=10 Hz), and 5.30 (2H, d, J=7 Hz), of 5.34 (2H, DQC, J=17, 1 Hz), 5,91 (2H, DDT, J=17, 10, 5 Hz), 7,28-7,34 (2H, m), 7,44 (1H, d, J=7 Hz).

IR-spectrum ν max CHCl3cm-1: 2956, 2931, 1259, 1018, 989, 839.

Mass spectrum m/z (FAB): 447 (M++1).

(3) Diallyl 2-chloro-6-(hydroxymethyl)benzyl phosphate

To a solution of diallyl 2-[(tert-butyldimethylsilyl)oxymethyl]-6-harbe is infostate (to 4.41 g, 9,87 mmol)obtained in example 27-(2), in tetrahydrofuran (50 ml) was added tetrabutylammonium fluoride (1 n solution in tetrahydrofuran, 10 ml, 10 mmol) and the mixture was stirred at room temperature for 40 minutes To the mixture was added water, then the product was extracted with ethyl acetate and the solvent drove under reduced pressure to obtain an oily residue. The residue was subjected to chromatography on a column of silica gel (50 g) (eluent: ethyl acetate:hexane=1:1˜3:1) to obtain specified in the connection header (2,71 g, yield 83%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 3,49 (1H, t, J=6 Hz), 4,47-4,51 (4H, m), 4,78 (2H, d, J=6 Hz), 5,23 (2H, user. d, J=10 Hz), 5,33 (2H, user. d, J=18 Hz), of 5.40 (2H, d, J=9 Hz), of 5.89 (2H, DDT, J=18, 10, 6 Hz), 7,32 (1H, t, J=8 Hz), 7,37-7,40 (2H, m).

IR-spectrum ν max CHCl3cm-1: 3608, 1732, 1268, 1028, 987.

Mass spectrum m/z (FAB): 333 (M++1).

(4) 2-[[Bis(allyloxy)phosphoryl]oxymethyl]-3-chlorbenzene acid

A solution of diallyl 2-chloro-6-(hydroxymethyl)benzylphosphonate (2,62 g, 7,88 mmol)obtained in example 27-(3), in acetone (25 ml) was cooled to 0°C was added Jones reagent (a mixture of chromic anhydride (5.34 g) and concentrated sulfuric acid (4.6 ml), diluted with water to a total volume of 20 ml, 12 ml, 32 mmol). The reaction mixture was stirred at room temperature for 1 hour and then to the mixture was added 2-propanol (1 ml) for OST the setting reaction. The insoluble substance was filtered and then the filtrate was concentrated under reduced pressure to obtain an oily residue. The remainder of the well was dried using a vacuum pump and then subjected to chromatography on a column of silica gel (40 g) (eluent: ethyl acetate:dichloromethane=1:10˜1:1) to obtain specified in the connection header (2,065 g, yield 76%) as a pale brown oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 4,50-to 4.62 (4H, m), 5,23 (2H, user. d, J=10 Hz), of 5.34 (2H, DQC, J=17, 1 Hz), 5,64 (2H, DD, J=7, 2 Hz), 5,91 (2H, DDT, J=17, 10, 6 Hz), 7,39 (1H, t, J=8 Hz), EUR 7.57 (1H, d, J=8 Hz), 7,81 (1H, d, J=8 Hz).

IR-spectrum ν max CHCl3cm-1: 2951, 1727, 1267, 1025.

Mass spectrum m/z (FAB): 347 (M++1).

(5) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-chlorobenzoate

A solution of 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-chlorbenzoyl acid (936,1 mg, 2.7 mmol)obtained in example 27-(4), in dichloromethane (15 ml) was cooled to 0°C and then added N,N-dimethylformamide (15 ml) and oxacillin (1,71 g, 13.5 mmol). After stirring the mixture at room temperature for 30 min the mixture was treated according to the method similar to that described in Example 1-(12)was subjected to reaction with obtaining the crude 2-[[bis(allyloxy)FOSFA the Rhyl]oxymethyl]-3-chlorobenzylchloride.

According to the method similar to that described in Example 1-(12), carried out the reaction of 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (976,7 mg of 1.80 mmol)described in reference example 1, sodium hydride (55% dispersion in mineral oil; about 78.5 mg, 1.8 mmol) and crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-chlorobenzylchloride obtained above in tetrahydrofuran (10 ml) and the reaction mixture was treated with obtaining after extraction is specified in the header connection in the form of crude oil. The crude oil was subjected to chromatography on a column of silica gel (100 g) (eluent: ethyl acetate:hexane=1:1˜5:1) to obtain specified in the connection header (1136 mg, yield 72%) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: the 1.44 (3H, DD, J=7, 2 Hz), to 3.02 (1H, TT, J=11, 5 Hz), of 3.45 (1H, t, J=11 Hz), 3,51 (1H, t, J=11 Hz), of 4.00 (1H, q, J=7 Hz), 4,07 (1H, DDD, J=11, 5, 2 Hz), 4,18 (1H, DDD, J=11, 5, 2 Hz), 4,45-4,58 (4H, m), 4,96 (1H, d, J=4 Hz), 5,20 (2H, user. d, J=10 Hz), 5,31 (2H, user. d, J=17 Hz), the 5.45 (1H, DD, J=15 and 3 Hz), the 5.51 (1H, d, J=15 Hz)to 5.56 (1H, DD, J=10, 6 Hz), 5,59 (1H, DD, J=10, 6 Hz), of 5.82 (1H, DD, J=15, 4 Hz), 5,85-5,94 (2H, m), 6,55 (1H, DD, J=15, 11 Hz), 6.73 x (1H, d, J=16 Hz), to 6.95 (1H, DD, J=16, 11 Hz), 6.87 in-7,03 (2H, m), 7,32 is 7.50 (5H, m), EUR 7.57 (1H, t, J=8 Hz), 7,63 (1H, DD, J=8, 1 Hz), 7,94 (1H, s), of 8.00 (1H, s).

IR-spectrum ν max CHCl3cm-1: 2233, 1732, 1504, 1276, 1140, 1019, 991.

Mass spectrum m/z (FAB): 871 ( ++1).

(6) Disodium 6-chloro-2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-benzylester (specified in the header of the target connection)

According to the method similar to that described in Example 1-(13), (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-chlorobenzoate (598,8 mg, 0.69 mmol)obtained in example 27-(5)were subjected to interaction with bis(triphenylphosphine)dichloropalladium (24,1 mg 0,034 mmol) and anti-hydride (429,9 mg and 1.51 mmol) and the reaction mixture was treated with obtaining after extraction is specified in the header of target compound in the form of crude oil. The crude oil was subjected to column chromatography with reversed phase using Cosmosil 75 C18-PREP (Nacalai Tesque, Inc.; 30 g) (eluent: water:methanol=4:6˜3:7). The fractions obtained were concentrated and the residue was liofilizovane obtaining specified in the title target compound (174,8 mg, 30%yield) as a colorless solid.

NMR-spectrum (400 MHz, CD3OD) δ ppm: to 1.42 (3H, DD, J=7, 2 Hz), 2,98 (1H, TT, J=11, 5 Hz), of 3.46 (1H, t, J=11 Hz), 3,52 (1H, t, J=11 Hz), 4,00-4,06 (2H, m), 4,14 (1H, DDD, J=11, 5, 2 Hz), 5,00 (1H, d, J=4 Hz), to 5.35 (1H, DD, J=11, 4 Hz), 5,42 (1H, DD, J=11, 4 Hz), of 5.53 (1H, DD, J=15 and 3 Hz), 5,67 (1H, d, J=15 Hz), of 5.83 (1H, DD, J=15, 4 Hz),6,55 (1H, DD, J=15, 11 Hz), 6,78 (1H, d, J=15 Hz), 7,00-7,16 (3H, m), 7,38 (1H, t, J=8 Hz), 7,49-rate of 7.54 (2H, m), 7,62-7,71 (3H, m), 7,78 (1H, t, J=8 Hz), 7,98 (1H, s), 8,63 (1H, s).

IR-spectrum ν max KBr cm-1: 2231, 1732, 1615, 1503, 1275, 1257, 1142, 1105, 1048, 974.

Mass spectrum m/z (FAB): 835 (M++1).

Specific rotation [α]D25+7,7° (c=1,20, MeOH).

[Example 28]

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[(2-aminoethoxy)methyl]benzoate (example 5-2)

(1) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[2-(allyloxycarbonyl-amino)acetoxy]methyl]benzoate

A solution of N-(allyloxycarbonyl)glycine (described in Chem. Pharm. Bull., 48, 716 (2000); 600 mg of 3.77 mmol) in dichloromethane (15 ml) was cooled to 0°C was added N,N-dimethylformamide (0,03 ml) and oxacillin (0.6 g, 4.7 mmol). The mixture was stirred at room temperature for 1 hour, then added toluene and the solvent drove under reduced pressure to obtain crude 2-(allyloxy-carbylamine)acetylchloride.

A solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-(hydroxymethyl)benzoate (800 mg, 1.18 mmol)obtained in the Example of the 17-(4), in dichloromethane (20 ml) was cooled to 0°C was added 4-(N,N-dimethylamino)pyridine (366,5 mg, 3 mmol) and crude 2-(allyloxycarbonyl)acetylchloride obtained above. The mixture was stirred at this temperature for 1 hour, diluted with dichloromethane, then the organic layer was sequentially washed with a saturated aqueous solution of sodium bicarbonate and water. The solvent is evaporated under reduced pressure and the residue was subjected to chromatography on a column of silica gel (40 g) (eluent: ethyl acetate:hexane=3:2) to obtain specified in the connection header (777,0 mg, yield 80%) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,47 (3H, DD, J=7, 2 Hz), 3,06 (1H, TT, J=11, 5 Hz), 3,50 (1H, t, J=11 Hz), 3,53 (1H, t, J=11 Hz), a 4.03-4,10 (3H, m), 4,13-is 4.21 (2H, m), 4,59 (2H, d, J=5 Hz), 4,99 (1H, d, J=4 Hz), to 5.21 (1H, DD, J=10, 1 Hz), and 5.30 (1H, DD, J=18, 1 Hz), 5,46-5,56 (3H, m), the ceiling of 5.60 (1H, d, J=14 Hz), of 5.84 (1H, DD, J=16 and 4 Hz), by 5.87-5,96 (1H, m), to 6.57 (1H, DD, J=16, 11 Hz), was 6.73 (1H, d, J=16 Hz), 6,88-to 7.00 (3H, m), 7,33 (1H, DD, J=10, 1 Hz), 7,39-7,46 (3H, m), 7,54 to 7.62 (3H, m), to 7.84 (1H, d, J=7 Hz), 7,89 (1H, s), of 7.96 (1H, s).

IR-spectrum ν max KBr cm-1: 2230, 1724, 1504, 1274, 1258, 1140, 1051.

Mass spectrum m/z (ESI): 818 (M++1).

(2) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[(2-aminoethoxy)-methyl]benzoate (specified in the header of the target connection)

To a solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-tzia is about 2 forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[2-(allyloxycarbonyl)acetoxy]methyl]benzoate (366,9 mg, 0,449 mmol)obtained in example 28-(1)in dichloromethane (10 ml) at room temperature was added bis(triphenylphosphine)dichloropalladium (15.7 mg, of 0.022 mmol) and then to the mixture was added dropwise the anti-hydride (156.8 mg, 0.54 mmol). The reaction solution was stirred at room temperature for 30 min, concentrated, and then the obtained oily residue was subjected to chromatography on a column of silica gel (10 g) (eluent: ethyl acetate:methanol=4:1) to obtain specified in the title target compound (of 282.5 mg, yield 86%) as a colorless amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: of 1.46 (3H, DD, J=7, 1 Hz), 3,05 (1H, TT, J=11, 5 Hz), 3,51 (1H, t, J=11 Hz), 3,53 (1H, t, J=11 Hz), 3,53 (2H, s), was 4.02 (1H, q, J=7 Hz), 4,10-is 4.21 (2H, m), 4,99 (1H, d, J=4 Hz), 5,47-5,57 (4H, m), of 5.85 (1H, DD, J=15, 4 Hz), to 6.57 (1H, DD, J=15, 11 Hz), was 6.73 (1H, d, J=16 Hz), 6,89-of 6.96 (3H, m), 7,34 (1H, d, J=10 Hz), 7,39-7,46 (3H, m), 7,53-to 7.59 (3H, m), 7,81 (1H, d, J=8 Hz), 7,89 (1H,s), 7,95 (1H, s).

IR-spectrum ν max KBr cm-1: 2230, 1726, 1503, 1274, 1257, 1140, 1051, 973.

Mass spectrum m/z (ESI): 734 (M++1).

Specific rotation [α]D25-5,2° (c=1,11, CHCl3).

To a solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[(2-aminoethoxy)methyl]benzoate (219,0 mg, 0,299 mmol)obtained above in ethyl acetate (5 ml) was added hydrogen chloride (4 n solution in ethyl acetate; 67 μl, 0.27 mmol who) and the mixture was stirred at 0° C for 5 minutes, the Solvent is kept at reduced pressure to obtain salts of hydrochloric acid specified in the title target compound (230 mg, quantitative yield) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: to 1.45 (3H, d, J=7 Hz), 3,03 (1H, TT, J=12, 5 Hz), 3,51 (1H, t, J=12 Hz), 3,52 (1H, t, J=12 Hz), 3,93 (2H, s), of 4.05 (1H, q, J=7 Hz), 4,10-4,18 (2H, m), 4,99 (1H, d, J=4 Hz), 5,38 (1H, d, J=14 Hz), 5,42 (1H, d, J=14 Hz), the 5.51 (1H, d, J=14 Hz), 5,67 (1H, d, J=14 Hz), of 5.84 (1H, DD, J=15, 4 Hz), 6,56 (1H, DD, J=15, 10 Hz), 6,72 (1H, d, J=16 Hz), 6,86-to 7.00 (3H, m), 7,32 (1H, DD, J=10, 1 Hz), 7,37-the 7.43 (3H, m), 7,52-7,58 (3H, m), a 7.85 (1H, s), to $ 7.91 (1H, d, J=7 Hz), of 8.09 (1H, s).

IR-spectrum ν max KBr cm-1: 2231, 1724, 1503, 1274, 1257, 1140, 1051, 973.

Mass spectrum m/z (FAB): 734 [M+(free base)+1].

Specific rotation [α]D25-16,1° (c=1,13, CHCl3).

[Example 29]

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[2-(N,N-dimethylamino)-acetoxy]methyl]benzoate (example number 5A-2)

A solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-(hydroxymethyl)benzoate (640,7 mg, 0.95 mmol)obtained in example 17-(4), in dichloromethane (20 ml) was cooled to 0°C and then were added 4-(N,N-dimethylamino)pyridine (254,5 mg, 2.1 mmol), N,N-dimethy the glycine (117,2 mg, to 1.14 mmol) and chloride 2-chloro-1,3-dimethylimidazolidine (256,1 mg of 1.52 mmol). The reaction mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate and then the organic layer was sequentially washed with a saturated aqueous solution of ammonium chloride and saturated aqueous sodium chloride. The solvent is evaporated under reduced pressure, the residue was subjected to chromatography on a column of silica gel (40 g) (eluent: ethyl acetate:methanol=100:3) to obtain the mixture specified in the connection header and 1,3-dimethyl-2-imidazolidinone. The mixture was purified circulating preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm e × 600 mm) and JAIGEL-2H (20 mm e × 600 mm)connected in series for use; solvent, chloroform] to obtain specified in the title target compound (368,1 mg, 51%yield) as a colorless amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: of 1.46 (3H, DD, J=7, 2 Hz), and 2.79 (6H, s), 3,05 (1H, TT, J=11, 5 Hz), with 3.27 (2H, s), 3,51 (1H, t, J=11 Hz), 3,53 (1H, t, J=11 Hz), was 4.02 (1H, q, J=7 Hz), 4,12-is 4.21 (2H, m), 4,99 (1H, d, J=5 Hz), of 5.48 (1H, DD, J=15 and 3 Hz), the 5.51 (2H, s)5,54 (1H, d, J=15 Hz), to 5.85 (1H, DD, J=15, 4 Hz), to 6.57 (1H, DD, J=15, 11 Hz), was 6.73 (1H, d, J=16 Hz), 6,89-of 6.96 (3H, m), 7,34 (1H, DD, J=10, 1 Hz), 7,38-7,42 (2H, m), 7,44 (1H, TD, J=9, 7 Hz), 7,52-to 7.61 (3H, m), 7,79 (1H, d, J=7 Hz), of 7.90 (1H, s), of 7.96 (1H, s).

IR-spectrum ν max KBrcm-1: 2230, 1726, 1503, 1275, 1257, 1140, 1052, 973.

Mass spectrum m/z (ESI):762 (M ++1).

To a solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[2-(N,N-dimethylamino)acetoxy]methyl]benzoate (215,0 mg, 0.28 mmol), obtained above in ethyl acetate (5 ml) was added hydrogen chloride (4 n solution in ethyl acetate; 66 μl, 0.27 mmol) and the mixture was stirred at 0°C for 5 minutes, the Solvent is kept under reduced pressure and the residue was dried in vacuum to obtain salts of hydrochloric acid specified in the title target compound (230 mg, quantitative yield) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: of 1.46 (3H, DD, J=7, 2 Hz), 2,60 (6H, s), 3,05 (1H, TT, J=11, 5 Hz), 3,48 is 3.57 (4H, m), a 4.03 (1H, q, J=7 Hz), 4,13-4,22 (2H, m), 4,99 (1H, d, J=4 Hz), the 5.45 of 5.53 (3H, m), to 5.58 (1H, d, J=14 Hz), to 5.85 (1H, DD, J=15, 4 Hz), to 6.57 (1H, DD, J=15, 10 Hz), 6,74 (1H, d, J=16 Hz), 6.89 in-to 7.00 (3H, m), 7,34 (1H, DD, J=10, 1 Hz), 7,39-7,47 (3H, m), 7,52-7,63 (3H, m), to 7.84 (1H, d, J=9 Hz), of 7.90 (1H, s), of 7.96 (1H, s).

IR-spectrum ν max KBr cm-1: 2230, 1726, 1503, 1275, 1257, 1140, 1051, 973.

Mass spectrum m/z (ESI): 762 [M+(free base)+1].

Specific rotation [α]D25-1,1° (c=1.07, and CHCl3).

[Example 30]

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[2-(4-methyl-1-piperazinil)acetoxy]methyl]benzoate (example number 5A-9)

A solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-(hydroxymethyl)benzoate (1,104 g, and 1.63 mmol)obtained in example 17-(4), in dichloromethane (25 ml) was cooled to 0°C and then were added 4-(N,N-dimethylamino)pyridine (299,1 mg, 2.45 mmol), 2-(4-methyl-1-piperazinil)acetic acid (described in J. Med. Chem., 43, 1493 (2000); 387,3 mg, 2.45 mmol) and 1-ethyl-3-[3-(N,N-dimethylamino)propyl]carbodiimide (625,5 mg, 3,26 mmol). The reaction solution was stirred at room temperature for 4 hours, diluted with dichloromethane and the organic layer was sequentially washed with water and saturated aqueous sodium chloride. The solvent is evaporated under reduced pressure and the residue was subjected to chromatography on a column of silica gel (40 g) (eluent: ethyl acetate:methanol=4:1) to obtain the mixture specified in the header of the target compound and 4-(N,N-dimethylamino)pyridine. The mixture was purified circulating preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm e × 600 mm) and JAIGEL-2H (20 mm e × 600 mm)connected in series for use; solvent, chloroform] to obtain specified in the title target compound (865,2 mg, yield 65%) as a colorless amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: of 1.46 (3H, DD, J=7, 2 Hz)to 2.29 (3H, s), 2,4-2,5 (4H, the Il. C), 2,6-2,7 (4H, user. C)3,05 (1H, TT, J=12, 5 Hz)and 3.31 (2H, s), 3,50 (1H, t, J=12 Hz), 3,53 (1H, t, J=12 Hz)to 4.01 (1H, q, J=7 Hz), 4,12-is 4.21 (2H, m), 4 99 (1H, d, J=4 Hz), the 5.45 to 5.55 (4H, m), of 5.84 (1H, DD, J=15, 4 Hz), to 6.57 (1H, DD, J=15, 10 Hz), was 6.73 (1H, d, J=16 Hz), 6,93 (1H, DD, J=16, 10 Hz), 6,88-7,00 (2H, m), 7,34 (1H, DD, J=11, 1 Hz), 7,27-7,46 (3H, m), 7,53-of 7.60 (3H, m), 7,79 (1H, DD, J=8, 1 Hz), of 7.90 (1H, s), 7,95 (1H, s).

IR-spectrum ν max KBr cm-1: 2230, 1726, 1503, 1275, 1257, 1051, 1140, 973.

Mass spectrum m/z (FAB): 817 (M++1).

Specific rotation [α]D25+0,4° (c=0.99, and CHCl3).

A solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[2-(4-methylpiperazin-1-yl)acetoxy]methyl]benzoate (280 mg, 0,343 mmol)obtained above in ethyl acetate (5 ml) was cooled to 0°C, was added hydrogen chloride (4 n solution in ethyl acetate; 95 μl, 0.38 mmol) and the mixture was stirred at 0°C for 5 minutes, the Solvent is evaporated under reduced pressure and the residue was dried in vacuum to obtain monohydrochloride specified in the title compound (298 mg, quantitative yield) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CD3OD) δ ppm: USD 1.43 (3H, DD, J=7, 1 Hz), 2,87 (3H, s), 2,8-3,4 (8H, usher.), totaling 3.04 (1H, TT, J=11, 5 Hz), 3,48 (1H, t, J=11 Hz), 3,53 (2H, s), of 3.54 (1H, t, J=11 Hz), 4,06 (1H, q, J=7 Hz), 4.04 the-4,08 (2H, m), 4,17 (1H, DDD, J=11, 5, 2 Hz), 5,20 (1H, d, J=4 Hz), 5,46 (1H, d, J=14 Hz), of 5.53 (1H, d, J=14 Hz), to 5.58 (2H, s), to 5.85 (1H, DD, J=15, 4 Hz), to 6.57 (1H, DD, J=15, 10 Hz), 6,79 (1H, d, J=16 Hz, 7,01-7,11 (2H, m), to 7.09 (1H, DD, J=16, 10 Hz), 7,46 (1H, TD, J=8, 1 Hz), 7,50-to 7.61 (3H, m), 7,63 (1H, arcs, J=7, 1 Hz), 7,78 (1H, t, J=8 Hz), 7,86 (1H, DD, J=7, 1 Hz), 7,95 (1H, s), a 8.34 (1H, s).

IR-spectrum ν max KBr cm-1: 2230, 1726, 1503, 1274, 1257, 1140, 1050, 973.

Mass spectrum m/z (FAB): 817 [M+(free base)+1].

Specific rotation [α]D25-1,9° (c=0,97, CHCl3).

A solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[2-(4-methylpiperazin-1-yl)acetoxy]methyl]benzoate (338,5 mg, 0.41 mmol)obtained above in ethyl acetate (5 ml) was cooled to 0°C, was added hydrogen chloride (4 n solution in ethyl acetate; 207 μl, 0.83 mmol) and the mixture was stirred at 0°C for 5 minutes, the Solvent is evaporated under reduced pressure and the residue was dried in vacuum to obtain bishydroxamic specified in the title compound (354 mg, quantitative yield) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, DMSO-d6) δ ppm: to 1.35 (3H, DD, J=7, 2 Hz), was 2.76 (3H, s), 2,82 of 2.92 (2H, usher.), to 2.99 (1H, TT, J=11, 5 Hz), 3,06-and 3.16 (4H, usher.), to 3.41 (2H, user. d, J=15 Hz), of 3.46 (1H, t, J=11 Hz), 3,47 (1H, t, J=11 Hz), 3,65 -3,75 (2H, usher.), with 3.79 (1H, q, J=7 Hz), of 3.96 (1H, DDD, J=11, 5, 2 Hz), 4,07 (1H, DDD, J=11, 5, 2 Hz), of 5.05 (1H, d, J=5 Hz), of 5.39 (1H, d, J=13 Hz), of 5.40 (1H, d, J=14 Hz), 5,49 (1H, d, J=13 Hz), to 5.56 (1H, d, J=14 Hz), 5,88 (1H, DD, J=15, 5 Hz), 6,56 (1H, DD, J=15, 11 Hz), PC 6.82 (1H, d, J=16 Hz), 7,16-7,20 (1H, m), 7,19 (1H, DD, J=16, 11 Hz), 7,31-7,37 (1H, m), 7,49-of 7.55 (1H, is), at 7.55 (1H, TD, J=9, 6 Hz), 7,60 (1H, d, J=7 Hz), to 7.67-7,71 (2H, m), 7,84-7,89 (3H, m), of 7.96 (1H, s), 8,44 (1H, s).

Mass spectrum m/z (FAB): 817 [M+(free base)+1].

Specific rotation [α]D25-3,1° (c=1,87, CHCl3).

[Example 31]

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl]2-[[3-(4-methyl-1-piperazinil)propionyl]oxymethyl]benzoate (example number 5A-19)

A solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-(hydroxymethyl)benzoate (993,3 mg, about 1.47 mmol)obtained in example 17-(4), in dichloromethane (20 ml) was cooled to 0°C and then were added 4-(N,N-dimethylamino)pyridine (358,7 mg, to 2.94 mmol), 3-(4-methyl-1-piperazinil)propionic acid (described in J. Med. Chem., 43, 1493 (2000); 454,8 mg of 2.64 mmol) and 1-ethyl-3-[3-(N,N-dimethylamino)propyl]carbodiimide (619,0 mg of 3.23 mmol). The reaction solution was stirred at room temperature for 2 hours and was diluted with dichloromethane, then the organic layer was sequentially washed with water and saturated aqueous sodium chloride. The solvent is evaporated under reduced pressure and the residue was subjected to chromatography on a column of silica gel (50 g) (eluent: ethyl acetate:methanol=4:1) to obtain the mixture specified in the header zelenogolovaja and 4-(N,N-dimethylamino)pyridine. The mixture was subjected to chromatography on a column of silica gel (50 g) (eluent: ethyl acetate:methanol=4:1) to obtain specified in the title target compound (576,1 mg, yield 47%) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: of 1.46 (3H, DD, J=7, 2 Hz), 2,3-2,5 (4H, usher.), of 2.28 (3H, s), 2,4-2,6 (4H, usher.), 2,61 (2H, t, J=7 Hz), a 2.75 (2H, t, J=7 Hz), 3,05 (1H, TT, J=11, 5 Hz), 3,50 (1H, t, J=11 Hz), 3,53 (1H, t, J=11 Hz), to 4.01 (1H, q, J=7 Hz), 4.04 the-4,20 (2H, m), to 4.98 (1H, d, J=4 Hz), 5,43-5,56 (4H, m)of 5.84 (1H, DD, J=15, 4 Hz), to 6.57 (1H, DD, J=15, 11 Hz), was 6.73 (1H, d, J=15 Hz), 6,88-to 7.00 (3H, m), 7,32-7,46 (4H, m), 7,52-to 7.61 (3H, m), 7,79 (1H, d, J=8 Hz), of 7.90 (1H, s), 7,94 (1H, s).

IR-spectrum ν max KBr cm-1: 2230, 1729, 1615, 1503, 1275, 1257, 1140, 1051, 973.

Mass spectrum m/z (ESI): 831 (M++1).

Specific rotation [α]D25to 1.4° (c=0,91, CHCl3).

A solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl]2-[[3-(4-methyl-1-piperazinil)propionyl]oxymethyl]benzoate (288,9 mg, 0.35 mmol)obtained above in ethyl acetate (5 ml) was cooled to 0°C, was added hydrogen chloride (4 n solution in ethyl acetate; 87 μl, 0.35 mmol) and the mixture was stirred at 0°C for 5 minutes, the Solvent is evaporated under reduced pressure and the residue was dried in vacuum to obtain monohydrochloride specified in the connection header (289,5 mg, yield 95%) as a pale yellow amorphous solid substance.

The Mr spectrum (400 MHz, CDCl3) δ ppm: 1,47 (3H, DD, J=7, 2 Hz), 2,68 (6H, usher.), 2,90 (9H, usher.), 3,05 (1H, TT, J=11, 5 Hz), 3,51 (1H, t, J=11 Hz), of 3.54 (1H, t, J=11 Hz), a 4.03 (1H, q, J=7 Hz), 4,15 (1H, DDD, J=11, 5,2 Hz), 4,19 (1H, DDD, J=11, 5, 2 Hz), 4,99 (1H, d, J=4 Hz), 5,44-5,57 (4H, m), of 5.84 (1H, DD, J=16 and 4 Hz), to 6.57 (1H, DD, J=16, 11 Hz), 6,74 (1H, d, J=16 Hz), 6.89 in-6,95 (2H, m)6,94 (1H, DD, J=16, 11 Hz), 7,34 (1H, DD, J=10, 1 Hz), 7,39-7,47 (3H, m), 7,55 to 7.62 (3H, m), a 7.85 (1H, d, J=8 Hz), 7,89 (1H, s), of 7.97 (1H, s).

IR-spectrum ν max KBr cm-1: 2230, 1729, 1614, 1503, 1273, 1257, 1139, 1050, 973.

Mass spectrum m/z (ESI): 831 [M+(free base)+1].

Specific rotation [α]D25-4,2° (c=1,08, CHCl3).

A solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl]2-[[3-(4-methyl-1-piperazinil)propionyl]oxymethyl]benzoate (260 mg, 0.31 mmol)obtained above in ethyl acetate (5 ml) was cooled to 0°C, was added hydrogen chloride (4 n solution in ethyl acetate; 156 μl, was 0.63 mmol) and the mixture was stirred at 0°C for 5 minutes, the Solvent is evaporated under reduced pressure, and the residue was dried in vacuum to obtain bishydroxamic specified in the title compound (277 mg, yield 98%) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, DMSO-d6) δ ppm: to 1.35 (3H, DD, J=7, 1 Hz), was 2.76 (4H, usher.), 2,98 (1H, TT, J=11, 5 Hz), 3,38 (12H, usher.), of 3.43 (1H, t, J=11 Hz), 3,47 (1H, t, J=11 Hz), 3,80 (1H, q, J=7 Hz), 3,95 (1H, DDD, J=11, 5, 2 Hz), 4,08 (1H, DDD, J=11, 5, 2 Hz), of 5.05 (1H, d, J=5 Hz), 5,7 (1H, d, J=15 Hz), of 5.40 (1H, d, J=14 Hz), 5,46 (1H, d, J=14 Hz), of 5.55 (1H, d, J=15 Hz), 5,88 (1H, DD, J=15, 5 Hz), 6,56 (1H, DD, J=15, 11 Hz), PC 6.82 (1H, d, J=16 Hz), 7,16-7,20 (1H, m), 7,19 (1H, DD, J=16, 11 Hz), 7,33-7,39 (1H, m), 7,50-to 7.59 (2H, m), 7,60 (1H, d, J=8 Hz), to 7.67-7,71 (2H, m), 7,83-7,89 (3H, m), of 7.96 (1H, s), 8,43 (1H, s).

IR-spectrum ν max KBr cm-1: 2230, 1729, 1615, 1503, 1273, 1257, 1139, 1050, 972.

Mass spectrum m/z (ESI): 831 [M(free base)++1].

Specific rotation [α]D25-5,3° (c=1.07, and CHCl3).

[Example 32]

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl]2-[[4-(4-methyl-1-piperazinil)butyryl]oxymethyl]benzoate (example number 5A-29)

A solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-(hydroxymethyl)benzoate (1.07 g, was 1.58 mmol)obtained in example 17-(4), in dichloromethane (20 ml) was cooled to 0°C was added 4-(N,N-dimethylamino)pyridine (386,1 mg, and 3.16 mmol), 4-(4-methyl-1-piperazinil)butane acid (described in J. Med. Chem., 43, 1493 (2000); 529,5 mg, 2,84 mmol) and 1-ethyl-3-[3-(N,N-dimethylamino)propyl]carbodiimide (666,8 mg of 3.48 mmol). The reaction solution was stirred at room temperature for 2 hours, diluted with dichloromethane and then the organic layer was sequentially washed with water and saturated aqueous sodium chloride. Dissolve the ü evaporated under reduced pressure and the residue was subjected to chromatography on a column of silica gel (50 g) (eluent: ethyl acetate:methanol=4:1) to obtain the mixture specified in the header of the target compound and 4-(N,N-dimethylamino)pyridine. The mixture was purified circulating preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm e × 600 mm) and JAIGEL-2H (20 mm e × 600 mm)connected in series for use; solvent, chloroform] to obtain specified in the title target compound (901,1 mg, yield 67%) as a colorless amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: of 1.46 (3H, DD, J=7, 2 Hz), of 1.85 (2H, Quint., J=7 Hz), and 2.27 (3H, s), 2,3-2,6 (8H, usher.), is 2.37 (2H, t, J=7 Hz), a 2.45 (2H, t, J=7 Hz), 3,05 (1H, TT, J=11, 5 Hz), 3,51 (1H, t, J=11 Hz), 3,53 (1H, t, J=11 Hz), to 4.01 (1H, q, J=7 Hz), 4,10-4,20 (2H, m), 4,99 (1H, d, J=4 Hz), and 5.30-5,56 (4H, m)of 5.85 (1H, DD, J=15, 4 Hz), to 6.57 (1H, DD, J=15, 10 Hz), was 6.73 (1H, d, J=15 Hz), 6,88-to 7.00 (3H, m), 7,34 (1H, DD, J=10, 1 Hz), 7,37-7,46 (3H, m), 7,52-of 7.60 (3H, m), 7,79 (1H, d, J=8 Hz), of 7.90 (1H with), to 7.95 (1H, s).

IR-spectrum ν max KBr cm-1: 2230, 1729, 1503, 1357, 1257, 1139, 1051, 973.

Mass spectrum m/z (ESI): 845 (M++1).

Specific rotation [α]D25-1,8° (c=1,06, CHCl3).

A solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl] 2-[[4-(4-methyl-1-piperazinil)butyryl]oxymethyl]benzoate (to 290.5 mg, 0.34 mmol)obtained above in ethyl acetate (5 ml) was cooled to 0°C, was added hydrogen chloride (4 n solution in ethyl acetate; 86 μl, 0.35 mmol) and the mixture is then stirred at 0°C for 5 minutes, the Solvent is kept under reduced pressure to get monolid is ochloride specified in the connection header (305,1 mg, quantitative yield) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: of 1.46 (3H, DD, J=7, 2 Hz), 1,90 (2H, usher.), 2,47 (2H, t, J=7 Hz), 2,6-2,8 (13H, user. d)3,05 (1H, TT, J=11, 5 Hz), 3,51 (1H, t, J=11 Hz), 3,53 (1H, t, J=11 Hz), to 4.01 (1H, q, J=7 Hz), 4,10-to 4.15 (1H, m), 4,18 (1H, DDD, J=11, 5, 2 Hz), 4,99 (1H, d, J=4 Hz), 5,44 (1H, d, J=14 Hz), 5,46-of 5.53 (2H, m), of 5.55 (1H, d, J=15 Hz), to 5.85 (1H, DD, J=15, 4 Hz), to 6.57 (1H, DD, J=15, 11 Hz), 6,74 (1H, d, J=15 Hz), 6.89 in-6,93 (2H, m)6,94 (1H, DD, J=15, 11 Hz), 7,34 (1H, DD, J=10, 1 Hz), 7,40-7,47 (3H, m), 7,54 to 7.62 (3H, m), to 7.84 (1H, d, J=7 Hz), 7,89 (1H, s), of 7.97 (1H, s).

IR-spectrum ν max KBr cm-1: 2230, 1729, 1503, 1274, 1256, 1139, 1051, 973.

Mass spectrum m/z (ESI): 845 [M(free base)++1].

Specific rotation [α]D25-4,5° (c=0,89, CHCl3).

[Example 33]

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl] 5-cyano-2-(hydroxymethyl)benzoate (example number 5A-75)

(1) 4-Methoxybenzyl 2-[(allyloxycarbonyl)oxymethyl]-5-cyanobenzoic

1-Oxo-1,3-dihydroisobenzofuran-6-carbonitrile (3,01 g of 18.9 mmol)obtained in example 5-(2), was dissolved in a mixed solvent (200 ml) of tetrahydrofuran-methanol (3:1) and within 10 min was added an aqueous solution of sodium hydroxide (1,004 n; 17,4 ml of 17.4 mmol). The mixture was stirred at room temperature for 30 min and the solvent GTG is issued under reduced pressure. The obtained residue was dried using a vacuum pump. The obtained solid substance was dissolved in N,N-dimethylformamide (40 ml) was added 4-methoxybenzylamine (2,96 g of 18.9 mmol). The mixture was heated at 70-80°C for 1 hour. After cooling the mixture to 0°C thereto was added dichloromethane (40 ml), then were added 4-(N,N-dimethylamino)pyridine (5,78 g of 47.3 mmol) and allylchloroformate (4,56 g of 37.9 mmol), the mixture is then stirred at this temperature for 30 minutes the Mixture was diluted with ethyl acetate and then washed with water and an aqueous solution of sodium chloride. The resulting mixture was dried over anhydrous magnesium sulfate and the solvent drove under reduced pressure to obtain an oily residue. The residue was subjected to chromatography on a column of silica gel (100 g) (eluent: hexane:ethyl acetate=3:1) to obtain the specified title compound (3.11 g, yield 43%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: a 3.83 (3H, s), of 4.67 (2H, user. d, J=6 Hz), 5,31 (2H, s), 5,31 (1H, d, J=10 Hz), of 5.39 (1H, DD, J=17, 1 Hz), to 5.66 (2H, s), 5,96 (1H, DDT, J=17, 10, 6 Hz), 6,93 (2H, d, J=9 Hz), 7,39 (2H, d, J=9 Hz), of 7.70 (1H, d, J=8 Hz), 7,81 (1H, DD, J=8, 1 Hz), 8,30 (1H, d, J=1 Hz).

IR-spectrum ν max CHCl3cm-1: 2236, 1725, 1296, 1256.

Mass spectrum m/z (FAB): 381 (M+).

(2) 2-[(Allyloxycarbonyl)oxymethyl]-5-cyanobenzoic acid

A mixture of 4-methoxybenzyl 2-[(allyloxycarbonyl)oxymethyl]-5-zenobe is Tata (3 g, 7.9 mmol) and anisole (3.5 g) was cooled to 0°C and added triperoxonane acid (10 ml). The mixture was stirred at room temperature for 15 min, diluted with toluene and the solvent is kept at reduced pressure. The residue was subjected to chromatography on a column of silica gel (35 g) (eluent: dichloromethane:ethyl acetate=1:1) to obtain specified in the connection header (1,95 g, yield 95%) as a colourless solid (TPL 81-83°C).

NMR-spectrum (400 MHz, CDCl3) δ ppm: 4,70 (2H, dt, J=6, 1 Hz), 5,32 (1H, DD, J=10, 1 Hz), 5,41 (1H, DD, J=17, 1 Hz), 5,71 (2H, s), 5,97 (1H, DDT, J=17, 10, 6 Hz), 7,89 (1H, d, J=8 Hz), of 7.90 (1H, DD, J=8, 1 Hz), 8,44 (1H, d, J=1 Hz).

IR-spectrum ν max KBr cm-1: 2236, 1754, 1700, 1278, 1251.

Mass spectrum m/z (FAB): 262 (M++1).

(3) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl]2-[(allyloxycarbonyl)oxymethyl]-5-cyanobenzoic

2-[(Allyloxycarbonyl)oxymethyl]-5-cyanobenzoic acid (1.6 g, 6.12 mmol)obtained in example 33-(2), was dissolved in dichloromethane (40 ml) was added N,N-dimethylformamide (0.05 ml) and oxacillin (2 g). The mixture was stirred at room temperature for 1 hour, then was diluted with toluene and the solvent drove under reduced pressure to obtain crude 2-[(allyloxycarbonyl)oxymethyl]-5-cyanobenzoate.

The reaction was carried out for the determination of the e, similar to that described in example 13-(2), using 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (2,56 g, 4.7 mmol)described in reference example 1, hydride sodium (55% dispersion in mineral oil; 246,7 mg, the 5.65 mmol) and 2-[(allyloxycarbonyl)oxymethyl]-5-cyanobenzoate obtained above. The obtained crude product was subjected to chromatography on a column of silica gel (50 g) (eluent: ethyl acetate:hexane=1:1˜4:1) mixture (2.67 g) specified in the connection header and 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (original substance). The number specified in the connection header was about 80%.

NMR-spectrum (400 MHz, CDCl3selected signals related to the specified header connection) δ ppm: 1,45 (3H, DD, J=7, 2 Hz), to 3.02 (1H, TT, J=11, 5 Hz), of 3.54 (1H, t, J=11 Hz), of 4.00 (1H, q, J=7 Hz), 4,10-4,19 (2H, m), of 4.67 (2H, m), free 5.01 (1H, d, J=4 Hz), 5,31 (1H user. d, J=10 Hz), from 5.29 (1H, DD, J=17, 1 Hz), 5,49 (2H, s), of 5.55 (1H, d, J=14 Hz), 5,62 (1H, d, J=14 Hz), by 5.87 (1H, DD, J=15, 4 Hz), 5,95 (1H, DDT, J=17, 10, 6 Hz), to 6.58 (1H, d, J=15, 11 Hz), 6.73 x (1H, d, J=15 Hz), 6.90 to-of 6.96 (3H, m), 7,32-of 7.60 (3H, m), to 7.77 (1H, t, J=9 Hz), 7,87 (1H, DD, J=8, 2 Hz), of 7.90 (1H, s), 7,98 (1H, s), 8,18 (1H, d, J=1 Hz).

Mass spectrum m/z (FAB): 786 (M++1).

(4) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dio the San-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl]5-cyano-2-(hydroxymethyl)benzoate (specified in the header of the target connection)

Was carried out by the procedure described in Example 11-(4), using a mixture (583,2 mg, the mixing ratio of about 8:2) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl]2-[(allyloxycarbonyl)-oxymethyl]-5-cyanobenzoate and 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate obtained in example 33-(3), bis(triphenylphosphine)dichloropalladium (13 mg) and anti-hydride (184 mg, to 0.63 mmol). The crude product was subjected to chromatography on a column of silica gel (50 g) (eluent: ethyl acetate:hexane=1:1˜4:0) to obtain specified in the title target compound (293,6 mg, yield 56%) as a colorless amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: of 1.46 (3H, DD, J=7, 2 Hz), 3,03 (1H, TT, J=12, 5 Hz)to 3.09 (1H, t, J=7 Hz), 3,55 (2H, t, J=12 Hz), was 4.02 (1H, q, J=7 Hz), 4,14-is 4.21 (2H, m), 4,91 (2H, t, J=7 Hz), free 5.01 (1H, d, J=5 Hz), of 5.50 (1H, d, J=14 Hz), the 5.51 (1H, d, J=14 Hz), 5,86 (1H, DD, J=15, 5 Hz), to 6.58 (1H, DD, J=15, 11 Hz), was 6.73 (1H, d, J=16 Hz), 6.90 to-6,97 (3H, m), 7,33 (1H, DD, J=7, 1 Hz), 7,37 (1H, TD, J=9, 6 Hz), EUR 7.57 (1H, t, J=8 Hz), to 7.77 (1H, d, J=8 Hz), 7,86-7,88 (2H, m), of 7.96 (1H, s), 8,18 (1H, s).

IR-spectrum ν max KBr cm-1: 2232, 1730, 1504, 1276, 1142, 1049.

Mass spectrum m/z (FAB): 702 (M++1).

Specific rotation [α]D25-21,9° (c=0,98, CHCl3).

[Example 34]

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-CFT is henyl)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[(4-methyl-1-piperazinil)-acetoxy]ethylcarbamate (example 4A-13)

(1) 2-Chloroethyl (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propylboronic

A mixture of potassium hydride (30% dispersion in mineral oil; 739 mg, of 5.53 mmol) and tetrahydrofuran (8 ml) was cooled to 0°C was added 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (1,00 g of 1.84 mmol)described in reference example 1 under stirring, then the mixture was stirred at room temperature for 30 minutes the Mixture was cooled to 0°C and then thereto was added with stirring a mixture of 2-chloroethylphosphonic (315 mg, 2.21 mmol) and tetrahydrofuran (1.5 ml). The resulting mixture was stirred at room temperature for 18 hours. After cooling, the mixture was distributed between ethyl acetate and water and the organic layer was sequentially washed with water and saturated aqueous sodium chloride and the solvent drove under reduced pressure to obtain an oily residue. The residue was subjected to column chromatography (eluent: ethyl acetate:hexane=1:1) to obtain the specified title compound (1.06 g, yield 88%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: to 1.35 (3H, DD, J=7, 2 Hz), 3.04 from (1H, m), 3,50(1H, t, J=11 Hz), 3,51 (1H, t, J=11 Hz), to 3.73 (2H, t, J=6 Hz), 3,88 (1H, q, J=7 Hz), 4,19 (1H, DDD, J=11, 4, 2 Hz), 4,32 (1H, DDD, J=11, 4, 2 Hz), 4,33-to 4.81 (2H, m), to 4.98 (1H, d, J=5 Hz), are 5.36 (1H, d, J=15 Hz), of 5.40 (1H, d, J=15 Hz), 5,86 (1H, DD, J=15, 4 Hz), to 6.58 (1H, DD, J=15, 11 Hz), 6,72 (1H, d, J=15 Hz), 6,76-of 6.96 (3H, m), 7,33 (1H, DD, J=11, 2 Hz), 7,39 (1H, d, J=8 Hz), 7,44-7,50 (1H, m), EUR 7.57 (1H, t, J=8 Hz), 7,95 (1H, s), of 7.97 (1H, s).

Mass spectrum m/z (FAB): 649 (M++1).

The mass spectrum of the high-resolution m/z (FAB; adding an aqueous solution of sodium iodide): Calculated for C30H28O5N4ClF3SNa (M++Na): 671,1318. Found: 671,1329.

(2) 2-(4-methyl-1-piperazinil)acetate cesium

A solution of 2-(4-methyl-1-piperazinil)acetic acid (described in J. Med. Chem., 43, 1493 (2000); 2,5 g, 16 mmol) in water (30 ml) was cooled to 0°C and added to it with stirring cesium carbonate (2.6 g, 7.9 mmol), then the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain specified in the connection header (4,49 g, yield 98%) as a pale yellow solid.

(3) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[(4-methyl-1-piperazinil)acetoxy]ethylcarbonate (specified in the header of the target connection)

A solution of 2-(4-methyl-1-piperazinil)of cesium acetate (939 mg, 6.0 mmol)obtained in example 34-(2), in N,N-dimethylformamide (5 ml) was cooled to 0°C and added the ri stirring, a solution of 2-chloroethyl (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl]carbonate (700 mg, 1.1 mmol)obtained in 34-(1)in N,N-dimethylformamide (5 ml) and 18-crown-6 (910 mg, 3.2 mmol). The mixture was stirred at room temperature for 1 hour and then heated to 40°C and was stirred for 3 hours. According to the method similar to that described in example 34-(1), the reaction mixture was treated with obtaining an oily residue. The residue was purified circulating preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm e × 600 mm) and JAIGEL-2H (20 mm e × 600 mm)connected in series for use; solvent, chloroform] to obtain specified in the title compound (568 mg, yield 68%) as a pale yellow oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: of 1.34 (3H, DD, J=7, 2 Hz), 2,28 (3H, s), 2,48 (4H, users), 2,61 (4H, bs), to 3.02 (1H, m), 3,24 (1H, d, J=16 Hz), with 3.27 (1H, d, J=16 Hz), 3,48 (1H, t, J=11 Hz), 3,49 (1H, t, J=11 Hz), 3,85 (1H, kV, J=7 Hz), 4,17 (1H, DDD, J=11, 5, 2 Hz), 4,27-of 4.44 (5H, m), equal to 4.97 (1H, d, J=5 Hz), are 5.36 (1H, d, J=15 Hz), of 5.39 (1H, d, J=15 Hz), of 5.84 (1H, DD, J=15, 4 Hz), to 6.57 (1H, DD, J=16, 11 Hz), 6,74 (1H, d, J=17 Hz), 6,86-to 7.00 (3H, m), 7,33 (1H, DD, J=10, 2 Hz), 7,39-of 7.48 (2H, m), EUR 7.57 (1H, t, J=7 Hz), 7,95 (1H, s), to 7.99 (1H, s).

Mass spectrum m/z (FAB): 771 (M++1).

The mass spectrum of the high-resolution m/z (FAB): Calculated for C37H42O7N6F3S (M++1): 771,2788. Found: 771,2751.

The compound (565 mg, 0.73 mmol), obtained above, was dissolved in ethyl acetate (12 ml) and the solution was cooled to 0°C, then added with stirring, chloroptera the (4 N. the solution in ethyl acetate; 183 μl, 0.73 mmol). The solvent drove under reduced pressure to obtain an oily residue. The residue was dissolved in water (18 ml) at 0°C and the solution was liofilizovane obtaining hydrochloride specified in the title target compound (590 mg, yield 92%) as a pale yellow solid.

NMR-spectrum (400 MHz, DMSO-d6) δ ppm: 1,24 (3H, d, J=7 Hz), 2,25-3,20 (11H, m), 2.91 in (1H, m), 3,28-to 3.36 (2H, m), 3,42 (1H, t, J=11 Hz), 3,44 (1H, t, J=11 Hz), of 3.57 (1H, q, J=7 Hz), Android 4.04 (1H, DDD, J=11, 5, 2 Hz), 4,13 (1H, DDD, J=11, 5, 2 Hz), 4,28 (2H, t, J=3 Hz), 4,35 (2H, t, J=3 Hz), to 5.03 (1H, d, J=4 Hz), 5,27 (1H, d, J=14 Hz), the 5.45 (1H, d, J=14 Hz), by 5.87 (1H, DD, J=15, 4 Hz), to 6.57 (1H, DD, J=15, 10 Hz), PC 6.82 (1H, d, J=16 Hz), 7,16-7,22 (2H, m), 7,33 (1H, DDD, J=13, 6, 2 Hz), 7,45-7,51 (1H, m), 7,68 (1H, DD, J=8, 2 Hz), 7,84-of 7.90 (2H, m), with 8.05 (1H, s), to 8.45 (1H, s), 9,71 (1H, user. C).

IR-spectrum ν max KBr cm-1: 2230, 1751, 1615, 1504.

Mass spectrum m/z (FAB): 771 (M++1).

[Example 35]

Disodium [4-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-3-furyl]methyl phosphate (disodium salt of example number 5C-18)

(1) [4-[(tert-Butyldimethylsilyl)oxymethyl]-3-furyl]methanol

According to the method similar to that described in example 21-(2), 3,4-furandione (described in J. Org. Chem., 65, 6153 (2000); 3,4 g of 26.5 mmol) was subjected to interaction with imidazole (1.80 g of 26.4 mmol who) and tert-butylimidazolium (4,00 g, of 26.5 mmol) in tetrahydrofuran (50 ml) and the reaction mixture was treated with a mixture specified in the title compound, 3,4-furandione and 3,4-bis[(tert-butyldimethylsilyl)oxymethyl]furan. The mixture was subjected to chromatography on a column of silica gel (50 g) (eluent:ethyl acetate:hexane=3:17˜4:16) to obtain specified in the connection header (3,20 g, yield 50%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 0,125 (6H, s), 0,916 (9H, s)3,177 (1H, t, J=6 Hz), 4,522 (2H, d, J=6 Hz), 4,640 (2H, s)7,317 (1H, s)7,371 (1H, s).

IR-spectrum ν max CHCl3cm-1: 3449, 2956, 2931, 2859, 1471, 1258, 1040.

Mass spectrum m/z (FAB): 243 (M++1).

(2) Diallyl[4-[(tert-butyldimethylsilyl)oxymethyl]-3-furyl]methylphosphate

[4-[(tert-Butyldimethylsilyl)oxymethyl]-3-furyl]methanol (174 mg, to 0.72 mmol)obtained in example 35-(1)were subjected to interaction in dichloromethane (3 ml) with tetrazole (61 mg, 0.87 mmol), bis(allyloxy)(diisopropylamino)phosphine (265 mg, of 1.08 mmol) and tert-butylhydroperoxide (80% solution of di-tert-Butlerova; Merck; 135 mg, 1.2 mmol), according to the method similar to that described in example 1-(10). The oily residue obtained by extraction was subjected to chromatography on a column of silica gel (5 g) (eluent: ethyl acetate:hexane=1:4) to obtain the specified title compound (273 mg, yield 93%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl 3) δ ppm: 0,083 (6H, s), 0,908 (9H, s), 4,55-4,55 (4H, m)4,627 (2H, s)5,003 (2H, d, J=8, 2 Hz), 5,328 (2H, DD, J=10,4, 1.2 Hz), 5,340 (1H, dddd, J=17 and 1.5, and 1.5, 1.2 Hz), 5,912 (2H, DDT, J=17, 10, 5 Hz), KZT 7,328 (1H, s)7,447 (1H, s).

IR-spectrum ν max CHCl3cm-1: 2956, 2931, 1258, 1010.

Mass spectrum m/z (FAB): 403 (M++1).

(3) Diallyl[4-[(hydroxymethyl)-3-furyl]methylphosphate

Diallyl [4-[(tert-butyldimethylsilyl)oxymethyl]-3-furyl]-methyl phosphate obtained in example 35-(2), was dissolved in tetrahydrofuran (3 ml) was added a mixture of tetrabutylammonium fluoride (1 n solution in tetrahydrofuran; of 1.34 ml of 1.34 mmol) and acetic acid (48 mg, 0.80 mmol) under stirring in an ice bath. The reaction mixture was stirred at room temperature for 2 hours and then was distributed between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent drove under reduced pressure to obtain a residue. The residue was subjected to chromatography on a column of silica gel (5 g) (eluent: ethyl acetate:hexane=3:2˜1:0) to obtain the specified title compound (148 mg, yield 76%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 3,168 (1H, t-like, J=around 6 Hz), 4,523 (4H, dt, J=7, 1.2 Hz), 4,580 (2H, d, J=6 Hz), 5,050 (2H, d, J=9.5 Hz), 5,255 (2H, DD-like, J=10, about 1.2 Hz, 5,350 (2H, dt-like, J=17, about 1.2 Hz), 5,917 (2H, DDT, J=17, 10, 6 Hz), 7,414 (1H, s)7,483 (1H, s).

IR-spectrum ν max CHCl3cm-1: 3401, 1602, 1554, 1462, 1424, 1267, 1022.

Mass spectrum m/z (FAB): 289 (M++1).

(4) Diallyl(4-formyl-3-furyl)methyl phosphate

Diallyl[4-[(hydroxymethyl)-3-furyl]methyl phosphate (113 mg, 0,39 mmol)obtained in example 35-(3), was dissolved in dichloromethane (2 ml) and cooled with ice was added activated manganese dioxide (0.52 g, 6.0 mmol), then the mixture was stirred at room temperature for 8 hours. The resulting mixture was left overnight (14 hours) and then added an additional amount of manganese dioxide (40 mg, 0.46 mmol). The mixture was stirred at room temperature for 1.5 hours, diluted with ethyl acetate and held by vacuum filtration to remove solids. The filtrate was concentrated under reduced pressure and the obtained residue was subjected to chromatography on a column of silica gel (3 g) (eluent: ethyl acetate:hexane=3:2˜1:0) to obtain the specified title compound (101 mg, yield 90%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 4,569 (4H, DD-like, J=7, 6 Hz), 5,245 (2H, DD-like, J=6, 1 Hz), 5,259 (2H, DD-like, J=11, 1 Hz), 5,369 (2H, DD-like, J=17, 1 Hz), 5,943 (2H, d, J=17, 11, 6 Hz), 7,569 (1H, user. C)8,046 (1H, d, J=1.6 Hz), 9,971 (1H, s).

IR-spectrum ν max CHCl3cm-1: 1689,1544, 1273, 1147, 1027.

Mass spectrum m/z (EI): 287 (M++1).

(5) 4-[[Bis(allyloxy)phosphoryl]oxymethyl]-3-francebuy acid

Diallyl (4-formyl-3-furyl)methylphosphate (97 mg, 0.34 mmol)obtained in example 35-(4), and 2-methyl-2-butene (1.18 g, to 19.9 mmol) was dissolved in tert-butyl alcohol (2,70 ml) and then with stirring in an ice bath was added a solution of sodium chlorite (122 mg, 1.35 mmol) and the dihydrate of sodium dihydrophosphate (to 1.034 g, 6,76 mmol)dissolved in water (1.2 ml). The mixture was stirred for 2 hours at her spontaneous heating to room temperature and distributed between ethyl acetate and aqueous solution of sodium chloride, then the organic layer was dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The residue was subjected to chromatography on a column of silica gel (2 g) (eluent: ethyl acetate) to obtain the specified title compound (74 mg, yield 72%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 4,572 (4H, DD-like, J=7, 6 Hz), a 5.25 (4H, d-like, J=9 Hz), 5,367 (2H, DD-like, J=17 and 1.4 Hz), 5,940 (2H, DDT, J=17, 10, 6 Hz), 7,533 (1H, d, J=about 1.4 Hz), 8,059 (1H, d, J=1.7 Hz).

IR-spectrum ν max CHCl3cm-1: 1736, 1697, 1549, 1269, 1149, 1029.

Mass spectrum m/z (EI): 303 (M++1).

(6) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-t is eazol-1-yl)methyl]propyl 4-[[bis(allyloxy)phosphoryl]oxymethyl]-3-furoate

4-[[Bis(allyloxy)phosphoryl]oxymethyl]-3-frankenboob acid (500 mg, of 1.65 mmol)obtained in example 35-(5), was dissolved in dichloromethane (10 ml) was added N,N-dimethylformamide (0,03 ml) and oxacillin (0.7 g, 5.5 mmol). The mixture was stirred at room temperature for 1 hour and was added toluene, and the solvent is then drove away under reduced pressure to obtain crude 4-[[bis(allyloxy)phosphoryl]oxymethyl]-3-frailcare.

According to the method similar to that described in example 13-(2)was subjected to the reaction of 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (690,5 mg of 1.27 mmol)described in reference example 1, sodium hydride (55% dispersion in mineral oil; to 66.5 mg, of 1.52 mmol) and the crude 4-[[bis(allyloxy)phosphoryl]oxymethyl]-3-frailcare and the reaction mixture was treated with obtaining after extraction is specified in the header connection in the form of crude oil. The crude product was subjected to chromatography on a column of silica gel (30 g) (eluent: ethyl acetate:hexane=2:1˜9:1) to obtain specified in the connection header (740,8 mg, yield 70%) as a colorless amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: USD 1.43 (3H, DD, J=7, 2 Hz), 3,05 (1H, TT, J=11, 5 Hz), 3,53 (2H, t, J=11 Hz), of 3.96 (1H, q, J=7 Hz), 4,14-4,22 (2H,m), a 4.53 (4H, user. t, J=7 Hz), free 5.01 (1H, d, J=5 Hz), 5,10-by 5.18 (2H, m), 5.25-inch (2H, d, J=10 Hz), to 5.35 (2H, DD, J=17, 1 Hz), of 5.40 (1H, DD, J=15 and 3 Hz), vs. 5.47 (1H, d, J=15 Hz), to 5.85 (1H, DD, J=15, 5 Hz), of 5.92 (2H, DDT, J=17, 10, 5 Hz), to 6.58 (1H, DD, J=15, 11 Hz), 6,74 (1H, d, J=16 Hz), 6,88-6,93 (2H, m), 6,93 (1H, DD, J=16, 11 Hz), 7,32-7,37 (2H, m), 7,40 (1H, DD, J=8, 1 Hz), 7,56-to 7.59 (2H, m), 7,89 (1H, s), 7,92 (2H, s).

IR-spectrum ν max KBr cm-1: 2230, 1727, 1615, 1504, 1276, 1258, 1143, 1051, 1021, 973.

Mass spectrum m/z (FAB): 827 (M++1).

(7) Disodium [4-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-3-furyl]methyl phosphate (specified in the header of the target connection)

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 4-[[bis(allyloxy)phosphoryl]-oxymethyl]-3-furoate (740 mg, 0,895 mmol)obtained in example 35-(6), was dissolved in dichloromethane (20 ml) and with stirring was added tetrakis(triphenylphosphine)palladium (31 mg, or 0.027 mmol) and pyrrolidine (1.27 g, to 17.9 mmol) at 0°C in an atmosphere of nitrogen gas. The mixture was heated to room temperature, was stirred for 1 hour, diluted with toluene and the solvent is kept at reduced pressure. The residue was subjected to column chromatography with reversed phase using Cosmosil 75 C18-PREP (Nacalai Tesque, Inc.; 30 g) (eluent: water:acetonitrile=3:1˜7:3). The fractions obtained were concentrated and the OS is atok were subjected to treatment with cation exchange resin (Dowex 50W-8X, in the sodium form, obtained using 1 N. aqueous sodium hydroxide solution; 5 ml) (eluent:water). The collected fractions were concentrated under reduced pressure and was liofilizovane obtaining specified in the title target compound (exports, as against 618.5 mg, yield 87%) as a colorless amorphous solid substance.

NMR-spectrum (400 MHz, CD3OD) δ ppm: to 1.38 (3H, DD, J=7, 2 Hz), of 3.07 (1H, TT, J=11, 5 Hz), of 3.54 (1H, t, J=11 Hz), 3,55 (1H, t, J=11 Hz), of 4.00 (1H, q, J=7 Hz), 4,16 (2H, DD, J=11, 5 Hz), to 4.98 (1H, DDD, J=15, 6, 1 Hz), to 5.03 (1H, DDD, J=15, 6, 1 Hz), of 5.05 (1H, d, J=4 Hz), the 5.51 (2H, s), 5,88 (1H, DD, J=15, 4 Hz), 6,59 (1H, DD, J=15, 11 Hz), 6,79 (1H, d, J=15 Hz), 6,97-7,06 (2H, m), 7,01 (1H, DD, J=15, 11 Hz), of 7.48-rate of 7.54 (3H, m), 7,69 (1H, q, J=2 Hz), 7,78 (1H, t, J=8 Hz), 7,92 (1H, s), to 7.99 (1H, d, J=1 Hz), of 8.27 (1H, s).

IR-spectrum ν max KBr cm-1: 2231, 1726, 1615, 1503, 1143, 1101, 1052, 975.

Mass spectrum m/z (ESI): 745 [M(not part of sodium)+1]-.

[Example 36]

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[4-(4-methyl-1-piperazinil)-4-oxobutyryl]oxymethyl]benzoate (example number 5A-20)

A solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-(hydroxymethyl)benzoate (1,11 g of 1.64 mmol)obtained in example 17, in dichloromethane (20 ml) was cooled to 0°C and then were added 4-(N,N-dimethylamino)pyridine (400,7 mg of 3.28 mm is l), 4-(4-methyl-1-piperazinil)-4-oxobutanoic acid (described in Bioorg. Med. Chem., 8, 2693 (2000); 590,4 mg, 2,95 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (691,8 mg, 3.61 mmol). The reaction mixture was stirred at room temperature for 1 hour, diluted with dichloromethane and the organic layer was sequentially washed with water and saturated aqueous sodium chloride and the solvent is then drove away under reduced pressure. The residue was subjected to chromatography on a column of silica gel (25 g) (eluent: ethyl acetate:methanol=4:1) mixture (about 1.4 g) is specified in the header of the target compounds and 4-(N,N-dimethylamino)pyridine. Part (0.95 g) the mixture was purified circulating preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm e × 600 mm) and JAIGEL-2H (20 mm e × 600 mm)connected in series for use; solvent, chloroform] to obtain specified in the title target compound (796,0 mg, yield 55%) as a colorless amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: of 1.46 (3H, DD, J=7, 2 Hz), 2,31 (3H, s), a 2.36 (2H, t, J=5 Hz), 2.40 a (2H, t, J=5 Hz), 2,65 of 2.68 (2H, m), was 2.76-2,78 (2H, m), 3,05 (1H, TT, J=11, 5 Hz), 3,48 of 3.56 (4H, m), 3,63 (2H, t, J=5 Hz)to 4.01 (1H, q, J=7 Hz), 4,15 (1H, DDD, J=11, 5, 2 Hz), 4,18 (1H, DDD, J=11, 5, 2 Hz), 4,99 (1H, d, J=4 Hz), 5,46 (1H, d, J=15 Hz), vs. 5.47 (1H, DD, J=15 and 3 Hz), 5,54 (1H, d, J=15 Hz), of 5.55 (1H, d, J=15 Hz), to 5.85 (1H, DD, J=15, 4 Hz), to 6.57 (1H, DD, J=15, 11 Hz), was 6.73 (1H, d, J=16 Hz), 6,88-6,93 (H, m), 6,93 (1H, DD, J=16, 11 Hz), 7,34 (1H, DD, J=10, 1 Hz), of 7.36 was 7.45 (3H, m), 7,56 (1H, d, J=8 Hz), EUR 7.57-of 7.60 (2H, m), 7,79 (1H, d, J=8 Hz), of 7.90 (1H, s), of 7.97 (1H, s).

IR-spectrum ν max KBrcm-1: 2230, 1729, 1645, 1503, 1274, 1257, 1141, 1051.

Mass spectrum m/z (FAB): 859 (M++1).

A solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[4-(4-methyl-1-piperazinil)-4-oxobutyryl]oxymethyl]benzoate (288,6 mg, 0.34 mmol)obtained above in ethyl acetate (5 ml) was cooled to 0°C and was added hydrogen chloride (4 mol/l solution in ethyl acetate; 74 μl, 0.30 mmol) followed by stirring at 0°C for 5 minutes, the Solvent is evaporated under reduced pressure and the residue was dried in vacuum to obtain a mono salt of hydrochloric acid specified in the connection header (296,6 mg, yield 99%) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: of 1.46 (3H, DD, J=7, 2 Hz), 2,6-3,1 (13H, usher.), 3,05 (1H, TT, J=11, 5 Hz), 3,51 (1H, t, J=11 Hz), 3,53 (1H, t, J=11 Hz), 3,9-4,0 (2H, usher.), of 4.00 (1H, q, J=7 Hz), 4,14-is 4.21 (2H, m), 4,99 (1H, d, J=4 Hz), 5,41 (1H, d, J=14 Hz), of 5.48 (1H, DD, J=15 and 3 Hz), of 5.55 (1H, d, J=15 Hz), to 5.57 (1H, d, J=14 Hz), of 5.84 (1H, DD, J=16 and 4 Hz), to 6.57 (1H, DD, J=16, 11 Hz), 6,74 (1H, d, J=15 Hz), 6,88-6,94 (2H, m)6,94 (1H, DD, J=16, 11 Hz), 7,34 (1H, DD, J=10, 1 Hz), 7,39-7,46 (3H, m), 7,56 to 7.62 (3H, m), 7,86 (1H, d, J=7 Hz), 7,88 (1H, s), to 7.99 (1H with).

IR-spectrum ν max KBrcm-1: 2230, 1729, 1652, 1503, 1419, 1274, 1257, 1140, 1051, 974.

Mass spectrum m/z (FAB): 85 [M +(free base)+1].

[Example 37]

Disodium [2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-3-thienyl]methyl phosphate (disodium salt of example number 5C-48)

(1) Methyl 3-(acetoxymethyl)-2-ENOAT

To a solution of methyl 3-(methyl bromide)-2-tenuate (described in Tetrahedron Lett., 22, 5097-5100, (1981); to 6.80 g of 28.9 mmol) in N,N-dimethylformamide (80 ml) was added sodium acetate (7,12 g, and 86.8 mmol). The mixture was stirred at room temperature for 24 hours and then stirred at 40°C for 1 hour. To the reaction mixture was added to phosphate buffer solution (pH 7, 100 ml) and product was extracted with ethyl acetate. The organic layer was washed three times with water and the solvent drove away under reduced pressure. The residue was subjected to chromatography on a column of silica gel (150 g) (eluent:ethyl acetate:hexane=1:10˜1:1) to obtain specified in the connection header (4,89 g, yield 79%) as a colourless solid (TPL 42-43°C).

NMR-spectrum (400 MHz, CDCl3) δ ppm: 2,13 (3H, s)to 3.89 (3H, s)5,49 (2H, s), 7,14 (1H, d, J=5 Hz), of 7.48 (1H, d, J=5 Hz).

IR-spectrum ν max KBr cm-1: 1742, 1707, 1439, 1416, 1353, 1261, 1249, 1229.

Mass spectrum m/z (EI): 214 (M+).

(2) Methyl 3-(hydroxymethyl)-2-ENOAT

To a solution of methyl 3-(acetoxymethyl)-2-tenuate (4,89 g of 22.8 mmol)obtained in example 37-(1)in methanol (60 ml) was added potassium carbonate (157,7 mg, to 1.14 mmol) and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added to phosphate buffer solution (pH 7, 20 ml) and the methanol evaporated under reduced pressure. The product was extracted with ethyl acetate and the solvent is then evaporated under reduced pressure. The obtained oily residue was subjected to chromatography on a column of silica gel (90 g) (eluent: ethyl acetate:hexane=1:2) to obtain the specified title compound (3.94 g, quantitative yield) in the form of needle-shaped crystals (TPL 35-36°C).

NMR-spectrum (400 MHz, CDCl3) δ ppm: of 3.78 (1H, t, J=7 Hz), 3,91 (3H, s), 4,84 (2H, d, J=7 Hz), 7,10 (1H, d, J=5 Hz), 7,47 (1H, d, J=5 Hz).

IR-spectrum ν max KBr cm-1: 1710, 1536, 1438, 1417, 1269, 1080.

Mass spectrum m/z (EI): 172 (M+).

(3) 4-Methoxybenzyl 3-[[bis(allyloxy)phosphoryl]-oxymethyl]-2-ENOAT

Methyl 3-(hydroxymethyl)-2-ENOAT (3.03 g, 17.6 mmol)obtained in 37-(2), was dissolved in a mixed solvent (tetrahydrofuran (20 ml) and methanol (5 ml)) was added sodium hydroxide (1,004 N. aqueous solution; 16,1 ml, 16.2 mmol). The mixture was stirred at room temperature for 1 hour, heated to 50°C and stirred for 1 hour. The solvent viparis is whether under reduced pressure to obtain a solid residue. The residue was dissolved in N,N-dimethylformamide (30 ml) was added 4-methoxybenzylamine (2,75 g, 17.6 mmol). The mixture was stirred at 70°C for 1.5 hours, then was cooled to 0°C and added to it dichloromethane (30 ml). To the mixture was added tetrazole (is 3.08 g, to 44.0 mmol) and bis(allyloxy) (aminobutiramida-amino)phosphine (described in Tetrahedron Lett., 30, 4219 (1989); 6,47 g of 26.4 mmol) and the resulting mixture was stirred at this temperature for 30 min, and then to the mixture was added methanol (0.5 ml) followed by stirring for another 5 minutes To the reaction mixture was added tert-butylhydroperoxide (80% solution of di-tert-butylperoxide; Merck; 2.7 g, 24 mmol) and the mixture was stirred for 30 min and then thereto was added an aqueous sodium hydrogen carbonate solution and aqueous sodium thiosulfate solution, then the product was extracted with ethyl acetate. The organic layer was washed three times with water and the solvent drove away under reduced pressure. The obtained oily residue was subjected to chromatography on a column of silica gel (100 g) (eluent: ethyl acetate:hexane=1:2˜3:2) to obtain the specified title compound (2.8 g, yield 36%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 3,81 (3H, s)4,55 (4H, t, J=7 Hz), 5,23 is 5.28 (2H, m), a 5.25 (2H, s), 5,33-of 5.40 (2H, m), vs. 5.47 (2H, d, J=8 Hz), of 5.92 (2H, DDT, J=17, 11, 6 Hz), make 6.90 (2H, d, J=9 Hz), 7,27 (1H, d, J=5 Hz), 7,37 (2H, d, J=9 Hz), of 7.48 (1H, d, J=5 Hz).

IR-spectrum ν max CHCl3cm-1 : 1705, 1613, 1516, 1424, 1267, 1250, 1035, 989.

Mass spectrum m/z (FAB): 439 (M++1).

(4) 3-[[Bis(allyloxy)phosphoryl]oxymethyl]-2-Tenova acid

A mixture of 4-methoxybenzyl 3-[[bis(allyloxy)phosphoryl]-oxymethyl]-2-tenuate (2,79 g, 6,36 mmol)obtained in 37-(3), and anisole (4 g) was cooled to 0°C and added triperoxonane acid (10 ml). The mixture was heated to room temperature and left for 20 min, and then to the mixture was added toluene followed by evaporation of the solvent under reduced pressure. The oily residue was subjected to chromatography on a column of silica gel (25 g) (eluent: ethyl acetate:dichloromethane=1:1) to obtain specified in the connection header (of 1.57 g, yield 78%) as oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 4,59 (4H, m), of 5.26 (2H, user. d, J=10 Hz), lower than the 5.37 (2H, user. d, J=17 Hz), of 5.53 (2H, d, J=8 Hz), 5,94 (2H, DDT, J=17, 10, 6 Hz), 7,28 (1H, d, J=5 Hz), 7,54 (1H, d, J=5 Hz).

IR-spectrum ν max CHCl3cm-1: 1679, 1543, 1432, 1273, 1033, 989.

Mass spectrum m/z (FAB): 319 (M++1).

(5) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 3-[[bis(allyloxy)phosphoryl]oxymethyl]-2-ENOAT

To a solution of 3-[[bis(allyloxy)phosphoryl]oxymethyl]-2-tenevoi acid (533 mg, by 1.68 mmol)obtained in 37(4), in dichloromethane (10 ml) was added N,N-dimethylformamide (0,02 ml) is oxalicacid (0.7 g). The mixture was stirred at room temperature for 30 min and after addition of toluene, the solvent is evaporated under reduced pressure to obtain crude 3-[[bis(allyloxy)phosphoryl]oxymethyl]-2-trailhead.

A solution of 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (699,1 mg, 1,29 mmol)described in reference example 1, 1,2-dimethoxyethane (10 ml) was cooled to 0°C, was added sodium hydride (55% dispersion in mineral oil; 67.5 mg, 1.55 mmol) and the resulting mixture was stirred at room temperature for 3 hours. To the mixture was added a solution of the crude 3-[[bis(allyloxy)phosphoryl]oxymethyl]-2-troillard, obtained above, in 1,2-dimethoxyethane (2 ml) and the mixture was stirred at room temperature for 20 min and cooled to 0°C, then to stop the reaction, to the reaction mixture was added to phosphate buffer solution (pH 7) and the product was extracted with ethyl acetate. The crude product was subjected to chromatography on a column of silica gel (40 g) (eluent: ethyl acetate:hexane=3:2˜5:1) to obtain specified in the connection header (520,6 mg, yield 48%) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,45 (3H, DD, J=7, 2 Hz), 3,12 (1H, TT, J=11, 5 Hz), 3,53 (1H, t, J=11 Hz), 3,55 (1H, t, J=11 Hz), to 3.92 (1H, q, J=7 Hz), 4,194,28 (2H, m), 4,55-4,59 (4H, m), 5,02 (1H, d, J=4 Hz), a 5.25 (2H, DD, J=10, 1 Hz), 5,34-5,48 (6H, m), by 5.87 (1H, DD, J=16 and 4 Hz), 5,94 (2H, DDT, J=17, 11, 5 Hz), 6,59 (1H, DD, J=16, 11 Hz), 6,74 (1H, d, J=15 Hz), 6,88-6,93 (2H, m)6,94 (1H, DD, J=15, 11 Hz), 7,33 (1H, d, J=15 Hz), 7,33-to 7.35 (1H, m), 7,39-7,46 (2H, m), 7,55 (1H, d, J=5 Hz), EUR 7.57 (1H, t, J=8 Hz), 7,86 (1H, s), to $ 7.91 (1H, s).

IR-spectrum ν max CHCl3cm-1: 2233, 1711, 1616, 1504, 1420, 1276, 1259, 1140, 1035, 991.

Mass spectrum m/z (FAB): 843 (M++1).

(6) Disodium 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-3-thienyl]methyl phosphate (specified in the header of the target connection)

A solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 3-[[bis(allyloxy)phosphoryl]oxymethyl]-2-tenuate (500 mg, 0,593 mmol)obtained in 37-(5), in dichloromethane (20 ml) was cooled to 0°C and was added tetrakis(triphenylphosphine)palladium (20.6 mg, 1,78×10-2mmol) and pyrrolidine (0.84 g, to 11.9 mmol) in an atmosphere of nitrogen gas. The mixture was stirred at room temperature for 30 min and then was added toluene followed by evaporation of the solvent under reduced pressure. The oily residue was subjected to column chromatography with reversed phase using Cosmosil 75 C18-PREP (Nacalai Tesque, Inc.; 35 g) (eluent: water:acetonitrile=3:1˜7:3). The fractions obtained were concentrated and the people headed the remainder were subjected to treatment with cation exchange resin (Dowex 50W-8X, in the sodium form, prepared using 1 N. aqueous sodium hydroxide solution; 8 ml) (eluent: water). The collected fractions were concentrated under reduced pressure and was liofilizovane obtaining specified in the title target compound (335,6 mg, yield 70%) as a colorless amorphous solid substance.

NMR-spectrum (400 MHz, CD3OD) δ ppm: of 1.41 (3H, DD, J=7, 2 Hz), 3,13 (1H, TT, J=12, 5 Hz), 3,52 (1H, t, J=12 Hz), 3,57 (1H, t, J=12 Hz), 3,99 (1H, q, J=7 Hz), 4,17-to 4.23 (2H, m), of 5.05 (1H, d, J=4 Hz), with 5.22 (1H, DD, J=16, 5 Hz), 5,27 (1H, DD, J=16, 6 Hz), 5,52 (1H, d, J=16 Hz), to 5.56 (1H, d, J=16 Hz), 5,88 (1H, DD, J=15, 4 Hz), 6,60 (1H, DD, J=15, 11 Hz), to 6.80 (1H, d, J=16 Hz), of 6.96-7,06 (2H, m), 7,10 (1H, DD, J=16, 11 Hz), 7,50-7,56 (3H, m), to 7.59 (1H, d, J=5 Hz), a 7.62 (1H, d, J=5 Hz), 7,79 (1H, t, J=8 Hz), of 7.90 (1H, s), compared to 8.26 (1H, s).

IR-spectrum ν max KBr cm-1: 2231, 1708, 1615, 1503, 1419, 1276, 1256, 1141, 1101, 1071, 1053, 975.

Mass spectrum m/z (FAB): 807 (M++1).

[Example 38]

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-[[4-(4-methyl-1-piperazinil)-4-oxobutyryl]oxymethyl]benzoate (example number 5A-105)

A solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-(hydroxymethyl)benzoate (1,38 g, 1.97 mmol)obtained in example 33, in dichloromethane (40 ml) was cooled to 0°C was added 4-(N,N-dimethylamino)pyrid is n (481,3 mg, of 3.94 mmol), 4-(4-methyl-1-piperazinil)-4-oxobutanoic acid (described in Bioorg. Med. Chem., 8, 2693 (2000); 708,0 mg, 3.54 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (830,8 mg, 4,33 mmol). The reaction mixture was stirred at this temperature for 2 hours and was diluted with dichloromethane, then the organic layer was sequentially washed with water and saturated aqueous sodium chloride. The solvent is evaporated under reduced pressure and the obtained residue was subjected to chromatography on a column of silica gel (30 g) (eluent: ethyl acetate:methanol=4:1) to obtain the mixture specified in the title compound and 4-(N,N-dimethylamino)pyridine (the ratio of the components; 6:1, 1,33 g). Part (790,8 mg) the mixture was separated circulation preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm e × 600 mm) and JAIGEL-2H (20 mm e × 600 mm)connected in series for use; solvent, chloroform] to obtain specified in the title target compound (763,0 mg, yield 44%) as a colorless amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,45 (3H, DD, J=7, 2 Hz), is 2.30 (3H, s), is 2.37 (2H, t, J=5 Hz), 2,30 (2H, t, J=5 Hz), 2,67-a 2.71 (2H, m), 2.77-to 2,80 (2H, m), to 3.02 (1H, TT, J=12, 5 Hz), 3,50 (2H, t, J=5 Hz), of 3.54 (1H, t, J=12 Hz), 3,55 (1H, t, J=12 Hz), 3,63 (2H, t, J=5 Hz), was 4.02 (1H, q, J=7 Hz), 4,14-4,19 (2H, m), free 5.01 (1H, d, J=4 Hz), 5,46 (1H, DD, J=15, 2 Hz), the 5.51 (1H, d, J=15 Hz), of 5.53 (1H, d, J=15 Hz), ceiling of 5.60 (1H, d, J=15 Hz), by 5.87 (1H, DD, J=15, 4 Hz), to 6.58(1H, DD, J=15, 10 Hz), was 6.73 (1H, d, J=16 Hz), 6.90 to-of 6.96 (2H, m), 6,93 (1H, DD, J=16, 10 Hz), 7,32-7,37 (2H, m), 7,40 (1H, d, J=8 Hz), EUR 7.57 (1H, t, J=8 Hz), 7,82-7,88 (2H, m), 7,89 (1H, s), 7,95 (1H, s), 8,18 (1H, d, J=1 Hz).

IR-spectrum ν max KBrcm-1: 2232, 1736, 1644, 1616, 1503, 1418, 1258, 1143.

Mass spectrum m/z (FAB): 884 (M++1).

A solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-[[4-(4-methyl-1-piperazinil)-4-oxobutyryl]oxymethyl]benzoate (264,3 mg, 0.30 mmol)obtained above in ethyl acetate (5 ml) was cooled to 0°C and then was added hydrogen chloride (4 mol/l solution in ethyl acetate; 68,8 μl, 0.27 mmol), then the mixture was stirred at 0°C for 5 minutes, the Solvent is evaporated under reduced pressure and the dried residue was dissolved in water (5 ml) and then was liofilizovane with getting mono salt of hydrochloric acid (238,3 mg, yield 87%) specified in the header of the target compound as a colourless solid amorphous substances.

NMR-spectrum (400 MHz, CD3OD) δ ppm: to 1.42 (3H, DD, J=7, 1 Hz), and 2.79 (4H, s), 2,82 (3H, s), 3,01 (1H, TT, J=11, 4 Hz), is 3.08-of 3.12 (2H, usher.), 3,16-3,20 (2H, usher.), 3,47 (1H, t, J=11 Hz), 3,53 (1H, t, J=11 Hz), 3,76-3,86 (4H, usher.), of 3.95 (1H, q, J=7 Hz), was 4.02 (1H, DDD, J=11, 4, 2 Hz), 4,16 (1H, DDD, J= 11, 4, 2 Hz), free 5.01 (1H, d, J=5 Hz), vs. 5.47 (1H, d, J=16 Hz), to 5.58 (2H, s)5,59 (2H, d, J=16 Hz), 5,88 (1H, DD, J=15, 5 Hz), to 6.57 (1H, DD, J=15, 11 Hz), 6,78 (1H, d, J=16 Hz), was 7.08 (1H, DD, J=16, 11 Hz), 7,02 for 7.12 (2H, m), 7,49-rate of 7.54 (2H, m), 7,58 (1H, TD, J=9, 6 Hz), to 7.77 (1H, t, J=8 Hz), 7,84 (1, d, J=8 Hz), 7,97-to 7.99 (1H, m), 7,98 (1H, s), 8,19 (1H, d, J=1 Hz), 8,44 (1H, s).

IR-spectrum ν max KBrcm-1: 2232, 1734, 1653, 1503, 1419, 1275, 1256, 1144, 1051.

Mass spectrum m/z (FAB): 884 [M+(free base)+1].

[Example 39]

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-hydroxyacetate (example 4A-1)

(1) 4-Methoxybenzyl 2-hydroxyacetate

Glycolic acid (15,21 g, 0.2 mmol) was dissolved in water (20 ml), was added sodium bicarbonate (to 16.8 g, 0.2 mmol) and the resulting mixture was left overnight. The solvent is evaporated under reduced pressure and the residue was dried to obtain the crude sodium salt of glycolic acid (19,62 g). To a solution of the crude glycolate, sodium (13.5 g, was 0.138 mmol) in N,N-dimethylformamide (70 ml) was added 4-methoxybenzylamine (21,6 g, was 0.138 mmol) and the mixture was stirred at 100°C for 1 hour. After cooling the mixture to room temperature, to the mixture was added water and the product was extracted with ethyl acetate. The organic layer was washed with water and the solvent was removed by distillation under reduced pressure to obtain an oily residue. The residue was purified column chromatography using silica gel (200 g; eluent: ethyl acetate:hexane=2:3) to obtain specified in the header soy is inane (16,17 g, yield 60%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 3,82 (3H, s), 4,17 (2H, d, J=5 Hz)to 5.17 (2H, s), make 6.90 (2H, d, J=9 Hz), 7,31 (2H, d, J=9 Hz).

IR-spectrum ν max CHCl3cm-1: 1738, 1613, 1516, 1253, 1175, 1085, 1035.

Mass spectrum m/z (EI): 196 (M+).

(2) 4-Methoxybenzyl 2-(allyloxycarbonyl)acetate

A solution of 4-methoxybenzylideneamino (1,46 g, 7.4 mmol)obtained in example 39-(1)in dichloromethane (20 ml) was cooled to 0°C and to the solution was added 4-(N,N-dimethylamino)pyridine (1,00 g, 8.2 mmol) and allylchloroformate (0,99 g, 8.2 mmol). The mixture was heated to room temperature and was stirred for 1 hour. The reaction was stopped by adding water. The product was extracted with dichloromethane and the solvent was removed by distillation under reduced pressure to obtain an oily residue. The residue was purified column chromatography using silica gel (40 g; eluent: ethyl acetate:hexane=1:5) to obtain the specified title compound (1.80 g, yield 86%) as a pale brown oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 3,81 (3H, s)and 4.65 (2H, s), of 4.67 (2H, DD, J=5, 1 Hz), further 5.15 (2H, s), 5,28 (1H, dt, J=11, 1 Hz), 5,38 (1H, DD, J=18, 1 Hz), to 5.93 (1H, DDT, J=18, 11, 5 Hz), 6.89 in (2H, d, J=8 Hz), 7,30 (2H, d, J=8 Hz).

IR-spectrum ν max CHCl3cm-1: 1752, 1614, 1516, 1299, 1282, 1255, 1175.

Mass spectrum m/z (EI): 280 (M+).

(3) 2-(Allyloxycarbonyl)acetic sour is and

A mixture of 4-methoxybenzyl 2-(allyloxycarbonyl)acetate (1.77 g, 6.3 mmol)obtained in example 39-(2), and anisole (2.0 g, 18.5 mmol) was cooled to 0°C and to the mixture was added triperoxonane acid (9 ml). The resulting mixture was left at room temperature for 20 minutes At the end of this time, to the mixture was added toluene (8 ml). The solvent was removed by distillation under reduced pressure to remove volatile components. To the mixture was added saturated aqueous solution of sodium bicarbonate. The aqueous layer was twice washed with hexane. To the solution was added 2 N. aqueous solution of hydrochloric acid and components back was extracted into ethyl acetate. The solvent was removed by distillation under reduced pressure to get crude specified in the connection header (1,00 g, quantitative yield) as a pale brown oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 4,69 (2H, d, J=6 Hz), 4,71 (2H, s), and 5.30 (1H, DD, J=10, 1 Hz), of 5.40 (1H, DD, J=10, 1 Hz), 5,95 (1H, DDT, J=17, 11, 6 Hz).

IR-spectrum ν max CHCl3cm-1: 1758, 1740, 1296, 1278, 1253.

Mass spectrum m/z (FAB): 161 (M++1).

(4) 2-(Allyloxycarbonyl)acetylchloride

A solution of 2-(allyloxycarbonyl)acetic acid (3.03 g, to 18.9 mmol)obtained in example 39-(3), in tetrahydrofuran (30 ml) was cooled to 0°C and to the solution was added oxalicacid (2.64 g, to 20.8 mmol) and N,N-dimethyl rmaed (30 μl). The mixture was heated to room temperature. After stirring the mixture for 30 min, the solvent is kept under reduced pressure and the obtained residue was purified by simple distillation under reduced pressure to obtain specified in the title compound (3.04 from g, yield 90%) as a colourless oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 4,70 (2H, d, J=6 Hz), is 4.93 (2H, s), 5,32 (1H, d, J=11 Hz), of 5.40 (1H, d, J=17 Hz), 5,94 (1H, DDT, J=17, 11, 6 Hz).

(5) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-(allyloxycarbonyl-hydroxy)acetate

To a solution of 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-[(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (542,6 mg, 1.00 mmol)obtained in Reference example 1 in tetrahydrofuran (13 ml) was added sodium hydride (55% dispersion in mineral oil; 104,7 mg of 2.40 mmol) and the mixture was treated with ultrasound for 30 min using a commercially available ultrasonic cleaner. The mixture was removed from the ultrasonic cleaner and cooled to 0°C was added 2-(allyloxycarbonyl)-acetylchloride (392,9 mg of 2.20 mmol)obtained in example 39-(4). The resulting mixture was stirred at room temperature for 40 min and then the reaction was stopped by adding water. The mixture was extracted with what dilatatum and the solvent was removed under reduced pressure. The obtained oily residue was purified column chromatography using silica gel (30 g; eluent: ethyl acetate:hexane=2:1) to obtain specified in the connection header (to 109.6 mg, yield 16%) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: to 1.37 (3H, DD, J=7, 2 Hz)of 3.00 (1H, TT, J=11, 5 Hz), 3,50 (1H, t, J=11 Hz), 3,51 (1H, t, J=11 Hz), 3,83 (1H, q, J=7 Hz), 4,11-is 4.21 (2H, m), of 4.66 (2H, d, J=2 Hz), 4,69 (2H, d, J=6 Hz), 4,99 (1H, d, J=4 Hz), and 5.30 (1H, d, J=11 Hz), 5,32-5,41 (3H, m), of 5.85 (1H, DD, J=15, 4 Hz), 5,94 (1H, DDT, J=17, 11, 6 Hz), to 6.58 (1H, DD, J=15, 10 Hz), 6,74 (1H, d, J=16 Hz), 6,86-6,94 (2H, m,), 6,93 (1H, DD, J=16, 10 Hz), 7,34 (1H, d, J=10 Hz), 7,35-7,39 (1H, m), 7,40 (1H, d, J=10 Hz), EUR 7.57 (1H, t, J=8 Hz), to 7.93 (1H, s), of 8.04 (1H, s).

IR-spectrum ν max KBrcm-1: 2231, 1754, 1504, 1419, 1277, 1188, 1141, 972.

Mass spectrum m/z (FAB): 685 (M++1).

(6) (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-hydroxyacetate (specified in the header of the target connection)

To a solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-(allyloxycarbonyl)acetate (250,7 mg of 0.37 mmol)obtained in example 39-(5), in dichloromethane (5 ml) was added bis(triphenylphosphine)dichloropalladium (12.9 mg, 0.018 mmol) and anti-hydride (106,5 mg, 0,366 mmol) and the mixture was stirred at room temperature for 30 minutes Poluchenno the mixture was purified column chromatography using silica gel (30 g; eluent: ethyl acetate:hexane=3:1) to obtain specified in the title target compound (230,7 mg, quantitative yield) as a colorless amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,36 (2H, DD, J=7, 2 Hz), 2,53 (1H, t, J=5 Hz), 3,03 (1H, TT, J=11, 5 Hz), 3,51 (2H, t, J=11 Hz), 3,90 (1H, q, J=7 Hz), 4,13-4,22 (3H, m), 4,27 (1H, DD, J=17, 5 Hz), 5,00 (1H, d, J=4 Hz) to 5.35 (1H, d, J=15 Hz), 5,42 (1H, DD, J=15, 2 Hz), to 5.85 (1H, DD, J=15, 4 Hz), 6,59 (1H, DD, J=15, 11 Hz), 6,74 (1H, d, J=16 Hz), 6.87 in-6,93 (2H, m), 6,93 (1H, DD, J=16, 11 Hz), 7,31-7,37 (2H, m), 7,40 (1H, d, J=8 Hz), EUR 7.57 (1H, t, J=8 Hz), 7,92 (2H, s).

IR-spectrum ν max KBrcm-1: 3433, 2231, 1757, 1615, 1503, 1419, 1276, 1141, 1100, 1051, 973.

Mass spectrum m/z (FAB): 601 (M++1).

[Example 40]

Sodium 2-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-2-oxoethylidene (sodium salt of example number 4A-2)

(1) Allyl 2-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-2-oxoethylidene (disodium salt of example number 4A-2)

A solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-hydroxyacetate (327,0 mg, 0.54 mmol)obtained in example 39, in dichloromethane (10 ml) was cooled to 0°C and the solution to allali the triethylamine (66,1 mg, of 0.65 mmol) and allyl 4-chloro-4-oxybutyrate (115,4 mg of 0.65 mmol)obtained in example 14-(1). The mixture was stirred at this temperature for 2 hours. At the end of this time the mixture was diluted with dichloromethane and washed with water, then saturated aqueous sodium chloride. Storytell was removed under reduced pressure. The obtained oily residue was purified column chromatography using silica gel (20 g; eluent: ethyl acetate:hexane=1:1) to obtain specified in the title target compound (311,8 mg, yield 77%) as a pale brown oil.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,36 (3H, DD, J=7, 2 Hz), 2,69-of 2.72 (2H, m), was 2.76-and 2.79 (2H, m), 3,01 (1H, TT, J=11, 5 Hz), 3,50 (1H, t, J=11 Hz), 3,51 (1H, t, J=11 Hz), 3,81 (1H, q, J=7 Hz), 4,13-4,20 (2H, m), 4,60 (2H, d, J=6 Hz), to 4.62 (1H, d, J=15 Hz), and 4.68 (1H, d, J=15 Hz), 4,99 (1H, d, J=4 Hz), 5,24 (1H, d, J=11 Hz), 5,32 (1H, d, J=17 Hz), 5,33 (1H, d, J=15 Hz), 5,38 (1H, DD, J=15, 2 Hz), to 5.85 (1H, DD, J=16, 5 Hz), 5,91 (1H, DDT, J=17, 11, 6 Hz), to 6.58 (1H, DD, J=16, 11 Hz), 6,74 (1H, d, J=15 Hz), 6,85-to 6.95 (2H, m), 6,93 (1H, DD, J=15, 11 Hz), 7,35-7,40 (1H, m), 7,34 (1H, d, J=10 Hz), 7,40 (1H, d, J=8 Hz), EUR 7.57 (1H, t, J=8 Hz), 7,94 (1H, s), 8,03 (1H, s).

IR-spectrum ν max KBrcm-1: 2231, 1741, 1615, 1504, 1419, 1276, 1145.

Mass spectrum m/z (FAB): 741 (M++1).

(2) Sodium 2-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-2-oxoethylidene (specified in the header of the target connection)

By methods which, similar to that described in Example 1-(13), by using allyl 2-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-2-oxoethylidene (297,8 mg, 0,402 mmol)obtained in (1), bis(triphenylphosphine)dichloropalladium (14.1 mg, 0.02 mmol) and anti-hydride (117,0 mg, 0.40 mmol) was obtained the crude specified in the header of the target compound in the form of oil.

The oil was subjected to column chromatography with reversed phase using Cosmosil 75 C18-PREP (Nacalai Tesque, Inc.; 20 g) (eluent: water:methanol=4:6˜3:7). The fractions obtained were concentrated and the residue was liofilizovane obtaining specified in the title target compound (100.0 mg, yield 34%) as a colourless solid.

NMR-spectrum (400 MHz, D2O) δ ppm: to 1.35 (3H, DD, J=7, 2 Hz), of 2.51 (2H, t, J=7 Hz), a 2.71 (2H, t, J=7 Hz), to 3.02 (1H, TT, J=11, 5 Hz), 3,57 (1H, t, J=11 Hz), to 3.58 (1H, t, J=11 Hz), of 3.78 (1H, d, J=7 Hz), 4,15 (1H, DDD, J=11, 5, 2 Hz), 4,19 (1H, DDD, J=11, 5, 2 Hz), 4,77-4,78 (2H, m), 5,11 (1H, d, J=5 Hz), of 5.40 (1H, d, J=15 Hz), the 5.51 (1H, d, J=15 Hz), of 5.89 (1H, DD, J=15, 5 Hz), 6,63 (1H, DD, J=15, 11 Hz), 6,83 (1H, d, J=16 Hz), 7.03 is for 7.12 (2H, m), 7,11 (1H, DD, J=16, 11 Hz), 7,51-to 7.61 (3H, m), 7,81 (1H, t, J=8 Hz), of 8.04 (1H, s), 8,40 (1H, s).

IR-spectrum ν max KBrcm-1: 2231, 1747, 1614, 1598, 1503, 1419, 1385, 1143.

Mass spectrum m/z (FAB): 723 (M++1).

[Example 41]

2-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-t is eazol-1-yl)methyl]propoxy]-2-oxoethyl phosphate sodium (sodium salt of example number 4A-2)

(1) Diallyl 2-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-2-oxoethyl phosphate

A solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-hydroxyacetate (343,2 mg, 0,571 mmol)obtained in example 39, in dichloromethane (10 ml) was cooled to 0°C and to the solution was added tetrazole (80,1 mg, 1.15 mmol) and bis(allyloxy)-(diisopropylamino)phosphine (described in Tetrahedron Lett., 30, 4219, (1989); 182,1 mg, 0,742 mmol). The mixture was stirred at this temperature for 20 minutes To the mixture was added methanol (0.1 ml) and the mixture was stirred for 5 minutes To the mixture was added tert-butylhydroperoxide (80% solution of di-tert-butylhydroperoxide; 0.27 g, 2.4 mmol) at 0°C and the mixture was stirred at room temperature for 15 minutes To the mixture was added saturated aqueous solution of sodium bicarbonate and sodium thiosulfate solution and the mixture was stirred for 10 minutes At the end of this time the product was extracted with ethyl acetate and the solvent was removed under reduced pressure. The obtained oily residue was purified column chromatography using silica gel (20 g; eluent: ethyl acetate:hexane=4:1) to obtain the specified reception in the e connection (365,4 mg, yield 84%) as a pale brown amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,36 (3H, DD, J=7, 2 Hz), 2,99 (1H, TT, J=11, 5 Hz), 3,50 (1H, t, J=11 Hz), 3,51 (1H, t, J=11 Hz), 3,83 (1H, q, J=7 Hz), 4,11-4,20 (2H, m), 4,56-4,71 (6H, m), 4,99 (1H, d, J=4 Hz), a 5.25-5.40 to (6H, m), of 5.84 (1H, DD, J=15, 4 Hz), 5,96 (2H, DDT, J=17, 11, 6 Hz), to 6.58 (1H, DD, J=15, 11 Hz), was 6.73 (1H, d, J=16 Hz), 6,86-6,93 (2H, m), 6,93 (1H, DD, J=16, 11 Hz), 7,33 (1H, d, J=10 Hz), 7,35-7,39 (1H, m), 7,40 (1H, d, J=8 Hz), EUR 7.57 (1H, t, J=8 Hz), to $ 7.91 (1H, s), 8,01 (1H, s).

IR-spectrum ν max CHCl3cm-1: 2233, 1772, 1616, 1504, 1277, 1259, 1140, 1041, 991.

Mass spectrum m/z (FAB): 761 (M++1).

(2) 2-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-2-oxoethyl phosphate sodium (specified in the header of the target connection)

According to the method similar to that described in Example 1-(13), using diallyl 2-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)-methyl]propoxy]-2-exoatmosphere (319.0 mg, 0.42 mmol)obtained in example 41-(1), bis(triphenylphosphine)dichloropalladium (14,7 mg, 0,021 mmol) and anti-hydride (292,9 mg, 1.01 mmol) was obtained the crude specified in the header of the target compound in the form of oil.

The resulting oil was subjected to column chromatography with reversed phase using Cosmosil 75 C18-PREP (Nacalai Tesque, Inc.; 25 g) (eluent: water:methanol=4:6˜3:7). P the obtained fractions were concentrated and the residue was liofilizovane obtaining specified in the title target compound (151,9 mg, yield 52%) as a colourless solid.

NMR-spectrum (400 MHz, D2O) δ ppm: to 1.21 (3H, d, J=7 Hz), 2.91 in (1H, TT, J=12, 5 Hz), 3,50 (1H, t, J=12 Hz), 3,53 (1H, t, J=12 Hz), to 3.64 (1H, q, J=7 Hz), 4.04 the-4,10 (2H, m)to 4.33 (1H, DD, J=17, 6 Hz), 4,42 (1H, DD, J=17, 6 Hz), of 5.05 (1H, d, J=5 Hz), to 5.21 (1H, d, J=15 Hz), of 5.39 (1H, d, J=15 Hz), 5,73 (1H, DD, J=15, 4 Hz), 6,51 (1H, DD, J=15, 11 Hz), was 6.73 (1H, d, J=16 Hz), 6,86-6,98 (3H, m), 7,37-7,41 (3H, m), to 7.59 (1H, t, J=8 Hz), 7,88 (1H, s), of 8.27 (1H, s).

IR-spectrum ν max KBrcm-1: 2231, 1755, 1615, 1503, 1418, 1385, 1277, 1140, 1050, 988, 976.

Mass spectrum m/z (FAB): 703 (M++1).

[Example 42]

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-[[2-(4-methyl-1-piperazinil)acetyl]oxymethyl]benzoate (example number 5A-94)

A solution of (1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-(hydroxymethyl)benzoate (666,1 mg, 0.95 mmol)obtained in example 33, in dichloromethane (20 ml) was cooled to 0°C and to the solution was added 4-(N,N-dimethylamino)pyridine (231,9 mg, 1,90 mmol), (4-methyl-1-piperazinil)acetic acid (J. Med. Chem., 43, 1493, (2000); 270,3 mg, 1,71 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (546,2 mg, 2,85 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane and the organic layer was washed with water, and C is the saturated aqueous solution of sodium chloride. The solvent was removed under reduced pressure. The obtained residue was purified circulating preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm e × 600 mm) and JAIGEL-2H (20 mm e × 600 mm)connected in series for use; solvent, chloroform] to obtain specified in the title target compound (of 306.7 mg, yield 38%) as a colorless amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: of 1.46 (3H, DD, J=7, 2 Hz), 2.40 a-2,73 (11H, usher.), to 3.02 (1H, TT, J=11, 5 Hz), 3,37 (2H, s), 3,50 (1H, t, J=11 Hz), 3,55 (1H, t, J=11 Hz), was 4.02 (1H, q, J=7 Hz), 4,13-4,20 (2H, m), free 5.01 (1H, d, J=4 Hz), 5,49 (2H, s)5,54 (1H, d, J=15 Hz), the ceiling of 5.60 (1H, d, J=15 Hz), 5,86 (1H, DD, J=15, 4 Hz), to 6.58 (1H, DD, J=15, 11 Hz), was 6.73 (1H, d, J=16 Hz), 6.90 to-6,94 (2H, m), 6,93 (1H, DD, J=16, 11 Hz), 7,33 (1H, DD, J=10, 1 Hz), of 7.36-7,41 (2H, m), EUR 7.57 (1H, t, J=8 Hz), 7,71 (1H, d, J=9 Hz), 7,86 (1H, DD, J=8, 1 Hz), 7,89 (1H, s), 7,95 (1H, s), 8,19 (1H, d, J=1 Hz).

IR-spectrum ν max KBrcm-1: 2232, 1733, 1614, 1504, 1418, 1276, 1182, 1167, 1142.

Mass spectrum m/z (FAB): 842 (M++1).

A solution of [(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl] 5-cyano-2-[[2-(4-methyl-1-piperazinil)acetyl]oxymethyl]benzoate (260,8 mg, 0.31 mmol)obtained above in ethyl acetate (5 ml) was cooled to 0°C and to the solution was added hydrogen chloride (4 n solution in ethyl acetate; 73,6 μl, 0.29 mmol). The mixture was stirred at 0°C for 5 min and the solvent was removed when eigendom the pressure receiving monohydrochloride specified in the connection header (277.2 M. mg, quantitative yield) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,46 (1H, DD, J=7, 1 Hz), a 2.75 (3H, s), 3,0-3,1 (9H, usher.), of 3.46 (2H, s), 3,55 (2H, t, J=12 Hz)to 4.01 (1H, q, J=7 Hz), 4,13-4,20 (2H, m), free 5.01 (1H, d, J=4 Hz), vs. 5.47 (1H, d, J=15 Hz), the 5.51 (1H, d, J=15 Hz), of 5.53 (1H, d, J=15 Hz), 5,64 (1H, d, J=15 Hz), 5,86 (1H, DD, J=15, 4 Hz), to 6.58 (1H, DD, J=15, 10 Hz), 6,74 (1H, d, J=16 Hz), 6.90 to-6,97 (3H, m), 7,33 (1H, DD, J=10, 1 Hz), 7,33-7,37 (1H, m), 7,40 (1H, DD, J=8, 1 Hz), 7,58 (1H, t, J=8 Hz), 7,70 (1H, d, J=8 Hz), 7,88 (1H, s), 7,89 (1H, DD, J=9, 2 Hz), of 7.97 (1H, s), 8,24 (1H, d, J=1 Hz).

IR-spectrum ν max KBr cm-1: 2232, 1733, 1614, 1504, 1418, 1275, 1257, 1183, 1143.

Mass spectrum m/z (FAB): 842 [M(free base)++1].

[Reference example 1]

4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-Differenl)-2-hydroxy-1-methyl-3-[(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate

(1) Diethyl-4-cyano-2-farbenindustrie

A mixture of 4-(methyl bromide)-3-perbenzoate (1.5 g, 7.0 mmol) [J. Med. Chem., 40, 2064 (1997)] and triethylphosphite (1.4 g, 8.4 mmol) was heated at 150°C for 2 hours. At the end of this time the reaction mixture was concentrated under reduced pressure. Volatile substances which have prisutstvovali in the obtained residue was removed by heating the above balances as at 100°C in vacuum for 1 hour to obtain specified in the title compound (1.97 g, quantitative yield) as oil, which hardened in morozilnik the E. This oily product was used in the next stage without additional purification.

NMR spectrum (270 MHz, CDCl3) δ ppm: of 1.27 (6H, t, J=7,1 Hz), 3,24 (2H, d, J=22,3 Hz), 4,00-of 4.05 (4H, m), 7,37 (1H, d, J=9,2 Hz), the 7.43 (1H, d, J=7.9 Hz), 7,51 (1H, TD, J=9,2, 2,6 Hz).

IR-spectrum ν max CHCl3cm-1: 2237, 1262, 1054, 1029.

Mass spectrum m/z (EI): 271 (M+), 139, 109(100%), 93.

(2) 3-Fluoro-4-[(1E,3E)-5-oxo-1,3-pentadienyl]benzonitrile

Utility (solution in hexane, 1,53 n, 0.5 ml, 0.77 mmol) was added dropwise to a solution of diethyl 4-cyano-2-farbenindustrie (209 mg, 0.77 mmol)obtained in Reference example 1-(1)in anhydrous tetrahydrofuran (4 ml) at -78°C under stirring. The mixture was stirred at -78°C within 30 minutes after the end of that time, to the mixture was added commercially available mono-dimethylacetal of fomaldehyde (100 mg, 0.77 mmol) in anhydrous tetrahydrofuran (2 ml) and the resulting mixture was stirred at -78°C for 2 hours. The cooling bath was then removed and the mixture was stirred in an ice bath for 15 minutes To the reaction mixture was added 0.1 G. of hydrochloric acid (3.9 ml to 0.39 mmol) and the mixture is then stirred for 30 min in an ice bath and then for 1 hour at room temperature. At the end of this time to the mixture in an ice bath was added a saturated aqueous solution of sodium bicarbonate. The resulting mixture was distributed between ethyl is the Etat and water, the organic layer was washed with water and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent is then drove away under reduced pressure. The resulting crystalline residue was recrystallized from a mixture of ethyl acetate and hexane to obtain specified in the title compound (127 mg, yield 82%) as pale yellow crystals.

TPL 174-177°C.

NMR spectrum (270 MHz, CDCl3) δ ppm: 6,36 (1H, DD, J=15, 8 Hz), 7,14 (1H, d-like, J=3 Hz), 7,16 (1H, d, J=8 Hz), 7,28 (1H, DDD, J=15, 8, 3 Hz), 7,40 (1H, DD, J=10, 1 Hz), 7,47 (1H, DD, J=8, 1 Hz), to 7.67 (1H, t, J=8 Hz), 9,68 (1H, d, J=8 Hz).

IR-spectrum ν max KBr cm-1: 2230, 1681, 1672, 1621, 1421, 1159, 1124.

Mass spectrum m/z (EI): 201 (M+), 172(100%), 158, 145.

Elemental analysis for C12H8FNO:

Calculated: C: 71,64; H: 4,01; N: Of 6.96.

Found: C: 71,84; H: 4,27; N: 6,83.

(3) 4-[(1E,3E)-4-[TRANS-5-[[(1R,2R)-2-(2,4-Differenl)-2-hydroxy-1-methyl-3-[(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-1,3-butadienyl]-3-perbenzoate (specified in the header of the target connection)

A mixture of 3-fluoro-4-[(1E,3E)-5-oxo-1,3-pentadienyl]benzonitrile (4,63 g, 23,0 mmol)obtained in Reference example 1-(2), (2R,3R)-2-(2,4-differenl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol (described in Japanese patent application (Kokai) No. Hei 8-333350, 8,73 g, a 24.3 mmol), monohydrate p-toluene-sulfonic acids (5,07 g, to 26.7 mmol) and anhydrous tetrahydrofuran (200 ml) was allowed to stand in what I at ambient temperature for 30 minutes At the end of this time the reaction mixture was concentrated using a rotary evaporator and dried in vacuum. The obtained residue was dissolved in anhydrous tetrahydrofuran (150 ml) and the resulting mixture is then evaporated to dryness in vacuo using a rotary evaporator. This operation was repeated two more times. A solution of the obtained residue in anhydrous tetrahydrofuran (150 ml) under stirring was poured into a saturated aqueous solution of sodium bicarbonate. Then the product was extracted with ethyl acetate and the organic layer was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residual oil was purified by chromatography on silica gel (500 g; eluent, ethyl acetate:hexane=2:1), obtaining specified in the title target compound (9,35 g, yield 74%) as a pale yellow amorphous solid substance.

NMR-spectrum (400 MHz, CDCl3) δ ppm: 1,19 (3H, d, J=7 Hz), to 3.33 (1H, q, J=7 Hz), 3,40 (1H, TT, J=11, 5 Hz), 3,62 (1H, t, J=11 Hz), to 3.64 (1H, t, J=11 Hz), 4,30 (1H, DDD, J=11, 5, 2 Hz), 4,43 (1H, DDD, J=11, 5, 2 Hz)of 4.83 (1H, d, J=14 Hz), free 5.01 (1H, s)of 5.03 (1H, d, J=14 Hz), 5,07 (1H, d, J=4 Hz), 5,90 (1H, DD, J=15, 4 Hz), 6,62 (1H, DD, J=15, 11 Hz), 6,7-6,8 (2H, m), of 6.73 (1H, d, J=16 Hz), to 6.95 (1H, DD, J=16, 11 Hz), 7.3 to 7.4 (1H, m), 7,34 (1H, d, J=9 Hz), 7,40 (1H, d, J=8 Hz), 7,58 (1H, t, J=8 Hz), 7,79 (2H, s).

IR-spectrum ν max (KBr)cm-1: 2232, 1616, 1499, 1418, 1140.

Mass spectrum m/z (FAB): 543 (M+

Specific rotation [α]D25-76,6° (c=1.00, it CHCl3).

(Test example 1) Test, confirming the formation of the active substances.

First, 1 mg of the test compound was weighed into a test tube, then the tube was added 100 μl of distilled water and macroscopically confirmed that the substance is soluble in distilled water at concentrations of 10 mg/ml and above.

The investigated compound was dissolved in the preparation of human liver microsomes (0.5 mg protein/ml, GENTEST Corporation) at an initial concentration of 1 μm and the mixture is incubated at 37°C.

After a certain period of time selected a small aliquot of the sample and by HPLC was determined by the degree of resistance of the source connection and the speed of the connection A, the active compounds, whose structure is shown below.

Results incubation of the compound of example 5 (disodium salt of example number 5-16) with a preparation of human liver microsomes is shown in figure 1.

As is clear, the amount of the compound of example 5 (disodium salt of example number 5-16) decreased immediately after the start of incubation, and this compound was fully converted to the compound A after incubation for 30 minutes Thus, it was demonstrated that the compounds according to the present izobreteny which are water-soluble and is converted in vivo hydrolysis in connection exhibiting antifungal activity.

(Test example 2) Determination of antifungal activity of compound A.

The antifungal activity of compound A was evaluated in accordance with the values of minimum inhibitory concentration (MIC), which was measured by methods described below.

Determination of antifungal activity against Candida: the values of MIC was determined by the method of microdesmidae broth. The investigated compound was dissolved in dimethyl sulfoxide (DMSO). Implemented serial double dilution of the compounds using DMSO and then carried out the final dilution using RPMI1640 medium (a product of the company Dainippon Pharmaceutical Co., Ltd.), buffered to pH 7.0 0,165 M 3-(morpholino)propanesulfonate (MOPS). The final concentration of DMSO did not exceed 1%. Colonies of the test fungus suspended in physiological solution with a further increase of the concentration from 5.0×102up to 2.5×103cells/ml with RPMI1640 medium, buffered to pH 7.0 with a solution of 0,165M MOPS. 100 μl of the suspension of the fungus and 100 µl of each diluted solution of the test compounds were mixed in each well of microtiter tablet before incubation at 35°C for 24-72 hours. When there was a clear increase in not containing the analyzed compound control wells was determined values for MICK and petyaev connection. The MIC was defined as the lowest concentration of the compound, causing at least 80% inhibition of growth compared to control.

Determination of antifungal activity against Cryptococcus neoformans: Values MICK was determined by the method of microdesmidae broth. The test compound was dissolved in dimethyl sulfoxide (DMSO). Implemented serial double dilution of the test compounds using DMSO and then carried out the final dilution using the yeast nutrient medium, containing a nitrogen base (a product of the company Difco Laboratories), buffered to pH 7.0 0,165 M 3-(morpholino)propanesulfonate (MOPS). The final concentration of DMSO did not exceed 1%. Colonies of the test fungus suspended in physiological solution with a further increase of the concentration from 5.0×102up to 2.5×103cells/ml using the yeast nutrient medium, containing a nitrogen base, buffered to pH 7.0 with a solution of 0,165M MOPS. 100 μl of the suspension of the fungus and 100 µl of each diluted solution of the test compounds were mixed in each well of microtiter tablet before incubation at 35°C for 48-72 hours. When there was a clear increase in not containing the test compound control wells, determine the values of MIC for the test compounds. The MIC was defined as the lowest end is Tracii connection causing, at least 50% inhibition of growth compared with the control, measured by light absorption at 485 nm.

Determination of antifungal activity against Aspergillus: the values of MIC was determined by the method of microdesmidae broth. The test compound was dissolved in dimethyl sulfoxide (DMSO). Implemented serial double dilution of the test compounds using DMSO and then carried out the final dilution using RPMI1640 medium (product of Dainippon Pharmaceutical Co., Ltd.), buffered to pH 7,0 0,165M MOPS. The final concentration of DMSO did not exceed 1%. Colonies studied fungus suspended in physiological solution and then bringing the concentration to 1.0×104cells/ml with RPMI1640 medium, buffered to pH 7.0 with a solution of 0,165M MOPS. 100 μl of the suspension of the fungus and 100 µl of each diluted solution of tested compound were mixed in each well of microtiter tablet before incubation at 30°C for 24-72 hours. When there was a clear increase in not containing the analyzed connection control holes, determine the values of MIC for the studied compounds. The MIC was defined as the lowest concentration of the compound, causing at least 80% inhibition of growth compared to control.

The lower the value MICK, the higher antifungal activity of the compounds.

The test results of antifungal activity of compounds As shown in Table α.

Table α

Antifungal activity
Test connectionThe values of MIC (mcg/ml)
C.a. (1)a)C.a. (2)b)C.a. (3)c)C.n.d)A.f.e)
Connection A0,25<=0,0080,063<=0,0080,031
a): C.a.(1) = Candida albicans ATCC 64550.
b): C.a.(2) = Candida albicans TIMM 3164.
c): C.a.(3) = Candida albicans TIMM 3165.
d): C.n. = Cryptococcus neoformans TIMM 0362.
e): A.f. = Aspergillus fumigatus SANK 10569.

As shown in the Table above, the compound A exhibits excellent antifungal activity.

(Example composition 1) Preparation for injection

The analyzed compound 1 (500 mg) dissolved in distilled water for injection (25 ml), passed through a sterilizing filter and lyophilizers. Thus, get liofilizovannye the drug for injection.

[Industrial applicability]

Water-soluble triazole antifungal agents, PR is dostavlennya General formula (I), i.e. representing the present invention have a high solubility and exhibit antifungal activity due to the rapid cleavage of the ester group. In addition, the compounds of the present invention are safe. Thus, these compounds are useful as medicines (in particular, as antifungal agents for injection).

1. The connection of a triazole of the General formula (I) or its pharmacologically acceptable salt

where X represents a group of General formula (II)

where R' represents a halogen atom;

R4represents a C1-C6alkyl;

L represents a group of General formula-LaLb-;

Larepresents a simple bond, oxygen atom, phenyl group, which optionally may be substituted with halogen, cyano, C1-C6the alkyl, C1-C6alkoxy or C1-C6the alkyl substituted by one group-O-P(=O)(OH)2, naftalina group, 5-membered heteroaryl group containing, as heteroatom atom of O or S, or C3-C7cycloalkyl group, which is substituted by a carboxyl group;

Lbrepresents a C1-C5 alkylenes group, which optionally can be substituted C1-6the alkyl, carboxyl group or di(C1-6alkyl)amino-C1-6alkyl group, and

R represents a hydrogen atom, a C1-C6alkanoyl, which optionally may be substituted by a group Q-NR2'R3'where Q represents a simple bond or a carbonyl group, and R2' and R3' together with the nitrogen atom to which they are bound, form a piperazinilnom ring, substituted C1-C6the alkyl and/or carboxyl group, or a group-O-P(=O)(OH)2.

2. The connection of a triazole or its pharmacologically acceptable salt according to claim 1, where Larepresents a phenyl group which is substituted as defined in claim 1, naftalina group, 5-membered heteroaryl group containing, as heteroatom atom S or3-C7cycloalkyl group, which is substituted by a carboxyl group.

3. The connection of a triazole or its pharmacologically acceptable salt according to claim 2, where the carbon atom in the group-La-associated with a group of the formula X-O-C(=O)-, and the carbon atom in the group-La-associated with a group of the formula-Lb-O-R are adjacent to each other.

4. The connection of a triazole or its pharmacologically acceptable salt according to any one of claims 1 to 3, where Lbrepresents a methylene group which optionally may be substituted C 1-6alkyl group, a carboxyl group or a di(C1-6alkyl) amino-C1-6alkyl group.

5. The connection of a triazole or its pharmacologically acceptable salt according to any one of claims 1 to 4, where L represents a group -(o-phenylene)-CH2- or a group -(o-phenylene)-CH2-that substituted C1-6alkyl group, a carboxyl group or a di(C1-6alkyl)amino-C1-6alkyl group.

6. The connection of a triazole or its pharmacologically acceptable salt according to claim 5, where L is a group -(o-phenylene)-CH2-that substituted C1-6alkyl group, a carboxyl group or a di(C1-6alkyl)amino-C1-6alkyl group.

7. The connection of a triazole or its pharmacologically acceptable salt according to any one of claims 1 to 6, where R is a hydrogen atom.

8. The connection of a triazole or its pharmacologically acceptable salt according to any one of claims 1 to 6, where R represents a C1-C6alkanoyl, which optionally may be substituted by a group Q-NR2'R3'where Q represents a simple bond or a carbonyl group, and R2'and R3'together with the nitrogen atom to which they are bound, form a piperazinilnom ring, substituted C1-C6the alkyl and/or carboxyl group, or a group-O-P(=O)(OH)2.

9. The connection of a triazole or its pharmacologically priemel who may salt according to any one of claims 1 to 6, where R represents a group-O-P(=O)(OH)2.

10. The connection of a triazole or its pharmacologically acceptable salt according to claim 1, where X represents a group of General formula(V)

11. The connection of a triazole or its pharmacologically acceptable salt according to claim 1 of General formula (I')

where X represents a group of General formula (II)

in which the substituents R' and R4defined in claim 1;

L' represents a C3-C4alkylenes group, which optionally can be substituted C1-6the alkyl, carboxyl group or di(C1-6alkyl) amino-C1-6alkyl group, a group-O-(C2-C3alkylen), which optionally may be substituted C1-6the alkyl, carboxyl group or di(C1-6alkyl) amino-C1-6alkyl group, a group -(related substituted phenyl)-CH2-, which optionally may be substituted with halogen, cyano, C1-C6the alkyl, C1-C6alkoxy or C1-C6the alkyl substituted by one group-O-P(=O)(OH)2or a group -(related substituted C3-C7cycloalkyl)-CH2-, which optionally may be substituted by a carboxyl group, and

R' represents an atom of odor is Yes, C1-C6alkanoyl, C1-C6alkanoyl, which is substituted by a group Q-NR2'R3',

where Q represents a simple bond or a carbonyl group, and R2'and R3'together with the nitrogen atom to which they are bound, form a piperazinilnom ring, substituted C1-C6the alkyl and/or carboxyl group, or a group-O-P(=O)(OH)2.

12. 4-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-4-oxobutyl dihydrophosphate,

4-[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]-2,2-dimethyl-4-oxobutyl dihydrophosphate,

2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]benzyl dihydrophosphate,

4-cyano-2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]benzyl dihydrophosphate,

2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-4-terbisil dihydrophosphate,

2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-is afterfeel)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-5-terbisil dihydrophosphate,

2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-b-terbisil dihydrophosphate,

2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-6-methylbenzyl dihydrophosphate,

2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-6-methoxybenzyl dihydrophosphate,

[8-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-1-naphthyl]methyl dihydrophosphate,

2-chloro-6-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]benzyl dihydrophosphate,

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 4-[2-(4-methyl-1-piperazinil)acetoxy]butyrate,

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 4-[[4-(4-methyl-1-piperazinil)-4-oxobutyryl]oxy]butyrate,

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-d is oxan-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[2-(N-methylamino)acetoxy]methyl]benzoate,

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[2-(N,N-dimethylamino)acetoxy]methyl]benzoate,

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[2-(4-methyl-1-piperazinil)acetoxy]methyl]benzoate,

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[3-(N-methylamino)propanol]oxymethyl]benzoate,

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[3-(N,N-dimethylamino)propionyl]oxymethyl]benzoate,

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[3-(4-methyl-1-piperazinil)propionyl]oxymethyl]benzoate,

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[4-(4-methyl-1-piperazinil)-4-oxobutyryl]oxymethyl]benzoate,

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[4-(N-methylamino)butyryl]oxymethyl]benzoate,

1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 2-[[4-(N,N-dimethylamino)butyryl]oxymethyl]benzoate,

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-[[2-(N-methylamino)acetoxy]methyl]benzoate,

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-[[2-(N,N-dimethylamino)acetoxy]methyl]benzoate,

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-[[2-(4-methyl-1-piperazinil)acetoxy]methyl]benzoate,

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-[[3-(N-methylamino)propanol]oxymethyl]benzoate,

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-[[3-(N,N-dimethylamino)propanol]oxymethyl]benzoate,

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-{2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-[[3-(4-methyl-1-piperazinil)propanol]oxymethyl]benzoate,

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-[[4-(4-methyl-1-piperazinil)-4-oxobutyryl]oximate is]benzoate,

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-[[4-(N-methylamino)butyryl]oxymethyl]benzoate, and

(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-Cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propyl 5-cyano-2-[[4-(N,N-dimethylamino)butyryl]oxymethyl]benzoate,

or their pharmacologically acceptable salts.

13. 4-Cyano-2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]benzyl dihydrophosphate or its pharmacologically acceptable salt.

14. 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]benzyl dihydrophosphate or its pharmacologically acceptable salt.

15. 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-4-terbisil dihydrophosphate or its pharmacologically acceptable salt.

16. 2-[[(1R,2R)-2-[[TRANS-2-[(1E,3E)-4-(4-cyano-2-forfinal)-1,3-butadienyl]-1,3-dioxane-5-yl]thio]-1-(2,4-differenl)-1-[(1H-1,2,4-triazole-1-yl)methyl]propoxy]carbonyl]-5-terbisil dihydrophosphate.

17. Pharmaceutical composition having antifungal activity, in the connection with the triazole according to any one of claims 1 to 16 or a pharmacologically acceptable salt.

18. Pharmaceutical composition for 17 prepared for administration by injection.

19. The connection of a triazole or its pharmacologically acceptable salt according to any one of claims 1 to 16 for use as antifungal agents.

20. The connection of a triazole or its pharmacologically acceptable salt according to any one of claims 1 to 16 for use as antifungal agents against fungi of the genus Candida, Aspergillus, Cryptococcus, Histoplasma, Blastomyces, Coccidioides, Trichophyton, Epidermophyton, Microsporum, Sporothrix, Fonsecaea, Exophiala, Cladosporium, Altemaria, Aureobasidium, Chaetomium, Curvularia, Scedosporium, Geotrichum, Trichosporon, Paecilomyces, Acremonium, Scopulariopsis, Saccharomyces or Rhizopus.

21. The use of compounds according to any one of claims 1 to 16 for receiving medicines to treat fungal infections caused by fungus of the genus Candida, Aspergillus or Cryptococcus.

22. Use item 21, where the drug is formulated for administration by injection.

23. A method of treating a fungal infection caused by the fungus Candida, Aspergillus or Cryptococcus in warm-blooded animal, comprising introducing the compound of the triazole or its pharmaceutically acceptable salt according to any one of claims 1 to 16.

24. The method according to item 23, where the specified introduction is carried out by injection.



 

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FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

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9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

EFFECT: improved method for inhibition, valuable medicinal properties of compounds.

33 cl, 7 tbl, 42 ex

FIELD: organic chemistry, medicinal biochemistry, pharmacy.

SUBSTANCE: invention relates to substituted benzimidazoles of the formula (I): and/or their stereoisomeric forms, and/or their physiologically acceptable salts wherein one of substitutes R1, R2, R3 and R4 means a residue of the formula (II): wherein D means -C(O)-; R8 means hydrogen atom or (C1-C4)-alkyl; R9 means: 1. (C1-C6)-alkyl wherein alkyl is linear or branched and can be free of substituted by one-, bi- or tri-fold; Z means: 1. a residue of 5-14-membered aromatic system that comprises from 1 to 4 heteroatoms as members of the cycle that represent nitrogen and oxygen atoms wherein aromatic system is free or substituted; 1.1 a heterocycle taken among the group of oxadiazole or oxadiazolone that can be unsubstituted or substituted; 2. (C1-C6)-alkyl wherein alkyl is a linear or branched and monosubstituted with phenyl or group -OH; or 3. -C(O)-R10 wherein R10 means -O-R11, -N(R11)2 or morpholinyl; or R8 and R9 in common with nitrogen atom and carbon atom with that they are bound, respectively, form heterocycle of the formula (IIa): wherein D, Z and R10 have values given in the formula (II); A means a residue -CH2-; B means a residue -CH-; Y is absent or means a residue -CH2-; or X and Y in common form phenyl. The cyclic system formed by N, A, X, Y, B and carbon atom is unsubstituted or monosubstituted with (C1-C8)-alkyl wherein alkyl is monosubstituted with phenyl, and other substitutes R1, R2, R3 and R4 mean independently of one another hydrogen atom, respectively; R5 means hydrogen atom; R6 means the heteroaromatic cyclic system with 5-14 members in cycle that comprises 1 or 2 nitrogen atoms and can be unsubstituted or substituted. Also, invention relates to a medicinal agent for inhibition of activity of IkB kinase based on these compounds and to a method for preparing the indicated agent. Invention provides preparing new compounds and medicinal agents based on thereof for aims for prophylaxis and treatment of diseases associated with the enhanced activity of NFkB.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 7 tbl, 224 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: present invention relates to new 4-piperazinyl-(8-quinolinyl)-methyl)-benzamides of general formula I

1, wherein R1 is phenyl, pyridinyl, thiophenyl, furanyl, and inidazolyl, and each phenyl or heteroaromatic ring is optionally and independently substituted with 1, 2 or 3 substituents, selected from linear or branched C1-C6-alkyl, NO2, CF3, C1-C6-alkoxy, halogen, or pharmaceutically acceptable salts thereof. Compounds of present invention are useful in therapy, in particular for pain alleviation. Also disclosed are pharmaceutical composition based on compounds of formula I and method for pain treatment.

EFFECT: new compounds and compositions for pain treatment.

12 ck, 19 ex, 3 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying compounds of the general formula (1):

as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):

and (1.2):

. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.

EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.

3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:

wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.

EFFECT: improved preparing method, improved inhibiting method, valuable medicinal properties of compounds.

26 cl, 4 tbl, 476 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)

or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group or wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.

EFFECT: valuable medicinal properties of compounds.

21 cl, 2 sch, 4 tbl, 183 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

Indole derivatives // 2256659

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indole of the formula (I): wherein R1 means phenyl substituted or unsubstituted radical R2 and/or R4; R2, R4 R5 and R6 in each case and independently of one another mean Hal; R3 mean substituted or unsubstituted radical R5 and/or R6 or means Het wherein Het means 2-furyl, 3-furyl, 2-thienyl or 3-thienyl; Hal means fluorine atom (F), chlorine atom (Cl), bromine atom (Br) or iodine atom (J), and their physiologically acceptable salts and solvates also. Compounds of the formula (I) are prepared by interaction of compound of the formula (I): wherein L means Cl, Br, J or free or reactive functional modified group OH; R3 has value indicated in the formula (I) with compound of the formula (III): . Compounds of the formula (I) show affinity to 5-HT2A receptors that allow their using in the pharmaceutical composition.

EFFECT: valuable medicinal and pharmacological properties of compounds.

4 cl, 10 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to quinazoline derivatives of the formula (I) or their pharmaceutically acceptable salts wherein m = 0 or 1; each group R1 can be similar or different and represents halogen atom, hydroxy- and (C1-C6)-alkoxy-group, or group of the formula Q3-X1 wherein X1 represents oxygen atom (O); Q3 represents phenyl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl, and wherein heteroaryl group represents aromatic 5- or 6-membered monocyclic rings with one or two nitrogen heteroatoms, and any heterocyclyl group defined as the group R1 represents non-aromatic saturated or partially saturated 3-6-membered monocyclic ring with one or two heteroatoms chosen from oxygen and nitrogen atoms, and wherein adjacent carbon atoms in any (C2-C6)-alkylene chain in the substitute R1 are separated optionally by incorporation of oxygen atom (O) in the chain, and wherein any group CH2 or CH3 in the substitute R1 comprises optionally in each of indicated groups CH2 or CH3 one or some halogen substitutes or a substitute chosen from hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkylsulfonyl or pyridyloxy-group, and wherein any heteroaryl or heterocyclyl group in the substitute R1 comprises optionally 1, 2 or 3 substitutes that can be similar or different and chosen from hydroxy-group, carbamoyl, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]-carbamoyl, (C1-C6)-alkoxy-(C1-C6)-alkyl and cyano-(C1-C6)-alkyl, or among group of the formula -X5-Q6 wherein X5 represents a direct bond or -CO, and Q6 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that comprises optionally (C1-C6)-alkyl as a substitute wherein heterocyclyl group represents non-aromatic, fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from nitrogen and oxygen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; Z represents a direct bond or oxygen atom; Q1 represents phenyl, (C3-C7)-cycloalkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl wherein heteroaryl group represents 5- or 6-membered aromatic monocyclic ring with I, 2 or 3 heteroatoms of nitrogen, and any heterocyclyl group represents non-aromatic fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from oxygen, nitrogen or sulfur atom, or when Z represents oxygen atom (O) then Q1 can represent (C1-C6)-alkyl or (C1-C6)-alkoxy-(C1-C6)-alkyl and wherein any heterocyclyl group in the group -Q1-Z- comprises substitutes chosen from (C1-C6)-alkyl, (C1-C)-alkoxycarbonyl and pyridylmethyl, and wherein any heterocyclyl group in the group -Q1-Z- comprises optionally 1 or 2 oxo-substitutes; Q2 represents aryl group of the formula (Ia): wherein G1 represents halogen atom, trifluoromethyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C2-C6)-alkanoyl, pyrrolyl, pyrrolidinyl, piperidinyl and morpholinomethyl, and each G2, G3, G4 and G5 that can be similar or different represents hydrogen, halogen atom, cyano-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group, or G1 and G2 form in common group of formulae -CH=CH-CH=CH-, -CH=CH-O- or -O-CH=CH- being each group carries optionally halogen atom as a substitute, or G1 and G2 form in common group of formulae -O-CH2-O- or -O-CH2-CH2-O-, or -O-CH2-CH2-O-, and each among G3 and G4 represents hydrogen atom, and G5 is chosen from hydrogen and halogen atom. Proposed compounds possess anti-tumor activity and designated for preparing a medicine preparation for its using as an anti-tumor agent for suppression and/or treatment of solid tumors. Also, invention relates to a pharmaceutical composition based on abovementioned compounds.

EFFECT: valuable medicinal properties of compounds.

20 cl, 7 tbl, 57 ex

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention relates to a novel heterocyclic compound, in particular, 3-(5-nitrofuryl)-7-(5-nitrofurfurylidene-3,3a,4,5,6,7-hexahydro-2H-indazole of the formula (1): that elicits an antibacterial activity with respect to bacterium of genus Staphylococcus and can be used in medicine. The compound of the formula 91) is prepared by reaction of 2,6-di-(5-nitrofurfurylidene)-cyclohexanone with hydrazine hydrate in propanol-2 medium. The yield is 80%, m. p. at 193-195°C, empirical formula is C16H14N4O6, LD50 value at intraperitoneal administration is 500 mg/kg. This compound exceeds activity of furacilinum and furazolidone by 16 and 2-31 times, respectively. Invention provides preparing compound possessing the higher and selective antibacterial activity and low toxicity.

EFFECT: valuable properties of compound.

1 cl, 3 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new derivatives of quinazoline of the formula (I):

wherein m = 0, 1, 2 or 3; each group R1 that can be similar or different is taken among halogen atom, trifluoromethyl, hydroxy-, amino-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy-, (C2-C6)-alkynyloxy-, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino- and (C2-C6)-alkanoylamino-group, or among the group of the formula: Q1-X1- wherein X1 represents oxygen atom (O); Q1 represents aryl-(C1-C6)-alkyl, heteroaryl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl and wherein neighboring carbon atoms in any (C2-C6)-alkylene chain in substitute at R1 are separated optionally by insertion to the chain the group taken among oxygen atom (O) and N(R5) wherein R5 represents hydrogen atom or (C1-C6)-alkyl, or when the inserted group represents N(R5); R5 can represent also (C2-C6)-alkanoyl and wherein any group -CH2 or -CH3 in substitute R1 carries one or more substitutes in each indicated group -CH2 or -CH3 and wherein these substitutes are taken among halogen atom or (C1-C6)-alkyl, or substitute taken among hydroxy-, amino-group, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino-, (C2-C6)-alkanoyloxy, (C2-C6)-alkanoylamino- and N-(C1-C6)-alktyl-(C2-C6)-alkanoylamino-group, or among the group of the formula: -X3-Q3wherein X3 represents oxygen atom (O) and Q3 represents heteroaryl, and wherein any aryl, heteroaryl or heterocyclyl group in substitute at R1 carries optionally 1, 2 or 3 substitutes that can be similar or different and taken among halogen atom, trifluoromethyl, cyano-, hydroxy-, amino-group, carbamoyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy, (C2-C6)-alkynyloxy,(C1-C6)-alkylthio-group, (C1-C)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino-group, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]carbamoyl, (C2-C6)-alkanoyl, (C2-C6)-alkanoyloxy-, (C2-C)-alkanoylamino- and N-(C1-C6)-alkyl-(C2-C6)-alkanoylamino-group, or among the group of the formula: -X4-R8 wherein X4 represents a simple bond and R8 represents hydroxy-(C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkyl, cyano-(C1-C6)-alkyl, amino-(C1-C6)-alkyl, (C1-C6)-alkylamino-(C1-C6)-alkyl or di-[(C1-C6)-alkyl]amino-(C1-C6)-alkyl, or among the group of the formula: -X5-Q4 wherein X5 represents a simple bond or -CO, and Q4 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that carries optionally 1 or 2 substitutes that can be similar or different and taken among halogen atom, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group and wherein any heterocyclyl group in substitute at R1 carries optionally 1 or 2 oxo-substitutes, and wherein any aryl group in the group R1 represents phenyl; any heteroaryl group in the group R1 is taken among pyrrolyl, imidazolyl, triazolyl and pyridyl, and any heterocyclyl group in the group R1 is taken among oxyranyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, 1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl; R2 represents hydrogen atom; n = 0, 1, 2 or 3; R3 represents halogen atom, trifluoromethyl, cyano-, hydroxy-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or (C1-C6)-alkoxy-group, or its pharmaceutically acceptable salt. Also, invention relates to methods for preparing compounds of the formula (1) and to pharmaceutical composition based on thereof for using as an anti-tumor agent. Invention provides preparing new derivatives of quinazoline possessing an anti-tumor activity.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 7 tbl, 7 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 4-aminopiptidine of the general formula (I): wherein R1 means (C1-C6)-alkyl, -(CH2)m-Y-Z11 or -(CH2)m-Z12 wherein Z11 means (C1-C6)-alkyl; Z12 means bis-phenyl, (C3-C7)-cycloalkyl, (C3-C7)-heterocycloalkyl with 1 or 2 heteroatoms taken among nitrogen (N) or oxygen (O) atoms, possibly substituted phenyl, naphthyl, possibly substituted (C5-C9)-heteroaryl wherein heteroatoms are taken among N; or Z12 means ; Y means O; or R1 means ; R2 means -C(Y)-NHX1, -C(O)X2 or -SO2X3; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C4)-alkenyl, possibly substituted heteroarylalkyl or -C(Y)-NHX1, -(CH2)n-C(O)X2 or -SO2X3 wherein X1-X3 have different values. Also, invention describes methods for preparing indicated substances by synthesis in liquid and solid phase. These compounds possessing good affinity to definite subtypes of somatostatin receptors can be used in treatment of pathological states or diseases caused by one or some somatostatin receptors.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

14 cl, 4 tbl, 778 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 1-aziridino-1-hydroxyiminomethyl of the general formula (I):

wherein R means a single bond or organic radical that can bind aziridinoxime groups by a covalent bond and taken among the group including saturated or unsaturated alkanes with normal or branched chain and comprising up to 6 carbon atoms, substituted azino-group -(R')C=N-N=C(R'') wherein R' and R'' represent independently of one another hydrogen atom or lower alkyl, heterocyclic compounds comprising from 3 to 6 atoms in ring and up to 4 heteroatoms taken among -N- and -O-, and aromatic compounds comprising up to 8 atoms in ring; R1 and R2 mean independently of one another -H, -COOH, -COOCH3, -COOC2H5 or -CONH2; n means a whole number 2 or 3; with exception the compound wherein R represents a single bond and R1 and R2 are both hydrogen atom, and also with exception the compound wherein R represents a single bond and one of substitutes is hydrogen atom among the group R1 and R2. Also, invention describes a method for their preparing and medicinal preparations comprising these compounds that possess an antitumor effect.

EFFECT: improved preparing method, valuable medicinal properties of compounds and preparations.

7 cl, 3 tbl, 19 ex

FIELD: organic chemistry, medicine, hormones.

SUBSTANCE: invention describes imidazole derivatives of the formula (I) , racemic-diastereomeric mixtures and optical isomers, pharmaceutical salts wherein ---- represents an optional bond; R1 represents hydrogen atom (H), -(CH2)m-C(O)-(CH2)m-Z1, -(CH2)m-Z1; R2 represents hydrogen atom (H), or R1 and R2 are joined with nitrogen atoms to which they are bound forming compounds represented by formulae (Ia), (Ib) or (Ic) wherein R3 represents -(CH2)m-E-(CH2)m-Z2; R4 represents hydrogen atom (H) or -(CH2)m-A1; R5 represents (C1-C12)-alkyl, (C0-C6)-alkyl-C(O)-NH-(CH2)m-Z3 and optionally substituted phenyl; R6 represents hydrogen atom (H); R7 represents (C1-C12)-alkyl or -(CH2)m-Z4; m = 0 or a whole number from 1 to 6; n is a whole number from 1 to 5. Proposed compounds bind with subtypes of somatostatin receptors selectively.

EFFECT: valuable properties of compounds.

20 cl, 13776 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of pyrrole of the formula (I): wherein R1 and R1' mean independently hydrogen atom (H) or (lower)-alkyl, unsubstituted or substituted (lower)-alkoxy-group; R2 means hydrogen atom (H), nitro-group (-NO2), cyano-group (-CN), halogen atom, unsubstituted (lower)-alkyl or substituted with halogen atom or (lower)-alkoxy-group; R2' means thiazolyl, thiophenyl, isothiazolyl, furanyl and pyrazolyl that is unsubstituted or substituted with (lower)-alkyl, pyrimidinyl, unsubstituted morpholinyl, unsubstituted pyrrolidinyl and imidazolyl that is unsubstituted or substituted with (lower)-alkyl, unsubstituted piperidinyl or piperazinyl that is unsubstituted or substituted with (lower)-alkyl, or ethoxy-group substituted with imidazolyl, or its pharmaceutically acceptable salt. Compounds of the formula (I) inhibit cell proliferation in G2/M phase of mitosis that allows their using in the pharmaceutical composition.

EFFECT: valuable biological properties of compounds.

36 cl, 4 sch, 1 tbl, 21 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonyl