Azole compounds, method of their production, antifungal pharmaceutical composition and method of treating fungal infection

 

(57) Abstract:

Describes the azole derivatives of the General formula (I), where R1represents: (I) C1-6alkyl, optionally mono - or disubstituted by substituents selected from 2-tetrahydrofuryl, C1-6acyloxy, hydroxy, C1-6alkoxycarbonyl, benzyloxycarbonyl, carboxy, C1-6alkanolamine, benzyloxy, C1-6alkoxy or 1,3-dioxolane-4-yl, which, in turn, can be substituted WITH1-4by alkyl; or (II) 1,3-dioxane-5-yl; n is 0 or 1; R2represents hydrogen or C1-6alkyl; X is halogen; Y is halogen; Z is-CH2-CH2- or-N=CH; R7when Z represents a group-CH2-CH2- is a 3-4-nitrogen-containing 5-membered heterocyclic residue, an optionally substituted C1-6the alkyl, which, in turn, substituted C1-6alloctype; when Z represents a group-N=CH-, R7represents C1-6alkoxygroup, substituted with halogen; antifungal pharmaceutical composition and a method of treating a fungal infection. Compounds (I) have a high solubility in water, exhibit improved internal absorption, and hence obladuirea relates to novel azole compounds possessing antifungal activity, their preparation and application.

Background of the invention

To date, there are various azole compounds with antifungal activity. For example, Japan patent Kokai Hei 6-293740 disclosed azole compound represented by the formula:

< / BR>
where AG represents a substituted phenyl group; R1and R2independently represent a hydrogen atom or a lower alkyl group, or R1and R2can be combined with the formation of the lower alkalinous group; R3is a group attached through a carbon atom; R4represents a hydrogen atom or acyl group; X represents a nitrogen atom or methine group; and Y and Z independently represent a nitrogen atom or a methine group which optionally may be substituted by a lower alkyl group, or its salt.

Publication of the Japan patent Kokai Hei 8-104676 discloses a compound represented by the formula:

< / BR>
where Ar represents optionally substituted phenyl; R1and R2being the same or different, represent a hydrogen atom or a lower alkyl group, or R1and R2can be combined is y; Y represents a nitrogen atom or methine group; and a represents optionally substituted saturated cyclic amide group associated through the first nitrogen atom, and salts thereof. WO 9625410 A1 (corresponds to published Japan patent Kokai No. Hei 9-183769) describes a compound represented by the formula:

< / BR>
where Ar is optionally substituted phenyl group; R1and R2identical or different, represent a hydrogen atom or a lower alkyl group, or R1and R2can be combined with the formation of the lower alkalinous group; R3represents a hydrogen atom or acyl group; X represents a nitrogen atom or methine group; a represents Y=Z (Y and Z, equal or different, represent a nitrogen atom or a methine group optionally substituted lower alkyl group or ethylene group optionally substituted lower alkyl group; n represents an integer from 0 to 2; and Z represents optionally substituted asailing group, or its salt.

On the other hand, currently known series of compounds related to soft drugs, which are derived asola (imidazole, triazole) type chetvertichnaya salts of derivatives of 1-methylimidazole was reported in the Journal of Medical Chemistry, Vol.23, page 469, 1980 (antimicrobial activity), ibidem, Vol. 23, 566, 1980 (antitumor activity), ibidem, Vol.23, 474, 1980 (anticholinergic activity) and ibid Vol.32, 493, 1989 (activity reactivation of acetylcholinesterase), and these Quaternary salts themselves have biological activity, and one of their distinguishing features is that their hydrolysis proceeds rapidly. On the other hand, azole derivatives of compounds of the type of Quaternary ammonium salts as procarcinogen funds were reported only in Pharmaceutical Research, Vol.9, page 372, 1992 (protivoglaucomny drug) and in Entomologia Experimentalis et Aplicata, Vol.44, page 295, 1987 (insecticide). In addition, an example of use as a synthetic intermediate compounds derived imidazole type Quaternary ammonium salts, using his ability to easily either hydrolyzed as described in Journal of Chemical Society, Perkin I, page 1341, 1979 in New Journal of Chemistry, Vol.16, page 107, 1992. Moreover, a number of derived type Quaternary ammonium salts described in U.S. patent 4061722 and 4160099. However, not previously known to enzymatic and/or refermentation gidrolizuacy azole derivatives of compounds of the type Quaternary salts having anti-fungal activity.

Abraxas stoimosti in water for use as injectable drugs is not always sufficient, and it's hard to say, sufficient for the manifestation of high therapeutic effect their absorption in the body. Therefore, it would be desirable to increase the water solubility and absorption in the body.

Detailed description of the invention

Under these circumstances, the authors of the present invention carried out intensive research. As a result, the authors of the present application found that a derivative obtained by quaternization of the nitrogen atoms contained in lH-imidazol-1-ilen group or 1H-1,2,4-triazole-1-ilen group azole compounds, has a high solubility in water and hydrolyzed by enzymatic and/or refermentation, giving connection with 1H-imidazol-1-ilen group or 1H-1,2,4-triazole group and possessing antifungal activity. Thus, the present invention is carried out on the basis of these results.

Namely, the present invention relates to stereoselectivity nitrogen-containing imidazol-1-ilen, or 1,2,4-triazole-1-ilen connection, in which one of the nitrogen atoms constituting the azole ring, and stereoselectivity Deputy capable chipped off in vivo, and the removal of the Deputy of the original connection of preverse the overall connection.

The above "stereoselectivity nitrogen-containing imidazole-1-ilen, or 1,2,4-triazole-1-ilen connection, in which one of the nitrogen atoms constituting the azole ring, and stereoselectivity Deputy capable chipped off in vivo, and the removal of the Deputy of the parent compound is converted to the anti-fungal azole compound [hereinafter, sometimes called compound (I)] is a compound containing in the molecule a group imidazol-1-yl or 1,2,4-triazole-1-yl, in which the nitrogen atom stereoselectivity due to the presence of substituent at the nitrogen atom in the 3-position of the imidazole-1-ilen group and the nitrogen atom in the 2 - or 4-position of the 1,2,4-triazole-1-ilen group, and Deputy hydrolyzed in vivo by cleavage, thus the connection is transformed into a compound containing the group imidazol-1-yl or a group of 1,2,4-triazole-1-yl, containing no stereoselectivity of the nitrogen atom and possessing antifungal activity.

Examples of such compounds include a compound represented by the formula:

< / BR>
where Q represents a group imidazol-1-yl or 1,2,4-triazole-1-yl, in which one of the nitrogen atoms constituting the azole ring, and stereoselectivity Deputy capable chipped off in vivo; Ar represents palaeolatitudinal substituted heterocyclic group; X1represents an oxygen atom or methylene group; X2is optionally oxidized sulfur atom; Tyr, respectively, represent 0 or 1; Y-represents an anion; and (1) R3, R4and R5may be the same or different and represent a hydrogen atom or a lower alkyl group, or (2) R3represents a hydrogen atom or a lower alkyl group, and R4and R5combined with each other, representing the lowest alkylenes group, or (3) R5represents a hydrogen atom or a lower alkyl group, and R3and R4combined with each other, representing the lowest alkylenes group, or its salt [hereinafter referred to sometimes as compound (Ia)].

"Deputy, capable chipped off in vivo" in "group, imidazol-1-yl or 1,2,4-triazole-1-yl, in which one of the nitrogen atoms constituting the azole ring, and stereoselectivity Deputy capable chipped off in vivo", represented by Q, can be any group which is cleaved in vivo and the group denoted by Q, includes groups represented by the formula (II):

< / BR>
where R1represents an optionally substituted hydrocarbon group or heterocyclic group; R2represents a hydrogen atom>/P>Examples of the "hydrocarbon group" in "optionally substituted hydrocarbon group" represented by R1include aliphatic hydrocarbon group, aromatic hydrocarbon group and aromaticheski-aliphatic hydrocarbon group. Examples of the aliphatic hydrocarbon group include alkyl group, cycloalkyl group, cycloalkenyl group, alkenylphenol group and alkylamino group. Examples of alkyl groups include linear or branched alkyl group having from 1 to 20 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, etc. and among them, a lower alkyl group having from 1 to 6 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and so forth), is especially preferred. Examples cycloalkyl groups include cycloalkyl group having from 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, substituted and so on , and among them cycloalkyl group having 3 to 5 carbon atoms (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so following 4 to 12 carbon atoms, such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and so on, and among them cycloalkylation group having 6 to 8 carbon atoms (for example, cyclopentylmethyl, cyclohexylmethyl and so on), is especially preferred. Examples alkenylphenol groups include groups having from 2 to 4 carbon atoms, such as vinyl, propenyl, butenyl and so on , and among them Alchemilla group having 2-3 carbon atoms (e.g. vinyl, propenyl), is especially preferred. Examples alkenylphenol groups include groups having from 2 to 4 carbon atoms, such as ethinyl, PROPYNYL, butynyl and so on, and among them Alchemilla group having 2-3 carbon atoms (for example, ethinyl, PROPYNYL) is particularly preferred.

Examples of the aromatic hydrocarbon group include groups having from 6 to 14 carbon atoms, such as phenyl, naphthyl, biphenylyl, antril, indenyl and so on , and among them aryl group having from 6 to 10 carbon atoms (for example, phenyl, naphthyl and so on) is particularly preferred.

Examples aromaticheski-aliphatic hydrocarbon groups include kalkilya group having from 7 to 15 carbon atoms, such as benzyl, phenethyl, phenylpropyl, naphthylmethyl, Indymedia from 7 to 11 carbon atoms (for example, benzyl, phenethyl, naphthyl-methyl, and so on), is especially preferred.

"Heterocyclic group" in "optionally substituted heterocyclic group" represented by R1is a group obtained by removing one hydrogen atom linked to the heterocyclic ring, and such heterocyclic ring is a 5-8-membered ring containing 1 or more, preferably from 1 to 4 heteroatoms (for example, a nitrogen atom (optionally oxidized), an oxygen atom, a sulfur atom, and so on), or a condensed ring.

Specific examples of the heterocyclic ring group include pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazole, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, pyrrolidinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinil, indolyl, pyranyl, tiopronin, dioxines, dioxole, hinely, pyrido[2,3-d]pyrimidyl, 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridine, thieno[2,3-d] pyridyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, DIOXOLANYL, dioxanes and that is but substituted heterocyclic group", presents R1include heterocyclic group, oxoprop, the hydroxy-group, C1-6alkoxygroup,3-10cycloalkylation, C6-10alloctype, C7-19aralkylated, heterocyclic ring-oxygraph, mercaptopropyl, C1-6allylthiourea (the sulfur atom may be oxidized), C3-10cycloalkylation (the sulfur atom may be oxidized), C6-10killigrew (the sulfur atom may be oxidized),

C7-19arkitip (the sulfur atom may be oxidized), a heterocyclic ring-togroup, heterocyclic ring-sulfonylurea, heterocyclic ring-sulfonylurea, amino, mono-C1-6killingray, di-C1-6alkylamino, three1-6alkylammonium,3-10cycloalkylation,6-10killingray, C7-19aralkylamines, heterocyclic ring-amino group, cyclic amino group, a nitro-group, halogen atom, cyano, carboxyl group,

C1-10alkoxycarbonyl group6-10aryloxyalkyl group, C7-19aracelikarsaalyna group6-10arylcarbamoyl group, C1-6alkanoglu,3-5alkanoglu,6-10NUU karbamoilnuyu group, optionally substituted thiocarbamoyl group optionally substituted by carbamoyloximes, C1-6alkanolamines,6-10arylcarboxamide group, C1-10alkoxycarbonyl,6-10aryloxychromones,

C7-19uralelectrocontactor, C1-10alkoxycarbonylmethyl,6-10aryloxypropanolamine, C7-19uralelectropech.ru,3-10cycloalkylcarbonyl, optionally substituted by raidgroup and so on, and they may be the same or different, and may contain from 1 to 4 substituents.

Examples of "C1-6alkoxygroup" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy and so on; examples of the "C3-10cycloalkylcarbonyl" include cyclopropylamino, cyclohexyloxy and so on; examples of the "C6-10alloctype" include phenoxy, naphthyloxy and so on; examples of C7-19aralkylated" include benzyloxy, 1-phenylethylene, 2-phenylethylene, benzhydrylamine and so on; examples of C1-6allylthiourea (the sulfur atom may be oxidized) " include methylthio, ethylthio, n-propylthio, n-butylthio, methylsulfinyl, methylsulphonyl, etc.;

Piloto, cyclopentylmethyl, cyclohexylmethyl and so on; examples of the "C6-10aristocraty (the sulfur atom may be oxidized)" include phenylthio, naphthylthio, phenylsulfinyl, phenylsulfonyl and so on; examples of the "C7-19arkitip (the sulfur atom may be oxidized)" include benzylthio, feniletilic, benzhydryl, benzylmorphine, benzylmethyl etc.;

examples of "mono-C1-6alkylamino include methylamino, ethylamino, n-propylamino, n-butylamino and so on; examples of the "di-C1-6alkylamino include dimethylamino, diethylamino, methylethylamine, di(n-propyl)amino, di(n-butyl)amino, and so on; examples of the "three-C1-6alkylammonium" include trimethylammonio and so on; examples of the "C3-10cycloalkylation" include cyclopropylamino, cyclopentylamine, cyclohexylamine and so on; examples of the "C6-10killingray" include aniline, N-methylaniline and so on; examples of C7-19aralkylamines" include benzylamino, 1 phenylethylamine, 2-phenylethylamine, benzhydrylamine etc.;

examples of the "cyclic amino group" include a 1-pyrrolidinyl, piperidino, 1-piperazinil, morpholino, thiomorpholine and so on; examples of the halogen atom include fluorine, chlorine, bromine, iodine and so on; examples of C1-10alkoxycarbonylmethyl, isobutoxide, tert-butoxycarbonyl, cyclopentanecarbonyl, cyclohexyloxycarbonyl, norbornenedicarboxylic and so on;6-10aryloxyalkyl group" includes phenoxycarbonyl, naphthalocyanines etc.;

examples of "C7-19aralkylamines group" include benzyloxycarbonyl, benzylaminocarbonyl and so on ; examples of the "C6-10arylcarboxylic group" include benzoyl, Naftoli, phenylacetyl and so on; examples of C1-6alkanoyloxy" include formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl, etc.; examples "3-5alkanoyloxy include acryloyl, crotonoyl and so on; examples of the "C6-10arylcarboxylic include benzoyloxy, naphthyloxy, phenylacetate and so on; examples of the "C2-6alkanoyloxy include acetoxy, propionyloxy, butyryloxy, valeriote, pivaloyloxy etc.;

examples "3-5alkanoyloxy" include acryloyloxy, crotonville and so on; examples of the "optionally substituted carbamoyl group" include carbamoyl group which may be substituted by one or two substituents selected from C1-4alkyl groups (e.g. methyl, ethyl, and so on), a phenyl group, a C1-7acyl group (e.g. acetyl, propionyl group, and its specific examples include carbarnoyl, N-methylcarbamoyl, N-ethylcarbazole, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-phenylcarbamoyl, N-acetylmuramyl, N-benzylcarbamoyl, N-(p-methoxyphenyl)carbarnoyl, 1-pyrrolidinylcarbonyl, piperidinylcarbonyl, 1-piperazinylcarbonyl, morpholinoethyl etc.;

examples of "optionally substituted thiocarbamoyl group" include thiocarbamoyl group which may be substituted by one or two substituents selected from C1-4alkyl groups (e.g. methyl, ethyl etc.,) and phenyl group, and its specific examples include thiocarbamoyl, N-methylthiocarbamate, N-phenylthiocarbamoyl and so on; examples of the "optionally substituted carbamoyloximes include carbamoyloximes, which can be substituted by one or two substituents selected from C1-4alkyl groups (e.g. methyl, ethyl etc.,) and phenyl groups, and their specific examples include carbamoylated, N-methylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbazole, N-phenylcarbamoyloxy etc.;

examples of "C1-6alkanolamines include acetamido, propionamido, butyramide, valeramide, pialligo and so on; examples of C6-10arylcarboxylic" include Benito (CH3N-), ethoxycarbonyl, tert-butoxycarbonylamino and so on; examples of the "C6-10kilometersnearby" include phenoxycarbonylamino (C6H5OCONH -), and so on; examples of the "C7-10uralelectrosetstroy" include benzyloxycarbonylamino (C6H5CH2OCONH-), benzylaminocarbonyl etc.;

examples of "C1-10alkoxycarbonylmethyl" include methoxycarbonylamino, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonylamino, n-ventilatsioonile, n-hexyldecanoic and so on ; examples of the "C6-10aryloxypropanolamine group" include phenoxycarbonylamino, naphthalocyanines and so on; examples of C7-19uralelectromontrage group" include benzyloxycarbonyloxy, 1 feniltiosemicarbazonele, 2-feniltiosemicarbazonele, benzylaminocarbonyl etc.;

examples "3-10cycloalkylcarbonyl group" include cyclopropanecarboxylate, cyclohexyloxycarbonyloxy and so on; and examples of the "optionally substituted raidgroup" include raidgroup, which may be substituted by 1-3 substituents selected from C1-4alkyl groups (e.g. methyl, e is telluride, 1,3-dimethylurea, 3 phenylurea etc.

In addition to those described above as the substituent of the "optionally substituted heterocyclic group" represented by R1use, for example, C1-6alkyl group, a C3-6cycloalkyl group4-7cycloalkylcarbonyl group2-3alkenylphenol group2-3alkylamino group6-10aryl group7-11aracelio group, etc. Examples, "C1-6alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and so forth; examples of the "C3-6cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.;

examples "4-7cycloalkylation group" include cyclopropylmethyl, cyclopentylmethyl and so on; examples of the "C2-3alkenylphenol groups include vinyl, propenyl and so on; examples of the "C2-3alkenylphenol group" include ethinyl, PROPYNYL, and so on ; examples of the "C6-10aryl group" include phenyl, naphthyl and so on; and examples "7-11aranceles group" include benzyl, phenethyl, naphthylmethyl and so on, the Number of these substituents in "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group", before what if there are several (2-4) deputies.

Heterocyclic group Deputy "hydrocarbon group" and "heterocyclic group and heterocyclic group in the heterocyclic ring exigrep, heterocyclic ring-tighrope, heterocyclic ring-sulfonylurea, heterocyclic ring-sulfonylurea and heterocyclic ring-amino group, respectively, represents a group obtained by removing one of the hydrogen atoms associated with the heterocyclic ring, and such heterocyclic ring is a 5-8-membered ring containing from 1 to several, preferably 1 to 4 heteroatoms (for example, a nitrogen atom (optionally oxidized), an oxygen atom, a sulfur atom, and so on), or a condensed ring.

Examples of heterocyclic groups include pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazole, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, pyrrolidinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinil, indolyl, pyranyl, tiopronin, dioxines, dioxole, hinely, pyrido[2,3-d]Piri is l, DIOXOLANYL, dioxane, etc., These heterocyclic groups may be substituted by 1-3 substituents selected from C1-4alkyl groups (e.g. methyl, ethyl, and so on ), hydroxyl group, carbonyl group and C1-4alkoxygroup (for example, methoxy, ethoxy and so on).

In the optionally substituted hydrocarbon group or heterocyclic group represented by R1as the "optionally substituted hydrocarbon group" is preferable to C1-6alkyl group (examples of C1-6alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and so on), which can be substituted by 1-3 substituents selected from hydroxyl, C1-6alkoxygroup,7-19aralkylated, C1-6allylthiourea, C1-6alkylsulfonyl, C1-6alkanolamines, C1-10alkoxycarbonyl group,

C7-19aracelikarsaalyna group, optionally substituted carbamoyl group, C1-10alkoxycarbonyl,7-10Uralelectromed and heterocyclic group (optionally substituted), and specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxymethyl, ethoxymethyl-2-propyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl,

1,3-dihydroxy-2-propyl, methylthiomethyl, methylsulfonylmethyl, atsetamidometil, 1-acetamidomethyl, 2-acetamidomethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, 1-ethoxycarbonylethyl, 2-ethoxycarbonylethyl, 1-methoxycarbonyl-1-methylethyl, 1-etoxycarbonyl-1-methylethyl, 1-tert-butoxycarbonyl-1-methylethyl, 1-benzyloxycarbonylation, 1-benzyloxycarbonyl-1-methylethyl, carbamoylmethyl, N,N-dimethylcarbamoyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, benzyloxycarbonylamino,

2-ethoxycarbonylethyl, 2-furylmethyl, 2-tetrahydrofuranyl, 1,3-dioxolane-2-ylmethyl, 1,3-dioxolane-4-ylmethyl, 2-oxo-1,3-dioxolane-4-ylmethyl, 2,2-dimethyl-1,3-dioxolane-4-ylmethyl, 1,3-dioxane-5-ylmethyl, 1-etoxycarbonyl-1-(2,3,4-trihydroxyphenyl)methyl, 1-acetamido-2-etoxycarbonyl, 1-acetamido-3-ethoxycarbonylphenyl, 2-acetamido-2-ethoxycarbonylethyl, 3-acetamido-3-ethoxycarbonylmethyl, 1-acetamido-2-carbamoylethyl, 1-acetamido-3-carbamoylmethyl etc.

In the row above C1-6alkyl groups which may be substituted by 1-3 substituents, preferred FCU is isopropyl, n-butyl, isobutyl, tert-butyl, and so on; and linear or branched C1-4alkyl groups, substituted hydroxyl group, C1-6alkoxygroup, C1-10alkoxycarbonyl group, a heterocyclic group (optionally substituted), etc. such as 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 1,3-dihydroxy-2-propyl, 2-methoxyethyl, 2-ethoxyethyl, 3-benzyloxyphenyl, ethoxycarbonylmethyl, 1-ethoxycarbonylethyl, 1-benzyloxycarbonylation, 2-furylmethyl, 2-tetrahydrofuranyl, 1,3-dioxolane-4-ylmethyl, 2-oxo-1,3-dioxolane-4-ylmethyl, 2,2-dimethyl-1,3-dioxolane-4-ylmethyl etc.

In the optionally substituted hydrocarbon group or heterocyclic group represented by R1as the "optionally substituted heterocyclic group" is preferable heterocyclic group substituted by 1-3 substituents selected from the carbonyl group, hydroxyl group, C1-6alkyl group, a C1-6alkoxygroup and so on, and its concrete examples include furyl, thienyl, pyranyl, tiopronin, dioxines, dioxole, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, DIOXOLANYL, dioxane, methylphenyl, hydroxyphenyl, matiltan, methoxyphenyl, 2-oxo-1,3-dioxole, 2,2-dimed. Among them, furyl, thienyl, dioxane, 2-oxo-1,3-dioxane, 2,2-dimethyl-1,3-dioxane are particularly preferred.

Examples of the lower alkyl groups represented by R2include a lower alkyl group having 1-4 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and so on), and methyl is particularly preferred.

As R2particularly preferred are a hydrogen atom or methyl.

X represents a nitrogen atom or a methine group, and preferred is a nitrogen atom.

Examples of the optionally oxidized sulfur atom represented by X2include tio, sulfinil and sulfonyl.

m and R respectively represent an integer of 0 or 1, and preferable is the case when both of them equal to 0.

Examples of the substituent in the "optionally substituted phenyl group represented by Ar, include halogen (e.g. fluorine, chlorine, bromine, iodine and so on), halogenated lower (C1-4) alkyl group (for example, vermeil, trifluoromethyl, chloromethyl, 1-foretel, 2-foretel, 1,1-dottorati, 1,2-dottorati and so on) and halogenated lower (C1-4) alkoxygroup (for example, ferredoxin, 2,2,2-triptoreline, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropane and so on). Preferably, the Deputy represents halogen (e.g. fluorine, chlorine, bromine, iodine and so on) and the most preferred fluorine. The number of substituents is preferably from 1 to 3, more preferably from 1 to 2.

Preferred examples of AG include halogenfrei group, a (halogenated lower (C1-4) alkyl)phenyl group, a (halogenated lower (C1-4) alkoxy) phenyl group, etc. Examples halogenfrei groups include 2,4-differenl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-forfinal, 2-chlorophenyl, 2-forfinal, 2-fluoro-4-chlorophenyl, 2-chloro-4-forfinal, 2,4,6-tryptophanyl, 4-bromophenyl etc. Examples (halogenated lower (C1-4) alkyl) phenyl group include 4-triptoreline etc. Examples (halogenated lower (C1-4) alkoxy) phenyl group include 4-trifloromethyl, 4-(1,1,2,2-tetrafluoroethoxy)phenyl, 4-(2,2,2-tripteroides)phenyl, 4-(2,2,3,3-tetrafluoropropoxy) phenyl, 4- (2,2,3,3,3-pentafluoropropane)phenyl, etc.

Particularly preferred examples AG is a phenyl group substituted by 1-2 halogen, such as 2,4-differenl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-forfinal, 2-chlorophenyl, 2-phthora, such as 4-forfinal, 2-forfinal, 2,4-differenl etc., is particularly preferred and most preferred 2-forfinal and 2,4-differenl.

The anion represented by Y-is an anion obtained by removing one proton from an organic acid or inorganic acid, and examples of organic acids include acetic acid, propionic acid, methanesulfonate acid, benzosulfimide acid, toluensulfonate acid, triftormetilfullerenov acid, triperoxonane acid and so on, and examples of inorganic acids include hydrochloric (hydrochloric) acid, sulfuric acid, phosphoric acid, hydrofluoric acid, Hydrobromic acid, idiscovered acid, water, etc. as Y-the anion resulting from removal of one proton from an inorganic acid, is preferred. Among them anion resulting from removal of one proton from halogen acids such as hydrochloric acid, hydrofluoric acid, Hydrobromic acid, itestosterone acid, etc. are preferable, and the anion obtained by removing one proton from chlorotoluron. Y-can be defined as a group that has a negative charge, and its preferred examples include CL-, F-, Br-I-, S3-, HSO4-N2RHO4-HE-and so on, Among them, CL-, F-, Br-I-are preferred and CL-, VG-and I-are particularly preferred.

Examples of the lower alkyl groups represented by R3, R4and R5include linear or branched alkyl group having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. Among them, methyl is particularly preferred.

When R3and R4or R4and R5combined with the formation of the lower alkalinous group, examples of the lower alkalinous groups include those which have from 1 to 4 carbon atoms, such as methylene, ethylene, propylene, butylene, etc., When R3and R4combined with the formation of the lower alkalinous group, methylene and ethylene are preferred. When R4and R5combined with the formation of the lower alkalinous group, ethylene is preferred.

R3hydrogen atoms or methyl groups, or one of them represents a hydrogen atom and the other represents a methyl group. More preferably, one of R4and R5represents a hydrogen atom, and the second represents methyl.

Examples of the "optionally substituted hydrocarbon group or optionally substituted heterocyclic group" represented And include the same groups as described for R1. Preferably a represents a group of the formula:

< / BR>
where R6represents an optionally substituted hydrocarbon group or aromatic heterocyclic group; and Z represents optionally substituted lower alkylenes group or a group of the formula:

-D=E-,

where D and E may be the same or different and represent a nitrogen atom or a methine group which may be substituted by lower alkyl)). Examples of the hydrocarbon group in the "optionally substituted hydrocarbon group" represented by R6include aliphatic hydrocarbon group, aromatic hydrocarbon group and aromaticheski-aliphatic hydrocarbon group.

Examples of the aliphatic hydrocarbon group include alkyl group, cycloalkyl, alkenyl, quinil etc. Examples alkylene is given to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, heptyl, octyl, nonyl, decyl, dodecyl, etc. Among them, lower alkyl groups having from 1 to 4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and so on), are particularly preferred.

Examples cycloalkyl groups include cycloalkyl group having from 3 to 8 carbon atoms. Their specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc. Among them cycloalkyl group having from 3 to 6 carbon atoms (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so on), is especially preferred. Examples alkenylphenol groups include alkenylphenol group having from 2 to 4 carbon atoms. Specific examples include vinyl, propenyl, butenyl etc. Among them Alchemilla group having 2-3 carbon atoms (e.g. vinyl, propenyl and so on), is especially preferred.

Examples alkenylphenol groups include alkylamino group having from 2 to 4 carbon atoms. Specific examples include ethinyl, PROPYNYL, butynyl etc. Among them Alchemilla group having 2-3 carbon atoms (for example, atopy include aryl group, having from 6 to 14 carbon atoms. Examples of aryl groups include phenyl, naphthyl, biphenylyl, antril, indenyl etc. Among them aryl group having from 6 to 10 carbon atoms (for example, phenyl, naphthyl and so on), is especially preferred.

Examples aromaticheski-aliphatic hydrocarbon groups include arylalkyl group having from 7 to 15 carbon atoms. Specific examples include benzyl, phenethyl, phenylpropyl, naphthylmethyl, indanyl, inanimate, 1,2,3,4-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthalene, biphenylyl, benzhydryl etc. Among them kalkilya group having from 7 to 11 carbon atoms (e.g. benzyl, phenethyl, naphthylmethyl and so on), is especially preferred.

Examples of the aromatic heterocyclic group in the "aromatic heterocyclic group which may have a substitute, presents R6include aromatic heterocyclic group containing at least one heteroatom selected from a nitrogen atom, sulfur atom and oxygen atom. Aromatic heterocyclic group may be condensed with a benzene ring or a 5 - or 6-membered heterocyclic ring.

Examples of the aromatic heterocycle pyrazolyl, predil, thiazolyl, thiadiazolyl, thienyl, furyl, pyrrolyl, pyrazinyl, pyrimidinyl, oxazolyl, isooxazolyl and so on; and condensed aromatic heterocyclic groups such as benzimidazolyl, imidazopyrimidines, imidazopyridines, imidazopyridines, imidazopyridines, benzothiazolyl, hinely, ethanolic, hintline, indolyl, etc. as the aromatic heterocyclic group are particularly preferred 5-or 6-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected optionally from nitrogen atom, sulfur atom and oxygen atom (for example, imidazolyl, triazolyl, thiazolyl, thiadiazolyl, thienyl, furyl, pyridyl, pyrimidinyl and so on).

Examples of the substituent in the "aliphatic or aromatic aromaticheski-aliphatic hydrocarbon group which may have a Deputy or an aromatic heterocyclic group which may have a substitute, presents R6include hydroxyl group, optionally esterified carboxyl group (for example, carboxyl, alkoxycarbonyl having from 1 to 6 carbon atoms, such as methoxycarbonyl, etoxycarbonyl, butoxycarbonyl and so on), the nitro-group, amino group, alluminare (n and so on),

the amino group which is mono - or tizamidine alkyl group having from 1 to 10 carbon atoms (for example, methylamino, dimethylamino, diethylamino, dibutylamino and so on), optionally substituted 5-6-membered cyclic amino group (for example, pyrrolidinyl, morpholino, piperidino, pyrazolidine, peligrosamente, piperazinil, 4-benzylpiperazine, 4-acetylpiperidine, 4-(4-trifloromethyl)-1-piperazinil, 4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl] -1-piperazinil, 4-[4-(2,2,3,3 - tetrafluoropropoxy)phenyl]-1-piperazinil, 4-[4-(2,2,2-triptoreline)phenyl] -1-piperazinil, 4-[4-(2,2,3,3,3-pentafluoropropane)phenyl] -1-piperazinil, 4-(4-triptoreline)-4-piperazinil and so on),

alkoxygroup having from 1 to 6 carbon atoms (e.g. methoxy, ethoxy, propoxy, butoxy and so on), halogen atom (e.g. fluorine, chlorine, bromine and so on ), the alkyl group having from 1 to 6 carbon atoms (e.g. methyl, propyl, butyl, and so on ), cycloalkyl group having from 3 to 6 carbon atoms (for example, cyclopropyl, cyclopentyl and so on), halogenating group having from 1 to 6 carbon atoms (for example, trifluoromethyl, dichloromethyl, triptorelin and so on), halogenlampe having from 1 to 6 carbon atoms (for example, triptoreline, 1,1,2,2-tetrafluoroethoxy, 2,2,2-triperoxonane, toolsgroup, mercaptopropyl, allylthiourea having from 1 to 6 carbon atoms (e.g. methylthio, ethylthio, butylthio and so on), alkylsulfonyl group having from 1 to 6 carbon atoms (for example, methanesulfonyl, econsultancy, butanesulfonyl and so on), alkanoyloxy group having from 1 to 10 carbon atoms (for example, acetyl, formyl, propionyl, butyryl and so on ), 5 - or 6-membered aromatic heterocyclic group (for example, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, furutani, 1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,4-thiadiazolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyridazinyl and so on)

and condensed aromatic heterocyclic group (for example, benzimidazolyl, imidazopyrimidines, imidazopyridines, imidazopyridines, imidazopyridines, benzothiazolyl, hinely, ethanolic, chinadoll, indolyl, and so on ). Among them halogenlampe having from 1 to 6 carbon atoms and a 5-membered aromatic heterocyclic group are preferred, and 1,1,2,2-tetrafluoroethoxy, 2,2,3,3-tetrafluoropropoxy, pyrazolyl (for example, 1H-pyrazole-1-yl), imidazolyl (for example, 1H-imidazol-1-yl), 1,2,3-triazolyl (for example, 1H-the-1-yl, 2H-tetrazol-2-yl) are particularly preferred.

Among the above substituents is preferably from 1 to 3, more preferably from 1 to 2.

Aliphatic, aromatic or aromaticheski-aliphatic hydrocarbon group which may have a Deputy, or an aromatic heterocyclic group which may have a Deputy, presents R6preferably represents an aromatic hydrocarbon group which may have a Deputy, more preferably a phenyl group having a substituent. Among them, particularly preferred are a phenyl group, substituted halogenoalkane group having from 1 to 6 carbon atoms (for example, 4-(1,1,2,2-tetrafluoroethoxy)phenyl, 4-(2,2,3,3-tetrafluoropropoxy)phenyl and phenyl group, a substituted 5-membered aromatic heterocyclic group [e.g., 4-(1H-pyrazolyl-1-yl)phenyl, 4-(1H-imidazol-1-yl)phenyl, 4-(1H-1,2,3-triazole-1-yl)phenyl, 4-(2H-1,2,3-triazole-2-yl)phenyl, 4-(1H-1,2,4-triazole-1-yl)phenyl, 4-(1H-tetrazol-1-yl)phenyl, 4-(2H-tetrazol-2-yl)phenyl].

Lower Allenova group in the "optionally substituted lower alkalinous group" represented by Z include groups having from 1 to 3 atoms uglier in the "optionally substituted lower alkalinous group" preferably represents a linear or branched alkyl group, having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc. Among them, methyl and ethyl are more preferred, and particularly preferred is methyl.

Preferred examples of the ethylene group which may be substituted by a lower alkyl group, which is represented by Z include ethylene, 1-mutilation, 1,1-dimethylethylene, 1,2-dimethylethylene, 1-ethylethylene, 1,2-diethylethylene etc. Among them, ethylene is particularly preferred.

When Z is D=E, examples of the lower alkyl groups in retinovoy group which may be substituted by lower alkyl group" represented by D or E, include linear or branched alkyl group having from 1 to 4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and so on). Among them, methyl is preferred.

Preferred examples of retinovoy group which may be substituted by a lower alkyl group represented by D or E, include Metin, tilidin (-C(CH3)=), propylidene (-C(CH2CH3)=), butylidene (-C(CH2CH2CH3= ), and so on, Among them, preferred are memom nitrogen, and the other is Metin; case when both D and E are Metin; case when both D and E are nitrogen atoms; and the case when one of D and E represents a nitrogen atom, and the other of them is ethylidene, are preferred. Among them the case when one of D and E represents a nitrogen atom and the other represents Metin, and the case when both D and E are Metin, are particularly preferred.

Specifically, Z preferably represents-N=CH-, -CH=N-, -CH=CH-, -N=N-N= C(CH3)-, -C(CH3)=N, -CH2-CH2and so on, Among them, N=CH-, -CH=N-, -CH=CH-, -CH2-CH2and so on are more preferable, a N=CH-, -CH2-CH2- are most preferred.

As the group represented by the formula:

< / BR>
for example, such groups as:

< / BR>
< / BR>
< / BR>
< / BR>
etc. are preferred. Among them

< / BR>
< / BR>
etc. are particularly preferred. Also, when reactive atom such as nitrogen atom, is present in the optionally substituted hydrocarbon group or optionally substituted heterocyclic group represented by a, group of the formula

< / BR>
wherein each symbol is as defined above, m is ical carbon atoms, there are two or more stereoisomers, and the stereoisomers and their mixtures are also included in the present invention. In the compound represented by the General formula (Ia), when Q is a group represented by the formula (II), And is

< / BR>
m and p are both equal to O, R4represents a hydrogen atom, and R5represents a methyl group, particularly preferred is an optically active compound in which both carbon, which is associated optional substituted phenyl group represented by Ar, and the carbon attached to R5have the (R) configuration.

In the formula (Ia), when Q is a group represented by the formula (II), formula (Ia) can also be expressed by the formula:

< / BR>
< / BR>
wherein each symbol is as defined above.

Compounds of the present invention may be a hydrate, and dehydrate. Compounds of the present invention are converted in vivo into compounds with antifungal activity, represented by the formula:

< / BR>
wherein each symbol is as defined above.

Specific examples of compounds according to the present invention are shown in tables 1-4, but are not limited to present the ing group, which can be chipped off in vivo, an antifungal compound containing an imidazole-1-ilen group or 1,2,4-triazole-1-ilen group.

Examples of antifungal compounds having an imidazole-1-ilen, or 1,2,4-triaal-1-ilen group include

known azole protivogribkovye compounds such as miconazole, ketoconazole, fluconazole, Itraconazole, saperconazole, clotrimazole, D0870, voriconazole, econazole, isoconazole, sulkonazol, butoconazole, tioconazole, bifonazole, oxiconazole, terconazole, SSY-726, CR-103, Sch-56592, Sch-51048, UR-9746, MFB-1041, UR-9751, UR-9728, UR-9825, ER-30346, T-8581, BAY-W-9279, fenticonazole, omoconazole, flutrimazole, Berganza, lanoconazole, neticonazole, sertaconazole, genkonsul croconazole and so on, but are not limited to known antifungal agents.

The compound (Ia-1) [compound (Ia), where Q is a group represented by the formula (II)] can be obtained, for example, by the interaction of the compound (III) with the compound represented by formula (IV):

< / BR>
where Y1represents a halogen atom, and other symbols are as defined above, hereinafter referred to sometimes as compound (IV) and optionally with subsequent anion exchange reaction product.

The atom halogeno compound (III) and compound (IV) is usually carried out in the presence of a solvent, which does not inhibit the reaction, or without it. As not inhibiting the reaction solvent used, for example, ketones (e.g. acetone, 2-butanone, 2-pentanone and so on), sulfoxidov (for example, dimethyl sulfoxide and so on), ethers (e.g. diethyl ether, tetrahydrofuran, dioxane and so on), NITRILES (e.g. acetonitrile, and so on ), aromatic hydrocarbons (e.g. benzene, toluene, xylene and so on), halogenated hydrocarbons (e.g. dichloromethane, chloroform, 1,2-dichloroethane and so on ), esters (e.g. ethyl acetate, and so on), amides (e.g. dimethylformamide, ndimethylacetamide, dimethylacetamide, 1-methyl-2-pyrolidinone and so on) and urea (for example, 1,3-dimethyl-2-imidazolidinone). These solvents may be used individually or in combination at an appropriate ratio.

The compound (IV) is used in an amount of from 1 to 100 equivalents, preferably 1 to 5 equivalents based on compound (III).

The reaction temperature is not limited to any particular way, but it usually ranges from 0 to 150oC, preferably from about 20 to 120oC.

The reaction time is from several minutes to several hundred hours (for example from 5 minutes to 100 hours, and so on).

-by anion exchange. Anion exchange can be carried out by treating the ion exchange resin of the anionic type, or salt of an alkali metal (e.g. sodium, potassium and so on ) of organic or inorganic acids described above for the Y-in the presence of water, a mixed solvent of water and an organic solvent (e.g. acetone, acetonitrile, tetrahydrofuran, methanol, ethanol, etc. or an organic solvent.

The compound (I) of the present invention (hereinafter referred to sometimes as the present compound (I) thus obtained can be isolated and purified from the reaction mixture using known by themselves methods, such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin layer chromatography, etc.

When the present compound (I) has one or more asymmetric carbon atoms in the molecule, there are two or more stereoisomers, these isomers may be, if desired, the obtained separately. For example, when the starting compound (III) and (IV) have an asymmetric carbon atom in the molecule, can be obtained individual isomer of this soy is e, individual isomer, the reaction of the compound (Ia) can be obtained by the implementation of the above reactions using individual isomer of the original compound (III). Also, in the case when the product is a mixture of two or more kinds of isomers, the product can be separated using conventional separation methods, for example, such methods of separation as various types of chromatography and fractional recrystallization.

When the original compound (III) of the present invention is a known himself described above, an antifungal agent, the method of obtaining such compounds are known, and also well-known in themselves ways of getting a number of compounds which are useful as antifungal agents, for example, the methods described in the publication of the Japan patent Kokai No.Hei 6-293740, publications of the Japan patent Kokai No.Hei 8-104676 and WO-9625410A. Furthermore, the method of obtaining the other starting compound (IV) is also known, and the connection can be obtained by the method described in Synthesis, page 588 (1971) and Synthetic Communications, Vol.25, page 2739 (1995), or a method based on this method.

As the present compound (I) has low toxicity and strong antifungal action is s Aspergillus [for example, Aspergillus niger, Aspergillus fumigatus, and so on ] , the genus Cryptococcus [e.g., Cryptococcus neoformans, and so on], genus Trichophyton [e.g., Trichophyton rubrum, Trichophton mentagrophytes and so on], genus Microsporum [e.g., Microsporum gypseum, and so on], genus Mallassezia [for example, Mallassezia furfur and so on] and so on, it can be used for the prevention and treatment of fungal infections [e.g., candidiasis of the mucous membrane (candidal stomatitis, angular stomatitis, vulvovaginal candidiasis, candidal balanoposthitis (inflammation of the skin of the glans penis) and urethritis), cutaneous candidiasis (mitigatory candidiasis, intertriginoznoy candidiasis (candidiasis of skin folds), perianal candidiasis, blastomycosis skin eczematous, candidiasis onychia (a fungal infection of the nails), candidiasis paradisia (inflammation okolonogtevogo tissues), candidiasis fibrillation, fungal infections of the skin, diffuse superficial candidiasis, granulomatous candidiasis, congenital cutaneous candidiasis, candids), chronic mucocutaneous candidiasis and systemic candidiasis (candidiasis respiratory tract candidiasis of the gastrointestinal tract, infection candidiasis, endocardial candidiasis, candidiasis of the urinary tract, Candida eyes, candidiasis of the Central nervous system, candidiasis of bones and joints, peritoneal candidiasis, candidiasis paragraph is about and disseminated histoplasmosis (disseminated) histoplasmosis, etc. due to the genus Histoplasma; aspergillosis respiratory (allergic aspergillosis, bronchial aspergillosis, aspergilloma, pulmonary aspergillosis (acute invasive pulmonary Aspergillus, chronic necrotizing pulmonary aspergillosis, Aspergillus empyema), disseminated aspergillosis aspergillosis of the Central nervous system Aspergillus endocarditis, Aspergillus myocarditis, Aspergillus pericarditis, Aspergillus of mycetoma, Aspergillus of otomycosis, the Aspergillus onihei, Aspergillus paronychia, Aspergillus keratitis, Aspergillus of endophthalmitis, cutaneous aspergillosis and nasal-orbital aspergillosis, etc. at the expense of the genus Aspergillus; pulmonary cryptococcosis, cryptococcosis of the Central nervous system, cutaneous and mucocutaneous of cryptococcosis, bone cryptococcosis, cryptococcosis lymph nodes, disseminated cryptococcosis and cryptococcosis hematopoietic organs (blood-forming organs), etc. at the expense of the genus Cryptococcus, ringworm, mange, kerÝon Celsus (infiltrative suppurative trichophytosis), tinea, trihofitii spotted-vesicular, trihofitii eczematous krugovidnoe, tropical krugovidnoe mycosis, trihofitii valderrabano, is mataikona colored, etc. due to the genus Mallassezia] in mammals (e.g. humans, domestic animals, poultry and so on) and also for the prophylaxis or treatment of idiopathic dermatitis. Moreover, the compound (I) of the present invention can be used as an agricultural antifungal agent.

When the present compound (I) is administered to human, it can be safely administered orally or parenterally in the form of pharmaceutical compositions, for example, oral administration (for example, powder, granule, tablet, capsule and so on), parenteral (e.g., injection, external agent (e.g., nasal introduction, subcutaneous administration, and so on) and suppository (e.g., rectal suppository, vaginal suppository, etc.)], alone or in combination with appropriate pharmaceutically acceptable carriers, excipients, diluents, etc.

These drugs can be obtained well-known in itself in a way that is usually used in the production process. The proportion of this compound (I) in preparations varies depending on their shape and can vary in the range normally used for antifungal agent. For example, it ranges from about 10 to 95% in interlego introduction.

For example, the preparation for injection can be obtained by mixing the present compound (I) with dispersing agents [e.g., Tween 80 (manufactured by Atlas Powder, USA), HCO 60 (manufactured by Nikko Chemicals Co. ), carboxymethylcellulose, sodium alginate, etc.], a preservative (e.g. methylparaben, propylparaben, benzyl alcohol, chlorobutanol and so on ) and isotonic agents (e.g. sodium chloride, glycerol, sorbitol, glucose etc ) with formation water injection solution, or by dissolving, suspension or emulsification in vegetable oils (such as olive oil, sesame oil, peanut oil, oil from cotton seeds, corn oil, and so on), propylene glycol, etc. with the formation of oil injection.

The preparation for oral administration can be obtained by adding excipients (e.g. lactose, sucrose, starch and so on), disintegrators (e.g., starch, calcium carbonate), binders (e.g. starch, gum Arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose and so on) and lubricants (e.g. talc, magnesium stearate, polyethylene glycol 6000, and so on) of the present compound (I), subjecting the mixture forms the mi by yourself ways to make property release in the intestine or property sustained release. As agent for coating, for example, can be used hypromellose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethyleneglycol, Tween 80, Pulronic P68, acetate phthalate cellulose phthalate of hydroxypropylmethylcellulose, acetate succinate of hydroxymethylcellulose, Oidora kid (produced Rhome Co., West Germany, the copolymer of methacrylic and acrylic acids) and a pigment (such as titanium oxide, iron oxide and so on).

The compound (I) according to the present invention can be used in the form of solid, semi-solid or liquid external drug. For example, solid outdoor product can be obtained by the use itself of the present compound (I) or by the addition of excipients (for example, glycerol, mannitol, starch, microcrystalline cellulose, and so on), thickeners (e.g., natural gums, cellulose derivatives, acrylic polymer, and so on) and so on to the present compound (I), followed by stirring with the formation of the powder composition. In the case of semi-external drug is preferable to use an aqueous or oily gel agent or ointments. In the case of liquid outside the drug he can for injection. To solid, semi-solid or water external preparations can be added pH regulators (for example, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, and so on) and preservatives (e.g., peroxybenzoate, chlorbutanol, chloride benzalconia and so on). In particular, the ointment containing petrolatum, lanolin, etc., in the form of foundations and from about 0.1 to 100 mg of the present compound (I) can be used for sterilization or disinfection of the skin or mucous membrane.

The present compound (I) can be incorporated into the oily or aqueous solid, semisolid or liquid suppository. In the case of a suppository examples of oil bases include glycerides of higher fatty acids [for example, cocoa butter, witepsol (produced by Dynamite Nobel Company) and so on ], the average fatty acid [e.g., microlevel acid (produced by Dynamite Nobel Company) and so on], and oil [e.g., sesame oil, soybean oil, lopokova oil]. Examples of aqueous bases include polyethylene glycols, propylene glycols and examples basics of water gels include natural gum, a derivative of cellulose, vinyl polymer, acrylic polymer, etc.

The dose of the present compound (I) is changed is antam (weight 50 kg) for the treatment of candidiasis dose is from about 0.01 to 100 mg/kg/day, preferably from about 0.1 to 50 mg/kg/day. More preferably, the dose is from about 0.5 to 10 mg/kg/day.

Two or more compounds of the present invention can be used to obtain preparations of the present invention and the compound of the present invention can be used in combination with one or more compounds with antifungal activity, different from the compounds of the present invention. When using the present compound (I) as an agricultural antifungal agent of the present compound (I) dissolved or suspended in a suitable liquid carrier (e.g. a solvent), or a mix, or absorb with a suitable solid carrier (e.g., diluent, filler and so on) and, if necessary, add emulsifiers, suspendida, spray, agents regulating the osmotic pressure, wetting agents, adhesives, stabilizers, etc. for the formation of the emulsion, hydrate, powder, granules, etc., These drugs can be obtained by known methods. To combat rice rot the amount of compound (I) of the present invention is preferably from about 25 can be used in combination with other agricultural antifungal agents.

As the liquid carrier can be used, for example, water, alcohols (e.g. methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, ethylene glycol and so on), ethers (e.g. dioxane, tetrahydrofuran, and so on), aliphatic hydrocarbons (e.g. kerosene, kerosene oil, fuel oil, and so on), aromatic hydrocarbons (e.g. benzene, toluene and so on). halogenated hydrocarbon (e.g. methylene chloride, chloroform, and so on), acid amides (e.g. dimethylformamide, dimethylacetamide, and so on), esters (e.g. ethyl acetate, butyl acetate, and so on) and NITRILES (e.g. acetonitrile, propionitrile and so on), and these liquid carriers may be used individually or combined in a suitable ratio.

As a solid carrier can be used, for example, vegetable flour (for example, soybean flour, tobacco flour, wheat flour, and so on), mineral powders (e.g. kaolin, bentonite and so on), alumina, sulfur powder, activated carbon and so on, and these solid carriers may be used individually or combined in a suitable ratio.

The best way of carrying out the invention

The following reference examples, examples, examples from the us to limit the scope of the invention.

1H-NMR spectra were registered on the spectrometer type Varian Gemini 200 (200 MHz) using tetramethylsilane as an external standard and all values are given in M. D. (ppm). Numerical values described in (a ) for the mixed solvent, represent the volume ratio when mixing for each solvent. "%" are given by weight, unless otherwise stated. The ratio of solvent by chromatography on silica gel presents a volume ratio of the mixed solvents.

The characters in the examples have the following meanings:

s: singlet; d: doublet; t: triplet, to: Quartet, DD, doublet of doublets, TT: triplet triplet, m: multiplet, ush.: broadened, J: the constant of spin-spin splitting.

Reference example 1

Tetrahydrofurfuryl alcohol (19,4 g) was dissolved in anhydrous diethyl ether (500 ml) and, after addition of pyridine (15 g) under ice cooling was added dropwise chloromethylphosphonate (25 g). After stirring the reaction mixture at room temperature for 17 hours, the precipitation of pyridine hydrochloride was removed by filtration and the filter cake washed with diethyl ether (50 ml of 2). Wash water and filtrate were combined, washed vodoy (2,3,4,5-tetrahydrofurfuryl)chlorocarbonate (33,9 g) as a colorless oily product.

1H-NMR (Dl3) : 1,59-of 1.73 (1H, m), 1,83-2,11 (3H, m), 3.75 to of 3.97 (2H, m), 4,11-4,34 (3H, m), 5,74 (2N, C).

(2,3,4,5-Tetrahydrofurfuryl)chlorocarbonate (3.4 g) and sodium iodide (10,46 g) was added to acetonitrile (70 ml) and then the mixture was heated at 60oC for 90 minutes. After cooling the reaction solution, the solvent is kept under reduced pressure and the residue was distributed between diethyl ether (70 ml) and saturated aqueous sodium chloride (50 ml). The organic layer is successively washed with aqueous 5% sodium thiosulfate solution (50 ml), water (50 ml) and saturated aqueous sodium chloride (50 ml) and then dried over anhydrous magnesium sulfate. The solvent is kept at reduced pressure, obtaining (2,3,4,5-tetrahydrofurfuryl) idletimeout (4.8 g) as a pale yellow oily product.

1H-NMR (Dl3) : 1,54-of 1.73 (1H, m), 1,84-2,11 (3H, m), of 3.73-of 3.96 (2H, m), 4,10-4,32 (3H, m), 5,96 (2N, C).

Reference example 2

Formal glycerol (14 g) was dissolved in anhydrous ether (400 ml) and after adding pyridine (15 g) at -10oC was added dropwise a solution of chloromethylphosphonate (25 g) in anhydrous diethyl ether (50 ml) for 10 minutes. After stirring the reaction solution at on ivali saturated aqueous sodium chloride (400 ml 2) and then dried over anhydrous magnesium sulfate. The residue obtained after removal of the solvent under reduced pressure was purified by chromatography on silica gel (eluent:ethyl acetate/hexane=1/5 --> ethyl acetate/hexane=1/3) to give (1,3-dioxane-5-yl)chlorocarbonate (1.7 g) as a colorless oily product.

1H-NMR (CDCl3) : of 4.05 (4H, d, J=3.2 Hz), of 4.67 (1H, quintet, J=3.2 Hz), 4,82 (1H, d, J=6.2 Hz), of 4.95 (1H, d, J=6.2 Hz), of 5.75 (2H, s).

The above compound (1.7 g) and sodium iodide (5,1 g) was added to acetonitrile (40 ml) and then the mixture was stirred under heating at 60oC for 2 hours. The residue obtained after removal of the solvent from the reaction mixture under reduced pressure, was dissolved in diethyl ether (100 ml). The solution is successively washed with aqueous 5% sodium thiosulfate solution (50 ml), water (50 ml) and saturated aqueous sodium chloride (50 ml) and then dried over magnesium sulfate. The solvent is kept at reduced pressure, obtaining (1,3-dioxane-5-yl)idletimeout (3.2 g) as a pale yellow oily product.

1H-NMR (CDCl3) : Android 4.04 (4H, d, J=3.0 Hz), of 4.66 (1H, quintet, J=3.0 Hz), to 4.81 (1H, d, J=6.2 Hz), of 4.95 (1H, d, J=6.2 Hz), 5,97 (2N, C).

Reference example 3

(R)-Glycerol acetonide (10 g) was dissolved in anhydrous simple everyoneat (10.7 g) in anhydrous diethyl ether (20 ml). After stirring the reaction mixture at room temperature for 20 hours the precipitation of pyridine hydrochloride was removed by filtration. The filtrate was washed with a saturated aqueous solution of sodium chloride (200 ml of 2) and then dried over anhydrous magnesium sulfate. The residue obtained after removal of the solvent under reduced pressure was purified by chromatography on silica gel (eluent: hexane --> ethyl acetate/hexane= 1/5 --> ethyl acetate/hexane=3/5), receiving [(4S)-2,2-dimethyl-1,3-dioxolane-4-yl)METHYLCHLOROSILANE (17 g) as a colorless oily product.

1H-NMR (CDCl3) : of 1.37 (3H, s) of 1.44 (3H, s), 3,80 (1H, DD, J=8,8, 5.8 Hz), 4,07 was 4.42 (4H, m), 5,74 (2-H, C).

The above compound (2 g) and sodium iodide (5.3 g) were added to acetonitrile (40 ml) and then the mixture was stirred under heating at 60oC for 2 hours. The residue obtained after removal of the solvent from the reaction mixture under reduced pressure, was dissolved in diethyl ether (50 ml). The solution is successively washed with aqueous 5% sodium thiosulfate solution (50 ml), water (50 ml) and saturated aqueous sodium chloride (50 ml) and then dried over magnesium sulfate. The solvent is kept at reduced pressure, obtaining [(4S)-2,2-dimethyl-1,3-di (Dl3) : of 1.37 (3H, s) of 1.44 (3H, s), with 3.79 (1H, DD, J=8,0, 5.0 Hz), 4,06-to 4.41 (4H, m), 5,96 (2N, C).

Reference example 4

To a solution of benzyl 4-hydroxybutanoic (synthesized by the method described by Weber et al., J. Med.Chern., 1991, 34, 2692-2701; 5.0 g) in diethyl ether (100 ml) was added pyridine (2.3 ml) under nitrogen atmosphere was added dropwise chloromethylphosphonate (3.7 g) at -10oC. the Reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was filtered through a glass filter and then the filtrate is then washed with water and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and the solvent is then drove away under reduced pressure, the thus obtained residue was subjected to column chromatography on silica gel, elwira a mixture of acetone/hexane (1:1 V/V) to give (3-benzyloxycarbonylamino)chlorocarbonate (7,25 g) as a colorless oily product.

1H-NMR (CDCl3) : 2,02-2,12 (2H, m), 2.49 USD (2H, t, J=7 Hz), 4,28 (2H, t, J=6 Hz), 5,13 (2H, s), 5,71 (2H, s), of 7.36 (5H, s).

To the solution obtained above compound (2.5 g) in acetonitrile (67 ml) was added sodium iodide (5.2 g) in a nitrogen atmosphere. The mixture was stirred at 60oWith over 8.5 hours. The solvent of othona the 5% aqueous solution of sodium thiosulfate, water and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure, obtaining (3-benzyloxycarbonylamino)idletimeout (2,98 g) as a pale yellow oily product.

1H-NMR (Dl3) : 2,01-of 2.08 (2H, m), 2.49 USD (2H, t, J=7 Hz), 4,28 (2H, t, J=6 Hz), 5,14. (2H, s) 5,94 (2H, s), of 7.36 (5H, s).

Reference example 5

To a mixture of ethyl (S)-lactate (23,6 g), pyridine (15,8 g) and diethyl ether (400 ml) was added dropwise a solution of chloromethylphosphonate (25.6 g) in diethyl ether (100 ml) with ice cooling for 40 minutes. After stirring at room temperature for 14 hours, the resulting solid product was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (250 ml). The solution was washed with water (150 ml 2) and saturated aqueous sodium chloride (150 ml). After drying over anhydrous magnesium sulfate, the solvent is kept at reduced pressure, obtaining [(1S)-1-(etoxycarbonyl)ethyl]chlorocarbonate (38,5 g) as a colourless liquid.

1H-NMR (Dl3) : of 1.30 (3H, t, J=7.2 Hz), of 1.57 (3H, d, J=7,0 Hz), 4,25 (2N, K, J= 7, 2 Hz), 5,07 (1N, K, J=7,0 Hz), 5,71 (1H, d, J=6.4 Hz), 5.80 (1H, d, J=6,4 Hz).

< dropwise under ice cooling over 30 minutes a solution of chloromethylphosphonate (of 21.9 g) in diethyl ether (100 ml). After stirring at room temperature for 5 hours, the resulting solid product was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (200 ml). The solution was washed with water (100 ml of 2) and saturated aqueous sodium chloride (100 ml). After drying over anhydrous magnesium sulfate, the solvent is kept at reduced pressure, obtaining [(1S)-1-(benzyloxycarbonyl)ethyl]chlorocarbonate (45,0 g) as a colourless liquid.

1H-NMR (CDCl3) : of 1.57 (3H, d, J=7 Hz), 5,07 is 5.28 (3H, m), 5,69 (1H, d, J=6 Hz), 5,78 (1H, d, J=6 Hz), 7.36 (5H, s).

[(1S)-1-(benzyloxycarbonyl)ethyl] chlorocarbonate (2.7 g) was dissolved in acetonitrile (4 ml) was added sodium iodide (6.0 g). The mixture was stirred at 60oC for 2 hours in argon atmosphere. After concentrating the reaction mixture under reduced pressure, to the residue was added diethyl ether (100 ml) and water (100 ml). A layer of diethyl ether was separated and sequentially washed with 5% aqueous sodium thiosulfate solution (80 ml), water (80 ml) and saturated aqueous sodium chloride (80 ml). After drying over anhydrous magnesium sulfate, the solvent is kept at reduced pressure, obtaining [(1S)-1-(benzyloxycarbonyl)e is 29 (3H, m) to 5.93 (1H, d, J=5 Hz), 5,98 (3H, d, J=5 Hz), 7.37 (5H, s).

Reference example 7

To a solution of 3-(benzyloxy)propanol (synthesized by the method described by Wei et al., J. Org.Chem., 54, 5768-5774 (1989); 15,1 g) and pyridine (7,18 g) in diethyl ether (150 ml) was added dropwise under ice cooling for 20 minutes a solution of chloromethylphosphonate (11,7 g) in diethyl ether (50 ml). After stirring at room temperature for 15 hours resulting solid product was removed by filtration and washed with ethyl acetate (100 ml). The filtrate and wash liquid were combined and washed with water (100 ml of 2) and saturated aqueous sodium chloride (50 ml). After drying the solution over anhydrous magnesium sulfate, the solvent is kept at reduced pressure. The residue was purified through chromatography on silica gel (silica gel 200 g, eluent: ethyl acetate-hexane= 1: 4) to give [3-(benzyloxy)propyl]-chlorocarbonate (21,0 g) as a colourless liquid.

1H-NMR (CDCl3) : 2,01 (2H, quintet, J=6.2 Hz), of 3.57 (2H, t, J=6.0 Hz), 4,36 (2H, t, J=6.4 Hz), 4,51 (2H, s), 5,71 (2H, s), 7,33 (5H, s).

[3-(Benzyloxy)propyl] chlorocarbonate (2.0 g) was dissolved in acetonitrile (3 ml) was added sodium iodide (4.6 g). The mixture was stirred in nitrogen atmosphere at 60oC for 2 hours. Recogni solution of sodium thiosulfate (50 ml of 2), water (50 ml of 2) and saturated aqueous sodium chloride (50 ml). After drying over anhydrous magnesium sulfate, the solvent is kept at reduced pressure, obtaining [3-(benzyloxy)propyl] idletimeout (2.5 g) as a pale yellow liquid.

1H-NMR (Dl3) : 2,00 (2H, quintet, J=6.2 Hz), of 3.57 (2H, t, J=6.0 Hz), 4,36 (2H, t, J=6.4 Hz), 4,51 (2H, s) 5,94 (2H, s), 7,34 (5H, s).

Reference example 8

To a mixture of 2-acetylaminophenol (20,0 g), pyridine (15.3 g) and tetrahydrofuran (100 ml) was added dropwise under ice cooling over 30 minutes a solution of chloromethylphosphonate of 25.2 g) in tetrahydrofuran (50 ml). After stirring at room temperature techenie 16 hours and the resulting solid product was removed by filtration and washed with tetrahydrofuran (30 ml). The filtrate and wash liquid were combined and concentrated under reduced pressure. To the residue was added ethyl acetate (300 ml) and water (100 ml) and the organic layer was separated. The aqueous layer was extracted twice with a mixture of ethyl acetate (150 ml) and tetrahydrofuran (50 ml). The organic layers were combined, washed with saturated aqueous sodium chloride (100 ml) and dried over anhydrous magnesium sulfate. The solvent is kept at reduced pressure. The residue was purified is the learn [2-(acetylamino)ethyl]chlorocarbonate (32,4 g) as a colourless oil.

1H-NMR (CDCl3) : a 2.01 (3H, s) to 3.58 (3H, K, J=Hz), 4,32 (2H, t, J=6 Hz), of 5.75 (2H, s), by 5.87 (1H, ush.)

[2-(Acetylamino)ethyl]chlorocarbonate (5.0 g) was dissolved in acetonitrile (15 ml) was added sodium iodide (15.0 g). The mixture was stirred at 60oC for 2 hours in argon atmosphere. The reaction mixture was poured into ice water (200 ml) and was extracted with ethyl acetate (200 ml). The extract is successively washed with 5% aqueous sodium thiosulfate solution (100 ml of 2), water (100 ml of 2) and saturated aqueous sodium chloride (50 ml). After drying over anhydrous magnesium sulfate, the solvent is kept at reduced pressure, obtaining [2-(acetylamino)ethyl]iodomethyl-carbonate (3.5 g) as a yellow oil.

1H-NMR (CDCl3) : 2,00 (3H, s), of 3.54 (3H, K, J=Hz), 4,28 (2H, t, J=6 Hz), to 5.93 (2H, s), 6,12 (1H, ush.)

Reference example 9

To a mixture of 3-(methoxy)propanol (6.0 g), pyridine (5.3 g) and diethyl ether (50 ml) was added dropwise over 15 minutes under ice cooling a solution of chloromethylphosphonate (8.6 g) in diethyl ether (10 ml). After stirring at room temperature for 16 hours was added water (100 ml) and ethyl acetate (100 ml) and the organic layer was separated. The organic layer was washed with water (100 ml) and saturated aqueous PI is the pressure. The residue was purified by chromatography on silica gel (silica gel 70 g, eluent:ethyl acetate-hexane=1:2) to give [3-(methoxy)propyl] chlorocarbonate (11,0 g) as a colourless liquid.

1H-NMR (l3) : of 1.97 (2H, quintet, J=6.2 Hz), to 3.34 (3H, s), 3,47 (2H, t, J=6.2 Hz), to 4.33 (2H, t, J=6.2 Hz), 5,74 (2N, C).

[3-(Methoxy)propyl] chlorocarbonate (3.7 g) was dissolved in acetonitrile (12 ml) was added sodium iodide (12.0 g). The mixture was stirred at 55oC for 4 hours in argon atmosphere. The reaction mixture was poured into water (100 ml) and was extracted with ethyl acetate (100 ml). An ethyl acetate layer is washed with aqueous 5% sodium thiosulfate solution (50 ml of 2), water (50 ml) and saturated aqueous sodium chloride (50 ml). After drying over anhydrous magnesium sulfate, the solvent is kept at reduced pressure, obtaining [3-(methoxy)propyl]idletimeout (5.0 g) as a pale yellow liquid.

1H-NMR (Dl3) : a 1.96 (2H, quintet, J=6.2 Hz), the 3.35 (3H, s), 3,47 (2H, t, J=6.2 Hz), to 4.33 (2H, t, J=6.2 Hz), 5,96 (2N, C).

Example 1

A mixture of 1-[(1R, 2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl] -3-[4-(1H-1,2,3-triazole-1-yl)phenyl] -2-imidazolidinone (0.25 g) and chloromethylphosphonate (3.0 g) was stirred for 24 hours at 100oC. Postcolonial chromatography on octadecyl-silicon dioxide (hereinafter briefly called ODK) (eluent:methanol/water= 3/2), getting chloride 1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3-triazole-1-yl)phenyl] -1-imidazolidinyl] butyl] -4-[(2,2-dimethylpropanoate)methyl] -1H-1,2,4-triazole (Connection 1, 0.10 g) as a white powder.

1H-NMR (d6-DMSO) : 0,97 (3H, d, J=7 Hz), 1,13 (N, C), 3,61~4,10 (4H, m), 4,65~ of 4.75 (1H, m), 4,89 (1H, d, J=14 Hz), 5,13 (1H, d, J=14 Hz), 6,17 (2H, s), 6,74 (1H, s), 6,91~7,01 (1H, m), 7,21~of 7.36 (2H, m), 7,82~to 7.93 (4H, m), 7,95 (1H, d, J=1.2 Hz), 8,79 (1H, d, J=1.2 Hz), 9,11 (1H, s), 10,53 (1H, s).

Example 2

A mixture of 1-[(1R, 2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl] -3-[4-(1H-1,2,3-triazole-1-yl)phenyl] -2-imidazolidinone (0.5 g) and chloromethylphosphonate (3.1 g) was stirred for 2 hours at 100oC. After cooling, the mixture was diluted with diisopropyl ether (10 ml) and the resulting powder was filtered. The powder was subjected to flash chromatography on silica gel (eluent: ethyl acetate --> acetone --> acetone/ethanol=10/1 --> acetone/ethanol= 5/1) to give chloride 1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3-triazole-1-yl)phenyl] -1-imidazolidinyl] butyl] -4-[(2,2-dimethylpropanoate)methyl] -1H-1,2,4-triazole (Connection 1, 0.34 g) as a white powder.

Example 3

A mixture of 1-[(1R, 2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl] -3-[4-(1H-1,2,3-triazole-1-yl)phenyl] -2-imide is followed by a session was diluted with diisopropyl ether (10 ml) and the resulting powder was filtered. The powder was subjected to column chromatography CHP-20P (eluent: water --> 5% aqueous solution of acetonitrile --> 30% aqueous solution of acetonitrile --> 5% aqueous solution of tetrahydrofuran --> 10% aqueous solution of tetrahydrofuran --> 20% aqueous solution of tetrahydrofuran), receiving dichloride, 1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-[3-(2,2-dimethylpropanoate)methyl-1(1H)-1,2,3-triazolo] phenyl]-1-imidazolidinyl]butyl]-4-(2,2-dimethylpropanoate)methyl] -1H-1,2,4-triazole (Compound 8, 134 mg) as a white powder and compound 1 (141 mg) as a white powder.

Compound 8: 1H-NMR (d6-DMSO) : 0,97 (3H, d, J=6.8 Hz), 1,13 (N, C), 1,21 (N, C), 3,63-3,66 (1H, m), 3,98-to 4.15 (3H, m), 4,62-4,78 (1H, m), 4,88 (1H, d, J= 14 Hz), 5,23 (1H, d, J=14 Hz), 6,17 (2H, s), only 6.64 (2H, s), to 6.88 (1H, s), 6.90 to-7,00 (1H, m), 7,21 and 7.36 (2H, m), 7,98 (2H, d, J=9.8 Hz), with 8.05 (2H, d, J=9.8 Hz), 9,10 (1H, s), 9,34 (1H, d, J=2.0 Hz), 9,68 (1H, d, J=2.0 Hz), at 10.64 (1H, s).

Example 4

To a mixture of 1-[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl] -3-[4-(1H-tetrazol-1-yl)phenyl] -2-imidazolidinone (0,48 g) and acetone (10 ml) was added climatereport (2,9 ml) and the mixture was stirred at the boil under reflux. After 88 hours to the mixture was added climatereport (1,45 ml). The mixture was additionally stirred for 14 hours at the boil is etilogy ether (8 ml) and the resulting powder was filtered. The powder was subjected to ODS column chromatography (eluent: methanol/water= 3/2), receiving chloride 1-[(2R/3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl] -4-[(2,2-dimethylpropanoate)methyl] -1H-1,2,4-triazole (Compound 2, 0.25 g) as a white powder.

1H-NMR (d6-DMSO) : 0,97 (3H, d, J=7 Hz), 1,13 (N, C), 3,61~4.09 to (4H, m), 4,65~ of 4.75 (1H, m), 4,88 (1H, d, J=14 Hz), 5,14 (1H, d, J=14 Hz), 6,16 (2H, s), of 6.75 (1H, s), 6, 91~7,01 (1H, m), 7,21~7,37 (2H, m), of 7.90 (4H, s), 9,10 (1H, s), 10,07 (1H, s), 10,53 (1H, s).

Example 5

A mixture of 1-[(1R, 2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl] -3-[4-(1H-tetrazol-1-yl)phenyl] -2-imidazolidinone (0.5 g), chloromethylphosphonate (15.7 g) and acetonitrile (2.4 g) was stirred for 6.5 hours at 100oC. After cooling, the mixture was diluted with diisopropyl ether (10 ml) and the resulting powder was filtered. The powder was subjected to column chromatography on silica gel (eluent: ethyl acetate --> acetone --> acetone/ethanol= 10/1 --> acetone/ethanol= 5/1) to give chloride 1-[(2R,3R)-2-(2,4-differenl) -2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl]-4-[(2,2-dimethylpropanoate)methyl]-1H-1,2,4-triazole (Compound 2, 0.32 g) as a white powder. The above compound 2 (0.4 g) was led from ethylacetate analysis: C28H32ClF2N9O4< / BR>
Calculated (%): C, 53,21; N, 5,10; N, 19,94

Found (percent): C, 53,17; N, 5,15; N, 19,76

Example 6

A mixture of 1-[(1R, 2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl] -3-[4-(1H-1,2,3-triazole-l-yl)phenyl] -2-imidazolidinone (0.3 g) and chlormethiazole (1.35 g) was stirred for 24 hours at 100oC. the Reaction mixture was concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent:methanol/water=3/2), receiving chloride 4-acetoxymethyl-1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3-triazole-1-yl)phenyl]-1-imidazolidinyl]butyl]-1H-1,2,4-triazole (Compound 3, 45 mg) as a white powder.

1H-NMR (d6-DMSO) : 0,97 (3H, d, J=7 Hz), of 2.08 (3H, s), 3,61~4,08 (4H, m), 4,65~ of 4.75 (1H, m), a 4.86 (1H, d, J=14 Hz), 5,11 (1H, d, J=14 Hz), 6,07~ of 6.20 (2H, m), 6,69 (1H, s), of 6.96~7,05 (1H, m), 7,25 was 7.36 (2H, m), 7,82~of 7.95 (5H, m), 8,78 (1H, s), 9,06 (1H, s), 10,46 (1H, s).

Example 7

To a mixture of 1-[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl] -3-[4-(1H-1,2,3-triazole-1-yl)phenyl] -2-imidazolidinone (0,63 g) and acetonitrile (20 ml) was added hlormetilsilatran (1,71 g) and the mixture was stirred for 130 hours at the boil under reflux. The reaction mixture was concentrated under reduced pressure. To the rest of Obamacare (eluent:methanol/water=3/2) and the eluate was concentrated in vacuo. The residue was dissolved in water (20 ml). The solution was liofilizovane getting chloride 1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3-triazole-1-yl)phenyl] -1-imidazolidinyl] butyl]-4-[(2-methylpropanoate)methyl] -lH-l,2,4-triazole (Compound 4, 0,335 g) as a white powder.

1H-NMR (d6-DMSO) : 0,97 (3H, d, J=7 Hz), 1,07 (6N, d, J=7 Hz), 2,59 (1H, quintet, J=7 Hz), 3,60~4.09 to (4H, m), 4,65~of 4.75 (1H, m), to 4.87 (1H, d, J= 14 Hz), 5,10 (1H, d, J=14 Hz), 6,10~to 6.22 (2H, m), 6,69 (1H, s), 6,93~7,02 (1H, m), 7.23 percent~of 7.35 (2H, m), 7,82~to 7.93 (4H, m), 7,95 (1H, s), 8,78 (1H, s), the remaining 9.08 (1H, s), 10,48 (1H, s).

Example 8

To a mixture of 1-[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl] -3-[4-(1H-tetrazol-1-yl)phenyl] -2-imidazolidinone (0.50 g) and acetone (20 ml) was added hlormetilsilatran (1,37 g) and the mixture was stirred for 50 hours at the boil under reflux. The reaction mixture was concentrated under reduced pressure. To the residue was added diisopropyl ether (10 ml) and the resulting powder was filtered. The powder was subjected to ODS column chromatography (eluent: methanol/water=3/2). The eluate was concentrated in vacuo. The residue was dissolved in water (20 ml). The solution was liofilizovane getting chloride 1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl]-4-[(2-methylpropanoyl, d, J=7 Hz), 1,07 (6N, d, J=7 Hz), 2,59 (1H, quintet, J=7 Hz), 3,61~4,08 (4H, m), 4,65~of 4.75 (1H, m), to 4.87 (1H, d, J= 14 Hz), 5,11 (1H, d, J=14 Hz), 6,14~to 6.22 (2H, m), 6,69 (1H, s), 6,92~7,03 (1H, m), 7,22~7,37 (2H, m), of 7.90 (4H, s), which is 9.09 (1H, s), 10,08 (1H, s), 10,48 (1H, s).

The product (50 mg) was led from a saturated aqueous solution of sodium chloride (1 ml) to give white poroshkoobraznye crystals of compound 5 (41 mg).

So pl.: 217-219oC (decomposition).

Elemental analysis: C27H30ClF2N9O40.5 H2O

Calculated (%): C, 51,72; N, TO 4.98; N, 20,10

Found (percent):C, 51,79; N, A 4.83; N, 20,04

Example 9

To a mixture of 1-[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-3-yl)propyl] -3-[4-(1H-1,2,3-triazole-1-yl)phenyl] -2-imidazolidinone (100 mg) and 1-chloroethyl-ethylcarbonate (1.0 g) was added acetonitrile (0.5 ml) and the mixture was stirred for 60 hours at 85oC. After cooling, the mixture was diluted with diisopropyl ether (4 ml) and the resulting powder was filtered. The powder was subjected to ODS column chromatography (eluent: methanol/water= 3/2). The eluate was concentrated in vacuo. The residue was dissolved in water (10 ml) and was liofilizovane getting chloride 1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3-triazole-1-yl)phenyl] -1-imidazolidinyl] butyl] -4-[1-(ethoxycarbonyl)ethyl] -1H-1,2,4-triazo, =7 Hz), of 1.80 (3H, d, J=6 Hz), 3,61-4,25 (6N, m), 4,63~5,09 (3H, m), 6,67~6,83 (2H, m), 6,94~ 7,03 (1H, m), 7,21~7,37 (2H, m), 7,82~with 8.05 (5H, m), 8,79 (1H, s), which 9.22 (0.5 N, C), 9,27 (0.5 N, C), 10,70 (0.5 N, C) 10,80 (0.5 N, C).

Example 10

To a mixture of 1-[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl] -3-[4-(lH-tetrazol-1-yl)phenyl] -2-imidazolidinone (0,61 g) and 1-chloroethyl-ethylcarbonate (3.7 g) was added acetonitrile (1 ml) and the mixture was stirred for 38 hours at 95oC. the Reaction mixture was concentrated under reduced pressure. To the residue was added diisopropyl ether (10 ml) and the resulting powder was filtered. The powder was subjected to ODS column chromatography (eluent: methanol/water=3/2). The eluate was concentrated in vacuo. The residue was dissolved in water (10 ml) and was liofilizovane getting chloride 1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(lH-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl] -4-[1-(ethoxycarbonyl)ethyl] -1H-1,2,4-triazole (Compound 7, 90 mg) as a white powder.

1H-NMR (d6-DMSO) : 0,97 (3H, d, J=7 Hz), 1,21, to 1.22 (3H, t, J=7 Hz), 1,79, of 1.80 (3H, d, J=6 Hz), 3,62~4,23 (6N, m), 4,65~5,10 (3H, m), 6,69~6,82 (2K, m), 6,94~? 7.04 baby mortality (1H, m), 7,26~7,38 (2H, m), of 7.90 (4H, s), 9,23 (0.5 N, C), 9,27 (0.5 N, C), 10,08 (1H, s), of 10.72 (0.5 N, C) 10,82 (0.5 N, C).

Example 11

A mixture of 1-[(1R, 2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl] remedial for 25 hours at 100oC. After cooling, the mixture was diluted with diisopropyl ether (10 ml) and the resulting powder was filtered and subjected to column chromatography on silica gel (eluent:ethyl acetate --> acetone --> acetone/ethanol= 10/1 --> acetone/ethanol=5/1). The solvent is kept under reduced pressure and the residue was led from ethyl acetate. The crystals were dissolved in water (10 ml). The aqueous solution was liofilizovane getting chloride 1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3-triazole-1-yl)phenyl] -1-imidazolidinyl] butyl] -4-[(isopropoxycarbonyl)methyl]-1H-1,2,4-triazole (Compound 9, 0.18 g) as a white powder.

1H-NMR (d6-DMSO) : 0,98 (3H, d, J= 7 Hz), 1,24 (6N, d, J=6.4 Hz), 3,52-to 3.67 (1H, m), 3,93-4,00 (3H, m), 4,69 (1N, K, J=7 Hz), 4,80 (1H, quintet, J= 6.4 Hz), 4,88 (1H, d, J=13,8 Hz), of 5.05 (1H, d, J=13,8 Hz), 6,12 (1H, d, J= 10,8 Hz), of 6.20 (1H, d, J=10,8 Hz), 6,98-7,03 (1H, m), 7.23 percent and 7.36 (2H, m), to 7.84 (2H, d, J=8 Hz), to $ 7.91 (2H, d, J=8 Hz), 7,94 (1H, d, J=1Hz), 8,77 (1H, d, J=1 Hz), 9,10 (1H, s), 10,38 (1.H, C). Obtained above liofilizovannye product of compound (9) (0.05 g) was recrystallized from acetonitrile (3 ml) to give white crystals (0.01 g) of compound (9).

Elemental analysis: C28H31ClF2N5O5H2O

Calculated (%): C, 51,65; N, 5,11; N, 17,21

Found (percent):C, TO 51.64; H, TO 4.68; N, 17,06

Example 12

asolidimage (0.5 g) and acetonitrile (10 ml) was added Bromeliaceae (0.1 ml) and the mixture was stirred for 24 hours at 50oC. the Reaction mixture was purified flash chromatography on silica gel (silica gel: 25 g, eluent:ethyl acetate --> acetone --> acetone/ethanol=10/1). The residue was purified by crystallization from ethanol, receiving bromide 4-acetoxymethyl-1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,4-triazole-1-yl)phenyl]-1-imidazolidinyl]butyl]-1H-1,2,4-triazole (Compound 10, is 0.135 g) as colorless crystals.

1H-NMR (d6-DMSO) : 0,98 (3H, d, J=7 Hz), of 2.08 (3H, s), 3,62-4,08 (4H, m), 4,66-of 4.75 (1H, m), to 4.87 (1H, d, J=14 Hz), 4,99 (1H, d, J=14 Hz), 6,07-6,21 (2H, m), 6,34 (1H, s), of 6.96-7,07 (1H, m), 7.24 to to 7.35 (2H, m), 7,83-7,94 (5H, m), 8,80 (1H, s), which is 9.09 (1H, s), 10,24 (1H, s).

Example 13

To a mixture of 1-[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]-3-[4-(1H-tetrazol-1-yl)phenyl]-2-imidazolidinone (0.5 g) and acetonitrile (10 ml) was added Bromeliaceae (0.2 ml) and the mixture was stirred at 50oC for 16 hours. The reaction mixture was purified flash chromatography on silica gel (silica gel: 25 g, eluent:ethyl acetate --> acetone --> acetone/ethanol= 10/1). The residue was purified by crystallization from ethanol, receiving bromide 4-acetoxymethyl-1-[ (2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl]butyl]-1H-1,2,4-triazole (Compound 11, 0.39 g) as colorless crystals.

1

Example 14

To a mixture of 1-[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]-3-[4-(lH-tetrazol-1-yl)phenyl]-2-imidazolidinone (0.5 g) and acetonitrile (10 ml) was added 2,3,4,5-tetrahydrofurfuryl)idletimeout (0,594 g) and the mixture was stirred for 15 hours at 50oC. the Reaction mixture was subjected to flash chromatography on silica gel (eluent: ethyl acetate --> acetone --> acetone/ethanol=10/1), and the fractions containing the target compound were concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent: methanol/water= 3/2). The fraction containing the target compound were concentrated and the residue was liofilizovane getting iodide 1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-[(2,3,4,5-tetrahydrofurfuryl)oxycarboxylic] -1H-1,2,4-triazole (Compound 30, 0.4 g) as colorless powder. The product was dissolved in water (15 ml) and the solution was subjected to the action of ion-exchange resin [Dowex h (CL-type)]. The fraction containing the target compound were concentrated under reduced pressure and lifelessly getting chloride 1-[ (2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]g) as colorless powder.

1H-NMR (d6-DMSO) : 0,97 (3H, d, J=7 Hz), 1,52 of 1.99 (4H, m), 3,61-4,17 (N, m), 4,67-4,82 (1H, m), a 4.86 (1H, d, J=14 Hz), 5,10 (1H, d, J=14 Hz), 6,11-of 6.25 (2H, m), of 6.65 (1H, s), 6,69-7,06 (1H, m), 7,28-7,39 (2H, m), of 7.90 (4H, s), 9,10 (1H, s), 10,08 (1H, s), of 10.47 (1H, S).

Example 15

Bromide 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl] -1H-1,2,4-triazole (Compound 11, 0,81 g) was subjected to the action of ion-exchange resin [Dowex h (CL-type) ] (eluent: water). The eluate was liofilizovane getting chloride 4-acetoxymethyl-1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl]butyl]-1H-1,2,4-triazole (Compound 12, and 0.61 g) as a white powder.

1H-NMR (d6-DMSO) : 0,97 (3H, d, J=7 Hz), of 2.08 (3H, s), 3,62-3,66 (1H, m), 3,90-4,07 (3H, m), 4,69 (1N, K, J=7,4 Hz), is 4.85 (1H, d, J=14.6 Hz), 5,04 (1H, d, J=14.6 Hz), 6,09 (1H, d, J=11 Hz), 6,16 (1H, d, J=11 Hz), 6,55 (1H, s), 6,98-7,06 (1H, m), 7.23 percent -7,38 (2H, m), of 7.90 (4H, s), 9,06 (1H, s) 10,06 (1H, s), 10,34 (1H, s).

Obtained above liofilizovannye product (1.1 g) compound 12 was recrystallized from ethanol (20 ml) to give compound 12 as white crystals (1 g).

Elemental analysis: C25H26ClF2N9O4< / BR>
Calculated (%): C; 50,89, N; Of 4.44, N; 21,37, Cl; 6,01

Found (Percent): C; 50,61, N; Of 4.38, N; 21,24, Cl; 5,80.

To the,61 g) of compound 12 as white crystals.

Elemental analysis: C25H26ClF2N9H2O

Calculated (%): C; 49,39, N; WITH 4.64, N; 20,73

Found (Percent): C; 49,56, N, With 4.64, N; 20,85.

Example 16

Bromide 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl] -1H-1,2,4-triazole (Compound 11, 0.5 g) was dissolved in tetrahydrofuran (100 ml). To the solution was added a saturated aqueous solution (100 ml) of sodium chloride. The mixture was shaken and the organic layer was separated. Shaking with a solution of sodium chloride, followed by separation of the organic layer was repeated five times. The organic layer was dried over magnesium sulfate and the solvent drove away. The residue was recrystallized from ethanol (5 ml), receiving chloride 4-acetoxymethyl-1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-1H-1,2,4-triazole (Compound 12, 0.28 g) as white crystals. Physico-chemical properties of this product were identical to the properties of crystals of compound 12 obtained by crystallization from ethanol in example 15.

Example 17

A mixture of 1-[(1R, 2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3- (1H-1,2,4-triazole-1-yl)propyl] -3-[4-(lH-tetrazol-1-yl)phenyl]-2-imidazolidinone (1 g), iodopyrazine (0.8 g) and acetonitrile (100 ml). The solution was washed once with a saturated aqueous solution (100 ml) of sodium chloride containing a small amount of sodium thiosulfate followed by washing for four times with a saturated aqueous solution (100 ml) of sodium chloride. The organic layer was dried over magnesium sulfate and the solvent is kept at reduced pressure. The residue was subjected to chromatography on silica gel (eluent:ethyl acetate --> acetone --> acetone/ethanol =10/1 --> acetone/ethanol= 5/1). The solvent is kept off and the residue was led from ethanol (10 ml), receiving chloride 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl] -1H-1,2,4-triazole (Compound 12, of 0.44 g) as white crystals. Physico-chemical properties of this product were identical to the properties of crystals of compound 12 obtained by crystallization from ethanol in example 15.

Example 18

Bromide 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3-triazole-1-yl)phenyl] -1-imidazolidinyl] butyl]-1H-1,2,4-triazole (Compound 10, 0.03 g) was subjected to the action of ion-exchange resin [Dowex h (CL-type)] (eluent: water). The eluate was liofilizovane getting chloride 4-acetoxymethyl-1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3-Tr is Elemental analysis: C26H27ClF2N8O4H2O

Calculated (%): C; 49,96, N.; 5,00, N; 17,93, Cl; 5,67

Found (percent): C; 49,98, N, 4,57, N; 17,95, Cl; 6,04

Example 19

A mixture of 1-[(1R, 2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl] -3-[4-(lH-tetrazol-1-yl)phenyl] -2-imidazolidinone (0.5 g), chlorotype. carbonate (3.2 g) and acetonitrile (1 ml) was stirred for 12 hours at 100oC. After cooling, the mixture was diluted with diisopropyl ether (10 ml) and the resulting powder was filtered. The powder was subjected to chromatography on silica gel (eluent: ethyl acetate --> acetone --> acetone/ethanol=10/1 --> acetone/ethanol=5/1). The solvent is kept off and the residue was subjected to ODS column chromatography (eluent:methanol/water=3/2), receiving chloride 1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(lH-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl]-4-propoxycarbonyl-lH-l,2,4-triazole (Compound 19, 0.02 g) as a white powder.

1H-NMR (d6-DMSO) : to 0.88 (3H, t, J=7,8 Hz) to 0.97 (3H, d, J=7,0 Hz) of 1.62 (2H, TC, J=7.8 Hz), 3,63-to 3.67 (1H, m), 3,80-of 4.05 (3H, m), 4.09 to (2H, t, J=7.8 Hz), 4,69 (1N, K, J=7,0 Hz), 4,88 (1H, d, J=14.4 Hz), of 5.05 (1H, d, J=14.4 Hz), 6,13 (1H, d, J=a 10.6 Hz), 6,21 (1H, d, J=a 10.6 Hz), of 6.52 (1H, s), 6,94-7,02 (1H, m), 7.24 to 7,33 (2H, m), of 7.90 (4H, s), 9,10 (1H, s), of 10.05 (1H, C5, accounted for 10.39 (1H, s).

Example 20

A mixture of 1-[(1R, 2R)-2-(2,4-dipropionate (0.9 g) and acetonitrile (15 ml) was stirred for 12 hours at 50-55oC. the Mixture was subjected to chromatography on silica gel (eluent: ethyl acetate/hexane= 5/1 --> ethyl acetate --> acetone --> acetone/ethanol= 10/1 --> acetone/ethanol=5/1) and then ODS column chromatography (eluent:methanol/water= 3/2), receiving iodide 1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl]butyl]-4-propoxycarbonyl-lH-l, 2,4-triazole (Compound 20, 1 g) as a pale yellow powder.

1H-NMR (d6-DMSO) : to 0.88 (3H, t, C=7,2 Hz), and 0.98 (3H, d, J=7,2 Hz), to 1.61 (2H, TC, J=7,2 Hz), 3,50-3,70 (1H, m), 3,84 is 4.13 (3H, m), 4.09 to (2H, t, J=7,2 Hz), and 4.68 (1H,, J=7,2 Hz), a 4.86 (1H, d, J=13,8 Hz), 4,96 (1H, d, J=a 13.8 Hz), 6,12 (1H, d, J=11 Hz), of 6.20 (1H, d, J=11 Hz), 6,33 (1H, s), 6,97-7,07 (1H, m), 7,21-7,38 (2H, m), of 7.90 (4H, s), 9,11 (1H, s), of 10.05 (1H, s) of 10.21 (1H, s).

Example 21

Iodide 1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl]-4-propoxycarbonyl-1H-1,2,4-triazole (Compound 20, 0.3 g) was dissolved in a mixture of tetrahydrofuran/ethyl acetate (3/1) (100 ml) and the solution was washed four times with saturated aqueous solution (50 ml) of sodium chloride. The organic layer was dried over sodium sulfate and the solvent drove away. The residue was led from ethanol/acetone, getting chloride 1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] .

Elemental analysis: C27H30lF2N9O50.5 N2ABOUT

Calculated (%): C; 50,43, N; A 4.86, N; 19,60, Cl; 5,51

Found (percent): C; 50,25, N, 4,71, N; 19,31, Cl; 5,42

Example 22

To a mixture of 1-[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl] -3-[4-(1H-1,2,3-triazole-1-yl)phenyl] -2-imidazolidinone (0,80 g) and chloromethyl propanate (4,07 g) was added acetonitrile (1.6 ml) and the mixture was stirred for 12 hours at 100oC in argon atmosphere. The reaction mixture was concentrated under reduced pressure and to the residue was added diisopropyl ether (8 ml). The resulting powder was filtered. The powder was subjected to flash chromatography on silica gel (eluent:ethyl acetate --> acetone --> acetone/ethanol= 9/1 --> 4/1) and the fraction containing the target compound were concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent:methanol/water=3/2). The eluate was concentrated in vacuo and the residue was dissolved in water (10 ml). The solution was liofilizovane getting chloride 1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3-triazole-1-yl)phenyl] -1-imidazolidinyl]butyl]-4-propenolatomethyl-1H-1,2,4-triazole (Compound 13, 0.11 g) as a white powder.

1H-NMR (d6-DMSO) : 0,92-1,12 (6N, m), 2,25-to 2.55 (2H, m), 3,60~4,10 (4H, m), 9,07 (1K, C) 10,42 (1H, s).

Example 23

To a mixture of 1-[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl] -3-[4-(1H-tetrazol-1-yl)phenyl] -2-imidazolidinone (0,80 g) and chloromethylphosphonate (4,07 g) was added acetonitrile (1.6 ml) and the mixture was stirred for 10 hours at 100oC in argon atmosphere. The reaction mixture was concentrated under reduced pressure and to the residue was added diisopropyl ether (8 ml). The resulting powder was filtered. The powder was subjected to flash chromatography on silica gel (eluent:ethyl acetate --> acetone --> acetone/ethanol= 9/1 --> 5/1) and the fraction containing the target compound were concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent:methanol/water=3/2). The eluate was concentrated in vacuo and the residue was dissolved in water (10 ml). The solution was liofilizovane getting chloride 1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl] -4-propenolatomethyl-1H-1,2,4-triazole (Compound 14, 0.04 g) as a white powder.

1H-NMR (d6-DMSO) : 0,97 (3H, d, J=7,4 Hz), a 1.01 (3H, t, J=7.4 Hz), of 2.38 (2H, K, J=7,4 Hz), 3,61-4.09 to (4H, m), 4,65-of 4.75 (1H, m), a 4.86 (1H, d, J=14 Hz), to 5.08 (1H, d, J=14 Hz), 6,11 (1H, d, J=11 Hz), to 6.19 (1H, d, J=11 Hz), is 6.61 (1H, s), of 6.96-7,06 (1H, m), 7,25-7,49 (2H, m), of 7.90 (4H, s), 9,07 (1H, s), 10,07 (opyl] -3-[4-(1H-1,2,3-triazole-1-yl)phenyl] -2-imidazolidinone (0.50 g) and chlorotrityl carbonate (2.9 g) was added acetonitrile (0.5 ml) and the mixture was stirred for 22 hours at 100oC. the Reaction mixture was concentrated under reduced pressure. To the residue was added diisopropyl ether (10 ml) and the resulting powder was filtered. The powder was subjected to flash chromatography on silica gel (eluent:ethyl acetate/acetone=1/1 --> acetone --> acetone/ethanol=9/1 --> 4/1) and the fraction containing the target compound were concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent: methanol/water=3/2). The eluate was concentrated in vacuo and the residue was dissolved in water (15 ml). The solution was liofilizovane getting chloride 1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3-triazole-1-yl)phenyl] -1-imidazolidinyl] butyl] -4-ethoxycarbonylmethyl-1H-1,2,4-triazole (Compound 15, 0.04 g) as a white powder.

1H-NMR (d6-DMSO) : 0,97 (3H, d, J=7 Hz), to 1.22 (3H, t, J=7 Hz), 3,60~ 4,08 (4H, m), 4,18 (2N, K, J=7 Hz), 4.63 to~to 4.73 (1H, m), to 4.87 (1H, d, J=14 Hz), 5,10 (1H, d, J=4 Hz), 6,13 (1H, d, J=11 Hz), 6,21 (1H, d, J=11 Hz), of 6.65 (1H, s), of 6.96~? 7.04 baby mortality (1H, m), 7.24 to~7,37 (2H, m), 7,82~of 7.95 (5H, s), 8,78 (1H, d, J=1 Hz), which is 9.09 (1H, s), 10,48 (1H, s).

Example 25

To a mixture of 1-[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl] -3-[4-(1H-tetrazol-1-yl)phenyl] -2-imidazolidinone (1.31 g) and atriotomy carbonate (1.25 g) was added acetonitrile (20 ml) and the mixture was stirred for 14 hours Egali flash chromatography on silica gel (eluent:the ethyl acetate --> acetone --> acetone/ethanol= 4/1). The fraction containing the target compound were concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent:methanol/water= 3/2), receiving iodide 1-[(2R,3R)-2-[2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-ethoxycarbonylmethyl-1H-1,2,4-triazole (Compound 17, 1.1 g) as a pale yellow powder.

1H-NMR (d6-DMSO) : 0,99 (3H, d, J=7 Hz), of 1.23 (3H, t, J=7 Hz), 3,64-of 4.05 (4H, m), 4,19 (2N, K, J=7 Hz), with 4.64-4,74 (1H, m), to 4.87 (1H, d, J=14 Hz), equal to 4.97 (1H, d, J=14 Hz), 6,13 (1H, d, J=11 Hz), 6,21 (1H, d, J=11 Hz), 6,33 (1H, usher.), 6,99-7,07 (1H, m), 7,22-7,39 (2H, m), to $ 7.91 (4H, s), 9,12 (1H, s) 10,06 (1H, s), 10,23 (1H, s).

Example 26

Iodide 1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl]butyl]-4-ethoxycarbonylmethyl-lH-1,2,4-triazole (Compound 17, 1.10 g) was subjected to ion-exchange chromatography (DOWEX h, CL-type, 300 ml) and the fraction containing the target compound were concentrated under reduced pressure. The residue was recrystallized from ethanol, getting chloride 1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl] -4-ethoxycarbonylmethyl-1H-1,2,4-triazole (Compound 16, 0,70 g) as colorless powder Krista is), to 4.87 (1H, d, J=14 Hz), 5,10 (1H, d, J=14 Hz), 6,13 (1H, d, J=11 Hz), 6,21 (1H, d, J=11 Hz), of 6.66 (1H, s), of 6.96? 7.04 baby mortality (1H, m), 7,24 and 7.36 (2H, m), of 7.90 (4H, c), which is 9.09 (1H, s), 10,07 (1H, s), 10,48 (1H, s).

Example 27

A mixture of 1-[(1R, 2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl] -3-[4-(1H-tetrazol-1-yl)phenyl] -2-imidazolidinone (0.5 g), chlormethiazole carbonate (3,17 g) and acetonitrile (1 ml) was stirred for 6 hours at 100oC. After cooling, the mixture was diluted with diisopropyl ether (10 ml). The resulting powder was filtered. The powder was subjected to chromatography on silica gel (eluent: ethyl acetate --> acetone --> acetone/ethanol=10/1 --> acetone/ethanol=5/1). The solvent is kept off and the residue was led from ethanol/acetone, getting chloride 1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl] -4-(isopropoxycarbonyl)methyl-1H-1,2,4-triazole (Compound 18, 110 mg) as white powdery crystals.

1H-NMR (d6-DMSO) : 0,98 (3H, d, J=7,4 Hz), 1,24 (6N, d, J=6.2 Hz), 3,62-3,66 (1H, m), 3,98-4,0 (3H, m), 4,69 (1N, K, J=7,4 Hz), 4,80 (1H, quintet, J= 6.2 Hz), to 4.87 (1H, d, J=14.4 Hz), 5,04 (1H, d, J=14.4 Hz), 6,11 (1H, d, J= 11 Hz), to 6.19 (1H, d, J=11 Hz), 6,51 (1H, s), of 6.96-7.03 is (1H, m), 7,22-7,38 (2H, m), of 7.90 (4H, s), 9,10 (1H, s) 10,06 (1H, s), 10,36 (1H, s).

Example 28

To a mixture of 1-[(1R,2R)-2-(2,4-differeni is)iodothyronine (3 g) was added acetonitrile (40 ml) and the mixture was stirred for 12 hours at 50-55oC. the Mixture was subjected to chromatography on silica gel (eluent:ethyl acetate/hexane=1/1 --> ethyl acetate/hexane= 10/1 --> ethyl acetate --> acetone --> acetone/ethanol=5/1) to give the iodide 1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl] -4-[(1,3-dioxane-5-yl)oxycarboxylic] -1H-1,2,4-triazole (Compound 31, 4,22 g) as a yellow powder.

1H-NMR (d6-DMSO) : 0,98 (3H, d, J=7 Hz), 3,55 of 3.75 (1H, m), a 3.87-was 4.02 (7H, m), 4,50-4,58 (1H, m), 4,67-4,93 (5H, m), 6,16 (1H, d, J=11 Hz), 6,24 (1H, d, J=11 Hz), 6,33 (1H, s), 6,97-7,07 (1H, m), 7,21-7,39 (2H, m), of 7.90 (4H, s), 9,12 (1H, s), of 10.05 (1H, s), 10,23 (1H, s).

Example 29

Iodide 1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-[(1,3-dioxane-5-yl)oxycarboxylic]-1H-1,2,4-triazole (Compound 31, 1 g) was subjected to the action of ion-exchange resin [Dowex h (CL-type)] (eluent:water) and the eluate was liofilizovane getting chloride 1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-[(1,3-dioxane-5-yl)oxycarboxylic] -1H-1,2,4-triazole (Connection 22, to 0.23 g) as white powder.

1H-NMR (d6-DMSO) : 0,97 (3H, d, J=6, 6 Hz), 3,63-3,66 (1H, m), a 3.87-was 4.02 (7H, m), to 4.52-4,59 (1H, m), 4,60-5,11 (5H, m), 6,17 (1H, d, J=11 Hz), and 6.25 (1H, d, J=11 Hz), 6,59 (1H, c), 6,97? 7.04 baby mortality (1 is compound 22 was led from ethanol (20 ml), getting white crystals of compound 22 (0.14 g).

Elemental analysis: C28H30ClF2N9O7< / BR>
Calculated (%): C, 49,60; N, TO 4.46; N, 18,59

Found (percent): C, 49,60; N, TO 4.46; N, IS 18.40

Example 30

To a mixture of 1-[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl] -3-[4-(1H-tetrazol-1-yl)phenyl] -2-imidazolidinone (0.50 g) and [(1S)-1-(etoxycarbonyl)ethyl] chlorocarbonate (1,09 g) was added acetonitrile (5 ml) and the mixture was stirred for 68 hours at 95oC. the Reaction mixture was concentrated under reduced pressure. To the residue was added diisopropyl ether (6 ml) and the resulting powder was filtered. The powder was subjected to flash chromatography on silica gel (eluent:ethyl acetate --> ethyl acetate/acetone=1/1 --> acetone --> acetone/ethanol=5/1). The fraction containing the target compound were concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent:methanol/water=3/2). The eluate was concentrated in vacuo and dissolved in water (50 ml). The solution was liofilizovane getting chloride 1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl] -4-[(1S)-l-ethoxycarbonylmethoxy] carbonyloxy] -1H-1,2,4-triazole (Compound 23 and 0.22 g) as a white powder.

Example 31

To a mixture of 1-[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]-3-[4-(1H-tetrazol-1-yl)phenyl]-2-imidazolidinone (1.0 g) and [(1S)-1-(benzyloxycarbonyl)ethyl] iodothyronine (1,53 g) was added acetonitrile (15 ml) and the mixture was stirred for 12 hours at 60oC in argon atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was subjected to flash chromatography on silica gel (eluent:ethyl acetate --> acetone --> acetone/ethanol= 4/1). The fraction containing the target compound were concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent: methanol/water= 3/2) and subjected to ion-exchange chromatography (DOWEX h, CL-type). The fraction containing the target compound were concentrated under reduced pressure, getting chloride 1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(lH-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl] -4-[[(1S)-l-(benzyloxycarbonyloxy] carbonyloxy] -1H-1,2,4-triazole (Compound 24, 0.25 g) as a white powder.

1H-NMR (d6-DMSO) : 0,97 (3H, d, J= 7 Hz), a 1.45 (3H, d, J=6.6 Hz), 3,60-4,08 (4H, m), 4,65-4,78 (1H,="ptx2">

Example 32

To a mixture of 1-[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]-3-[4-(1H-tetrazol-1-yl)phenyl]-2-imidazolidinone (2.0 g) and 3-(benzyloxyphenyl)iodothyronine (2.9 g) was added acetonitrile (20 ml) and the mixture was stirred for 20 hours at 50~55oC in argon atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in a mixture of ethyl acetate (100 ml) and tetrahydrofuran (50 ml). To the solution was added a saturated aqueous solution of sodium chloride (50 ml) and 5% aqueous sodium thiosulfate solution (0.1 ml) and the mixture was shaken. The organic layer was washed saturated aqueous sodium chloride (50 ml) four times. The organic layer was dried over anhydrous magnesium sulfate and the solvent drove away. The residue was subjected to flash chromatography on silica gel (eluent:ethyl acetate --> acetone --> acetone/ethanol=4/1). The fraction containing the target compound were concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent: methanol/water= 3/2) and then the eluate was subjected to ion-exchange chromatography (DOWEX h, CL-type). The fraction containing the target compound were concentrated under reduced pressure, getting chloride 1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[Solia (Compound 25, 0,79 g) as a white powder.

1H-NMR (d6-DMSO) : 0,97 (3H, d, J=7,2 Hz), 1,89 (2H, quintet, J=6.4 Hz), 3,47 (2H, t, J=6.2 Hz), 3,60-4.09 to (4H, m), 4,22 (2H, t, J=6.6 Hz), of 4.44 (2H, s), 4,65-of 4.75 (1H, m), a 4.86 (1H, d, J=14 Hz), 5,09 (1H, q, j 14 Hz), 6,12 (1H, d, J= 11 Hz), of 6.20 (1H, d, J=11 Hz), 6,62 (1H, s), 6,94? 7.04 baby mortality (1H, m), 7,24 and 7.36 (7H, m), 7,9 (4H, s), which is 9.09 (1H, s), 10,07 (1H, s), 10,45 (1H, s).

Example 33

Chloride 1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl] -4-[(3-benzyloxypropionic)carbonyloxy] -1H-1,2,4-triazole (Compound 25, 0.66 g) was dissolved in methanol (25 ml) and to the solution was added 1 N. hydrochloric acid (0,89 ml) and 11% palladium-on-coal (50% wet., 0.33 g). The mixture was stirred for 1.5 hours at room temperature in a hydrogen atmosphere. The catalyst was filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent:methanol/water=3/2) and recrystallized from ethanol, getting chloride 1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl]-4-[(3-hydroxypropoxy)carbonyloxy]-1H-1,2,4-triazole (Compound 26, 0,19 g) in the form of colorless poroshkoobraznyh crystals.

1H-NMR (d6-DMSO) : 0,98 (3H, d, J=7,2 Hz), total 1.74 (2H, quintet, J=6 Hz), 3,44 (2N, THE N, d, J=11 Hz), 6,63 (1H, s), 6,95-7,05 (1H, m), 7,25-7,37 (2H, m), 7,89 (4H, s), which is 9.09 (1H, s) 10,06 (1H, s), 10,48 (1H, s).

Example 34

A mixture of 1-[(1R, 2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]-3-[4-(1H-tetrazol-1-yl)phenyl]-2-imidazolidinone (1.6 g) and [(4S)-2,2-dimethyl-1,3-dioxolane-4-yl] motiliummotilium (2.1 g) were added to acetonitrile (20 ml) and the mixture was stirred for 15 hours at 55oC. the resulting mixture was subjected to chromatography on silica gel (eluent:ethyl acetate --> acetone --> acetone/ethanol=5/1) and then the eluate was subjected to the action of ion-exchange resin (Dowex h, CL-), (eluent: water). The eluate was evaporated in vacuum and the residue was subjected to ODS column chromatography (eluent: methanol/water=3/2). The solvent is kept under reduced pressure and the residue was led from ethanol, getting chloride 1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl]-4-[[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl] methoxycarbonylmethyl] -1H-1,2,4-triazole (Compound 27, 0.4 g) in the form of white crystals.

1H-NMR (d6-DMSO) : 0,98 (3H, d, J=7,0 Hz) of 1.26 (3H, s) of 1.30 (3H, s), 3,62-and 3.72 (2H, m), 3,97-4,34 (7H, m), 4,70 (1N, K, J=7,0 Hz), 4,88 (1H, d, J= 14 Hz), 5,12 (1H, d, of 14.2 Hz), 6,16 (1H, d, J=11,0 Hz), 6,24 (1H, d, J= to 11.0 Hz), of 6.66 (1H, s), 6,94-7,03 (1H, m), 7,21-7,38 (2H, m), 7,89 (4H, s), 9,10 (1H, with the-1-yl)phenyl] -1-imidazolidinyl] butyl] -4-[[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl] methoxycarbonylmethyl]-1H-1,2,4-triazole (Compound 27, 0.1 g) was dissolved in tetrahydrofuran (1.5 ml) and to the solution was added 1 n hydrochloric acid (1.5 ml) under cooling with ice. The mixture was stirred for 4 hours at room temperature. The resulting mixture was subjected to ODS column chromatography (eluent:methanol/water=3/2), receiving chloride 1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl]butyl]-4-[[(2S)-2,3-dihydroxy-propoxy]carbonyloxy] -1H-1,2,4-triazole (Compound 28, 0.05 g) in the form of a white powder.

1H-NMR (d6-DMSO) : 0,98 (3H, d, J=7,0 Hz), 3,26-4,24 (N, m), 4,70 (1N, K, J= 7,0 Hz), a 4.86 (1H, d, J=14.6 Hz), 5,09 (1H, q, j 14.6 Hz), x 6.15 (1H, d, J= 11,0 Hz), to 6.22 (1H, d, J= 11,0 Hz), 6,63 (1H, s), of 6.96-7,06 (1H, m), 7.23 percent and 7.36 (2H, m), of 7.90 (4H, s), 9,10 (1H, s) 10,06 (1H, s), 10,46 (1H, s).

Example 36

To a solution of 1-[(1R, 2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl] -3-[4-(lH-tetrazol-1-yl)phenyl] -2-imidazolidinone (1.0 g) in acetonitrile (15 ml) was added (3-benzyloxycarbonylamino) idletimeout (1.0 g) under nitrogen atmosphere and the mixture was stirred for 20 hours at 45-50oC. the Reaction mixture was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent:ethyl acetate --> acetone) and the fraction containing the target compound, conze), getting iodide 4-[(3-benzyloxycarbonyloxy)carbonylmethyl] -1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl] -1H-1,2,4-triazole (Compound 32, 1.47 g) as a yellow powder.

1H-NMR (d6-DMSO) : was 1.04 (3H, d, J=7 Hz), 1,83-of 1.97 (2H, m), of 2.45 (2H, t, J=7 Hz), 3,57 at 3.69 (2H, m), 3,90-4.09 to (2H, m), 4,18 (2H, t, J=7 Hz), 4,69 (1H,, J=7 Hz), to 4.87 (1H, d, J=14 Hz), to 4.98 (1H, d, J=14 Hz), to 5.08 (2H, s), 6,14 (1H, d, J=11 Hz), to 6.22 (1H, d, J=11 Hz), 6,33 (1H, s), 6,99-was 7.08 (1H, m), 7.23 percent-to 7.32 (2H, m), 7,35 (5H, s), to $ 7.91 (4H, s), 9,12 (1H, s), 10,07 (1H, s), 10,24 (1H, s).

Example 37

Iodide 4-[(3-benzyloxycarbonyloxy)carbonylmethyl] -1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl]-1H-1,2,4-triazole (Compound 32, 1.47 g) was subjected to ion-exchange chromatography (Dowex h, CL-type, 500 ml) and the fraction containing the target product was concentrated under reduced pressure, getting chloride 4-[(3-benzyloxycarbonyloxy) carbonylmethyl] -1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl]butyl]-1H-1,2,4-triazole (Compound 29, 893 mg) as a white powder.

1H-NMR (d6-DMSO) d: was 1.04 (3H, d, J=7 Hz), 1,82 of 1.99 (2H, m) 2,44 (2H, t, J=7 Hz), 3,53-to 3.67 (2H, m), 3.95 to a 4.03 (2H, m), 4,17 (2H, t, J=7 Hz), and 4.68 (1H,, J=7 Hz), to 4.87 (1H, d, JH, C) 10,07 (1H, s), 10,41 (1H, s).

Example 38

Chloride 4-[(3-benzyloxycarbonyloxy) carbonylmethyl] -1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl] -1H-1,2,4-triazole (Compound 29, 155 mg) was dissolved in methanol (6 ml). To the solution was added 1 n hydrochloric acid (0.2 ml) and 10% palladium-on-coal (50% wet., 77 mg). The mixture was stirred for 0.5 hours at room temperature in a hydrogen atmosphere. The catalyst was filtered and to the filtrate was added distilled water. The mixture was concentrated under reduced pressure and the concentrated solution was liofilizovane getting chloride 1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(lH-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl] -4-[(3-carboxypropanoyl) carbonyloxy] -1H-1,2,4-triazole (Compound 33, 122 mg) as a white powder.

1H-NMR (d6-DMSO) d: and 0.98 (3H, d, J=7 Hz), of 1.78-1.90 (2H, m) to 2.29 (2H, t, J=7 Hz), 3,54 at 3.69 (2H, m), 3,94-Android 4.04 (2H, m) to 4.16 (2H, t, J=7 Hz), 4,69 (1N, K, J=7 Hz), to 4.87 (1H, d, J=14 Hz), is 5.06 (1H, d, J=14 Hz), 6,13 (1H, d, J= 11 Hz), 6,21 (1H, d, J=11 Hz), is 6.54 (1H, s), 6,95-7,10 (1H, m), 7.24 to 7,37 (2H, m), of 7.90 (4H, s), 8,31 (1H, s), which is 9.09 (1H, s) 10,06 (1H, s), 10,34 (1H, s).

Example 39

The solution Bromeliaceae (2.4 g) and sodium iodide (2.3 g) in acetonitrile (75 ml) was stirred mechatronical and to the filtrate was added 1-[(1R, 2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl] -3-[4-(1H-tetrazol-1-yl)phenyl]-2-imidazolidin he (5 g). The mixture was stirred for 16 hours at 45oC. From the reaction mixture, the precipitate was filtered and the solvent drove away. The residue was dissolved in tetrahydrofuran (150 ml). The solution was washed with a mixture of saturated aqueous solution of sodium chloride (150 ml) and 5% aqueous sodium thiosulfate solution (10 ml). The organic layer was washed twice with a saturated aqueous solution of sodium chloride (150 ml). Tertrahydrofuran ring layer was dried over anhydrous magnesium sulfate and the solvent drove away. To the residue was added ethanol (50 ml) and the solvent drove away. To the residue was added acetone (3 ml) and ethanol (1.3 ml) and the mixture was left for 2 hours at 0oC. To the resulting white solid product was added ethanol (3 ml). The solid product was filtered and dried under reduced pressure. The obtained white powder was dissolved in a mixture of tetrahydrofuran (400 ml) and methanol (70 ml). The solution was washed with a saturated aqueous solution of sodium chloride (250 ml) seven times. The organic layer was dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The residue was dissolved in a mixture of ethanol (150 ml) and acetone (50 ml) and rastvoritelei pressure. To the residue was added a mixture of ethanol (150 ml) and acetone (50 ml). The solvent drove to the volume of solution in 20 ml and the solution was left for 2 hours at room temperature. The obtained solid product was filtered, getting chloride 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl] butyl]-1H-1,2,4-triazole (Compound 12, 3.6 g) as white crystals. Physico-chemical properties of this product were identical to the properties of crystals of compound 12 obtained by crystallization from ethanol in example 15.

Example 40

To a mixture of 1-[(1R, 2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl] -3-[4-(1H-tetrazol-1-yl)phenyl] -2-imidazolidinone (2.0 g) and [2-(acetylamino)ethyl]iodothyronine (2.9 g) was added acetonitrile (20 ml) and the mixture was stirred for 20 hours at 50~55oC in argon atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in a mixture of ethyl acetate (100 ml) and tetrahydrofuran (50 ml). To the mixture was added a mixture of saturated aqueous sodium chloride (50 ml) and 5% aqueous sodium thiosulfate solution (0.1 ml) and the mixture was shaken. The organic layer was washed 4 times with saturated aqueous sodium chloride (50 ml). Organisatie on silica gel (eluent: ethyl acetate --> acetone --> acetone/ethanol=4/1). The fraction containing the target compound were concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent:methanol/water=3/2) and the eluate was subjected to ion-exchange chromatography (Dowex h, CL-type). The fraction containing the target compound were concentrated under reduced pressure, getting chloride 1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-[(2-acetylbenzoate)carbonyloxy] -1H-1,2,4-triazole (Compound 34, 0.5 g) as a white powder.

1H-NMR (d6-DMSO) : 0,97 (3H, d, J=7 Hz), 1.77 in (3H, s), 3,30 (2N, K, J=6 Hz), 3,60-and 3.72 (1H, m), 3,92-4,08 (3H, m), of 4.12 (2H, t, J=6 Hz), 4,65-of 4.75 (1H, m), to 4.87 (1H, d, J=14 Hz), 5,10 (1H, d, J=14 Hz), 6,14 (1H, d, J=11 Hz), 6,23 (1H, d, J=11 Hz), 6,63 (1H, s), 6,95-7,05 (1H, m), 7,26-7,37 (2H, m), of 7.90 (4H, s), of 8.09 (1H, t, J=6 Hz), 9,10 (1H, s), 10,07 (1H, s), 10,49 (1H, s).

Example 41

To a mixture of 1-[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]-3-[4-(1H-tetrazol-1-yl)phenyl]-2-imidazolidinone (1.0 g) and [3-(methoxy)propyl]iodothyronine (1.1 g) was added acetonitrile (10 ml) and the mixture was stirred for 15 hours at 40~50oC in argon atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in a mixture of acetonitrile and 5% aqueous sodium thiosulfate solution (0.1 ml). The organic layer was washed four times with saturated aqueous sodium chloride (50 ml). The organic layer was dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The residue was subjected to flash chromatography on silica gel (eluent: ethyl acetate --> acetone --> acetone/ethanol=4/1). The fraction containing the target compound were concentrated under reduced pressure. The residue was subjected to ion-exchange chromatography (Dowex h, CL-type), and then the eluate was subjected to ODS column chromatography (eluent:methanol/water=3/2), receiving chloride 1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(lH-tetrazol-1-yl)phenyl] -1-imidazolidinyl]butyl]-4-[(3-methoxypropane) carbonyloxy] -1H-1,2,4-triazole (Compound 35, 0,80 g) in the form of a white powder.

1H-NMR (d6-DMSO) : 0,97 (3H, d, J=7 Hz) and 1.83 (2H, quintet, J=6 Hz), 3,20 (3H, s) to 3.35 (2H, t, J=6 Hz), 3,55-3,70 (1H, m), 3,90-4,10 (3H, m), 4,18 (2H, t, J=6 Hz), with 4.64-of 4.75 (1H, m), to 4.87 (1H, d, J=14 Hz), of 5.11 (1H, d, J= 14 Hz), 6,14 (1H, d, J= 11 Hz), to 6.22 (1H, d, J=11 Hz), of 6.66 (1H, s), 6,95-7,05 (1H, m), 7,25-7,39 (2H, m), of 7.90 (4H, s), 9,10 (1H, s), 10,07 (1H, s), 10,48 (1H, s).

Example 42

The solution Bromeliaceae (424 mg) and sodium iodide (415 mg) in acetonitrile (15 ml) was stirred for 2 hours at 80oC. the Reaction mixture was cooled to room so the 1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl] -4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H, 4H)-1,2,4-triazole (1 g) and the mixture was stirred for 16 hours at 45oC. Sludge precipitated from the reaction mixture, was filtered and the solvent drove away under reduced pressure. The residue was dissolved in tetrahydrofuran (30 ml) and washed with a mixture of saturated aqueous solution of sodium chloride (30 ml) and 5% aqueous sodium thiosulfate solution (2 ml) and then washed twice with a saturated aqueous solution of sodium chloride (30 ml). Tertrahydrofuran ring layer was dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The residue was subjected to chromatography on silica gel (eluent:ethyl acetate --> ethyl acetate/ethanol= 10/1 --> 4/1), and then subjected to the action of ion-exchange resin [Dowex 1x8 (Cl-type)] (eluent:water). The fraction containing the target product was liofilizovane getting chloride 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[4,5-dihydro-5-oxo-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1H-1,2,4-triazole-1-yl]butyl-1H-1,2,4-triazole (Compound 36, 294 mg) as a white powder.

1H-NMR (d6-DMSO) : 1,22 (3H, d, J=7 Hz), of 2.08 (3H, s), of 4.66 (2H, t, J= 14 Hz), is 4.85 (1H, d, J=14 Hz), 4,89 (1N, K, J=7 Hz), to 4.98 (1H, d, J=14 Hz), 6,09 (1H, d, J=11 Hz), to 6.19 (1H, d, J=11 Hz), of 6.26 (1H, C) 6,69 (1H, TT, J= 52, 5 Hz), 6,97-7,06 (1H, m), 7.23 percent (2H, d, J=9 Hz), 7,25-7,41 (2H, m), of 7.69 (2H, d, J=9 Hz), 8,58 (1H, C1-yl)propyl] -3-[4-(1H-tetrazol-1-yl)phenyl] -2-imidazolidinone (200 mg) and Bromeliaceae (77,1 mg) in acetonitrile (2 ml) was stirred for hours at 80oC in argon atmosphere. The reaction mixture was diluted with acetonitrile (11 ml) and the resulting mixture was stirred at 80oC to dissolve crystals precipitated from the mixture in the sediment. After cooling to room temperature was added silica gel (400 mg) and the mixture was stirred for 10 minutes at room temperature. The silica gel was filtered and washed with a mixture of acetonitrile and tetrahydrofuran (1/1, 2 ml of 3). The mother liquor and the washing liquid were combined and added to a saturated aqueous solution of sodium chloride (10 ml). The resulting mixture was stirred for 30 minutes at room temperature and the organic layer was separated. The same action, namely, the addition of a saturated aqueous solution of sodium chloride (10 ml) followed by stirring for 30 minutes at room temperature and subsequent separation of the organic layer, optionally carried out three times. The organic layer was dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The residue was dissolved in tetrahydrofuran (3 ml) and the solution was left for 5 hours at room temperature. Precipitated precipitated solid product (179 mg) was filtered and dissolved in a mixture of methanol and tetrahydrofuran (1/1, 4 ml). The solution kasov at room temperature. Precipitated precipitated powdery crystals (167 mg) was filtered and dissolved in a mixture of ethanol (6 ml) and acetone (0.5 ml). The solution was concentrated under reduced pressure to a volume of about 2 ml and left for 3 hours at room temperature. Precipitated precipitated solid product was filtered, getting chloride 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-1H-1,2,4-triazole (Compound 12, 126 mg) as white crystals. Physico-chemical properties of the product were identical to the properties of crystals of compound 12 obtained by crystallization from ethanol in example 15.

The drug 1

Using the compound 2 obtained in example 4, a solution for injection that contains the following components.

Compound 2 obtained in example 4 to 100 mg

5% glucose solution for injection 100 ml

Drug 2

Using compound 1 obtained in example 1 was mixed the following components. The mixture was Packed in gelatin capsules, receiving capsules, each of which contained compound 1 in the amount of 50 mg, mg:

Connection 1 - 50

Lactose - 100

Corn starch - 40

Magnesium stearate - 10

Only 200

PR is on starch. The obtained product was dried and then mixed with lactose and corn starch. The mixture was subjected to compression molding, receiving the tablets containing the following components, mg:

Compound 2 obtained in example 4 - 50

Lactose - 65

Corn starch - 30

Soluble starch - 35

Magnesium stearate - 20

Only 200

Experiment 1

Method: female mice Crj:CDFl five weeks of age were infected intravenously minimum lethal dose of Candida albicans. The test compound was dissolved in 5% glucose solution and injected into mice intravenously immediately after infection. Protective effect of compounds were expressed as 50% effective dose (ED50), calculated using the method of reed and Munch (Reed and Muench) according to the degree of survival on day 7 after infection.

The result: a Protective effect of the compounds in experimental infection in mice is shown below

Connection - Ed50 (Ámol/kg) centuries

1 - 2,3

2 - 1,5

Experiment 2

Method: female mice Crj:CDF1 five weeks of age were infected intravenously minimum lethal dose of Candida albicans. The test compound was dissolved in 5% glucose solution was administered to mice orally Tannoy with ispolzovaniem method of reed and Munch (Reed and Muench) according to the degree of survival on day 7 after infection.

The result: a Protective effect of the compounds in experimental infection in mice is shown below

Connection - Ed50 (Ámol/kg) p. O.

1 - 2,9

2 - 1,8

Experiment 3

Method: female mice Crj:CDF1 five weeks of age were infected intravenously minimum lethal dose of Candida albicans. The test compound was dissolved in 5% glucose solution and injected into mice intravenously (centuries) or orally (p. O.) in the dose of 1.04 Ámol/kg immediately after infection. Protective effect of each compound was expressed as the number of survivors on day 7 after infitsirovanija and the number of days for mice that died before the 7th day after infection.

The result: a protective effect of the compounds in experimental infection in mice is shown in table.5. In table.5 includes the value of protective actions for the reference compounds, identified by a number (V). Reference compound suspended in 0.5% carboxymethylcellulose sodium was administered to mice orally at a dose of 1.04 Ámol/kg immediately after infection.

Industrial applicability

Compounds of the present invention have improved solubility in water and are best utilized for injection, and the present invention will have a good effect in the treatment of disease.

Brief description of drawings

In Fig.1 shows x-ray diffraction spectrum (Cu, 40 kV, 50 mA). Form I crystals (not hydrated, crystallized from ethanol) compound 12 obtained in example 15. Transverse axis (x-axis) shows the angle of diraction processes (2), and the ordinate axis shows the intensity of the peak.

In Fig.2 shows x-ray diffraction spectrum (cu, 40 kV, 50 mA). Form II crystals (hydrate, crystallized from water) compound 12 obtained in example 15. Transverse axis (x-axis) shows the angle of diraction processes (2), and the ordinate axis shows the intensity of the peak.

1. Azole compounds represented by formula I

< / BR>
where R1is:

I) C1-6alkyl, optionally mono - or disubstituted by substituents selected from: 2-tetrahydrofuryl; C1-6acyloxy; hydroxy; C1-6alkoxycarbonyl; benzyloxycarbonyl; carboxy; C1-6alkanolamine; benzyloxy; C1-6alkoxy; 1,3-dioxolane-4-yl, which, in turn, can be substituted C1-4by alkyl;

II) 1,3-dioxane-5-yl;

n = 0 or 1;

R2represents hydrogen or C1-6alkyl;

X represents halogen;

Y represents halogen;

Z predstavlyaemoi 3-4-nitrogen-containing 5-membered heterocyclic residue, optionally substituted C1-6the alkyl, which, in turn, substituted C1-6alloctype; when Z represents a group-N= CH-, R7represents C1-6alkoxygroup, substituted with halogen.

2. Connection on p. 1, which represents the chloride 4-acetoxymethyl-1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,2-triazole-1-yl)phenyl] -1-imidazolidinyl] -butyl] -1H-1,2,4-triazole.

3. Connection on p. 1, which represents the chloride 4-acetoxymethyl-1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl] -1H-1,2,4-triazole.

4. Connection on p. 1, which represents chloride 1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3-triazole-1-yl)phenyl] -1-imidazolidinyl] butyl] -4-ethoxy-carbonylmethyl-1H-1,2,4-triazole.

5. Connection on p. 1, which represents chloride 1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl] -1-imidazolidinyl] butyl] -4-ethoxycarbonylmethyl-1H-1,2,4-triazole.

6. Connection on p. 1, which represents the chloride 4-acetoxymethyl-1-[(2R, 3R)-2-(2,4-differenl)-2-hydroxy-3-[4,5-dihydro-5-oxo-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl] -1H-1,2,4-triazole-1-yl] butyl] -1H-1,2,4-triazole.

7. The connection p is which includes connection p. 1 and at least one pharmaceutically acceptable carrier, diluent or excipient.

9. A method of treating a fungal infection caused by Candida albicans THAT that includes the introduction of a patient suffering from a fungal infection, an effective amount of the compounds on p. 1, optionally together with a pharmaceutically acceptable carrier, diluent or excipient.

10. The method of obtaining the compounds of formula I

< / BR>
where the values of R1, R2, R7X, Y, Z and n are specified in paragraph 1, which includes the interaction of the compounds represented by formula

< / BR>
each character has the above values,

with the compound represented by formula

< / BR>
where Y1represents a halogen atom, and other symbols have the above values,

and the resulting product is optionally subjected to anion exchange.

Priority signs:

31.03.1997 - PP. 1-10;

08.07.1997 and 08.12.1997 - clarification of signs on PP. 1-10 formulas in the description.

 

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