BACKGROUND OF THE INVENTION

The present invention relates to novel cyclohexanone oxime derivatives, a process for their manufacture, an antifungal composition containing them and use thereof.

The cyclohexane derivatives described in EP-0524439A1 show improved chemical stability and in vitro antifungal activity over the tetrahydropyran derivatives discovered in the cultured broth of the Penicillium sp. (U.S.Patent No. 4,952,604) . However, these compounds are not sufficiently active against Aspergillus fumigatus which is one of the most important and life threatening fungi in the systemic mycoses in human. To date, there is still strong medical need to develop new antifungal agents which are effective against Aspergillus sp. and have good safety profiles.

SUMMARY OF THE INVENTION The present invention relates to cyclohexanone oxime derivatives exhibiting excellent antifungal activity against Aspergi llus sp.

These novel cyclohexanone oxime derivatives have the general formula (I) ,

wherein X is -0- or -CH2-; l - is lower-alkyl or lower-alkoxy which may be substituted with 1 to 4 fluorine atom(s) ; R2 is a hydrogen atom or lower-alkyl; Me/So 5.3.96

R3 is methyl or -(CH2)2 ^R ^ i ⁿ which R ⁴ is hydroxy, amino, mono- or disubstituted lower-alkylamino, lower-alkoxy, lower-alkylthio, lower-alkylsulfonyl, a 5- or 6-membered heterocyclic ring containing one or more nitrogen atom(s) which may further contain an oxygen or sulfur atom, or -(S or N) -Het wherein Het means heteroaryl; as well as pharmaceutically acceptable salts thereof, and hydrates or solvates of the compounds of the formula (I) or their salts.

DETAILED DESCRIPTION OF THE INVENTION

The term "lower", as used throughout the specification, refers to carbon chain preferably containing up to and including 3 carbon atoms, unless otherwise indicated.

R! is a lower-alkyl or lower-alkoxy which may be substituted with 1 to 4 fluorine atom(s) such as methyl, ethyl, propyl, trifluoromethyl, trifluoromethoxy, 1,1- difluoroethoxy, 1, 1, 2,2-tetrafluoroethoxy, 2,2,3,3- tetrafluoropropoxy and the like. Of these, methyl, ethyl, trifluoromethyl, trifluoromethoxy are especially preferred.

R2 is a hydrogen atom or a lower-alkyl such as methyl, ethyl, propyl, preferably a hydrogen atom or methyl.

R ³ is a methyl or -(CH2.2R ⁴ wherein R ⁴ is a hydroxy, amino; mono- or disubstituted lower-alkylamino such as methylamino, di ethylamino, diethyla ino; lower-alkoxy such as methoxy, ethoxy and propoxy, preferably methoxy; lower- alkyl hio such as methylthio, ethylthio and propylthio, preferably methylthio; lower-alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, and propylsulfonyl preferably methylsulfonyl; a 5- or 6-membered heterocyclic ring containing one or more nitrogen atom(s) which may further contain an oxygen or sulfur atom such as 1, 3-imidazol-l-yl, 1, 2-imidazol-l-yl, 1,2, 4-triazol-l-yl, 1,2, 3, 4-tetrazol-5-yl, morpholino and the like; or -(S or N) -Het wherein Het means heteroaryl such as l-methylimidazol-2-ylthio, 1-methyl-

1,2, 3 ,4-tetrazol-5-ylthio, 1, 3-pyridazin-2-ylthio, 3-methyl- l,2-thiazol-5-ylamino, 5-methyl-l, 3 , 4-thiaziazol-2-ylamino and the like.

The novel cyclohexane derivatives represented by the formula (I) can be produced according to the following methods.

Process A: Compounds represented by the formula (I) [in which R ³ is -(CH2.2R in which R ⁴ is a hydroxy, and R ¹ , R ² and X are as defined above] can be produced by removal of the protecting group of the primary alcohol function of a compound represented by the formula (II) ,

wherein Y is a hydroxy protecting radical, and R^- _' R ² and X are the same as defined above.

Process B:

Compounds represented by the formula (I) [in which R ² is a lower-alkyl, R ³ is -(CH2)2R ⁴ i ⁿ which R ⁴ is an amino, mono- or disubstituted lower-alkylamino, lower-alkoxy, lower- alkylthio, lower-alkylsulfonyl, 5- or 6-membered heterocyclic ring containing one or more nitrogen atom(s) which may further contain an oxygen or sulfur atom, or -(S or N) -Het wherein Het means heteroaryl, and R^ and X are the same as defined above] can be produced by first reacting a compound represented by the formula (III) ,

wherein R ² is a lower-alkyl, R^ and X are the same as defined above, with mesyl chloride in the presence of acid acceptor, followed by reacting the resulting mesylate with a nucleophile R ⁴ -H or its alkali metal salt (R ⁴ is the same meaning as defined above) in the presence or absence of base.

Process C:

Compounds represented by the formula (I) [in which R ¹ , R ² , R ³ and X are the same as defined above] can be produced by reacting a compound represented by the formula (IV) ,

wherein R ¹ ' R ³ and X are the same as defined above, with hydroxylamine acid addition salt in the presence of an acid acceptor, followed, if necessary, by O-alkylation of the resulting oxime group.

Process D:

Compounds represented by the formula (I) [in which R ² is a lower-alkyl, R^, R ³ and X are the same as defined above] can be produced by reacting a compound represented by the formula (IV) , wherein R ¹ , R ³ and X are the same as defined above, with O-alkylhydroxylamine acid addition salt in the presence of an acid acceptor.

Process E :

Compounds represented by the general formula (I) [in which R ³ is -(CH2)2R ⁴ wherein R ⁴ is a lower-alkylsulfonyl, R!,R ² and X are the same as defined above] can be produced by oxidizing a compound represented by the formula (V) ,

wherein R^ is a lower-alkyl, Rl, R ² and X are the same as defined above, with an oxidizing agent.

Process F:

Compounds represented by the formula (I) [in which R ² is a lower-alkyl, R ³ is -(CH2)2R ⁴ wherein R ⁴ is a lower-alkoxy, and Rl and X are the same as defined above] can be produced by O-alkylation of a compound represented by the formula (III) , [in which R ² is a hydrogen or lower-alkyl, R^ and X are the same as defined above] .

In the following, the process for producing cyclohexanone oxime derivatives represented by the formula (I) according to the present invention will be explained in more detail .

Process A:

Examples of hydroxy-protecting group Y are benzyl, 4-methoxybenzyl, trityl or acyl such as acetyl, pivaloyl, benzoyl and the like.

Specific examples of the compound represented by the general formula (II) include:

(2S, 5R, 6R) -2- [ 2- (benzyloxy) ethyl] -2-methyl-6- (1H-1,2, 4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone O-methy1oxime,

(2S, 5R, 6R) -2- [2- (benzyloxy) ethyl] -2-methyl-β- (1H-1, 2, 4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy] ethyl] - cyclohexanone oxime,

(2S, 5R, 6R) -2- [2- (4-methoxybenzyloxy) ethyl] -2-methyl-6- (lH-l,2,4-triazol-l-ylmethyl)-5-[ [4- (trifluoromethoxy) - phenoxy]methyl] -cyclohexanone O-methyloxime, (2S, 5R, 6R) -2- [2- (4-methoxybenzyloxy) ethyl] -2-methyl-6- (lH-l,2,4-triazol-l-ylmethyl)-5-[ [4- (trifluoromethoxy) - phenoxy]methyl] -cyclohexanone oxime,

(2S, 5R, 6R) -2- [2- (trityloxy)ethyl] -2-methyl-6- (1H-1,2, 4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone O-methyloxime,

(2S, 5R, 6R) -2- [2- (trityloxy)ethyl] -2-methyl-6- (1H-1,2,4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone oxime,

(2S, 5R, 6R) -2- (2-acetoxyethyl) -2-methyl-6- (1H-1, 2, 4- triazol-1-ylmethyl) -5- [4- (trifluoromethoxy)phenoxymethyl] - cyclohexanone O-methyloxime,

(2S, 5R, 6R) -2- (2-acetoxyethyl) -2-methyl-6- (1H-1, 2, 4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone oxime, (2S, 5R, 6R) -2- [2- (pivaroyloxy)ethyl] -2-methyl-6- (1H-1,2,4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone O-methyloxime,

(2S, 5R, 6R) -2- [2- (pivaroyloxy)ethyl] -2-methyl-6- (1H-1, 2,4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone oxime,

(2S, 5R,6R) -2- [2- (benzoyloxy)ethyl] -2-methyl-6- (1H-1, 2, 4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone O-methyloxime,

(2S, 5R, 6R) -2- [2- (benzoyloxy)ethyl] -2-methyl-6- (1H-1,2,4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone oxime,

(2S, 5R, 6R) -2- [2- (benzyloxy) ethyl] -2-methyl-6- (1H-1,2,4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy] ethyl] - cyclohexanone O-ethyloxime,

(2S, 5R, 6R) -2- [2- (benzyloxy) ethyl] -2-methyl-6- (1H-1, 2, 4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone O-propyloxime,

(2S, 5R, 6R) -2- [2- (benzyloxy) ethyl] -2-methyl-6- (1H-1, 2, 4- triazol-1-ylmethyl) -5-[ [4- (trifluoromethyl)phenoxy]methyl] - cyclohexanone O-methyloxime, (2S, 5R, 6R) -2- [2- (benzyloxy)ethyl] -2-methyl-6- (1H-1,2, 4- triazol-1-ylmethyl) -5- [ [4- (1, 1,2,2-tetrafluoroethoxy)phenoxy] methyl] -cyclohexanone O-methyloxime,

(2S, 5R, 6R) -2- [2- (benzyloxy)ethyl] -5- [2- (4-ethylphenyl) - ethyl] -2-methyl-6- (1H-1, 2, 4-triazol-l-ylmethyl) cyclohexanone O-methyloxime,

(2S, 5R, 6R) -2- [2- (benzyloxy)ethyl] -2-methyl-6- (1H-1, 2, 4- triazol-1-ylmethyl) -5- [2- (4-methylphenyl)ethyl]cyclohexanone O-methyloxime,

(2S, 5R, 6R) -2- [2- (benzyloxy) ethyl] -2-methyl-6- (1H-1,2, 4- triazol-1-ylmethyl) -5- [2- [4- (trifluoromethyl)phenyl]ethyl] - cyclohexanone O-methyloxime,

(2S, 5R, 6R) -2- [2- (benzyloxy)ethyl] -2-methyl-6- (1H-1,2,4- triazol-1-ylmethyl) -5- [2- [4- (trifluoromethoxy)phenyl]ethyl] - cyclohexanone O-methyloxime.

The protecting groups Y can be removed by the procedures known to those skilled in the art.

Process B: Specific examples of the compound represented by the general formula (III) include:

(2S, 5R,6R) -2-(2-hydroxyethyl)-2-methyl-6- (1H-1,2,4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone O-methyloxime,

(2S, 5R, 6R)-2-(2-hydroxyethyl)-2-methyl-6- (1H-1,2,4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone O-ethyloxime,

- 8 -

(2S, 5R, 6R) -2- (2-hydroxyethyl) -2-methyl-6- (1H-1, 2,4- triazol-l-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone O-propyloxime,

(2S,5R,6R)-2-(2-hydroxyethyl)-2-methyl-6-(lH-l,2,4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethyl)phenoxy]methyl] - cyclohexanone O-methyloxime,

(2S, 5R, 6R) -2- (2-hydroxyethyl) -2-methyl-6- (1H-1, 2, 4- triazol-1-ylmethyl) -5-[[4-(l,l,2, 2-tetrafluoroethoxy) - phenoxy]methyl] -cyclohexanone O-methyloxime, (2S, 5R, 6R) -5- [2- (4-ethylphenyl) ethyl] -2- (2-hydroxyethyl) - 2-methyl-6- (1H-1,2, 4-triazol-l-ylmethyl) cyclohexanone O- methyloxime,

(2S, 5R, 6R) -2- (2-hydroxyethyl) -2-methyl-6- (1H-1, 2, 4- triazol-1-ylmethyl) -5- [2- (4-methylphenyl)ethyl]cyclohexanone O-methyloxime,

(2S, 5R, 6R) -2- (2-hydroxyethyl) -2-methyl-6- (1H-1, 2,4- triazol-1-ylmethyl) -5- [2- [4- (trifluoromethyl)phenyl]ethyl] - cyclohexanone O-methyloxime, and

(2S, 5R, 6R) -2- (2-hydroxyethyl) -2-methyl-6- (1H-1, 2, 4- triazol-1-ylmethyl) -5- [2- [4- (trifluoromethoxy)phenyl] ethyl] - cyclohexanone O-methyloxime.

The mesylation can be performed by treatment of a compound represented by the general formula (III) with mesyl chloride in the presence of acid acceptor such as pyridine, 2, 6-lutidine, 2, 4, 6-collidine, triethylamine or N,N- diisopropylethylamine.

This reaction proceeds in a solvent such as chloroform, dichloromethane, pyridine, and the like, and at a temperature between -20 and 60°C, preferably between 0 and 25°C.

The nucreophilic substitution of the resulting mesylate can be performed with a nucleophile R ⁴ -H or its alkali metal salt (R ⁴ being the same as defined above) in the presence or absence of base such as sodium hydride, potassium hydride, lithium hydride and the like.

This reaction proceeds in a solvent such as chloroform, dichloromethane, N,N-dimethylformamide, and the like, and at a temperature between -20 and 60°C, preferably between 0 and 25°C.

Process C:

Specific examples of the compound represented by the general formula (IV) include:

(2R, 3R) -3- [2- (4-ethylphenyl)ethyl] -6, 6-dimethyl-2- (1H- 1,2, 4-triazol-l-ylmethyl)cyclohexanone,

(2R,3R) -6, 6, -Dimethyl-2- (1H-1,2 ,4-triazol-l-ylmethyl) -3- [ [4- (trifluoromethoxy) henoxy]methyl]cyclohexanone,

(2S, 5R, 6R) -2-Methyl-2- [2- (methylthio)ethyl] -6- (1H-1, 2, 4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy) henoxy]methyl] - eye1ohexanone

(2S, 5R, 6R) -2- (2-Methanesulfonylethyl) -2-methyl-6- (1H- 1,2,4-triazol-l-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy] - methyl] -cyclohexanone, (2S, 5R, 6R) -2- (2-imidazol-l-yl-ethyl) -2-methyl-6- (1H- 1,2, 4-triazol-l-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy] - methyl] -cyclohexanone,

(2S, 5R, 6R) -5- [ [4- (trifluoromethoxy)phenoxy] -methyl] -2- methyl-2- [2- (l-methyl-lH-imidazol-2-ylthio) ethyl] -6- (1H-1, 2, 4- triazol-1-ylmethyl)cyclohexanone,

(2S, 5R, 6R) -2- [2- (1-methyl-l,2, 3, 4-tetrazol-5-ylthio) - ethyl] -2-methyl-6- (1H-1,2, 4-triazol-l-ylmethyl) -5- [ [4- (trifluoromethoxy) -phenoxy]methyl]cyclohexanone,

(2S,5R, 6R)-[2-[2-(pyrimidinylthio)ethyl] -6- (1H-1,2,4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone,

(2S, 5R, 6R) -2- (2-hydroxyethyl) -methyl-6- (1H-1,2, 4-triazol- 1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone, (2S, 5R, 6R) -2- (2-methoxyethyl) -2-methyl-6- (1H-1, 2, 4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy) henoxy]methyl] - cyclohexanone,

(2S, 5R, 6R) -2- [2- (pyrimidinylthio)ethyl] -6- (1H-1,2,4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone,

(2S, 5R, 6R) -2- (2-morpholinoethyl) -6- (1H-1, 2, 4-triazol-l- ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone,

(2S, 5R, 6R) -2- (2-methoxyethyl) -2-methyl-6- (1H-1, 2,4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethyl) henoxy]methyl] - cyclohexanone, (2S, 5R, 6R) -2- (2-methoxyethyl) -2-methyl-6- (1H-1, 2,4- triazol-1-ylmethyl) -5- [ [4- (1,1,2,2-tetrafluoroethoxy) - phenoxy]methyl] -cyclohexanone,

(2S,5R, 6R) -5- [2- (4-ethylphenyl)ethyl] -2- (2-methoxyethyl) - 2-methyl-6- (1H-1,2, 4-triazol-l-ylmethyl)cyclohexanone, and (2S, 5R, 6R)-2- (2-methoxyethyl) -2-methyl-6- (1H-1, 2, 4- triazol-1-ylmethyl) -5- [2- (4-methylphenyl)ethyl]cyclohexanone.

The formation of oxime can be performed by treatment of a compound (IV) with hydroxylamine acid addition salt such as hydrochloride, sulfonate, phosphate in the presence of an acid acceptor such as pyridine, 2, 6-lutidine, 2, 4, 6-collidine, triethylamine or N,N-diisopropylethylamine.

This reaction proceeds in a solvent such as chloroform, dichloromethane, pyridine, ethanol, methanol and the like, and at a temperature between 20 and 150°C, preferably between 50 and 120°C.

The preparation of compound (I) wherein R2 is a lower alkoxy can be performed by O-alkylation of the resulting oxime with alkyl halide such as methyl iodide, ethyl iodide, propyl iodide and the like in the presence of base such as sodium hydride, potassium hydride, lithium hydride and the like.

This reaction proceeds in a solvent such as N,N- dimethylformamide and at a temperature between 0 and 60°C, preferably between 0 and 25°C.

Process D :

In that process, the same starting material as described in the above Process C can be used.

The formation of oxime ether can be performed by treatment of a compound (IV) with alkoxyhydroxylamine acid addition salt such as O-methylhydroxylamine hydrochloride, 0- ethylhydroxylamine hydrochloride in the presence of an acid acceptor such as pyridine, 2, 6-lutidine, 2, 4, 6-collidine, triethylamine or N,N-diisopropylethylamine.

This reaction proceeds in a solvent such as chloroform, dichloromethane, pyridine, ethanol, methanol and the like, and at a temperature between 20 and 150°C, preferably between 50 and 120°C.

Process E:

Specific examples of the compound represented by the general formula (V) include:

(2S, 5R, 6R) -2- [2- (methylthio) ethyl] -2-methyl-6- (1H-1, 2, 4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone O-methyloxime,

(2S, 5R, 6R)-2- [2- (ethylthio)ethyl] -2-methyl-6- (1H-1, 2, 4- triazol-1-ylmethyl)-5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone O-methyloxime,

(2S, 5R, 6R) -2- [2- (methylthio)ethyl] -2-methyl-6- (1H-1, 2 , 4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone O-ethyloxime, (2S, 5R, 6R) -2- [2- (methylthio) ethyl] -2-methyl-6- (1H-1, 2 , 4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy) henoxy]methyl] - cyclohexanone O-propyloxime,

(2S, 5R, 6R) -2- [2- (methylthio) ethyl] -2-methyl-6- (1H-1, 2, 4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethyl)phenoxy]methyl] - cyclohexanone O-methyloxime,

(2S, 5R, 6R) -2- [2- (methylthio) ethyl]-2-methyl-6-(1H-1, 2, 4- triazol-1-ylmethyl) -5-[[4-(l,l,2, 2-tetrafluoroethoxy)phenoxy] - methyl] -cyclohexanone O-methyloxime,

(2S, 5R, 6R) -2- [2- (methylthio) ethyl] -2-methyl-6- (1H-1,2,4- triazol-1-ylmethyl) -5- [2- (4-ethylphenyl) ethyl] cyclohexanone 0- methyloxime,

(2S, 5R, 6R) -2- [2- (methylthio) ethyl] -2-methyl-6- (1H-1,2 , 4- triazol-1-ylmethyl) -5- [2- (4-methylphenyl)ethyl] cyclohexanone O-methyloxime,

(2S, 5R, 6R) -2- [2- (methylthio) ethyl] -2-methyl-6- (1H-1, 2,4- triazol-1-ylmethyl) -5- [2- [4- (trifluoromethyl)phenyl]ethyl] - cyclohexanone O-methyloxime, and (2S, 5R, 6R) -2- [2- (methylthio) ethyl] -2-methyl-6- (1H-1, 2, 4- triazol-1-ylmethyl) -5- [2- [4- (trifluoromethoxy) henyl]ethyl] - cyclohexanone O-methyloxime,

The sulfide group of compound (V) can be oxidized with an oxidizing agent such as oxone® or m-chloroperbenzoic acid.

This reaction proceeds in aqueous alcohol, and at a temperature between 0 and 60°C, preferably between 0 and 25°C.

Process F:

O-Alkylation of a compound represented by the formula (III) , [in which R ² is a hydrogen or lower-alkyl, R^ and X are the same as defined above] can be performed by treatment with alkyl halide such as methyl iodide, ethyl iodide, propyl iodide and the like in the presence of a base such as sodium hydride, potassium hydride, lithium hydride and the like.

This reaction proceeds in a solvent such as N,N- dimethylformamide and at a temperature between 0 and 60°C, preferably between 0 and 25°C.

The manufacture of the pharmaceutically acceptable acid addition salts of the compound represented by the general formula (I) can be carried out by treatment of a free base of the compound represented by the general formula (I) with an acid in a per se conventional procedure for salt formation. Examples of therapeutically acceptable acids useful in the above process are inorganic acids (e.g. hydrochloric acid,

hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid) and organic acids (e.g. oxalic acid, acetic acid, formic acid, trifluoroacetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid, lactic acid) .

The starting compounds of formulas II, III, IV and V are novel compounds, and can be prepared in accordance with the following flow sheets 1, 2, 3 and 4:

In the flow sheet 1, trans-carveol (2) was prepared by the method described in Tetrahedron 47_, (20/21) , 3485 (1991) . The compound (2) was converted to the cyclic acetal (4) by a method similar to that described in Synthetic Commun . , 2J. (9), 1221 (1992) for the synthesis of the diastereomer of 4 from cis-carveol.

a) Compounds represented by the formula (II) [in which R ¹ , R ² , X and Y are the same as defined above] can be manufactured according to the flow sheet 1, 2 and 3 as follows.

b) Compounds represented by the formula (III) [in which R ² is a lower-alkyl, X is an oxygen and R ¹ is the same as defined above] can be manufactured according to the flow sheet 1, 2 and 3 as follows.

c) Compounds represented by the formula (III) [in which R ² is a lower-alkyl, X is a methylene and R^- is the same as defined above] can be manufactured according to the flow sheet 1 and 3 as follows.

d) Compounds represented by the formula (IV), [in which R^' R ³ and X are the same as defined above] can be manufactured according to the flow sheet 1 and 4 as follows.

e) Compounds represented by the formula (V) , [in which R ⁵ is a lower-alkyl, R ¹ , R ² and X are the same as defined above] can be manufactured by process B.

R-(-)-carvone (1)

(3)

lysis

EtO 1 radical cyclization reduction of HO X&

OH aldehyde

(4)

(5)

methoxycarbonylation

(6) (7)

i) O-methylation ii) reduction of ester (8) 0)

i) ozonolysis ii) haloform reaction

(10)

(11)

flow sheet 1

^' dealkylation

(13)

(14a):R = Me (14b) : R =H

(15) Y = protecting group

(ll) (III)

flow sheet 2

(12) (16)

demethylation

(17)

removal of

O-protecting group

(III)

(ll)

flow sheet 3

( IV ): R ³ -. CH ₃ or -(CH ₂ ) ₂ R ⁴ flow Sheet 4 ('described in EP-0524439A1 )

The compounds provided according to the present invention exhibits a broad antifungal activity against various fungi including Aspergillus fumigatus and can be used as agents for treatment and prophylaxis of fungal infectious diseases. The in vi tro antifungal activities and acute toxicity of the compounds of the present invention are shown as follows:

The in vi tro antifungal activities of the representative compounds of the present invention were evaluated by determining the 80 % inhibitory concentration (IC80), which was calculated as the lowest concentration of the compounds of the present invention to inhibit the growth of fungus to 20 % turbidity compared with the drug-free control.

The IC80 values were determined by a broth micro-dilution procedure based on a standard procedure with some minor modifications. The standard procedure, used for determining the broth dilution antifungal susceptibility for yeasts, is described in Document 27-P, National Committee for Clinical Laboratory Standards, Villanova, Pa., 1992. Yeast Nitrogen Base (YNB; Difco Lab.) supplemented with 1 % glucose and 0.25% K2HPO4 was used as testing medium for yeast. It was solidified with 0.2 % low melting point agarose and was used for

filamentous fungi. Inoculum size was 1 x 10^ cells /ml, and incubation was performed for 2 days at 27 °C. The IC80 values (μg/ml) are shown in Table 1. The reference compounds are fluconazole (FCZ) and the compound of Example 81 in EP- 0524439A1.

Table 1 In vitro Antifungal activity IC80 (μg/ml)

Compound (Example No.)

Compound (Example No.)

12 13 14 15 16 17 18 19

Candida albicans CY3003 1.2 0.18 0.35 0.023 0.22 0.12 0.024 0.74 0.05

Cryptococcus neoformans CY1057 3.3 21 >200 130 13 7.6 0.48 112 1.0

Aspergillus fumigatus CF1003 4.7 0.45 7.7 0.001 4.6 0.6 0.057 32 0.6

The acute toxicity (LD50) of the representative compounds (Examples 14, 17 and 19) of the present invention was examined by oral administration in mice. The respective LD50 values of the compounds obtained in the Examples as mentioned below are more than 500 mg/kg.

The compounds of the formula (I) and pharmaceutically acceptable salts thereof are very active antimycotic agents. They are active against a variety of fungal species including Candida albicans, Cryptotoccus neoformans, Aspergillus fumiga¬ tus, Trichophyton spp., Microsporum spp. , Exophiala spp., -3-lastσιπyces dermati tidis , and Histoplasma capsulatum.

Thus, the compounds of the present invention are useful for topical and systemic treatment of mycoses in animals as well as in human. For example, they are useful in treating topical and mucosal fungal infections caused by, among other species, Candida, Trichophyton, or Microsporum. They may also be used in the treatment of systemic fungal infections caused by, for example, Candida, Cryptococcus, Aspergillus, Paracoccidiodes , Sporotrix, Exophiala, Blastomyces, or Histoplasma .

For clinical use, the antifungals (I) or salt forms thereof can be administered alone, but will generally be administered in pharmaceutical admixture formulated as appropriate to the particular use and purpose desired, by mixing with an excipient, binding agent, lubricant, disintegrating agent, coating material, emulsifier, suspending agent, solvent, stabilizer, absorption enhancer and/or ointment base. The admixture can be used for oral, injectable, rectal or topical administration.

Pharmaceutical formulation for oral administration may be granules, tablets, sugar coated tablets, capsules, pills, suspensions or emulsions. For parenteral injection, for example, intravenous, intramuscular or subcutaneous injection, the antifungal may be used in the form of a sterile aqueous solution which may contain other substances, for example,

salts or glucose to make the solution isotonic. The antifungal can also be administered in the form of a suppository or pessary, or may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.

The daily dosage level of the antifungal compounds of the formula (I) is from 0.1 to 50 mg/kg (in divided doses) when administered by either the oral or parenteral route. Thus tablets or capsules can contain from 5.mg to 0.5 g of active compound for administration singly or two or more at a time as appropriate. In any event the actual dosage can be determined by the physician and it may be varied upon the age, weight and response of the particular patient.

In addition, the compounds of the formula (I) and their salts have activity against a variety of plant pathogenic fungi, including for example Pyricularia oryzae, Pythium aphanider a turn, Al ternaria spp., and Paecilomyces variotii .

Thus, they can be applied for agricultural and horticul¬ tural purposes preferably in the form of a composition formu¬ lated as appropriate to the particular use and purpose desired, for example dusting powders, or granules, seed dressings, aqueous solutions, dispersions or emulsions, dips, sprays or aerosols. Such compositions may contain such conventional carriers, diluents or adjuvants as are known and acceptable in agriculture and horticulture. Other compounds having herbicidal or insecticidal, or additional antifungal can be incorporated in the compositions. The compounds and compositions can be applied in a number of ways, for example they can be applied directly to the plant foliage, stems, branches, seeds or roots or to the soil or other growing medium, and they may be used not only to eradicate disease, but also prophylactically to protect the plants or seeds from attack.

The following examples illustrate the preferred methods for the preparation of the compounds of the present invention,'

which are not intended to limit the scope of the invention thereto.

Preparation of starting materials

Reference Example 1:

Preparation of (IS.2S, 5R) -2- (2-hvdroxyethyl) -5-isopropenyl-2- methylcvclohexanol

(a) To a cold (-60 °C) , magnetically stirred solution of (5R.2S) -5-isopropenyl-2-methyl-cyclohex-2-enol (205.7 g, 1.35 mol) and ethyl vinyl ether (516 ml, 5.4 mol) in dry methylene chloride (4.5 L) was added a methylene chloride solution (2 L) of N-bromosuccinimide (409.5 g) over a period of 4 hr. The reaction mixture was stirred and allowed to warm up to room temperature over a period of 2 hour. The reaction mixture was washed successively with 0.5 N aqueous sodium hydroxide, water and brine, and dried over anhydrous sodium sulfate. Evaporation of the solvent and purification of the residue by a silica gel column chromatography using ethylacetate-hexane (1:50) as eluent furnished (4R, 6S) -6- (2-bromo-l-ethoxyethoxy) - 4-isopropenyl-l-methylcyclohexene (319.1 g, 78 %) .

(b) A solution of (4R, 6S) -6- (2-bromo-l-ethoxyethoxy) -4- isopropenyl-1-ιτιethylcyclohexene (275 g, 0.91 mol), tri-n- butyltin chloride (27.5 ml), sodium cyanoborohydride (86.4 g) and α,α' -azobis(isobutyronitrile) (100 mg) in t-butanol (4 L) was refluxed for 1 hour. t-Butanol was removed under reduced pressure and the residue was diluted with ether, washed with 1 % aqueous NH ₃ followed by brine, and dried over anhydrous sodium sulfate. Evaporation of the solvent gave crude (3aS, 6R, 7aS) -2-ethoxy-6-isopropenyl-3a-methyl-octahydrobenzo- furan (164.3 g, 81 %) , which was used directly in the next reaction.

(c) A solution of (3aS, 6R,7aS) -2-ethoxy-6-isopropenyl-3a- octahydrobenzofuran (200 g, 0.89 mol) and cone. HCl (150 ml) in THF (6 L) and H ₂ 0 (2 L) was stirred at room temperature for

12 hr. The reaction mixture was neutralized with sat. NaOH solution, and THF was removed under reduced pressure. The resulting residue was partitioned between ether and water. The aqueous layer was extracted with ether. The combined extract was washed with brine, dried over anhydrous sodium sulfate. Evaporation of solvent gave crude (3aS, 6R, 7aS) -6- isopropenyl-3a-methyl-octahydrobenzofuran-2-ol which was directly used in the next reaction.

(d) To a cold (0 °C) , magnetically stirred solution of lithium aluminum hydride (25 g) in diethyl ether (2 L) was added dropwise the solution of the above alcohol in ether (0.5 L) . After stirring at room temperature for 2 hr, the reaction mixture was treated by successive dropwise addition of 25 ml of water, 25 ml of 15 % sodium hydroxide solution, and 75 ml of water. The resulting white precipitate was filtered, and the filtrate was concentrated. Recrystallization of the residue from n-hexane/ethylacetate gave pure (IS,2S, 5R) -2- (2-hydroxy-ethyl) -5-isopropenyl-2-methylcyclo- hexanol as white crystal (79.3 g, 45 %, 2 steps) ; El-MS: m/z 198 (M ⁺ ) ; -H-NMR (CDC1 ₃ )5: 0.93 (3H,s), 1.1-1.9 (8H,m), 1.72

(3H,s) , 2.30 (lH,tt,J=3.6 & 11.9Hz), 2.63 (IH, brs) , 3.24 (lH.brs) , 3.7-3.9 (3H,m) , 4.70 (2H,s) .

Reference Example 2 :

Preparation of (2S, 5R) -5-isopropenyl-2-methyl-2- (2-trityloxy- ethyl) cyclohexanone

(a) A solution of (IS, 2S, 5R) -2- (2-hydroxyethyl) -5- isopropenyl-2-methylcyclohexanol (200 g, 1.01 mol), trityl chloride (295.7 g) , and 4-dimethylaminopyridine (135.7 g) in DMF (2.8 L) was heated at 80 °C for 6 hr. After cooling the reaction mixture, it was diluted with H ₂ 0 (2 L) and extracted with diethyl ether (1.5 L x 2) . The combined extract was washed with brine, dried over anhydrous sodium sulfate. And the solvent was removed under reduced pressure to give crude (IS,2S, 5R) -5-isoproponyl-2-methyl-2- (2-trityloxyethyl) - cyclohexanol, which was used in the next reaction directly.

(b) A mixture of the above alcohol, pridinium chlorochromate (625 g) , and molecular series 4A (750 g) in dichloromethane (6 L) was stirred at room temperature for 4 hr. The reaction mixture was diluted with diethyl ether (6 L) and filtered with silica gel packed column, which was eluted with ether. The eluent was condensed under reduced pressure to give the crude product, which was purified by silica gel column chromatography to give (2S,5R) -5-isopropenyl-2-methyl- 2- (2-trityloxyethyl) cyclohexanone as colorless oil (367.1 g, 83 %) ; EI-MS: m/z 438 (M ⁺ ) ; ⁱ H-NMR (CDCl ₃ )δ: 1.05 (3H,s) ,

1.4-2.0 (6H,m), 1.69 (3H,s), 2.2-2.5 (3H,m) , 3.12 (2H,t,J=6.9Hz) , 4.67 (lH,s), 4.74 (lH,s) , 7.2-7.5 (15H,m) .

Reference Example 3 :

Preparation of (IS,2R, 3S.6R) -2-hvdroxy-6-isopropenyl-3-methyl- 3- (2-trityloxyethyl) cvclohexanecarboxylic acid methyl ester

(a) To a cooled (0 °C) , magnetically stirred solution of lithium diisopropyl amide (428 ml, 1.5 M solution in cyclohexane) in dry tetrahydrofurane (1 L) was added dropwise (2S, 5R) -5-isopropenyl-2-methyl-2- (2-trityloxyethyl) - cyclohexanone (234.6 g, 0.53 mol) in tetrahydrofuran (200 ml) . After stirring at 0 °C for 1 hr, the mixture was cooled to -78 °C. To this solution, hexamethylphosphoric triamide (112 ml) and methyl cyanoformate were added. After stirring at -78 °C for 1 hr, the reaction was quenched with water. And the reaction mixture was partitioned between H ₂ 0 and diethyl ether. The ethereal solution was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give crude (3S, 6R) -6-isopropenyl-3- methyl-2-oxo-3- (2-trityloxyethyl) cyclohexane carboxylic acid methyl ester, which was directly used in the next reaction.

(b) To a cooled (0 °C) , magnetically stirred solution of the above crude keto-ester in methanol (6 L) was added sodium borohydride (40.0 g) . After stirring at room temperature for 1 hour, the reaction mixture was neutralized with cone. HCl.

And methanol was removed under reduced pressure. The resulting residue was partitioned between H ₂ 0 and ether. The ethereal layer was washed with brine and dried over anhydrous sodium sulfate. Removal of solvent gave crude product, which was directly used in the next reaction.

(c) To a stirred solution of above crude product in methanol (6 L) , was added sodium methoxide (1.5 L, 28 % in methanol) at room temperature. After heating the solution at 80 °C, the reaction mixture was cooled to room temperature, and neutralized with cone. HCl. And methanol was removed under reduced pressure. The resulting residue was partitioned between H ₂ 0 and diethyl ether. The ethereal layer was washed with brine and dried over anhydrous sodium sulfate. Removal of solvent gave crude product, which was purified by silica gel column chromatography to give (IS,2R,3S, 6R) -2-hydroxy-6- isopropenyl-3-methyl-3- (2-trithyloxyethyl) cyclohexane- carboxylic acid methyl ester as colorless oil (118.7 g, 45 %, 3 steps); EI-MS: m/z 508 (M ⁺ ) ; ^l -H-NMR (CDCl ₃ )δ: 0.80 (3H,s), 1.2-1.8 (6H,m), 1.68 (3H _# m) _# ^' 2.27 (lH,m), 2.55

(lH,t,J=10.7Hz) , 3.1-3.3 (2H,m) , 3.48 (IH,d,J=4.3Hz) , 3.62 (3H.s) , 3.74 (lH,dd,J=4.3 & 9.2Hz), 4.68 (brs) , 4.71 (brs) , 7.1-7.5 (15H.S) .

Reference Example 4 :

Preparation of (1R, 2R, 3S, 6R) - r6-isopropenyl-2-methoxy-3- methyl-3- (2-trityloxyethyl. cvclohexyll ethanol

(a) To a cooled (0 °C) , stirred solution of sodium hydride (13.2 g, 60 % oil suspension, washed with dry hexane) in dry dimethylforma ide (2 L) , was added dropwise (IS,2R, 3S, 6R) -2-hydroxy-6-isopropenyl-3-methyl-3- (2- trityloxyethyl) -cyclohexanecarboxylic acid methyl ester 136.4 g (0.274 mol) in dry DMF (200 ml) . After stirring for 30 min. at 0 °C, methyl iodide (20.5 ml) was added dropwise. The reaction mixture was stirred at 40 °C for 4 hr. After the reaction mixture was cooled to room temperature, the reaction was quenched by added water (500 ml) , and neutralized with

cone. HCl. The resulting solution was partitioned between water and diethyl ether. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure to give crude (IS, 2R, 3S, 6R) -6-isopropenyl-2-methoxy-3-methyl-3- (2- trityloxyethyl) cyclohexanecarboxylic acid methyl ester, which was directly used in the next reaction.

(b) To a cooled (0 °C) , magnetically stirred solution of lithium aluminum hydride (50 g, 1.31 mol) in dry diethyl ether (3.5 L) was added dropwise the crude above ester in dry diethyl ether (750 ml) . After stirring at room temperature for 2 hr, the reaction mixture was treated by successive dropwise addition of 50 ml of water, 50 ml of 15 % sodium hydroxide solution, and 150 ml of water with cooling. The resulting white precipitate was filtered and washed with ether. The filtrate was condensed under reduced pressure to give (1R,2R, 3S, 6R) - [6-isopropenyl-2-methoxy-3-methyl-3- (2- trityloxyethyl)cyclohexyl]methanol as colorless oil (100.8 g, 76 %, 2 steps); EI-MS: m/z 484 (M ⁺ ) ; ^l -H-NMR (CDCl ₃ )δ: 0.82

(3H,s) , 1.1-1.7 (6H,m) , 1.65 (3H,s), 1.85-1.95 (2H,m) , 2.84 (lH,d,J=10.6Hz) , 3.18 (2H,t,J=7.3Hz) , 3.46 (3H,s), 3.51 (lH,dd,J=4.6 & 11.2Hz), 3.64 (lH,dd,J=2.3 & 11.2Hz) , 4.73 (2H,brs), 7.15-7.5 (15H,m) .

Reference Example 5 :

Preparation of 1- I (1R.2R.3S, 6R) -6-isopropenyl-2-methoxy-3- methyl-3- (2-trityloxyethyl) cvclohexylmethyll -IH- .1,2 ,41 - triazole

(a) To a cold (0 °C) , magnetically stirred solution of (1R,2R, 3S, 6R) - [6-isopropenyl-2-methoxy-3-methyl-3- (2- trityloxy-ethyl) cyclohexyl]methanol (110 g, 0.227 mol) and triethyl amine (95 ml) in dry dichloromethane (2 L) , was added dropwise mesylchloride (53 ml) . After stirring at room temperature for 1 hr, the reaction was quenched by addition of water (500 ml) . The organic layer was separated and was washed with IN HCl solution, sat. NaHC0 ₃ solution and brine

successively. The organic layer was dried over anhydrous sodium sulfate. Removal of the solvent gave (1R, 2R, 3S, 6R) - methanesulfonic acid 6-isopropenyl-2-methoxy-3-methyl-3- (2- trityloxyethyl) -cyclohexylmethyl ester, which was directly used in the next reaction.

(b) To a cold (0 °C) , stirred solution of sodium hydride (57 g, 60 % oil suspension washed with dry n-hexane) in dry DMF (500 ml), 1,2, 4-triazole (99.1 g) was added by portions. After stirring at room temperature for 1 hr, a solution of the above mesylate in dry DMF (500 ml) was added, and the mixture was stirred at room temperature for 12 hr. The reaction was quenched by addition of water (500 ml), neutralized with cone. HCl, and the mixture was extracted with diethyl ether. The combined ethereal layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude residue was purified by silica gel column chromatography to afford 1- [ (1R, 2R, 3S, 6R) -6-isopropenyl-2-methoxy-3-methyl-3- (2- trityloxyethyl)cyclohexylmethyl] -IH- [1,2,4]triazole as colorless oil (87.8 g, 71 %, 2 steps); FAB-MS: m/z 546 (MH ⁺ ) ; ¹ H-NMR (CDCl ₃ )δ: 0.83 (3H,s) , 1.0-1.8 (6H,m), 1.58 (brs),

1.85-2.05 (2H,m), 3.10 (IH,d,J=10.2Hz) , 3.16 (2H, t,J=7.6Hz) , 3.60 (3H,s), 4.10 (lH,dd,J=4.0 & 13.9Hz), 4.32 (lH,dd,J=2.6 & 13.9Hz) , 4.65 (lH,brs), 4.82 (lH.brs) , 7.15-7.5 (15H,m) , 7.87 (1H,S) , 7.95 (1H,S) .

Reference Example 6:

Preparation of (1R,2R, 3R, 4S) - r3-methoxy-4-methyl-2- (lH-1,2 , 4- triazol-1-ylmethyl) -4- (2-trityloxyethyl) cyclohexylImethanol

(a) A stream of 0 ₃ was bubbled through a solution of 1- [ (1R,2R, 3S, 6R) -6-isopropenyl-2-methoxy-3-methyl-3- (2- trityloxyethyl) cyclohexylmethyl] -IH- [1, 2, 4]triazole (194.1 g, 0.173 mol) in CHC1 ₃ (3 L) and methanol (600 ml) at -78 °C until the blue color persisted. N ₂ was bubbled through the system, and dimethyl sulfide (100 ml) and potassium carbonate (50 g) were added. The cold bath was removed, and the mixture was allowed to stir at room temperature for 4 hr. After

concentration of the reaction mixture, the residue was partitioned between water and diethyl ether. The ethereal solution was washed with brine, and dried over anhydrous sodium sulfate. Removal of the solvent gave crude 1- [ (1R,2R, 3R, 4S) -3-methoxy-4-methyl-2- (1H-1, 2, 4-triazol-l- ylmethyl) -4- (2-trityloxyethyl)cyclohexyl]ethanone, which was directly used in the next reaction.

(b) A solution of 82 g of sodium hydroxide in 720 ml of water was placed in a round bottomed flask. And the solution was cooled to -5 °C in an ice salt bath. The stirring was started, and 86 g of bromine was added from a separatory funnel at such a rate that the temperature remained below 0°C. The ice-cold solution was diluted with 480 ml of dioxane that was pre-cooled to 13 - 14 °C. The solution was kept at 0 °C until required.

A solution of the above ketone in 2200 ml of dioxane was diluted with 680 ml of water. The stirring was started and the mixture was cooled with ice bath. When the internal temperature has fallen to 8 °C, the cold hypobromite solution was added in a steady stream. The temperature of the reaction mixture was maintained below 10 °C throughout the reaction. The mixture was stirred for 1 hr, and then the excess sodium hypobromite was destroyed by the addition of a solution of sodium sulfite in water. The mixture was acidified by the addition of cone, hydrochloric acid. The mixture was extracted with diethyl ether, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give crude (1R,2R, 3R,4S) -3- methoxy-4-methyl-2- (1H-1,2,4-triazol-l-ylmethyl) -4- (2- trityloxyethyl)cyclohexanecarboxylic acid, which was directly used in the next reaction.

(c) To a solution of crude (1R,2R,3R,4S) -3-methoxy-4- methyl-2- (1H-1,2, 4-triazol-l-ylmethyl) -4- (2-trityloxyethyl) - cyclohexanecarboxylic acid (115 g) in dry diethyl ether (2.5 L) at 0 °C, was added lithium aluminum hydride (16.0 g) in

small portions. The mixture was stirred for 1 hour at room temperature. After the mixture was cooled to 0 °C, it was treated by successive dropwise addition of 16 ml of water, 16 ml of 15 % sodium hydroxide solution and 48 ml of water. The resulting granular white precipitate was filtered, and the filtrate was concentrated. Purification of the residue with silica gel chromatography gave (1R, 2R, 3R, 4S) - [3-methoxy-4- methyl-2-(lH-l,2,4-triazol-l-ylmethyl)-4-(2-trityloxyethyl)- cyclohexyl]methanol as colorless oil (56 g, 62 %, 3 steps) ; FAB-MS: m/z 526 (MH ⁺ ) ; ^-H-NMR (CDCl ₃ )δ: 0.78 (3H,s), 1.0-2.0

(8H,m), 2.73 (IH,d,J=10.9Hz) , 3.15 (2H, t,J=7.6Hz) , 3.55 (3H,s), 3.5-3.8 (2H,m) , 4.36 (lH,s), 4.37 (lH,s) , 7.2-7.5 (15H,m), 7.92 (lH,s), 8.07 (lH,s) .

Reference Example 7:

Preparation of 2- r (IS,2R.3R, 4R) -2-methoxy-l-methyl-3- (1H- 1,2, 4-triazol-l-ylmethyl) -4- \ T4- (trifluoromethoxy)phenoxy1 - methyl1 -cyclohexyl] ethanol

(a) To a cold (0 °C) , magnetically stirred solution of (1R,2R,3R,4S) - [3-methoxy-4-methyl-2- (1H-1,2, 4-triazol-l- ylmethyl) -4- (2-trityloxyethyl) cyclohexyl]methanol (15.0 g, 0.028 mol) triethylamine (5.5 ml) in dry dichloromethane (200 ml) , was added dropwise mesyl chloride (5.0 ml) . After stirring at room temperature for 1 hr, the reaction was quenched by addition of water. The organic layer was separated, washed with IN HCl solution, sat. NaHC0 ₃ solution and brine successively, and dried over anhydrous sodium sulfate. Removal of the solvent gave methanesulfonic acid (1R,2R,3R,4S) -3-methoxy-4-methyl-2- (1H-1, 2, 4-triazol-l- ylmethyl) -4- (2-trityloxyethyl) cyclohexyl methyl ester, which was directly used in the next reaction.

(b) To a cold (0 °C) , stirred solution of sodium hydride (1.61 g, 60 % oil suspension, washed with dry n-hexane) in dry DMF (100 ml), was added dropwise 4- (trifluoromethoxy)phenol (6.0 g) . After stirring at room temperature for 1 hr, a solution of above mesylate in DMF (10 ml) was added, and the

mixture was stirred at room temperature for 12 hr. The reaction was quenched by addition of water, neutralized with cone. HCl, and then extracted with diethyl ether. The combined ethereal layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude residue was purified by silica gel column chromatography to give l-[ (1R,2R, 3S, 6R) -2-methoxy-3-methyl-6- [ [4- (trifluoro¬ methoxy)phenoxy]methyl] -3- (2-trityloxyethyl) cyclohexylmethyl] - 1H-[1,2, 4] triazole (14.0 g, 73 %, 2 steps) .

(c) A solution of 1- [ (1R,2R,3S, 6R) -2-methoxy-3-methyl-6- [ [4- (trifluoromethoxy)phenoxy]methyl] -3- (2-trityloxyethyl) - cyclohexylmethyl] -IH- [1,2, 4]triazole (28 g, 0.04 mol) and cone. HCl (0.5 ml) in methanol (100 ml) was stirred at 40 °C for 3 hr and then at room temperature for 14 hr. After the reaction mixture was neutralized with 5N NaOH aq, methanol was evaporated under reduced pressure. The resulting residue was partitioned between ether and water. The ethereal layer was washed with brine, and dried over anhydrous sodium sulfate. After removal of the solvent, the resulting crude product was purified by silica gel column chromatography to give 2- [ (IS, 2R, 3R, 4R) -2-methoxy-l-methyl-3- (1H-1, 2, 4-triazol-l- ylmethyl) -4-[ [4- (trifluoromethoxy)phenoxy]methyl]cyclohexyl] - ethanol as colorless oil (13 g, 73 %) ; FAB-MS: m/z 444 (MH ⁺ ) ; ⁱ H-NMR (CDCl ₃ )δ: 1.00 (3H,s), 1.4-1.8 (6H,m) , 1.90 (lH,m),

2.15 (lH,m), 3.05 (IH,d,J=10.9Hz) , 3.66 (3H,s), 3.76 (2H,t,J=7.3Hz) , 3.92 (lH,dd,J=3 & 9.6Hz), 4.07 (lH,dd,J=4.0 & 9.6Hz), 4.32 (lH,dd,J=3.6 & 14.5Hz), 4.52 (lH,dd,J=3.0 & 14.5Hz) , 6.86 (2H,d,J=9.2Hz) , 7.13 (2H,d,J=8.6Hz) , 7.91 (lH,s) , 8.14 (lH,s) .

Reference Example 8 :

Preparation of (1R.2S, 5R.6R) -2- (2-benzyloxyethyl) -2-methyl-6- (1H-1.2.4-triazol-l-ylmethyl) -5- f T4- (trifluoromethoxy)phenoxyl -methyl1cvclohexanol

(a) To a cold (0 °C) , stirred solution of sodium iodide (5.86 g) and anhydrous aluminium chloride (5.21 g) in

- 31 - dichloromethane (25 ml) and acetonitrile (50 ml) was added a solution of 2- [ (IS,2R, 3R, 4R) -2-methoxy-l-methyl-3- (1H-1,2,4- triazol-1-ylmethyl) -4- [ [4- (trifluoromethoxy)phenoxy] - methyl] cyclohexyl]ethanol (1.73 g, 3.91 mmol) in acetonitrile (5 ml) . After stirring at room temperature for 13 hr, the reaction was quenched by addition of water, and the mixture was neutralized with 20 % NaOH aq. The mixture was extracted with diethyl ether, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by silica gel column chromatography gave (1R,2S, 5R, 6R) -2- (2- hydroxyethyl)-2-methyl-6- (1H-1,2, 4-triazol-l-ylmethyl) -5-[ [4- (trifluoromethoxy)phenoxy] -methyl]cyclohexanol (1.27 g, 76 %) .

(b) A mixture of the (1R, 2S, 5R, 6R) -2- (2-hydroxyethyl) -2- methyl-6- (1H-1, 2, 4-triazol-l-ylmethyl) -5- [ [4- (trifluoro¬ methoxy) -phenoxy]methyl]cyclohexanol (294 mg, 0,69 mmol) and sodium hydride (54 mg, 60 % dispersion in oil) and benzyl bromide (0.1 ml) in dry N.N-dimethylformamide (10 ml) was stirred for 10 hrs at room temperature. After the mixture was cooled to 0 °C, the reaction was quenched by addition of water. The pH of the mixture was adjusted to pH 7 with 0.1 N hydrochloric acid. The mixture was extracted with diethyl ether, and the combined organic laye'rs were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by flush column chromatography gave (1R,2S, 5R, 6R) -2- (2-benzyloxyethyl) -2- methyl-6-(lH-l,2,4-triazol-l-ylmethyl)-5-[ [4- (trifluoro¬ methoxy)phenoxy]methyl]cyclohexanol as white crystals; FAB- MS: m/z 520 (MH ⁺ ); ⁱ H- MR (CDCl ₃ )δ: 0.98 (3H,s), 1.10-1.90

(7H,m) , 2.03 (lH,br.t) , 2.81 (IH,dd,J=10.7 & 2.5Hz), 3.40- 3.54 (lH,m) , 3.62 (lH,m), 4.08 (IH,d,J=9.5Hz) , 4.25 (lH,dd,J=13.8 & 2.3Hz) , 4.39 (lH,dd,J=9.5 & 4.1Hz), 4.53 (2H,d,J=1.7Hz) , 4.71 (IH,dd,J=13.8 & 4.2Hz), 6.95 (2H,d,J=9.2Hz) , 7.15 (2H,d,J=9.2Hz) , 7.30-7.50 (5H,m) , 7.89 (1H,S) , 8.02 (lH,s) .

Reference Example 9 :

Preparation of (2S, 5R.6R) -2- (2-benzyloxyethyl) -2-methyl-6- .1H- 1.2.4-triazol-l-ylmethyl) —5— f f4— (trifluoromethoxy)phenoxy1 - methyl] cyclohexanone O-methyloxime

(a) N-Chlorosuccinimide (22.6 mg, 0.17 mmol) was suspended in dry toluene (0.5 ml) , and dimethyl sulfide (0.05 ml, 0.68 mmol) was added to this suspension at -30 °C under nitrogen atmosphere. After stirring at -30 °C for 30 minutes, (1R,2S, 5R, 6R) -2- (2-benzyloxyethyl) -2-methyl-6- (1H-1, 2, 4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanol (11.2 mg, 0.02 mmol) dissolved in dry toluene (1 ml) was added dropwise to it. After the stirring was continued for an hour, dry triethyl amine (0.07 ml, 0.50 mmol) was added. The temperature was raised up to the room temperature and quenched by adding water after 1.5 hours. The reaction mixture was extracted with diethyl ether. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic solvent was removed, and the residual colorless oil was purified by silica gel chromato¬ graphy (CH ₂ Cl ₂ /MeOH = 30/1) to give (2S, 5R, 6R) -2- (2-benzyloxy- ethyl) -2-methyl-6- (1H-1,2, 4-triazol-l-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] cyclohexanone was obtained in 81 % yield as colorless oil.

(b) (2S, 5R, 6R) -2- (2-Benzyloxyethyl) -2-methyl-6- (1H-1, 2 , 4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy) -phenoxy]methyl] - cyclohexanone (172.1 mg, 0.33 mmol) , O-methylhydroxylamine hydrochloride (574.7 mg, 6.88 mmol) and pyridine (1.0 ml, 12.36 mmol) were dissolved in ethanol. This solution was refluxed for 4.5 hours, but the starting material still remained. So, n-propanol (20 ml) was added and the mixture was refluxed for 17 hours and quenched by adding water. The reaction mixture was extracted with dichloromethane. The organic layer was washed with brine, and dried over magnesium sulfate. The organic solvent was removed, and the residual colorless oil was purified by silica gel chromatography (CHCl ₃ / 2-propanol / 25 % aq. NH ₃ = 100/2/1 and 100/1/1) to give

(2S, 5R, 6R) -2- (2-benzyloxyethyl) -2-methyl-6- (1H-1,2, 4-triazol- 1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl]cyclo¬ hexanone O-methyloxime was obtained in 75 % yield as colorless oil; FAB-MS: m/z 547 (MH ⁺ ) ; ^l -H-NMR (CDCl ₃ )δ: 1.19 (3H,s), 1.20-1.35 (lH. ), 1.60-1.80 (3H,m) , 1.90-2.10 (2H,m) , 2.12- 2.30 (lH,m), 3.40-3.70 (4H,m) , 3.75 (lH,m) , 3.85 (3H,s) , 4.15-4.25 (2H,m), 4.40-4.55 (2H,m) , 6.74 (2H,d,J=9.1Hz) , 7.09 (2H,d,J=9.1Hz) , 7.27-7.40 (5H,m), 7.89 (lH,s), 8.00 (lH,s) .

Reference Example 10:

Preparation of 5- \ 2 - ϊ (1R, 2R, 3R, 4R) -2-methoxy-l-methyl-3- (1H- 1,2, 4-triazol-l-ylmethyl) -4- r [4- (trifluoromethoxy)phenoxy] - methyl] cvclohexy] ethylthio] -1-methyl-lH-tetrazole

(a) To a cold (0 °C) , magnetically stirred solution of 2- [ (1S.2R, 3R,4R) -2-methoxy-1-methyl-3- (1H-1,2,4-triazol-l- ylmethyl) -4- [ [4- (trifluoromethoxy)phenoxy]methyl]cyclohexyl] - ethanol (2.5 g, 5.64 mmol) and triethylamine (1.0 ml) in dry dichloromethane (50 ml) was added dropwise mesyl chloride (1.1 ml) . After stirring at room temperature for 1 hr, the reaction was quenched by addition of water. The organic layer was separated and was washed with IN HCl solution, sat. NaHC0 ₃ solution and brine successively. The organic layer was dried over anhydrous sodium sulfate. Removal of the solvent gave crude methanesulfonic acid 2- [ (IS,2R, 3R, 4R) -2-methoxy-l- methyl-3- (1H-1,2, 4-triazol-l-ylmethyl) -4-[ [4- ( rifluoro¬ methoxy) -phenoxy]methyl]cyclohexyl]ethyl ester which was directly used in the next reaction.

(b) A solution of the above mesylate and 5-mercapto-l- methyltetrazole sodium salt hydrate (3.89 g) in dry DMF (1 ml) was stirred at room temperature for 13 hr. The reaction was quenched by addition of water (3 ml) , and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. Removal of the solvent gave the crude product, which was purified by preparative TLC to give 5- [2- [ (IS,2R,3R,4R) -2-methoxy-1-methyl-3- (1H-1,2,4-triazol-l-

ylmethyl) -4-[ [4- (trifluoromethoxy)phenoxy]methyl]cyclohexyl] - ethylthio] -1-methyl-lH-tetrazole (2.32 g, 76 %, 2 steps); FAB-MS: m/z 542 (MH ⁺ ) ; ⁱ H- MR (CDCl ₃ )δ: 1.01 (3H,s), 1.25

(lH,m), 1.5-1.8 (2H,m) , 1.83 (lH,m) , 2.0-2.3 (2H,m) , 3.08 (lH,d,J=10.8Hz) , 3.33 (2H,m) , 3.61 (3H,s), 3.88 (3H,s) , 3.89 (lH,m) , 4.04 (lH,dd,J=3.3 & 9.2Hz), 4.29 (lH,dd,J=3.β & 14.5Hz), 4.49 (lH,dd,J=2.6 & 14.5Hz), 6.83 (2H,d, =8.9Hz) , 7.11 (lH,d,J=8.9Hz) , 7.89 (lH,s) , 8.10 (lH,s) .

Reference Example 11 :

Preparation of (2S, 5R, 6R) -2-methyl-2- f2- (1-methyl-lH-tetrazol- 5-ylthio) ethyll -6- (1H-1.2.4-triazol-l-ylmethyl) -5- r T4- (trifluoromethoxy)phenoxy] ethyllcyclohexanone

(a) To a cold (0 °C) , stirred solution of sodium iodide (5.8 g) and anhydrous aluminium chloride (5.1 g) in dichloromethane (25 ml) and acetonitrile (50 ml) was added a solution of 5- [2-[ (IS,2R,3R, 4R) -2-methoxy-l-methyl-3- (1H- 1,2, 4-triazol-l-ylmethyl) -4- [ [4- (trifluoromethoxy)phenoxy] - cyclohexyl] ethylthio] -1-methyl-lH-tetrazole (2.1g, 3.88 mmol) in acetonitrile (5 ml) . After stirring at room temperature for 13 hr, the reaction was quenched by addition of water, and the mixture was neutralized with 20 % NaOH aq. The mixture was extracted with diethyl ether, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by silica gel column chromatography gave (1R,2S, 5R, 6R) -2-methyl-2-[2-(l-methyl-lH-tetrazol-5-ylthio) - ethyl] -6- (1H-1, 2, 4-triazol-l-ylmethyl) -5- [ [4- (trifluoro- methoxy)phenoxy] ethyl] cyclohexanol (1.27 g, 62 %) .

(b) N-Chlorosuccinimide (22.6 mg, 0.17 mmol) was suspended in dry toluene (0,5 ml) , and dimethyl sulfide (0.05 ml, 0.68 mmol) was added to this suspension at -30 °C under nitrogen atmosphere. After stirring at -30 °C for 30 minutes, a solution of (1R,2S, 5R, 6R) -2-methyl-2- [2- (1-methyl-lH- tetrazol-5-ylthio) -ethyl] -6- (1H-1,2,4-triazol-l-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl]cyclohexanol (11.2 mg,

0.02 mmol) in dry toluene (1 ml) was added dropwise to it. The stirring was continued for an hour and then, dry triethyl amine (0.07 ml, 0.50 mmol) was added. The temperature was raised up to the room temperature and quenched by adding water after 1.5 hours. The reaction mixture was extracted with diethyl ether. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic solvent was removed, and the residual colorless oil was purified by silica gel chromatography. Colorless oil of (2S, 5R, 6R) -2-methyl-2- [2-(l-methyl-lH-tetrazol-5-ylthio)ethyl]-6-(lH-l,2,4-triazol - 1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl]cyclo¬ hexanone was obtained in 81 % yield; FAB-MS: m/z 526 (MH ⁺ ) ; ^X H-NMR (CDCl ₃ )δ: 1.30 (3H,s), 1.5-2.3 (7H,m) , 3.2-3.6 (3H,m) ,

3.91 (3H,s) , 4.07 (lH,dd,J=2.6 & 9.6Hz) , 4.35-4.45 (2H,m) , 4.64 (lH,dd,J=2.3 & 14.1Hz), 6.95 (2H,d,J=9.2Hz) , 7.16 (2H,d,J=9.2Hz) , 7.83 (lH,s), 8.27 (lH,s) .

Example 1:

Preparation of (2S, 5R, 6R) -2- (2-hvdroxyethyl) -2-methyl-6- (1H- 1,2, 4-triazol-l-ylmethyl) —5— T f4— (trifluoromethoxy) -phenoxy] - methyl]cyclohexanone O-methyloxime

To a methanol solution of (2S, 5R, 6R) -2- (2-benzyloxy- ethyl) -2-methyl-6- (1H-1,2, 4-triazol-l-ylmethyl) -5-[ [4- (trifluoromethoxy)phenoxy]methyl] cyclohexanone O-methyloxime (44.0 mg, 0.08 mmol) was added 20 % Pd(OH) ₂ /C (27.0 mg) . The mixture was stirred under hydrogen atmosphere. The catalyst was removed by filtration through celite and the solvent was removed under reduced pressure. The residual colorless oil was purified by silica gel chromatography to give (2S, 5R, 6R) -2- (2- hydroxyethyl) -2-methyl-6- (1H-1, 2, 4-triazol-l-ylmethyl) -5- [ [4-

(trifluoromethoxy)phenoxy]methyl]cyclohexanone O-methyloxime was obtained in 72 % yield as white solid; FAB-MS: m/z 457

(MH ⁺ ); ^X H-NMR (CDCl ₃ )δ: 1.18 (3H,s), 1.20-1.50 (4H,m), 1.50-1.80 (2H,m) , 2.02 (lH,m) , 3.22 (2H,d, 6.9Hz) , 3.53 (2H,d, 6.9Hz) , 3.61 (3H,s) , 3.70-4.10 (3H,m) , 6.33 (2H,d, 8.7Hz) , 6.83 (2H,d, 8.7Hz) , 7.72 (lH,s), 7.94 (lH,s) .

The compound in Example 2 was obtained according to a manner analogous to that of Example 1.

Example 2 : (2S, 5R, 6R) -2- (2-Hvdroxyethyl) -2-methyl-6- (1H-1.2.4-triazol-l- ylmethyl) -5- [ f4- (trifluoromethoxy)phenoxyImethyll - cyclohexanone oxime; Colorless heavy syrup; FAB-MS: m/z 443 (MH ⁺ ) ; ^X H-NMR (CDCl ₃ )δ: 1.20 (3H,s), 1.46-2.68 (8H,m), 3.64-

3.80 (4H,m), 3.97 (lH,brt,J=6.3Hz) , 4.34-4.55 (2H,m) , 6.77 (2H,d,J=9.23Hz) , 7.07 (2H,d,J=8.25Hz) , 7.91 (lH,s), 8.22 (lH,s) , 8.31 (lH,brs) .

Example 3 :

Preparation of (2S, 5R, 6R) -2-methyl-2- 2 - (methylthio) -ethyll -6- (1H-1 , 2 , 4-triazol-l-ylmethyl) -5- \ T4- (trifluoromethoxy) - phenoxylmethyl1cyclohexanone O-methyloxime

To a cold solution of (2S, 5R, 6R) -2- (2-hydroxyethyl) -2- methyl-6- (1H-1,2, 4-triazol-l-ylmethyl) -5- [ [4- (trifluoro- methoxy) -phenoxy]methyl]cyclohexanone O-methyloxime (402.2 mg, 0.882 mmol) in dry DMF (8 ml) were added 2, 4, 6-collidine (1.2 ml, 9.08 mmol, 10.3 eq. ) and methanesulfonyl chloride (0.70 ml, 9.04 mmol, 10.4 eq.) at 0 °C. After stirring for 50 min., sodium thiomethoxide (1.4 g, 20.0 mmol, 23 eq.) was added. The reaction mixture was stirred at room temperature for 3 h, quenched with ice water, and extracted with diethyl ether. The combined ethereal layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to afford (2S, 5R, 6R) -2-Methyl-2- [2- (methylthio) -ethyl] -6- (1H-1,2, 4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone O-methyloxime (358.1 mg, 0.737 mmol, 84 % yield); Liquid; FAB-MS: m/z 487 (MH ⁺ ) ; ¹ H-NMR (CDCl ₃ )δ:

1.18 (3H,s), 1.5-1.8 (4H,m), 1.8-2.0 (2H,m), 2.13 (3H,s), 2.22 (lH,m) , 2.35-2.6 (2H,m) , 3.68 (2H,m), 3.81

(brt,J=5.0Hz) , 3.86 (3H,s), 4.28 (2H,d,J=6.6Hz) , 6.75 (2H,d,J=9.2Hz) , 7.09 (2H,d,J=9.2Hz) , 7.91 (lH,s), 8.15 (lH,s) .

Example 4 :

Prepration of (2S.5R, 6R) -2-methyl-2- Ϊ2- (1-methyl-l.2 , 3.4- tetrazol-5-ylthio)ethvπ -6- (1H-1, 2 , 4-triazol-l-ylmethyl) -5- T r4- (trifluoromethoxy)phenoxy]methyl]cyclohexanone oxime

(2S, 5R, 6R) -2-methyl-2- [2- (1-methyl-l,2, 3 , 4-tetrazol-5- ylthio)ethyl] -6- (1H-1,2 ,4-triazol-l-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] cyclohexanone (400 mg) , hydroxylamine hydrochloride (530 mg, 7.6 mmol) and pyridine

(2.0 ml) were dissolved in ethanol (25.0 ml) and this solution was refluxed for 12 hours. The reaction was quenched by adding water and the mixture was extracted with dichloro¬ methane. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography. Colorless oil of (2S, 5R, 6R) -2-methyl-2- [2- (1- methyl-1, 2,3, 4-tetrazol-5-ylthio) ethyl] -6- (1H-1, 2, 4-triazol-l- ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] cyclohexanone oxime was obtained. (300 mg, 73 %) ; Heavy syrup; FAB-MS: m/z 540 (MH ⁺ ) ; ^X H-NMR (CDCl ₃ )δ: 1.27 (3H,s), 1.5-1.9 (4H,m) , 2.03

(lH,m), 2.2-2.4 (2H,m) , 3.26 (2H,m) , 3.71 (2H,d,J=5.6Hz) , 3.90 (3H,s), 4.01 (IH,brdd,J=3.0 ci 9.6Hz), 4.46 (lH,dd,J=4.6 & 13.5Hz), 4.54 (lH,dd,J=9.9 & 13.5Hz) , 6.76 (2H,d,J=9.2Hz) , 7.09 (2H,d,J=9.2Hz) , 7.92 (lH,s) , 8.29 (lH,s) .

Example 5 :

Preparation of (2S, 5R, 6R) -2-methyl-2- Ϊ2- (1-methyl-l,2 , 3 , 4- tetrazol-5-ylthio. ethyl] -6- (1H-1, 2 , 4-triazol-l-ylmethyl) -5- [ f4- ( rifluoromethoxy)phenoxy]methyl]cyclohexanone O- methy1oxime

To a cooled (0 °C) , stirred solution of sodium hydride (34 mg, 60 % oil suspension) in dry N,N-dimethylformamide (5 ml) , was added the oxime of example 4 (300 mg) in dry N,N- dimethylform--UTU.de (1 ml) . After stirring for 15 min. at 0 °C, methyl iodide (100 ml) was added dropwise. The mixture was stirred at 0 °C for 30 min. The reaction was quenched by

addition of water and neutralized with IN HCl. The resulting solution was partitioned between water and dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure to give crude product, which was purified by silica gel chromatography. Amorphous powder of (2S, 5R, 6R) -2-methyl-2- [2- (l-methyl-lH-tetrazol-5-ylthio) - ethyl] -6- (1H-1, 2, 4-triazol-l-ylmethyl) -5- [ [4- (trifluoro¬ methoxy)phenoxy]methyl]cyclohexanone O-methyloxime was obtained. (262 mg, 85 %) ; Amorphous powder; FAB-MS: m/z 555 (MH ⁺ ) ; ^X H-NMR (CDCl ₃ )δ: 1.27 (3H,s), 1.5-2.35 (7H,m) , 3.28

(2H,m) , 3.69 (2H,brd,J=7.2Hz) , 3.86 (3H,s), 3.89 (lH,m) , 3.91 (3H,s), 4.39 (IH,dd,J=4.9 & 13.5Hz) , 4.50 (lH,dd,J=9.9 & 13.5Hz), 6.77 (2H,d,J=8.9Hz) , 7.09 (2H,d,J=8.9Hz) , 7.90 (lH,s) , 8.23 (lH,s) .

The following compounds in Example 6-14 were obtained according to a manner analogous to that of Example 4 and 5.

Example 6 :

(2S.5R, 6R) -5- T f4- (trifluoromethoxy)phenoxylmethyl] -2-methyl-2- Ϊ2 - (l-methyl-lH-imidazol-2-ylthio. ethyll -6- (lH-1,2, 4-triazol- 1-ylmethyl) cyclohexanone O-methyloxime; Heavy syrup; FAB-MS: m/z 553 (MH ⁺ ) ; ^X H-NMR (CDCl ₃ )δ: 1.20 (3H,s), 1.5-2.2 (7H,m), 2.93-3.00 (2H,m), 3.51-3.85 (3H,m) , 3.63 (3H,s), 3.85 (3H,s), 4.19-4.22 (2H,m) , 6.74 (2H,d,J=8.9Hz) , 6.91 (lH,d,J=1.3Hz) , 7.00 (lH,d,J=l.0Hz) , 7.09 (2H,d,J=8.9Hz) , 7.90 (lH,s) , 8.14 (lH,s) .

Example 7 :

■2S, 5R, 6R) - 12- \2- (pyrimidinylthio) ethyll -6- (1H-1 , 2 , 4-triazol- 1-ylmethyl) -5- f f4- (trifluoromethoxy)phenoxyl -methyl]cyclo¬ hexanone O-methyloxime; Heavy syrup; FAB-MS: m/z 551 (MH ⁺ ) ; ^X H-NMR (CDCl ₃ )δ: 1.25 (3H,s), 1.5-2.4 (7H,m) , 3.15 (2H,t,J=9.1Hz) , 3.69 (2H,m), 3.86 (3H,s), 3.97 (IH, t,J=7.5Hz) ,

4.54 (lH,d,J=7.1Hz) , 6.76 (2H,d,J=8.9Hz) , 6.95 (IH,d,J=4.7Hz) ,

7.08 (2H,d,J=8.9Hz) , 7.92 (lH,s), 8.22 (lH,s), 8.53 (2H,d,J=4.7Hz) .

Example 8 :

(2S, 5R.6R. -2- (2-imidazol-l-ylethyl) -2-methyl-6- (1H-1.2 , 4- triazol-1-ylmethyl) —5— T T4— (trifluoromethoxy)phenoxylmethyll - cyclohexanone oxime: White amorphous; FAB-MS: m/z 493 (MH ⁺ ) ; ^X H-NMR (CDCl ₃ )δ: 1.20 (3H,s), 1.20-2.20 (6H,m), 2.31 (lH,m) ,

3.60-3.80 (2H,m), 3.80-4.20 (3H,m) , 4.32 (2H,m) , 6.78 (2H,d, 8.9Hz) , 6.94 (lH,s) , 7.08 (lH,s), 7.10 (2H,d, 9.1Hz) , 7.61 (lH,s), 7.90 (lH,s) , 8.25 (lH,s) .

Example 9 :

(2S.5R.6R. -2- Ϊ2- (pyrimidinylthio) ethyll -6- (1H-1.2 , 4-triazol-l- ylmethyl) -5- \ [4- (trifluoromethoxy)phenoxγl -methyllcyclo¬ hexanone oxime; White amorphous; FAB-MS: m/z 537 (MH ⁺ ) ; ^X H- NMR (CDCl ₃ )δ: 1.28 (3H,s) , 1.5-2.4 (7H,m), 3.06 (2H, t,J=9.3Hz) ,

3.70 (2H,m) , 3.97 (IH, t,J=7.3Hz) , 4.49 (IH,d,J=7.2Hz) , 6.75 (2H,d,J=8.8Hz) , 6.95 (IH, t,J=4.8Hz) , 7.08 (2H,d,J=8.8Hz) , 7.93 (1H,S) , 8.26 (lH,s), 8.49 (2H,d,J=4.8Hz) .

Example 10:

(2S.5R,6R)-5-rr4- (trifluoromethoxy)phenoxylmethyll -2-methyl-2- T2- (l-methyl-lH-imidazol-2-ylthio)ethyl1 -6- (1H-1.2 , 4-triazol- 1-ylmethyl)cyclohexanone oxime; Heavy syrup; FAB-MS: m/z 539 (MH ⁺ ) ; ^X H-NMR (CDCl ₃ )δ: 1.1-2.3 (7H,m), 1.22 (3H,s), 2.93- 3.05 (2H,m) , 3.62-3.65 (2H,m) , 3.65 (3H,s), 3.92 (lH,m) , 4.12 (lH,brt), 4.34 (lH,dd,J=3.6 &. 13.5Hz) , 6.72 (2H,d,J=9.2Hz) , 6.92 (lH,s), 6.99 (lH,s), 7.07 (2H,d,J=8.9Hz) , 7.93 (lH,s), 8.23 (lH,s), 9.70 (lH.brs) .

Example 11:

(2S.5R, 6R) -2- (2-morpholinoethyl. -6- (1H-1.2 , 4-triazol-l- ylmethyl) -5- f T4- (trifluoromethoxy)phenoxylmethyllcyclohexanone oxime; Heavy syrup; FAB-MS: m/z 512 (MH ⁺ ) ; ^X H-NMR (CDCl ₃ )δ: 1.19 (3H,s) , 1.27 (lH,m), 1.5-1.8 (3H,m) , 2.1-2.3 (3H,m) , 2.37 (2H,brt,J=8.2Hz) , 2.47 (4H,brs), 3.73 (4H,brt,J=6.5Hz) , 3.95 (lH,m), 4.39 (IH,dd,J=4.8 & 11.3Hz) , 4.61 (lH,dd,J=7.8 &11.3HZ) , 6.81 (2H,d,J=8.9Hz) , 7.01 (2H,d,J=8.9Hz) , 7.90 (lH,s) , 8.25 (lH,s) .

Example 12 :

(2S, 5R, 6R) -2-Methyl-2- \ 2- (methylthio) ethyll -6- (1H-1.2.4- triazol-1-ylmethyl) -5-f f4- (trifluoromethoxy)phenoxyl - methyl1 cyclohexanone oxime: Colorless solid; FAB-MS: m/z 473 (MH ⁺ ); ¹ H-NMR (CDCl ₃ )δ: 1.19 (3H,s), 1.53-2.15 (6H,m), 2.13 (3H.s), 2.19-2.59 (3H,m) , 3.61-3.76 (2H,m) , 3.96 (lH,brt,J=6.6Hz) , 4.27-4.42 (2H,m) , 6.74 (2H,d,J=9.2Hz) ,

7.09 (2H,d,J=8.2Hz) , 7.93 (lH,s), 8.21 (lH,s), 8.54 (lH,s) .

Example 13 :

(5R, 6R) -2 , 2-Dimethyl-6- r (1H-1.2.4-triazol-l-yl.methyll -5- r T4- (trifluoromethoxy)phenoxylmethyllcyclohexanone oxime; EI-MS: m/z 412 (M ⁺ ) ; ^X H-NMR (CDCl ₃ )δ: 1.21 (3H,s) , 1.23 (3H,s), 1.42-1.78 (4H,m), 2.29 (IH, br) , 3.68 (lH,dd,J=6.9 & 9.2Hz), 3.73 (lH,dd,J=6.9 & 9.2Hz) , 3.93 (lH,m) , 4.37 (2H,m) , 6.76 (2H,d,J=8.9Hz) , 7.09 (2H,d,J=8.9Hz) , 7.92 (lH,s), 8.20 (lH,s) .

Example 14:

(2R.3R) -3- T2- (4-ethylphenyl)ethyll -6, 6-dimethyl-2- (1H-1,2 , 4- triazol-1-ylmethyl) cyclohexanone oxime: EI-MS: m/z 354 (M ⁺ ) ; ^X H-NMR (CDCl ₃ )δ: 1.19 (6H,s), 1.20 (3H,t,J=8.2Hz) , 1.4-1.6

(4H,m), 1.6-1.8 (2H,m) , 1.99 (lH.dt,J=4.4 & 13.9Hz), 2.3- 2.5 (2H,m), 2.59 (2H,q,J=7.3Hz) , 3.87 (lH,m) , 4.33 (2H,m), 6.49 (2H,d,J=7.3Hz) , 7.06 (2H,d,J=7.3Hz) , 7.96 (lH,s), 8.26 (lH.brs) .

Example 15: Preparation of (2S, 5R, 6R) -2- (2-imidazol-l-ylethyl) -2-methyl-6- (1H-1.2.4-triazol-l-ylmethyl) -5- f [4- (trifluoromethoxy) - phenoxylmethyl1cyclohexanone O-methyloxime;

(2S, 5R, 6R) -2- (2-Imidazol-l-ylethyl) -2-methyl-6- (1H-1, 2, 4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy] - methyl]cyclohexanone (400 mg, 0.84 mmol), O-methylhydroxyl- amine hydrochloride (1.76 g, 21.1 mmol) and pyridine (2.0 ml, 24.7 mmol) were dissolved in ethanol (25.0 ml), and the

solution was refluxed for 20 hours. It was quenched by adding water and extracted with dichloromethane. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic solvent was removed, and the residual colorless oil was purified by silica gel chromatography (CH ₂ Cl ₂ /MeOH = 20/1) . Colorless oil of (2S, 5R, 6R) -2- (2- imidazol-l-ylethyl)-2-methyl-6- (1H-1,2,4-triazol-l-ylmethyl) - 5- [ [4- (trifluoromethoxy)phenoxy] -methyl]cyclohexanone O- methyloxime was obtained in 63 % yield; Colorless oil; FAB- MS: m/z 507 (MH ⁺ ) ; ^- R (CDCl ₃ )δ: 1.27 (3H,m) , 1.50-2.20

(6H,m), 2.26 (lH,m) , 3.72 (2H,m) , 3.82 (lH,m) , 3.85 (3H,s), 4.01 (2H,m), 4.29 (2H,m) , 6.78 (2H,d, 8.7Hz) , 6.95 (lH,d, 8.9Hz) , 7.10 (lH,s), 7.11 (2H,d, 8.7Hz) , 7.56 (lH,br.s), 7.90 (lH,s), 8.15 (lH,s) .

The following compounds in Example 16 and 17 were obtained according to a manner analogous to that of Example 15.

Example 16:

(5R.6R) -2.2-Dimethyl-6- (1H-1,2.4-triazol-l-ylmethyl) -5- r T4- (trifluoromethoxy)phenoxylmethyllcyclohexanone O-methyloxime; FAB-MS: m/z 427 (MH ⁺ ) ; ^X H-NMR (CDCl ₃ )δ: 1.19 (3H,s), 1.23

(3H,s), 1.42-1.78 (3H,m), 2.00 (lH,m) , 2.25 (lH,m), 3.68 (lH,dd,J=6.9 & 9.2Hz), 3.71 (lH,dd,J=7.1 & 9.2Hz), 3.81 (lH,m) , 3.83 (3H,s) , 4.31 (lH,dd,J=5.1 & 13.7Hz), 4.34 (lH,dd,J=9.4 & 13.7Hz), 6.77 (2H,d,J=9.2Hz) , 7.10 (2H,d,J=9.2Hz) , 7.91 (lH,s), 8.14 (lH,s) .

Example 17 :

(2R.3R) -3- T2- (4-ethylphenyl)ethyll -6.6-dimethyl-2- (1H-1.2,4- triazol-1-ylmethyl) cyclohexanone O-methyloxime; EI-MS: m/z 368 (M ⁺ ) ; ^X H-NMR (CDCl ₃ )δ: 1.19 (3H,s), 1.21 (3H, ,J=7.3Hz) ,

1.3-1.6 (3H,m) , 1.6-1.8 (2H,m), 1.9-2.1 (2H,m) , 2.40 (2H,m), 2.60 (2H,q,J=7.3Hz) , 3.74 (lH,m), 3.80 (3H,s), 4.2-4.4 (2H,m) , 6.95 (2H,d,J=8.1Hz) , 7.07 (2H,d,J=8.1Hz) , 7.95 (lH,s), 8.18 (lH,s).

Example 18 :

Preparation of (2S, 5R, 6R) -2- (2-Methanesulfonylethyl) -2-methyl- 6- (1H-1 , 2.4-triazol-l-ylmethyl) -5- r T4- (trifluoromethoxy) - phenoxylmethyl1cyclohexanone O-methyloxime;

To a cold solution of the sulfide obtained in example 3 (263.4 mg, 0.542 mmol) in methanol (21 ml) was added dropwise 0.2 M aqueous solution of oxone (8.5 ml, 1.7 mmol, 3.1 eq.) at 0 °C. Then resulting suspension was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure, and the residue was extracted with diethyl ether. The combined ethereal layer was dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to afford (2S, 5R, 6R) -2- (2-Methanesulfonylethyl) -2-methyl-6- (1H-1,2, 4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone O-methyloxime; Amorphous powder; FAB-MS: m/z 519 (MH ⁺ ) ; ^X H-NMR (CDCl ₃ )δ: 1.18 (3H,s), 1.5-2.1 (5H,m),

2.25 (2H,m) , 2.96 (3H,s), 3.11 (2H,m) , 3.71 (2H,m) , 3.81 (3H,s), 3.84 (lH,m), 4.32 (2H,m), 6.77 (2H,d,J=9.2Hz) , 7.10 (2H,d,J=9.2Hz) , 7.90 (lH,s) , 8.14 (lH,s) .

Example 19 :

Preparation of (2S.5R, 6R) -2- (2-methoxyethyl) -2-methyl-6- (1H- 1,2.4-triazol-l-ylmethyl) -5- ϊ T4- (trifluoromethoxy)phenoxyl - methyl! cyclohexanone O-methyloxime

(2S, 5R, 6R) -2- (2-Hydroxyethyl) -2-methyl-6- (1H-1, 2, 4- triazol-1-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy]methyl] - cyclohexanone O-methyloxime (57.4 mg, 0.13 mmol) and 60 % NaH in oil (16.3 mg, 0.41 mmol) was dissolved in dry DMF (2.0 ml) at 0 °C under nitrogen atmosphere. 10 minutes later, methyl iodide was added and stirred for 1.5 hours. Then additional methyl iodide (0.03 ml, 0.48 mmol) was added and the stirring was continued for additional 1 hr. The reaction was quenched by adding water and the reaction mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over sodium sulfate. The organic solvent was removed

and the residual colorless oil was purified by silica gel chromatography (ethyl acetate) . A colorless oil of (2S,5R,6R)- 2- (2-methoxyethyl) -2-methyl-6- (1H-1, 2, 4-triazol-l-ylmethyl) -5- [ [4- (trifluoromethoxy)phenoxy] -methyl] cyclohexanone O-methyl- oxime was obtained in 75 % yield; Colorless oil; FAB-MS: m/z 471 (MH ⁺ ) ; ^X H-NMR (CDCl ₃ )δ: 1.20 (3H,s), 1.50-1.85 (4H,m),

1.85-2.10 (2H,m), 2.20-2.25 (lH,m) , 3.31 (3H,s), 3.52-3.50 (2H,m) , 3.60-3.75 (2H,m) , 3.86 (3H,s) , 4.30 (2H,d,J=7.3Hz) , 6.75 (2H,d,J=8.9Hz) , 7.09 (2H,d,J=8.9Hz) , 7.91 (lH,s) , 8.14 (lH,s) .

Example A :

Hard gelatin capsules each containing the following ingredients were manufactured in a conventional manner:

(2R, 3R) -3- [2- (4-ethylphenyl) ethyl] -6,6- dimethyl-2- (1H-1, 2, 4-triazol-l-ylmethyl) - cyclohexanone oxime 100 mg Lactose 56 mg

Crystalline Cellulose 30 mg Silicic acid, Light Anhydrous 10 mg Talc 3 mg Magnesium stearate 1 mq

Total 200 mg

Example B:

Tablets each containing the following ingredients were manufactured in a conventional manner:

(2R, 3R) -3- [2- (4-ethylphenyl)ethyl] -6, 6- dimethyl-2- (1H-1, 2,4-triazol-l-ylmethyl) - cyclohexanone oxime 100 mg

Lactose 60 mg

Corn starch 20 mg

Sodium Starch Glycolate 10 mg Polyvinylpyrrolidone 6 mg

Talc 3 mg

Magnesium stearate 1 mq

Total 200 mg