5-Substituted-3-(2-naphthalenyl)-3-[(1H-imidazol-1-ylmethyl or (1H-1,2,4-triazol-1-ylmethyl)]-2-methylisoxazolidines are useful as antifungal agents.

BACKGROUND OF THE INVENTION 
This invention relates generally to substituted 2-methylisoxazolidines and 
more specifically to 
5-substituted-3-(2-naphthalenyl)-3-[(1H-imidazol-1-ylmethyl) or 
(1H-1,2,4-triazol-1-ylmethyl)]-2-methylisoxazolidines and related 
derivatives which are useful as antifungal agents. 
BRIEF SUMMARY OF THE INVENTION 
In accordance with this invention there are provided compounds of the 
formula: 
##STR1## 
and the pharmaceutically acceptable acid addition salts thereof, in the 
form of their enantiomers or mixtures of their enantiomers including 
diastereomeric pairs of such enantiomers, wherein; 
R is selected from phenyl, substituted phenyl, phenoxymethyl, substituted 
phenoxymethyl, (phenylthio)methyl, substituted (phenylthio)methyl, styryl 
and C.sub.2 to C.sub.18 alkyl, wherein the substituents on the substituted 
phenyl rings are selected from one or more of halogen, lower alkyl, lower 
alkoxy groups and combinations thereof, and 
X is selected from CH or N. 
DETAILED DESCRIPTION OF THE INVENTION 
The compounds of this invention are useful as antifungal agents. They have 
in vitro activity against yeast and systemic mycoses and dermatophytes as 
determined by broth and agar testing techniques [McGinnis, M. R., 
Laboratory Handbook of Medical Mycology, Academic Press, New York, N.Y. 
(1980)]. The compound prepared in Example 1 was found to have good to 
moderate inhibitory activity against a variety or organisms including 
Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton tonsurans, 
Trichophyton schoenleinii, Epidermophyton floccosum, Microsporum canis, 
Aspergillus fumigatus, Candida albicans and Candida stellatoidea (minimum 
inhibitory concentration, MIC, of 0.2 to 70 .mu.g/ml). 
Because of the antifungal activity of the compounds of the invention they 
can be used, for example, in suitable liquid, semi-solid or solid carriers 
in the form of solutions, emulsions, suspensions, dispersions, ointments, 
aerosols, soaps, detergents, and powders in amounts effective to combat 
systemic and dermatophylic fungal infections in warm blooded animals (1 to 
20 percent active ingredient). 
The compounds of this invention are those of the formula: 
##STR2## 
and the pharmaceutically acceptable acid addition salts thereof, in the 
form of their enantiomers or mixtures of their enantiomers including 
diastereomeric pairs of such enantiomers, wherein, 
R is selected from phenyl, substituted phenyl, phenoxymethyl, substituted 
phenoxymethyl, (phenylthio)methyl, substituted (phenylthio)methyl, styryl 
and C.sub.2 to C.sub.18 alkyl, which can have a branched or unbranched 
chain. The substituents on the substituted phenyl rings are selected from 
one or more (and preferably one or two) halogen, lower alkyl, lower alkoxy 
groups and combinations thereof, and 
X is selected from CH or N. 
By halogen is meant chlorine, bromine, fluorine and iodine, with chlorine 
and fluorine being preferred. By lower alkyl and lower alkoxy is meant 
groups containing one to six carbons; such groups with three or more 
carbons can have a branched or unbranched chain. 
The 5-substituted-3-(2-naphthalenyl)-3-[(1H-imidazol-1-ylmethyl) or 
(1H-1,2,4-triazol-1-ylmethyl)]-2-methylisoxazolidines of this invention 
are obtained as mixtures of cis- and trans-diastereomers due to the 
presence in the isoxazolidine ring of two asymmetric carbon atoms. The 
diastereomeric mixture is conveniently separated by flash chromatography 
on silica gel using halogenated hydrocarbons (preferably dichloromethane 
and chloroform), alkanols (preferably methanol and ethanol), ethyl acetate 
and such, as eluents. The eluents may be utilized alone or in 
combinations, such as the ones comprised of 95-99% by volume halogenated 
hydrocarbon and 1-5% by volume alkanol. The stereochemistry of the two 
asymmetric carbon atoms in the isoxazolidine ring may be determined by 
conventional methods that include x-ray crystallography, nuclear magnetic 
resonance, circular dichroism and optical rotatory dispersion. Both the 
cis and trans-diastereomers are resolvable into their optical enantiomers 
with (+)- and (-)-optical rotations by standard techniques such as 
fractional recrystallizations of the diastereomeric salts with optically 
active organic acids, such as (+)- and (-)-tartaric acid, (+)- and 
(-)-dibenzoyltartaric acid and the like. 
As illustrated in the following diagram, the compounds of this invention 
can be synthesized starting with the reaction of 
2-imidazolyl-2'-acetonaphthone (1) with N-methylhydroxylamine 
hydrochloride to furnish the corresponding nitrone derivative 2. The 
preparation of such nitrones is described in our copending application 
Ser. No. 900,856 filed Aug. 27, 1986 whose disclosure is incorporated 
herein by reference. Subsequent reaction of compound 2 with 1-alkene 
derivatives provides diastereomeric mixtures of the desired cis- and 
trans-isoxazolidine compounds 3. 
Similarly by using 2-(1H-1,2,4-triazol-1-yl)acetonaphthone the 
corresponding 3-(1H-1,2,4-triazol-1-ylmethyl)isoxazolidines can be 
prepared. 
##STR3## 
The compounds of this invention are all basic and thus can form salts with 
pharmaceutically acceptable inorganic and organic acids such as, for 
example, acetic acid, maleic acid, malic acid, fumaric acid, succinic 
acid, succinamic acid, tartaric acid, citric acid, lactic acid, 
hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, 
sulfuric acid and phosphoric acid. 
The preparation of the compounds of this invention is further illustrated 
by the following synthesis of intermediates and in the Examples. 
PREATION OF INTERMEDIATES 
2-Imidazolyl-2'-acetonaphthone (1) 
To a solution of 68.32 g (1.004 mol) of imidazole dissolved in 150 ml of 
methanol at 0.degree. C. (ice-bath) is added dropwise a solution of 
2-bromo-2'-acetonaphthone (50 g, 0.201 mol) in 100 ml of dioxane and 25 ml 
of ether, while keeping the temperature at 0.degree. C. After about 3 
hours at 0.degree. C., the mixture is allowed to warm to room temperature 
where it is stirred for 20 hours. The mixture is then filtered and added 
to 500 ml of water, extracted 3 times with 500 ml of chloroform, dried 
over magnesium sulfate, and evaporated under reduced pressure. The brown 
oil that remaines is crystallized with a small amount of ethyl acetate and 
hexane and collected by filtration. The solid is heated in ethyl acetate 
and filtered hot then concentrated enough to recrystallized the produce as 
a light tan solid. Yield: 31.07 g (65%); m.p. 125.degree.-126.degree. C. 
(Found: C, 76.03; H, 5.25; N, 11.81. C.sub.15 H.sub.12 N.sub.2 O 
requires: C, 76.25; H, 5.12; N, 11.86). 
2-(1H-Imidazol-1-yl)-N-methyl-1-(2-naphthalenyl)ethanimine N-oxide (2) 
A mixture of 2-imidazolyl-2'-acetonaphthone (19.63 g, 0.083 mol), 
N-methylhydroxylamine-HCl (12.50 g, 0.150 mol), and sodium acetate (12.30 
g, 0.150 mol), in 500 ml of absolute ethanol is stirred under nitrogen for 
72 hours at 25.degree. C. The mixture was filtered, added to water, 
extracted with chloroform, dried over magnesium sulfate, and evaporated to 
dryness. The oil that remained is crystallized with a small amount of 
ethyl acetate and ether. Yield: 14.93 g (68%); m.p. 
112.degree.-114.degree. C. (Found:C, 72.14; H, 5.79; N, 15.74. C.sub.16 
H.sub.15 N.sub.3 O requires: C, 72.43; H, 5.70; N, 15.84).