Azole derivatives and antifungal drugs containing the same as an active component

An azole derivative represented by the following formula (I): ##STR1## wherein X is a nitrogen atom or CH, Y is an oxygen atom, a sulfur atom, an imino group, a methylimino group or a group represented by .dbd.N.about.O--, Z is one or two halogen atoms, n stands for a number of 1 or 2, the wavy line means that stereochemistry of the double bond is either E or Z; or an acid adduct thereof. They exhibit strong antifungal activities and are very useful in the therapy for fungus diseases. Also disclosed is an antifungal drug containing said compound as an active ingredient.

BACKGROUND OF THE INVENTION 
1) Field of the Invention: 
This invention relates to novel azole derivatives having strong antifungal 
activities and antifungal drugs containing the same as an active 
component. 
2) Description of the Background Art: 
Some azole derivatives are known to have antifungal activities, which 
include clotrimazole, miconazole, sulconazole, ketoconazole, fluconazole 
and the like. 
In the treatment of fungus diseases, medicines should desirably have 
possibly broadest antifungal spectra and should act not only topically but 
also systemically, in view that fungi which normally don't cause 
infections are sometimes responsible for mycoses as observed in the 
superinfection or the opportunistic infections, and that serious 
deep-seated mycoses are sometimes caused. 
Development of novel medicines capable of overcoming the resistance against 
conventional chemotherapeutic drugs has still been demanded. 
Under such circumstances, the present investors have undertaken extensive 
studies and have found that novel compounds represented by the following 
formula (I) exhibited strong antifungal activities and useful for the 
therapy of fungus diseases. This finding has led to the completion of this 
invention. 
SUMMARY OF THE INVENTION 
Accordingly, a primary object of the present invention is to provide an 
azole derivative represented by the following formula (I): 
##STR2## 
wherein X is a nitrogen atom or CH, Y is an oxygen atom, a sulfur atom, an 
imino group, a methylimino group or a group represented by 
.dbd.N.about.O--, Z is a hydrogen atom, one or two halogen atoms, a nitro 
group or a trifluoromethyl group, n stands for a number of 1 or 2, the 
wavy line means that stereochemistry of the double bond is of either E or 
Z; or an acid adduct thereof. 
A further object of the invention is to provide an antifungal drug 
containing the same as an active component.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS 
The compounds of formula (I) can be prepared, for example, by the reaction 
of compound (III) with alkenyl halide (II) in the absence or the presence 
of a base according to the following reaction scheme: 
##STR3## 
wherein X, Y, Z and n have the same meanings as defined before, and A is a 
halogen atom. 
The reaction for the preparation of compound (I) may be carried out using 
1.0 to 3.0 moles of compound (II) based on 1 mole of compound (III) at 
-10.degree. C. to 200.degree. C., preferably 30.degree. C. to 100.degree. 
C., with stirring for several hours. Any bases may be used so far as they 
don't inhibit the reaction. Preferable examples of the base are sodium 
hydride, sodium amide, potassium carbonate, sodium carbonate, potassium 
hydroxide and sodium hydroxide. Any solvents may be used so far as they 
are inert to the reaction. Preferable examples of the solvent are 
N,N-dimethylformamide, dimethylsulfoxide, ethylene glycol diethylether, 
tetrahydrofuran, ethanol and methanol. After the reaction is completed, 
the solvent is evaporated and the target compound is isolated by column 
chromatography or the like. 
Another method may be given for the preparation of the compound of formula 
(Ia) which has a sulfur atom at Y of formula (I), where a halide (IV) 
reacts with mercaptan (V) in the absence or the presence of a base 
according to the following reaction scheme: 
##STR4## 
wherein X, Z, n and A have the same meanings as defined before. 
This reaction may be carried out using 1.0 to 2.0 moles of compound (V) 
based on 1 mole of compound (IV) at -10.degree. C. to 100.degree. C., 
preferably 30.degree. C. to 70.degree. C., with stirring for several 
hours. Any bases may be used so far as they don't inhibit the reaction. 
Preferable examples of the base are sodium hydride, sodium amide, 
potassium carbonate, sodium carbonate, potassium hydroxide and sodium 
hydroxide. Any solvents may be used so far as they are inert to the 
reaction. Preferable examples of the solvent are N,N-dimethylformamide, 
ethanol and methanol. After the reaction is completed, the solvent is 
evaporated and the target compound (Ia) is isolated by column 
chromatography or the like. 
The thus obtained compounds (I) of the present invention can be converted 
into acid adducts as needed through any conventional method. Examples of 
such acid adducts are inorganic acid adducts such as nitrate, 
hydrochloride and the like; and organic acid adducts such as fumarate, 
maleate, tartarate, citrate and the like. 
Hereinafter are presented test results of compound (I) of the present 
invention in terms of pharmaceutical actions and acute toxicity. 
(1) Antifungal activities (in vitro): 
A plate of a series of diluted specimen was prepared under steriled 
conditions using Sabouraud's agar medium (glucose 2%, peptone 1%, agar 
1.5%), to which 1 .mu.l of each of the test fungus solutions was 
inoculated by using a quantitative platinum loop. Trichophyton sp. which 
belongs to the dermatophytes and Candida sp. which belongs to the yeast 
were cultured at 27.degree. C. and 37.degree. C., respectively, and their 
growthes were evaluated seven days after and two days after respectively 
to obtain minimum growth-inhibitory concentrations (MIC). The results are 
shown in Table 1. 
TABLE 1 
______________________________________ 
MIC (.mu.g/ml) 
Strains 
Compound Nos. Trichophyton sp. 
Candida sp. 
______________________________________ 
1 5.about.10 40 
2 40.about.80 &gt;80 
3 0.16.about.5.0 
20.about.40 
4 1.25.about.20 
20 
5 5.0 20 
6 5.about.10 20.about.40 
7 &gt;80 &gt;80 
8 10.about.20 40 
9 10.about.20 40 
10 20 &gt;80 
11 5.about.20 40 
______________________________________ 
(2) Inhibitory action against ergosterol biosynthesis: 
Inhibitory action against ergosterol biosynthesis, which is one of the 
characteristic actions of azole antifungal drugs, was evaluated. 
T. mentagrophytes (TIMM 1189) and C. albicans (TIMM 0144) were used in the 
test as representatives of the dermatophytes and yeast, respectively. 
Microconidia of T. mentagrophytes (TIMM 1189) were collected by way of 
gauze filtration and cultured in a Sabouraud glucose liquid medium at a 
concentration of 1.times.10.sup.6 /ml at 27.degree. C. until no increase 
was observed. Concerning C. albicans (TIMM 0144), fresh cultures were 
prepared and cultured in GPY broth at a concentration of 1.times.10.sup.6 
/ml at 37.degree. C. until they reached the logarithmic growth phase. T. 
mentagrophytes (TIMM 1189) and C. albicans (TIMM 0144) were allowed to 
intake [.sup.14 C] sodium acetate over 2 hours in the presence of a test 
compound at concentrations of 10.sup.-1 to 10.sup.-6 .mu.g/ml and 
10.sup.-1 to 10.sup.-4 .mu.g/ml, respectively, and sterols were measured 
by TLC. Inhibitory action against C-14 demethylation depending on 
cytochrome P450 was obtained. 
The results are shown in Table 2. 
TABLE 2 
______________________________________ 
ED.sub.50 (g/ml) 
Strains 
T. mentagraphytes 
C. albicans 
Compounds Nos. 
(TIMM 1189) (TIMM 0144) 
______________________________________ 
1 1.0 .times. 10.sup.-5 
6.9 .times. 10.sup.-3 
2 4.2 .times. 10.sup.-2 
4.7 .times. 10.sup.-2 
6 -- 4.0 .times. 10.sup.-2 
8 -- 9.7 .times. 10.sup.-3 
9 -- 7.2 .times. 10.sup.-2 
10 -- 5.2 .times. 10.sup.-2 
______________________________________ 
(3) Direct cell-membrane damaging: 
Direct cell-membrane damaging, which is one of the characteristic actions 
of azole antifungal drugs, was evaluated. 
As a test strain, C. albicans (TIMM 0144) was used. Fresh cultures of C. 
albicans (TIMM 0144) were washed to make a deionized aqueous solution 
containing the same at a concentration of 1.times.10.sup.8 /ml. In the 
presence of a test compound at a concentration of 40 .mu.g/ml, potassium 
ion leakage concentration was measured 15 minutes after by way of atomic 
absorption spectrometry to evaluate the direct cell-membrane damaging. The 
results are shown in Table 3. 
TABLE 3 
______________________________________ 
Potassium ion 
Compound Nos. leakage rate (%) 
______________________________________ 
1 81 
2 55 
6 74 
8 65 
10 47 
______________________________________ 
(4) Antifungal activities (in vivo): 
Hartley white female guinea pigs were used in this test. The back hair were 
depilated to form a round area having a diameter of 2 cm. 1.times.10.sup.8 
microconidia of T. mentagrophytes (TIMM 1189) were inoculated therein for 
infection. From the fifth day of the inoculation, a composition containing 
1% test compound (base: white petrolatum) was applied once a day for 6 
consecutive days. Thereafter, the animals were left for 1 day, and 
slaughtered while removing the blood. The suffered skin was taken, cut and 
subjected to the retro-culture. The negative ratio of the strain was 
measured. The results are shown in Table 4. 
TABLE 4 
______________________________________ 
Compound Nos. Negative ratio (%) 
______________________________________ 
1 95 
6 89 
8 46 
9 34 
10 37 
Clotrimazole 24 
Miconazole 27 
______________________________________ 
(5) Acute Toxicity: 
Compound (I) of the present invention, which was obtained in Example 1 
described hereinafter, was found to have a LD.sub.50 value of 1000 mg/kg 
or more when dosed orally on mice. 
As described above, compounds (I) of the present invention or acid adducts 
thereof have excellent antifungal activities and high safety. These 
compounds can be formulated to antifungal drugs solely or in combination 
with a conventional base and other active ingredients. Thus formulated 
antifungal drugs according to the present invention can be administered 
orally, externally, by injection or in any other forms. The dose may be 
controlled depending on the age, weight, symptom or the like. In case of 
oral administration, preferable amount on the basis of compound (I) is 100 
to 3000 mg, more preferably 200 to 1400 mg for an adult, and in case of 
intravenous-injection, 50 to 1000 mg, more preferably 100 to 300 mg for an 
adult. Compounds (I) of the present invention can be formed into tablets, 
granules, powders, capsules, suspensions, injections, supositories, 
external applications or the like for the therapy of fungus diseases. 
Summing up the effects of the invention compounds, it is noted that azole 
derivatives (I) of the present invention have strong activities in terms 
of ergosterol biosynthesis inhibition and direct cell-membrane damaging. 
Their toxicity is very low, and LD.sub.50 values when dosed orally on mice 
are all 1000 mg/kg or more. Thus, it is concluded that the compounds (I) 
of the present invention are very useful as an antifungal drug for fungus 
diseases of animals including the human. They are especially useful for 
treating topical mycoses caused by Candida, Trichophyton, Microsporum, or 
Epidermophyton, and mucous infections such as thrush or the vaginal 
candida caused by Candida albicans. Moreover, they are useful for treating 
systemic mycoses caused by Candida albicans, Cryptococcus neoformans, 
Aspergillus flavus, Aspergillus fumigatus, Coccidioides, Paracoccidioides, 
Histoplasma or Blastomyces. 
EXAMPLES 
The present invention will hereinafter be described in further detail by 
the following Examples. It should however be borne in mind that the 
present invention is not necessarily be limited thereto. 
EXAMPLE 1 
Preparation of 
1-[2-(2,4-dichlorophenyl)-2-((E)-3,7-dimethylocta-2,6-dienyloxy)ethyl]-1H- 
imidazole (Compound 1) 
##STR5## 
To a stirred solution of 
1-(2,4-dichlorophenyl)-2-(1H-imidazole-1-yl)ethanol (2.06 g=8.0 mmol) in 
dimethylformamide (25 ml) was gradually added sodium hydride (0.48 g=12.0 
mmol) at room temperature. The reaction mixture was stirred at 40.degree. 
C. for 30 minutes. And to the stirred reaction mixture was added 
(E)-3,7-dimethylocta-2,6-dienyl-1-bromide (2.60 g=12.0 mmol) in 
dimethylformamide and the reaction mixture was stirred for 15 minutes at 
80.degree. C. After evaporation of the solvent under reduced pressure, the 
residue was diluted with chloroform. The chloroform layer was washed with 
water and dried over anhydrous sodium sulfate. Concentration followed by 
column chromatography on silica gel (chloroform:methanol=100:1.about.75:1) 
gave 1.46 g of Compound 1 as a colorless oil. 
.sup.1 H-NMR(CDCl.sub.3) .delta. ppm: 1.50(s,3H), 1.60(s,3H), 1.69(s,3H), 
1.87.about.2.22(m,4H), 3.79(dd,1H,J=7.3, 11.7 Hz), 3.91(dd,1H,J=6.6, 11.7 
Hz), 3.99(dd,1H,J=7.3, 14.3 Hz), 4.15(dd,1H,J=2.7, 14.3 Hz), 
4.92(dd,1H,J=2.7, 7.3 Hz), 5.03.about.5.12(m,1H), 5.17.about.5.24(m,1H), 
6.93(s,1H), 7.02(s,1H), 7.22.about.7.38(m,2H), 7.38.about.7.43(m,1H), 
7.48(s,1H). 
IR .nu..sup.neat cm.sup.-1 : 2868, 2932, 2860, 1590, 1506, 1473, 1440, 
1386, 1287, 1233, 1218, 1107, 1095, 1077, 1044, 1005, 909, 867, 825, 789, 
756, 663, 627 
The obtained oil was dissolved in a proper amount of ethanol, and added 
0.43 g of fumaric acid in ethanol. After removal of the ethanol, a small 
amount of ether and then hexane were added to give white crystals. The 
crystals were collected by filtration and recrystallized from 
isopropylether-hexane. 0.97 g of fumarate of Compound 1 was obtained as 
white crystals. 
EXAMPLE 2 
Preparation of 
1-[2-(2,4-dichlorophenyl)-2-((E,E)-3,7,11-trimethyldodeca-2,6,10-trienylox 
y)ethyl]-1H-imidazole (Compound 2) 
##STR6## 
Procedures of Example 1 were followed, and a colorless oil was obtained. 
.sup.1 H-NMR(CDCl.sub.3) .delta. ppm: 1.50 (s, 3H), 1.60 (s, 6H), 1.68 (s, 
3H), 1.84.about.2.22 (m, 8H), 3.78 (dd, 1H, J=7.5, 11.6 Hz), 3.90 (dd, 1H, 
J=6.5, 11.6 Hz), 3.98 (dd, 1H, J=7.3, 14.4 Hz), 4.16 (dd, 1H, J=2.8, 14.4 
Hz), 4.91 (dd, 1H, J=2.8, 7.3 Hz), 5.01.about.5.29 (m, 3H), 6.93 (s, 1H), 
7.02 (s, 1H), 7.26.about.7.32 (m, 2H), 7.38.about.7.42 (m, 1H), 7.45 (s, 
1H). 
IR .nu..sup.neat cm.sup.-1 : 2928, 2860, 1592, 1506, 1472, 1442, 1386, 
1232, 1108, 1092, 1044, 824, 790, 662 
Procedures of Example 1 were followed, and white crystals of fumarate of 
Compound 2 were obtained. 
EXAMPLE 3 
Preparation of 
1-[2-((E)-3,7-dimethylocta-2,6-dienyloxy)-2-(2-nitrophenyl)ethyl]-1H-imada 
zole (Compound 3) 
##STR7## 
Procedures of Example 1 were followed using 
2-(1H)-imidazole-1-yl)-1-(2-nitrophenyl)ethanol as a starting material, 
and a light-yellow oil was obtained. 
.sup.1 H NMR (CDCl.sub.3 .delta. ppm) 
1.43(s,3H),1.60(s,3H),1.68(s,3H),1.90.about.2.14(m,4H), 
3.72(dd,1H,J=11.6,7.5 Hz),3.84(dd,1H,J=11.6,7.5 Hz), 4.09(dd,1H,J=14.2,7.4 
Hz),4.37(dd,1H,J=14.2,2.2 Hz), 
5.00.about.5.19(m,3H),7.04(s,2H),7.45.about.7.58(m,2H)7.65(s,1H), 
7.67(s,1H),8.06(t,1H,J=8.1 Hz) 
IR .nu..sup.neat cm.sup.-1 : 2936, 2860, 1528, 1446, 1348, 1288, 1232, 
1098, 1076, 1032, 1002, 818, 790, 752, 726, 662. 
Procedures of Example 1 were followed, and fumarate of Compound 3 was 
obtained as light-yellow crystals. 
EXAMPLE 4 
Preparation of 
1-[2-((E)-3,7-dimethylocta-2,6-dienyloxy)-2-(2-trifluoromethylphenyl)ethyl 
]-1H-imidazole (Compound 4) 
##STR8## 
Procedures of Example 1 were followed using 
2-(1H-imidazole-1-yl)-1-(2-trifluoromethylphenyl)ethanol as a starting 
material, and a colorless oil was obtained. 
.sup.1 H NMR (CDCl.sub.3 .delta. ppm): 
1.46(s,3H),1.60(s,3H),1.68(s,3H),1.83.about.2.15(m,4H), 
3.75(dd,1H,J=11.6,7.5 Hz),3.85(dd,1H,J=11.6,6.4 Hz), 3.99(dd,1H,J=14.5,7.6 
Hz),4.11(dd,1H,J=14.5,2.5 Hz), 
4.86.about.4.99(m,1H),5.00.about.5.10(m,1H),5.16(t,1H,J=6.8 Hz), 
6.96(s,1H),7.04(s,1H), 7.40.about.7.75(m,5H) 
IR .nu..sup.neat cm.sup.-1 : 2972, 2932, 2864, 1506, 1456, 1380, 1316, 
1288, 1264, 1232, 1164, 1122, 1076, 1056, 1034, 662, 774. 
Procedures of Example 1 were followed, and fumarate of Compound 4 was 
obtained as white crystals. 
EXAMPLE 5 
Preparation of 
1-[2-((E)-3,7-dimethylocta-2,6-dienyloxy)-2-phenylethyl]-1H-imidazole 
(Compound 5) 
##STR9## 
Procedures of Example 1 were followed using 
2-(1H-imidazole-1-yl)-1-phenylethanol as a starting material, and a 
colorless oil was obtained. 
.sup.1 H NMR (CDCl.sub.3 .delta. ppm): 
1.48(s,3H),1.60(s,3H),1.69(s,3H),1.96.about.2.20(m,4H), 
3.77(dd,1H,J=11.6,7.4 Hz),3.91(dd,1H,J=11.6,6.4 Hz), 4.05(dd,1H,J=14.2,4.5 
Hz),4.14(dd,1H,J=14.2,7.2 Hz), 4.49(dd,1H,J=7.2,4.5 
Hz),5.01.about.5.18(m,1H), 5.24(t,1H,J=6.4 Hz),6.89(s,1H),7.00(s,1H), 
7.20.about.7.38(m,5H),7.40(s,1H). 
IR .nu..sup.neat cm.sup.-1 : 3032, 2972, 2928, 2860, 1670, 1506, 1456, 
1382, 1286, 1232, 1106, 1074, 1028, 906, 816, 760, 724, 700, 662, 630. 
Procedures of Example 1 were followed, and fumarate of Compound 5 was 
obtained as white crystals. 
EXAMPLE 6 
Preparation of 
1-[2-(2,4-dichlorophenyl)-2-((Z)-3,7-dimethylocta-2,6-dienyloxy)ethyl]-1H- 
imidazole (Compound 6) 
##STR10## 
Procedures of Example 1 were followed, and a colorless oil was obtained. 
.sup.1 H-NMR(CDCl.sub.3) .delta. ppm: 1.52(s,3H), 1.64(s,3H), 1.71(s,3H), 
1.82.about.2.10(m,4H), 3.76(dd,1H,J=7.3,11.4 Hz), 3.89(dd,1H,J=6.6,11.4 
Hz), 4.00(dd,1H,J=7.3,14.4 Hz), 4.17(dd,1H,J=2.9,14.4 Hz), 
4.91(dd,1H,J=2.9,7.3 Hz), 4.98(m,1H), 5.20(dd,1H,J=6.6,7.3 Hz), 
6.93(s,1H), 7.01(s,1H), 7.20.about.7.39(m,2H), 7.41(d,1H,J=1.7 Hz), 
7.45(s,1H). 
IR .nu..sup.neat cm.sup.-1 : 2968, 2926, 2860, 1590, 1566, 1506, 1473, 
1449, 1383, 1287, 1233, 1107, 1095, 1077, 1044, 1008, 867, 825, 789, 735, 
663, 627. 
Procedures of Example 1 were followed, and white crystals of fumarate of 
Compound 6 were obtained. 
EXAMPLE 7 
Preparation of 
1-[2-(4-bromophenyl)-2-((E)-3,7-dimethylocta-2,6-dienyloxy)ethyl]-1H-triaz 
ole (Compound 7) 
##STR11## 
To a stirred solution of 1-(4-bromophenyl)-2-(1H-triazole-1-yl)ethanol 
(1.00 g=3.7 mmol) in dimethylformamide (10 ml) was gradually added sodium 
hydride (0.16 g=4.1 mmol) at room temperature. The reaction mixture was 
stirred at room temperature for 90 minutes. And to the stirred reaction 
mixture was added (E)-3,7-dimethylocta-2,6-dienyl-1-bromide (0.82 ml=4.1 
mmol) in dimethylformamide. Stirring was continued for 60 minutes at room 
temperature. After evaporation of the solvent under reduced pressure, the 
residue was diluted with ethyl acetate, washed with water, followed by 
drying over anhydrous sodium sulfate. Concentration followed by column 
chromatography on Silica gel (ethyl acetatehexane=3:1) gave 1.12 g of 
Compound 4 as a colorless oil. 
.sup.1 H-NMR(CDCl.sub.3) .delta. ppm: 1.46(s,3H), 1.60(s,3H), 1.68(s,3H), 
1.84.about.2.13(m,4H), 3.73(dd, 1H,J=7.5,11.6 Hz), 3.88(dd,1H,J=6.4,11.6 
Hz), 4.27(dd,1H,J=5.2,14.0 Hz), 4.30(dd,1H,J=7.4,14.0 Hz), 
4.66(dd,1H,J=5.2,7.4 Hz), 4.97.about.5.19(m,2H), 7.20(d,2H,J=8.3 Hz), 
7.52(d,2H,J=8.3 Hz), 7.95(s,1H), 8.11(s,1H). 
IR .nu..sup.neat cm.sup.-1 : 2928, 1506, 1490, 1450, 1276, 1140, 1072, 
1012, 824, 680. 
The thus obtained oil was dissolved in a proper amount of ethanol, and 
added fumaric acid (0.47 g ) in ethanol. After removal of the ethanol, the 
residue was recrystallized from acetone-hexane. 0.52 g of fumarate of 
Compound 4 was obtained as white crystals. 
EXAMPLE 8 
Preparation of 
1-[2-(2,4-dichlorophenyl)-2-((E)-3,7-dimethylocta-2,6-dienylamino)ethyl]-1 
H-imidazole (Compound 8): 
##STR12## 
To a stirred solution of 
1-(2,4-dichlorophenyl)-2-(1H-imidazole-1-yl)ethylamine (2.50 g=9.8 mmol) 
in dimethylformamide (30 ml) was added potassium carbonate (1.35 g=9.8 
mmol) and (E)-3,7-dimethylocta-2,6-dienyl-1-bromide(1.94 ml=9.8 mmol) at 
room temperature. Stirring was continued for 30 minutes at room 
temperature. After evaporation of the solvent under reduced pressure, the 
residue was diluted with ethyl acetate, washed with water, followed by 
drying over anhydrous sodium sulfate. Concentration followed by column 
chromatography on silica gel (chloroform:methanol=150:1) gave 1.08 g of 
Compound 8 as a colorless oil. 
.sup.1 H-NMR(CDCl.sub.3) .delta. ppm: 1.25(s,1H), 1.44(s,3H), 1.60(s,3H), 
1.68(s,3H), 1.73.about.2.17(m,4H), 2.99(dd,1H,J=7.5, 13.6 Hz), 3.04(dd, 
1H, J=6.6, 13.6 Hz), 3.97(dd, 1H, J=7.7, 14.0 Hz), 4.18(dd, 1H, J=4.2, 
14.0 Hz), 4.51(dd, 1H, J=4.2, 7.7 Hz), 4.98.about.5.15(m,2H), 6.87(s, 1H), 
7.04(s, 1H), 7.23.about.7.45(m, 4H). 
IR .nu..sup.neat cm.sup.-1 : 2968, 2928, 2856, 1590, 1506, 1470, 1440, 
1386, 1284, 1232, 1108, 1078, 1046, 1032, 864, 824, 788, 754, 662. 
The thus obtained oil was dissolved in a proper amount of ethanol, and 
added fumaric acid (1.08 g) in ethanol. The residue was recrystallized 
from acetone-hexane. 0.89 g of fumarate of Compound 8 was obtained as 
white crystals. 
EXAMPLE 9 
Preparation of 
1-[2-(2,4-dichlorophenyl)-2-{N-((E)-3,7-dimethylocta-2,6-dienyl)-N-methyla 
mino}ethyl]-1H-imidazole (Compound 9) 
##STR13## 
Procedures of Example 8 were followed, and a colorless oil was obtained. 
.sup.1 H-NMR(CDCl.sub.3) .delta. ppm: 1.52(s, 3H), 1.60(s, 3H), 1.68(s, 
3H), 1.89.about.2.20(m, 4H), 2.31(s, 3H), 3.02 (d, 2H,J=6.8 Hz), 
4.12.about.4.40(m, 3H), 5.03.about.5.12(m, 1H), 5.12.about.5.23(m, 1H), 
6.70(s, 1H), 6.92(s, 1H), 7.14.about.7.25(m, 3H), 7.33(d, 1H,J=1.6 Hz). 
IR .nu..sup.neat cm.sup.-1 : 2972, 2924, 2860, 1590, 1508, 1472, 1454, 
1386, 1234, 1108, 1080, 1050, 822, 664. 
Procedures of Example 8 were followed, and fumarate of Compound 9 was 
obtained as white crystals. 
EXAMPLE 10 
Preparation of 
1-[2-(2,4-dichlorophenyl)-2-((E)-3,7-dimethylocta-2,6-dienylthio)ethyl]-1H 
-imidazole (Compound 10) 
##STR14## 
To a stirred solution of (E)-3,7-dimethylocta-2,6-dienylmercaptan (1.00 
g=5.9 mmol) in methanol (40 ) was added potassium hydroxide (0.33 g=5.8 
mmol) and 1-chloro-1-(2,4-dichlorophenyl)-2-(1H-imidazole-1-yl)ethane 
(1.62 g=5.9 mmol) in ethanol at room temperature, and then the reaction 
mixture was refluxed for 90 minutes. After cooling, the methanol was 
evaporated, and then the residue was diluted with chloroform. The 
chloroform layer was washed with water, followed by drying over anhydrous 
sodium sulfate. Concentration followed by column chromatography on silica 
gel (ethyl acetate:hexane=2:3) gave 1.32 g of Compound 10 as a colorless 
oil. 
.sup.1 H-NMR(CDCl.sub.3) .delta. ppm: 1.46(s, 3H), 1.59(s, 3H), 1.67(s, 
3H), 1.90.about.2.17(m, 4H), 3.01(d, 2H,J=8.0 Hz), 4.25(d, 2H, J=6.4 Hz), 
4.60(t, 1H,J=6.4 Hz), 4.98.about.5.18(m, 2H), 6.77(s, 1H), 6.98(s, 1H), 
7.25(dd, 1H, J=2.1, 8.4 Hz), 7.29(s, 1H), 7.37(d, 1H, J=2.1 Hz), 7.42(d, 
1H, J=8.4 Hz). 
IR .nu..sup.neat cm.sup.-1 : 2976, 2928, 2860, 1590, 1506, 1474, 1448, 
1386, 1288, 1232, 1108, 1078, 1052, 866, 826, 784, 734, 662. 
1.04 g of the thus obtained oil was dissolved in a proper amount of 
ethanol, and added fumaric acid (0.44 g) in ethanol. After removal of the 
ethanol, the residue was recrystallized from acetone-hexane. 0.72 g of 
fumarate of Compound 10 was obtained as white crystals. 
EXAMPLE 11 
Preparation of 
(Z)-1-(2,4-dichlorophenyl)-2-(1H-imidazole-1-yl)-O-((E)-3,7-dimethylocta-2 
,6-dienyl) ethanonoxime (Compound 11) 
##STR15## 
To a stirred suspension of 
(Z)-1-(2,4-dichlorophenyl)-2-(1H-imidazole-yl)ethanonhydroxime (2.00 g=7.4 
mmol) in acetone (30 ml) was added crashed potassium hydroxide (0.38 g=6.7 
mmol) at room temperature. Stirring continued for one hour and the 
reaction mixture was cooled to 0.degree. C. 
(E)-3,7-dimethylocta-2,6-dienyl-1-bromide (1.47 g=7.4 mmol) was added 
dropwise to the mixture with stirring. The mixture was stirred for 30 
minutes at room temperature, and 200 ml of saturated saline was added 
thereto. Extraction with ethyl acetate, drying (Na.sub.2 SO.sub.4), and 
concentration followed by column chromatography on silica gel (ethyl 
acetate: hexane=2:3) gave 0.52 g of Compound 11 as a colorless oil. 
.sup.1 H-NMR(CDCl.sub.3) .delta. ppm: 1.62(s, 3H), 1.69(s, 3H), 1.74(s, 
3H), 1.98.about.2.24(m, 4H), 4.77(d, 1H, J=6.9 Hz), 5.08.about.5.19(m, 
1H), 5.20(s, 2H), 5.49(t, 1H, J=6.9 Hz), 6.76(s, 1H), 6.91(s, 1H), 7.00(d, 
1H, J=8.2 Hz), 7.17(dd, 1H, J=8.2, 2.0 Hz), 7.37(s, 1H), 7.38(d, 1H, J=2.0 
Hz). 
IR .nu..sup.neat cm.sup.-1 : 2968, 2926, 1590, 1506, 1479, 1446, 1383, 
1233, 1107, 1077, 1005, 822.