JPH04312579A - Imidazole derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound, having excellent antifungal activity and useful for treating mycotic infectious diseases. CONSTITUTION:A compound, e.g. 1-[2-(2,4-dichlorophenyl)-2-(N-methyl-4-tert- butylbenzylamino)ethyl]-1H-imidazole expressed by formula I (R<1> is H or lower alkyl; R<2> is 4-tert-butylphenyl, naphthyl or 5,5-dimethyl-1-hexen-3-yne). Furthermore, the aforementioned compound is obtained by reacting a compound expressed by formula II with a compound expressed by the formula X-CH2-R<2>(X is leaving group) in an amount of 1.0-3.0mol based on one mol compound expressed by formula II in the presence of a base such as sodium hydroxide in a solvent such as DMF at 20-100 deg.C for 2-5hr.

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION The present invention relates to imidazole derivatives or acid addition salts thereof having strong antifungal activity.

0002

[Prior art and problems to be solved by the invention] Conventionally,
Some azole derivatives are known to have antifungal activity, such as clotrimazole, miconazole, sulconazole, ketoconazole, and the like.

[0003] However, fungal infections are often caused by fungi that do not normally cause infections, as seen in bacterial alternation and opportunistic infections, and once infected, they can become serious, such as deep-seated infections. , the prognosis is often not favorable. Furthermore, some fungi are resistant to conventional antifungal agents.

[0004]Therefore, there has been a desire for a new antifungal substance that has stronger antifungal activity than conventional antifungal substances, has a broader antifungal spectrum, acts systemically, and can overcome resistance.

[0005]

[Means for Solving the Problems] Under these circumstances, the present inventors conducted intensive research and found that a novel compound represented by the general formula (1) below has strong antifungal activity and is effective against fungal infections. The present invention was completed based on the discovery that the present invention is extremely useful for the treatment of cancer.

That is, the present invention provides the following general formula (1)

[
0007

[Case 2]

(wherein R1 represents a hydrogen atom or a lower alkyl group, R2 represents a 4-t-butylphenyl group, a naphthyl group or a 5,5-dimethyl-1-hexen-3-yne group) The present invention provides imidazole derivatives or acid addition salts thereof.

In the present invention, in the general formula (1), R
Examples of the lower alkyl group represented by 1 include alkyl groups having 1 to 5 carbon atoms, such as methyl group, ethyl group, n-propyl group, and iso-propyl group.

The imidazole derivative (1) of the present invention can be obtained by reacting the compound (3) with the compound (2) having a leaving group X in a solvent in the presence of a base, for example, according to the method shown in the following formula. can be manufactured.

[0011]

[Chemical formula 3]

(wherein, X represents a leaving group, R1 and R2
has the same meaning as above)

Compound (3) used as a raw material can be produced, for example, according to the method described in JP-A-59-175472. Further, as the leaving group X of compound (2), for example, p-toluenesulfonic acid residue,
Examples include halogen atoms.

The reaction is carried out between compound (3) and this compound (3).
) 1.0 to 3.0 mol of compound (2
) in a solvent in the presence of a base at -10°C to 200°C.
, preferably by stirring at 20°C to 100°C for 0.5 to 8 hours, preferably 2 to 5 hours. The base used here is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include sodium hydride, sodium amide, potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide. Further, the solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include N,N-dimethylformamide, dimethyl sulfoxide, ethylene glycol diethyl ether, tetrahydrofuran, ethanol, and methanol. After the reaction is completed, the imidazole derivative (1) of the present invention can be obtained by distilling off the solvent and purifying by a known method such as chromatography.

The imidazole derivative (1) of the present invention thus obtained can be treated with inorganic salts such as nitrates and hydrochlorides, or with inorganic salts such as fumaric acid, maleic acid, tartaric acid, citric acid, etc. by conventional methods, if necessary. It can also be an organic acid salt.

[0016]

Effects of the Invention The imidazole derivative (1) or its acid addition salt of the present invention has excellent antifungal activity.

[0017]

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples. Example 1 1-[2-(2,4-dichlorophenyl)-2-(N-
Methyl-4-t-butylbenzylamino)ethyl]-1
Synthesis of H-imidazole (compound number 1): N-methyl-1-(2,4-dichlorophenyl)-2-(1H
-imidazol-1-yl)ethylamine 1.08 g (
4 mmol), 4-t-butylbenzyl bromide 0
．． 91g (4mmol) and potassium carbonate 0.55g
(4 mmol) was stirred in ethanol at 40°C for 4 hours. After the solvent was distilled off under reduced pressure, water was added and the mixture was extracted with chloroform. Next, the organic layer was washed with water and dried by adding anhydrous sodium sulfate. Furthermore, the solvent was distilled off under reduced pressure,
The residue was subjected to silica gel column chromatography, and from the eluate of chloroform:methanol=100:1,
0.43 g of the desired title compound was obtained as an oil. 1H
-NMR (CDCl3) δ (ppm): 1.30 (
s, 9H), 2.26 (s, 3H), 3.39 (d
, 1H, J=13Hz), 3.56(d, 1H, J=
13Hz), 4.15-4.50 (m, 3H), 6
．． 77 (s, 1H), 6.97 (s, 1H), 7.
07~7.41 (m, 8H) IR νmax (Ne
at) cm-1: 2964, 1588, 151
0, 1474, 1368, 1232, 1108
, 820, 756 The above oil was dissolved in an appropriate amount of ethanol, and to this was added 0.18 g of fumaric acid dissolved in an appropriate amount of ethanol. Ethanol was distilled off, the residue was crystallized from ethanol-diethyl ether, and the produced fumarate was collected by filtration.

Example 2 1-[2-(4-t-butylbenzylamino)-2-(
Synthesis of 2,4-dichlorophenyl)ethyl]-1H-imidazole (compound number 2): 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethylamine 1.02 g (4 mmol), 4 -t-
Butylbenzyl bromide 0.91g (4mmol)
and using 0.55 g (4 mmol) of potassium carbonate,
In the same manner as in Example 1, 0.48 g of the title compound was obtained as an oil. 1H-NMR (CDCl3) δ (ppm
): 1.30 (s, 9H), 2.00 (bs, 1H)
), 3.46 (d, 1H, J=13Hz), 3.6
0 (d, 1H, J=13Hz), 3.96 (dd, 1
H, J = 14,8 Hz), 4.15 (dd, 1 H, J
=14,4Hz), 4.49(dd,1H, J=8,
4Hz), 6.82(s, 1H), 7.01(s,
1H), 7.04-7.44 (m, 8H) IR ν
max (Neat) cm-1:2962, 15
90, 1509, 1473, 1230, 110
7,822,753 The above oil was dissolved in an appropriate amount of ethanol, and to this was added 0.14 g of fumaric acid dissolved in an appropriate amount of ethanol. Ethanol was distilled off, the residue was crystallized from ethanol-diethyl ether, and the produced fumarate was collected by filtration.

Example 3 1-[2-(2,4-dichlorophenyl)-2-{(E
)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methylamino}ethyl]-1H-imidazole (Compound No. 3) Synthesis: N-methyl-1-(2
,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethylamine 1.08g (4mmol)
, 1-bromo-6,6-dimethyl-2-heptene-4-
0.86 g (4 mmol) of inine and 0.86 g (4 mmol) of potassium carbonate.
Using 55 g (4 mmol), 0.24 g of the title compound was obtained as an oil in the same manner as in Example 1. 1H-N
MR (CDCl3) δ (ppm): 1.24 (s,
9H), 2.33(s, 3H), 2.96(dd,
1H, J=14,7Hz), 3.10(dd, 1H,
J=14,5Hz), 4.05~4.42(m, 3H
), 5.58 (d, 1H, J=16Hz), 5.9
4(dt, 1H, J=16,6Hz), 6.72(s
, 1H), 6.94 (s, 1H), 7.17 ~7
．． 50 (m, 4H) IR νmax (Neat)
cm-1: 2968, 1587, 1509, 1
473, 1233, 1107, 966, 822
, 756 The above oil was dissolved in an appropriate amount of ethanol, and 2 equivalents of methanol-diluted nitric acid were added thereto. The solvent was distilled off, the residue was crystallized from ethyl acetate-diethyl ether, and the produced nitrate was collected by filtration.

Example 4 1-[2-(2,4-dichlorophenyl)-2-(N-
Methyl-1-naphthalenemethylamino)ethyl]-1H
-Synthesis of imidazole (compound number 4): N-methyl-1-(2,4-dichlorophenyl)-2-(1H-
imidazol-1-yl)ethylamine 1.08 g (4
mmol), 1-chloromethylnaphthalene 0.71g
(4 mmol) and potassium carbonate 0.55 g (4 mmol)
The title compound 0 was prepared in the same manner as in Example 1 using
．． 15 g was obtained as a pale yellow solid. Melting point: 120-121°C 1H-NMR (CDCl3) δ (ppm): 2.1
8 (s, 3H), 3.79 (d, 1H, J=13Hz
), 4.06 (d, 1H, J=13Hz), 4.1
9 (dd, 1H, J=14,7Hz), 4.43 (d
d, 1H, J=14,7Hz), 4.82(t, 1H
, J=7Hz), 6.78(s, 1H), 7.00
(s, 1H), 7.16-7.55 (m, 8H),
7.67-7.96 (m, 3H) IR νmax (
Neat) cm-1:2944, 2854, 1
590, 1506, 1473, 1386, 12
87, 1230, 1107, 1047, 1011
, 795

Test Example 1 The imidazole derivatives of the present invention obtained in Examples 1 to 4 (
Regarding 1), the antifungal effect was investigated by the following method. The results are shown in Table 1. (Test method) The compound of the present invention (
A serial dilution plate of 1) was prepared aseptically, and a test bacterial solution [Trichophyton sp.
．． ), Candida sp.] 1μ
After 7 days at 27°C for Trichophyton and 2 days at 37°C for Candida, the growth status was determined and the minimum inhibitory concentration (MIC) was determined.

[0022]

[Table 1]

Claims (1)

[Claims] Claim 1: The following general formula (1) [Formula 1] (wherein, R1 represents a hydrogen atom or a lower alkyl group, and R
2 is 4-t-butylphenyl group, naphthyl group or 5,5
-dimethyl-1-hexen-3-yne group) or an acid addition salt thereof.