JPH02115180A - 1-(2-substituted-2-phenylethyl)-1h-1,2,4-triazole derivative - Google Patents

Abstract

NEW MATERIAL:1-(2-Substituted-2-phenylethyl)-1H-1,2,4-triazole derivative of formula I (Ar is phenyl or mono- or di-halophenyl; R<1> is lower alkyl; R<2> is 2-, 3- or 4-pyridylmethyl, 2-thienyl methyl, 2-furylmethyl, nicotinoyl, 2- thiophenecarbonyl or 2-furoyl) and a salt thereof. EXAMPLE:1-[2-(2,4-dichlorophenyl)-2-(3-pyridylmethyloxypropyl)-1H-1,2,4- triazole.dinitrate]. USE:A mycosis-treating and preventing agent having a strong hypha growth- inhibiting activity. Low toxicity. PREPARATION:A compound of formula II is reacted with a halogenating agent in the presence of a base in a solvent at -10-100 deg.C to provide the compound of formula I.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides 1-(2-substituted-2-ferethyl)-1 which has a strong mycelial growth inhibiting effect and is useful for the treatment and prevention of mycoses. ) 1-1.2.4- This relates to triazole derivatives.

(Prior art) α-aryl-IH-1,2,4-triazole-1-
Ethanol neck as a fungicide, JP-A-55-1227
71.

[Problem to be solved by the invention]

We have been conducting intensive research with the aim of developing new antifungal agents. In the process, α-aryl-18-1
, 2,4-triazole-1-ethanol exhibits a strong antifungal effect, but has been found to be highly toxic and unsuitable as a pharmaceutical product. As a result of further research aimed at reducing toxicity, a new compound with low toxicity was discovered and the present invention was completed.

[Means and effects for solving the above problems] The present invention relates to a compound represented by the following maximum (1) and a pharmacologically acceptable salt thereof, 6Ar (wherein, Ar is a phenyl group, 171 represents a 7- or di-halophenyl group; 171 represents a lower alkyl group;

R1 is 2-. 3- or 4-pyridylmethyl group, 2-thienylmethyl group, 2-furylmethyl group, nicotinoyl group, 2-thiophenecarbonyl group or 2-furoyl group) -i (1), with regard to Ar, Specifically, phenyl L 2-chlorophenyl L310 lophenyl l, 4-chlorophenyl group, 2-fluorophenyl L3-fluorophenyl group, 4-fluorophenyl group, 2. Examples include 4-dichlorophenyl group and 2,4-difluorophenyl group. Regarding lt+, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, ter
Examples include t-butyl group. R2 is 2-pyridylmethyl group, 3pyridylmethyl group, 4-pyridylmethyl group, 2
Examples include -thienylmethyl group, 2-furylmethyl group, nicotinoyl group, 2-thiophenecarbonyl group, and 2-furoyl group.

The compound of the present invention can be easily produced by the method shown in [Reaction formula-■] below.

[Reaction formula-I]

0 ■ Ar [In the formula, Ar, R', and R'' have the same meanings as above.

Or represents a chlorine, bromine or iodine atom. ] That is, the compound (1) of the present invention can be produced by reacting the compound [11] with a halide (Rx). The reaction from (r I) to (1) - is carried out in a solvent in the presence of a base.

Suitable solvents used in this reaction include, for example, tetrahydrofuran, N,N-dimethylformamide, dioxane, dimethyl sulfoxide, and the like. In addition, as the base, sodium hydride, potassium tert,
-Inorganic bases such as butoxide are preferred. The reaction temperature is 10°C to 100°C, and the reaction time is 10 hours to 24°C.
It's time.

The compound [■] used in this reaction is a known compound, and is synthesized according to a known method, for example, the method described in JP-A-55-122771.

The compounds of this reaction contain one or more asymmetric centers, and the present invention includes both resolved and unresolved centers.

Preferred pharmacologically acceptable salts are acid addition salts.

Acid addition salts are non-toxic acid addition salts containing pharmacologically acceptable anions such as hydrochloride, hydrobromide, nitrate, sulfate, etc. It is formed from strong acids that form salts. The nucleic acid is collected in a conventional manner, eg, by mixing a solution containing mu base and an equivalent amount of the desired acid, and filtration (if insoluble) or solvent evaporation.

Compound N) of the present invention exhibits a strong antifungal effect and is effective against superficial mycoses and deep mycoses in mammals including humans. Therefore, it is usually administered orally in the form of solid preparations such as tablets, granules, powders, and capsules, or in ointments, jellies, and creams.

It is preferable to use it in the form of external preparations such as powders, solutions, emulsions, or sprays.

There is no particular difficulty in formulating these formulations, using appropriate excipients and using known methods. The drug may be formulated based on the following information.

Preferred excipients include, for example, dextrose, sig sugar, lactose, glucose, sodium chloride, gelatin, starch, magnesium stearate, talc, animal/vegetable fats, etc. for solid preparations, and for external preparations. In the case of, animal and vegetable fats, paraffin, starch tragacanth, cellulose derivatives, silicone, silica, bentonite, talc, zinc oxide, lactose, aluminum hydroxide, calcium silicate, polyamide powder, water, ethanol, isopropyl alcohol, propylene glycol. , polyethylene glycol, benzyl alcohol, ethyl carbonate, benzyl benzoate, glycerin, N, N
Examples include -dimethylformamide, glycerin formal, fatty acid esters of sorbitol, and chlorofluorohydrocarbons as propellants.

The concentration of compound (1) in the external preparation is 0.1 to 5% by weight.
A range of is preferred. In addition, the oral dosage depends on age, weight,
Although it varies depending on the symptoms, the dosage is usually increased or decreased as appropriate within the range of about 50 to 1000 mg per day for adults.

Next, the present invention will be explained with reference to Examples.

[Example 1] 1,-(2-(2,4-dichlorophenyl)-2-(
3-pyridylmethyloxy)propyl]4)1-1.2
．． 4-) Synthesis of Riadur dinitrate! ? ,! 2. Add 1.0 g of 60χ sodium hydride to 20 ml of l-dimethylformamide. Comb, 2- (
2,4-dichlorophenyl)-1~(il!-12,
4-triazol-1-yl)propan-2-ol 2
．． 7 g was added and stirred at room temperature for 30 minutes. Under water cooling, 2-
1.6 g of (chloromethyl)pyridine hydrochloride was added, and the mixture was stirred at room temperature overnight.

) After evaporating the solvent under reduced pressure, water was added to the residue and extracted twice with chloroform. After drying the organic layer, the solvent was distilled off, and the obtained oil was dissolved in ethanol, and 60% nitric acid 2.0% was added. The precipitated crystals were collected by filtration and recrystallized from ethanol to obtain the title compound (9.1 g, 100%).

Melting point 149-153'C.

Elemental analysis: C,,)1. , CI□N4・2HNO,
Theory (direct (χ): C, 41, 73: I+
, 3.71; N, 17.18 Actual value (X):
C, 41,79; H, 3,75; N, 16.93N
MR(D?l5O-d,) δ: 1.77
(38,s, CHz), 4.51(1)1. d, J=
13.2Hz, C1 (-triazolyl), 4.7
3(IH, dJ=13.21(z, C11-tria
zolyl), 4.88 (2H,m, CL-py
ridyl) 7.43 (2+I, s, Ar-1t)
, 7.67 (1M, S, Ar-11), 8.08 (1)
1. s, Lr1azolyl-3-11),
8.12 (18, m, Ar-H), 8.60
(I Hd, J=8.1)1z, Ar-H), 8.6
9(IH,s, triazolyl-5-)1)8.
91 (21(,s,8r-)1).

Mass(m)z): 327 (M'-CI
) (Examples 2 to 25) In the same manner as in Example 1, the compounds shown in Table 1 were synthesized.

Table 1 [Formulation Example 1] Compound of the present invention Lactose crystalline cellulose Magnesium stearate 0 mg 00 mg 0 mg mg The above mixture was mixed in a conventional manner and tableted to obtain tablets containing 50 ml of crude drug.

[Formulation Example 2] Compound of the present invention 50 mg Lactose 200 mg Corn starch 60 m Talc 30 mg Magnesium stearate lomg The above mixture was granulated according to a conventional method to prepare granules.

[Formulation Example 3] Compound of the present invention 2.0g White petrolatum 25.0g Stearyl alcohol 25.0g Propylene glycol 1
2.0g Sodium lauryl sulfate 1.5g Ethyl paraoxybenzoate 0.5g Further, deionized water was added to make a total of 1100.0g.The above mixture was uniformly mixed according to a conventional method to prepare a cream.

[Pharmacological experiments] (1) Candida albicans (Candida albicans)
ICR male mice (Charles River, Japan;
(5 to 6 weeks old, weight 25 to 32 g) were used.

Candida albicans cultured for 24 hours on Sabouraud agar medium supplemented with 1% yeast extract was incubated at 5XIO'cel.
A cell suspension of ls/In1 was prepared and 0.2 ml per mouse was intravenously administered. 0°5 of each test compound
It was suspended in χ carboxymethylcellulose solution and administered orally. The drug was administered once 1 hour after infection at a dose of 25 mg per kg body weight. The life prolonging effect of a drug is calculated by the average survival days (Mediu
m 5urvival Days: Gate SD) and T
Determined by e5t/Control (T/C).

The results are shown in Table 2.

MSo, 50! Number of days maintaining survival rate above (n)
X: Number of animals per archipelago Table 2 Pharmacological experiment IcR weighing 20-25 g combed in cellulose aqueous solution
It was orally administered to male mice (5 mice per group) and observed for 7 days after administration. The results are shown in Table 3.

In addition, as a comparative substance, 2-(2,4-dichlorophenyl)-3-(IH-1,2,4-triazol-1-yl)-pyropan-2-ol (test compound: A) (JP-A-55 -122771) was used.

Table 32, Sexual toxicity test (2) Acute toxicity test Each test compound was mixed with 0.5% carboxymethyl [Effects of the invention] The compounds of the present invention exhibited an excellent survival effect in a lethal acute infection model caused by Candida albicans, and Low toxicity was confirmed in animal experiments.

The compound of the present invention is characterized by excellent effects as an antifungal drug. Patent applicant: Morishita Pharmaceutical Co., Ltd.

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [ I ] (In the formula, Ar represents a phenyl group, mono- or di-halophenyl group. R^1 represents a lower alkyl group. R^2 is 2-, 3-, or 4-pyridylmethyl group, 2-thienylmethyl group, 2-furylmethyl group, nicotinoyl group,
Indicates a 2-thiophenecarbonyl group or a 2-furoyl group. ) 1-(2-substituted-2-phenylethyl)
-1H-1,2,4-triazole derivatives and pharmacologically acceptable salts thereof.