JPS61271280A - Novel azole derivative, manufacture and use - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [In the formula, RI and R1 are independently hydrogen, nitro, halogen, or lower alkenyl, each of which may be optionally mono- or polysubstituted with halogen;
lower alkylthi, lower alkylthiosulfinyl, lower alkylsulfonyl, lower alkyl, or lower alkoxy, R3 is optionally halogen, carboxy, lower alkoxycarbonyl, lower alkoxy, lower alkylthio, amino, lower alkanoylamino, lower alkoxycarbonylamino, lower Lower alkyl, lower alkenyl, or lower alkynyl, which may be mono- or polysubstituted by alkylamino or lower dialkylamino; or optionally halogen, lower alkyl, lower alkoxy, amino, lower alkanoylamino,
lower alkoxycarbonylamino, lower alkylamino, lower dialkylamino, I-piperazinyl, or 4
- phenyl optionally substituted by lower alkanoyl-l-piperazinyl (wherein each alkyl, alkenyl or alkynyl contained in R3 can be mono- or polysubstituted with halogen), X is N or CH.

Azole derivatives in the form of enantiomers or racemates, where n is an integer from 2 to 5, and methods for producing the same, and pharmaceuticals, such as antifungal drugs,
or for use as a pesticide, such as a fungicide.

Lower alkyl groups especially have 1 to 5 carbon atoms, preferably 1 to 4, for example 1 or 2 carbon atoms. This also applies to lower alkyl moieties contained in other groups. Lower alkenyl and lower alkynyl groups especially have 3 to 6 carbon atoms, especially 3 or 4 carbon atoms. Halogen in particular represents P, CQ, Br or ■, preferably F or CI2. The cycloalkyl group contained in the compounds of this invention is conveniently a 3- to 6-membered ring, preferably a 3-membered ring (n=2).

In this invention, the compound of formula (1) may be used in free form or in salt form, for example in the form of acid addition salts of organic or inorganic acids, in the form of ethanolade salts, or in the form of metal complexes, such as copper or zinc. Ib, Ira, II of the periodic table
It can exist in the form of a metal complex consisting of a metal belonging to group b, VIb1b or group II and an anion such as chloride ion, sulfate ion or nitrate ion. Salt forms and metal complexes can be prepared in conventional manner from the corresponding free forms, and vice versa.

In this invention, the compound of formula (I) can be produced by the method (a) or (b) below.

(a) Formula (■): (In the formula, A, Ra, Ra, and n have the same meanings as above, and R4 is a leaving group.) A compound represented by the formula (■): ( In the formula, X has the same meaning as above, M represents hydrogen or a scratched substance such as a metal, or (b) a compound represented by the formula (■): The compound shown in III) is reacted with methylated methylsulfonium or ethylated dimethylsulfonium, or a precursor of these compounds, and in this case, if an amino group is present, it is protected with a corresponding protecting group, and the reaction is carried out. Compounds of formula (I) can be prepared by eliminating this after completion of , and recovering the compound thus obtained in free form or salt form.

Reaction (a) can be carried out, for example, by formula (II) t- or formula (IIa)
and the azole itself represented by the formula (II) (
M=H) or its metal compound form (M=gold metal, especially with an alkali metal salt such as the sodium salt) in an inert solvent such as dimethylformamide at a temperature from room temperature to the boiling point of the reaction mixture. This can be accomplished by reacting with

Reaction (b) can be carried out using conventional methods, such as those described in The Journal of the American Chemical Society (JA
CS), vol. 84, p. 3782 (1982), Heterocyc 1es, vol. 8, 39
7 (1977), and The Journal of the American Chemical Society (JACS).
, Vol. 87, p. 1353 (1965).

As protecting groups and leaving groups, groups commonly used in this type of reaction are used. Protective groups can be introduced and removed by conventional methods.

The compound of formula (1) contains an asymmetric carbon atom.

These compounds can therefore exist in the form of enantiomers or in the form of mixtures thereof which can be separated by conventional methods.

The use of optically active starting materials gives the corresponding target products. This invention concerns both virtually pure enantiomers as well as mixtures thereof, where R+ = CQ or Br.

R, = H1R3=CH3, if n=2, (+)
-Enantiomers are preferred.

As a substituent (a) hydrogen for R1 and R7; (b) halogen; R3 is lower alkyl, especially methyl, (a) N to X.

(b) CH is preferred; n=2.

Preferred compounds of formula (1) contain any combination of these substituents.

Compounds of formula (II) are new and can be prepared from compounds of formula (IV) by a method analogous to reaction (b). Formula (I
The compound la) can be produced, for example, from the compound of formula (II) by a conventional method.

Some of the compounds of formula (IV) are new and can be prepared by conventional methods, for example, (a) formula (■): 1(al (wherein R1, R9 and n are as defined above, H
aQ represents a halogen) and a thiol of the formula (■): HS-R3(■) (R is the same meaning as above) in the free form or as a salt in the presence of a convenient base. or (b) by reacting the formula (IK): (in which R + SRt, n and Haσ are as defined above) with a halogen, for example an ether/dioxane mixture of l3rt, Formula (■): (In the formula, R
3, R2, n and Ha12 are as defined above) and then reacting this with a thiol of formula (Vl), conveniently in the presence of a base, in free form or in salt form, It can be produced by producing a compound of formula (■): and cyclizing it.

Unless otherwise specified with respect to the preparation of starting materials, they are known or can be prepared by methods known or analogous to those described herein.

The desired product and starting materials can be isolated and purified by conventional methods.

The compounds of this invention have interesting biological properties, in particular antifungal properties, making them useful as pharmaceuticals, especially as antifungal agents. Antifungal activity can be demonstrated by in vitro testing, e.g., in vitro against various families and species of fungi such as yeasts, filamentous fungi and dermatophytes. /IIQ concentrations can be demonstrated by serial dilution method, and in vivo tests have shown that, for example, rats infected intravaginally with Candida albicans have a concentration of about 0.1 to IO*g/&9 (body weight) (2 This can be demonstrated by systemically orally administering an amount of 100 mg/day).

In the above applications, the dosage will vary depending on the compound used, the mode of administration, and the desired treatment.

It is natural to do so, but in general, 0.
Satisfactory results are obtained by dividing the daily dosage of 5-10 n/9k into 1 to 4 times a day and conveniently administering certain C) in controlled release form. A corresponding daily dosage for a large mammal weighing approximately 70 kg is, for example, in the range 40 to 700119, e.g. a dosage form suitable for oral administration contains 10 to 700 rtt9 of active ingredient. .

The compounds of this invention are compatible with known comparator drugs used for such indications, such as itraconazole (I traco
nazole).

The suitable daily dosage is determined by a number of factors, such as relative potency of activity. For example, according to the pathological model of candidiasis in rats, preferred compounds according to the invention, (+)-α-(4-chlorophenyl)-α-[(1-
methylthio)cyclopropyl]-1N-1,2,4-)
The proportion of lyazole-1-ethanol was significantly lower than that of itraconazole, 2 x 0, 6 m9/kg/
It was found that oral administration of the drug showed a curative effect.

Therefore, these compounds can be used at doses equal to or lower than the usual doses of itraconazole.

The compounds of this invention can be used in free base form or in the form of pharmaceutically acceptable salts (acid addition salts or enolates). Generally, the salt form has similar activity as the free base.

Examples of such salts include hydrochloride, acid fumarate, and naphthalene-1,5-disulfonate.

These compounds can be mixed with conventional pharmaceutically acceptable diluents or carriers, and optionally with other excipients, to form preparations such as tablets, capsules, creams, tinctures, or injectable preparations. It can be administered orally, topically, intravenously, or parenterally.

Such compositions also form part of this invention. Therefore, in this invention, in order to suppress infections and diseases caused by fungi, the formula (1) is applied to a target that requires treatment.
A method for controlling the above-mentioned subject comprising administering an effective amount of the compound in the form of its free base or pharmaceutically acceptable salt;
and the use of such compounds as pharmaceuticals, especially as antifungal agents.

The compounds of the invention, in the form of free base or agriculturally acceptable salts or metal complexes, are also suitable for the control of phytopathogenic fungi. This fungicidal activity was tested under in vivo conditions in the common bean Uromyces avendiculatus (e.g. Uromyces appe).
ndicul niuS: a rust fungus of the Fabaceae family) and other rust fungi of coffee, wheat, flax and ornamental plants (e.g. geraniums, snapper grass) (e.g. Hemilenia).
enia), and Puccinia. In addition, the cucumber powdery mildew fungus U Erysiphe cicolacearum (Erysiphe
cichoracearum)] and other powdery mildews of wheat, barley, apples and grapes [e.g. Erysiphe graminis subsp. tritiki (E, gram-
4nis f, sp, tritici), Erysiphe graminis subspecies hordei (E, gralTl
, f, sp, hordei), Bodosphaera
Leucotorica (Podosphaeraleuco)
, tricha), Unicinula recator (Unic
Antifungal activity can also be observed against the genus i-nula recator).

[Example code] The following examples further illustrate the invention.

Example 1 α-(410 Lofenyl)-α-(+-Me-F)Ii
Thio)cyclopropyl-I H-1,2,4-)lyazole-1-ethanol (Production method b) Iodization was carried out in a suspension of 3.2 g of sodium hydride (50%) in 120 yen of anhydrous dimethylformamide. Add 14.89 g of trimethylsulfoxonium in small portions and continue stirring for 45 minutes. At the same time, anhydrous dimethylformamide 1
A solution was prepared by adding 3.2 g of sodium hydride (50%) and 4.6 g of 1,2.4-triazole little by little to 20 m12, stirred for 45 minutes, and combined with the above suspension. Make it one. Then add 4 to this mixture
A solution of 106 g of -chlorophenyl-1-methylthiocyclopropyl ketone dissolved in 50 JlQ of anhydrous dimethylformamide is added dropwise at room temperature. After stirring the reaction mixture at room temperature for 7 days, the solvent is distilled off at 50° C. under a reduced pressure of 1 torr. The oily residue was partitioned between chloroform and water,
The organic layer is collected, washed with water and saturated aqueous NaCl solution, dried over sodium sulfate, and concentrated. The title compound is obtained as colorless crystals by silica gel column chromatography (ethyl acetate). mp131~1
33℃.

Example 2 α-(4-bromophenyl)-α-(f-methylthio)
Cyclopropyl-IH-1,2,4-1-lyazole-
1-Ethanol (Production method b) Obtained by a method similar to Example 1. mp125~
127℃.

Example 3 (+)-α-(4·-chlorophenyl)-α-(1-methylthio)cyclopropyl-IH-1,2,4-triazole-1-ethanol (Production method a) (+)-4-chloro -α-(1-methylthio)cyclopropyl-α-mesyloxymethyl-benzyl alcohol 1291g, 1.2
．． A mixture of 53 parts of 4-triazole, 105 parts of potassium carbonate and 10 parts of dry dimethylformamide is stirred at 70°C for 4 hours. The mixture is then poured into water, extracted with ethyl acetate, and the organic layer is dried over M g SO 4 and concentrated by evaporation. The residue is chromatographed with ethyl acetate on silica gel. Obtain colorless crystals. mp
H2~114°C; [α-(acetone) (acetate) = +40.2° Example 4 (+)-α-(4-chlorophenyl)-α-(1-methylthio)cyclopropyl-IH-1,2 , 4-triazole-1-ethanol (Production method a) Obtained by a method similar to Example 3.

[αko″6 (acetone) = −40°.

The starting materials can be produced, for example, as described below.

(A) 4-chlorophenyl-1-methylthiocyclopropyl ketone (Starting material for Example 1) (a) 4-chlorophenyl-3-chloro-1-bromopropyl ketone 4-chlorophenyl-3-chloropropyl ketone 65.
19 is dissolved in a mixed solvent consisting of anhydrous ether 120+++ (and anhydrous dioxane 60x+2) and treated with 48 g of bromine under heating.
After stirring for a minute, the reaction mixture was poured onto 300 ml of water,
Extract with ether. The organic layers are combined, dried over sodium sulfate, and concentrated.

The solid residue is crystallized from petroleum ether. mp67~
69℃.

(b) 4-chlorophenyl-3-chloro-1-methylthiopropylketone methanethiol sodium IO,69 anhydrous 1°2-
The suspension in 200ml of dimethoxyethane was
4-chlorophenyl-3-chloro-1-1' lomobropyl ketone 45.2 while keeping the temperature below °C and without stirring.
A solution of 59 dissolved in 10oxc of anhydrous 1,2-dimethoxyethane is added dropwise to this solution.

After stirring the reaction mixture at room temperature for 2 hours, water! Carefully dilute with 50 ml of ether and 250 ml of ether.

Wash the organic layer with water, dry and concentrate. Silica gel column chromatography (n-hexane/ethyl acetate = 98
/2) to purify the title compound.

Colorless oil. Rf=0. 12 (n=hexane/ethyl acetate=98/2).

(c) 4-chlorophenyl-1-methylthiocyclopropyl ketone Potassium hydroxide 10.8 G9 in methanol 45 ml
The solution dissolved in 4-chlorophenyl-3-chloro-1
-Methylthiopropyl ketone 24.39 methanol 4
It is added dropwise to a solution dissolved in 5i12 to react. After stirring the reaction mixture for 1 hour at room temperature, it is concentrated on a rotary evaporator, the residue is partitioned between toluene and water, the organic layer is collected, washed with water, dried and evaporated. The oily residue is crystallized from petroleum ether. Obtain colorless crystals. mp30-32℃.

(B) 4-Bromophenyl-1-methylthiocyclopropyl ketone (starting material for Example 2) Produced in a similar manner to (A).

(a) 4-bromophenyl-3-chloro-1-bromopropyl ketone mp 92-94°C (b) 4-bromophenyl-3-chloro-1-methylthiopropyl ketone Rf = 0.13 (n-hexane/ethyl acetate =98/2
).

(c) 4-bromophenyl-1-methylthiocyclopropyl ketone mp 43-45°C.

(C) 4-chloro-α-(l-methylthio)cyclopropyl-α-mesyloxymethyl-benzyl alcohol (
Starting Materials for Examples 3 and 4) (a) I-(4-chlorophenyl)-1-(1-methylthio)cyclopropyl-
To a suspension of 0.739 of oxirane sodium hydride (80%) in 5011 Ig of dry dimethylformamide, 5.349 of trimethylsulfoxonium iodide is added in portions and the mixture is stirred for 45 minutes.

Then, a solution of 5 g of 4-chlorophenyl-1-methylthiocyclopropyl ketone dissolved in dimethylformamide F25tQ is added dropwise thereto, and the mixture is stirred at room temperature for 18 hours. The mixture is concentrated under reduced pressure (l) and the residue is partitioned between acetic acid/water. The organic layer was separated and M g S O4
Dry and evaporate.

Obtain a colorless oil.

'H-NMR: 7.1-7.6 (m, 4H); 2.
76-3.0 (AB-system, 2H); 1.98
(s, 3H); 0.7-1.3 (+n, 4H).

(b) 4-chloro-α-hydroxymethyl-α-(l-
Methylthio)cyclopropyl-benzyl alcohol, 0.3M-KOH-dimethylsulfoxide/water (4/
l) 1-(4-chlorophenyl)-1-( together with the solution
1-Methylthio)cyclopropyl-oxirane 0.2g
Stir at 60°C for 20 hours. Then mix the mixture with 50% water
Dilute with m12 and extract with ethyl acetate. The extracted solution is dried over NatSOa and concentrated by evaporation. The crude product,
It can be purified by chromatography on silica gel using a hexane/ethyl acetate (4/1) mixture.

Obtain colorless crystals. mp86-91'C0 (c) optical enantiomer resolution racemic product 2.659 is dissolved in pyridine 50RQ,
Add camphoric acid chloride 2 to this solution while cooling with ice water.
．． Add 67 g little by little. After the addition, the mixture is stirred at room temperature for 20 hours. The mixture is poured into water-cooled dilute sulfuric acid and extracted with ethyl acetate.

The organic layer is dried with M g SO+ and concentrated by evaporation. The mixture of diastereomeric esters was purified by silica gel chromatography using hexane/ethyl acetate (4/1
) Separate the mixture.

Diastereomer A: mpl 22-124℃, [♂
] 20 (acetone) = +28° diastereomer B: mp 125-127°C, [I]”
(Acetone) = -43,6° diastereomer A29 and strong basic ion exchange resin 39
in a mixture of methanol and water at reflux temperature for 15 minutes.
Stir for an hour. The dextrorotatory enantiomer is obtained as colorless crystals by filtration and evaporation. mp60~62℃
.

[α]D” (acetone) = +79.7°.

(dX+)-4-chloro-α-(l-methylthio)cyclopropyl-α-mesyloxymethiebenzyl alcohol (+)-4-chloro-α-hydroxymethyl-α-(1
-Methylthio)cyclopropyl-benzyl alcohol 1
．． 279 to dry pyridine 201! Water-cooled mesyl chloride 0.6 B9 is added dropwise to the solution. 0 mixture
After stirring for 2.5 hours at ~5°C, pour into water-cooled dilute sulfuric acid. Extract with ethyl acetate, and extract the organic layer with M g S 04
After drying and evaporation, a colorless oil is obtained.

'H-NlvIR: 7.2-7.65 (m, 4H):
4.5-5.22 (AB-system, 2H); 3.
0 (s, 3H), 1.52 (s, 3H), 0.5-1.
4 (m, 4H).

[α%”=+57.4°.

The (-) monoenantiomer can be obtained by an analogous method.

Claims (1)

[Claims] 1. Formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_1 and R_2 are independently hydrogen, nitro, halogen, or each halogen as desired. lower alkenyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkyl, or lower alkoxy, which may be mono- or polysubstituted by , lower alkyl, lower alkenyl, or lower alkynyl, which may be mono- or polysubstituted by amino, lower alkanoylamino, lower alkoxycarbonylamino, lower alkylamino, or lower dialkylamino; or optionally halogen, lower alkyl, lower Phenyl optionally substituted by alkoxy, amino, lower alkanoylamino, lower alkoxycarbonylamino, lower alkylamino, lower dialkylamino, 1-piperazinyl, or 4-lower alkanoyl-1-piperazinyl (where R_3 contains Each alkyl, alkenyl or alkynyl can be mono- or polysubstituted by halogen)
, X is N or CH, n is an integer of 2 to 5] An azole derivative in the form of an enantiomer or a racemate. 2. The compound according to claim 1, wherein R_1 and R_2 are independently hydrogen or halogen, R_3 is lower alkyl, and n is 2. 3. Formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 and R_2 are independently hydrogen, nitro, halogen, or if desired, each is mono- or polysubstituted with halogen. lower alkenyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkyl, or lower alkoxy which may be , lower alkyl, lower alkenyl, or lower alkynyl, which may be mono- or polysubstituted by lower alkoxycarbonylamino, lower alkylamino, or lower dialkylamino; or optionally halogen, lower alkyl, lower alkoxy, amino, lower alkanoyl phenyl optionally substituted with amino, lower alkoxycarbonylamino, lower alkylamino, lower dialkylamino, 1-piperazinyl, or 4-lower alkanoyl-1-piperazinyl) X is N or CH, n is an integer of 2 to 5 azole derivatives in the enantiomeric or racemic form of 4. The compound according to any one of claims 1, 2, or 3, which is in free form. 5. The compound according to any one of claims 1, 2, or 3, which is in the form of a salt. 6. (+)-α-(4-chlorophenyl)-α-[1-methylthio)cyclopropyl]-1 in free or salt form
H-1,2,4-triazole-1-ethanol. 7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 in the form of a free or pharmaceutically acceptable salt together with a pharmaceutically acceptable diluent or carrier. 8. A compound in the form of a free or pharmaceutically acceptable salt according to any one of claims 1 to 6, which can be used as a pharmaceutical. 9. Claims 1 to 6 that can be used as an antifungal agent
A compound according to any one of paragraphs 1 to 9, in free or pharmaceutically acceptable salt form. 10, (a) Formula (II): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R_1, R_2, R_3 and n have the same meanings as above) or Formula (IIa): ▲ Mathematical formula , chemical formulas, tables, etc. ▼(IIa) (In the formula, R_1, R_2, R_3 and n have the same meanings as above, and R_4 is a leaving group) The compound represented by the formula (III) ▲Math. , chemical formulas, tables, etc. ▼(III) (wherein, X has the same meaning as above and M represents hydrogen or a metal equivalent) or (b) react with a compound of formula (IV): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) (In the formula, R_1, R_2, R_3 and n have the same meanings as above) The compound represented by the above formula (III) and methyl dimethylsulfonium chloride or ethylated dimethylsulfonium, or precursors of these compounds, in which case the amino group, if present, is protected with a corresponding protecting group, and after the reaction is complete, it is reacted with Claim 1 consisting of elimination and recovery of the compound thus obtained in free or salt form.
A method for producing the compounds described in Section 1 in free form or in salt form.