JPH0859633A - Triazole derivative, its production method and its synthetic intermediate - Google Patents

Abstract

(57) [Summary] [Structure] General formula [I] (In the formula, Ar is a phenyl group having 1 to 2 substituents,
R ¹ is a lower alkyl group, R ² is a lower alkyl group or a lower alkoxy lower alkyl group, R ³ is a (1) hydrogen atom,
Lower alkyl group, phenyl lower alkyl group, (2) lower alkanoyl group optionally having 1 to 2 substituents selected from the group consisting of amino group, hydroxyl group and carboxyl group, (3) lower alkylsulfonyl group Represents an arylsulfonyl group or (4) pyrrolidinylcarbonyl group. ] The triazole derivative shown by these, or its pharmacologically acceptable salt. [Effect] It is possible to provide a triazole derivative having excellent antifungal activity against various fungi such as Aspergillus, Candida, and Cryptococcus.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel triazole derivative having excellent antifungal activity, a process for producing the same, and a synthetic intermediate thereof.

[0002]

2. Description of the Related Art Recently, the genus Candida, the genus Aspergillus,
Although deep-seated mycoses due to opportunistic infections of cryptococcus and other fungi tend to increase, although amphotericin B has long been used to treat these deep-seated mycoses, this drug has side effects. It had the drawback of being strong. To improve this point, the use of triazole antifungal agents such as fluconazole and itraconazole has been investigated, but these compounds have a relatively narrow antifungal spectrum or weak antifungal activity in immunocompromised patients. There were some difficulties.

[0003]

DISCLOSURE OF THE INVENTION The present invention provides a novel triazole derivative having excellent antifungal activity.

[0004]

The present invention relates to novel triazole derivatives represented by the following general formula [I] and salts thereof.

General formula [I]

[0006]

[Chemical 13]

(In the formula, Ar is a phenyl group having 1 to 2 substituents, R ¹ is a lower alkyl group, R ² is a lower alkyl group or a lower alkoxy lower alkyl group, R ³ is a (1) hydrogen atom, Lower alkyl group, phenyl lower alkyl group, (2) lower alkanoyl group optionally having 1 to 2 substituents selected from the group consisting of amino group, hydroxyl group and carboxyl group, (3) lower alkylsulfonyl group Represents an arylsulfonyl group or (4) pyrrolidinylcarbonyl group.) Specific examples of the triazole derivative [I] of the present invention include:
For example, 1 to 1 (A) Ar is selected from a halogen atom (eg, chlorine atom, fluorine atom, etc.) and a trihalogeno lower alkyl group (eg, trifluoromethyl group).
A phenyl group having two substituents, R ¹ is a lower alkyl group (eg, methyl group, ethyl group, etc.), R 1
² is a lower alkyl group or a lower alkoxy lower alkyl group (eg, methoxymethyl group, methoxyethyl group, etc.)
And a compound in which R ³ is a hydrogen atom, or (B) A
r is a phenyl group substituted with 1 to 2 halogen atoms, R ¹ is a lower alkyl group, R ² is a lower alkyl group, and R ³ is (1) a lower alkyl group or a phenyl lower alkyl group. , (2) a lower alkanoyl group optionally having 1 to 2 substituents selected from the group consisting of an amino group, a hydroxyl group and a carboxyl group (eg, acetyl group, 2-hydroxyacetyl group, 2-aminoacetyl Group, 4-carboxybutanoyl group, 3-amino-3-carboxypropionyl group, etc.), (3) lower alkylsulfonyl group (methanesulfonyl group, etc.), arylsulfonyl group (eg, phenylsulfonyl group, p-toluenesulfonyl group) Unsubstituted or lower alkyl-substituted phenylsulfonyl group etc.) or (4) pyrrolidinylcarbonyl group (eg 2 Compound is a pyrrolidinylcarbonyl group, etc.).

Among the above compounds [I], preferred compounds [I] include, for example, Ar being a phenyl group substituted with 1 to 2 halogen atoms, and R ² being a lower alkyl group or a lower alkoxy lower alkyl. A compound in which R ³ is a hydrogen atom is a group.

Another preferred compound [I] is, for example, Ar which is a phenyl group substituted with 1 to 2 halogen atoms, R ¹ is a lower alkyl group, and R ¹ is a lower alkyl group.
Examples include compounds in which ² is a lower alkyl group, and R ³ is a lower alkanoyl group which may have 1 or 2 substituents selected from the group consisting of an amino group and a hydroxyl group, or a pyrrolidinylcarbonyl group. .

As a more preferred compound [I], for example, Ar is a dihalogenophenyl group, R ¹ is a lower alkyl group, R ² is a lower alkyl group, R ³ is a hydrogen atom or amino lower alkanoyl. The compound which is a group is mentioned.

Of the above, the compound [I] which is preferable in terms of medicinal effect
Examples thereof include compounds in which Ar is a 2,4-dihalogenophenyl group, R ¹ is a lower alkyl group, R ² is a lower alkyl group, and R ³ is a hydrogen atom.

The object of the present invention may include optical isomers based on an asymmetric carbon atom and an asymmetric sulfur atom, but the present invention includes all of these optical isomers and mixtures thereof (diastereomer mixture, etc.). It includes.

The object [I] of the present invention can be used in medicinal use either in a free form or in the form of a pharmaceutically acceptable salt thereof. Examples of the pharmacologically acceptable salt include, for example,
Inorganic acid salts such as hydrochloride and sulfate, organic acid salts such as p-toluenesulfonate, acetate, citrate, maleate and fumarate, or inorganic bases such as sodium salt and potassium salt I can give you some salt.

The object [I] of the present invention and a pharmaceutically acceptable salt thereof can be administered orally or parenterally and mixed with a conventional excipient suitable for these administration routes. Then
It can be used as a pharmaceutical formulation. Further, the pharmaceutical preparation may be a solid preparation such as a tablet, a capsule or a powder, or a liquid preparation such as a solution, a suspension or an emulsion. Furthermore, in the case of parenteral administration, it can be used in the form of injection.

The dose of the object of the present invention depends on the age of the patient,
Although it depends on the body weight or the degree of disease, the usual daily dose is 0.05 to 20 mg in the case of oral administration.
/ Kg, especially 0.2 to 5 mg / kg, in the case of parenteral administration, 0.05 to 20 mg / kg, especially 0.2
It is preferably about 5 mg / kg.

According to the present invention, the object [I] is (A-
1) General formula [II]

[0017]

Embedded image

(In the formula, Ar is a phenyl group having 1 to 2 substituents, R ¹ is a lower alkyl group, R ² is a lower alkyl group or a lower alkoxy lower alkyl group, R ³¹ is a hydrogen atom, a lower alkylsulfonyl group. Group or an arylsulfonyl group) is oxidized to give a compound of the general formula [Ia]

[0019]

[Chemical 15]

(In the formula, symbols have the same meanings as described above.)
Or (B-1) the general formula [V]

[0021]

Embedded image

(In the formula, symbols have the same meanings as described above.)
On the sulfur atom of the compound represented by
NR ³¹ (wherein R ³¹ has the same meaning as described above) is reacted with an imino group (or substituted imino group) -donating compound to which a group represented by the formula [Ia] can be added.

[0023]

[Chemical 17]

(In the formula, symbols have the same meanings as described above.)
Then, if the group R ^{31 of the} compound (Ia) (2) is a lower alkylsulfonyl group or an arylsulfonyl group, the group is removed to give a compound of the general formula [Ib ]

[0025]

Embedded image

(In the formula, symbols have the same meanings as described above.)
The compound [Ib] and the general formula [III] R ^32- X ¹ [III] (wherein R ³² is a lower alkyl group, a phenyl lower alkyl group, a lower alkylsulfonyl group or An arylsulfonyl group, X ¹ represents a reactive residue) or a compound represented by the general formula [IV] R ³³ OH [IV] (in the formula, R ³³ is an optionally protected amino group or a protected group). A lower alkanoyl group optionally having 1 to 2 substituents selected from an optionally substituted hydroxyl group and an optionally protected carboxyl group, or a pyrrolidinylcarbonyl group) or a compound thereof. It can be prepared by reacting with a reactive derivative and then, if necessary, removing the protecting group on the group R ^{33 of the} product.

The oxidation of compound [II] can be carried out by treating the compound with a conventional oxidizing agent in the presence or absence of a suitable base in an inert solvent.

Examples of the oxidizing agent include hydrogen peroxide, peracetic acid, alkali metal perchlorate, m-chloroperbenzoic acid or alkali metal periodate (used in the presence of a catalytic amount of ruthenium oxide or ruthenium chloride). can give.
The amount of the oxidizing agent used is preferably 1 to 6 equivalents, and more preferably 4 to 5 equivalents, relative to compound [II].

As the solvent, any solvent which is inert to the compound [II] and the base can be used, and examples of such a solvent include acetone, methylene chloride, chloroform and the like.

Examples of the base include inorganic weak bases such as alkali metal hydrogencarbonates such as sodium hydrogencarbonate and alkali metal carbonates such as sodium carbonate, and the amount of the base used is 1 to the compound [II]. 6 equivalents, especially 4
~ 5 equivalents are preferred.

This reaction is preferably carried out under cooling or heating, especially at room temperature.

A group represented by the formula: NR ³¹ (wherein R ³¹ represents a hydrogen atom, a lower alkylsulfonyl group or an arylsulfonyl group) is added to the compound [V] and the sulfur atom of the compound [V]. The reaction with a possible imino group (or substituted imino group) -donating compound can be carried out in a suitable solvent.

Examples of the imino group (or substituted imino group) -donating compound capable of adding the group represented by the formula = NR ³¹ to the sulfur atom of the compound [V] include, for example, N-chloro-p-toluenesulfonamide sodium salt. N-halogeno-arylsulfonamide such as (chloramine T), lower alkylsulfonyl azide such as methylsulfonyl azide, phenylsulfonyl azide, p-toluenesulfonyl azide, p-methoxyphenylsulfonyl azide, p-nitrophenylsulfonyl azide, etc. And arylsulfonyloxyamines such as mesitylsulfonyloxyamine, hydrogen nitride and the like.

In this reaction, when an N-halogeno-arylsulfonamide alkali metal or arylsulfonyl azide is used as the imino (or substituted imino) group-donating compound, an arylsulfonyl group is present on the sulfur atom of the compound [V]. An imino group substituted with can be added.

On the other hand, when a lower alkylsulfonyl azide is used as the imino (or substituted imino) group-donating compound, an imino group substituted with a lower alkylsulfonyl group is added to the sulfur atom of the compound [V].

The above reaction can also be carried out in the presence of a catalyst such as copper powder depending on the kind of the imino group (or substituted imino group) donating compound.

Examples of the solvent used in this reaction include methylene chloride, chloroform and the like.

The temperature of this reaction may be appropriately selected according to the kind of the imino group (or substituted imino group) -donating compound to be used. For example, when N-halogeno-arylsulfonamido alkali metal is used as the imino group-donating compound. In particular, this reaction can be carried out at 0 to 100 ° C., and room temperature is particularly preferable.

The removal of the substituent on the imino group of the compound [Ia] can be carried out by a conventional method depending on the kind of the substituent. For example, when the substituent is a tosyl group, It can be carried out by treating the compound [Ia] with a detosylating agent (eg concentrated sulfuric acid etc.) in the absence of solvent or an appropriate solvent (eg methylene chloride, chloroform etc.).

This reaction is carried out under cooling or heating, especially at 0 ° C.
~ It is preferable to carry out at room temperature.

The reaction between the compound [Ib] and the compound [III] can be carried out, for example, by reacting the reactive residue X as the compound [III].
¹ is a halogen atom (chlorine atom, bromine atom, iodine atom)
Can be carried out in the presence of a base in a suitable solvent.

The amount of the compound [III] used is the compound [I
-B] is preferably 1 to 2 equivalents, more preferably 1 equivalent.

Examples of the solvent include tetrahydrofuran, N, N-dimethylformamide, 1,2-dimethoxyethane, acetone, methylene chloride, chloroform, acetonitrile and the like.

Examples of the base include inorganic strong bases or weak bases such as alkali metal hydrides such as sodium hydride, alkali metal hydrogencarbonates such as sodium hydrogencarbonate or alkali metal carbonates such as sodium carbonate. The amount of the base used is preferably 1 to 2 equivalents, and particularly preferably 2 equivalents to the compound [Ib].

This reaction is carried out under cooling or heating, especially at 0 ° C.
~ It can be suitably carried out at room temperature.

The reaction of the compound [Ib] with the carboxylic acid [IV] can be carried out in the presence of a condensing agent in a suitable solvent.

Examples of the condensing agent include dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and the like.
The solvent may be any solvent inert to the condensing agent and compound [Ib], and examples of such a solvent include N, N-dimethylformamide, tetrahydrofuran, methylene chloride, chloroform, acetonitrile and the like. .

This reaction is carried out under cooling or heating, especially at 0 ° C.
~ It can be suitably carried out at room temperature.

The reaction of the compound [Ib] with the reactive derivative of the carboxylic acid [IV] can be carried out, for example, by using an acid anhydride or acid chloride as the reactive derivative of the compound [IV] in a suitable solvent in a base. Can be carried out in the presence of

As the solvent, any solvent inert to acid anhydrides or acid chlorides, for example, the solvent used for the reaction of compound [Ib] and carboxylic acid [IV] can be used. Examples of the base include organic bases such as pyridine and triethylamine. The amount of the base used is preferably 1 to 2 equivalents, especially 1 equivalent to the compound [Ib]. When an acid anhydride is used as the reactive derivative of the compound [IV], the base may be used in an excess amount. . This reaction can be carried out under cooling or heating, especially at 0 ° C to room temperature.

The starting compound [II] of the present invention is a novel compound and can be produced, for example, as follows.

That is, the starting compound [II] was prepared as described in JP-A-57 / 57.
According to the method described in 165370, i) General formula [VI]

[0053]

[Chemical 19]

(In the formula, symbols have the same meanings as described above.)
And an epoxy compound represented by the general formula [VIII] R ²¹ -SM [VIII] (in the formula, R ²¹ represents a lower alkyl group or a lower alkyl group substituted with a hydroxyl group, and M represents an alkali metal atom). Reaction with a thiolate compound gives the product radical R ²¹
When is a lower alkyl group substituted with a hydroxyl group,
If necessary, the hydroxyl group is alkylated with an appropriate alkylating agent (alkali metal hydride, lower alkyl halide, etc.) to give a compound of the general formula [VII]

[0055]

Embedded image

(In the formula, symbols have the same meanings as described above.)
And then ii) aldrikimica.
Actor (Aldrichimica Acta), Volume 18, Issue 1 (1
985), according to the method described on pages 3 to 10, the group = NR ³⁴ (wherein R ³⁴ represents a lower alkylsulfonyl group or an arylsulfonyl group) on the sulfur atom of the compound and the compound [VII]. ) Can be added to a substituted imino group-donating compound in a suitable solvent (lower alkanol, etc.), and if necessary, the product is treated with a strong acid (eg concentrated sulfuric acid, etc.) to form the group R ³⁴ . It can be manufactured by removing. Examples of the substituted imino group-donating compound used in the addition reaction of the group = NR ³⁴ include lower alkylsulfonyl azides such as methylsulfonyl azide, arylsulfonyl azides such as p-toluenesulfonyl azide, N-chloro-p-toluenesulfonamide N- such as sodium salt
Examples thereof include halogeno-lower alkylphenyl sulfonamide alkali metal, and N-halogeno-lower alkylphenyl sulfonamide alkali metal is particularly preferable.
This addition reaction can be suitably carried out at 0 to 60 ° C., especially room temperature.

The starting compound [V] is obtained by, for example, converting the above-mentioned compound [VII] into a conventional oxidizing agent (for example,
It can be produced by treating with hydrogen peroxide, peracetic acid, alkali metal perchlorate, m-chloroperbenzoic acid, etc.).

In the present invention, the lower alkyl group is an alkyl group having 1 to 6 carbon atoms, and the lower alkoxy group is 1 carbon atoms.
~ 6 alkoxy and lower alkanoyl groups have 2 carbon atoms
Represents the alkanoyl group of ~ 7.

[0059]

【Example】

Example 1 (1) S- [2-((2R, 3R) -3- (2,4-difluorophenyl) -3-hydroxy-4- (1H-
1,2,4-triazol-1-yl) butyl)]-S
-Methyl-N-((4-methylphenyl) sulfonyl)
350m of acetone solution of 11.42g of sulfilimine
5.17 g of anhydrous sodium carbonate and 10.51 g of m-chloroperbenzoic acid were added to 1 and stirred at room temperature for 30 hours [anhydrous sodium carbonate (5.17 g and 2.59 g, respectively, 7 hours and 23 hours after starting stirring). ) And m-chloroperbenzoic acid (10.51 g and 5.26 g each) were added to the reaction mixture]. The solvent is distilled off from the reaction solution under reduced pressure, saturated aqueous sodium hydrogen carbonate solution is added to the residue, and the mixture is extracted with ethyl acetate. The extract is washed and dried, the solvent is evaporated, and the residue is purified by silica gel column chromatography (solvent; chloroform-ethyl acetate) to give (R)-
S- [2-((2R, 3R) -3- (2,4-difluorophenyl) -3-hydroxy-4- (1H-1,2,
11.53 g of 4-triazol-1-yl) butyl)]-S-methyl-N-((4-methylphenyl) sulfonyl) sulfoximine are obtained as colorless caramel.

¹ H-NMR (CDCl ₃ ): δ 1.3
6 (3H, d, J = 7.1Hz), 2.40 (3H,
s), 3.40 (3H, s), 4.82 (1H, dql
ike, J = 1.1, 7.0 Hz), 5.00 (1H,
d, J = 14.7 Hz), 5.40 (1H, d, J = 1)
4.6Hz), 5.75 (1H, d, J = 2.0H
z), 6.71-6.84 (2H, m), 7.26 (1
H, ddd, J = 6.2, 9.0, 9.0 Hz), 7.
30 (2H, dlike, J = 7.7 Hz), 7.73
(1H, s), 7.78 (1H, s), 7.89 (2
(H, dlike, J = 8.4 Hz) (2) To 1.05 g of this product was added 4 ml of concentrated sulfuric acid under ice cooling, and the mixture was stirred at room temperature for 15 minutes. The reaction solution is ice water 5
Pour into 0 ml and neutralize with 5% aqueous sodium hydroxide solution, then add sodium chloride. The mixture is extracted with ethyl acetate, the extract is washed, dried and the solvent is evaporated. The residue was purified by silica gel column chromatography (solvent; ethyl acetate-methanol) to give S-
[2-((2R, 3R) -3- (2,4-difluorophenyl) -3-hydroxy-4- (1H-1,2,4-
Triazol-1-yl) butyl)]-S-methylsulfoximine 450 mg is obtained as colorless crystals. m.
p. 185-186 ° C. ¹ H-NMR (CDCl ₃ ): δ 1.34 (3H, d
d, J = 0.9, 7.3 Hz), 1.67 (1H, br
s), 3.14 (3H, s), 3.57 (1H, q, J
= 7.2 Hz), 4.93 (1H, dd, J = 0.8,
14.4Hz), 5.45 (1H, d, J = 14.4H
z), 6.02 (1H, s), 6.72-6.82 (2
H, m), 7.36 (1H, ddd, J = 6.5, 9.
3, 9.3 Hz), 7.76 (1 H, s), 7.88
(1H, s) Examples 2 to 10 (1) The corresponding raw material compounds are treated in the same manner as in Example 1- (1) to obtain the compounds shown in Tables 1 to 4 below.

[0061]

[Table 1]

[0062]

[Table 2]

[0063]

[Table 3]

[0064]

[Table 4]

(2) The compounds shown in Tables 1 to 4 are treated in the same manner as in Example 1- (2) to obtain the compounds shown in Tables 5 to 7 below.

[0066]

[Table 5]

[0067]

[Table 6]

[0068]

[Table 7]

Example 11 A suspension of 146 mg of 35% oily potassium hydride in 3 ml of 1,2-dimethoxyethane at room temperature (RS) -S-2-
((2RS, 3RS) -3- (2,4-difluorophenyl) -3-hydroxy-4- (1H-1,2,4-triazol-1-yl) butyl) -S-methylsulfoxiimine 200 mg Add and stir the mixture for 20 minutes. 11 mg of cetyltrimethylammonium bromide and 86 μl of benzyl bromide were added to the reaction solution, and the mixture was stirred at room temperature for 21.5 hours. 30 ml of saturated saline and 20 ml of saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. After the extract is washed and dried, the solvent is distilled off.

The residue was purified by silica gel column chromatography (solvent; chloroform-ethyl acetate) to give (RS) -N-benzyl- [2-S-((2
RS, 3RS) -3- (2,4-difluorophenyl)
125 mg of -3-hydroxy-4- (1H-1,2,4-triazol-1-yl) butyl)]-S-methylsulfoximine are obtained as colorless caramel.

¹ H-NMR (CDCl ₃ ): δ 1.2
9 (3H, dd, J = 1.3, 7.2Hz), 3.08
(3H, s), 3.67 (1H, q, J = 7.2H
z), 4.31 (2H, s), 4.83 (1H, d, J
= 14.0 Hz), 5.29 (1H, d, J = 14.3)
Hz), 6.67-6.82 (3H, m), 7.22-
7.41 (6H, m), 7.73 (1H, s), 7.8
9 (1H, s) Example 12 (RS) -S- [2-((2RS, 3RS) -3-
(2,4-Difluorophenyl) -3-hydroxy-4
0.5 ml of acetic anhydride and 0.5 ml of pyridine are added to 200 mg of-(1H-1,2,4-triazol-1-yl) butyl)]-S-methylsulfoximine, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is extracted with ethyl acetate. After washing and drying the extract, the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform-methanol) to give (RS)
-N-acetyl-S- [2-((2RS, 3RS) -3
-(2,4-Difluorophenyl) -3-hydroxy-
189 mg of 4- (1H-1,2,4-triazol-1-yl) butyl)]-S-methylsulfoximine are obtained as colorless crystals. m. p. 157-159 ° C Example 13 (RS) -S- [2-((2RS, 3RS) -3-
(2,4-Difluorophenyl) -3-hydroxy-4
-(1H-1,2,4-triazol-1-yl) butyl)]-S-methylsulfoximine and methyl iodide were treated as in Example 11 to give (RS) -N-methyl-.
S- [2-((2RS, 3RS) -3- (2,4-difluorophenyl) -3-hydroxy-4- (1H-1,
A colorless oil of 2,4-triazol-1-yl) butyl)]-S-methylsulfoximine is obtained.

¹ H-NMR (CDCl ₃ ): δ 1.2
9 (3H, dd, J = 1.3, 7.3Hz), 2.82
(3H, s), 3.09 (3H, s), 3.74 (1
H, q, J = 7.2 Hz), 4.89 (1H, dd, J
= 1.3, 14.2 Hz), 5.30 (1H, d, J =
14.3 Hz), 6.65-6.80 (1H, br),
6.73-6.82 (2H, m), 7.74 (1H,
s), 7.39 (1H, ddd, J = 6.5, 8.4,
9.1 Hz), 7.93 (1 H, s) The product 2p-toluenesulfonate: m.p. p. 70-8
0 ° C. Example 14 (R) -S- [2-((2R, 3R) -3- (2,4-
Difluorophenyl) -3-hydroxy-4- (1H-
1,2,4-triazol-1-yl) butyl)]-S
-Methylsulfoximine and methanesulphonyl chloride were treated as in Example 12 to give (R) -S- [2-
((2R, 3R) -3- (2,4-Difluorophenyl) -3-hydroxy-4- (1H-1,2,4-triazol-1-yl) butyl)]-N-methylsulfonyl-S- Colorless crystals of methyl sulfoximine are obtained.
m. p. 98-100 ° C ¹ H-NMR (CDCl ₃ ): δ 1.34 (3H,
d, J = 7.0 Hz), 3.16 (3H, s), 3.4
2 (3H, s), 4.88 (1H, dq, J = 1.5,
7.0 Hz), 5.00 (1H, d, J = 14.7H
z), 5.48 (1H, d, J = 14.6Hz), 5.
80 (1H, d, J = 2.2 Hz), 6.70-6.8
5 (2H, m), 7.27 (1H, dddlike, J
= 6.2, 9.2, 9.2 Hz), 7.74 (1H,
s), 7.80 (1H, s) Example 15 (1) N-benzyloxycarbonyl-L-proline 1
4.5 mg of 81 mg N, N-dimethylformamide solution
l-N-hydroxybenzotriazole 98 mg under ice cooling
And 162 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride are added and stirred for 30 minutes. (R) -S- [2-((2
R, 3R) -3- (2,4-difluorophenyl) -3
-Hydroxy-4- (1H-1,2,4-triazol-1-yl) butyl)]-S-methylsulfoxiimine (200 mg) is added, and the mixture is stirred for 5 hours while gradually raising the temperature to room temperature. To the reaction mixture are added ice water (30 ml) and saturated aqueous sodium hydrogen carbonate solution (30 ml), and the mixture is extracted with ethyl acetate. After the extract is washed and dried, the solvent is distilled off. By purifying the residue by silica gel column chromatography (solvent; chloroform-methanol),
(R) -N- [L- (N-benzyloxycarbonyl)
Prolyl] -S- [2-((2R, 3R) -3- (2
4-difluorophenyl) -3-hydroxy-4- (1
H-1,2,4-triazol-1-yl) butyl)]
363 mg of -S-methylsulfoximine are obtained as colorless crystals.

M. p. 73-78 ° C (2) Acetic acid 1 was added to a solution of 348 mg of this product in 6 ml of methanol.
Drops and 0.16 g of 10% palladium on carbon. Is added and catalytic reduction is carried out under normal pressure. After filtering the reaction mixture, the solvent is distilled off from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (solvent; chloroform-methanol) to give (R) -S- [2-((2R, 3R)
-3- (2,4-Difluorophenyl) -3-hydroxy-4- (1H-1,2,4-triazol-1-yl) butyl)]-S-methyl-N- (L-prolyl) sulfoximine 162 mg Is obtained as colorless crystals.

M. p. 127-134 ° C Example 16 (R) -S- [2-((2R, 3R) -3- (2,4-
Difluorophenyl) -3-hydroxy-4- (1H-
1,2,4-triazol-1-yl) butyl)]-S
-Methylsulfoximine and 290 mg N-benzyloxycarbonylglycine 220 mg in Example 15-
By treating in the same manner as in (1) and then treating 640 mg of the product in the same manner as in Example 15- (2), (R)-
N-aminoacetyl-S- [2-((2R, 3R) -3
-(2,4-Difluorophenyl) -3-hydroxy-
4- (1H-1,2,4-triazol-1-yl) butyl)]-S-methylsulfoximine 340 mg is obtained as colorless crystals. m. p. 154-160 ° C Example 17 (R) -S- [2-((2R, 3R) -3- (2,4-
Difluorophenyl) -3-hydroxy-4- (1H-
1,2,4-triazol-1-yl) butyl)]-S
-Methyl sulfoximine 100 mg and glycolic acid 2
8 mg was treated in the same manner as in Example 15- (1) (R)
-S- [2-((2R, 3R) -3- (2,4-difluorophenyl) -3-hydroxy-4- (1H-1,
2,4-triazol-1-yl) butyl)]-N-hydroxyacetyl-S-methylsulfoximine 90m
g are obtained as colorless crystals. m. p. 125-128 ° C Example 18 (R) -S- [2-((2R, 3R) -3- (2,4-
Difluorophenyl) -3-hydroxy-4- (1H-
1,2,4-triazol-1-yl) butyl)]-S
-Methylsulfoxyimine (150 mg) and glutaric acid monobenzyl ester (121 mg) were used in Example 15- (1).
Treated in the same manner as described above, then 204 mg of product
-By treating in the same manner as (2), (R) -N- (4
-Carboxybutyryl) -S- [2-((2R, 3R)
-3- (2,4-Difluorophenyl) -3-hydroxy-4- (1H-1,2,4-triazol-1-yl) butyl)]-S-methylsulfoximine 157m
g are obtained as colorless crystals.

M. p. 39-49 ° C Example 19 (R) -S- [2-((2R, 3R) -3- (2,4-
Difluorophenyl) -3-hydroxy-4- (1H-
1,2,4-triazol-1-yl) butyl)]-S
-Methylsulfoximine 200 mg and N-benzyloxycarbonyl-L-aspartic acid benzyl ester 260 mg were treated as in Example 15- (1), then 347 mg of the product was treated as in Example 15- (2). (R) -N-[(S)-(3-amino-3-carboxy) propionyl] -S- [2-((2
R, 3R) -3- (2,4-difluorophenyl) -3
200 mg of -hydroxy-4- (1H-1,2,4-triazol-1-yl) butyl)]-S-methylsulfoximine are obtained as colorless crystals. m. p. 137-1
41 ° C. (decomposition) Example 20 S- [2-((2RS, 3RS) -3- (2,4-difluorophenyl) -3-hydroxy-4- (1H-1,
2,4-Triazol-1-yl) butyl)]-S-methylsulfoxide (200 mg) was added to methylene chloride (3 ml) at room temperature, and mesitylsulfonyloxyamine (370 mg) was added thereto, and the mixture was stirred for 7 hours.

To the reaction mixture was added 6% of 10% aqueous sodium hydroxide solution under ice cooling, and the mixture was extracted with methylene chloride and ethyl acetate. The extracts are combined, washed and dried, and then the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent; ethyl acetate-methanol) to give (SR) -S- [2-((2RS, 3RS) -3.
-(2,4-Difluorophenyl) -3-hydroxy-
4- (1H-1,2,4-triazol-1-yl) butyl)]-S-methylsulfoximine is obtained as a colorless caramel-like substance (100 mg).

¹ H-NMR (CDCl ₃ ): δ 1.3
5 (3H, dd, J = 0.9, 7.0Hz), 3.0-
3.3 (1H, br), 3.74 (1H, q, J = 7.
0 Hz), 5.03 (1H, dd, J = 1.6, 14.
5Hz), 5.47 (1H, d, J = 14.4Hz),
6.67 (1H, brs), 6.70-6.83 (2
H, m), 7.34 (1H, ddd, J = 6.5, 9.
0, 9.2 Hz), 7.66 (1H, s), 7.94
(1H, s) Reference Example 1 (2R, 3S) -2- (2,4-difluorophenyl)
-3-Methyl-2-[(1H-1,2,4-triazol-1-yl) methyl] oxirane 7.00 g of N, N
-Add 20 ml of 15% methyl mercaptan sodium salt aqueous solution to 20 ml of dimethylformamide solution, and add 75 ° C.
Stir for 3 hours. After cooling the reaction mixture, ice water is added and the mixture is extracted with ethyl acetate. After washing and drying the extract, the solvent is distilled off under reduced pressure. The residue was crystallized from diisopropyl ether to give (2R, 3R) -3-methylthio-2.
-(2,4-difluorophenyl) -1- (1H-1,
2.39 g of 2,4-triazol-1-yl) -2-butanol are obtained as colorless crystals. m. p. 137-1
39 ° C. Reference Example 2 To a suspension of 60% oily sodium hydride (0.54 g) in N, N-dimethylformamide (5 ml) was added benzylmercaptan (1.59 ml) under ice-cooling, and the mixture was stirred for 30 minutes.
Under ice cooling (2RS, 3SR) -2- (2,4)
-Difluorophenyl) -3-methyl-2-[(1H-
1,2,4-triazol-1-yl) methyl] oxirane 1.70 g N, N-dimethylformamide solution 9
After dropwise adding ml, the mixture is stirred at room temperature for 30 minutes. Ice water and saturated brine are added to the reaction solution, and the mixture is extracted with ethyl acetate. After the extract is washed and dried, the solvent is distilled off. By purifying the residue by silica gel column chromatography (solvent; chloroform-ethyl acetate), (2RS, 3RS)-
2.22 g of 3-benzylthio-2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) -2-butanol are obtained as a colorless oil.

Reference Example 3 A solution of 9.01 g of N-chloro-p-toluenesulfonamide sodium salt in 50 ml of methanol (2R, 3
R) -2- (2-, 4-Difluorophenyl) -3-methylthio-1- (1H-1,2,4-triazole-1
100 ml of a methanol solution of 4.79 g of -yl) -2-butanol was added dropwise at room temperature, followed by stirring for 2 hours. A 5% aqueous sodium hydroxide solution and water are added to the reaction solution under ice cooling, and the mixture is extracted with chloroform. After the extract is washed and dried, the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; chloroform: methanol) to give S- [2-((2R, 3R) -3- (2,4-
Difluorophenyl) -3-hydroxy-4- (1H-
1,2,4-triazol-1-yl) butyl)]-S
-Methyl-N-((4-methylphenyl) sulfonyl)
5.91 g of sulfilimine are obtained as a colorless caramel.

¹ H-NMR (CDCl ₃ ): δ 1.1
9 (3H, d, J = 7.1Hz), 2.42 (3H,
s), 2.70 (3H, s), 3.81 (1H, dd)
q, J = 0.7, 0.7, 7.0 Hz), 5.01 (2
H, s), 5.76 (1H, d, J = 2.2 Hz),
6.70-6.83 (2H, m), 7.19 (1H.d)
dd, J = 6.2, 8.9, 8.9 Hz), 7.28
(2H, dlike, J = 8.4 Hz), 7.81 (1
H, s), 7.82 (1H, s), 7.83 (2H, d
like, J = 8.4 Hz) Reference Examples 4 to 9 (1) The corresponding compounds are treated in the same manner as in Reference Example 1 or 2 to obtain the compounds shown in Table 8 below.

[0080]

[Table 8]

(2) The corresponding compound is treated in the same manner as in Reference Example 3 to obtain the compounds shown in Tables 9 to 11 below.

[0082]

[Table 9]

[0083]

[Table 10]

[0084]

[Table 11]

Reference Example 10 (1) (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-2-[(1H-1,2,4-triazol-1-yl) methyl] Oxirane and 2-mercaptoethanol were treated as in Reference Example 1 (2R,
3R) -2- (2,4-difluorophenyl) -3-
(2-hydroxyethyl) thio-1- (1H-1,2,2
Colorless crystals of 4-triazol-1-yl) -2-butanol are obtained.

M. p. 90-91 ° C. (2) 60% oily sodium hydride under cooling in 40 ml of a solution of 7.74 g of this product in N, N-dimethylformamide.
Add 94 g and stir for 30 minutes. To this mixture was added 2.9 ml of methyl iodide, and the mixture was stirred for 1 hour under ice cooling.
Saturated saline is added to the reaction mixture, and the mixture is extracted with ethyl acetate. After washing and drying the extract, the solvent is distilled off under reduced pressure. By purifying the residue by silica gel column chromatography (solvent; chloroform-methanol), (2
R, 3R) -2- (2,4-difluorophenyl) -3
-(2-Methoxyethyl) thio-1- (1H-, 1,
6.27 g of colorless crystals of 2,4-triazol-1-yl) -2-butanol are obtained.

M. p. 52-54 ° C (3) This product was treated in the same manner as in Reference Example 3 to give S- [2-
((2R, 3R) -3- (2,4-Difluorophenyl) -3-hydroxy-4- (1H-1,2,4-triazol-1-yl) butyl)]-S- (2-methoxyethyl ) -N- (p-toluenesulfonyl) sulfilimine (α-form) and its corresponding diastereomer (β-form) are obtained.

Α-form: m. p. 129-131 ° C. ¹ H-NMR (CDCl ₃ ): δ 1.19 (3H,
d, J = 7.1 Hz), 2.41 (3H, s), 2.9
3-3.01 (1H, m), 2.99 (3H, s),
3.30-3.46 (2H, m), 3.54-3.60
(1H, m), 3.83 (1H, brq, J = 7.3H
z), 5.06 (1H, d, J = 14.3Hz), 5.
12 (1H, d, J = 14.6Hz), 5.77 (1
H, d, J = 2.2 Hz), 6.70-6.82 (2
H, m), 7.22 (1H.ddd, J = 6.4, 8.
9,8.9 Hz), 7.29 (2H, dlike, J =
8.1 Hz), 7.80 (1 H, s), 7.84 (1
H, s), 7.86 (2H, dlike, J = 8.3H
z).

Β-form: colorless oil ¹ H-NMR (CDCl ₃ ): δ 1.28 (3H, d
d, J = 0.7, 7.0 Hz), 2.40 (3H,
s), 3.11 (3H, s), 3.16 (1H, dd)
d, J = 3.1, 3.1, 12.9 Hz), 3.29
(1H, ddd, J = 4.1, 10.5, 12.9H
z), 3.48 (1H, ddd, J = 2.9, 10.
1,10.1 Hz), 3.62 (1H, ddd, J =
3.9, 3.9, 10.7 Hz), 3.81 (1H, b
rq, J = 7.0 Hz), 4.84 (1H, d, J = 1)
4.3Hz), 5.00 (1H, d, J = 14.2H
z), 5.66 (1H, s), 6.73 (1H, dd
d, J = 2.6, 8.4, 12.3 Hz), 6.78-
6.86 (1H, m), 7.27 (2H, dlike,
J = 8.1 Hz), 7.52 (1H, ddd, J = 6.
5,9.1,9.1 Hz), 7.70 (1H, s),
7.82 (2H, dlike, J = 8.3 Hz), 7.
87 (1H, s) Reference Examples 11 to 13 The corresponding compounds are treated in the same manner as in Reference Example 10 to obtain the compounds shown in Table 12 below.

[0090]

[Table 12]

Reference Example 14 (2RS, 3RS) -2- (2,4-Difluorophenyl) -3-methylthio-1- (1H-1,2,4-triazol-1-yl) -2-butanol 3. 20 ml of a chloroform solution of 2.52 g of m-chloroperbenzoic acid was added to a 20 ml solution of 50 g of chloroform under ice cooling, and the mixture was stirred for 40 minutes. The reaction mixture is diluted with chloroform, washed and dried, and then the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent; chloroform-methanol) to give S- [2-((2RS,
3RS) -2- (2,4-difluorophenyl) -3-
Hydroxy-4- (1H-, 1,2,4-triazol-1-yl) butyl)]-S-methyl sulfoxide (α
Body, 1.12 g, m.p. p. 161-164 ° C.) and its diastereomer (β form, 1.67 g, mp. 159)
Colorless crystals (-161 ° C.) are obtained.

[0092]

INDUSTRIAL APPLICABILITY The triazole derivative [I] and its pharmacologically acceptable salts, which are the objects of the present invention, have excellent antibacterial activity against a wide variety of fungi such as Candida, Aspergillus and Cryptococcus. . For this reason,
It is useful as a prophylactic / therapeutic agent for diseases such as fungalemia due to infection with these fungi, pulmonary mycosis, gastrointestinal mycosis, urinary mycosis, fungal meningitis.

Further, since the object [I] of the present invention contains a compound exhibiting a strong antifungal activity even in a mouse immunosuppressive model, it is also an excellent pharmaceutical compound for the prevention / treatment of mycosis in immunocompromised patients. I will get it.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Motoaki Ohashi 4-9-2 Maehara-cho, Koganei-shi, Tokyo

Claims (13)

[Claims] 1. A compound represented by the general formula [I]: (In the formula, Ar is a phenyl group having 1 to 2 substituents,
R ¹ is a lower alkyl group, R ² is a lower alkyl group or a lower alkoxy lower alkyl group, R ³ is a (1) hydrogen atom,
Lower alkyl group, phenyl lower alkyl group, (2) lower alkanoyl group optionally having 1 to 2 substituents selected from the group consisting of amino group, hydroxyl group and carboxyl group, (3) lower alkylsulfonyl group Represents an arylsulfonyl group or (4) pyrrolidinylcarbonyl group. ] The triazole derivative shown by these, or its pharmacologically acceptable salt. 2. The compound according to claim 1, wherein R ³ is a hydrogen atom. 3. Ar is a phenyl group having 1 to 2 substituents selected from a halogen atom and a halogeno lower alkyl group, R ² is a lower alkyl group, and R ³ is a (1) lower alkyl group or Phenyl lower alkyl group,
(2) a lower alkanoyl group optionally having 1 to 2 substituents selected from the group consisting of an amino group, a hydroxyl group and a carboxyl group, (3) a lower alkylsulfonyl group, an unsubstituted or lower alkyl substituted phenylsulfonyl group The compound according to claim 1, which is a group or (4) pyrrolidinylcarbonyl group. 4. Ar is a dihalogenophenyl group and R
The compound according to claim 2, wherein ² is a lower alkyl group. 5. R ³ is a lower alkanoyl group optionally having 1 to 2 substituents selected from the group consisting of an amino group, a hydroxyl group and a carboxyl group, a phenyl lower alkyl group, a lower alkylsulfonyl group, The compound according to claim 3, which is an unsubstituted or lower alkyl-substituted phenylsulfonyl group or a pyrrolidinylcarbonyl group. 6. Ar is a 2,4-dihalogenophenyl group,
The compound according to claim 1, wherein R ¹ is a lower alkyl group, R ² is a lower alkyl group, and R ³ is a hydrogen atom. 7. (1) General formula [II]: (In the formula, Ar is a phenyl group having 1 to 2 substituents,
R ¹ represents a lower alkyl group, R ² represents a lower alkyl group or a lower alkoxy lower alkyl group, and R ³¹ represents a hydrogen atom, a lower alkylsulfonyl group or an arylsulfonyl group. ) Is oxidized to give a compound of the general formula [Ia] (Wherein the symbols have the same meanings as described above), and then, if desired, the compound (Ia) (2).
When the group R ^{31 of} is a lower alkylsulfonyl group or an arylsulfonyl group, the group is removed to remove the compound of the general formula [Ib] (Wherein the symbols have the same meanings as described above), the compound [Ib] and the general formula [III] R ^32- X ¹ [III] (wherein R ³² is A lower alkyl group, a phenyl lower alkyl group, a lower alkylsulfonyl group or an arylsulfonyl group, X ¹ represents a reactive residue) or a compound of the general formula [IV] R ³³ OH [IV] (wherein R is ³³ is a lower alkanoyl group optionally having 1 to 2 substituents selected from the group consisting of an optionally protected amino group, an optionally protected hydroxyl group and an optionally protected carboxyl group. Or a pyrrolidinylcarbonyl group) or a reactive derivative thereof, and then, if necessary, the protecting group is removed from the product of the general formula [I] ] (In the formula, R ³ has 1 to 2 substituents selected from the group consisting of (1) hydrogen atom, lower alkyl group, phenyl lower alkyl group, (2) amino group, hydroxyl group and carboxyl group; Represents a lower alkanoyl group, (3) lower alkylsulfonyl group, arylsulfonyl group or (4) pyrrolidinylcarbonyl group, and other symbols have the same meanings as described above.). 8. (1) General formula [V]: (In the formula, Ar is a phenyl group having 1 to 2 substituents,
R ¹ represents a lower alkyl group, and R ² represents a lower alkyl group or a lower alkoxy lower alkyl group. ) And the sulfur atom of the compound [V] is represented by the formula: NR ³¹ (wherein
R ³¹ represents a hydrogen atom, a lower alkylsulfonyl group or an arylsulfonyl group. ) Is reacted with an imino group (or substituted imino group) donor compound capable of adding a group represented by the formula (Wherein the symbols have the same meanings as described above), and then, if desired, the compound (Ia) (2).
When the group R ^{31 in} is a lower alkylsulfonyl group or an arylsulfonyl group, the group is removed to remove the compound of the general formula [Ib] (Wherein the symbols have the same meanings as described above), the compound [Ib] and the general formula [II
I] R ^32- X ¹ [III] (wherein, R ³² represents a lower alkyl group, a phenyl lower alkyl group, a lower alkylsulfonyl group or an arylsulfonyl group, and X ¹ represents a reactive residue.) Alternatively, a compound of the general formula [IV] R ³³ OH [IV] (In the formula, R ³³ is selected from the group consisting of an optionally protected amino group, an optionally protected hydroxyl group and an optionally protected carboxyl group. A lower alkanoyl group which may have 1 to 2 substituents or a pyrrolidinylcarbonyl group) or a reactive derivative thereof, and then, if necessary, protected from the product. The general formula [I] is characterized in that the group is removed. (In the formula, R ³ has 1 to 2 substituents selected from the group consisting of (1) hydrogen atom, lower alkyl group, phenyl lower alkyl group, (2) amino group, hydroxyl group and carboxyl group; Represents a lower alkanoyl group, (3) lower alkylsulfonyl group, arylsulfonyl group or (4) pyrrolidinylcarbonyl group, and other symbols have the same meanings as described above.). 9. The imino group (or substituted imino group) -donating compound is a compound selected from lower alkylsulfonyl azide, arylsulfonyl azide, N-halogeno-arylsulfonamide alkali metal, arylsulfonyloxyamine and hydrogen nitride. 8. The production method according to 8. 10. A compound represented by the general formula [II]: (In the formula, Ar is a phenyl group having 1 to 2 substituents,
R ¹ represents a lower alkyl group, R ² represents a lower alkyl group or a lower alkoxy lower alkyl group, R ³¹ represents a hydrogen atom, a lower alkylsulfonyl group or an unsubstituted or lower alkyl-substituted phenylsulfonyl group. ) The triazole derivative shown by. 11. A compound represented by the general formula [VII]: (In the formula, Ar is a phenyl group having 1 to 2 substituents,
R ¹ lower alkyl and R ² represent a lower alkyl group or a lower alkoxy lower alkyl group. ) And the sulfur atom of the compound [VII] on the sulfur atom of formula NR ³⁴ (wherein
R ³⁴ represents a lower alkylsulfonyl group or an arylsulfonyl group. ) The compound represented by the general formula [II] is characterized by reacting with a substituted imino group-donating compound capable of adding a group represented by (In the formula, R ³¹ represents a hydrogen atom, a lower alkylsulfonyl group or an arylsulfonyl group, and other symbols have the same meanings as described above.). 12. The method according to claim 11, wherein the substituted imino group-donating compound is a compound selected from lower alkylsulfonyl azide, arylsulfonyl azide and N-halogeno-aryl sulfonamide alkali metal. 13. The method according to claim 12, wherein the alkali metal N-halogeno-arylsulfonamide is N-chloro-p-toluenesulfonamide sodium salt.