JPS60136570A - 1,2,4-triazolylpropanol - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R is 5C alkyl) and an acid addition salt thereof. EXAMPLE:2-(2,4-Dichlorophenyl)3-n-pentylsulfinyl-1-(1,2,4-triazol-1-yl )-propan-2-ol. USE:An antifungal agent. PREPARATION:A compound expressed by formula II is reacted with a compound expressed by formula III (M1 is alkali metal atom) in a solvent, e.g. tetrahydrofuran (THF) or dimethylformamide (DMF), at 10-60 deg.C to afford a compound expressed by formula IV, which is then oxidized with m-chloroperbenzoic acid, etc. as an oxidizing agent in a solvent, e.g. a halogenated hydrocarbon, at 0 deg.C- room temperature to give the aimed compound expressed by formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 1,2,4-triazolyl propatols represented by the general formula (41 () [in the formula, 几 represents an alkyl group consisting of 5 carbon atoms] and The present invention relates to an acid addition salt thereof and an antifungal agent containing it as an active ingredient.

In the general formula (1), the alkyl group having 5 carbon atoms is an n-pentyl group, 1so-pentyl group, 5ee-pentyl group, tCrt-pentyl group, ■-methylbutyl group,
It represents a linear or branched alkyl group having 5 carbon atoms, such as a 2-methylbutyl group or a 2,2-dimethylpropyl group.

The compound of the present invention has at least two asymmetric centers, and diastereomers of 2' Pi or more exist, which can be separated by conventional methods such as chromatography.

Each diastereomer can be further divided into optically active forms by conventional techniques. The present invention encompasses both the state in which these stereoisomers are separated and the state in which they are not separated.

l represented by general formula (1), which is a compound of the present invention.

2.4-Triazolylpropertools were first produced by the present inventors and are particularly effective drugs against fungal diseases in animals including humans.

Fungal infections have increased rapidly in recent years and have become a medical problem. In particular, deep-seated mycoses have rapidly increased with the spread of antibacterial agents, and opportunistic infections caused by fungi that are not originally pathogenic have become frequent. Father's cancer, leukemia,
Hakama is not used when anti-cancer drugs or immunosuppressive drugs are administered to treat various immune diseases, but when fungal diseases occur, which in fact becomes the direct cause of death.

Amphoterici is currently used as a treatment for deep mycosis: /
Amphotericin B (Amphotericin B) and the like have been used, but they have serious problems such as toxicity, and their use is severely restricted. In addition, regarding griseofulvin, which is used as an oral treatment for superficial mycosis caused by mycobacteria,
Since its carcinogenicity has been recognized and its use has become restricted, there is a desire for an alternative antifungal agent that can be taken orally.

Against this background, research on azole synthetic antifungal agents has been actively conducted in recent years. Recently, ketoconazole (toconazole) has been attracting attention as it has been commercially available in Europe and America as an oral antifungal agent. The main feature is that it can be administered orally, has a wide antifungal spectrum, and is far less toxic than the aforementioned amphotericin B. However, it is difficult to say that the drug is necessarily satisfactory in principle. When used in humans, hepatotoxicity is a problem, and it is difficult to say that the efficacy is sufficient. Therefore, there is a strong desire to develop antifungal agents that have even stronger antifungal activity and lower toxicity.

In view of these circumstances, the present inventors conducted intensive studies with the aim of developing an orally administrable antifungal agent, and as a result, the present invention 1,2゜4-triazolyl propazole represented by the general formula (1) in Fail. It was discovered that the genus has a broad antifungal spectrum and strong anti-Al activity against medically important fungi such as Candida, Aspercillus, Trichophyton, and Cryptococcus, and that the effect is significant when administered continuously. Furthermore, it was discovered that the compound of the present invention not only has high antifungal activity, but also has an excellent % & of low toxicity in terms of toxicity such as acute toxicity and effects on the liver, and completed the present invention. I came to the conclusion. That is, the compound of the present invention is useful as an antifungal agent with a high chemotherapeutic index.
As related compounds of the compound of the present invention represented by the general formula (1), JP-A-58-185571 discloses a group of compounds including the compound of the present invention. 8-Methylsulfonyl-2-(2,4-dichlorophenyl)-1-(
1-1,2,4-triazol-1-yl)propan-2-ol is disclosed as the most preferred compound. However, there is no specific description of the compound of the present invention, and there is no description that the compound of the present invention has particularly excellent antifungal activity. The present inventors further investigated and found that the compound of the present invention has the above 3-methylsulfonyl-
2-(2,4-dichlorophenyl)-1-(l■-1,
It has been found that it not only has stronger antifungal activity than 2,4-1-riazol-1-yl)propan-2-ol, but also has excellent characteristics of far lower toxicity. In addition, the 8-methylsulfonyl-2
-(2,4-dichlorophenyl)-1-(In-1,2
, 4-triazol-1-yl)propan-2-ol is a sulfonyl compound, whereas the compound of the present invention has the structural feature of being a sulfinyl compound. Surprisingly, the antifungal activity of the sulfonyl compound corresponding to the compound of the present invention was much weaker than that of the sulfinyl compound of the compound of the present invention.

The compound of the present invention can be produced, for example, by the following two methods.

The first method is shown by the following equation.

(4) [In the formula, Ntl represents an alkali metal atom, and the atom is as described above. ] Examples of the alkali metal atoms include sodium, potassium, and lithium.

That is, the sulfide compound represented by the general formula (4) can be produced by reacting the epoxy derivative represented by the formula (2) with the alkali metal salt of the thiol derivative represented by the general formula (3) in a solvent. . Furthermore, 1,,2,4-triazolyl propatols represented by general formula (1) can be produced by oxidizing the sulfide compound represented by general formula (4).

Examples of solvents used in the production of the sulfide compound represented by the general formula (4) include ether solvents such as tetrahedron, dimethylformamide, etc., but are not particularly limited to these3. ℃ to the PN point of the leech, preferably 10℃ to 60℃
It is. Thiol derivative (3) is 1 for compound (2)
Preferably, ~2 equivalents are used.

The raw material compound represented by formula (2) used in this reaction is known.

'Next, the oxidation reaction of the compound represented by general formula (4) is carried out at -80°C to the boiling point of the solvent, preferably at 0°C to room temperature. The oxidizing agent used in this case is, for example, a peracid such as 111-chloroperbenzoic acid, and is usually used in an amount of about Is based on compound (4). Further, as the reaction solvent, halogenated hydrocarbons such as chloroform are used, but the reaction solvent is not particularly limited thereto.

The second method is shown by the following equation.

CI! (5) ((i+ (8) [In the formula, M2 represents an alkali gold mine atom, and 几 is as described above.] Examples of the alkali metal atom include sodium and potassium.

The compound represented by the general formula (7) is prepared by combining the ketone compound represented by the general formula (5) and the dimethyloxosulfonium methylide of the formula (6) in a solvent such as dimethyl sulfoxide at a temperature of 30°C to 60°C. It can be produced by reaction. The amount of dimethyloxosulfonium methylide used is ˜5 equivalents, preferably ˜2 equivalents, relative to the ketone compound. Then the compound (
A sulfide compound represented by general formula (4) can be produced by reacting 7) with an alkali q&Fli of a 1,2,4-triazole derivative represented by general formula (8) in a solvent. The amount of alkali metal salt used is 1 to 5 equivalents, preferably 1 to 3 equivalents, based on compound (7). Furthermore, compound (1) can be obtained by oxidizing compound (4) in the same manner as the method described in Flit's No. 1 method.

The solvent used for producing the sulfide compound represented by the general formula (4) includes, for example, dimethylformamide, but is not particularly limited thereto. The reaction temperature is from room temperature to the boiling point of the solvent, preferably 7
It is carried out at 0°C to 120°C.

The raw material compound represented by the general formula (5) can be obtained by a known method [U.S. Patent No. 4,128,581 specification (1978
)] can be easily manufactured.

Acid addition salts of the compound of general formula (1) are physiologically acceptable acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid,
These are salts of salicylic acid, sorbic acid, lactic acid, etc., and such acid addition salts can be obtained by conventional general methods, if necessary.

The compound of the present invention is used alone or in combination with other excipients, diluents, dispersants, and other additives in the form of a dosage form for oral or parenteral administration. Such dosage forms include solutions, suspensions, powders, and more! ! l'1
Examples include granules, capsules, tablets, injections, ointments, tinctures, etc., and these preparations can be prepared according to conventional methods for formulation.

The dose and frequency of administration vary depending on symptoms, age, body weight, administration form, etc., but in the case of oral administration, the dose is usually 50 to 2000 η per day for adults, preferably 100 to 6 Q.
It is possible to administer (lmy) in one or several doses.

The present invention will be explained in more detail with reference to examples and examples.

Reference example 1 (30% sodium hydride 0.89/(22.2mm
ol) was added to dimethylformamide 20-. Next was ice-cold Fl-pentanethiol 2.75+++7! (
22,2+W1T10I) was added dropwise. Then 2-(2
,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)methylφ oxirane 8.0 y-(11,1mrnol)
Dimethylformamide 5-solution was added dropwise. 8 at room temperature
After stirring for an hour, the solvent was distilled off, water was added, and the mixture was extracted with chloroform. After washing with water, it was dried with magnesium sulfate. The oil obtained by adding chloroform was subjected to silica gel column chromatography. Chloro [eluted with J form,
Oily 2-(2,4-dichlorotubonyl)-B-11-
Pentylthio-1-(1,2,4-triazole-1-
yl)-propan-2-ol was obtained. 8.89P (yield 81.5%) N13 (CDCI!3) δ: o, s6
<su, t), t, o ~ 1.6 (6111, m),
2.25 (2El, t), 2.90 and 8.
64 (respectively in, d, J=14 Fiz), 4.60 (
lI(,S), 4.70 and 5.0 (IEI, respectively)
d, J==14fiz), 7.12~7.70
(8H, m), 7.80 and 8.00 (1I each
li, s) Motoichi was made into a sulfate salt to obtain a salt with a melting point of 88-86°C.

Example 1 2-(2,4-dichlorophenyl)-8-11-pentylthio-1-(1,2,4-triazol-1-yl)
-Propan-2-ol 1.46 F (8,9 m1n
A small amount of nl-chloroperbenzoic acid (0.67y-(3,g+n+nol)) was added to a solution of 0.67y-(3,g+n+nol) and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water, made basic with aqueous ammonia, extracted with chloroform, washed with water, and dried over magnesium sulfate. The oil obtained by distilling off the chloroform was subjected to silica gel column chromatography.

(A) Elution with chloroform gave an oily substance. The oily substance was made into an oxalate salt with an oxalic acid-ether solution in ether, and the melting point was 6.
2-(2゜4-dichlorophenyl)-3 at 5-68℃
-n-pentylsulfinyl-1-(1,2,4-triazol-1-yl)-propan-2-ol oxalate (IA) was obtained. 0.84 P (yield 44.8%) (B) Further elution with chloroform resulted in a melting point of 117-1
1,0.8 diastereomer (lB) obtained at 19°C
g- (yield 19.7%) Reference example 2 60% sodium hydride 2.97y-(7,i, 2mm
7.7 B P (74.2 mmol) was added dropwise to 60 nrl of dimethylformamide.

After stirring at room temperature for 1 hour, cool with water 2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)
Methyl-oxirane 10.02y-(37.1mmol
15 mg of dimethylformamide solution of ) was added dropwise.

After stirring at room temperature for 3 hours, the reaction solution was poured into ice water. Sodium chloride was added and extracted with ether. After washing with an aqueous sodium chloride solution, it was dried with red sea bream sulfate and sium. The oil obtained by distilling off the ether was subjected to medium pressure preparative chromatography.

Elution with chloroform yielded an oily 2-(2,4ert-diglophenyl)-B-11pentylthio-1-(
1,2,4-triazol-l-yl)-propane-2
- Got oar.

lt, 4oy (yield 82.1%) NMIL (CDCl3) δ: 0.80-1.69
(l IH, m).

2.88 and 8.62 (1B, d, ,T-ta respectively
■z ) + 4°8B (In, S), 4.81 and 4.97 (In, d,, 1=1411z, respectively).

7.12-7.68 (3If, m), 7.82 and 8
．． 07 (lli, s respectively) Example 2 2-(2,4-dichlorophenyl)-8-azole-1
-yl)-propane-2-o, TI/ 11.40
To a solution of P ("a 0.5 nlr" 0]) dissolved in chloroform 84 me, m-chloroperbenzoic acid 5.26Si'- (80.5 mmol) was added little by little under ice cooling, and 1.5 mmol was added at room temperature. I stirred the clock. Thereafter, the reaction solution was poured into ice water, made basic with aqueous ammonia, extracted with chloroform, washed with water, and dried over magnesium sulfate. The oily substance obtained by distilling off chloroform was subjected to medium pressure preparative chromatography, and chloroform:methanol=50
: It was eluted with a solution of 1 to obtain an oily substance.

After adding n-hexane to the oil and crystallizing it, the n-hexane-ethyl acetate mixture was recrystallized to give a melting point of 112.5-1.
2-(2,4eit-dichlorophenyl)-8-◆-pentylsulfinyl-1-(1,2,4-triacyl-l-yl)-propan-2-ol (2 people) at 14.5°C was obtained. Ta. 5.865' (yield 49.8cm) NMIL (CD(3za)δ: o, s
o ~1.68 (11)1. ff1).

2.58 and 8.88 (IH, d, J = 1311 respectively
z), 4.42 (IH, d, J=14Hz)
.

4.94 (in, d, d, J=14Hz, J=2Hz)
, 5.91 (111, d, J = 2fiz).

7.28-7.46 (2R, m), 7.89 (1H.

d.

Table 1 Antifungal activity (in vivo test) [Experimental method] Cancita albica precultured at 80°C for 4 days (andida albioans) KB -
8 strains were suspended in physiological saline and inoculated into male DDY mice (5 weeks old: 10 mice per group) by venous inoculation with 10 cells per mouse. Infection 0, 5, 24.48 A dose of 20 η/Kf of the drug suspended in 0.51 methylcellulose is orally administered over 4 hours after the infection, and survival is monitored for 10 days after infection. The results were expressed as the average survival days of 10 animals in each group and compared with the no-medication group (control).

〔Experimental result〕

Table 2 shows the in vivo activity against Cancita albicans of representative compounds of the present invention and the compounds of JP-A-185571.
.

Activity) Φ 0 Japanese Patent Publication No. 58-18557 Compound Test Example 2 Activity against Aspercillus fumicates and Cryptococcus neoformasis [Experimental Method] Aspergillus fumigates (Aspergi l1us I'umigaLus) pre-cultured at 80°C for 4 days
) MTIJ 16001 strain or Urypcococcus neofofo
rytans) M i' U IB g 01 strain was suspended in physiological saline and divided into 1 group of 10 LIDY male mice.
2 cells per animal (5 weeks old, N24-272)
Inoculate and infect 10× tail veins. Infection 0
．． 5,24° 4 times after 48 hours, drug 2otay/Kglk'x suspended in 0.5% methylcellulose
Administer orally and monitor survival for 10 days after infection.

Results are expressed as mean survival days and no medication group (Con I/Role)
compared with.

〔Experimental result〕

Table 8 shows the compound of the present invention (2A) and JP-A-58-1855.
No. 71 Compound Ridge” (D)
It showed activity.

Table-3 In vivo activity acute toxicity test against Aspercillus fumigates and Crybutococcus neoformasis Each drug suspended in 0.5% methylcellulose was tested using DIJY.
In the system, sex mice (5 weeks old; 10 mice in group ■) were given a common ratio of 18 to 5.
The dose was administered orally and symptoms were observed. LDso was calculated by the Probit method from the mortality rate 7 days after administration.

Table 4 shows the pulp.

Table 4 Test Example 4 Measured weight increase test during continuous oral administration [Experimental method] 1) Cancita albicans KB-B was added to DY male and female mice (5 weeks old; 20 mice per group) at a concentration of 2 cells per mouse.
The mice were infected by intravenously inoculating 105 mice at a time, and the drug suspended in 0.5% methylcellulose was administered orally once a day from the day of infection, and the weight of surviving mice was measured 20 days later.

〔Experimental result〕

The test results are shown in Table-5.

Table 5 As shown in Table 4, no increase in the measured weight of IA was observed when the dose was less than 4 μ/Kf.

On the other hand, the compound of JP-A No. 58-185571 is 1.0 kg/
A significant increase in measured weight was observed above Kf.

Claims (2)

[Claims] (1) In General Formula 1, 1L represents an alkyl group having 5 carbon atoms. 1,2,4-triazolyl propatools represented by J or acid addition salts thereof (2) General formula C In the formula, R represents an alkyl group having 5 carbon atoms. ] An antifungal agent containing 1,2,4-triazolylpropertools represented by or its acid addition salt as an f11 component.