JP3030780B2 - Optically active ketene dithioacetal derivative and method for producing the same - Google Patents

Description

The present invention relates to an optically active ketene dithioacetal derivative having antifungal activity and a pharmaceutically acceptable salt thereof.

Formula (I): The compound represented by is a compound described in JP-A-60-218387, and JP-A-62-93227 describes that it is useful as an antifungal agent.

Since the compounds of formula (I) have one asymmetric carbon atom, optical and stereoisomers may exist. However,
The publication does not describe these isomers.

The present inventors have examined the pharmacological action of the optically active form of the above compound and found that the (+) enantiomer has remarkably stronger antifungal activity than the (-) enantiomer, and completed the present invention.

The compound of the present invention can be produced by the following method using an optically active starting compound.

(In the formula, M represents an alkali metal atom, R represents a methanesulfonyl group, a benzenesulfonyl group, or a p-toluenesulfonyl group, and ^* C represents an asymmetric carbon atom.) 1- represented by the structural formula (VII) Reaction of cyanomethylimidazole with carbon disulfide in the presence of a base and a solvent to give an intermediate represented by the structural formula (III), without isolation of the intermediate represented by the compound represented by the general formula (II) To give a compound represented by the formula (I).

The solvent that can be used in the present invention may be any solvent that does not inhibit the progress of this reaction. For example, alcohols such as methanol, ethanol, and isopropanol: polar solvents such as dimethyl sulfoxide, dimethylformamide, and hexamethylene phosphoramide: water and These mixed solvents can be used.

Bases that can be used in this reaction include sodium carbonate,
Examples thereof include potassium carbonate, sodium hydroxide, potassium hydroxide, and potassium tert-butoxide. These can be used as a solid or can be used by dissolving in a solution.

The reaction temperature may be selected from the range of 0 to 80 ° C.,
In particular, it is desirable to perform the process at around room temperature.

The reaction time may be appropriately selected from the range of 0.5 to 24 hours.

The amount of the base used may be selected from the range of 2 to 4 moles per mole of the compound represented by the structural formula (VII). The compound of the formula (II) is used in an equimolar amount or a slight excess with respect to the compound of the formula (VII).

Methods for separating the resulting mixture of geometric isomers and isolating the desired compound include silica gel column chromatography and fractional crystallization. Examples of the solvent used in the fractional crystallization method include, but are not particularly limited to, ethanol, ethyl acetate, ether, hexane, acetonitrile, and acetone. When sufficient purity cannot be obtained by the fractional crystallization method, a pure optically active substance can be isolated by recrystallization from the solvent used in the fractional crystallization method.

The compound of the formula (II) used in this reaction is obtained by reacting the compound of the formula (IV) with the compound of the formula (V) in a suitable solvent in the presence of a base.

(Wherein R is the same as above) Examples of the reaction solvent used in the present reaction include ethers such as tetrahydrofuran and diethyl ether; and organic chlorine-based solvents such as dichloromethane and chloroform.
It is not particularly limited to this. Examples of the base include pyridine, triethylamine, N, N-diethylaniline and the like.

 The reaction temperature is suitably from -10 to 30 ° C.

The reaction molar ratio of the compound of the formula (V) to the compound of the formula (IV) is 2 to 2.4 molar equivalents.

As an optically active compound of the compound (IV), R-(−)-2-chlorophenylethylene glycol having an optical rotation of (−) is known [J. Chem. Soc. (C), 1971, 89].
8]. However, S-(+)-2- which indicates the optical rotation of (+)
Chlorophenylethylene glycol is a novel compound not described in the literature. The synthesis of the optically active compound of the formula (IV) can be carried out by the method described in the above-mentioned document and the method described in another document [J.
Chem. Soc. (C), 1968, 1853].

Pharmaceutically acceptable salts of the compounds of formula (I) include, for example, hydrochloride, sulfate, succinate, tartrate and the like.

 Hereinafter, examples of the present invention will be described.

Example 1 R-(+)-(E) -α- [4- (2-chlorophenyl) -1,3-dithiolan-2-ylidene] -1H
-Imidazole-1-acetonitrile and R-(+)-
Synthesis of (Z) -α- [4- (2-chlorophenyl) -1,3-dithiolan-2-ylidene] -1H-imidazole-1-acetonitrile 9.0 g (85% purity, 0.137 mol) of potassium hydroxide powder was obtained. 30 m of dimethyl sulfoxide containing 6.1 g (0.057 mol) of 1-cyanomethylimidazole and 4.4 g (0.0057 mol) of carbon disulfide in addition to 70 m of dimethyl sulfoxide.
Was added dropwise over 30 minutes under water cooling. Stirring was continued at room temperature for 1 hour to obtain a dithiolate solution. This is (S)-
18.8 g (0.057 mol) of (+)-1,2-dimesyloxy-1- (2-chlorophenyl) ethane in dimethyl sulfoxide
It was added dropwise to the 170 m solution at room temperature for 30 minutes. 2 as it is
After continuing stirring for 500 hours, 500 m of ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO ₄ ) and concentrated to a viscous oily α- [4- (2-chlorophenyl) -1,3-
Dithiolan-2-ylidene] -1H-imidazole-1-
Acetonitrile (mixture of geometric isomers, E / Z = 6/4) was obtained. 18.2 g of gain.

18.2 g of a mixture of geometric isomers was dissolved in 20 m of ethyl acetate / n-hexane (60/40, v / v), and left overnight at room temperature to precipitate crystals. The amount obtained is 9.1 g (yield 50.1%). When this was further recrystallized from acetonitrile 100 m, the melting point was 168.5 to 169.5.
Pure geometric isomers were obtained which showed ° C. 7.8 g (yield
42.9%), optical rotation ▲ [α] ²⁴ _D ▼ = + 45 ° (C = 1.0, chloroform).

The absolute configuration and stereoisomerism of this dextrorotatory compound are
Determined by X-ray crystal structure analysis, the absolute configuration is "R",
The stereoisomer was "E". Therefore, the compound is represented by R-
(+)-(E) -α- [4- (2-chlorophenyl)-
1,3-dithiolan-2-ylidene] -1H-imidazole-1-acetonitrile.

Further, the crystallized mother liquor was concentrated to obtain a viscous oil. This was dissolved in 20 m of ethanol, and allowed to stand overnight under ice cooling to precipitate crystals. 6.0 g (yield 33.0%). The compound is
Mp 117-118 ° C., ▲ [α] ²⁴ _D ▼ = + 67 ° (C = 1.0, chloroform) shows a "Z" isomers, i.e., R - (+) -
(Z) -α- [4- (2-chlorophenyl) -1,3-dithiolan-2-ylidene-1H-imidazole-1-acetonitrile.

Example 2 S-(-)-(E) -α- [4- (2-chlorophenyl) -1,3-dithiolan-2-ylidene] -1H
-Imidazole-1-acetonitrile and S-(-)-
Synthesis of (Z) -α- [4- (2-chlorophenyl) -1,3-dithiolan-2-ylidene] -1H-imidazole-1-acetonitrile S-(+)-1,2-dimesyloxy of Example 1 -1-
S-(-)-1, instead of (2-chlorophenyl) ethane
The following two compounds were obtained using 2-dimesyloxy-1- (2-chlorophenyl) ethane.

S-(-)-(E) form; melting point 168.5 ° C ▲ [α] ²⁵ _D ▼ = -45 ゜ (C = 1.0, chloroform) S-(−)-(Z) form; melting point 117-118 ° C., ▲ [α] ²⁴ _D ▼ = -69 ゜ (C = 1.0, chloroform) Example 3 S-(+)-1,2-dimesyloxy-1- (2
Synthesis of -chlorophenyl) ethane S-(+)-2-chlorophenylethylene glycol
13.5 g (0.078 mol) and 18.9 g (0.187 mol) of triethylamine are dissolved in 150 m of anhydrous dichloromethane, and 19.7 g (0.172 mol) of methanesulfonyl chloride is added to the solution.
It was added dropwise at ° C. After the dropwise addition, the mixture was stirred at 0 to 5 ° C. for 1 hour, and then returned to room temperature and stirred for 1 hour. The mixture was treated with a 1N-HCl aqueous solution under ice-cooling, and the organic layer was washed with a saturated NaHCO ₃ aqueous solution and then with water.
Dried (MgSO ₄ ) and concentrated. The obtained viscous oil was dissolved in 50 m of ether and allowed to stand under ice cooling for 3 hours to precipitate crystals. The amount obtained is 21.1 g (yield 84.5%).

This compound was S-(+)-1,2-dimesyloxy-1- (2-chlorophenyl) ethane having a melting point of 90 to 91.5 ° C. and [[α] ²³ _D ▼ = + 74 ° (C = 1.0, acetone). .

Example 4 R-(-)-1,2-dimesyloxy-1- (2
Synthesis of -chlorophenyl) ethane Instead of S-(+)-2-chlorophenylethylene glycol in Example 3, synthesis was performed using R-(-)-2-chlorophenylethylene glycol. The obtained compound has a melting point of 90-91.5 ° C., 〔[α] ²⁵ _D ▼ = -71 ゜ (C = 1.
0, acetone) of R-(-)-1,2-dimesyloxy-1-
(2-chlorophenyl) ethane.

Example 5 Synthesis of S-(+)-2-chlorophenylethylene glycol 5.0 g (0.13 mol) of lithium aluminum hydride was suspended in 200 m of anhydrous ether, and 14.3 g of S-(+)-2-chloromandelic acid was added thereto. 0.076 mol) anhydrous ether 80m
Was added dropwise at room temperature for 1 hour. After the addition, the mixture was stirred under reflux for 1 hour. The mixture was treated with a 3N-HCl aqueous solution under ice cooling, the organic layer was separated, and the aqueous layer was extracted with ether. Combine the organic layers,
Wash with saturated aqueous NaHCO ₃ then brine, dry (MgSO 4)
₄ ) and concentrated to give a colorless viscous oil. 13.1 g (yield
100%). This compound was S-(+)-2-chlorophenylethylene glycol having n _D : 1.5550550 [α] ²⁵ _D ＝= + 75 ゜ (C = 1.0, ethanol).

Example 6 Synthesis of R-(−)-2-chlorophenylethylene glycol Using the R-(−)-2-chloromandelic acid of Example 5, n _D : 1.5557, 〔[α] ²⁵ _D ▼ = −75 ゜. R-(-)-2-chlorophenylethylene glycol (C = 1.0, ethanol) was obtained (95% yield).

Example 7 Optical resolution of (±) -2-chloromandelic acid 112 g (0.6 mol) of (±) -2-chloromandelic acid and l
-121 g (0.6 mol) of ephedrine hydrochloride in 500 ethanol
m, and at room temperature, 41.4 g of anhydrous potassium carbonate powder (0.
3 mol) was added slowly in small portions. Thereafter, stirring was continued for 3 hours under reflux. The insolubles were filtered while hot, and the filtrate was
After concentrating to 3 volumes, the mixture was allowed to stand overnight under ice cooling to precipitate crystals. 88 g (41.7% yield). This was treated with concentrated hydrochloric acid and extracted with ether. Concentrate the organic layer,
The obtained residue was recrystallized twice from benzene. Gain 35g
(Yield 31.5%), melting point of 119-120 ° C, ▲ [α]
²⁵ _D ▼ = R-(+)-at -156 ° C (C = 1.0, acetone)
2-chloromandelic acid.

The fractionated crystal mother liquor was concentrated, treated with concentrated hydrochloric acid, and extracted with ether. The organic layer was washed with water, dried (MgSO ₄ ), and concentrated, and the obtained residue was recrystallized three times from benzene. 34.3g
(Yield 30.8%), melting point of 119-120 ° C, ▲ [α]
²⁵ _D ▼ = + 161 ° (C = 1.0, acetone) S of - (+) -
2-chloromandelic acid.

Example 8 Compound of the present invention 1 part Polyethylene glycol 300 99 parts was mixed and dissolved to prepare a coating solvent.

Example 9 Compound of the present invention 2 parts Polyethylene glycol 400 40 parts Polyethylene glycol 1500 58 parts were mixed while heating, and then cooled to obtain an ointment.

Example 10 Compound of the present invention 2 parts 1,2-propanediol 5 parts Glycerostearate 5 parts Whale wax 5 parts Isopropyl myristate 10 parts Polysorbate 4 parts A mixture of heated, cooled and then stirred with 69 parts of water To make a cream.

Example 11 One part of the compound of the present invention, 5 parts of benzyl alcohol, 30 parts of ethanol and 47 parts of propylene glycol were mixed and dissolved, and then 1 part of Hibis Kowa 104 and 15 parts of purified water were added to this solution.
Was added to obtain a uniform solution. Next, 1 part of diisopropanolamine was added with stirring to obtain a gel.

Example 12 One part of the compound of the present invention, 5 parts of benzyl alcohol, 20 parts of ethanol and 59 parts of propylene glycol were mixed and dissolved, and then an aqueous solution consisting of 15 parts of purified water was added to this solution to obtain a liquid preparation.

Example 13 1 part of the present compound was dissolved in 5 parts of benzyl alcohol and 5 parts of diethyl sebacate, and 5 parts of cetyl alcohol, 6 parts of stearyl alcohol, 1 part of sorbitan monostearate and 8 parts of polyoxyethylene sorbitan monostearate were dissolved. In addition, it was dissolved by heating to 70 ° C. While maintaining the obtained homogeneous solution at 70 ° C., purified water heated to 70 ° C. was added, and then cooled while continuing stirring to obtain a cream composition.

 Parts in Examples 8 to 13 represent parts by weight.

The compound of the present invention can be mixed with a conventional chemotherapeutically acceptable diluent or carrier and, if desired, other excipients, and used in the form of solvents, creams, ointments, suppositories, tablets and the like. Can be.

When the compound of the present invention is used as an antifungal agent in the form of a topical application, it can be used in the form of creams, ointments, solutions and the like.

0.1% practical concentration when used as a coating agent
That's all.

Test example Trichophyton mentagrophytes IFO-
5810) and Candida albicans (Candida albicans IFO-1270)
Sabouraud medium containing 10 g of peptone and 40 g of glucose dissolved in water 1, adjusted to pH 6.0, and containing a predetermined concentration of an active ingredient (1% dimethyl sulfoxide solution)
3 m was passed through a Petri dish having a diameter of 3.5 cm to prepare an agar plate medium. 0.1m of pre-cultured bacteria is planted in a petri dish and kept at 28 ℃
After culturing for 6 days, the minimum inhibitory concentration (MIC) was determined. Table 1 shows the results.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 409/06 CAPLUS (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. Structural formula (In the formula, ^* C represents an asymmetric carbon atom.) R-(+)-(E) -α- [4- (2-chlorophenyl) -1,3-dithiolan-2-ylidene ] -1H
-Imidazole-1-acetonitrile and its salts. 2. Formula (II): (Wherein ^* C represents an asymmetric carbon atom, R represents a methanesulfonyl group, a benzenesulfonyl group or a p-toluenesulfonyl group), and shows an optical rotation of (+) in an acetone solution. Optically active chemicals and formula (III) (Wherein M represents an alkali metal atom). R-(+)-(E) -α- [4-
(2-Chlorophenyl) -1,3-dithiolan-2-ylidene] -1H-imidazole-1-acetonitrile. 3. The formula (IV): (Wherein ^* C represents an asymmetric carbon atom) and an optically active phenylethylene glycol derivative having an optical rotation of (+) in an ethanol solution and a general formula (V): RCl (V) (Wherein, R represents a methanesulfonyl group, a p-toluenesulfonyl group or a benzenesulfonyl group). The compound represented by the formula (II): (Wherein ^* C represents an asymmetric carbon atom, R represents a methanesulfonyl group, a benzenesulfonyl group or a p-toluenesulfonyl group), and shows an optical rotation of (+) in an acetone solution. An optically active compound represented by the formula (III) (Wherein M represents an alkali metal atom). R-(+)-(E) -α- [4-
(2-Chlorophenyl) -1,3-dithiolan-2-ylidene] -1H-imidazole-1-acetonitrile. 4. Formula (I): (Wherein ^* C represents an asymmetric carbon atom) or a pharmaceutically acceptable salt thereof as an active ingredient.