JPH02157287A - Benzyltriphenylphosphonium salt derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R is lower alkyl; X is halogen; the substituted position of benzothiazolyl group is the 3- or 4-position. EXAMPLE:4-(Benzothiazol-2-yl)benzyltri(4-toluyl)phosphonium bromide. USE:An antifungal and antibacterial agents. PREPARATION:A compound expressed by formula II {e.g. 2-[4-(bromomethyl) phenyl]benzothiazole} is reacted with one equiv. compound expressed by formula III (e.g. tri-p-toluylphosphine) in an inert organic solvent, such as benzene or toluene, under conditions of ambient temperature to refluxing temperature of the solvent for 1-50hr.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention provides novel benzyltriphenylphosphonyl (in the formula:
R is a lower alkyl group, X is a halogen atom,
Furthermore, the substitution position of the benzthiazolyl group is the 3rd or 4th position. ) The present invention relates to a benzyltriphenylphosphonium salt derivative represented by:

(Prior Art) Various benzyltriphenylphosphonium salt derivatives have been known. Among them, U.S. Patent No. 4.039,53
1 (1977) describes 4-(benzoxazol-2-yl)penzyltriphenylphosphonium bromide (compound A) having a benzoxazole group as an intermediate for the production of an optical brightener.

By the way, for superficial fungal infections of the skin, oral cavity, vagina, etc.
In some cases, bacterial mixed infection or some kind of etiological involvement is presumed. A typical example of this is keratinitis, in which in addition to Candida albicans, 5 taphylococcus and β-hemolytic Streptococcus pyogenes can be found in the affected area.
s) is separated at a high rate. In addition, secondary to dermatophytosis such as white line, 5taphylococcus or 5tr
It is also known that secondary infections caused by Eptococcus etc. occur (CHEMOTHERAPY, 3
2.825 (1984), TOKYO).

[Problem to be solved by the invention]

Therefore, it is desired that a topical antifungal agent have excellent antibacterial activity not only against fungi but also against the above-mentioned bacteria.

[Means to solve the problem]

Under these circumstances, the present inventors investigated the antibacterial activity of a large number of compounds and found that the maximum (I)
The present invention was completed based on the discovery that a novel benzyltriphenylphosphonium salt derivative represented by the following formula satisfies such requirements.

- At maximum (I), lower alkyl groups include C1C
4, a straight chain or branched alkyl group. Further, examples of the halogen atom include a chlorine atom, a bromine atom, an iodine atom, and the like.

Compound (I) of the present invention can be produced, for example, by the following method.

(Hereinafter, in the margin) (In the formula, R, The compound (I) of the present invention can be produced by reacting in an inert organic solvent such as benzene or toluene at a temperature ranging from room temperature to the reflux temperature of the solvent for 1 to 50 hours.

The compound (I) of the present invention obtained as described above can be isolated and purified by column chromatography, recrystallization, etc.

Compound (II
) is for example J, Med, Chem, 1971, 14.
1223-1225.

Note that a compound in which X is an iodine atom in compound (II) can be produced by reacting sodium iodide with a compound in which X is a bromine atom in compound (II) (see production side below).

Further, compound (III) is, for example, described by Justus Lie
bLgsAnn, Chem, 1973.1494-1
504, J, Chem, Soc, Perkinl, 1
980, (10), 2233-2237.

[Function and effect of the invention]

As shown in Test Examples 1 and 2 below, the compound of the present invention (
I) is Candida albicans and Tri
Not only fungi such as cho-phyton rubrum, but also taphylococcus and β
-Hemolytic streptococcus (St-reptococcus)
It is particularly useful as a topical antifungal agent because it has very strong antibacterial activity against bacteria such as P. pyogenes.

Although Compound A exhibited antibacterial activity against the above bacteria, its antibacterial activity against fungi was weak.

Test Example 1 Measurement of minimum inhibitory concentration (MIC) against fungi: [Test compound] (1) 4-(benzthiazol-2-yl)benzyltri(4-tolyl)phosphonium bromide monohydrate (Example 1) (2) 4-(benzthiazol-2-yl)benzyltri(4-tolyl)phosphonium chloride monohydrate (compound of Example 2) (3) 4-(benzthiazol-2-yl)benzyltri(4-tolyl)phosphonium chloride monohydrate (4-Toluyl)phosphonium iosito (compound of Example 3) (4) 4-(benzthiazol-2-yl)benzyltri(4-ethylphenyl)phosphonium bromide (
Compound of Example 4) (5) 3-(Benzthiazol-2-yl)benzyltri(4-toluyl)phosphonium bromide (Compound of Example 5) (6) 3-(Benzthiazol-2-yl)benzyltri( 4-ethylphenyl)phosphonium bromide (
Compound of Example 6) (7) 3-(benzthiazol-2-yl)benzyltri(4-isopropylphenyl)phosphonium bromide hemihydrate (compound of Example 7) (8) 4-(benzthiazol-2-yl)benzyltri(4-isopropylphenyl)phosphonium bromide hemihydrate Oxazol-2-yl)benzyltriphenylphosphonium bromide (Compound 1 No A) [Test method] After dissolving the test compound in the minimum volume of dimethyl sulfoxide, add a small amount of ethanol, and add 1,000 ml of sterile purified water.
The concentration was adjusted to μg/ffLQ and used as a standard solution.

The inoculum solution was prepared as follows. For yeast-like fungi, potato dextrose agar medium (Hinaga)
After pre-cultivating the bacteria on a plate, collect the bacterial mass and add 0.1% (w/v)
suspended in Tween 80 phosphate buffered saline,
A solution prepared to approximately 106 CFU/ITLQ was used. For filamentous fungi, the suspension obtained in the same manner as above was filtered through gauze, and the filtrate was a spore stock solution (approximately 107 CF
U/d) was used.

Sensitivity measurements were performed by the agar plate dilution method. That is, a final concentration of 0.0 was added to potato dextrose agar medium (Hinaga).
A 2-fold dilution series of medium containing the test compound in the range of 5-100 μg/− was prepared. The test compound solution was added to 1710 volumes of agar medium. Next, about 0.005 m of the inoculum solution prepared by the above method! :1 was taken and inoculated into each plate culture medium in the form of a spot of 4 mm in diameter. Judgments were made after culturing at 30°C for 148 hours in the case of yeast-like fungi, and after culturing at 27°C for 3 weeks in the case of filamentous fungi.

[Test results] The test results are shown in Table 1.

Test Example 2 Measurement of minimum inhibitory concentration (MIC) against bacteria = [Test compound] Same as in Test Example 1.

[Test Method] A standard solution of 1000 μg/ITLQ was prepared in the same manner as in Test Example 1. After that, the Japanese Society of Chemotherapy Finger Method (CHEMOTHERAPY 29.76-79 (19
81), TOKYO).

[Test results] The test results are shown in Table 2.

〔Example〕

The present invention will be explained in more detail below with reference to Production Examples and Examples.

Production Example 1 2-(4-(iodomethyl)phenyl]benzthiazole: 1.5 g of sodium iodide was dissolved in 6 d of acetone, and 2-(4-(bromomethyl)) was dissolved in a mixed solvent of 30 d of acetone and 10 d of tetrahydrofuran. Phenyl]
3.0 g of benzthiazole was added and left at room temperature for 15 hours. After the reaction, the reaction solution was filtered to remove insoluble materials, and the solvent was distilled off under reduced pressure. Benzene 2 is added to the resulting residue.
50 mi was added and stirred, and insoluble matter was filtered off. The filtrate was washed with 1z sodium thiosulfate aqueous solution (300 g), washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [elution with benzene] to obtain 1.2 g of 2-(4-(iodomethyl)phenyl)benzthiazole.A portion of this was taken and mixed with cyclohexane-benzene. The product recrystallized from the solvent showed the following physical properties.

mp 148.0°C (decomposition) NMR (CDC: 13.δppm): 4.50 (2H
, s), 7.3-7.6 (4H.

m), 7.8-8.2 (4H, m).

Elemental analysis value (C14HI.as INS): Calculated value (%
) C, 47,88, H, 2,87, N, 3.99 Actual value (%) C, 47,90; H, 2,90; N, 3.9
8 Example 1 3.0 g of 2-(4-(bromomethyl)phenyl)benzthiazole was dissolved in 60 d of benzene, 3.0 g of tri-p-tolylphosphine was added thereto, and the mixture was refluxed for 3 hours. The crystals precipitated after the reaction were It was collected by filtration while hot, dried, and then subjected to silica gel column chromatography [eluted with chloroform-methanol (20/1, v/v)] to obtain 4-
5.4 g of (benzthiazol-2-yl)benzyltri(4-tolyl)phosphonium bromide was obtained. In addition,
A portion of this was recrystallized from ethanol and showed the following physical properties.

mp 290.0°C (decomposition) NMR (CDC13, δppm): 2.45 (9H,
s), 5.41 (2H, d).

7.2-8.0 (20H, m).

Elemental analysis value (as C35H3□BrNPS-H2O)
- Calculated value (%) C, 67,03; H, 5,31; N,
2.24 Actual value (%) C, 67, 15, H, 5, 25
;N, 2.24 Example 2 140.0 g of 2-(4-(chloromethyl)phenyl)benzthiazole was dissolved in 1500 d of benzene, and 164.0 g of trip-p-tolylphosphine was added thereto.
It was refluxed for 2 hours. After the reaction, the precipitated crystals were collected by filtration while hot, dried, dissolved in 1600-chloroform, and dissolved in activated carbon 6.
．． After adding 0 g and stirring for 0.5 hours, the activated carbon was filtered off.

300 d of ethyl acetate was added to the filtrate, and after stirring at room temperature for 16 hours, the precipitated crystals were collected by filtration, and 4-(benzthiazole-
185.0 g of 2-yl)benzyltri(4-tolyl)phosphonium chloride was obtained.

mp 305.0°C (decomposition) NMR (CDCI: +, δppm): 2.45 (9H
,s), 5.53(2H,d).

7.2-8.0 (20H, m).

Elemental analysis value (as C+sH+□CINPS-H2O)
: Calculated value (%) C, 72, 21; H, 5, 71; N,
2.41 Actual value (%) C, 72,10; H, 5,64
;N, 2.50 Example 3 1.2 g of 2-(4-(iodomethyl)phenyl)benzthiazole (see Production Example 1) was dissolved in 30 d of benzene, and 1.1 g of tri-p-)lylphosphine was added thereto. The mixture was refluxed for 1 hour. After the reaction, the precipitated crystals were collected by filtration while hot, washed with a small amount of benzene, and dried to obtain 1.9 g of 4(benzthiazol-2-yl)benzyltri(4-tolyl)phosphonium iosite. A portion of this was recrystallized from ethanol and showed the following physical properties.

mp 293.0℃ (decomposition) NMR (DMSO-d6.δppm): 2.47 (9
H,s), 5.21 (2H.

d), 7.1-7.7 (16H, m), 7.9-8.
2 (4H, m).

Elemental analysis value (as 635H3□TNPS): Calculated value (
%) C, 64,12; H, 4,77; N, 2.14 Actual value (%) C, 64,09, H, 4°77; N, 2.
13 Example 4 1.2 g of 2-(4-(solomomethyl)phenyl)benzthiazole was dissolved in 50 d of benzene, and tri(
1.4 g of 4-ethylphenyl)phosphine was added and the mixture was refluxed for 3 hours. After the reaction, the precipitated crystals were collected by filtration while hot, washed with a small amount of benzene, and dried to give 4-(benzthiazole-2).
2.1 g of benzyltri(4-ethylphenyl)phosphonium bromide was obtained. A portion of this was recrystallized from isopropyl alcohol and showed the following physical properties.

mp 282.0°C (decomposition) NMR (CDC13, δppm): 1.27 (9H,
t), 2.74(6H,q).

5, 53 (2H, d), 7.2-8.0 (20H, m
).

Elemental analysis value (as C36H3JrNPS): Calculated value (
%) C, 70,14; H, 5,73; N, 2.15 Actual value (%) C, 70,11; H, 5,73; N, 2.
22 Example 5 1.5 g of 2-(3-(th7momethyl)phenyl)benzthiazole was dissolved in benzene 30ITLQ, 1.5 g of tri-p-tolylphosphine was added thereto, and the mixture was refluxed for 2 hours. After the reaction, the precipitated crystals were removed while hot, washed with a small amount of benzene, and dried to give 3-(benzthiazole-2-
2.6 g of benzyltri(4-tolyl)phosphonium bromide was obtained. A portion of this was recrystallized from ethanol and showed the following physical properties.

mp 311.0°C (decomposition) NMR (CDC13, δppm): 2.42 (9H,
s), 5.33 (2H, d).

7.2-8.0 (208, m).

Elemental analysis value (as C35H3□BrNPS): Calculated value (%) C, 69,07; H, 5,13; N, 2.30
Actual value (%) C, 69,01; H, 5,04, N, 2
．． 25 Example 6 0.45 g of 2-(3-(bromomethyl)phenyl)benzthiazole was dissolved in benzene 20ITLQ, 0.39 g of tri(4-ethylphenyl)phosphine was added thereto, and the mixture was refluxed for 4 hours. After the reaction, the precipitated crystals were collected by filtration while hot, washed with a small amount of benzene, and dried to obtain 0.52 g of 3-(benzthiazol-2-yl)benzyltri(4-ethylphenyl)phosphonium bromide. A portion of this was recrystallized from isopropyl alcohol and showed the following physical properties.

mp 281.0°C (decomposition) NMR (CDC13, δppm): 1.23 (9H,
t), 2.72(6H,q).

5.43 (2H, d), 7.2-8.1 (20H, m
).

Elemental analysis value (as C+aH+JrNPS): Calculated value (
%) C, 70,14; H, 5,73; N, 2.15 Actual value (%) C, 70,01; H, 5,68, N, 2.
23 Example 7 3-(benzthiazol-2-yl)benzyltri(4
-isopropylphenyl)phosphonium bromide: Dissolve 0.23 g of 2-(3-(bromomethyl)phenyl)benzthiazole in benzene 5d, and add tri(
0.3 g of 4-isopropylphenyl)phosphine was added and the mixture was refluxed for 5 hours. After the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography [eluted with chloroform-methanol (10/1°v/v)] to obtain 3-(benzthiazol-2-yl). 0.28 g of benzyltri(4-isopropylphenyl)phosphonium bromide was obtained. A portion of this was recrystallized from a mixed solvent of ethyl acetate and cyclohexane and exhibited the following physical properties.

mp 174.0°C (decomposition) NMR (CDCI+, δppm): 1.24 (18H,
d), 2.3-3.1 (3H.

m), 5.44 (2H, d), 7.2-8.1 (
20H, m).

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R is a lower alkyl group, Benzyltriphenylphosphonium salt derivative represented by