JPH04297461A - 2-thiohydantoin derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as a medicine, showing various pharmaceutical actions such as antimicrobial action, antiviral action, anti- inflammatory action, antirheumatic action, etc. CONSTITUTION:Compound shown by formula I (R<1> is lower alkyl, lower alkenyl, phenyl lower alkyl, phenyl, etc.; R<2> is H or lower alkanoyl; R<3> is H, lower alkylphenyl, lower alkylthio lower alkyl, etc.) such as 3-(3,5-di-tert-butyl-4- hydroxyphenyl)-5-benzylthiomethyl-2-thiohydantoin. The compound shown by formula I is obtained by reacting an isothiocyanate derivative shown by the formula R<1>-NCS with a compound shown by formula II in an inert solvent (e.g. DMF) at room temperature-100 deg.C for 1-5 hours and treating with an acid (e.g. acetic acid).

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION This invention relates to novel 2-thiohydantoin derivatives.

0002

BACKGROUND OF THE INVENTION The compound of the present invention is a novel compound that has not been described in any literature.

0003

OBJECTS OF THE INVENTION The object of the present invention is to provide compounds useful as pharmaceuticals, as described below.

0004

According to the present invention, a 2-thiohydantoin derivative represented by the following general formula (1) is provided.

[0005]

[Formula R1 is a lower alkyl group, a lower alkenyl group, a phenyl lower alkyl group, or a group selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a lower alkoxycarbonyl group, and a hydroxyl group as a substituent from 1 to 3] R2 is a hydrogen atom or a lower alkanoyl group, and R3 is a hydrogen atom, a lower alkyl group, a phenyl group, a phenyl lower alkyl group, or a phenyl group that may have a lower alkoxy group. Lower alkylthio lower alkyl group which may be substituted. However, R1 is a methyl group, R2 is a hydrogen atom, and R3
Excludes those in which is a methylthiomethyl group. ]

2- of the present invention represented by the above general formula (1)
Thiohydantoin derivatives exhibit various pharmacological actions such as antibacterial, antiviral, antiinflammatory, and antirheumatic, and are useful as pharmaceuticals such as antibacterial agents, antiviral agents, antiinflammatory agents, and antirheumatic agents.

[0007] In the above general formula (1) showing the compound of the present invention and others in this specification, the lower alkyl group is:
Examples include linear or branched lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl groups. Examples of lower alkenyl groups include vinyl, allyl,
2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-pentenyl, 3-methyl-2-butenyl, 2
-hexenyl group, etc. can be exemplified. Examples of phenyl lower alkyl groups include benzyl, α-phenethyl, β-phenethyl, 3-phenylpropyl, 4-phenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, and the like. can be exemplified. Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy groups. Examples of lower alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxy groups. Halogen atoms include fluorine atoms, chlorine atoms, bromine atoms and iodine atoms. Examples of lower alkanoyl groups include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, trimethylacetyl,
Examples include hexanoyl groups. Examples of the phenyl group having 1 to 3 groups selected from a lower alkyl group, a lower alkoxy group, a halogen atom, a lower alkoxycarbonyl group, and a hydroxyl group as substituents include 4-methylphenyl, 3-methylphenyl, and 4-ethylphenyl. , 4-methoxyphenyl, 3-methoxyphenyl, 3,4-dimethoxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 4-bromophenyl, 4-methoxycarbonylphenyl, 4-ethoxycarbonylphenyl, 4-hydroxyphenyl, 4- Hydroxy-3,5-di-tert-
Examples include butylphenyl group. Examples of the lower alkylthio lower alkyl group optionally substituted with 1 to 3 phenyl groups that may have a lower alkoxy group include methylthiomethyl, benzylthiomethyl, 4-methoxybenzylthiomethyl, triphenylmethylthiomethyl, 2-benzylthioethyl, 1-benzylthioethyl, ethylthiomethyl, ethylthioethyl, α-phenethylthiomethyl, β-phenethylthiomethyl, 3-benzylthiopropyl, 3-(3-phenylpropylthio)propyl group, etc. I can give an example.

The 2-thiohydantoin derivative of the present invention is
It can be manufactured by various methods. A specific example thereof is shown in the reaction scheme below. <Reaction scheme-1>

[0009]

[Chemical formula 3] [In the formula, R1 and R3 are each the same as above. ]

0
The reaction between the isothiocyanate derivative (2) shown in the above reaction scheme-1 and the compound (3) can be carried out in the following manner. That is, compound (2) and compound (3) are heated in a suitable inert solvent and then treated with an acid. In the above, as the inert solvent, for example, N,N-dimethylformamide (DMF), ethanol, etc. can be used. As the heating conditions, it is generally possible to adopt a temperature range of room temperature to 100° C. for about 1 to 5 hours. The crude product obtained is
Subsequently, with an acid such as acetic acid or polyphosphoric acid, the
The target compound (1a) can be obtained by treatment at a temperature of about 10 to 60 minutes. <Reaction scheme-2>

[0011]

embedded image [In the formula, R1 and R3 are the same as above. R2a represents a lower alkanoyl group. ]

In the above reaction scheme-2, compound (1
The alkanoylation reaction a) can be carried out by reacting the starting compound and the acid anhydride in a basic solvent or in an inert solvent in the presence of a basic catalyst. As the basic solvent, for example, pyridine, collidine, lutidine, triethylamine, etc. can be used. As the inert solvent, for example, THF, diethyl ether, chloroform, dichloromethane, DMF, etc. can be used, and in this case, the above-mentioned basic solvent is used in combination as a base catalyst in about 1 to 3 times the molar amount. Further, as the acid anhydride, for example, acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, caproic anhydride, heptanoic anhydride, etc. can be used. The reaction is completed in about 1 to 24 hours under a temperature condition of 0 to 100°C, and thus the target compound (1b) is obtained.

The target compounds in each of the above steps can be easily isolated and purified by conventional separation means. Examples of this separation means include various commonly used methods, such as solvent extraction, recrystallization, adsorption chromatography, and ion exchange chromatography.

[0014]

EXAMPLES In order to explain the present invention in more detail, examples of the production of the compounds of the present invention will be given below as examples.

[0015]

[Example 1] 3-(3,5-di-tert-butyl-4
-hydroxyphenyl)-5-benzylthiomethyl-2
-Preparation of thiohydantoin 5 g of 4-phenyl-3,5-di-tert-butylphenyl isothiocyanate and S-benzyl cysteine 4.
1 g was dissolved in 300 ml of DMF and stirred at 80° C. for 1.8 hours. Add water to the reaction solution, extract with ethyl acetate,
The ethyl acetate layer was dried over anhydrous magnesium carbonate and concentrated to obtain an oily substance. This oil was then dissolved in 100 ml of acetic acid and stirred at 95-100°C for 45 minutes. Acetic acid was distilled off under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with chloroform. After drying the chloroform layer over anhydrous magnesium carbonate, the resulting crude product was purified by silica gel column chromatography (developing solvent: chloroform: ethyl acetate = 30:1) to obtain 7.7 g of the target compound. . The structure and physical properties of the obtained compound are shown in Table 1 as Compound 1.

[0016]

Examples 2 to 13 The compounds shown in Table 1 (compounds 2 to 13) were produced in the same manner as in Example 1. The structure and physical properties of each compound obtained are also listed in Table 1.

[0017]

[Example 14] Production of 1-acetyl-3-methyl-5-benzylthiomethyl-2-thiohydantoin To 300 mg of the compound obtained in Example 8 (compound 8) was added 3 m of pyridine.
1 and 0.3 ml of acetic anhydride were added, and the mixture was stirred at room temperature overnight. The reaction mixture was placed in ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (developing solvent: diethyl ether: n-hexane = 1:3) to obtain the target compound 3.
17 mg was obtained. The structure and physical properties of the obtained compound are shown in Table 1.

[0018]

Example 15 The compound shown in Table 1 (Compound 15) was produced in the same manner as in Example 14. The structure and physical properties of the obtained compound are also listed in Table 1.

[0019]

Examples 16 to 21 In the same manner as in Example 1, the compounds shown in Table 1 (Compounds 16 to 21) were produced. The structure and physical properties of each compound obtained are also listed in Table 1.

[0020]

[Table 1]

[0021]

[Table 2]

[0022]

[Table 3]

[0023]

[Table 4]

[0024]

[Table 5]

[0025]

[Table 6]

Claims (1)

[Claims] Claim 1: General formula [Formula 1] [In the formula, R1 is a lower alkyl group, a lower alkenyl group, a phenyl lower alkyl group, or a lower alkyl group, a lower alkoxy group, a halogen atom, a lower alkoxycarbonyl group, or a hydroxyl group as a substituent] A phenyl group having 1 to 3 selected groups, R2 is a hydrogen atom or a lower alkanoyl group, and R3 is a phenyl group that may have a hydrogen atom, a lower alkyl group, a phenyl group, a phenyl lower alkyl group, or a lower alkoxy group. represents a lower alkylthio lower alkyl group which may be substituted with 1 to 3 of the following. However, R1 is a methyl group, R2 is a hydrogen atom, and R3
Excludes those in which is a methylthiomethyl group. ] A 2-thiohydantoin derivative represented by.