JPS6157313B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula (In the formula, one of R ¹ and R ² is hydrogen, the other is alkyl,
The present invention relates to a pseudomonic acid amide derivative or a salt thereof represented by (representing an alkyl, aryl or aralkyl substituted with carboxyl or hydroxycarbamoyl) and a method for producing the same. In the definition of the above formula (), alkyl is methyl,
Ethyl, propyl, butyl, isobutyl, etc.
Aryl means phenyl, naphthyl, etc., and aralkyl means benzyl, phenethyl, phenylpropyl, etc. The present inventors previously invented a method for producing pseudomonic acid, a novel antibacterial substance, and found that it has strong antibacterial activity, and is particularly effective against Gram-positive bacteria. However, subsequent studies showed that pseudomonic acid has a strong effect when administered immediately after infection in mouse infection experiments;
It was found that the drug has the disadvantage that the effect is significantly reduced if the drug is administered over time. As a result of measuring the blood concentration in mice, it was also found that the concentration rapidly decreases in vivo. Based on these studies, the present inventors have
As a result of further studies, it was discovered that the compound () of the present invention has strong efficacy and that the effect lasts, and the present invention was completed. The compound ( ) of the present invention comprises a known pseudomonic acid, a salt thereof, or a reactive derivative thereof, and a general formula R ¹ -NH-O-R ² () (in which each symbol has the same meaning as above). It is easily produced by reacting with the indicated compound. Examples of reactive derivatives of pseudomonic acid include alkyl esters such as methyl esters and ethyl esters, acid halides, acid anhydrides, and mixed acid anhydrides. As reaction conditions, methods used in ordinary peptide chemistry are employed as long as other substituents are not affected. Among these, the mixed acid anhydride method is particularly conveniently carried out. That is, inorganic salts (such as sodium or potassium salts) or organic salts (such as triethylamine salts) of pseudomonic acid and monoalkyl carbonate esters such as ethyl chlorocarbonate or isobutyl chlorocarbonate, or organic acid halides such as isovaleroyl chloride or pivaloyl chloride. react,
Once the corresponding mixed acid anhydride is formed and reacted with the compound of general formula (), the desired compound () can be easily produced. The reaction solvent used is an inert solvent such as tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, dimethylalumamide, etc. The reaction temperature and reaction time are not particularly limited, but are usually -50°C to room temperature for 1 to 20 hours. It will be held in In addition, the desired product can also be obtained by alkylating N-hydroxyshudomonic acid amide as a raw material, examples of which include a method using a diazo compound and a method using an alkyl halide. . As the salt of the compound () of the present invention, inorganic salts such as sodium salt, potassium salt or aluminum salt are preferable. The compound of the present invention () is a compound of Staphylococcus spp.
aureus, Streptococcus pyogenes,
It has strong antibacterial activity against Gram-positive bacteria such as Streptococcus pneumoniae and is also effective against these penicillin-resistant and macrolide-resistant bacteria, so it is effective against infections caused by these bacteria in humans and animals. It can be used to treat. The following test examples demonstrate that the compound () of the present invention has excellent pharmacological action. Test Example 1 Antibacterial spectrum The antibacterial spectrum of the test compound was measured according to the standard method of the Japanese Society of Chemotherapy. The results are shown in Table 1.

【table】

[Table] (Trypto soy agar medium was used as the medium, and trypto soy agar medium containing 10% blood was used for bacteria marked with an asterisk.) Test example 2 Infection protection effect Staphylococcus aureus 308A-1 was administered intraperitoneally to male mice. Infection by intravenous administration, and then
The infection-preventing effect was measured from the survival rate for 5 days in cases where the test compound was immediately administered subcutaneously and when the test compound was subcutaneously administered 2 hours before and then intraperitoneally infected. The results are shown in Table 2.

[Table] When the compound of the present invention is used as a medicament, it may be used as such or mixed with an appropriate pharmacologically acceptable carrier, excipient, diluent, etc. in the form of powder, granules, tablets, capsules, injections, etc. It can be administered orally or parenterally. Although the dosage varies depending on the target disease, symptom, and compound, it is usually about 50 to 2,500 mg per day for adults when administered orally, and about 100 to 3,000 mg when administered parenterally. Additionally, it may be used as a conventional topical cream or ointment containing 0.01-0.1% of the compound of the invention. Reference example: 30g of pseudomonic acid and 150g of methylene chloride
ml and add 9 ml of triethylamine to dissolve. Cool the solution to -30°C and add 6 ml of ethyl chlorocarbonate while stirring. −30℃～−20
Stir at ℃ for 20 minutes, then warm to room temperature. The reaction solution is washed successively with saturated brine and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure at 30° C. or below. The residue is crystallized by adding 250 ml of isopropyl ether, cooled on ice, and filtered under suction to obtain pseudomonic acid ethoxycarbonyl ester, which is a mixed acid anhydride, as white crystals. Yield: 32g. Melting point 64-66
°C (decomposition). Example 1 Eudomonic acid ethoxycarbonyl ester
Dissolve 570mg in 8ml of methylene chloride and store at -20℃.
Cool to ~-30°C. Add N-methylhydroxylamine hydrochloride 100% to this solution while stirring.
Dissolve mg in 4 ml of methanol, and add a solution adjusted to pH=8 with 30% aqueous sodium hydroxide. Heat to room temperature and concentrate under reduced pressure. Ethyl acetate and water are added to the residue, and the pH is adjusted to 3.0 with dilute hydrochloric acid. The organic layer is separated, dried over magnesium sulfate, and concentrated under reduced pressure. When the residue was purified by column chromatography (23 g of silica gel, eluent: chloroform:methanol = 10:1), N-hydroxy-N-methylshudomonic acid amide was obtained as a yellowish brown oil in high yield. It can be obtained with Thin layer chromatography (developed with chloroform:methanol = 10:1) Rf = 0.27 (colored with ultraviolet light, iodine, ferric chloride) Proton NMR (internal standard: tetramethylsilane, solvent
_CD3OD )

[Formula] 3.11ppm Example 2 Eudomonic acid ethoxycarbonyl ester
Dissolve 570mg in 8ml of methylene chloride and store at -20℃.
While cooling and stirring, dissolve 100 mg of O-methylhydroxylamine hydrochloride in 4 ml of methanol, and add a solution adjusted to pH=8.0 with 30% sodium hydroxide. The temperature is raised to room temperature, concentrated under reduced pressure, water is added to the residue, and the oil that separates is extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to quantitatively obtain N-methoxysudemonic acid amide as a colorless transparent oil. Thin layer chromatography (developed with chloroform:methanol = 5:1) Rf = 0.57 Proton NMR (internal standard: tetramethylsilane, solvent
_CD3OD )-CO-NH- _OCH3 : 3.7ppm The following compound is produced in the same manner. ◎N-Hydroxy-N-phenylshudomonic acid amide, yellowish brown oil Thin layer chromatography (Developed with chloroform:methanol = 10:1) Rf = 0.43 (Colored with ultraviolet light, iodine, ferric chloride) ) ◎N-benzyloxyshudomonic acid amide, colorless transparent oil Thin layer chromatography (developed with chloroform:methanol = 10:1) Rf = 0.36 Proton NMR (internal standard: tetramethylsilane, solvent
_CD3OD )

【formula】

[Formula] ◎N-carboxymethyloxysudemonic acid amide, colorless transparent oil Thin layer chromatography (developed with chloroform:methanol = 5:1) Rf = 0.23 Proton NMR (internal standard: tetramethylsilane, solvent
CD ₃ OD) -CONH-OCH ₂ -: 4.44ppm ◎N-(N-hydroxycarbamoylmethyloxy) pseudomonic acid amide, yellow-brown transparent oil Thin layer chromatography (developed with chloroform:methanol = 5:1) Rf =0.44 Proton NMR (internal standard tetramethylsilane, solvent
CD ₃ OD) -CONH-OCH ₂ -: 4.36ppm ◎N-Hydroxy-N-(α-naphthyl) pseudomonic acid amide, pale yellow transparent oil Thin layer chromatography (developed with chloroform:methanol = 10:1) Rf=0.27 (Colored by ultraviolet light, iodine, and ferric chloride)

Claims (1)

[Claims] 1. General formula (In the formula, one of R ¹ and R ² is hydrogen, the other is alkyl,
Indicates alkyl, aryl or aralkyl substituted with carboxyl or hydroxycarbamoyl. ) A pseudomonic acid amide derivative or a salt thereof.