JPS63122697A - Carbomycin derivative - Google Patents

Abstract

NEW MATERIAL:A 9-deoxo-9-iminocarbomycin derivative expressed by formula I (R<1> is formyl or hydroxymethyl; R<2> is H or lower alkyl; R<3> and R<4> are H or lower acyl; a broken line is single bond, double bonds or bond expressed by formula II). EXAMPLE:9-Deoxo-9-methylhydroxyiminocarbomycin B expressed by formula III. USE:An antimicrobial agent. PREPARATION:A carbomycin derivative expressed by formula IV (R<1a> is formyl or hydroxymethyl) wherein a formyl group in the 18-position may be protected or a dihydrocarbomycin derivative wherein a formyl group in the 18-position is dihydrogenized is reacted with (substituted)hydroxylamine expressed by the formula R<2>O-NH2 to provide a compound expressed by formula V, which is as necessary oxidized in a deprotecting group and/or a hydroxymethyl group in the 18-position.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to macrolactone compounds exhibiting antibacterial activity. More specifically, the present invention relates to a 9-thioquine-9-iminocarbomycin derivative represented by the following general formula.

[In the formula, R1 represents a formyl group or a hydroxymethyl group.

R2 is a hydrogen atom or a lower alkyl group of.

R3 and R4 are hydrogen atoms or lower acyl groups.

The wavy line means a single bond or a double bond, respectively. (Prior Art) The compound of the present invention is characterized in its chemical structure in that the 9-position of the macrolactone ring of carbomycin is an oxime. There are no documents describing such compounds (・.

(Means for Solving the Problems) The compound represented by the above general formula (I) will be further explained as follows.

The "lower alkyl group" meant by R2 is a linear or branched hydrocarbon group having 1 to 6 carbon atoms. Typical examples of the lower alkyl groups are methyl, ethyl, and propyl groups.

Impropyl group, butyl group, isobutyl group, 5ee-
It is a butyl group. Also, l(3 and R4 mean “
Examples of "lower decyl group" include acetyl group, propionyl group, butyryl group, imbutyryl group, valeryl group,
Mention may be made of isovaleryl group.

Although geometric isomers exist for the group R10-N= in general formula (I), the compounds of the present invention may be a mixture of isomers, and may be syn- or anti-isomers.

The compound of the present invention can be produced by the method shown by the following reaction formula.

(I) [In the formula, R'a represents a formyl group, a hydroxymethyl group, or a protected formyl group; To carry out this method, a carbomycin derivative (II) in which the formyl group at the 18th position is optionally protected or a dihydrocarbomycin derivative (II) in which the formyl group at the 18th position is dihydrated is used. The substituted or unsubstituted hydroxylamine represented by (m) is reacted (first step), and then, when the formyl group is protected, the protecting group is removed, and/or the hydroxymethyl group at the 18th position is removed. is oxidized (second step).

The protected formyl group in this production method is one protected in the form of acetal (or thioacetal), specifically dimethyl acetal, diethylacetal, dimethylthioacetal, ethylene acetal, glopylene acetal, or any of these. It has a substituent such as a methyl group.

The reaction between compound (rl) and compound (I'[I) (first step) involves reacting compound (m) in an amount corresponding to 9 reactions with compound (n) in a solvent inert to this reaction.

Compound (m) may be subjected to the reaction as a free base or as a salt with an acid. When used in the reaction as a free base, an acid such as pyridine P-toluenesulfonate 10-camphorsulfonic acid may also be added.

When the reaction is performed as a salt with an acid, an inorganic base such as sodium bicarbonate, sodium carbonate, or potassium carbonate, or an organic base such as pyridine, triethylamine, or piperidine may be added. When adding acids or bases.

Good results can be obtained by adjusting the pH of the reaction solution to about 4 to 5.

As the reaction solvent, water, alcohol, tetrahydrofuran, acetonitrile, benzene, etc. are used. The reaction is carried out at room temperature or under heating (refluxing) for 1 to 2 hours to 2 to 3 days.

Next, removal of the protecting group of the formyl group is preferably carried out under mild conditions that do not involve detachment of mycarose (usually in a solvent such as water-acetonitrile or water-acetone). This is done using an acid such as difluoroacetic acid or para-toluenesulfonate.

Further, the oxidation of the hydroxymethyl group at the 18th position to the formyl group is performed using a mild oxidizing agent.

As an oxidizing agent, for example, dimethyl sulfoxide (D
MSO)-acetic anhydride, DMSO-pyridine-trifluoroacetate, DMSO-oxalyl chloride-triethylamine, pyridinium chloro in dichloromethane
Chromate (FCC) or the like is used. As the reaction solvent, DMSO can also serve as a solvent, but if necessary, an inert solvent such as benzene or toluene can be used.

The produced target compound (I) is isolated and purified by extraction with an organic solvent, concentration, and column chromatography.

(Effects of the Invention) Compound (I) of the present invention exhibits antibacterial activity against various pathogenic bacteria. Especially in terms of internal dynamics.

Blood and organ white concentrations are 2-5 compared to josamycin.
It has excellent characteristics due to its double increase.

To use the compound of the present invention as a medicine, it can be prepared into tablets, powders, granules, capsules, injections, etc. using conventional pharmaceutical carriers.

Administer orally or parenterally. Administration.

Adults: 50 to 2,000 mg per day, divided into 1 to 4 doses.

(Example) Next, the nine compounds of the present invention and the method for producing the same will be further explained with reference to Examples. In addition, as a reference example, a method for producing the raw material compounds used in the examples is shown.

Reference example 1 Dissolve 8.3 g of josamycin in 80 ml of methanol, and dissolve at -40°C in sodium chloride and robidoride 500.
mg was added little by little. After confirming the disappearance of the raw materials by TLC (chloroform-methanol-28% aqueous ammonia 20:1:0.1), the mixture was concentrated under reduced pressure. Add this to chloroform 3
After washing with 9 ml of saline, drying over magnesium sulfate and concentrating, 8 g of 18-dihydrojosamycin was obtained. This material exhibits the following physical and chemical properties.

Mass spectrum (m/z): 830 (M+1)
Nuclear magnetic resonance spectra (CDCIs) δ (ppm) H number Assignment 0.98 6H4″-0COCH2CH tooth 22
．． 16 3 H3-0Ac2.52
6H3'-NMe23.62
3 H4-OMe Reference Example 2 6 g of 18-dihydrojosamycin was dissolved in 60 ml of tertiary butanol, and 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ)2
．． Added 8g. TLC (benzene-acetone 2:1)
When Rfo, 35 became the main product, the two reaction solutions were concentrated. The residue was dissolved in 300 ml of ethyl acetate.

The mixture was washed several times with a 1M aqueous sodium carbonate solution, dried over Boh's salt, and then concentrated under reduced pressure. Next, a column (benzene-acetone 3
:1) to obtain 2.7 g of 18-dihydrocarbomycin B. This material exhibits the following physical and chemical properties.

Mass spectrum (m/z): 828 (M+1) Nuclear magnetic resonance spectrum (CDCIs) δ (ppm) H number Attribution 0.98 6) (4”-0COCH2Cshi2
．． 18 3 H3-0Ac2.52
6 kI3'-NMe23.56 3H
40Me Example 1 2.2 g of 18-dihydrocarbomycin B was dissolved in 22 m7 of methanol, 0.63 ml of pyridine, O
- Add 0.67 g of methylhydroxylamine hydrochloride,
It was left at room temperature for 4 hours. The reaction solution was TLC (chloroform-methanol-28% ammonia water 20:1:0.1)
After confirming that the raw materials had disappeared, the mixture was concentrated under reduced pressure. The residue was dissolved in 100 rnl of chloroform, washed several times with a saturated aqueous sodium bicarbonate solution, dried over boron sulfate, and concentrated under reduced pressure. Purification was performed using a column (benzene-acetone 3:1) to obtain 2 g of 18-dihydro-9-deoxo-9-methylhydroxyiminocarbomycin B.

The physical and chemical properties of this product are shown.

Mass spectrum (m/z): 857 (M+1) Nuclear magnetic resonance spectrum (CDC13) δ (ppm) H number Assignment 0.98 6 H4″OCOCHzCHMez2.
12 3 H3-0Ac 2.53 6 H3' NMe2 3.61 3H40Me 3,90 3 H9-NOMe Example 2 81.4 g of 18-dihydro-9-deoxo-9-methylhydroxyiminocarbomycin was added to benzene 7c
al, dissolved in 7 ml of dimethyl sulfoxide.

0.63 g of pyridinium trifluoroacetite and 0.52 g of synchhexylcarbodiimide were added thereto at room temperature, and the mixture was stirred day and night. After confirming the disappearance of the raw materials by TLC (benzene-acetone 4:1), the reaction solution was poured into a solution of 0.35 g of sulfuric acid in 10 ml of dioxane. Insoluble materials were filtered and concentrated under reduced pressure. 150m of benzene
7, washed several times with a saturated aqueous sodium bicarbonate solution, dried over boron sulfate, and concentrated under reduced pressure. This was purified using a column (benzene-acetone 5:1) to obtain 0.7 g of 9-deoxo-9-methylhydroxyiminocarbomycin B. The physical and chemical properties of this product are shown.

Mass spectrum (m/z): 855 (M+1) Nuclear magnetic resonance spectrum (CDCl5) δ (ppm) H number Attribution 0.98 6 H4”-OCOCH2CHM
e.

2.18 3 H3-0Ac2, 52
6 H3'-NMe23.55 3
H4-OMe3.82 3 H9-NOMe
9.58 1 H18-CHO Example 3 Carbomycin B3. Dissolve Og in 15 ml of anhydrous methanol and prepare pyridinium valatoluene sulfonator)1.
2 g was added and left overnight at room temperature.

After confirming the completion of the reaction by TLC, 2 mZ of diethylamine was added and the mixture was concentrated under reduced pressure. The obtained solid was dissolved in chloroform, washed with a saturated aqueous sodium bicarbonate solution, dried over boron sulfate, and concentrated under reduced pressure. This was subjected to column chromatography (reroform-methanol-28% ammonia water 3
5:1:0.1).

1.2 g of carbomycin B dimethyl acetal was obtained.

Next, dissolve in 24 ml of anhydrous methanol and add 0 pyridine.
．． 32+nt, 0.34 g of 0-methylhydroxylamine hydrochloride was added and left to stand at room temperature for 3 hours. The reaction solution is T
After confirming the disappearance of the raw materials by LC, the mixture was concentrated under reduced pressure. The residue was dissolved in chloroform, washed with a saturated aqueous sodium bicarbonate solution, dried with boron sulfate, and concentrated under reduced pressure to give 9-dioquine-9-
Methylhydroxyiminocarbomine B 1.1 g of dimethylacecool was obtained.

Subsequently, it was dissolved in 22 ml of 30% water-acetonitrile.

O,=i g of difluoroacetic acid was added and allowed to stand at room temperature for 8 hours.

After checking the reaction solution by TLC, it was poured into a saturated aqueous solution of hydrogen carbonate. The extract was extracted with chloroform, dried over Boh's salt, and then concentrated under reduced pressure. This was subjected to column chromatography (benzene-acetone 5:1) to obtain 0.5 g of 9-deoxo-9-methylhydroquiniminocarbomycin B. The physicochemical properties of the compound obtained here were consistent with those obtained in Example 2.

Claims (1)

[Claims] General formula▲ Numerical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is a formyl group or a hydroxymethyl group, R^2 is a hydrogen atom or a lower alkyl group, R^3 and R ^4 means a hydrogen atom or a lower acyl group, a wavy line means a single bond or a double bond, and a dotted line means a single bond, a double bond, or a bond represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ . ] A carbomycin derivative represented by.