JPS6139958B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel derivative of antibiotic XK-62-2 and a process for its production. More specifically, the present invention is based on the general formula () [In the formula, R ₁ is a hydrogen atom or

An antibiotic represented by [formula] (in which n represents an integer from 1 to 4)
At least one of the amino groups or methylamino groups at the 1, 3, 2', 6', 3'' and 1-ω positions of XK-62-2 or its 1-N-acyl derivative is -
CHRSO ₃ M ₁ group (wherein R represents a hydrogen atom, an alkyl group or substituted alkyl group, an alkenyl group or substituted alkenyl group, a phenyl group or substituted phenyl group, a naphthyl group or a substituted naphthyl group, M ₁ is a hydrogen atom, ammonium ion, alkali metal or alkaline earth metal) or -CH ₂ SO ₂ M ₂ group (wherein M ₂ represents a hydrogen atom, an ammonium ion or an alkali metal). Related to derivatives and methods for producing them. The present invention provides low toxicity derivatives of the antibiotic XK-62-2 and its 1-N-acyl derivatives. XK-62-2 represented by the general formula () (when R ₁ is a hydrogen atom) and its 1-N-acyl derivative [where R ₁ is

In the case of [Formula] group] is itself a useful antibiotic that has strong antibacterial activity [Patent Publication No. 50-39155 (UKP 1399578), Japanese Patent Publication No. 50-88050, Japanese Patent Application Publication No. 1987-88051, Japanese Patent Publication No. 1983-1989 −
101336, Japanese Patent Publication No. 50-117748, Japanese Patent Application Publication No. 51-19744, etc.). However, XK-62-2 and its 1-N-
Acyl derivatives have excellent characteristics such as strong antibacterial activity and a wide antibacterial spectrum, but there is still room for improvement in toxicity. Therefore, there was a need for derivatives of these compounds that have strong antibacterial activity and lower toxicity. Conventionally,
Regarding the reduction of toxicity of aminoglycoside antibiotics, it is known that the toxicity can be reduced by converting the antibiotic 3',4'-dideoxykanamycin B into an N-methanesulfonic acid derivative (Japanese Unexamined Patent Publication No.
52−39653). According to the present invention, low toxicity N-methanesulfonic acid or N-methanesulfinic acid derivatives of XK-62-2 and its 1-N-acyl derivatives, and methods for producing the same are provided. Among the target compounds of the present invention, N-methanesulfonic acid derivatives of XK-62-2 and its 1-N-acyl derivatives are compounds of general formula (), general formula RCHO
(in the formula, R has the same meaning as above), and the general formula M ₁ HSO ₃ (in the formula, M ₁
has the same meaning as above)). Among the target compounds of the present invention, XK-62
N-methanesulfinic acid derivatives of -2 and its 1-N-acyl derivatives can be obtained by reacting a compound of general formula () with formaldehyde sulfoxylic acid or formaldehyde sulfoxylate. Next, the present invention will be explained in detail. In the definition of R in the aldehyde represented by RCHO used in the present invention, the alkyl group, substituted alkyl group, alkenyl group, or substituted alkenyl group has 1 to 17 carbon atoms, and the substituted phenyl group has 6 to 17 carbon atoms. As the substituted naphthyl group, those having 10 to 17 carbon atoms are preferably used. Specific aldehydes include formaldehyde, acetaldehyde, monochloroacetaldehyde, dichloroacetaldehyde, monohydroxyacetaldehyde, propionaldehyde, normal butyraldehyde, isobutyraldehyde, capronaldehyde, laurylaldehyde,
Reducing sugars such as stearylaldehyde, oleylaldehyde, linolenylaldehyde, glyoxal, sodium glyoxylate, acrolein, glycolaldehyde, glyceraldehyde, glycose, benzaldehyde, para-anisaldehyde, salicylaldehyde, orthochlorobenzaldehyde, parachlorobenzaldehyde, meth Nitrobenzaldehyde, cinnamaldehyde, 3.5
Examples include -di-tert-butylbenzaldehyde, vanillin, piperonal, verataldehyde, α- and β-naphthylaldehyde, and the like. Specific examples of sulfite or hydrogen sulfite represented by the general formula M ₁ HSO ₃ used in the present invention include sulfurous acid; ammonium hydrogen sulfite; alkali metal hydrogen sulfite salts such as sodium hydrogen sulfite, potassium hydrogen sulfite, lithium hydrogen sulfite, etc. ; and bisulfite alkaline earth metal salts such as magnesium bisulfite. When sulfurous acid is used, it can be used in the form of sulfurous acid gas. As the formaldehyde sulfoxylate, alkali metal salts such as sodium and potassium salts of formaldehyde sulfoxylic acid, ammonium salts, and the like are used. Hydrous salts such as Rongarit (formaldehyde sodium sulfoxylate dihydrate) can also be used. The reaction is generally carried out in a solvent. Water is commonly used as a solvent. However, if the aldehyde is poorly soluble in water, it is preferable to add a minimum amount of methanol or ethanol to the aldehyde/water system to dissolve the aldehyde, and then carry out the reaction. Compounds of general formula (), RCHO and M ₁ HSO ₃
The reaction may be carried out by mixing the three components at the same time, or by first mixing any two components to produce an adduct, and then reacting with the remaining component. When the reaction is carried out in two parts, the first adduct is separated and the remaining adduct is reacted with the other adduct. Some adducts of RCHO and M ₁ HSO ₃ are commercially available, such as sodium hydroxymethanesulfonate (an adduct of formaldehyde and sodium bisulfite) and glyoxal sodium bisulfite. A case where such a commercially available product is reacted with a compound of general formula () also falls within the scope of the present invention. The compound of general formula () has a total of 5 amino groups and methylamino groups, and an integer number of 1 to 5 -CHRSO ₃ M ₁ group or -CH ₂ SO ₂ M ₂ groups can be introduced. Depends on how many -CHRSO ₃ M ₁ group or -CH ₂ SO ₂ M ₂ groups are introduced into the compound of general formula ().
The amount of RCHO and M ₁ HSO ₃ used or the amount of formaldehyde sulfoxylic acid or formaldehyde sulfoxylate is determined. The usage ratio of each raw material may be calculated. The reaction temperature is 0° to 70°C, preferably 5° to 30°C.
The reaction time is 30 minutes to 24 hours, generally 5 to 24 hours.
It takes about 15 hours. In order to obtain the target product from the reaction solution, a solvent that can be mixed with water such as methanol, ethanol, propanol, tetrahydrofuran, dimethylformamide, or dioxane is added to the reaction solution, or conversely, a reaction mixture is added to the reaction solution. A method is used in which a solution is dropped to precipitate the target product as a powder, which is then separated, washed with alcohol, and dried under reduced pressure. Compounds of general formula () are generally easily soluble in water, but tend to be poorly soluble in methanol and ethanol. However, as the molecular weight of aldehyde increases, its solubility in methanol and ethanol tends to increase. It is preferable to use tetrahydrofuran, dimethylformamide, dioxane, or the like as the solvent to be added dropwise. It is clear from the results of the MIC values of various derivatives determined by the agar dilution method (PH7.2) shown in Table 1 that the compound of the present invention has the same broad antibacterial spectrum and strong activity as the raw material compound. It is. Table 2 shows the MIC values of target compounds of the present invention other than those shown in Table 1, determined by the agar dilution method (PH8.0). Table 3 shows the LD ₅₀ of the compound of the present invention and the raw material compound, and it is clear from Table 3 that the compound of the present invention has significantly reduced toxicity.

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[Table] In Table 1, XK-62-2 sulfate and 1-N-
The L-(-)-α-hydroxy-γ-aminobutyryl-XK-62-2 sulfate salts are both expressed as free base weights, and the N-methanesulfonic acid derivatives are expressed as pure weights. Also, in Table 2
XK-62-2 sulfate, N-methanesulfonic acid derivatives and N-methanesulfinate are expressed by weight.

[Table] Salt The present invention will be explained below with reference to Examples. Example 1 1.39 g (3.0 mmol) of XK-62-2 in 3.0 ml of water
0.94 g (9.0 mmol) of sodium bisulfite, then 0.27 g of paraformaldehyde
(9.0 mmol) was added and reacted overnight with stirring at room temperature. By dropping the above reaction solution little by little into 70 ml of cold ethanol, separating the precipitated white precipitate, washing thoroughly with ethanol, and drying under reduced pressure,
2.26 g (yield 93%) of tri-N-methanesulfonic acid sodium salt of XK-62-2 was obtained. Elemental analysis as C ₂₃ H ₄₄ N ₅ O ₁₆ S ₃ Na ₃ Actual value:
C 34.51, H 5.71, N 8.92, S 12.14% Calculated values:
C 34.03, H 5.46, N 8.63, S 11.85% 1637cm ^-1 , 1189 in infrared absorption spectrum
A peak specific to methanesulfonate was observed at cm ^-1 and 1043 cm ^-1 . [α] ²² ° _D = +76.7° (C = 1.0, water) Melting point: It began to turn brown at 200°C, but did not decompose or melt until 300°C. Example 2 208 mg (2.0 mmol) of sodium bisulfite is dissolved in 1.1 ml of water, and 60 mg (2.0 mmol) of paraformaldehyde is added to the solution. Paraformaldehyde does not dissolve, but with stirring at room temperature
When 463 mg (1.0 mmol) of XX-62-2 is added, a slight heat is generated and the paraformaldehyde immediately dissolves to form a homogeneous solution. Continue the reaction overnight at room temperature. The reaction solution was added dropwise to 50 ml of cold ethanol, the white precipitate formed was separated, washed with ethanol, and then vacuum dried to obtain the target XK-62-2 di-precipitate.
N-methanesulfonic acid sodium salt 577 mg (yield
83.0%) was obtained. Elemental analysis as C ₂₂ H ₄₃ N ₅ O ₁₃ Na ₂ S ₂ Actual value: S 9.29% Calculated value: S 8.62% [α] ²² ° _D = +91.6° (C = 1.0, water) Example 3 XK- 62-2 463 mg (1.0 mmol) in 1.0 ml of water
608 mg (4.0 mmol) of sodium hydroxymethanesulfonate monohydrate, which is an adduct of formaldehyde and sodium bisulfite, is added to immediately obtain a homogeneous solution. After reacting overnight at room temperature, the reaction solution was added dropwise to 30 ml of cold ethanol. The precipitated white precipitate was collected, thoroughly washed with ethanol, and dried under reduced pressure to obtain the target product, XK-62.
900.0 mg (yield 97.0%) of -2-tetra-N-methanesulfonic acid sodium salt was obtained. Elemental analysis C ₂₄ H ₄₅ N ₅ O ₁₉ Na ₄ S ₄ Actual value: S 13.52% Calculated value: S 13.82% Example 4 463 mg (1.0 mmol) of XK-62-2 was added to 1.2 ml of water
312 mg of sodium bisulfite dissolved in this
(3.0 mmol), followed by 318 mg of benzaldehyde.
(3.0 mmol) was added and the reaction was carried out overnight at room temperature. This reaction solution was added dropwise to 60 ml of cold tetrahydrofuran, and after separating the white precipitate, it was dried under reduced pressure.
945 mg (yield 91.0%) of tri-N-phenylmethanesulfonic acid sodium salt of XK-62-2 was obtained. Elemental analysis C ₄₁ H ₅₆ N ₅ O ₁₆ Na ₃ S ₃ Actual value: S 9.57% Calculated value: S 9.25% [α] ²² ° _D = +55.0° (C = 1.0, water) Example 5 XK- 62-2 463 mg (1.0 mmol) in 1.2 ml of water
165 mg of 80% acetaldehyde dissolved in it
(3.0 mmol), then sodium bisulfite 312
mg (3.0 mmol) was added and allowed to react overnight at room temperature. This reaction solution was added dropwise to 50 ml of cold tetrahydrofuran to precipitate a white precipitate, which was separately dried under reduced pressure to obtain 807 mg of tri-N-methylmethanesulfonic acid sodium salt of XK-62-2 (yield: 89.0).
%) was obtained. Elemental analysis C ₂₆ H ₅₀ N ₅ O ₁₆ Na ₃ S ₃ Actual value: S 11.61% Calculated value: S 11.27% Example 6 926 mg (2.0 mmol) of XK-62-2 was added to 2.5 ml of water
384 mg (6.0 mmol) of dry sulfur dioxide gas was absorbed into the resulting solution, and then 180 mg (6.0 mmol) of paraformaldehyde was added, and the mixture was allowed to react overnight at room temperature. The resulting reaction solution was added dropwise to 70 ml of cold ethanol to form a white precipitate, which was separated, washed well with ethanol, and dried in vacuum to give 1356 mg of tri-N-methanesulfonic acid (yield 91.0%) of XK-62-2. ) was obtained. Elemental analysis C ₂₃ H ₄₇ N ₅ O ₁₆ S ₃ Actual value: S 13.27% Calculated value: S 12.89% Example 7 463 mg (1.0 mmol) of XK-62-2 was added to 1.2 ml of water.
208mg of sodium bisulfite dissolved in it
(2.0 mmol) and n-butyraldehyde 144
mg (2.0 mmol) and reacted overnight at room temperature, then the reaction solution was mixed with 50 ml of cold tetrahydrofuran.
Drip into. The produced white precipitate was separated, thoroughly washed with tetrahydrofuran, and then vacuum dried to obtain the desired di-N-n-n-propyl methanesulfonic acid sodium salt of XK-62-2.
746.8 mg (absorption rate 96.0%) was obtained. Elemental analysis as C ₂₈ H ₅₃ N ₅ O ₁₃ Na ₂ S ₂ Actual value: S 8.16% Calculated value: S 8.24% [α] ²⁰ ° _D = +80.6° (C = 1.0, water) Example 8 Hydrogen sulfite Sodium 1.04g and vanillin 1.52g
Suspend in 10ml of water. When stirred at room temperature, the solution soon becomes homogeneous. Then, the solution was concentrated to dryness under reduced pressure to obtain a white crystalline powder. After thorough vacuum drying of the adduct of vanillin and sodium bisulfite thus obtained, 256 mg (1.0 mmol) was taken and dissolved in 1.0 ml of water. Then, 463 mg (1.0 mmol) of XK-62-2 was added and dissolved in the solution, and the mixture was allowed to react overnight at room temperature.The resulting reaction solution was added dropwise to 50 ml of cold tetrahydrofuran.
A white precipitate is deposited. Separate the product,
After thorough washing with tetrahydrofuran and drying under reduced pressure, the N-(4-hydroxy-
680.7 mg (yield 97.0%) of 3-methoxy)phenylmethanesulfonic acid sodium salt was obtained. Elemental analysis C ₂₈ H ₄₈ N ₅ O ₁₂ As NaS Actual value: S 4.48% Calculated value: S 4.57% Example 9 463 mg (1.0 mmol) of XK-62-2 was added to 1.5 ml of water.
and then 208 mg (2.0 mmol) of sodium sulfite and 157 mg of monochloroacetaldehyde.
(2.0 mmol) was added and allowed to react overnight at room temperature.
The obtained reaction solution was added dropwise to 70 ml of cold tetrahydrofuran, and the white precipitate formed was separated and dried to obtain 769 mg of the desired sodium di-N-chloromethylmethanesulfonic acid salt of XK-62-2 (yield
96%). Elemental analysis C ₂₄ H ₄₅ N ₅ O ₁₃ Na ₂ S ₂ Cl Actual value: S 8.31% Calculated value: S 8.09% Example 10 1-N-L-(-)-α-hydroxy-γ-aminobutyryl-XK -62-2 564 mg (1.0 mmol) was dissolved in 2.0 ml of water, and then 208 mg (2.0 mmol) of sodium bisulfite and 60 mg (2.0 mmol) of paraformaldehyde were added, and the mixture was reacted overnight at room temperature. The resulting reaction solution was added dropwise to 70 ml of cold ethanol, and the white precipitate formed was separated and dried to obtain the desired 1-N-L-(-)α-hydroxy-γ-aminobutyryl-XK-62-2. 748 mg (yield 94.0%) of di-N-methanesulfonic acid sodium salt was obtained. Elemental analysis as C ₂₆ H ₅₀ N ₆ O ₁₅ Na ₂ S ₂ Actual value: S 8.39% Calculated value: S 8.44% Example 11 1-N-L-(-)-α-hydroxy-γ-aminobutyryl XK-62 564 mg (1.0 mmol) of -2 was dissolved in 2.0 ml of water, and then 416 mg (4.0 mmol) of sodium bisulfite and 120 mg (4.0 mmol) of paraformaldehyde were added, and the mixture was reacted overnight at room temperature. The obtained reaction solution was added dropwise to 70 ml of cold ethanol, and the white precipitate formed was separated and dried to obtain the desired 1-N-L-(-)-α-hydroxy-γ-aminobutyryl XK-62-2. Tetra-N-methanesulfonic acid sodium salt 998mg
(yield 97.0%). Elemental analysis C ₂₈ H ₅₂ N ₆ O ₂₁ Na ₄ S ₄ Actual value: S 13.01% Calculated value: S 12.46% Example 12 1-N-L-(-)-α-hydroxy-γ-aminobutyryl-XK- 564 mg (1.0 mmol) of 62-2 was dissolved in 2.0 ml of water, and then 312 mg (3.0 mmol) of sodium bisulfite and 90 mg (3.0 mmol) of paraformaldehyde were added, and the mixture was allowed to react at room temperature overnight. The obtained reaction solution was added dropwise to 70 ml of cold ethanol, and the white precipitate formed was separated and dried to obtain the desired trioxygenate of 1-N-L-(-)-α-hydroxy-γ-aminobutyryl XK-62-2. −
876.4 mg (yield 96%) of N-methanesulfonic acid sodium salt was obtained. Elemental analysis as C ₂₇ H ₅₁ N ₆ O ₁₈ Na ₃ S ₃ Actual value: S 10.82% Calculated value: S 10.54% Example 13 1-N-DL-α-hydroxy-β-aminopropionyl-XK-62-2 Dissolve 550 mg (1.0 mmol) in 2.0 ml of water and add 104 mg (1.0 mmol) of sodium bisulfite to the solution. 184 mg of lauryl aldehyde was added to the solution thus obtained.
(1.0 mmol) was added and the reaction was carried out overnight at room temperature with vigorous stirring. The resulting reaction solution was added dropwise to 50 ml of cold tetrahydrofuran to precipitate a white precipitate. The product was separated, thoroughly washed with tetrahydrofuran, and then dried in vacuum to obtain the desired 1-N-DL-α-
Hydroxy-β-aminopropionyl-XK-
780.2 mg (yield 95.0%) of N-undecyl methanesulfonic acid sodium salt of 62-2 was obtained. Elemental analysis C ₃₅ H ₆₉ N ₆ O ₁₂ as NaS Actual value: S 3.95% Calculated value: S 3.90% Example 14 1-N-L-(-)-α-hydroxy-ε-aminocaproyl-XK-62 592 mg (1.0 mmol) of -2 was dissolved in 2.0 ml of water, then 312 mg (3.0 mmol) of sodium bisulfite and 90 mg (3.0 mmol) of paraformaldehyde were added, and the mixture was reacted overnight at room temperature. The obtained reaction solution was added dropwise to 70 ml of cold ethanol, and the white precipitate formed was separated and dried to obtain the desired 1-N-L-(-)-α-hydroxy-ε-aminocaproyl XK-62-. 941 mg (yield 95%) of tri-N-methanesulfonic acid sodium salt of No. 2 was obtained. Elemental analysis C ₂₉ H ₅₅ N ₆ O ₁₈ Na ₃ S ₃ Actual value: S 10.54% Calculated value: S 10.22% Example 15 463 mg (1.0 mmol) of XK-62-2 was added to 1.5 ml of water.
Sodium formaldehyde sulfoxylate dihydrate (HOCH ₂ SO ₂ Na・2H ₂ O
Generic name Rongarit) 308 mg (2.0 mmol)
was added and reacted overnight at room temperature. The resulting reaction solution was added dropwise to 70 ml of cold tetrahydrofuran, the white precipitate formed was separated, and the desired amount was obtained by drying.
650 mg (yield 98%) of di-N-methanesulfinic acid sodium salt of XK-62-2 was obtained. Elemental analysis as C ₂₂ H ₄₃ N ₅ O ₁₁ Na ₂ S ₂ Actual value:
C 39.35, H 6.88, N 10.31, S 9.71% Calculated values:
C 39.81, H 6.53, N 10.55, S 9.66% A peak specific to methanesulfinate was observed at 1025 cm ^-1 in the infrared absorption spectrum. [α] ²² ° _D = +100.0° (C = 1.0, water) Melting point: Browning started at around 170°C, but no clear melting point was shown. Examples 16-26 463 mg (1.0 mmol) of XK-62-2 in 1.5 ml of water
2.0% of the aldehyde shown in Table 4 was dissolved in
mmol or 3.0 mmol, then sodium bisulfite in an equimolar amount with the aldehyde [208 mg
(2.0 mmol) or 312 mg (3.0 mmol)]
and the reaction was carried out overnight at room temperature. This reaction solution was added dropwise to 50 ml of cold tetrahydrofuran, and the precipitated white precipitate was separated and dried under reduced pressure.
-2 N-methanesulfonic acid derivative yield 95-99
Obtained in %.

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Claims (1)

[Claims] 1 General formula () [In the formula, R ₁ represents a hydrogen atom or [Formula] (in the formula, n represents an integer from 1 to 4)]
At least one of the amino groups or methylamino groups at the 1, 3, 2', 6', 3'' and 1-ω positions of XK-62-2 or its 1-N-acyl derivative is -
CHRSO ₃ M ₁ group (wherein R represents a hydrogen atom, an alkyl group or a substituted alkyl group, a substituted alkenyl group, a phenyl group or a substituted phenyl group, -COONa, or [Formula], M ₁ is a hydrogen atom, an ammonium ion, represents an alkali metal or alkaline earth metal) or -
A novel derivative of the antibiotic XK-62-2 substituted with a CH ₂ SO ₂ M ₂ group (wherein M ₂ represents a hydrogen atom, an ammonium ion, or an alkali metal). 2 General formula () [In the formula, R ₁ represents a hydrogen atom or [Formula] (in the formula, n represents an integer from 1 to 4)]
XK-62-2 or its 1-N-acyl derivative,
Aldehydes represented by the general formula RCHO (wherein R represents a hydrogen atom, an alkyl group, a substituted alkyl group, a substituted alkenyl group, a phenyl group, a substituted phenyl group -COONa, or [formula]), and the general formula M ₁ HSO ₃ (in formula
M ₁ represents a hydrogen atom, ammonium ion, alkali metal or alkaline earth metal), or XK-62-2 represented by the general formula () or its 1
-N-acyl derivative and formaldehyde sulfoxylic acid or formaldehyde sulfoxylate represented by the general formula HOCH ₂ SO ₂ M ₂ (wherein M ₂ represents a hydrogen atom, an ammonium ion or an alkali metal). 1 of the compound of the general formula ()
At least one of the amino groups or methylamino groups at the 3, 2', 6', 3'' and 1-ω positions is -CHRSO ₃ M ₁ (wherein R and M ₁ have the same meanings as above) or - CH ₂ SO ₂ M ₂ (M ₂ in the formula
has the same meaning as above)) A method for producing a novel derivative of antibiotic XK-62-2.